Long-term Effects of Ospemifene on densitometric and bone metabolism biomarkers in Postmenopausal Women reporting Vulvar and Vaginal Atrophy (VVA)

Long-term Effects of Ospemifene on densitometric and bone metabolism biomarkers in Postmenopausal Women reporting Vulvar and Vaginal Atrophy (VVA) | 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 Long-term Effects of Ospemifene on densitometric and bone metabolism biomarkers in Postmenopausal Women reporting Vulvar and Vaginal Atrophy (VVA) Silvia Maffei, Alessia Formica, Dario Corsini, Michela Franchini This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8584043/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2026 Read the published version in BMC Women's Health → Version 1 posted 11 You are reading this latest preprint version Abstract Ospemifene (OSP) a Selective Estrogen Receptor Modulator (SERM), is recommended for treating vulvovaginal atrophy (VVA) in postmenopausal women (PMW). Previous 12mm data suggested that OSP therapy had beneficial effects on bone mineral and biochemical markers in a similar VVA population. Objective This real-life study sought to evaluate the long-term effects (24mm) of Ospemifene therapy on bone metabolism and mineral parameters compared with a control group. Methods PMW aged 40–64 years with VVA symptoms and a baseline bone health assessment were included in the study. A total of 72 subjects treated with Ospemifene 60 mg/day (OSPG) were compared with a control group (CG, n = 49) over 24 months. Bone mineral density (BMD) at the femoral neck, total femur, and lumbar spine was assessed by DEXA, and biochemical markers of bone metabolism were measured in blood samples at baseline and 24 months. Results In the control group, BMD and T-scores significantly decreased at the femoral neck (-0,029; -0,26) and lumbar spine (-0,049; -0,32). In contrast, the OSPG showed no significant decline in BMD at any measured site (+ 0,005; +0,005;+0,009). The CG also exhibited a significant increase in bone turnover markers (BAP: +2.7; OC: +4.2). Conversely, the OSPG demonstrated significant reductions in bone alkaline phosphatase (BAP: -2.5) and osteocalcin (OC: -2.8), biomarkers of bone formation. Conclusions Long-term ospemifene treatment effectively preserves bone health at all sites, counteracting the expected menopause-associated bone loss and protecting against bone density reduction in healthy PMW with VVA. bone metabolism postmenopausal women ospemifene VVA osteoporosis Figures Figure 1 Figure 2 Figure 3 1. Background The hormone profile shifts associated with the menopausal transition and post-menopause can impact numerous organ systems. A consequence of reduced estrogen concentrations is the atrophy of estrogen-dependent tissues, notably in the vaginal and vulvar areas. Clinically, this manifests as Vulvovaginal Atrophy (VVA) or the more encompassing diagnosis of Genitourinary Syndrome of Menopause (GSM) , being one of the most widespread and disabling post-menopausal disorders [ 1 ] causing vaginal dryness and dyspareunia [ 2 ]. The hormonal changes accompanying menopause cause a distinct surge in bone mineral density (BMD) loss, with the greatest reduction occurring in the peri-menopausal three-year window [ 3 , 4 ]. A reduced estrogen environment stimulates osteoclast activity, thereby accelerating bone resorption. This process ultimately diminishes overall skeletal mass, culminating in conditions like osteopenia or osteoporosis. Defined as a systemic skeletal condition that advances over time, osteoporosis involves diminished bone mass and the degradation of the tissue's microarchitecture [ 5 ]. Postmenopausal osteoporosis warrants special attention, as it is a major contributor to elevated fracture risk, which subsequently carries adverse consequences for the health status of elderly women. Therefore, menopause presents a finite "window of opportunity" to intervene and halt the rapid decline in bone mass and prevent damage to the microarchitecture of the bone, which is key to preventing future osteoporosis [ 6 ]. Hormone replacement therapy (HRT) regimens are widely supported by research [ 7 ] as an effective treatment for osteoporosis and for relieving climacteric symptoms, positioning bone protection as a major secondary benefit of the therapy. Nevertheless, HRT is not universally suitable: some women are ineligible, others refuse it due to fear of breast cancer, and for a subset of the population it is medically contraindicated. As a result, new treatment options are urgently needed for menopausal women who cannot, or choose not to, use HRT. Ospemifene (OSP), a Selective Estrogen Receptor Modulator (SERM), now offers a new treatment option for postmenopausal women suffering from Vulvovaginal Atrophy (VVA) [ 8 , 9 ]. OSP is used for VVA because it specifically stimulates hormone receptors in the vaginal mucosa but exhibits a neutral effect in the uterus and an antagonistic effect on breast estrogen receptors [ 10 , 11 ]. Notably, OSP holds the distinction of being the sole medication approved by EMA for VVA in female patients who have completed treatment for breast cancer, including adjuvant therapies [ 12 ]. Its safety profile concerning thrombotic risk and metabolic markers has been well established through extensive research [ 13 , 14 ]. To date, few studies have focused on the effect of Ospemifene on bone biochemical markers and bone quality, and data collection is limited to three or six months [ 15 , 16 , 17 ]. A previous study based on a similar sample of women followed by the Endocrinological-Cardiovascular Gynaecology Outpatient Clinic and the Osteoporosis Study Centre of the Gabriele Monasterio Tuscan Foundation in Pisa, Italy was conducted with an observation period of 12 months [ 18 ] The aim of the present study was to evaluate the long-term effects (24 months) of ospemifene therapy on bone metabolism and bone mineral parameters in postmenopausal women reporting VVA/GSM. 2. Materials and Methods 2.1. Study Design The study, with a new sample of subjects and a longer period of observation is based on the same protocol as the previous one [ 13 ]. The protocol has been approved by the Ethics Committee l (Prot No. 37981, study 3605, 20/06/2012) The study was also registered at ClinicalTrials.gov with the identification code NCT03699150. The new sample of this interventional and prospective-control study consisted of post menopausal women who had attended the Endocrinological-Cardiovascular Gynaecology Outpatient Clinic and the Osteoporosis Study Centre of the Gabriele Monasterio Tuscan Foundation in Pisa, Italy, for at least 24 months and reported symptoms related to VVA. Participant recruitment followed the criteria applied in the previous study [ 13 ], which encompassed a 12-month observational period. In this work, the bone health profile was assessed in a subgroup of 72 subjects (OSPG) who were continuously treated with ospemifene at an oral daily dose of 60 mg throughout the observation period. Outcomes in the OSPG were compared with those of a matched control group (CG) of 49 women with VVA who did not receive ospemifene treatment. Women whose baseline blood vitamin D levels were below 30 ng/mL were provided supplementation tailored to their baseline measurements. In both groups, bone-related parameters were evaluated at baseline (T0) and after 24 months (T1). The bone health profile evaluation was assessed based on the bone mineral density (BMD) values at the overall femur (TF), femoral neck (FN) and lumbar spine (L1–L4) levels. T-score indices [ 19 ] at the same anatomical sites were also analyzed.Finally, the bone health profile was also assessed using the following blood biomarkers: total calcium, serum vitamin D, bone alkaline phosphatase; osteocalcin, and phosphorus. Further details regarding bone health profile measurements and methodological procedures are reported in a previous publication [ 13 ]. OSPG and CG characteristics (family history, pregnancies, menopausal age, dyslipidemia, thyropathy, smoking and alcohol habits and comorbidities) were recorded and reported in table 1. 2.2. Patients Mean age at the start of study was 54.2 ± 3.2 years in the OSPG and 55.0 ± 5.7 years in the CG (p = 0.74). The BMI was 23.0 ± 3.3 kg/m2 in the OSPG and 23.8 ± 2.7 kg/m2 in the CG (p = 0.33). The presence of a family history of osteoporosis was 37.1% in the OSPG and 12.9% in the GG (0 = 0.026) (table 1). Table 1 Controls n = 49 Ospemifene n = 72 mean SD mean SD p Age 55.0 5.7 54.2 3.2 N.S. Weight 61.8 8.4 60.0 8.5 N.S. Height 160.9 6.1 162.0 5.5 N.S. BMI 23.8 2.7 23.0 3.3 N.S. BSA 1.6 0.1 1.6 0.1 N.S. Menopause age 49.3 3.9 49.3 3.8 N.S. No. of pregnancies 1.7 0.7 1.7 0.7 N.S. Comorbidities 3.2% 12.9% N.S. Hypertension 16.1% 7.1% N.S. Diabetes 0.0% 0.0% Dysplipidemia 6.5% 8.6% N.S. Thyropathy 16.1% 10.0% N.S. Familiarity with Diabetes 6.5% 11.4% N.S. Familiarity with Osteoporosis 12.9% 37.1% 0.026 % female smokers 12.9% 14.3% N.S. % ex-smokers 0.0% 2.9% Occasional alcohol 3.2% 25.7% p = 0.014 Frequent alcohol consumption 6.5% 11.4% N.S. means p > 0.05 2.3. Statistical Analysis Continuous variables were reported as the mean ± standard deviation, and categorical variables as frequencies. The Independent Student’s t-test was used to compare the baseline characteristics between the subgroup of treated women and controls, while the dependent Student’s t-test was used to compare T0 values with T1 values (0 and 24 months). All the analyses were carried out using IBM-SPSS software. The result was considered statistically significant when p < 0.05. 3. Results All assessments were carried out at baseline T0 and at T1. Table 2 lists the DEXA values and biochemical parameters in the control group (CG) and the ospemifene group (OSPG) at T0 and T1. Table 2 CONTROL GROUP OSPEMIFENE GROUP CG t0 CG t1 Diff p OSPG t0 OSPG t1 Diff p BMD and T score BMD (g/cm2) FN 0.68 0.65 -0.029 0.026 0.64 0.65 0.005 0.516 T score FN -1.6 -1.9 -0.30 0.000 -1.9 -1.9 0.00 0.986 BMD_(g/cm2) TF 0.86 0.84 -0.017 0.246 0.84 0.85 0.005 0.629 T score TF -1.4 -1.6 -0.20 0.000 -1.4 -1.4 0.00 0.819 BMD (g/cm2) L1–L4 0.88 0.83 -0.049 0.004 0.80 0.81 0.009 0.153 T score L1–L4 -1.7 -2.0 -0.30 0.011 -2.2 -2.0 0.20 0.006 Plasma Bone Turnover Biomarkers 25-OH-D 28.46 36.6 8.155 0.000 33.45 40.48 7.030 0.000 Osteocalcin 16.80 21 4.199 0.000 21.24 18.45 -2.789 0.001 Total Calcium 9.33 9.35 0.002 0.975 9.49 9.46 -0.024 0.634 Phosphorus (mg/dL) 3.36 6.11 2.760 0.047 3.56 3.53 -0.032 0.663 Bone Alkaline phosphatase 11.06 13.74 2.682 0.000 12.05 9.51 -2.541 0.000 Diff=difference between t0 and t1; p= test t1-t2 At baseline, the OPSG showed lower BMD values ​​in the three bone districts analyzed (FN, TF and L1–L4), with FN and L1–L4 values showing a statistical difference compared to CG. At T1 these values improved slightly in the OSPG (FN: +0,005, p = 0.52; L1-L4: +0.009; p = 0.15; TF:+0.005; p = 0.63), while in the CG BMD decrease was statistically significant in two of the three bone districts analyzed (FN and L1–L4), as shown in Table 2 and Fig. 1 . The T score was assessed at baseline and after 24 months. At baseline, the OSPG showed lower values in the femoral neck and lumbar vertebrae, and the difference in values between the two groups was significant for the lumbar spine (Fig. 2 ). As shown in Fig. 2 , after 24 months the OSPG showed very similar values to the control group in the three regions (FN, TF and L1-L4). Furthermore, T-scores declined significantly in all three regions among control subjects, whereas women in the OSPG demonstrated a significant improvement in the lumbar region, with T-scores remaining stable at the femoral neck and total femur (Fig. 2 ). N.S. means p > 0.05 A significant increase in 25-OH-D levels was recorded after 24 months of treatment compared to basal levels in the CG (+ 8.16; p ≤ 0.001) and OSPG (+ 7.00; p ≤ 0.003). At 24 months CG and OSPG exhibited optimal 25-OH-D levels (≥ 30 ng/mL) (table 2). Additionally, the CG group showed a significant increase in phosphorus, bone alkaline phosphatase, and osteocalcin levels, whereas the OSPG group demonstrated a significant decrease in the latter two bone formation biomarkers, which are released into the bloodstream during the bone remodeling process. Overall, these findings confirm a differential response to treatment at 24 months: the OSPG group maintained BMD values across the three analyzed skeletal sites (FN, TF, and L1–L4) and showed a significant reduction in bone remodeling markers. In contrast, the CG group exhibited a significant decline in BMD at the FN and L1–L4 sites, along with a notable increase in bone turnover markers. N.S. means p > 0.05 4. Discussion SERMs are non-steroidal, manufactured drugs that act selectively, either promoting or inhibiting estrogen effects in different parts of the body. Their variability stems from how their binding modifies the estrogen receptor's structure, which dictates the resulting transcriptional effect. Therefore, these compounds are ligands that activate estrogen receptors in some tissues but use competitive inhibition to block natural estrogen from binding to the same receptors in other tissues. Because of its targeted mechanism of action, the SERM ospemifene has been introduced as a new treatment option for VVA in postmenopausal women [ 8 ]. While it specifically stimulates hormone receptors in the vaginal lining, OSP has the benefit of acting neutrally on estrogen receptors found in the uterus [ 10 ], since it acts as antagonist on breast estrogen receptors, and at the same time acts as agonist on bone and vaginal tissues [ 11 ]. According to clinical data, OSP's impact on bone markers is significantly better than that of a placebo [ 21 ]. Its effects are on a par with those observed in oral estrogen therapies and other approved SERMs, like raloxifene and bazedoxifene, which are currently used to treat and prevent osteoporosis [ 21 ]. Experimental data reveals that ospemifene's impact on bone health mirrored the effects of raloxifene and estradiol, particularly in the context of ovariectomized (OVX) versus sham-operated rats. Furthermore, Qu Q and colleagues observed that both ospemifene and raloxifene exerted significant bone protective actions, achieving a decrease in bone turnover and the preservation of bone volume in the OVX rat model [ 22 ]. Other studies on rat models confirm the positive effects of ospemifene on bone strength, bone mineral content, BMD, and bone structure [ 23 ]. One and two-phase studies on postmenopausal women showed a dose-dependent decrease in bone turnover markers with ospemifene versus a placebo, similar to raloxifene over 12 weeks of treatment [ 15 – 17 ]. In a phase 3 study, ospemifene at 60 mg/day for 12 weeks showed improvements in all VVA parameters (first endpoint) and significantly greater decreases in 7 of 9 bone biomarkers versus a placebo (second endpoint) [ 17 ]. Lower bone resorption markers were noted in women receiving OSP therapy, and this outcome held true across all subgroups [ 24 ]. The findings were independent of the elapsed time since menopause (less or more than five years) or of the baseline classification of bone mineral density (i.e. whether the patient had normal BMD, osteopenia, or osteoporosis). This work sought to evaluate the effects of 24-month Ospemifene therapy on bone metabolism and bone mineral parameters in postmenopausal women reporting VVA/GSM. Previous data concerning the effects of Ospemifene therapy at 12 months showed, in the CG, a statistically significant decrease in BMD and T-score in the three bone districts analyzed (FN, TF and L1–L4). In the OSPG only BMD and T-score at the FN level significantly decreased, with FT and L1-L4 values unchanged [ 18 ]. After 24 months, OSP’s effectiveness in counteracting bone loss was confirmed. OSPG maintained the BMD values in the three bone districts analyzed (FN, TF and L1–L4), while CG demonstrated a significant decrease in the BMD and T-score values detected at FN and L1–L4 levels. Additionally, the Ospemifene-treated women demonstrated a significant improvement in the lumbar region, with T-scores remaining stable at the femoral neck and total femur. As expected, 24 months of observation also confirmed the significant increase in 25-OH-D levels already recorded in CG and OSPG after 12 months of treatment compared to basal levels. Unlike the 12-month results, which showed no significant changes in osteocalcin or phosphorus, both biomarkers significantly increased at 24 months in the CG group, along with a rise in BAP levels. In the OSPG group, the significant decrease in BAP observed at 12 months was confirmed and further supported by a corresponding reduction in osteocalcin. Considering the fact that osteocalcin and BAP are both markers of bone formation, produced by osteoblasts and released into the bloodstream during the bone remodeling process, the OPSG results strongly suggest that ospemifene has positive long-term effects on bone markers. These findings confirm previous data on the effect of Ospemifene on Bone biochemical markers in shorter observation periods [ 17 , 18 ] The Strengths and Weaknesses of the Study The study's primary strength is the use of an unselected patient sample, sourced from individuals who spontaneously contacted the clinic, which enhances the study’s ecological validity ("real-life data"). Additionally, the study's validity is reinforced by the use of a control group that shared the same core characteristics. The most relevant feature of this study is the long observational period of 24 months. The only weakness of the study might be the relatively limited panel of biochemical markers of bone metabolism, due to the fact that the women enrolled initially came under observation for menopausal symptoms. 5. Conclusions Our data confirm the hypothesis that a 24-month period of treatment with OSP improves bone mineral markers and counteracts menopausal bone loss in healthy post menopausal women with VVA compared to untreated healthy PMW with VVA (Fig. 3 ). In conclusion, ospemifene can be considered not only a safe and effective treatment of VVA but also an option to counteract physiological bone loss in postmenopausal women. Declarations Ethics approval and consent to participate The study The study was conducted in accordance with the Declaration of Helsinki and was approved by the Local Ethics Committee of the Italian National Research Council–Gabriele Monasterio Tuscan Foundation, Pisa, Italy (Protocol No. 37981, Study No. 3605, approved on 20 June 2012). Written informed consent was obtained from all participants at the baseline visit. The study was registered at ClinicalTrials.gov with the identification code NCT03699150. Consent for publication: t he subjects included in the study provided their written consent for the publication of the results. Availability of Data and Materials : The datasets generated and/or analysed during the current study are not publicly available due to legal restrictions under Italian personal data protection legislation. Anonymized data are available from the corresponding author upon reasonable request. Competing Interests : The authors declare no conflict of interest. Funding and Acknowledgements. We wish to acknowledge Shionogi SRL for the unconditional financial support for the publication process. Medical writing support and editorial assistance was provided by Informapro srl (Italy). Author Contributions. Conceptualization, S.M .; methodology, S.M.; software, and analysis: S.M and M.F.; data curation, A.F.; writing—original draft preparation, S.M. and M.F. and D.C..; writing—review and editing, S.M., M.F. and D.C. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement : The study was conducted in accordance with the Declaration of Helsinki, and approved by Italian National Research Council Gabriele Monasterio Tuscan Foundation in Pisa, Italy. The study was authorized by the local ethics committee (Ref. No. 37981, study 3605, 20/06/2012). The study was registered at ClinicalTrials.gov with the identification code NCT03699150. References Nappi RE, Martini E, Cucinella L, Martella S, Tiranini L, Inzoli A, Brambilla E, Bosoni D, Cassani C, Gardella B. Addressing Vulvovaginal Atrophy (VVA)/Genitourinary Syndrome of Menopause (GSM) for Healthy Aging in Women. Front Endocrinol. 2019;10:561. Bachmann G. Urogenital ageing: An old problem newly recognized. Maturitas. 1995;22:S1–5. Greendale GA, Sowers M, Han W, Huang MH, Finkelstein JS, Crandall CJ, Lee JS, Karlamangla AS. Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: Results from the Study of Women’s Health Across the Nation (SWAN). J Bone Min Res. 2011;27:111–8. Crandall CJ, Tseng CH, Karlamangla AS, Finkelstein JS, Randolph JF, Thurston RC, Huang MH, Zheng H, Greendale GA. Serum sex steroid levels and longitudinal changes in bone density in relation to the final menstrual period. J Clin Endocrinol Metab. 2013;98:E654–63. Moilanen A, Juho Kopra J, Kröger H, Sund R, Rikkonen T, Sirola J. Characteristics of Long-Term Femoral Neck Bone Loss in Postmenopausal Women: A 25-Year Follow-Up. J Bone Min Res. 2022;37:173–8. Riis BJ, Hansen MA, Jensen A, Overgaard K, Christiansen C. Low bone mass and fast rate of bone loss at menopause: Equal risk factors for future fracture: A 15-year follow-up study. Bone. 1996;19:9–12. Gallagher JC. Moderation of the daily dose of HRT: Prevention of osteoporosis. Maturitas. 1999;33:S57–63. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: Results from a pivotal phase 3 study. Menopause. 2010;17:480–90. Palacios S, Cancelo MJ. Clinical update on the use of Ospemifene in the treatment of severe symptomatic vulvar and vaginal atrophy. Int J Womens Health. 2016;8:617–26. DeGregorio MW, Zerbe RL, Wurz GT, Ospemifene. A first-in-class, non-hormonal selective estrogen receptor modulator approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Steroids. 2014;90:82–93. European Public Assessment Report European Medicines Agency. 2014. Available online: https://www.ema.europa.eu/en/documents/smopinitial/chmp-summary-positive-opinion-senshio_en.pdf (accessed on 20 October 2022). European Medicines Agency. Senshio Public Assessment Report (03/2022) Annex I Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/senshio#assessment-history-section (accessed on 20 October 2022). Maffei S, Papa A, di Cecco P, Guiducci L. Effect of Ospemifene on Cardiometabolic Risk in Postmenopausal Women Reporting Vulvo and Vaginal Atrophy (VVA): Results of a 12-Month Prospective Study. J Women’s Health Gynecol. 2021;8:1–12. Goldstein SR, Bachmann GA, Koninckx PR, Lin VH, Portman DJ, Ylikorkala O, Ospemifene Study Group. Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric. 2014;17:173–82. Constantine GD, Kagan R, Miller PD. Effects of Ospemifene on bone parameters including clinical biomarkers in postmenopausal women. Menopause. 2016;23:638–44. Komi J, Heikkinen J, Rutanen M, Halonen K, Lammintausta R, Ylikorkala O. Effects of Ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol. 2004;18:152–8. Komi J, Lankinen KS, DeGregorio M, Heikkinen J, Saarikoski S, Tuppurainen M, Halonen K, Lammintausta R, Väänänen K, Ylikorkala O, et al. Effects of Ospemifene and Raloxifene on biochemical markers of bone turnover in postmenopausal women. J Bone Min Metab. 2006;24:314–8. Maffei S, Guiducci L. Effect of Ospemifene on Densitometric and Plasma Bone Metabolism Biomarkers in Postmenopausal Women Reporting Vulvar and Vaginal Atrophy (VVA). J Clin Med. 2022;11:6316. Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Synopsis of a WHO report. WHO Study Group. Osteoporos Int. 1994;4:368–81. Karlamangla AS, Burnett-Bowie SAM, Crandall CJ. Bone Health During the Menopause Transition and Beyond. Obstet. Gynecol. Clin N Am. 2018;45:695–708. de Villiers TJ, Altomare C, Particco M, Gambacciani M. Effects of Ospemifene on bone in postmenopausal women. Climacteric. 2019;22:442–7. Qu Q, Zheng H, Dahllund J, Laine A, Cockcroft N, Peng Z, Koskinen M, Hemminki K, Kangas L, Väänänen K, et al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology. 2000;141:809–20. Kangas L, Unkila M. Tissue selectivity of Ospemifene: Pharmacologic profile and clinical implications. Steroids. 2013;78:1273–80. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Report of a WHO study group (meeting held in Rome from Jun 22–25, 1992). World Health Organ Tech Rep Ser. 1994;843:1–129. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2026 Read the published version in BMC Women's Health → Version 1 posted Editorial decision: Revision requested 09 Mar, 2026 Reviews received at journal 02 Mar, 2026 Reviews received at journal 25 Feb, 2026 Reviewers agreed at journal 22 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers invited by journal 11 Feb, 2026 Editor assigned by journal 07 Feb, 2026 Editor invited by journal 04 Feb, 2026 Submission checks completed at journal 30 Jan, 2026 First submitted to journal 30 Jan, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8584043","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589518612,"identity":"faa1f234-2de6-4586-b31b-9286e5909294","order_by":0,"name":"Silvia Maffei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIie3RsYoCMRCA4QkDa2kbEcwrjFzrc9jYJFintxBZEdZO2wNFX0Eb60gglW9g4foGXnNsIeK6nmCV1e6Q/FUIfMyEAIRC/zHEGGRx2KYge43i0vgJ+yNRl0DuvnhB/CYn8CAsuRPvGDFmCU/70KkmyNLjggaibZg9eQjZnEgH+tshktoQb+6lfzFCNiIZgY4PU8fV5sybsxIiRjdyAb10WMnUnMoJWDZMVQJ65TACFRMX9bLFCjLhep2/JX8U1VZ1FZudb7GpNdvst6UXDtlP1qeqmHXtqedb7B5/mmseP/Vy4l0QCoVCH98VzElSC09qVsMAAAAASUVORK5CYII=","orcid":"","institution":"CNR Tuscany Region G.Monasterio Foundation","correspondingAuthor":true,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Maffei","suffix":""},{"id":589518613,"identity":"03a1a09a-ba61-4197-a85e-e96e29304e76","order_by":1,"name":"Alessia Formica","email":"","orcid":"","institution":"Institute of Clinical Physiology of the national Research Council of Italy (IFC CNR)","correspondingAuthor":false,"prefix":"","firstName":"Alessia","middleName":"","lastName":"Formica","suffix":""},{"id":589518614,"identity":"3a102ba8-012b-48da-b96e-be6eef47efb4","order_by":2,"name":"Dario Corsini","email":"","orcid":"","institution":"(3)\tEuresist network GEIE","correspondingAuthor":false,"prefix":"","firstName":"Dario","middleName":"","lastName":"Corsini","suffix":""},{"id":589518615,"identity":"755f3e02-4b47-4704-b81e-a842c4ffac5e","order_by":3,"name":"Michela Franchini","email":"","orcid":"","institution":"Institute of Clinical Physiology of the national Research Council of Italy (IFC CNR)","correspondingAuthor":false,"prefix":"","firstName":"Michela","middleName":"","lastName":"Franchini","suffix":""}],"badges":[],"createdAt":"2026-01-12 16:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8584043/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8584043/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-026-04474-3","type":"published","date":"2026-04-28T15:57:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102753992,"identity":"20c83b7a-337d-4a01-93eb-b01aab9cb198","added_by":"auto","created_at":"2026-02-16 09:36:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":62816,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eN.S. means p\u0026gt;0.05\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8584043/v1/d3342e9cbe474f20938a45b3.png"},{"id":102753867,"identity":"58dfaa37-c964-4d08-942c-889db39bf896","added_by":"auto","created_at":"2026-02-16 09:36:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79549,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eN.S. means p\u0026gt;0.05\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8584043/v1/ab4eb3b4496716eee08eee7d.png"},{"id":102753236,"identity":"33f14fc3-7661-4c93-b0ee-183e5b27d8e2","added_by":"auto","created_at":"2026-02-16 09:34:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":159879,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Maffei2025Figure3RGB.png","url":"https://assets-eu.researchsquare.com/files/rs-8584043/v1/a3710e6c9fc77fd14b937eed.png"},{"id":108437631,"identity":"7fb7481e-519e-4abd-a655-110d9b9bdfb4","added_by":"auto","created_at":"2026-05-04 16:00:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":549164,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8584043/v1/5bfa9cc0-f10c-4882-a506-0c64350ad66f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLong-term Effects of Ospemifene on densitometric and bone metabolism biomarkers in Postmenopausal Women reporting Vulvar and Vaginal Atrophy (VVA)\u003c/p\u003e","fulltext":[{"header":"1. Background","content":"\u003cp\u003eThe \u003cb\u003ehormone profile shifts\u003c/b\u003e associated with the menopausal transition and post-menopause can impact numerous organ systems. A consequence of reduced \u003cb\u003eestrogen\u003c/b\u003e concentrations is the \u003cb\u003eatrophy\u003c/b\u003e of estrogen-dependent tissues, notably in the vaginal and vulvar areas. Clinically, this manifests as \u003cb\u003eVulvovaginal Atrophy (VVA)\u003c/b\u003e or the more encompassing diagnosis of \u003cb\u003eGenitourinary Syndrome of Menopause (GSM)\u003c/b\u003e, being one of the most widespread and disabling post-menopausal disorders [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] causing vaginal dryness and dyspareunia [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe hormonal changes accompanying menopause cause a distinct surge in bone mineral density (BMD) loss, with the greatest reduction occurring in the peri-menopausal three-year window [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A reduced estrogen environment stimulates osteoclast activity, thereby accelerating bone resorption. This process ultimately diminishes overall skeletal mass, culminating in conditions like osteopenia or osteoporosis. Defined as a systemic skeletal condition that advances over time, osteoporosis involves diminished bone mass and the degradation of the tissue's microarchitecture [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Postmenopausal osteoporosis warrants special attention, as it is a major contributor to elevated fracture risk, which subsequently carries adverse consequences for the health status of elderly women.\u003c/p\u003e \u003cp\u003eTherefore, menopause presents a finite \"window of opportunity\" to intervene and halt the rapid decline in bone mass and prevent damage to the microarchitecture of the bone, which is key to preventing future osteoporosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Hormone replacement therapy (HRT) regimens are widely supported by research [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] as an effective treatment for osteoporosis and for relieving climacteric symptoms, positioning bone protection as a major secondary benefit of the therapy. Nevertheless, HRT is not universally suitable: some women are ineligible, others refuse it due to fear of breast cancer, and for a subset of the population it is medically contraindicated. As a result, new treatment options are urgently needed for menopausal women who cannot, or choose not to, use HRT.\u003c/p\u003e \u003cp\u003eOspemifene (OSP), a Selective Estrogen Receptor Modulator (SERM), now offers a new treatment option for postmenopausal women suffering from Vulvovaginal Atrophy (VVA) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. OSP is used for VVA because it specifically stimulates hormone receptors in the vaginal mucosa but exhibits a neutral effect in the uterus and an antagonistic effect on breast estrogen receptors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Notably, OSP holds the distinction of being the sole medication approved by EMA for VVA in female patients who have completed treatment for breast cancer, including adjuvant therapies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Its safety profile concerning thrombotic risk and metabolic markers has been well established through extensive research [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, few studies have focused on the effect of Ospemifene on bone biochemical markers and bone quality, and data collection is limited to three or six months [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA previous study based on a similar sample of women followed by the Endocrinological-Cardiovascular Gynaecology Outpatient Clinic and the Osteoporosis Study Centre of the Gabriele Monasterio Tuscan Foundation in Pisa, Italy was conducted with an observation period of 12 months [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe aim of the present study was to evaluate the long-term effects (24 months) of ospemifene therapy on bone metabolism and bone mineral parameters in postmenopausal women reporting VVA/GSM.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study Design\u003c/h2\u003e \u003cp\u003eThe study, with a new sample of subjects and a longer period of observation is based on the same protocol as the previous one [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The protocol has been approved by the Ethics Committee l (Prot No. 37981, study 3605, 20/06/2012) The study was also registered at ClinicalTrials.gov with the identification code NCT03699150.\u003c/p\u003e \u003cp\u003eThe new sample of this interventional and prospective-control study consisted of post menopausal women who had attended the Endocrinological-Cardiovascular Gynaecology Outpatient Clinic and the Osteoporosis Study Centre of the Gabriele Monasterio Tuscan Foundation in Pisa, Italy, for at least 24 months and reported symptoms related to VVA. Participant recruitment followed the criteria applied in the previous study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which encompassed a 12-month observational period.\u003c/p\u003e \u003cp\u003eIn this work, the bone health profile was assessed in a subgroup of 72 subjects (OSPG) who were continuously treated with ospemifene at an oral daily dose of 60 mg throughout the observation period. Outcomes in the OSPG were compared with those of a matched control group (CG) of 49 women with VVA who did not receive ospemifene treatment. Women whose baseline blood vitamin D levels were below 30 ng/mL were provided supplementation tailored to their baseline measurements.\u003c/p\u003e \u003cp\u003eIn both groups, bone-related parameters were evaluated at baseline (T0) and after 24 months (T1). The bone health profile evaluation was assessed based on the bone mineral density (BMD) values at the overall femur (TF), femoral neck (FN) and lumbar spine (L1\u0026ndash;L4) levels. T-score indices [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] at the same anatomical sites were also analyzed.Finally, the bone health profile was also assessed using the following blood biomarkers: total calcium, serum vitamin D, bone alkaline phosphatase; osteocalcin, and phosphorus. Further details regarding bone health profile measurements and methodological procedures are reported in a previous publication [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOSPG and CG characteristics (family history, pregnancies, menopausal age, dyslipidemia, thyropathy, smoking and alcohol habits and comorbidities) were recorded and reported in table 1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Patients\u003c/h2\u003e \u003cp\u003eMean age at the start of study was 54.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 years in the OSPG and 55.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 years in the CG (p\u0026thinsp;=\u0026thinsp;0.74). The BMI was 23.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 kg/m2 in the OSPG and 23.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 kg/m2 in the CG (p\u0026thinsp;=\u0026thinsp;0.33). The presence of a family history of osteoporosis was 37.1% in the OSPG and 12.9% in the GG (0\u0026thinsp;=\u0026thinsp;0.026) (table 1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eControls n\u0026thinsp;=\u0026thinsp;49\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eOspemifene n\u0026thinsp;=\u0026thinsp;72\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003emean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003emean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e60.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e160.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e162.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenopause age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of pregnancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysplipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamiliarity with Diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamiliarity with Osteoporosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e37.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% female smokers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eN.S.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% ex-smokers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccasional alcohol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrequent alcohol consumption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eN.S. means p\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Statistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were reported as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and categorical variables as frequencies. The Independent Student\u0026rsquo;s t-test was used to compare the baseline characteristics between the subgroup of treated women and controls, while the dependent Student\u0026rsquo;s t-test was used to compare T0 values with T1 values (0 and 24 months). All the analyses were carried out using IBM-SPSS software. The result was considered statistically significant when p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eAll assessments were carried out at baseline T0 and at T1. Table\u0026nbsp;2 lists the DEXA values and biochemical parameters in the control group (CG) and the ospemifene group (OSPG) at T0 and T1.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"9\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eCONTROL GROUP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eOSPEMIFENE GROUP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCG t0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eCG t1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDiff\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eOSPG t0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eOSPG t1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDiff\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMD and T score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMD (g/cm2) FN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.516\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT score FN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.986\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMD_(g/cm2) TF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT score TF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.819\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMD (g/cm2) L1\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT score L1\u0026ndash;L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlasma Bone Turnover Biomarkers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25-OH-D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOsteocalcin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-2.789\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Calcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.975\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.634\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.760\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.047\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.663\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone Alkaline phosphatase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.682\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-2.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cem\u003eDiff=difference between t0 and t1; p= test t1-t2\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt baseline, the OPSG showed lower BMD values ​​in the three bone districts analyzed (FN, TF and L1\u0026ndash;L4), with FN and L1\u0026ndash;L4 values showing a statistical difference compared to CG. At T1 these values improved slightly in the OSPG (FN: +0,005, p\u0026thinsp;=\u0026thinsp;0.52; L1-L4: +0.009; p\u0026thinsp;=\u0026thinsp;0.15; TF:+0.005; p\u0026thinsp;=\u0026thinsp;0.63), while in the CG BMD decrease was statistically significant in two of the three bone districts analyzed (FN and L1\u0026ndash;L4), as shown in Table\u0026nbsp;2 and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe T score was assessed at baseline and after 24 months. At baseline, the OSPG showed lower values in the femoral neck and lumbar vertebrae, and the difference in values between the two groups was significant for the lumbar spine (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, after 24 months the OSPG showed very similar values to the control group in the three regions (FN, TF and L1-L4). Furthermore, T-scores declined significantly in all three regions among control subjects, whereas women in the OSPG demonstrated a significant improvement in the lumbar region, with T-scores remaining stable at the femoral neck and total femur (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eN.S. means p\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/em\u003e \u003c/p\u003e \u003cp\u003eA significant increase in 25-OH-D levels was recorded after 24 months of treatment compared to basal levels in the CG (+\u0026thinsp;8.16; p\u0026thinsp;\u0026le;\u0026thinsp;0.001) and OSPG (+\u0026thinsp;7.00; p\u0026thinsp;\u0026le;\u0026thinsp;0.003). At 24 months CG and OSPG exhibited optimal 25-OH-D levels (\u0026ge;\u0026thinsp;30 ng/mL) (table 2).\u003c/p\u003e \u003cp\u003eAdditionally, the CG group showed a significant increase in phosphorus, bone alkaline phosphatase, and osteocalcin levels, whereas the OSPG group demonstrated a significant decrease in the latter two bone formation biomarkers, which are released into the bloodstream during the bone remodeling process.\u003c/p\u003e \u003cp\u003eOverall, these findings confirm a differential response to treatment at 24 months: the OSPG group maintained BMD values across the three analyzed skeletal sites (FN, TF, and L1\u0026ndash;L4) and showed a significant reduction in bone remodeling markers. In contrast, the CG group exhibited a significant decline in BMD at the FN and L1\u0026ndash;L4 sites, along with a notable increase in bone turnover markers.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eN.S. means p\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/em\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eSERMs are non-steroidal, manufactured drugs that act selectively, either promoting or inhibiting estrogen effects in different parts of the body. Their variability stems from how their binding modifies the estrogen receptor's structure, which dictates the resulting transcriptional effect. Therefore, these compounds are ligands that activate estrogen receptors in some tissues but use competitive inhibition to block natural estrogen from binding to the same receptors in other tissues.\u003c/p\u003e \u003cp\u003eBecause of its targeted mechanism of action, the SERM ospemifene has been introduced as a new treatment option for VVA in postmenopausal women [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. While it specifically stimulates hormone receptors in the vaginal lining, OSP has the benefit of acting neutrally on estrogen receptors found in the uterus [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], since it acts as antagonist on breast estrogen receptors, and at the same time acts as agonist on bone and vaginal tissues [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to clinical data, OSP's impact on bone markers is significantly better than that of a placebo [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Its effects are on a par with those observed in oral estrogen therapies and other approved SERMs, like raloxifene and bazedoxifene, which are currently used to treat and prevent osteoporosis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExperimental data reveals that ospemifene's impact on bone health mirrored the effects of raloxifene and estradiol, particularly in the context of ovariectomized (OVX) versus sham-operated rats. Furthermore, Qu Q and colleagues observed that both ospemifene and raloxifene exerted significant bone protective actions, achieving a \u003cb\u003edecrease in bone turnover\u003c/b\u003e and the preservation of bone volume in the OVX rat model [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOther studies on rat models confirm the positive effects of ospemifene on bone strength, bone mineral content, BMD, and bone structure [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne and two-phase studies on postmenopausal women showed a dose-dependent decrease in bone turnover markers with ospemifene versus a placebo, similar to raloxifene over 12 weeks of treatment [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a phase 3 study, ospemifene at 60 mg/day for 12 weeks showed improvements in all VVA parameters (first endpoint) and significantly greater decreases in 7 of 9 bone biomarkers versus a placebo (second endpoint) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLower bone resorption markers were noted in women receiving OSP therapy, and this outcome held true \u003cb\u003eacross all subgroups\u003c/b\u003e [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The findings were independent of the elapsed time since menopause (less or more than five years) or of the baseline classification of bone mineral density (i.e. whether the patient had normal BMD, osteopenia, or osteoporosis).\u003c/p\u003e \u003cp\u003eThis work sought to evaluate the effects of 24-month Ospemifene therapy on bone metabolism and bone mineral parameters in postmenopausal women reporting VVA/GSM. Previous data concerning the effects of Ospemifene therapy at 12 months showed, in the CG, a statistically significant decrease in BMD and T-score in the three bone districts analyzed (FN, TF and L1\u0026ndash;L4). In the OSPG only BMD and T-score at the FN level significantly decreased, with FT and L1-L4 values unchanged [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAfter 24 months, OSP\u0026rsquo;s effectiveness in counteracting bone loss was confirmed. OSPG maintained the BMD values in the three bone districts analyzed (FN, TF and L1\u0026ndash;L4), while CG demonstrated a significant decrease in the BMD and T-score values detected at FN and L1\u0026ndash;L4 levels. Additionally, the Ospemifene-treated women demonstrated a significant improvement in the lumbar region, with T-scores remaining stable at the femoral neck and total femur.\u003c/p\u003e \u003cp\u003eAs expected, 24 months of observation also confirmed the significant increase in 25-OH-D levels already recorded in CG and OSPG after 12 months of treatment compared to basal levels.\u003c/p\u003e \u003cp\u003eUnlike the 12-month results, which showed no significant changes in osteocalcin or phosphorus, both biomarkers significantly increased at 24 months in the CG group, along with a rise in BAP levels. In the OSPG group, the significant decrease in BAP observed at 12 months was confirmed and further supported by a corresponding reduction in osteocalcin. Considering the fact that osteocalcin and BAP are both markers of bone formation, produced by osteoblasts and released into the bloodstream during the bone remodeling process, the OPSG results strongly suggest that ospemifene has positive long-term effects on bone markers. These findings confirm previous data on the effect of Ospemifene on Bone biochemical markers in shorter observation periods [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe Strengths and Weaknesses of the Study\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe study's primary strength is the use of an unselected patient sample, sourced from individuals who spontaneously contacted the clinic, which enhances the study\u0026rsquo;s ecological validity (\"real-life data\"). Additionally, the study's validity is reinforced by the use of a control group that shared the same core characteristics. The most relevant feature of this study is the long observational period of 24 months.\u003c/p\u003e \u003cp\u003eThe only weakness of the study might be the relatively limited panel of biochemical markers of bone metabolism, due to the fact that the women enrolled initially came under observation for menopausal symptoms.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eOur data confirm the hypothesis that a 24-month period of treatment with OSP improves bone mineral markers and counteracts menopausal bone loss in healthy post menopausal women with VVA compared to untreated healthy PMW with VVA (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn conclusion, ospemifene can be considered not only a safe and effective treatment of VVA but also an option to counteract physiological bone loss in postmenopausal women.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study The study was conducted in accordance with the Declaration of Helsinki and was approved by the Local Ethics Committee of the Italian National Research Council\u0026ndash;Gabriele Monasterio Tuscan Foundation, Pisa, Italy (Protocol No. 37981, Study No. 3605, approved on 20 June 2012). Written informed consent was obtained from all participants at the baseline visit. The study was registered at ClinicalTrials.gov with the identification code NCT03699150.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication: t\u003c/strong\u003ehe subjects included in the study provided their written consent for the publication of the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e: The datasets generated and/or analysed during the current study are not publicly available due to legal restrictions under Italian personal data protection legislation. Anonymized data are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e: The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and Acknowledgements.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to acknowledge Shionogi SRL for the unconditional financial support for the publication process.\u003c/p\u003e\n\u003cp\u003eMedical writing support and editorial assistance was provided by Informapro srl (Italy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions.\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConceptualization, S.M .; methodology, S.M.; software, and analysis: S.M and M.F.; data curation, A.F.; writing\u0026mdash;original draft preparation, S.M. and M.F. and \u0026nbsp;D.C..; writing\u0026mdash;review and editing, S.M., M.F. and D.C. All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement\u003c/strong\u003e: The study was conducted in accordance with the Declaration of Helsinki, and approved by Italian National Research Council Gabriele Monasterio Tuscan Foundation in Pisa, Italy. The study was authorized by the local ethics committee (Ref. No. 37981, study 3605, 20/06/2012). The study was registered at ClinicalTrials.gov with the identification code NCT03699150.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNappi RE, Martini E, Cucinella L, Martella S, Tiranini L, Inzoli A, Brambilla E, Bosoni D, Cassani C, Gardella B. Addressing Vulvovaginal Atrophy (VVA)/Genitourinary Syndrome of Menopause (GSM) for Healthy Aging in Women. Front Endocrinol. 2019;10:561.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBachmann G. Urogenital ageing: An old problem newly recognized. Maturitas. 1995;22:S1\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreendale GA, Sowers M, Han W, Huang MH, Finkelstein JS, Crandall CJ, Lee JS, Karlamangla AS. Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: Results from the Study of Women\u0026rsquo;s Health Across the Nation (SWAN). J Bone Min Res. 2011;27:111\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrandall CJ, Tseng CH, Karlamangla AS, Finkelstein JS, Randolph JF, Thurston RC, Huang MH, Zheng H, Greendale GA. Serum sex steroid levels and longitudinal changes in bone density in relation to the final menstrual period. J Clin Endocrinol Metab. 2013;98:E654\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoilanen A, Juho Kopra J, Kr\u0026ouml;ger H, Sund R, Rikkonen T, Sirola J. Characteristics of Long-Term Femoral Neck Bone Loss in Postmenopausal Women: A 25-Year Follow-Up. J Bone Min Res. 2022;37:173\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiis BJ, Hansen MA, Jensen A, Overgaard K, Christiansen C. Low bone mass and fast rate of bone loss at menopause: Equal risk factors for future fracture: A 15-year follow-up study. Bone. 1996;19:9\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallagher JC. Moderation of the daily dose of HRT: Prevention of osteoporosis. Maturitas. 1999;33:S57\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: Results from a pivotal phase 3 study. Menopause. 2010;17:480\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalacios S, Cancelo MJ. Clinical update on the use of Ospemifene in the treatment of severe symptomatic vulvar and vaginal atrophy. Int J Womens Health. 2016;8:617\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeGregorio MW, Zerbe RL, Wurz GT, Ospemifene. A first-in-class, non-hormonal selective estrogen receptor modulator approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Steroids. 2014;90:82\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Public Assessment Report European Medicines Agency. 2014. Available online: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ema.europa.eu/en/documents/smopinitial/chmp-summary-positive-opinion-senshio_en.pdf\u003c/span\u003e\u003cspan address=\"https://www.ema.europa.eu/en/documents/smopinitial/chmp-summary-positive-opinion-senshio_en.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on 20 October 2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Medicines Agency. Senshio Public Assessment Report (03/2022) Annex I Summary of Product Characteristics. Available online: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ema.europa.eu/en/medicines/human/EPAR/senshio#assessment-history-section\u003c/span\u003e\u003cspan address=\"https://www.ema.europa.eu/en/medicines/human/EPAR/senshio#assessment-history-section\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on 20 October 2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaffei S, Papa A, di Cecco P, Guiducci L. Effect of Ospemifene on Cardiometabolic Risk in Postmenopausal Women Reporting Vulvo and Vaginal Atrophy (VVA): Results of a 12-Month Prospective Study. J Women\u0026rsquo;s Health Gynecol. 2021;8:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldstein SR, Bachmann GA, Koninckx PR, Lin VH, Portman DJ, Ylikorkala O, Ospemifene Study Group. Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric. 2014;17:173\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConstantine GD, Kagan R, Miller PD. Effects of Ospemifene on bone parameters including clinical biomarkers in postmenopausal women. Menopause. 2016;23:638\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKomi J, Heikkinen J, Rutanen M, Halonen K, Lammintausta R, Ylikorkala O. Effects of Ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol. 2004;18:152\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKomi J, Lankinen KS, DeGregorio M, Heikkinen J, Saarikoski S, Tuppurainen M, Halonen K, Lammintausta R, V\u0026auml;\u0026auml;n\u0026auml;nen K, Ylikorkala O, et al. Effects of Ospemifene and Raloxifene on biochemical markers of bone turnover in postmenopausal women. J Bone Min Metab. 2006;24:314\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaffei S, Guiducci L. Effect of Ospemifene on Densitometric and Plasma Bone Metabolism Biomarkers in Postmenopausal Women Reporting Vulvar and Vaginal Atrophy (VVA). J Clin Med. 2022;11:6316.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Synopsis of a WHO report. WHO Study Group. Osteoporos Int. 1994;4:368\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarlamangla AS, Burnett-Bowie SAM, Crandall CJ. Bone Health During the Menopause Transition and Beyond. Obstet. Gynecol. Clin N Am. 2018;45:695\u0026ndash;708.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Villiers TJ, Altomare C, Particco M, Gambacciani M. Effects of Ospemifene on bone in postmenopausal women. Climacteric. 2019;22:442\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQu Q, Zheng H, Dahllund J, Laine A, Cockcroft N, Peng Z, Koskinen M, Hemminki K, Kangas L, V\u0026auml;\u0026auml;n\u0026auml;nen K, et al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology. 2000;141:809\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKangas L, Unkila M. Tissue selectivity of Ospemifene: Pharmacologic profile and clinical implications. Steroids. 2013;78:1273\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Report of a WHO study group (meeting held in Rome from Jun 22\u0026ndash;25, 1992). World Health Organ Tech Rep Ser. 1994;843:1\u0026ndash;129.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"bone metabolism, postmenopausal women, ospemifene, VVA, osteoporosis","lastPublishedDoi":"10.21203/rs.3.rs-8584043/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8584043/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eOspemifene (OSP)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea Selective Estrogen Receptor Modulator (SERM), is recommended for treating vulvovaginal atrophy (VVA) in postmenopausal women (PMW). Previous 12mm data suggested that OSP therapy had beneficial effects on bone mineral and biochemical markers in a similar VVA population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis real-life study sought to evaluate the long-term effects (24mm) of Ospemifene therapy on bone metabolism and mineral parameters compared with a control group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePMW aged 40–64 years with VVA symptoms and a baseline bone health assessment were included in the study. A total of 72 subjects treated with Ospemifene 60 mg/day (OSPG) were compared with a control group (CG, n = 49) over 24 months. Bone mineral density (BMD) at the femoral neck, total femur, and lumbar spine was assessed by DEXA, and biochemical markers of bone metabolism were measured in blood samples at baseline and 24 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the control group, BMD and T-scores significantly \u003cstrong\u003edecreased\u003c/strong\u003e at the femoral neck (-0,029; -0,26) and lumbar spine (-0,049; -0,32). In contrast, the OSPG showed \u003cstrong\u003eno significant decline\u003c/strong\u003e in BMD at any measured site (+ 0,005; +0,005;+0,009). The CG also exhibited a significant \u003cstrong\u003eincrease\u003c/strong\u003e in bone turnover markers (BAP: +2.7; OC: +4.2). Conversely, the OSPG demonstrated significant \u003cstrong\u003ereductions\u003c/strong\u003e in bone alkaline phosphatase (BAP: -2.5) and osteocalcin (OC: -2.8), biomarkers of bone formation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLong-term ospemifene treatment effectively \u003cstrong\u003epreserves bone health\u003c/strong\u003e at all sites, counteracting the expected menopause-associated bone loss and protecting against bone density reduction in healthy PMW with VVA.\u003c/p\u003e","manuscriptTitle":"Long-term Effects of Ospemifene on densitometric and bone metabolism biomarkers in Postmenopausal Women reporting Vulvar and Vaginal Atrophy (VVA)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 09:12:53","doi":"10.21203/rs.3.rs-8584043/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-09T17:48:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T08:43:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-25T17:07:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134365325598500695333208216238141836049","date":"2026-02-23T01:19:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328639031286693863830472536114400141884","date":"2026-02-21T00:08:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334503526440140748321121279718994000255","date":"2026-02-18T12:27:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-11T06:52:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-07T14:31:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-04T14:52:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-30T13:05:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2026-01-30T11:40:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"10a36c53-1bd3-4e21-acea-40522e3c5f10","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:00:00+00:00","versionOfRecord":{"articleIdentity":"rs-8584043","link":"https://doi.org/10.1186/s12905-026-04474-3","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2026-04-28 15:57:24","publishedOnDateReadable":"April 28th, 2026"},"versionCreatedAt":"2026-02-16 09:12:53","video":"","vorDoi":"10.1186/s12905-026-04474-3","vorDoiUrl":"https://doi.org/10.1186/s12905-026-04474-3","workflowStages":[]},"version":"v1","identity":"rs-8584043","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8584043","identity":"rs-8584043","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}