The Effect of Vitamin D Status on Bone Mineral Density (BMD) and Aromatase-Induced Musculoskeletal Syndrome (AIMSS) in Post- menopausal Women Receiving An AI for Early Breast cancer

The Effect of Vitamin D Status on Bone Mineral Density (BMD) and Aromatase-Induced Musculoskeletal Syndrome (AIMSS) in Post- menopausal Women Receiving An AI for Early Breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of Vitamin D Status on Bone Mineral Density (BMD) and Aromatase-Induced Musculoskeletal Syndrome (AIMSS) in Post- menopausal Women Receiving An AI for Early Breast cancer Chanyoot Bandidwattanawong, Pitchaporn Phudphong, Pimchanok Chittanavakun This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6956411/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: An AI use is associated with bone health and musculoskeletal adverse events. Appropriate vitamin D supplementation would mitigate such side effects. Patients and Methods: Post-menopausal breast cancer patients taking adjuvant letrozole were recruited. Baseline plasma 25(OH)D, BMD and HAQ-DI questionnaire were obtained to determine the aromatase-induced bone loss (AIBL) and musculoskeletal syndrome (AIMSS). The prevalences of vitamin D insufficiency/deficiency, AIBL and AIMSS and the effect of vitamin D repletion on AIMSS were investigated. Results: Eighty-eight patients were participated. Forty-two (42%) percent and 18.2% of women had vitamin D insufficiency and deficiency, respectively. High BMI ( > 25 kg/m 2 ) (OR 3.66, 95% C.I., 1.31-10.22; p = 0.013) and formulations/dosages of vitamin D supplementation with lower equivalent dose than calciferol of 20,000 IU/week (OR 3.84, 95%C.I., 1.34-10.97; p = 0.012) were independently correlated with low plasma 25(OH)D level (≤30 ng/ml). Ageing ( > 65 years) (OR 6.77, 95% C.I., 1.36-33.63 p= 0.019), low BMD (OR 5.59, 95% C.I., 1.07-29.23; p = 0.041) and low plasma 25(OH)D level (OR 8.98, 95% C.I., 1.52 - 53.19 ; p = 0.016) were the significant predictors of developing osteoporosis. Nineteen of the participants (21.6%) had AIMSS and 68.4% of them also had low baseline 25(OH)D level. Upon restoration of vitamin D level, the musculoskeletal pain was statistically improved. Conclusions: The prevalences of both vitamin D insufficiency/deficiency and osteoporosis were comparable to the Western countries. To examine plasma 25(OH)D and BMD prior to and during adjuvant AI in accordance with appropriate vitamin D repletion are strongly recommended. Adjuvant AI postmenopausal breast cancer patients vitamin D supplementation AIBL AIMSS Figures Figure 1 Figure 2 Introduction According to the GLOBOCAN, breast cancer is the worldwide second leading cause of cancer incidence in 2022 just behind lung cancer. Approximately 2.3 million new cases were diagnosed, accounting for 11.6% of all cancer cases. This cancer was also the fourth leading cause of cancer mortality worldwide, roughly 666,000 deaths (6.9% of all cancer deaths). Right now, breast cancer is not only the most commonly diagnosed cancer, but also it is the leading cause of cancer deaths globally including Thailand. ( 1 ) The population-based cross-sectional study included data from 18 cancer registries in the Surveillance, Epidemiology and End Results (SEER) database by Acheampong et al. ( 2 ) reported that most of the breast cancer patients were hormonal-receptor positive, 72.6% and 11.2% of them had luminal A and B, respectively. The luminal (hormonal receptor positive) breast cancer patients need anti-hormonal agents as either an adjuvant treatment in early/locally advanced setting or a palliative treatment in metastatic setting. Since the patient-level meta-analysis of the randomized trials by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has demonstrated the superiority of an aromatase inhibitor (AI) over tamoxifen in terms of reductions in both breast cancer recurrences and mortality ( 3 ) , an AI is the most commonly used hormonal agent. However, its use is limited to patients with complete loss of ovarian function to optimize its estrogen deprivation effect. ( 4 – 7 ) As adjuvant AI therapy provides longer disease-free survival, its long-term use in adjuvant setting has raised the concern regarding its association with bone density losses and detrimental effect on lipids and cardiovascular risk. ( 8 ) In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, anastrozole led to a significant increased risk of fractures in comparison with tamoxifen (11.0% vs 7.7%, p < 0.0001). (5) While the International Exemestane Study (IES) revealed that exemestane was associated with an increased incidence of osteoporosis (7.3% vs 5.5%, p = 0.01) and bone fractures (4.3% vs 3.1%, p = 0.03) compared to tamoxifen. ( 7 ) Hadji et al. have proposed that all patients initiating AI treatment, fracture risk assessment should be determined. Exercise and calcium/vitamin D supplementation are advocated. Bone-directed therapy should be provided to all patients with osteoporosis (T-score of < -2 SD) and patients with osteopenia (T-score of < -1.5 SD) with one additional risk factor, or with ≥ 2 risk factors (without BMD) for the duration of AI treatment. ( 9 ) Moreover, the AI-induced musculoskeletal symptoms (AIMSS) have been increasingly a worrisome issue, both as a major suffering adverse events and as a notable cause of premature discontinuation of the adjuvant therapy. ( 10 ) Calcium and vitamin D supplementation has been universally recommended in order to preserve bone health and ameliorate AIMSS, even though the results from clinical trials evaluating its benefit on bone mineral density (BMD) in postmenopausal breast cancer patients taking hormonal therapy indicated that supplementation with 500–1500 mg calcium and 200–1000 IU vitamin D was insufficient to prevent bone loss. Furthermore, every study reported that women still substantially lost BMD at almost every site. Due to lack of an unsupplemented control group, it is unimaginable to conclude the net contribution of the supplementation on BMD. ( 11 ) Since most of the supplementation dosages are usually empiric and it is conceivable that most of the physicians do not tailor the dosages according to their patients’ vitamin D status, bone health and fracture risk anymore, inadequate supplementation would result in considerable risk of musculoskeletal adverse events. Imtiaz et al. compared serum vitamin D levels among Indian breast cancer patients in comparison with the matched control group and demonstrated that the mean serum vitamin D level in the breast cancer patients was significantly lower than the control group (9.3 vs 14.9 ng/ml; p < 0.001). Vitamin D deficiency was found in nearly all of their breast cancer patients (95.6%) and significantly more prevalent than in the matched control group (77%) (p < 0.001). Premenopausal breast cancer women had a mean serum vitamin D level less than the postmenopausal ones (10.5 vs 13.5 ng/ml; p = 0.015). Interestingly, the investigators revealed that low BMD did not associate significantly with vitamin D deficiency (p = 0.787). Moreover, the tumor characteristics (histology, grade, stage, and receptor status) did not predict any significant associations with vitamin D status. ( 12 ) In line with the report by Kayah et al. that performed in Turkish patients with early or locally advanced breast cancer, the mean vitamin D level was 13.91 ng/ml. Vitamin D deficiency and insufficiency were determined in 81.28% and 10.87% of their patients, respectively. ( 13 ) Even among breast cancer patients living in a Mediterranean country, the prevalence was also high. Nogues et al. reported a fascinatingly high prevalence of vitamin D insufficiency/deficiency among breast cancer patients taking an AI in adjuvant setting, 88.1% of their cohort of patients in Spain had 25(OH)D level of < 30 ng/ml and 21.2% had severe deficiency (< 10 ng/ml). They also revealed its relationship between baseline BMD. BMD at femoral neck, in particular, was significantly correlated with low 25(OH)D concentrations; this association remained to be independent after adjustment by age, BMI and season of sample collection. ( 14 ) The B-ABLE study conducted among Spanish breast cancer patients also revealed that 90% of patients had 25(OH)D level of < 30 ng/ml. This study also demonstrated that at 3 months after correction of the plasma 25(OH)D level to levels of 40 ng/ml or more led to protection of lumbar spine (LS) bone loss by 1.70% (95% C.I., 0.4–3.0%; adjusted p = 0.005) compared to those with low 25(OH)D levels (< 30 ng/ml). (15) The prospective cohort BEGYN study conducted in Germany by Zemlin et al. also revealed remarkably high prevalence (64.8%) of vitamin D deficiency among non-metastatic breast cancer patients. They also reported that patients’ age, BMI, alcohol, smoking, skin type, and prior cancer history did not significantly affect the vitamin D levels. Patients who had moderate vitamin D deficiency were more likely to harbor luminal B carcinomas, on the other hand, other prognostic factors, such as Ki-67, histologic grading and tumor stage (cT and cN+) were not the significant predictor of low vitamin D levels. ( 16 ) An observational study from the USA by Khan et al. also found that 63% of women taking an AI in adjuvant setting had either vitamin D deficiency (< 20 ng/ml) or insufficiency (20–31 ng/ml). They also demonstrated that upon restoration of 25(OH)D level, those with AIMSS reported improvement of symptoms. ( 17 ) These evidences emphasized us that the prevalences of vitamin D insufficiency/deficiency in patients with early and locally advanced breast cancer are substantially higher than general population and ubiquitous across both sides of the world. Since Thailand is located in a tropical area of the world, most of the Thai physicians are reluctant to determine their patients’ vitamin D levels and prescribe recommended dosages and formulations of vitamin D. Moreover, no particular recommendation regarding the proper dosage and formulation of vitamin D supplementation and repletion for Thai breast cancer patients has been established. The investigators intended to determine the prevalence of vitamin D insufficiency/deficiency and AIMSS among post-menopausal Thai breast cancer patients taking an AI as the adjuvant therapy, its effect to bone health and whether appropriate vitamin D repletion contributed to improvement in musculoskeletal symptoms. Methods Study design Prospective non-randomized observational cohort study Study site The study was conducted in single center at Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Vajira Hospital, Navamindhradhiraj University, Bangkok, Thailand. Subjects Any early breast cancer patients who had started treatment with an AI as an adjuvant therapy for at least 8 weeks were enrolled. Those who were pregnant, smoker or had history of pre-existing documented vitamin D deficiency, nephrolithiasis, CKD stage 3 or higher (eGFR 11 mg/dL) were excluded. Patients with history of any bone diseases including osteomalacia, rheumatoid arthritis, metabolic or endocrine diseases, pre-existing diagnosis of Paget’s bone disease, concurrent or previous treatment with oral corticosteroids, bisphosphonates, or any other agents affecting bone minerals were also ruled out. Demographic data including age, BMI, TNM staging using AJCC 8th edition ( 16 ) , histologic subtype (luminal A or luminal B), type of previous systemic cancer treatment (hormonal therapy with or without chemotherapy), detailed types and dosages of calcium and vitamin D supplements, and Charleson Co-morbidity Index were collected. From December 18th, 2023 to March 28th, 2025, post-menopausal women with early hormonal positive breast cancer who were taking letrozole or recently switched from tamoxifen to letrozole were screened. They were invited to participate in the clinical trial and, after signing informed consent, they were recruited into the study. Figure 1 showed the consort diagram. Most of the excluded patients were those with underlying condition supposed to have pre-existing poor BMD i.e. CKD stage 3 (eGFR < 60 ml/min), receiving a bisphosphonate due to established osteoporosis, receiving high dose vitamin D to treat vitamin D insufficiency/ deficiency, receiving corticosteroid and pre-existing rheumatoid arthritis. Measurements At baseline, blood checks for serum 25(OH)D, total calcium (Ca), phosphate (P), alkaline phosphatase (ALP), albumin, intact parathyroid hormone (iPTH), blood urea nitrogen (BUN) and creatinine (Cr) levels were obtained. Plasma concentrations of 25(OH)D were determined using the electrochemiluminescence (ECL) technology by Roche Diagnostics Cobas 8000 analyzer with a module (e801) for 25(OH)D total assay. Bone mineral density (BMD) was measured at lumbar spine (LS; L2–L4), femoral neck (FN) and total hip (TH) using dual-energy X-ray absorptiometry (DXA) (Discovery TM QDR series, Hologic®, Marlborough, MA, USA). Osteoporosis was diagnosed based on the Thai Osteoporosis Foundation Guideline 2021. ( 17 ) The participants had to respond to the Health Assessment Questionnaire-Disability Index (HAQ-DI). ( 18 ) Those who responded to HAQ-DI and were documented to have at least mild disability were diagnosed to have AIMSS. The participants then self-evaluated their degrees of pain suffering using the Pain Score and Visual Analogue Scale (VAS). The pain severity coding of each participant was then translated into measurement scale. ( 19 ) Intervention After plasma 25(OH)D level was determined, the participants were divided into 3 groups: patients with normal (> 30–100 ng/mL), vitamin D insufficiency (20–30 ng/ml), or vitamin D deficiency (< 20 ng/mL) according to the consensus from the Task Force of the Endocrine Society. ( 20 ) Those with vitamin D sufficiency were allowed to continue the same dosages and formulations of calcium and vitamin D supplements. On the other hand, those with vitamin D insufficiency or deficiency were treated according to the protocol designed by the expert endocrinologist (see Supplement). Due to various formulations and dosages of vitamin D supplementation, the investigators had collected this data and then divided into two groups, those who were taking calciferol at least 20,000 IU/week and those taking other dosages and/or other vitamin D formulations with lower equivalent dosages. After vitamin D repletion, plasma 25(OH)D level as well as serum total Ca, P, ALP, albumin, iPTH, BUN, Cr levels were repeated 8 weeks later. Those who still had insufficient or deficient level of vitamin D were sent to the expert endocrinologist to adjust dosages and follow up. After BMD results were reported, those who had osteopenia or osteoporosis were also sent to the expert endocrinologist for proper management including adjustment of calcium and vitamin D supplementation and bisphosphonates, if indicated. Follow-up BMD evaluation was subject to the consultant endocrinologist’s discretion. After vitamin D restoration was successful, the participants with vitamin D insufficiency or deficiency were requested to respond to post-treatment HAQ-DI and VAS to determine whether vitamin D repletion was attributable to improvement of AIMSS. Outcomes The primary outcome was the prevalence of vitamin D insufficiency and deficiency in breast cancer patients taking letrozole in the adjuvant setting. The secondary outcomes included the prevalence of AIMSS, the correlation between vitamin D status and BMD, the pattern of BMD loss among those with vitamin D insufficiency/deficiency, the correlation between vitamin D status and AIMSS, the success rate of vitamin D repletion protocol for patients with vitamin D insufficiency/deficiency and whether vitamin D repletion was associated with improvement in AIMSS. Statistical analysis Based on the study by Zemlin et al . ( 14 ) , with α = 0.05 and d = 0.10, the investigators calculated the sample size of 88 patients. Statistical analyses were performed using SPSS 28.0 (IBM, Armonk, NY, USA). Qualitative parameters (e.g., tumor stage) were displayed in numbers and per cent. Quantitative parameters were displayed as mean and standard deviation (SD) or median with inter-quartile range (IQR), whatever appropriate. Associations between baseline plasma 25(OH)D levels and pre-specified co-variates were assessed using simple linear regression, and then further adjusted in multivariate models (multiple linear regression) using forward stepwise methods. A possible correlation between 25(OH)D levels and the BMD and occurrence of AIMSS were examined using the Mann–Whitney U test for metric and ordinal variables with asymptotic p-value. Nominal variables were tested with cross tabulation and the Chi-Square test or Fishers’ exact test, whatever appropriate. All analyses were two-tailed, and p values were considered statically significant when it was less than 0.05. Results The investigators recruited 88 patients with early breast cancer taking an adjuvant AI. Since letrozole is the only AI enlisted in Thailand’s Essential Drug List, all of the participants received letrozole. Baseline characteristics of eligible participants were shown in Table 1 . Baseline mean (± SD) plasma 25(OH)D level was relatively low (28.24 ± 9.72 ng/ml). Median age of the participants (IQR) was 65.5 (61–72) years and median BMI (IQR) was 25.48 (22.36–28.79) kg/m 2 . The participant almost harbored minimal co-morbidity (mean Charleson Co-morbidity Index was 4). Most of the participants had stage 1 or 2 breast cancer (63 patients, 71.6%). Nearly half of the participants (42 patients, 47.7%) had luminal A disease. Approximately one-third (32 patients, 36.4%) of the participants had taken tamoxifen and three-fourths (67 patients, 76.1%) had received adjuvant chemotherapy before they were enrolled into the trial. The exact time of taking tamoxifen prior to switching to letrozole was impossible because substantial numbers of the participants had been referred or transferred from a surgeon or a primary hospital. Since calcium and vitamin D dosages and formulations for supplementation were subject to an attending physician’s discretion, the investigators documented only the most recently prescribed dosages and forms prior to subject enrollment. Regarding the calcium and vitamin D supplementation, most (78 patients, 88.6%) of the participants had received adequate (as defined as receiving ≥ 1500 mg/day) dosages of calcium supplements, while only one-third (29 patients, 33%) were taking at least 20,000 IU of calciferol per week) before they were enrolled into the trial. The prevalence of vitamin D insufficiency and deficiency were 42% and 18.2%, respectively. Table 1 showed baseline demographic data and oncological characteristics of participants. Characteristics All patients (n = 88) All patients 88 (100.0) Serum 25[OH]D (ng/mL) (± SD) 28.24 ± 9.72 Min. – Max. (9.89–60.00) Age (years) (median, IQR) 65.5 (61–72) Body weight (kg) (median, IQR) 61 (53–68) Body mass index (kg/m²) (median, IQR) 25.48 (22.36–28.79) < 25.0 kg/m² (no., %) 40 (45.5) ≥ 25.0 kg/m² (no., %) 48 (54.5) Staging (no., %) Stage 1–2 63 (71.6) Stage 3 25 (28.4) Subtype (no., %) Luminal A 42 (47.7) Luminal B/HER2-Negative 39 (44.3) Luminal B/HER2-Positive 7 (8.0) Previous tamoxifen (no, %) 32 (36.4) Previous chemotherapy (no, %) 67 (76.1) Calcium supplement (no, %) 88 (100.0) < 1500 mg 10 (11.4) ≥ 1500 mg 78 (88.6) Previous vitamin D supplement (no., %) 88 (100.0) Calciferol (20,000 IU/week) 29 (33.0) Others 59 (67.0) Charlson Comorbidity Index (median, IQR) 4 (4–5) BMD status, (n = 84) (no., %) Normal 19 (22.6) Osteopenia 45 (53.6) Osteoporosis 20 (23.8) T-score (± SD) -1.68 ± 1.14 ECOG - no. (%) 0 71 (80.7) 1 17 (19.3) Data are presented as number and per cent, mean and standard deviation (SD) or median and interquartile range (IQR). Regarding the correlation between vitamin D insufficiency/deficiency and baseline demographics. Table 2 showed the uni- and multi-variate analyses to explore the association. The investigators demonstrated that only patients with high BMI (≥ 25 kg/m 2 ) (OR adj 3.66, 95% C.I.,1.31–10.22; p = 0.013) and those who were not taking vitamin D supplementations other than calciferol at least 20,000 IU (or equivalent dose)/week (OR adj 3.84, 95% C.I.,1.34–10.97; p = 0.012) were the significant factors predicting chances of developing vitamin D insufficiency/deficiency. Table 2 showed the uni- and multi-variate analyses of factors associated with vitamin D insufficiency and deficiency (Serum 25(OH)D ≤ 30 ng/ml) Factors Univariable analysis Multivariable analysis Crude OR† (95%CI) p-value Adjusted OR‡ (95%CI) p-value Age < 65 years 1.00 Reference 1.00 Reference ≥ 65 years 0.98 (0.41–2.32) 0.960 0.48 (0.17–1.41) 0.184 Body mass index < 25.0 kg/m² 1.00 Reference 1.00 Reference ≥ 25.0 kg/m² 3.29 (1.35–8.02) 0.009 3.66 (1.31–10.22) 0.013 Stage Stage I-II 1.00 Reference 1.00 Reference Stage III 0.78 (0.31–2.00) 0.610 0.92 (0.30–2.80) 0.880 Histologic subtype Luminal A 1.39 (0.59–3.27) 0.458 1.09 (0.39–3.01) 0.875 Luminal B 1.00 Reference 1.00 Reference Previous tamoxifen Yes 0.63 (0.26–1.52) 0.305 0.51 (0.18–1.42) 0.196 No 1.00 Reference 1.00 Reference Previous chemotherapy Yes 0.39 (0.13–1.17) 0.093 0.47 (0.12–1.76) 0.262 No 1.00 Reference 1.00 Reference Previous vitamin D supplement Calciferol (20,000 IU/week) 1.00 Reference 1.00 Reference Others 3.23 (1.28–8.13) 0.013 3.84 (1.34–10.97) 0.012 Abbreviations: CI, confidence interval; OR, odds ratio; NA, data not applicable. †Crude odds ratio estimated by Logistic regression model. ‡Adjusted odds ratio estimated by Logistic regression model adjusting for age, body mass index, stage, previous tamoxifen, previous chemotherapy, calcium, phosphate and PTH. Figure 2 showed the bar chart to exhibit the proportion of patients with normal BMD, osteopenia and osteoporosis across the three subgroups of vitamin D status. Astonishingly, at baseline, half (45 patients, 53.6%) and one-fourth (20 patients, 23.8%) of participants had osteopenia and osteoporosis, respectively. Twenty per cent (20%), 27.3% and 25% of patients with baseline vitamin D sufficiency, insufficiency and deficiency were diagnosed to have osteoporosis, respectively. Although there was not significant difference in terms of proportion of patients with osteopenia/osteoporosis among three subgroups of vitamin D status, the investigators demonstrated that vitamin D deficiency had a strongly predictive chance of developing osteopenia and osteoporosis in multi-variate analysis. In case of osteoporosis, besides ageing ( ≥ 65 years) (OR adj 6.77, 95% C.I.,1.36–33.63 p = 0.019) and low BMD (OR adj = 5.59, 95% C.I., 1.07–29.23; p = 0.041), vitamin D deficiency or insufficiency (OR adj = 8.98, 95% C.I., (1.52–53.19); p = 0.016) were also another significant predictive factors ( Table 3 ) . Table 3 showed the uni-variated and multi-variated analyses of associations between baseline demographic data and bone health (osteopenia and osteoporosis). Factors Univariable analysis Multivariable analysis Multivariable analysis Osteopenia Osteoporosis Osteopenia Osteoporosis Crude OR† (95%CI) p-value Crude OR† (95%CI) p-value Adjusted OR‡ (95%CI) p-value Adjusted OR‡ (95%CI) p-value Age < 65 years 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference ≥ 65 years 1.52 (0.52–4.47) 0.446 2.59 (0.70–9.64) 0.155 2.30 (0.66–8.03) 0.192 6.77 (1.36–33.63) 0.019 Body mass index < 25.0 kg/m² 1.00 (0.34–2.98) 0.993 1.68 (0.47–5.97) 0.422 1.77 (0.44–7.10) 0.419 5.59 (1.07–29.23) 0.041 ≥ 25.0 kg/m² 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Stage Stage I-II 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Stage III 1.40 (0.42–4.62) 0.581 0.93 (0.22–3.93) 0.925 0.88 (0.21–3.66) 0.866 1.12 (0.20–6.45) 0.896 Histologic subtype Luminal A 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Luminal B 1.88 (0.64–5.57) 0.254 1.13 (0.32–3.99) 0.855 1.84 (0.53–6.41) 0.340 1.07 (0.24–4.80) 0.933 Previous tamoxifen Yes 0.77 (0.25–2.39) 0.656 2.10 (0.58–7.56) 0.258 0.98 (0.27–3.54) 0.973 4.29 (0.93–19.73) 0.061 No 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Previous chemotherapy Yes 2.13 (0.62–7.32) 0.228 1.08 (0.28–4.20) 0.915 3.18 (0.65–15.48) 0.152 1.26 (0.20–7.74) 0.804 No 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Previous vitamin D supplement Calciferol (20,000 IU/week) 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Others 0.71 (0.22–2.36) 0.581 0.66 (0.17–2.62) 0.558 0.32 (0.07–1.40) 0.130 0.24 (0.04–1.35) 0.106 Vitamin D value Normal 1.00 Reference 1.00 Reference 1.00 Reference 1.00 Reference Insufficiency or Deficiency 2.26 (0.76–6.75) 0.142 2.55 (0.70–9.31) 0.156 6.08 (1.29–28.68) 0.023 8.98 (1.52–53.19) 0.016 Abbreviations: CI, confidence interval; OR, odds ratio; NA, data not applicable. †Crude odds ratio estimated by Multinomial logistic regression model. ‡Adjusted odds ratio estimated by Multinomial logistic regression model adjusting for age, body mass index, stage, previous tamoxifen, previous chemotherapy, calcium, phosphate and PTH. Table 4 exhibited the comparison of the BMD status across three groups of vitamin D status. The distribution of BMD status did not differ significantly across the groups (p = 0.426). Overall, 22.6% had normal BMD, 53.6% had osteopenia, and 23.8% had osteoporosis. The proportion of participants with normal BMD was highest in the vitamin D sufficient group (31.4%), compared to 25.0% in the deficient group and 12.1% in the insufficient group. Osteopenia was the most prevalent condition in all groups. With respect to the dominant site of bone loss, the lumbar spine (LS) was the most commonly affected region overall (51.2%), with the highest prevalence in the deficient group (62.5%), followed by the insufficient (51.5%) and sufficient (45.7%) groups, respectively. However, due to small sample size, these differences were not statistically significant (p = 0.713). The femoral neck (FN) was the second most common site (41.7%), while hip (H) involvement was relatively uncommon (7.1%) and fascinatingly absent in the vitamin D deficient group. Mean T-scores across three groups of different vitamin D status were also comparable. The overall mean total T-score was − 1.68 ± 1.14, with slightly better but not statistically different score in the sufficient group (− 1.52 ± 1.28) compared to the deficient (− 1.63 ± 1.10) and insufficient (− 1.88 ± 0.98) groups (p = 0.430). Similarly, no significant difference was observed in site-specific T-scores, LS (p = 0.936), H (p = 0.615), and FN (p = 0.370). Variables Total (n = 84) Deficient group (n = 16) Insufficient group (n = 33) Sufficient group (n = 35) p-value BMD status, (n = 84) N (%) N (%) n (%) n (%) Normal 19 (22.6) 4 (25.0) 4 (12.1) 11 (31.4) 0.426 b Osteopenia 45 (53.6) 8 (50.0) 20 (60.6) 17 (48.6) Osteoporosis 20 (23.8) 4 (25.0) 9 (27.3) 7 (20.0) Dominant, (n = 84) Lumbar 43 (51.2) 10 (62.5) 17 (51.5) 16 (45.7) 0.713 b Femoral neck 35 (41.7) 6 (37.5) 14 (42.4) 15 (42.9) Hip 6 (7.1) 0 (0.0) 2 (6.1) 4 (11.4) T-score -1.68 ± 1.14 -1.63 ± 1.10 -1.88 ± 0.98 -1.52 ± 1.28 0.430 a T-score Lumbar -1.10 ± 1.46 -1.21 ± 1.58 -1.11 ± 1.48 -1.05 ± 1.42 0.936 a T-score Hip -0.50 ± 1.12 -0.41 ± 1.21 -0.65 ± 1.01 -0.40 ± 1.20 0.615 a T-score Femoral neck -1.29 ± 1.20 -1.31 ± 1.11 -1.49 ± 1.08 -1.08 ± 1.33 0.370 a Abbreviations: NA, data not applicable. Data are presented as number (%), mean ± standard deviation or median (interquartile range). P-value corresponds to a One-way ANOVA, or b Fisher’s exact test. Table 4 showed the comparison of the prevalences of AIMSS across three subgroups of vitamin D status. Table 5 displayed the comparison of the prevalences of AIMSS across three groups of vitamin D status. On condition that those with abnormal HAQ-DI (at least mild degree of severity index) was legitimate to have the AIMSS, 19 patients of the cohort (21.6%) had AIMSS. Specifically, AIMSS was reported in 3 patients (18.8%) in the vitamin D deficient group, 10 patients (27.0%) in the vitamin D insufficient group, and 6 patients (17.1%) in the sufficient vitamin D group. Although this difference was not statistically significant (p = 0.568) across groups of different vitamin D status, the investigators speculated that more than two-thirds of patients (68.4%) of those with AIMSS had low vitamin D status (insufficiency and deficiency). Table 5 showed the comparison of the prevalences of AIMSS across three groups of vitamin D status. Variable Total (n = 88) Deficient group (n = 16) Insufficient group (n = 37) Sufficient group (n = 35) p-value N (%) N (%) n (%) N (%) AIMSS 19 (21.6) 3 (18.8) 10 (27.0) 6 (17.1) 0.568 P-value corresponds to Chi-square test The investigators further explored the effect of vitamin D repletion on the improvement of AIMSS and demonstrated that upon normalization of 25(OH)D level, the severity of AIMSS as determined by HAQ-DI was not significantly different. Nevertheless, when only the pain domain was re-evaluated, the severity of pain as assessed by both Pain Scale and visual analogue scale (VAS) were significantly ameliorated after vitamin D repletion among participants with baseline low vitamin D levels (Table 6 ). Table 6 showed effect of vitamin D repletion on AIMSS as evaluated by the HAQ-DI, Pain Scale and VAS. Vitamin D level AIMSS (disability index including mild, moderate, severe degree) Baseline After 8 weeks Difference in percent (%) P-value † n (%) n (%) Deficiency 3 (18.8) 2 (12.5) -6.3 1.000 Insufficiency 10 (27.0) 11 (29.7) 2.7 1.000 All patients who had vitamin D level ≤ 30 ng/dL 13 (24.5) 13 (24.5) 0.0 1.000 Vitamin D level Pain scale (0–3) Baseline After 8 weeks Mean difference (95%CI) P-value † Mean ± SD Mean ± SD Deficiency 0.75 ± 0.60 0.49 ± 0.45 -0.26 (-0.43, -0.10) 0.004 Insufficiency 0.75 ± 0.63 0.50 ± 0.50 -0.25 (-0.35, -0.15) < 0.001 All patients who had vitamin D level ≤ 30 ng/dL 0.75 ± 0.62 0.50 ± 0.48 -0.25(-0.34, -0.17) < 0.001 Vitamin D level VAS score (0–10) Baseline After 8 weeks Mean difference (95%CI) p-value † Mean ± SD Mean ± SD Deficiency 2.50 ± 2.00 1.63 ± 1.50 -0.88(-1.42, -0.33) 0.004 Insufficiency 2.59 ± 2.06 1.73 ± 1.63 -0.87(-1.19, -0.54) < 0.001 All patients who had vitamin D level ≤ 30 ng/dL 2.57 ± 2.02 1.70 ± 1.58 -0.87(-1.14, -0.60) < 0.001 †P-value corresponds to McNemar test. † Paired samples t-test *Significant at p-value < 0.05 The investigators also assessed the effectiveness of vitamin D repletion protocol as suggested by an expert endocrinologist (see Supplement) and proved that the protocol could restore plasma 25(OH)D level efficiently (100% response rate) without undesired AEs. Upon repletion of plasma 25(OH)D level, the investigators also found that only serum total calcium level was increased minimally but significantly compared with the levels prior to repletion, while phosphate, alkaline phosphatase and iPTH levels were insignificantly changed (data not shown). Discussion The investigators demonstrated that 42% and 18.2% of women receiving adjuvant letrozole therapy had vitamin D insufficiency and deficiency, respectively. Moreover, the mean plasma 25(OH)D of the entire cohort was only 28.24 ng/ml. In comparison with the study by Nogues et al. among Spanish post-menopausal breast cancer patients taking an adjuvant AI, 88.1% of their patients had plasma 25(OH)D level of less than 30 ng/ml with the mean level of only 18.5 ng/ml. (14) While the results from the B-ABLE study by Pietro-Alhambra et al. revealed that 90% of Spanish patients taking an adjuvant AI had plasma 25(OH)D level of less than 30 ng/ml as well. ( 15 ) This prevalence in Thai post-menopausal women taking an adjuvant AI is astonishingly comparable to reports from Asian and Western countries. Regarding the factors associated with vitamin D insufficiency/deficiency, the investigators found that higher BMI ( ≥ 25kg/m 2 ) (OR adj = 3.66, 95% C.I. 1.31–10.22; p = 0.013) and formulations or dosages of vitamin D supplementation less than calciferol of 20,000 IU or eqivalent/week (OR adj = 3.84, 95%C.I. 1.34–10.97; p = 0.012) were independently correlated with vitamin D insufficiency/deficiency (≤ 30 ng/ml) condition, while age, histologic subtype, stage, previous tamoxifen or adjuvant chemotherapy were not. Imtiaz, et al. conducted a study in newly diagnosed breast cancer Indian patients also demonstrated that the tumor characteristics (histology, grade, stage, and receptor status) were not the predictive factor associated with low baseline vitamin D levels. Pre-menopausal breast cancer patients seemed to have lower vitamin D level than post-menopausal ones’ (10.5 ng/ml vs 13.5 ng/ml; p = 0.015). (12) The study by Noges et al. also supports the investigators’ finding that high BMI was strongly associated with low baseline vitamin D levels, whereas seasons when blood samples were corrected and age had borderline correlation. ( 14 ) The result from Zemlin et al. also substantiates that vitamin D supplementation resulted in higher vitamin D levels besides sample collection in summer season. Notably, they reported that patients with moderate vitamin D deficiency were more likely to have Luminal B subtype, while other prognostic factors (Ki67, histologic grading, and tumor stage (cT and cN+) were not the predictive factor. ( 16 ) With respect to the association between baseline 25(OH)D levels and bone health. The investigators revealed that 27.3% and 25% of patients with baseline vitamin D insufficiency and deficiency, respectively were diagnosed to have osteoporosis. Intriguingly, the prevalence of osteoporosis among those with sufficient vitamin D level was also high at 20%. Although no statistical difference in proportion of patients with osteopenia and osteoporosis among three groups of different levels of vitamin D, the investigators demonstrated in multi-variate analysis that those with older ages ( ≥ 65 years) (OR adj = 6.77, 95% C.I. 1.36–33.63; p = 0.019), lower BMI (< 25 kg/m 2 ) (OR adj = 5.59, 95% C.I. 1.07–29.23; p = 0.041), and plasma 25(OH)D level in deficient or insufficiency level (OR adj = 8.98, 95% C.I. 1.52–53.19; p = 0.016) had independent tendency towards developing osteoporosis. The investigators revealed the powerful trend toward higher rate of normal BMD and less negative T-scores in the vitamin D sufficient group suggested a potential protective role of adequate vitamin D levels on bone health. The LS was the most common site of bone loss across all groups of vitamin D status, particularly among individuals with vitamin D deficiency. These findings highlight the importance of close monitoring of LS BMD among post-menopausal individuals with hormonal receptor positive and taking an AI with vitamin D deficiency. Provocatively, these results support to promote of restoration of vitamin D status as part of the bone health improvement strategies, especially in populations at heightened risk of developing osteopenia or osteoporosis, including post-menopausal women and breast cancer patients receiving an AI who are known to experience accelerated bone loss due to absolute estrogen depletion. Given the relatively small sample size and short duration of follow up, future studies with larger cohorts and longitudinal designs are recommended to further clarify the relationship between vitamin D status and site-specific BMD changes. Additionally, the impact of confounding factors such as calcium intake, physical activity, and hormonal status should be examined in more details. Nogues et al. also confirms the correlation between plasma 25(OH)D level and bone loss, especially the femoral neck BMD that was still consistent after adjustment by age, BMI and season of blood sample collection. ( 14 ) De Sire et al. performed a machine learning approach to prove the relationship between vitamin D deficiency and osteoporosis in patients taking an AI and indicated that there was a scant number of patients with adequate bone health and a normal vitamin D3 status, therefore they deduced that both BMD and vitamin D3 status should be assessed and restored properly to decrease the risk of osteoporotic fractures in breast cancer women. ( 23 ) The Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG has proposed the guideline of management of aromatase inhibitor-associated bone loss (AIBL) in post-menopausal women with hormone sensitive breast cancer. The experts recommend adequate calcium and vitamin D supplementation and consider denosumab or a bisphosphonate, if T score ≤ -2.0 or ≥ 2 clinic risk factors for fracture. Denosumab has stronger clinical evidences in improving bone health than a bisphosphonate; however, zoledronic acid has robust evidences in preventing cancer recurrence. ( 24 ) The investigators concerned the musculoskeletal related adverse effects from adjuvant AI. Since these troublesome side effects led to the 13–22% premature discontinuation rate ( 25 ) , the investigators also determined the prevalence of AIMSS among breast cancer patients taking letrozole. Due to no specific definition of AIMSS, the investigators used the HAQ-DI questionnaire as the study by Khan et al. ( 17 ) did to determine the prevalence of AIMSS. The investigators found that 21.6% of the participants had at least mild degree of disability index. More than two-third of them had vitamin D insufficiency/deficiency. Even though those with vitamin D insufficiency/deficiency had been treated, there was no significant improvement as assessed by HAQ-DI obtained 8 weeks after repletion. Nevertheless, the pain domain was statistically ameliorated as determined by pain scale (mean difference after vitamin D repletion = -0.25 (95% C.I. -0.34 - -0.17; p < 0.001) and VAS score (mean difference after vitamin D repletion = -0.87 (95% C.I. -1.14 - -0.60; p < 0.001). According to the study by Khan et al. , those taking an adjuvant AI were allowed to receive additional vitamin D supplementation, if they had baseline 25(OH)D level of less than 40 ng/ml. They found that 4 weeks after receiving extra dose of vitamin D (16 weeks after start an adjuvant AI), significantly higher number of women with 25(OH)D levels of more than the median level (> 66 ng/ml) reported no disability from joint pain than women with levels < 66 ng/ml (52 vs. 19%; p = 0.026). (17) The report from the B-ABLE study also confirms the contribution of vitamin D repletion on AIMSS. Vitamin D supplementation at the start of AI treatment decreased the risk of both incident joint pain and its worsening. Pineda-Moncusí, et al suggested that the effective threshold of serum 25(OH)D to relieve joint pain should be 40 ng/ml or more. However, this threshold was not significantly associated with bone changes at one year of follow-up. ( 26 ) A study by Arul Vijaya Vani et al. conducted in Indian breast cancer patients taking adjuvant letrozole is another study supporting the evidence of vitamin D3 and calcium supplementation in reduction of musculoskeletal side effects. They demonstrated that patients who had low serum 25(OH)D concentrations suffered more from musculoskeletal symptoms which were improved following supplementation (9.14 vs 8.10; p = 0.000). (27) Even though the Cochrane’s systematic review by Roberts et al. ( 28 ) declared that there were scant evidences supporting the safe and effective systemic therapies in preventing the AIMSS, Gupta et al. proposed the algorithm for preventing and managing AIMSS including vitamin D measurement and correction to improve bone health and suggested the alternative therapies like strengthening exercises and acupuncture, medication (duloxetine) and food supplement (omega-3 fatty acid, if BMI > 30 kg/m 2 ) for patients with mild to moderate symptoms and permanent discontinuation or alternative hormonal therapies, if no improvement after such interventions or with severe distress from an AI. ( 29 ) Conclusion The investigators demonstrated that 42% and 18.2% of Thai women receiving adjuvant letrozole therapy had vitamin D insufficiency and deficiency, respectively. Those with higher BMI ( ≥ 25 kg/m 2 ) and receiving inadequate dosages/formulations of vitamin D supplementation had significant trend towards lower vitamin D level. Twenty per cent, 27.3% and 25% of patients with baseline vitamin D sufficiency, insufficiency and deficiency, respectively had osteoporosis. Older ages ( ≥ 65 years), lower BMI (< 25 kg/m 2 ) and plasma 25(OH)D level in deficient level were the significant predictors of developing osteoporosis. The 21.6% prevalence of AIMSS was also reported with 68.4% of them had pre-existing either vitamin D insufficiency or deficiency. Upon repletion, the patients reported less joint pain. The investigators advocate that a physician should determine plasma 25(OH)D level and BMD, if possible prior to starting an adjuvant AI and restore its level if a patient has plasma 25(OH)D level ≤ 30 ng/ml and properly treat patients with pre-existing osteoporosis. Furthermore, repletion of the vitamin D level would ameliorate AIMSS. Strengths The investigators conducted a non-randomized prospective cohort trial to determine both prevalences of vitamin D insufficiency/deficiency, AIBL and AIMSS in patients taking an adjuvant AI. Both biochemical data and quality of life were collected and analyzed to determine the independent predictors of developing vitamin D insufficiency/deficiency, AIBL and AIMSS. Concomitantly, the investigators also testified the effect of restoration of vitamin D status on the improvement of the musculoskeletal symptoms. Limitations Due to limited time to conduct the study, the investigators did not obtain follow-up assessment of BMD and HRQoL. Longer and periodic determinations of BMD and quality of life would let to more robust evidences of the effect of sustained sufficiency of vitamin D level on bone health and musculoskeletal adverse effects. Declarations Ethics approval The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the by the Human Research Review Committee of Navamindhradhiraj University (COA 098/2567). Consent to participate All patients gave their informed consent for inclusion prior to participating in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Funding Open Access funding enabled and organized by Research Facilitation Division, Navamindradhiraj University. Author Contribution Conceptualization, C.B.; data curation, C.B., P.P. and P.C.; formal analysis, C.B. and P.C.; funding acquisition, C.B. and P.C.; investigation, P.P., P.C.; methodology, C.B. project administration, C.B.; resources, C.B. and P.P.; supervision, C.B.; validation, C.B. and P.P.; visualization, P.C.; writing—original draft preparation, C.B. and P.C.; writing—review and editing, C.B. All authors have read and approved the final manuscript. Acknowledgement The authors would like to thank all breast cancer patients during surveillance program for their participation in this study. The authors also thank to Mr. Anucha Kamsom who was responsible for statistical analysis of this research. Data Availability Upon request, our authors can provide any raw research data and supplemental data. References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229–263. Acheampong T, Kehm RD, Terry MB, Argov EL, Tehranifar P. Incidence Trends of Breast Cancer Molecular Subtypes by Age and Race/Ethnicity in the US From 2010 to 2016. JAMA Netw Open. 2020;3(8):e2013226. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). 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Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat. 2010;119(1):111–8. Giuliano AE, Edge SB, Hortobagyi GN. Eighth Edition of the AJCC Cancer Staging Manual: Breast Cancer. Annals of surgical oncology. 2018;25(7):1783–5 Charatcharoenwitthaya N, Jaisamrarn U, Songpatanasilp T, Kuptniratsaikul V, Unnanuntana A, Sritara C, Nimitphong H, Wattanachanya L, Chotiyarnwong P, Amphansap T, Phruetthiphat OA, Valleenukul T, Chaiamnuay S, Petchlorlian A, Srinonprasert V, Tejavanija S, Kitisomprayoonkul W, Dajpratham P, Chaikittisilpa S, Somboonporn W. Summary of the Thai Osteoporosis Foundation (TOPF) Clinical Practice Guideline on the diagnosis and management of osteoporosis 2021. Osteoporos Sarcopenia. 2023;9(2):45–52. Katchamart W, Benjamanukul S, Chiowchanwesawakit P. Validation of the Thai version of the Health Assessment Questionnaire for patients with psoriatic arthritis. International journal of rheumatic diseases. 2014;17(2):181–5 Ramey DR, Raynauld JP, Fries JF. The health assessment questionnaire 1992: status and review. Arthritis care and research : the official journal of the Arthritis Health Professions Association. 1992;5(3):119–29 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–30. de Sire A, Gallelli L, Marotta N, Lippi L, Fusco N, Calafiore D, Cione E, Muraca L, Maconi A, De Sarro G, Ammendolia A, Invernizzi M. Vitamin D Deficiency in Women with Breast Cancer: A Correlation with Osteoporosis? A Machine Learning Approach with Multiple Factor Analysis. Nutrients. 2022;14(8):1586. Hadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY, Zillikens MC, Glüer CC, de Villiers T, Baber R, Roodman GD, Cooper C, Langdahl B, Palacios S, Kanis J, Al-Daghri N, Nogues X, Eriksen EF, Kurth A, Rizzoli R, Coleman RE. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7:1–12. Niravath P. Aromatase inhibitor-induced arthralgia: a review. Ann Oncol. 2013;24(6):1443–9. Pineda-Moncusí M, Servitja S, Extebarria Foronda I, García-Vives E, Cos ML, Giménez-Argente C, Rodríguez-Morera J, et al. Effect of Vitamin D Supplementation on Aromatase Inhibitor-Related Musculoskeletal Side Effects for Breast Cancer: B-ABLE Cohort. Rev Osteoporosis Metab Miner. 2021;13 (2): 66–71. Arul Vijaya Vani S, Ananthanarayanan PH, Kadambari D, Harichandrakumar KT, Niranjjan R, Nandeesha H. Effects of vitamin D and calcium supplementation on side effects profile in patients of breast cancer treated with letrozole. Clin Chim Acta. 2016;459:53–56. Roberts KE, Adsett IT, Rickett K, Conroy SM, Chatfield MD, Woodward NE. Systemic therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer. Cochrane Database Syst Rev. 2022;1(1):CD013167. Gupta A, Henry NL, Loprinzi CL. Management of Aromatase Inhibitor-Induced Musculoskeletal Symptoms. JCO Oncol Pract. 2020;16(11):733–739. Additional Declarations No competing interests reported. Supplementary Files SupplementData.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6956411","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":494434142,"identity":"a8c4a1ac-1264-42d2-86d9-5c49e93276aa","order_by":0,"name":"Chanyoot Bandidwattanawong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDACCTgr+QCIK0O0FiCVlgCieUjRkmMAYhDWwj+7+dljngqbOt32nM+vbtRY8DCwHz66Aa8ld46ZG/OcSZMwO/N2m3XOMaDDeNLSbuDTYiCRYCbN23ZYwuxG7jbjHDagFgkeMwJa0r9BteQ8M875R5SWHJgtOcyPc9uI0CJxI6dMcs6ZNMltZ56ZMef2SfCwEfIL/4z0bRJvKmz4zY4nP/6c861Ojp/98DG8WkCACRoXbOA4YiOkHAQYf0Bo5g/EqB4Fo2AUjIKRBwB3D0SWs5p6zgAAAABJRU5ErkJggg==","orcid":"","institution":"Navamindhradhiraj University","correspondingAuthor":true,"prefix":"","firstName":"Chanyoot","middleName":"","lastName":"Bandidwattanawong","suffix":""},{"id":494434143,"identity":"67f8a940-00d0-4883-a615-8b1e75578a12","order_by":1,"name":"Pitchaporn Phudphong","email":"","orcid":"","institution":"Navamindhradhiraj University","correspondingAuthor":false,"prefix":"","firstName":"Pitchaporn","middleName":"","lastName":"Phudphong","suffix":""},{"id":494434145,"identity":"097a81ea-e1fa-4042-8269-533f77cf5753","order_by":2,"name":"Pimchanok Chittanavakun","email":"","orcid":"","institution":"Navamindhradhiraj University","correspondingAuthor":false,"prefix":"","firstName":"Pimchanok","middleName":"","lastName":"Chittanavakun","suffix":""}],"badges":[],"createdAt":"2025-06-23 11:38:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6956411/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6956411/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88422253,"identity":"a61f68d1-75e7-48ff-bfa0-d01d8dbf36d5","added_by":"auto","created_at":"2025-08-06 09:34:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":132698,"visible":true,"origin":"","legend":"\u003cp\u003eshowed the consort diagram.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6956411/v1/18ad3cde477a7b4f6bf02e20.png"},{"id":88424055,"identity":"172bef95-a65a-4c1e-90c0-e0a4161e5fc1","added_by":"auto","created_at":"2025-08-06 09:42:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":40573,"visible":true,"origin":"","legend":"\u003cp\u003eshowed the bar chart to exhibit the proportion of patients with normal BMD, osteopenia and osteoporosis across the three subgroups of vitamin D status.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6956411/v1/dea2d13c69b582f39b62b89d.png"},{"id":100370571,"identity":"295677a1-c933-4a2b-8fad-069206c77f2c","added_by":"auto","created_at":"2026-01-16 08:06:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1694593,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6956411/v1/fed7842c-1c56-4aaf-a630-13fb1a9d24bf.pdf"},{"id":88424054,"identity":"eca4baef-ee0b-499f-8b22-f038c2334c62","added_by":"auto","created_at":"2025-08-06 09:42:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":43539,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementData.docx","url":"https://assets-eu.researchsquare.com/files/rs-6956411/v1/4079cee4b1f1c7410e1aa3b1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of Vitamin D Status on Bone Mineral Density (BMD) and Aromatase-Induced Musculoskeletal Syndrome (AIMSS) in Post- menopausal Women Receiving An AI for Early Breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccording to the GLOBOCAN, breast cancer is the worldwide second leading cause of cancer incidence in 2022 just behind lung cancer. Approximately 2.3\u0026nbsp;million new cases were diagnosed, accounting for 11.6% of all cancer cases. This cancer was also the fourth leading cause of cancer mortality worldwide, roughly 666,000 deaths (6.9% of all cancer deaths). Right now, breast cancer is not only the most commonly diagnosed cancer, but also it is the leading cause of cancer deaths globally including Thailand.\u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/sup\u003e The population-based cross-sectional study included data from 18 cancer registries in the Surveillance, Epidemiology and End Results (SEER) database by Acheampong et al.\u003csup\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003ereported that most of the breast cancer patients were hormonal-receptor positive, 72.6% and 11.2% of them had luminal A and B, respectively. The luminal (hormonal receptor positive) breast cancer patients need anti-hormonal agents as either an adjuvant treatment in early/locally advanced setting or a palliative treatment in metastatic setting. Since the patient-level meta-analysis of the randomized trials by the Early Breast Cancer Trialists\u0026rsquo; Collaborative Group (EBCTCG) has demonstrated the superiority of an aromatase inhibitor (AI) over tamoxifen in terms of reductions in both breast cancer recurrences and mortality\u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e, an AI is the most commonly used hormonal agent. However, its use is limited to patients with complete loss of ovarian function to optimize its estrogen deprivation effect.\u003csup\u003e(\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e As adjuvant AI therapy provides longer disease-free survival, its long-term use in adjuvant setting has raised the concern regarding its association with bone density losses and detrimental effect on lipids and cardiovascular risk.\u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/sup\u003e In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, anastrozole led to a significant increased risk of fractures in comparison with tamoxifen (11.0% vs 7.7%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003csup\u003e(5)\u003c/sup\u003e While the International Exemestane Study (IES) revealed that exemestane was associated with an increased incidence of osteoporosis (7.3% vs 5.5%, p\u0026thinsp;=\u0026thinsp;0.01) and bone fractures (4.3% vs 3.1%, p\u0026thinsp;=\u0026thinsp;0.03) compared to tamoxifen.\u003csup\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e Hadji et al. have proposed that all patients initiating AI treatment, fracture risk assessment should be determined. Exercise and calcium/vitamin D supplementation are advocated. Bone-directed therapy should be provided to all patients with osteoporosis (T-score of \u0026lt; -2 SD) and patients with osteopenia (T-score of \u0026lt; -1.5 SD) with one additional risk factor, or with \u0026ge;\u0026thinsp;2 risk factors (without BMD) for the duration of AI treatment.\u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e Moreover, the AI-induced musculoskeletal symptoms (AIMSS) have been increasingly a worrisome issue, both as a major suffering adverse events and as a notable cause of premature discontinuation of the adjuvant therapy.\u003csup\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/sup\u003e Calcium and vitamin D supplementation has been universally recommended in order to preserve bone health and ameliorate AIMSS, even though the results from clinical trials evaluating its benefit on bone mineral density (BMD) in postmenopausal breast cancer patients taking hormonal therapy indicated that supplementation with 500\u0026ndash;1500 mg calcium and 200\u0026ndash;1000 IU vitamin D was insufficient to prevent bone loss. Furthermore, every study reported that women still substantially lost BMD at almost every site. Due to lack of an unsupplemented control group, it is unimaginable to conclude the net contribution of the supplementation on BMD.\u003csup\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/sup\u003e Since most of the supplementation dosages are usually empiric and it is conceivable that most of the physicians do not tailor the dosages according to their patients\u0026rsquo; vitamin D status, bone health and fracture risk anymore, inadequate supplementation would result in considerable risk of musculoskeletal adverse events.\u003c/p\u003e\u003cp\u003eImtiaz \u003cem\u003eet al.\u003c/em\u003e compared serum vitamin D levels among Indian breast cancer patients in comparison with the matched control group and demonstrated that the mean serum vitamin D level in the breast cancer patients was significantly lower than the control group (9.3 vs 14.9 ng/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Vitamin D deficiency was found in nearly all of their breast cancer patients (95.6%) and significantly more prevalent than in the matched control group (77%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Premenopausal breast cancer women had a mean serum vitamin D level less than the postmenopausal ones (10.5 vs 13.5 ng/ml; p\u0026thinsp;=\u0026thinsp;0.015). Interestingly, the investigators revealed that low BMD did not associate significantly with vitamin D deficiency (p\u0026thinsp;=\u0026thinsp;0.787). Moreover, the tumor characteristics (histology, grade, stage, and receptor status) did not predict any significant associations with vitamin D status.\u003csup\u003e(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/sup\u003e In line with the report by Kayah \u003cem\u003eet al.\u003c/em\u003e that performed in Turkish patients with early or locally advanced breast cancer, the mean vitamin D level was 13.91 ng/ml. Vitamin D deficiency and insufficiency were determined in 81.28% and 10.87% of their patients, respectively.\u003csup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/sup\u003e Even among breast cancer patients living in a Mediterranean country, the prevalence was also high. Nogues \u003cem\u003eet al.\u003c/em\u003e reported a fascinatingly high prevalence of vitamin D insufficiency/deficiency among breast cancer patients taking an AI in adjuvant setting, 88.1% of their cohort of patients in Spain had 25(OH)D level of \u0026lt;\u0026thinsp;30 ng/ml and 21.2% had severe deficiency (\u0026lt;\u0026thinsp;10 ng/ml). They also revealed its relationship between baseline BMD. BMD at femoral neck, in particular, was significantly correlated with low 25(OH)D concentrations; this association remained to be independent after adjustment by age, BMI and season of sample collection.\u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e The B-ABLE study conducted among Spanish breast cancer patients also revealed that 90% of patients had 25(OH)D level of \u0026lt;\u0026thinsp;30 ng/ml. This study also demonstrated that at 3 months after correction of the plasma 25(OH)D level to levels of 40 ng/ml or more led to protection of lumbar spine (LS) bone loss by 1.70% (95% C.I., 0.4\u0026ndash;3.0%; adjusted p\u0026thinsp;=\u0026thinsp;0.005) compared to those with low 25(OH)D levels (\u0026lt;\u0026thinsp;30 ng/ml).\u003csup\u003e(15)\u003c/sup\u003eThe prospective cohort BEGYN study conducted in Germany by Zemlin \u003cem\u003eet al.\u003c/em\u003e also revealed remarkably high prevalence (64.8%) of vitamin D deficiency among non-metastatic breast cancer patients. They also reported that patients\u0026rsquo; age, BMI, alcohol, smoking, skin type, and prior cancer history did not significantly affect the vitamin D levels. Patients who had moderate vitamin D deficiency were more likely to harbor luminal B carcinomas, on the other hand, other prognostic factors, such as Ki-67, histologic grading and tumor stage (cT and cN+) were not the significant predictor of low vitamin D levels.\u003csup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/sup\u003e An observational study from the USA by Khan \u003cem\u003eet al.\u003c/em\u003e also found that 63% of women taking an AI in adjuvant setting had either vitamin D deficiency (\u0026lt;\u0026thinsp;20 ng/ml) or insufficiency (20\u0026ndash;31 ng/ml). They also demonstrated that upon restoration of 25(OH)D level, those with AIMSS reported improvement of symptoms.\u003csup\u003e(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThese evidences emphasized us that the prevalences of vitamin D insufficiency/deficiency in patients with early and locally advanced breast cancer are substantially higher than general population and ubiquitous across both sides of the world. Since Thailand is located in a tropical area of the world, most of the Thai physicians are reluctant to determine their patients\u0026rsquo; vitamin D levels and prescribe recommended dosages and formulations of vitamin D. Moreover, no particular recommendation regarding the proper dosage and formulation of vitamin D supplementation and repletion for Thai breast cancer patients has been established. The investigators intended to determine the prevalence of vitamin D insufficiency/deficiency and AIMSS among post-menopausal Thai breast cancer patients taking an AI as the adjuvant therapy, its effect to bone health and whether appropriate vitamin D repletion contributed to improvement in musculoskeletal symptoms.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eProspective non-randomized observational cohort study\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy site\u003c/h3\u003e\n\u003cp\u003eThe study was conducted in single center at Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Vajira Hospital, Navamindhradhiraj University, Bangkok, Thailand.\u003c/p\u003e\n\u003ch3\u003eSubjects\u003c/h3\u003e\n\u003cp\u003eAny early breast cancer patients who had started treatment with an AI as an adjuvant therapy for at least 8 weeks were enrolled. Those who were pregnant, smoker or had history of pre-existing documented vitamin D deficiency, nephrolithiasis, CKD stage 3 or higher (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min), hypercalcemia (serum total calcium\u0026thinsp;\u0026gt;\u0026thinsp;11 mg/dL) were excluded. Patients with history of any bone diseases including osteomalacia, rheumatoid arthritis, metabolic or endocrine diseases, pre-existing diagnosis of Paget\u0026rsquo;s bone disease, concurrent or previous treatment with oral corticosteroids, bisphosphonates, or any other agents affecting bone minerals were also ruled out. Demographic data including age, BMI, TNM staging using AJCC 8th edition\u003csup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/sup\u003e, histologic subtype (luminal A or luminal B), type of previous systemic cancer treatment (hormonal therapy with or without chemotherapy), detailed types and dosages of calcium and vitamin D supplements, and Charleson Co-morbidity Index were collected. From December 18th, 2023 to March 28th, 2025, post-menopausal women with early hormonal positive breast cancer who were taking letrozole or recently switched from tamoxifen to letrozole were screened. They were invited to participate in the clinical trial and, after signing informed consent, they were recruited into the study. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e showed the consort diagram. Most of the excluded patients were those with underlying condition supposed to have pre-existing poor BMD i.e. CKD stage 3 (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min), receiving a bisphosphonate due to established osteoporosis, receiving high dose vitamin D to treat vitamin D insufficiency/ deficiency, receiving corticosteroid and pre-existing rheumatoid arthritis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eMeasurements\u003c/h3\u003e\n\u003cp\u003eAt baseline, blood checks for serum 25(OH)D, total calcium (Ca), phosphate (P), alkaline phosphatase (ALP), albumin, intact parathyroid hormone (iPTH), blood urea nitrogen (BUN) and creatinine (Cr) levels were obtained. Plasma concentrations of 25(OH)D were determined using the electrochemiluminescence (ECL) technology by Roche Diagnostics Cobas 8000 analyzer with a module (e801) for 25(OH)D total assay. Bone mineral density (BMD) was measured at lumbar spine (LS; L2\u0026ndash;L4), femoral neck (FN) and total hip (TH) using dual-energy X-ray absorptiometry (DXA) (Discovery \u003csup\u003eTM\u003c/sup\u003e QDR series, Hologic\u0026reg;, Marlborough, MA, USA). Osteoporosis was diagnosed based on the Thai Osteoporosis Foundation Guideline 2021.\u003csup\u003e(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/sup\u003e The participants had to respond to the Health Assessment Questionnaire-Disability Index (HAQ-DI).\u003csup\u003e(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/sup\u003e Those who responded to HAQ-DI and were documented to have at least mild disability were diagnosed to have AIMSS. The participants then self-evaluated their degrees of pain suffering using the Pain Score and Visual Analogue Scale (VAS). The pain severity coding of each participant was then translated into measurement scale.\u003csup\u003e(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eAfter plasma 25(OH)D level was determined, the participants were divided into 3 groups: patients with normal (\u0026gt;\u0026thinsp;30\u0026ndash;100 ng/mL), vitamin D insufficiency (20\u0026ndash;30 ng/ml), or vitamin D deficiency (\u0026lt;\u0026thinsp;20 ng/mL) according to the consensus from the Task Force of the Endocrine Society.\u003csup\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/sup\u003e Those with vitamin D sufficiency were allowed to continue the same dosages and formulations of calcium and vitamin D supplements. On the other hand, those with vitamin D insufficiency or deficiency were treated according to the protocol designed by the expert endocrinologist (see Supplement). Due to various formulations and dosages of vitamin D supplementation, the investigators had collected this data and then divided into two groups, those who were taking calciferol at least 20,000 IU/week and those taking other dosages and/or other vitamin D formulations with lower equivalent dosages. After vitamin D repletion, plasma 25(OH)D level as well as serum total Ca, P, ALP, albumin, iPTH, BUN, Cr levels were repeated 8 weeks later. Those who still had insufficient or deficient level of vitamin D were sent to the expert endocrinologist to adjust dosages and follow up. After BMD results were reported, those who had osteopenia or osteoporosis were also sent to the expert endocrinologist for proper management including adjustment of calcium and vitamin D supplementation and bisphosphonates, if indicated. Follow-up BMD evaluation was subject to the consultant endocrinologist\u0026rsquo;s discretion. After vitamin D restoration was successful, the participants with vitamin D insufficiency or deficiency were requested to respond to post-treatment HAQ-DI and VAS to determine whether vitamin D repletion was attributable to improvement of AIMSS.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eOutcomes\u003c/h2\u003e\u003cp\u003eThe primary outcome was the prevalence of vitamin D insufficiency and deficiency in breast cancer patients taking letrozole in the adjuvant setting. The secondary outcomes included the prevalence of AIMSS, the correlation between vitamin D status and BMD, the pattern of BMD loss among those with vitamin D insufficiency/deficiency, the correlation between vitamin D status and AIMSS, the success rate of vitamin D repletion protocol for patients with vitamin D insufficiency/deficiency and whether vitamin D repletion was associated with improvement in AIMSS.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eBased on the study by Zemlin \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e, with \u003cem\u003eα\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05 and \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.10, the investigators calculated the sample size of 88 patients. Statistical analyses were performed using SPSS 28.0 (IBM, Armonk, NY, USA). Qualitative parameters (e.g., tumor stage) were displayed in numbers and per cent. Quantitative parameters were displayed as mean and standard deviation (SD) or median with inter-quartile range (IQR), whatever appropriate. Associations between baseline plasma 25(OH)D levels and pre-specified co-variates were assessed using simple linear regression, and then further adjusted in multivariate models (multiple linear regression) using forward stepwise methods. A possible correlation between 25(OH)D levels and the BMD and occurrence of AIMSS were examined using the Mann\u0026ndash;Whitney U test for metric and ordinal variables with asymptotic p-value. Nominal variables were tested with cross tabulation and the Chi-Square test or Fishers\u0026rsquo; exact test, whatever appropriate. All analyses were two-tailed, and p values were considered statically significant when it was less than 0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe investigators recruited 88 patients with early breast cancer taking an adjuvant AI. Since letrozole is the only AI enlisted in Thailand\u0026rsquo;s Essential Drug List, all of the participants received letrozole. Baseline characteristics of eligible participants were shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Baseline mean (\u0026plusmn;\u0026thinsp;SD) plasma 25(OH)D level was relatively low (28.24\u0026thinsp;\u0026plusmn;\u0026thinsp;9.72 ng/ml). Median age of the participants (IQR) was 65.5 (61\u0026ndash;72) years and median BMI (IQR) was 25.48 (22.36\u0026ndash;28.79) kg/m\u003csup\u003e2\u003c/sup\u003e. The participant almost harbored minimal co-morbidity (mean Charleson Co-morbidity Index was 4). Most of the participants had stage 1 or 2 breast cancer (63 patients, 71.6%). Nearly half of the participants (42 patients, 47.7%) had luminal A disease. Approximately one-third (32 patients, 36.4%) of the participants had taken tamoxifen and three-fourths (67 patients, 76.1%) had received adjuvant chemotherapy before they were enrolled into the trial. The exact time of taking tamoxifen prior to switching to letrozole was impossible because substantial numbers of the participants had been referred or transferred from a surgeon or a primary hospital. Since calcium and vitamin D dosages and formulations for supplementation were subject to an attending physician\u0026rsquo;s discretion, the investigators documented only the most recently prescribed dosages and forms prior to subject enrollment. Regarding the calcium and vitamin D supplementation, most (78 patients, 88.6%) of the participants had received adequate (as defined as receiving\u0026thinsp;\u0026ge;\u0026thinsp;1500 mg/day) dosages of calcium supplements, while only one-third (29 patients, 33%) were taking at least 20,000 IU of calciferol per week) before they were enrolled into the trial. The prevalence of vitamin D insufficiency and deficiency were 42% and 18.2%, respectively.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowed baseline demographic data and oncological characteristics of participants.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(100.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum 25[OH]D (ng/mL) (\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;9.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e(9.89\u0026ndash;60.00)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years) (median, IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e65.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(61\u0026ndash;72)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody weight (kg) (median, IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(53\u0026ndash;68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody mass index (kg/m\u0026sup2;) (median, IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(22.36\u0026ndash;28.79)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;25.0 kg/m\u0026sup2; (no., %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(45.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;25.0 kg/m\u0026sup2; (no., %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(54.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStaging (no., %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage 1\u0026ndash;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(71.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(28.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubtype (no., %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(47.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal B/HER2-Negative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(44.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal B/HER2-Positive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(8.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious tamoxifen (no, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(36.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious chemotherapy (no, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(76.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCalcium supplement (no, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(100.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;1500 mg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(11.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1500 mg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(88.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious vitamin D supplement (no., %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(100.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCalciferol (20,000 IU/week)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(33.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(67.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharlson Comorbidity Index (median, IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(4\u0026ndash;5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMD status, (n\u0026thinsp;=\u0026thinsp;84) (no., %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(22.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(53.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteoporosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(23.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT-score (\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG - no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(80.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(19.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eData are presented as number and per cent, mean and standard deviation (SD) or median and interquartile range (IQR).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eRegarding the correlation between vitamin D insufficiency/deficiency and baseline demographics. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e showed the uni- and multi-variate analyses to explore the association. The investigators demonstrated that only patients with high BMI (\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) (OR\u003csub\u003eadj\u003c/sub\u003e 3.66, 95% C.I.,1.31\u0026ndash;10.22; p\u0026thinsp;=\u0026thinsp;0.013) and those who were not taking vitamin D supplementations other than calciferol at least 20,000 IU (or equivalent dose)/week (OR\u003csub\u003eadj\u003c/sub\u003e 3.84, 95% C.I.,1.34\u0026ndash;10.97; p\u0026thinsp;=\u0026thinsp;0.012) were the significant factors predicting chances of developing vitamin D insufficiency/deficiency.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowed the uni- and multi-variate analyses of factors associated with vitamin D insufficiency and deficiency (Serum 25(OH)D\u0026thinsp;\u0026le;\u0026thinsp;30 ng/ml)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eFactors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eUnivariable analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eMultivariable analysis\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCrude OR\u0026dagger; (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eAdjusted OR\u0026Dagger; (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;65 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;65 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.41\u0026ndash;2.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.960\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.17\u0026ndash;1.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.184\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody mass index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;25.0 kg/m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;25.0 kg/m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(1.35\u0026ndash;8.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.31\u0026ndash;10.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage I-II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage III\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.31\u0026ndash;2.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.610\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.30\u0026ndash;2.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.880\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistologic subtype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.59\u0026ndash;3.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.458\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.39\u0026ndash;3.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.875\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious tamoxifen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.26\u0026ndash;1.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.305\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.18\u0026ndash;1.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.196\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious chemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.13\u0026ndash;1.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.093\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.12\u0026ndash;1.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.262\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious vitamin D supplement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCalciferol (20,000 IU/week)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(1.28\u0026ndash;8.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1.34\u0026ndash;10.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eAbbreviations: CI, confidence interval; OR, odds ratio; NA, data not applicable.\u003c/p\u003e\u003cp\u003e\u0026dagger;Crude odds ratio estimated by Logistic regression model.\u003c/p\u003e\u003cp\u003e\u0026Dagger;Adjusted odds ratio estimated by Logistic regression model adjusting for age, body mass index, stage, previous tamoxifen, previous chemotherapy, calcium, phosphate and PTH.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e showed the bar chart to exhibit the proportion of patients with normal BMD, osteopenia and osteoporosis across the three subgroups of vitamin D status. Astonishingly, at baseline, half (45 patients, 53.6%) and one-fourth (20 patients, 23.8%) of participants had osteopenia and osteoporosis, respectively. Twenty per cent (20%), 27.3% and 25% of patients with baseline vitamin D sufficiency, insufficiency and deficiency were diagnosed to have osteoporosis, respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAlthough there was not significant difference in terms of proportion of patients with osteopenia/osteoporosis among three subgroups of vitamin D status, the investigators demonstrated that vitamin D deficiency had a strongly predictive chance of developing osteopenia and osteoporosis in multi-variate analysis. In case of osteoporosis, besides ageing (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;65 years) (OR\u003csub\u003eadj\u003c/sub\u003e 6.77, 95% C.I.,1.36\u0026ndash;33.63 p\u0026thinsp;=\u0026thinsp;0.019) and low BMD (OR\u003csub\u003eadj\u003c/sub\u003e = 5.59, 95% C.I., 1.07\u0026ndash;29.23; p\u0026thinsp;=\u0026thinsp;0.041), vitamin D deficiency or insufficiency (OR\u003csub\u003eadj\u003c/sub\u003e = 8.98, 95% C.I., (1.52\u0026ndash;53.19); p\u0026thinsp;=\u0026thinsp;0.016) were also another significant predictive factors \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowed the uni-variated and multi-variated analyses of associations between baseline demographic data and bone health (osteopenia and osteoporosis).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"13\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eFactors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u003cp\u003eUnivariable analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eMultivariable analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eMultivariable analysis\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eOsteopenia\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eOsteoporosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eOsteopenia\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c13\" namest=\"c11\"\u003e\u003cp\u003eOsteoporosis\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCrude OR\u0026dagger; (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eCrude OR\u0026dagger; (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003eAdjusted OR\u0026Dagger; (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003eAdjusted OR\u0026Dagger; (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;65 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;65 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.52\u0026ndash;4.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.446\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.70\u0026ndash;9.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.155\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.66\u0026ndash;8.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.192\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e6.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(1.36\u0026ndash;33.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody mass index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;25.0 kg/m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.34\u0026ndash;2.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.993\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.47\u0026ndash;5.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.422\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.44\u0026ndash;7.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.419\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e5.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(1.07\u0026ndash;29.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.041\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;25.0 kg/m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage I-II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage III\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.42\u0026ndash;4.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.581\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.22\u0026ndash;3.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.925\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.21\u0026ndash;3.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.866\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(0.20\u0026ndash;6.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.896\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistologic subtype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.64\u0026ndash;5.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.254\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.32\u0026ndash;3.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.855\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.53\u0026ndash;6.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.340\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(0.24\u0026ndash;4.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.933\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious tamoxifen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.25\u0026ndash;2.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.656\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.58\u0026ndash;7.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.258\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.27\u0026ndash;3.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.973\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e4.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(0.93\u0026ndash;19.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.061\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious chemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.62\u0026ndash;7.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.228\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.28\u0026ndash;4.20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.915\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.65\u0026ndash;15.48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.152\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(0.20\u0026ndash;7.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.804\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious vitamin D supplement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCalciferol (20,000 IU/week)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.22\u0026ndash;2.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.581\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.17\u0026ndash;2.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.558\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(0.07\u0026ndash;1.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(0.04\u0026ndash;1.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.106\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVitamin D value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsufficiency or Deficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0.76\u0026ndash;6.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.142\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(0.70\u0026ndash;9.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.156\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e6.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(1.29\u0026ndash;28.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e8.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e(1.52\u0026ndash;53.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.016\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"13\" nameend=\"c13\" namest=\"c1\"\u003e\u003cp\u003eAbbreviations: CI, confidence interval; OR, odds ratio; NA, data not applicable.\u003c/p\u003e\u003cp\u003e\u0026dagger;Crude odds ratio estimated by Multinomial logistic regression model.\u003c/p\u003e\u003cp\u003e\u0026Dagger;Adjusted odds ratio estimated by Multinomial logistic regression model adjusting for age, body mass index, stage, previous tamoxifen, previous chemotherapy, calcium, phosphate and PTH.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eexhibited the comparison of the BMD status across three groups of vitamin D status. The distribution of BMD status did not differ significantly across the groups (p\u0026thinsp;=\u0026thinsp;0.426). Overall, 22.6% had normal BMD, 53.6% had osteopenia, and 23.8% had osteoporosis. The proportion of participants with normal BMD was highest in the vitamin D sufficient group (31.4%), compared to 25.0% in the deficient group and 12.1% in the insufficient group. Osteopenia was the most prevalent condition in all groups. With respect to the dominant site of bone loss, the lumbar spine (LS) was the most commonly affected region overall (51.2%), with the highest prevalence in the deficient group (62.5%), followed by the insufficient (51.5%) and sufficient (45.7%) groups, respectively. However, due to small sample size, these differences were not statistically significant (p\u0026thinsp;=\u0026thinsp;0.713). The femoral neck (FN) was the second most common site (41.7%), while hip (H) involvement was relatively uncommon (7.1%) and fascinatingly absent in the vitamin D deficient group. Mean T-scores across three groups of different vitamin D status were also comparable. The overall mean total T-score was \u0026minus;\u0026thinsp;1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14, with slightly better but not statistically different score in the sufficient group (\u0026minus;\u0026thinsp;1.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.28) compared to the deficient (\u0026minus;\u0026thinsp;1.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10) and insufficient (\u0026minus;\u0026thinsp;1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98) groups (p\u0026thinsp;=\u0026thinsp;0.430). Similarly, no significant difference was observed in site-specific T-scores, LS (p\u0026thinsp;=\u0026thinsp;0.936), H (p\u0026thinsp;=\u0026thinsp;0.615), and FN (p\u0026thinsp;=\u0026thinsp;0.370).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;84)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eDeficient group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eInsufficient group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003eSufficient group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMD status, (n\u0026thinsp;=\u0026thinsp;84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(22.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(12.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(31.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.426\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(53.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(60.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(48.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteoporosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(23.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(27.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDominant, (n\u0026thinsp;=\u0026thinsp;84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"10\" nameend=\"c11\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLumbar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(51.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(62.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(51.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(45.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.713\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemoral neck\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(41.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(37.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(42.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHip\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(6.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(11.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT-score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e-1.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e-1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e-1.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.430\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT-score Lumbar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-1.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e-1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e-1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;1.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e-1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.936\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT-score Hip\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e-0.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e-0.65\u0026thinsp;\u0026plusmn;\u0026thinsp;1.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e-0.40\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.615\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT-score Femoral neck\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e-1.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e-1.31\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e-1.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003e-1.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.370\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"11\" nameend=\"c11\" namest=\"c1\"\u003e\u003cp\u003eAbbreviations: NA, data not applicable.\u003c/p\u003e\u003cp\u003eData are presented as number (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range).\u003c/p\u003e\u003cp\u003eP-value corresponds to \u003csup\u003ea\u003c/sup\u003eOne-way ANOVA, or \u003csup\u003eb\u003c/sup\u003eFisher\u0026rsquo;s exact test.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e showed the comparison of the prevalences of AIMSS across three subgroups of vitamin D status.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e displayed the comparison of the prevalences of AIMSS across three groups of vitamin D status. On condition that those with abnormal HAQ-DI (at least mild degree of severity index) was legitimate to have the AIMSS, 19 patients of the cohort (21.6%) had AIMSS. Specifically, AIMSS was reported in 3 patients (18.8%) in the vitamin D deficient group, 10 patients (27.0%) in the vitamin D insufficient group, and 6 patients (17.1%) in the sufficient vitamin D group. Although this difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.568) across groups of different vitamin D status, the investigators speculated that more than two-thirds of patients (68.4%) of those with AIMSS had low vitamin D status (insufficiency and deficiency).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowed the comparison of the prevalences of AIMSS across three groups of vitamin D status.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eDeficient group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eInsufficient group (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003eSufficient group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAIMSS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(21.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(18.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(27.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(17.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.568\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e\u003cp\u003eP-value corresponds to Chi-square test\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe investigators further explored the effect of vitamin D repletion on the improvement of AIMSS and demonstrated that upon normalization of 25(OH)D level, the severity of AIMSS as determined by HAQ-DI was not significantly different. Nevertheless, when only the pain domain was re-evaluated, the severity of pain as assessed by both Pain Scale and visual analogue scale (VAS) were significantly ameliorated after vitamin D repletion among participants with baseline low vitamin D levels (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowed effect of vitamin D repletion on AIMSS as evaluated by the HAQ-DI, Pain Scale and VAS.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eVitamin D level\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u003cp\u003eAIMSS (disability index including mild, moderate, severe degree)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cb\u003eAfter 8 weeks\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eDifference in percent (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u0026dagger;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e(%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e(%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(18.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-6.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(27.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(29.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll patients who had vitamin D level\u0026thinsp;\u0026le;\u0026thinsp;30 ng/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(24.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(24.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eVitamin D level\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003ePain scale (0\u0026ndash;3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cb\u003eAfter 8 weeks\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMean difference\u003c/b\u003e\u003c/p\u003e\u003cp\u003e(95%CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.26 (-0.43, -0.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.25 (-0.35, -0.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll patients who had vitamin D level\u0026thinsp;\u0026le;\u0026thinsp;30 ng/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.25(-0.34, -0.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eVitamin D level\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eVAS score (0\u0026ndash;10)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cb\u003eAfter 8 weeks\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMean difference\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(95%CI)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e2.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.88(-1.42, -0.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e2.59\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.87(-1.19, -0.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll patients who had vitamin D level\u0026thinsp;\u0026le;\u0026thinsp;30 ng/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.70\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.87(-1.14, -0.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003e\u0026dagger;P-value corresponds to McNemar test.\u003c/p\u003e\u003cp\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003ePaired samples t-test\u003c/p\u003e\u003cp\u003e*Significant at p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe investigators also assessed the effectiveness of vitamin D repletion protocol as suggested by an expert endocrinologist (see Supplement) and proved that the protocol could restore plasma 25(OH)D level efficiently (100% response rate) without undesired AEs. Upon repletion of plasma 25(OH)D level, the investigators also found that only serum total calcium level was increased minimally but significantly compared with the levels prior to repletion, while phosphate, alkaline phosphatase and iPTH levels were insignificantly changed (data not shown).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe investigators demonstrated that 42% and 18.2% of women receiving adjuvant letrozole therapy had vitamin D insufficiency and deficiency, respectively. Moreover, the mean plasma 25(OH)D of the entire cohort was only 28.24 ng/ml. In comparison with the study by Nogues \u003cem\u003eet al.\u003c/em\u003e among Spanish post-menopausal breast cancer patients taking an adjuvant AI, 88.1% of their patients had plasma 25(OH)D level of less than 30 ng/ml with the mean level of only 18.5 ng/ml.\u003csup\u003e(14)\u003c/sup\u003e While the results from the B-ABLE study by Pietro-Alhambra \u003cem\u003eet al.\u003c/em\u003e revealed that 90% of Spanish patients taking an adjuvant AI had plasma 25(OH)D level of less than 30 ng/ml as well.\u003csup\u003e(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/sup\u003e This prevalence in Thai post-menopausal women taking an adjuvant AI is astonishingly comparable to reports from Asian and Western countries.\u003c/p\u003e\u003cp\u003eRegarding the factors associated with vitamin D insufficiency/deficiency, the investigators found that higher BMI (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;25kg/m\u003csup\u003e2\u003c/sup\u003e) (OR\u003csub\u003eadj\u003c/sub\u003e = 3.66, 95% C.I. 1.31\u0026ndash;10.22; p\u0026thinsp;=\u0026thinsp;0.013) and formulations or dosages of vitamin D supplementation less than calciferol of 20,000 IU or eqivalent/week (OR\u003csub\u003eadj\u003c/sub\u003e = 3.84, 95%C.I. 1.34\u0026ndash;10.97; p\u0026thinsp;=\u0026thinsp;0.012) were independently correlated with vitamin D insufficiency/deficiency (\u0026le;\u0026thinsp;30 ng/ml) condition, while age, histologic subtype, stage, previous tamoxifen or adjuvant chemotherapy were not. Imtiaz, \u003cem\u003eet al.\u003c/em\u003e conducted a study in newly diagnosed breast cancer Indian patients also demonstrated that the tumor characteristics (histology, grade, stage, and receptor status) were not the predictive factor associated with low baseline vitamin D levels. Pre-menopausal breast cancer patients seemed to have lower vitamin D level than post-menopausal ones\u0026rsquo; (10.5 ng/ml vs 13.5 ng/ml; p\u0026thinsp;=\u0026thinsp;0.015).\u003csup\u003e(12)\u003c/sup\u003e The study by Noges \u003cem\u003eet al.\u003c/em\u003e also supports the investigators\u0026rsquo; finding that high BMI was strongly associated with low baseline vitamin D levels, whereas seasons when blood samples were corrected and age had borderline correlation.\u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e The result from Zemlin \u003cem\u003eet al.\u003c/em\u003e also substantiates that vitamin D supplementation resulted in higher vitamin D levels besides sample collection in summer season. Notably, they reported that patients with moderate vitamin D deficiency were more likely to have Luminal B subtype, while other prognostic factors (Ki67, histologic grading, and tumor stage (cT and cN+) were not the predictive factor.\u003csup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eWith respect to the association between baseline 25(OH)D levels and bone health. The investigators revealed that 27.3% and 25% of patients with baseline vitamin D insufficiency and deficiency, respectively were diagnosed to have osteoporosis. Intriguingly, the prevalence of osteoporosis among those with sufficient vitamin D level was also high at 20%. Although no statistical difference in proportion of patients with osteopenia and osteoporosis among three groups of different levels of vitamin D, the investigators demonstrated in multi-variate analysis that those with older ages (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;65 years) (OR\u003csub\u003eadj\u003c/sub\u003e = 6.77, 95% C.I. 1.36\u0026ndash;33.63; p\u0026thinsp;=\u0026thinsp;0.019), lower BMI (\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) (OR\u003csub\u003eadj\u003c/sub\u003e = 5.59, 95% C.I. 1.07\u0026ndash;29.23; p\u0026thinsp;=\u0026thinsp;0.041), and plasma 25(OH)D level in deficient or insufficiency level (OR\u003csub\u003eadj\u003c/sub\u003e = 8.98, 95% C.I. 1.52\u0026ndash;53.19; p\u0026thinsp;=\u0026thinsp;0.016) had independent tendency towards developing osteoporosis. The investigators revealed the powerful trend toward higher rate of normal BMD and less negative T-scores in the vitamin D sufficient group suggested a potential protective role of adequate vitamin D levels on bone health. The LS was the most common site of bone loss across all groups of vitamin D status, particularly among individuals with vitamin D deficiency. These findings highlight the importance of close monitoring of LS BMD among post-menopausal individuals with hormonal receptor positive and taking an AI with vitamin D deficiency. Provocatively, these results support to promote of restoration of vitamin D status as part of the bone health improvement strategies, especially in populations at heightened risk of developing osteopenia or osteoporosis, including post-menopausal women and breast cancer patients receiving an AI who are known to experience accelerated bone loss due to absolute estrogen depletion. Given the relatively small sample size and short duration of follow up, future studies with larger cohorts and longitudinal designs are recommended to further clarify the relationship between vitamin D status and site-specific BMD changes. Additionally, the impact of confounding factors such as calcium intake, physical activity, and hormonal status should be examined in more details. Nogues \u003cem\u003eet al.\u003c/em\u003e also confirms the correlation between plasma 25(OH)D level and bone loss, especially the femoral neck BMD that was still consistent after adjustment by age, BMI and season of blood sample collection.\u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e De Sire \u003cem\u003eet al.\u003c/em\u003e performed a machine learning approach to prove the relationship between vitamin D deficiency and osteoporosis in patients taking an AI and indicated that there was a scant number of patients with adequate bone health and a normal vitamin D3 status, therefore they deduced that both BMD and vitamin D3 status should be assessed and restored properly to decrease the risk of osteoporotic fractures in breast cancer women.\u003csup\u003e(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/sup\u003eThe Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG has proposed the guideline of management of aromatase inhibitor-associated bone loss (AIBL) in post-menopausal women with hormone sensitive breast cancer. The experts recommend adequate calcium and vitamin D supplementation and consider denosumab or a bisphosphonate, if T score \u0026le; -2.0 or \u0026ge;\u0026thinsp;2 clinic risk factors for fracture. Denosumab has stronger clinical evidences in improving bone health than a bisphosphonate; however, zoledronic acid has robust evidences in preventing cancer recurrence.\u003csup\u003e(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe investigators concerned the musculoskeletal related adverse effects from adjuvant AI. Since these troublesome side effects led to the 13\u0026ndash;22% premature discontinuation rate\u003csup\u003e(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/sup\u003e, the investigators also determined the prevalence of AIMSS among breast cancer patients taking letrozole. Due to no specific definition of AIMSS, the investigators used the HAQ-DI questionnaire as the study by Khan \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/sup\u003e did to determine the prevalence of AIMSS. The investigators found that 21.6% of the participants had at least mild degree of disability index. More than two-third of them had vitamin D insufficiency/deficiency. Even though those with vitamin D insufficiency/deficiency had been treated, there was no significant improvement as assessed by HAQ-DI obtained 8 weeks after repletion. Nevertheless, the pain domain was statistically ameliorated as determined by pain scale (mean difference after vitamin D repletion = -0.25 (95% C.I. -0.34 - -0.17; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and VAS score (mean difference after vitamin D repletion = -0.87 (95% C.I. -1.14 - -0.60; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). According to the study by Khan \u003cem\u003eet al.\u003c/em\u003e, those taking an adjuvant AI were allowed to receive additional vitamin D supplementation, if they had baseline 25(OH)D level of less than 40 ng/ml. They found that 4 weeks after receiving extra dose of vitamin D (16 weeks after start an adjuvant AI), significantly higher number of women with 25(OH)D levels of more than the median level (\u0026gt;\u0026thinsp;66 ng/ml) reported no disability from joint pain than women with levels\u0026thinsp;\u0026lt;\u0026thinsp;66 ng/ml (52 vs. 19%; p\u0026thinsp;=\u0026thinsp;0.026).\u003csup\u003e(17)\u003c/sup\u003eThe report from the B-ABLE study also confirms the contribution of vitamin D repletion on AIMSS. Vitamin D supplementation at the start of AI treatment decreased the risk of both incident joint pain and its worsening. Pineda-Moncus\u0026iacute;, \u003cem\u003eet al\u003c/em\u003e suggested that the effective threshold of serum 25(OH)D to relieve joint pain should be 40 ng/ml or more. However, this threshold was not significantly associated with bone changes at one year of follow-up.\u003csup\u003e(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/sup\u003eA study by Arul Vijaya Vani \u003cem\u003eet al.\u003c/em\u003e conducted in Indian breast cancer patients taking adjuvant letrozole is another study supporting the evidence of vitamin D3 and calcium supplementation in reduction of musculoskeletal side effects. They demonstrated that patients who had low serum 25(OH)D concentrations suffered more from musculoskeletal symptoms which were improved following supplementation (9.14 vs 8.10; p\u0026thinsp;=\u0026thinsp;0.000).\u003csup\u003e(27)\u003c/sup\u003eEven though the Cochrane\u0026rsquo;s systematic review by Roberts \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e)\u003c/sup\u003e declared that there were scant evidences supporting the safe and effective systemic therapies in preventing the AIMSS, Gupta \u003cem\u003eet al.\u003c/em\u003e proposed the algorithm for preventing and managing AIMSS including vitamin D measurement and correction to improve bone health and suggested the alternative therapies like strengthening exercises and acupuncture, medication (duloxetine) and food supplement (omega-3 fatty acid, if BMI\u0026thinsp;\u0026gt;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e) for patients with mild to moderate symptoms and permanent discontinuation or alternative hormonal therapies, if no improvement after such interventions or with severe distress from an AI.\u003csup\u003e(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe investigators demonstrated that 42% and 18.2% of Thai women receiving adjuvant letrozole therapy had vitamin D insufficiency and deficiency, respectively. Those with higher BMI (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) and receiving inadequate dosages/formulations of vitamin D supplementation had significant trend towards lower vitamin D level. Twenty per cent, 27.3% and 25% of patients with baseline vitamin D sufficiency, insufficiency and deficiency, respectively had osteoporosis. Older ages (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;65 years), lower BMI (\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) and plasma 25(OH)D level in deficient level were the significant predictors of developing osteoporosis. The 21.6% prevalence of AIMSS was also reported with 68.4% of them had pre-existing either vitamin D insufficiency or deficiency. Upon repletion, the patients reported less joint pain. The investigators advocate that a physician should determine plasma 25(OH)D level and BMD, if possible prior to starting an adjuvant AI and restore its level if a patient has plasma 25(OH)D level\u0026thinsp;\u0026le;\u0026thinsp;30 ng/ml and properly treat patients with pre-existing osteoporosis. Furthermore, repletion of the vitamin D level would ameliorate AIMSS.\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eStrengths\u003c/h2\u003e\u003cp\u003eThe investigators conducted a non-randomized prospective cohort trial to determine both prevalences of vitamin D insufficiency/deficiency, AIBL and AIMSS in patients taking an adjuvant AI. Both biochemical data and quality of life were collected and analyzed to determine the independent predictors of developing vitamin D insufficiency/deficiency, AIBL and AIMSS. Concomitantly, the investigators also testified the effect of restoration of vitamin D status on the improvement of the musculoskeletal symptoms.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eDue to limited time to conduct the study, the investigators did not obtain follow-up assessment of BMD and HRQoL. Longer and periodic determinations of BMD and quality of life would let to more robust evidences of the effect of sustained sufficiency of vitamin D level on bone health and musculoskeletal adverse effects.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the by the Human Research Review Committee of Navamindhradhiraj University (COA 098/2567).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003cp\u003eAll patients gave their informed consent for inclusion prior to participating in the study.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eOpen Access funding enabled and organized by Research Facilitation Division, Navamindradhiraj University.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization, C.B.; data curation, C.B., P.P. and P.C.; formal analysis, C.B. and P.C.; funding acquisition, C.B. and P.C.; investigation, P.P., P.C.; methodology, C.B. project administration, C.B.; resources, C.B. and P.P.; supervision, C.B.; validation, C.B. and P.P.; visualization, P.C.; writing\u0026mdash;original draft preparation, C.B. and P.C.; writing\u0026mdash;review and editing, C.B. All authors have read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank all breast cancer patients during surveillance program for their participation in this study. The authors also thank to Mr. Anucha Kamsom who was responsible for statistical analysis of this research.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eUpon request, our authors can provide any raw research data and supplemental data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229\u0026ndash;263.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAcheampong T, Kehm RD, Terry MB, Argov EL, Tehranifar P. 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Lancet. 2005 Aug 6\u0026ndash;12;366(9484):455\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorden JP, Alvarez I, Bertelli G, Coates AS, Coleman R, Fallowfield L, Jassem J, Jones S, Kilburn L, L\u0026oslash;nning PE, Ortmann O, Snowdon C, van de Velde C, Andersen J, Del Mastro L, Dodwell D, Holmberg S, Nicholas H, Paridaens R, Bliss JM, Coombes RC. Long-Term Follow-Up of the Intergroup Exemestane Study. J Clin Oncol. 2017;35(22):2507\u0026ndash;2514.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNabholtz JM. Long-term safety of aromatase inhibitors in the treatment of breast cancer. Ther Clin Risk Manag. 2008;4(1):189\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY, Zillikens MC, Gl\u0026uuml;er CC, de Villiers T, Baber R, Roodman GD, Cooper C, Langdahl B, Palacios S, Kanis J, Al-Daghri N, Nogues X, Eriksen EF, Kurth A, Rizzoli R, Coleman RE. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta A, Henry NL, Loprinzi CL. Management of Aromatase Inhibitor-Induced Musculoskeletal Symptoms. JCO Oncol Pract. 2020;16(11):733\u0026ndash;739.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDatta M, Schwartz GG. Calcium and vitamin D supplementation and loss of bone mineral density in women undergoing breast cancer therapy. Crit Rev Oncol Hematol. 2013;88(3):613\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eImtiaz S, Siddiqui N, Raza SA, Loya A, Muhammad A. Vitamin D deficiency in newly diagnosed breast cancer patients. 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Eighth Edition of the AJCC Cancer Staging Manual: Breast Cancer. Annals of surgical oncology. 2018;25(7):1783\u0026ndash;5\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCharatcharoenwitthaya N, Jaisamrarn U, Songpatanasilp T, Kuptniratsaikul V, Unnanuntana A, Sritara C, Nimitphong H, Wattanachanya L, Chotiyarnwong P, Amphansap T, Phruetthiphat OA, Valleenukul T, Chaiamnuay S, Petchlorlian A, Srinonprasert V, Tejavanija S, Kitisomprayoonkul W, Dajpratham P, Chaikittisilpa S, Somboonporn W. Summary of the Thai Osteoporosis Foundation (TOPF) Clinical Practice Guideline on the diagnosis and management of osteoporosis 2021. Osteoporos Sarcopenia. 2023;9(2):45\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKatchamart W, Benjamanukul S, Chiowchanwesawakit P. Validation of the Thai version of the Health Assessment Questionnaire for patients with psoriatic arthritis. International journal of rheumatic diseases. 2014;17(2):181\u0026ndash;5\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRamey DR, Raynauld JP, Fries JF. The health assessment questionnaire 1992: status and review. Arthritis care and research : the official journal of the Arthritis Health Professions Association. 1992;5(3):119\u0026ndash;29\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHolick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Sire A, Gallelli L, Marotta N, Lippi L, Fusco N, Calafiore D, Cione E, Muraca L, Maconi A, De Sarro G, Ammendolia A, Invernizzi M. Vitamin D Deficiency in Women with Breast Cancer: A Correlation with Osteoporosis? A Machine Learning Approach with Multiple Factor Analysis. Nutrients. 2022;14(8):1586.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY, Zillikens MC, Gl\u0026uuml;er CC, de Villiers T, Baber R, Roodman GD, Cooper C, Langdahl B, Palacios S, Kanis J, Al-Daghri N, Nogues X, Eriksen EF, Kurth A, Rizzoli R, Coleman RE. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNiravath P. Aromatase inhibitor-induced arthralgia: a review. Ann Oncol. 2013;24(6):1443\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePineda-Moncus\u0026iacute; M, Servitja S, Extebarria Foronda I, Garc\u0026iacute;a-Vives E, Cos ML, Gim\u0026eacute;nez-Argente C, Rodr\u0026iacute;guez-Morera J, et al. Effect of Vitamin D Supplementation on Aromatase Inhibitor-Related Musculoskeletal Side Effects for Breast Cancer: B-ABLE Cohort. Rev Osteoporosis Metab Miner. 2021;13 (2): 66\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArul Vijaya Vani S, Ananthanarayanan PH, Kadambari D, Harichandrakumar KT, Niranjjan R, Nandeesha H. Effects of vitamin D and calcium supplementation on side effects profile in patients of breast cancer treated with letrozole. Clin Chim Acta. 2016;459:53\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoberts KE, Adsett IT, Rickett K, Conroy SM, Chatfield MD, Woodward NE. Systemic therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer. Cochrane Database Syst Rev. 2022;1(1):CD013167.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta A, Henry NL, Loprinzi CL. Management of Aromatase Inhibitor-Induced Musculoskeletal Symptoms. JCO Oncol Pract. 2020;16(11):733\u0026ndash;739.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adjuvant AI, postmenopausal breast cancer patients, vitamin D supplementation, AIBL, AIMSS","lastPublishedDoi":"10.21203/rs.3.rs-6956411/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6956411/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u0026nbsp;\u003c/strong\u003eAn AI use is associated with bone health and musculoskeletal adverse events. Appropriate vitamin D supplementation would mitigate such side effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and Methods:\u003c/strong\u003e\u0026nbsp;Post-menopausal breast cancer patients taking adjuvant letrozole were recruited. Baseline plasma 25(OH)D,\u0026nbsp;BMD and HAQ-DI questionnaire were obtained to determine the aromatase-induced bone loss (AIBL)\u0026nbsp;and musculoskeletal syndrome (AIMSS). The prevalences of vitamin D insufficiency/deficiency, AIBL and AIMSS and the effect of vitamin D repletion on AIMSS were investigated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u0026nbsp;Eighty-eight patients were participated. Forty-two (42%) percent and 18.2% of women had vitamin D insufficiency and deficiency, respectively. High BMI (\u003cu\u003e\u0026gt;\u003c/u\u003e\u0026nbsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e) (OR 3.66, 95% C.I., 1.31-10.22; p = 0.013) and formulations/dosages of vitamin D supplementation with lower\u0026nbsp;equivalent dose than calciferol of 20,000 IU/week (OR 3.84, 95%C.I., 1.34-10.97; p = 0.012) were independently correlated with low plasma 25(OH)D level (≤30 ng/ml).\u0026nbsp;Ageing (\u003cu\u003e\u0026gt;\u003c/u\u003e\u0026nbsp;65 years) (OR\u0026nbsp;6.77, 95% C.I., 1.36-33.63 p= 0.019), low BMD (OR\u0026nbsp;5.59, 95% C.I., 1.07-29.23; p = 0.041) and low plasma 25(OH)D level (OR\u0026nbsp;8.98, 95% C.I., 1.52 - 53.19 ; p = 0.016) were the significant predictors of developing osteoporosis. Nineteen of the participants (21.6%) had AIMSS and 68.4% of them also had low baseline 25(OH)D level. Upon restoration\u0026nbsp;of vitamin D level, the musculoskeletal pain was statistically improved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u0026nbsp;The prevalences of both vitamin D insufficiency/deficiency and osteoporosis were comparable to the Western countries. To examine plasma 25(OH)D and BMD prior to and during adjuvant AI in accordance with appropriate vitamin D repletion are strongly recommended.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"The Effect of Vitamin D Status on Bone Mineral Density (BMD) and Aromatase-Induced Musculoskeletal Syndrome (AIMSS) in Post- menopausal Women Receiving An AI for Early Breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 09:34:52","doi":"10.21203/rs.3.rs-6956411/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5bb5545-a164-4b52-9a6d-159c67a9ec03","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-14T02:39:22+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-06 09:34:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6956411","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6956411","identity":"rs-6956411","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}