The Effect of Bisphosphonates on Kidney Function in Osteoporotic Geriatric Patients with Impaired Renal Function

The Effect of Bisphosphonates on Kidney Function in Osteoporotic Geriatric Patients with Impaired Renal Function | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of Bisphosphonates on Kidney Function in Osteoporotic Geriatric Patients with Impaired Renal Function Akarawin Tweekittikul, Varalak Srinonprasert, Unchana Sura-amonrattana This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7024056/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2025 Read the published version in BMC Geriatrics → Version 1 posted 17 You are reading this latest preprint version Abstract Background Bisphosphonates are the mainstay treatment for osteoporosis, with initiation guided by creatinine clearance (CrCl) from the Cockcroft-Gault equation. However, many clinicians use estimated glomerular filtration rate (eGFR) from the CKD-EPI equation, primarily for chronic kidney disease (CKD) staging. Objectives To compare renal function assessments derived from the two equations and evaluate changes over a 12-month treatment. Methods A retrospective cohort study compared renal outcomes in osteoporotic geriatric patients with an eGFR ranging from 35 to 60 mL/min/1.73m² who received bisphosphonate between January 2015 and December 2022. Patients were categorized based on CrCl: <35 mL/min and ≥ 35 mL/min using the Cockcroft-Gault equation Results A total of 222 patients (190 [85.6%] female; mean age 80 ± 6.54 years) were analyzed, with 109 (49.1%) in the CrCl < 35 group and 113 (50.9%) in the CrCl ≥ 35 group. No significant differences in overall renal function changes were observed. The CrCl < 35 group had higher relative risk (RR) of renal function change events with an adjusted RR of 6.77 (95% CI: 1.53 to 29.88; p = 0.012) at 6 months and an adjusted RR of 3.75 (95% CI: 1.04 to 13.50; p = 0.043) at 12 months. Conclusions Calculating CrCl using the Cockcroft-Gault equation is crucial in older patients before bisphosphonate therapy. Although no significant differences in overall renal function changes were observed, the CrCl < 35 group demonstrated trends of renal function decline and higher relative risk of renal function change events at months 6 and 12. Osteoporosis Bisphosphonate Renal function Creatinine clearance Older adults Figures Figure 1 Figure 2 Figure 3 Figure 4 Key Points • Bisphosphonates are common in older adults osteoporosis care, requiring renal assessment. • FDA recommends using CrCl from the Cockcroft-Gault equation to guide bisphosphonate prescribing. • eGFR from CKD-EPI equation may overestimate renal function in older adults. • Older adults with CrCl <35 mL/min who received bisphosphonates had a significantly higher risk of renal function change events at 6 and 12 months. Introduction Osteoporosis is a chronic and progressive skeletal disease marked by diminished bone strength, which includes both a reduction in bone density and a deterioration in bone quality[ 1 ]. These structural changes render bones fragile and susceptible to fractures. The primary cause of osteoporosis lies in an imbalance between bone formation and resorption, influenced by factors such as genetic predisposition, aging and hormonal changes, particularly estrogen deficiency. As individuals age, the prevalence of osteoporosis rises significantly. Despite its widespread nature, the condition often remains asymptomatic until a fragility fracture occurs, osteoporotic fractures are associated with significant morbidity, reduced quality of life and mortality in the older adults[ 2 ]. The cornerstone of osteoporosis management lies in reducing fracture risk and maintaining bone strength. Treatment strategies involve a combination of non-pharmacological and pharmacological approaches. Non-pharmacological measures include lifestyle modifications, such as regular weight-bearing exercises, fall prevention, and adequate intake of calcium and vitamin D through dietary supplementation. Among pharmacological options, bisphosphonates (BPs) are highly recommended due to their well-established safety and efficacy profiles. These medications work by inhibiting osteoclast-mediated bone resorption, effectively preserving bone mass and significantly reducing the risk of fractures[ 3 ]. Despite their proven benefits in osteoporosis management, bisphosphonates are associated with potential renal toxicity, posing a significant concern in certain patient populations. The mechanisms underlying acute kidney injury (AKI) are hypothesized to include mitochondrial dysfunction, inhibition of adenosine triphosphate (ATP) production, and disruption of the mevalonate pathway. These disturbances can lead to cellular dysfunction, apoptosis, and structural changes within renal cells, particularly in nephrons and podocytes[ 4 , 5 ]. Moreover, drug precipitation may exacerbate renal impairment, especially in individuals with pre-existing kidney dysfunction. Since bisphosphonates are primarily excreted via the kidneys, impaired renal function increases the risk of drug accumulation, potentially resulting in heightened toxicity[ 6 – 8 ]. Based on growing evidence of renal adverse effects, the United States Food and Drug Administration (FDA) advises against the use of bisphosphonates in patients with a creatinine clearance (CrCl) below 35 mL/min, as calculated by the Cockcroft-Gault formula[ 9 – 12 ]. This precaution has led to the exclusion of patients with renal impairment from most clinical trials, thereby limiting available data on the safety and efficacy of bisphosphonates in this population[ 13 – 15 ]. However, emerging studies in patients with chronic kidney disease have not shown significant worsening of renal function following bisphosphonate administration. These findings suggest that, with careful patient selection and monitoring, bisphosphonates may remain a viable option for managing osteoporosis in select individuals with compromised kidney function[ 16 , 17 ]. Accurate renal function assessment is essential to determine the suitability of bisphosphonate therapy. In clinical practice, the estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (eGFR: CKD-EPI), is frequently used. However, eGFR and creatinine clearance are not directly interchangeable. CrCl, calculated using the Cockcroft-Gault formula (CrCl: Cockcroft-Gault), incorporates body weight and is reported in mL/min, whereas eGFR: CKD-EPI is expressed in mL/min/1.73m² and does not consider body weight[ 18 , 19 ]. This discrepancy may lead to misclassification of renal status, especially in older adults with reduced muscle mass, as studies have shown that CKD-EPI-derived eGFR may overestimate kidney function compared to measured GFR (mGFR), such as that obtained through iohexol clearance techniques[ 20 , 21 ]. This review aims to analyze historical data to identify older adults with osteoporosis who were prescribed bisphosphonates despite discrepancies between eGFR: CKD-EPI ≥ 35 mL/min/1.73m² and CrCl: Cockcroft-Gault < 35 mL/min. Additionally, it seeks to evaluate changes in renal function at 3, 6, and 12 months after initiating bisphosphonate therapy, while also assessing other potential adverse effects associated with bisphosphonate use. Moreover, the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines recommend that renal function estimates for drug dosing should rely on creatinine clearance, particularly in older adults, frail individuals, or those with abnormal body composition[ 22 ]. Methods Study design and data collection This study was a retrospective cohort conducted at a university hospital in Thailand, exporting the patients’ characteristics from the hospital electronic database between January 2015 and December 2022. The study received ethical approval from the Siriraj Institutional Review Board. Study population and eligibility criteria This research focused on patients aged 65 years or older who were diagnosed with osteoporosis with impaired renal function and had been undergoing bisphosphonate treatments, including alendronate, ibandronate, risedronate and zoledronic acid, either orally or intravenously, for more than one year. The identification of osteoporosis patients was conducted using the International Classification of Diseases and Related Health Problem 10th Revision (ICD-10) coding, combined with a review of medical histories to confirm that the patients met the diagnostic criteria for osteoporosis based on the American Association of Clinical Endocrinologists (AACE) 2020 guidelines[ 23 ]. Baseline kidney function was assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, with values between 35 and 60 mL/min/1.73m² recorded within one month prior to the initiation of treatment. Patients were excluded if they were prescribed bisphosphonates for non-osteoporotic conditions, such as hypercalcemia. Additionally, individuals who switched from bisphosphonates to alternative treatments within the first year of therapy or those with active kidney diseases requiring specific medical interventions, such as nephrotic syndrome, nephritis syndrome or autoimmune diseases, were excluded. Further exclusions applied to individuals with conditions interfering with serum creatinine-based kidney function assessments, such as severe malnutrition or rhabdomyolysis. Patients with fewer than three annual serum creatinine measurements or incomplete medical records, which precluded proper kidney function assessment, were also excluded. Eligible patients were categorized into two groups based on their kidney function prior to initiating bisphosphonate therapy: CrCl < 35 mL/min group : Patients with an eGFR: CKD-EPI of at least 35 mL/min/1.73m² but a CrCl: Cockcroft-Gault of less than 35 mL/min. CrCl ≥ 35 mL/min group : Patients with an eGFR: CKD-EPI of at least 35 mL/min/1.73m² and a CrCl: Cockcroft-Gault of at least 35 mL/min. Data collection and measurements The reviewer sorted the records in reverse chronological order, starting from the most recent individual who received the medication within the requested timeframe. The process was conducted sequentially without skipping any cases, continuing until the required number of participants meeting the eligibility criteria for this study was obtained. Baseline characteristics and laboratory data were collected by reviewing patient medical records and blood test results using the hospital information system. Data collection began on the day bisphosphonate therapy was initiated, with follow-up data recorded at 3 months, 6 months and 12 months post-treatment initiation. Data from each follow-up point was included in the analysis if recorded within 4 weeks, before or after the specified timeframe. If no data was available for the specified period, they were excluded from the analysis. Renal function was assessed for all patients using serum creatinine, eGFR: CKD-EPI and CrCl: Cockcroft-Gault. The actual recorded weight of the patient during the specified timeframe was used in the analysis. The study also monitored significant renal function changes, including the incidence of acute kidney injury as defined by the Acute Kidney Injury Network (AKIN) criteria[ 24 ], and the initiation of new renal replacement therapy (RRT). Renal Function Estimation Equations Cockcroft-Gault Formula[ 18 ] CKD-EPI Formula[ 19 ] eGFR [mL/min/1.73 m²] = 142 X min (S cr /K, 1) α X max (S cr /K, 1) -1.200 X 0.9938 Age X 1.012 K = 0.7 (females) or 0.9 (males) α = -0.241 (females) or -0.302 (males) min = indicates the minimum of Scr/K or 1 max = indicates the maximum of Scr/K or 1 Outcomes Primary outcome The primary outcome is to assess changes in renal function among older adults with osteoporosis who are treated with bisphosphonates, with comparisons made between patient groups at 3, 6, and 12 months after treatment initiation. Renal function outcomes were evaluated using changes in serum creatinine, estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCl) over the specified time points. Secondary outcomes The secondary outcomes also monitored the incidence of significant renal function changes that consisted of worsening renal function; characterized by a notable decline in estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) values, new-onset acute kidney injury (AKI); diagnosed according to the Acute Kidney Injury Network (AKIN) criteria and initiation of renal replacement therapy; Indicating severe renal impairment requiring intervention. Moreover, this study focused on evaluating adverse effects and complications associated with bisphosphonate use in older adults with osteoporosis. These outcomes provide critical insights into the safety profile of bisphosphonate therapy, encompassing both gastrointestinal and renal-related events. Statistical Analysis The sample size calculation was based on the study by Takashi Shigematsu et al. [ 25 ], which evaluated 852 osteoporosis patients receiving risedronate. In their study, the change in renal function in patients with normal renal function showed a mean of -7.35 and a standard deviation (SD) of 15.9, while in patients with mildly impaired renal function, the mean change was − 1.35 with an SD of 10.92. The appropriate sample size formula for comparing the means of two independent groups was used, with a significant level of 5% and a power (1-β) of 90%. The calculation determined that at least 109 participants per group were required, resulting in a total sample size of 218 participants for both groups. Baseline characteristics were summarized both overall and stratified by groups. Continuous variables were reported as mean and standard deviation (SD) for normally distributed data or as median with interquartile range (IQR) for non-normally distributed data. Categorical variables were presented as frequencies and percentages. Comparisons of baseline characteristics between groups were performed using the independent samples t-test for normally distributed continuous variables, the Mann-Whitney U test for non-normally distributed continuous variables, and the Chi-square test for categorical variables. For the primary outcome on changes in renal function, statistical analysis was performed using generalized estimating equations (GEE), adjusted for potential confounders including age, gender, body weight, hypertension, diabetes mellitus, urinary tract infections (UTI), non-steroidal anti-inflammatory drug (NSAID) use and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) use. The incidence of significant renal function changes over time was evaluated using relative risk (RR), adjusted for potential confounders including age and diabetes mellitus through log-binomial model. Sensitivity analysis was not performed; however, the wide confidence intervals observed in adjusted relative risks suggest that results regarding adverse events must be interpreted cautiously. All statistical analyses were conducted using IBM SPSS Statistics, version 29. Statistical tests were two-tailed, and p-values < 0.05 were considered indicative of statistical significance Results A total of 737 osteoporotic patients aged 65 years and older with impaired renal function who underwent bisphosphonate treatment between January 2015 and December 2022 were identified. After applying the exclusion criteria, 515 patients were excluded, resulting in 222 patients eligible for analysis. Among these, 109 patients (49.1%) were categorized in the CrCl < 35 mL/min group, while 113 patients (50.9%) were categorized in the CrCl ≥ 35 mL/min group (Fig. 1 ). Patients in the CrCl < 35 group were older, with a mean age of 82.39 ± 6.11 years, compared to 77.68 ± 6.11 years in the CrCl ≥ 35 group (p < 0.001). Additionally, a greater proportion of patients aged ≥ 80 years was found in the CrCl < 35 group (71.6%) compared to the CrCl ≥ 35 group (38.1%) (p < 0.001). Female patients predominated in both groups, but the proportion was significantly higher in the CrCl < 35 group (92.7%) than in the CrCl ≥ 35 group (78.8%) (p = 0.003). Significant differences were observed in body weight and body mass index (BMI) between the two groups. Patients in the CrCl < 35 group had a lower mean body weight (49.10 ± 7.86 kg) compared to the CrCl ≥ 35 group (60.95 ± 8.93 kg) (p < 0.001). Similarly, the BMI was lower in the CrCl < 35 group (22.22 ± 3.39 kg/m²) than in the CrCl ≥ 35 group (26.05 ± 3.99 kg/m²) (p < 0.001). This finding strongly suggests that body weight is a critical parameter influencing CrCl values. Since creatinine clearance is partially dependent on muscle mass, which correlates with body weight, a lower body weight in the CrCl < 35 group reflects its importance in renal function assessment. Moreover, the significantly lower BMI in the CrCl < 35 group aligns with the hypothesis that patients with reduced renal function are more likely to exhibit frailty or nutritional deficiencies. Renal function metrics demonstrated substantial differences. The CrCl < 35 group had higher serum creatinine levels (1.25 ± 0.28 mg/dL) than the CrCl ≥ 35 group (1.12 ± 0.19 mg/dL) (p < 0.001). Estimated glomerular filtration rate (eGFR) and creatinine clearance were significantly lower in the CrCl < 35 group (43.09 ± 8.65 mL/min/1.73m² and 27.72 ± 5.06 mL/min, respectively) compared to the CrCl ≥ 35 group (51.32 ± 6.57 mL/min/1.73m² and 41.61 ± 5.42 mL/min, respectively) (p < 0.001 for both). The prevalence of hypertension was high and consistent between the groups, with 90.7% in the CrCl < 35 group and 89.4% in the CrCl ≥ 35 group (p = 0.736). No significant differences were observed in the prevalence of diabetes mellitus (39.5% in the CrCl < 35 group vs. 45.1% in the CrCl ≥ 35 group; p = 0.392) or dementia status (15.6% in the CrCl < 35 group vs. 14.2% in the CrCl ≥ 35 group; p = 0.763). The Charlson Comorbidity Index (CCI) was comparable between the groups, with a median value of 5 [IQR: 4–7] in both groups and similar proportions of patients having a CCI score ≥ 5 (p = 0.638). Baseline medication use was largely similar across the groups. The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers (ACEis/ARBs) was comparable between the CrCl < 35 group (46.8%) and the CrCl ≥ 35 group (49.1%) (p = 0.730). However, nonsteroidal anti-inflammatory drugs (NSAIDs) use was significantly higher in the CrCl ≥ 35 group (10.71%) compared to the CrCl < 35 group (3.7%) (p = 0.043). No significant differences were observed in the use of bisphosphonates, including alendronate, zoledronic acid and others. Table 1 Baseline characteristics of patients stratified by creatinine clearance (CrCl) Characteristic Total (n = 222) CrCl < 35 group (n = 109) CrCl ≥ 35 group (n = 113) p-value Age, years, mean ± SD ≥ 80 years, n (%) 80.00 ± 6.54 121 (54.4) 82.39 ± 6.11 78 (71.6) 77.68 ± 6.11 43 (38.1) < 0.001 < 0.001 Female, n (%) 190 (85.6) 101 (92.7) 89 (78.8) 0.003 BW*, kg., mean ± SD 55.14 ± 10.29 49.10 ± 7.86 60.95 ± 8.93 < 0.001 BMI*, kg/m 2 , mean ± SD 24.18 ± 4.17 22.22 ± 3.39 26.05 ± 3.99 < 0.001 Comorbidity, n (%) Hypertension 199 (89.6) 98 (90.7) 101 (89.4) 0.736 Diabetes mellitus 94 (42.3) 43 (39.5) 51 (45.1) 0.392 Dementia 33 (14.9) 17 (15.6) 16 (14.2) 0.763 CCI*, Median [IQR] 5 [ 4 , 7 ] 5 [ 4 , 7 ] 5 [ 4 , 7 ] 0.856 CCI ≥ 5, n (%) 152 (68.5) 73 (67.0) 79 (69.9) 0.638 Albumin, g/dL, mean ± SD 3.89 ± 0.52 3.89 ± 0.49 3.89 ± 0.54 0.971 Serum creatinine, mg/dL , mean ± SD 1.18 ± 0.25 1.25 ± 0.28 1.12 ± 0.19 < 0.001 eGFR, mL/min/1.73m 2 , mean ± SD 47.28 ± 8.68 43.09 ± 8.65 51.32 ± 6.57 < 0.001 CrCl, mL/min, mean ± SD 34.79 ± 8.71 27.72 ± 5.06 41.61 ± 5.42 < 0.001 Serum calcium, mg/dL , mean ± SD 9.17 ± 0.53 9.17 ± 0.52 9.17 ± 0.55 0.991 Serum phosphate, mg/dL , mean ± SD 3.35 ± 0.63 3.42 ± 0.62 3.28 ± 0.63 0.240 Serum PTH*, pg/mL, mean ± SD 52.27 ± 26.09 53.67 ± 32.64 50.90 ± 17.80 0.624 Serum 25-(OH)D level, ng/mL, mean ± SD 32.54 ± 11.63 32.00 ± 10.99 33.01 ± 12.21 0.597 Baseline medication use, n (%) ACEis / ARBs* 106 (47.8) 51 (46.8) 55 (49.1) 0.730 NSAIDs* 16 (7.2) 4 (3.7) 12 (10.7) 0.043 Diuretics 27 (12.2) 16 (14.7) 11 (9.8) 0.270 Bisphosphonates, n (%) Alendronate 68 (30.6) 32 (29.4) 36 (31.9) 0.622 Alendronate + vitamin D3 100 (45.1) 54 (49.5) 46 (40.7) 0.177 Ibandronate 4 (1.8) 3 (2.8) 1 (0.9) 0.363 Risedronate 27 (12.2) 11 (10.1) 16 (14.2) 0.354 Zoledronic acid 23 (10.4) 9 (8.3) 14 (12.4) 0.312 Bisphosphonates reported poor compliance, n (%) 3 (1.4) 1 (0.9) 2 (1.8) 1.000 *BW – Body weight, BMI - Body mass index, CCI - Charlson Comorbidity Index, PTH – Parathyroid hormone, ACEis/ARBs - The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, NSAIDs - Nonsteroidal anti-inflammatory drugs For the primary outcome, no significant differences in overall renal function changes were observed between the groups (Table 2, Figs. 2 and 3 ). However, In the CrCl < 35 group, serum creatinine levels remained unchanged at 3 months (0 mg/dL; 95% CI: -0.06 to 0.06, p = 1.000) but increased slightly at 6 months (+ 0.03 mg/dL; 95% CI: -0.05 to 0.11, p = 1.000) and at 12 months (+ 0.06 mg/dL; 95% CI: -0.02 to 0.14, p = 0.370). Similarly, the CrCl ≥ 35 group showed negligible changes at all time points. Moreover, serum creatinine levels showed a slight increase at 12 months (0.02 mg/dL; 95% CI: -0.03 to 0.06, p = 1.000). The estimated glomerular filtration rate (eGFR) in the CrCl < 35 group showed a slight, non-significant increase at 3 months (+ 1.57 mL/min/1.73m²; 95% CI: -0.51 to 3.64, p = 0.278) and 6 months (+ 1.00 mL/min/1.73m²; 95% CI: -1.18 to 3.18, p = 1.000), followed by a minor decrease at 12 months (-0.41 mL/min/1.73m²; 95% CI: -2.79 to 1.97, p = 1.000). The CrCl ≥ 35 group demonstrated a significant increase at 3 months (+ 2.42 mL/min/1.73m²; 95% CI: 0.16 to 4.67, p = 0.028) but non-significant increase at 6 months (+ 1.91 mL/min/1.73m²; 95% CI: -0.17 to 4.00, p = 0.092) and 12 months (+ 0.12 mL/min/1.73m²; 95% CI: -2.40 to 2.64, p = 1.000). Creatinine clearance (CrCl) remained stable in both groups. In the CrCl < 35 group, CrCl showed a slight increase at 3 months (+ 0.84 mL/min; 95% CI: -0.32 to 2.00, p = 0.338) and 6 months (0.79 mL/min; 95% CI: -0.75 to 2.34, p = 1.000) but declined modestly at 12 months (-0.25 mL/min; 95% CI: -1.63 to 1.13, p = 1.000). The CrCl ≥ 35 group exhibited comparable stability, with a marginal increase at 6 months (+ 0.64 mL/min; 95% CI: -0.93 to 2.21, p = 1.000) and declined slightly at 12 months (-0.64 mL/min; 95% CI: -2.69 to 1.41, p = 1.000). When comparing changes in renal function from baseline between the two groups, no statistically significant differences were observed at any time point during the data collection period. Table 2: Renal function changes over 12 months by CrCl group using generalized estimating equations (GEE) analysis. p-value b 0.241 0.108 0.123 0.540 0.540 0.704 0.830 0.680 0.474 Adjusted with age, gender, body weight, hypertension, diabetes mellitus, urinary tract infection, ACEis/ARBs - The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, NSAIDs - Nonsteroidal anti-inflammatory drugs. The mean difference from baseline is statistically significant at p-value < 0.05. a p-value of within-group effect. b p-value of interaction effect (difference of difference from baseline between groups). CrCl ≥ 35 group p-value a 0.795 1.000 1.000 0.028 0.092 1.000 0.498 1.000 1.000 Mean difference from baseline (95%CI) -0.02 (-0.06, 0.02) -0.02 (-0.05, 0.02) 0.02 (-0.03, 0.06) 2.42 (0.16, 4.67) 1.91 (-0.17, 4.00) 0.12 (-2.40, 2.64) 1.19 (-0.62, 3.00) 0.64 (-0.93, 2.21) -0.64 (-2.69, 1.41) Mean ± SD 1.02 ± 0.56 0.99 ± 0.55 1.00 ± 0.55 1.03 ± 0.54 56.94 ± 15.03 59.36 ± 17.40 58.86 ± 16.66 57.07 ± 17.46 43.09 ± 12.25 44.27 ± 14.15 43.72 ± 13.33 42.44 ± 14.52 CrCl < 35 group p-value a 1.000 1.000 0.370 0.28 1.000 1.000 0.338 1.000 1.000 Mean difference from baseline (95%CI) 0.00 (-0.06, 0.06) 0.03 (-0.05, 0.11) 0.06 (-0.02, 0.14) 1.57 (-0.51, 3.64) 1.00 (-1.18, 3.18) -0.41 (-2.79, 1.97) 0.84 (-0.32, 2.00) 0.79 (-0.75, 2.34) -0.25 (-1.63, 1.13) Mean ± SD 1.29 ± 0.51 1.29 ± 0.52 1.32 ± 0.51 1.35 ± 0.48 45.27 ± 15.69 46.83 ± 18.45 46.27 ± 18.73 44.86 ± 18.62 30.64 ± 11.03 31.48 ± 12.02 31.43 ± 12.97 30.39 ± 12.35 Visit Baseline 3 months 6 months 12 months Baseline 3 months 6 months 12 months Baseline 3 months 6 months 12 months Variable Creatinine (mg/dL) eGFR (mL/min/1.73m 2 ) CrCl (mL/min) Renal-related adverse events were more frequent in the CrCl < 35 group compared to CrCl ≥ 35 group, particularly at 6 and 12 months. At 6 months, specific renal-related adverse events occurred in 13.2% of the CrCl < 35 group patients compared to 1.9% in the CrCl ≥ 35 group, with an adjusted relative risk (RR) of 6.77 (95% CI: 1.53 to 29.88, p = 0.012). By 12 months, these events were reported in 10.4% of the CrCl < 35 group patients compared to 2.8% in the CrCl ≥ 35 group, with an adjusted RR of 3.75 (95% CI: 1.04 to 13.50, p = 0.043) (Table 3 ). Table 3 Incidence and RR of renal-related adverse events by CrCl group over 12 months. CrCl < 35 group (n = 109) CrCl ≥ 35 group (n = 113) Crude RR (95% CI) p-value Adjusted RR* (95% CI) p-value At month 3 n (%) 4 (4.7) 2 (2.1) 2.26 (0.42, 12.02) 0.340 3.13 (0.57, 17.04) 0.187 At month 6 n (%) 14 (13.2) 2 (1.9) 7.07 (1.65, 30.34) 0.009 6.77 (1.53, 29.88) 0.012 At month 12 n (%) 11 (10.4) 3 (2.8) 3.70 (1.06, 12.89) 0.040 3.75 (1.04, 13.50) 0.043 *Adjusted with age, diabetes mellitus. Statistically significant at the 0.05 level Confounding factors that may affect kidney function were observed. Overall, body weight was lower in the CrCl < 35 mL/min group compared to the CrCl ≥ 35 mL/min group. At 12 months, body weight increased slightly in the CrCl < 35 group but decreased slightly in the CrCl ≥ 35 group. For medications, both ACEIs/ARBs and diuretics were prescribed at similar rates in both groups from baseline to 12 months. However, NSAIDs use was consistently higher in the CrCl ≥ 35 group compared to the CrCl < 35 group at baseline and at 3, 6 and 12 months with significantly higher prescriptions at baseline. The incidence of UTI in the CrCl < 35 group was slightly higher than in the CrCl ≥ 35 group at 6 and 12 months, however, the difference was not statistically significant. (Table 4 ). Table 4 Distribution of potential confounding factors related to renal function over 12 months Variables Visit CrCl < 35 group CrCl ≥ 35 group p-value Body weight, kg., Mean ± SD Baseline 49.1 ± 7.86 60.95 ± 8.93 < 0.001 Month 3 49.36 ± 7.99 59.99 ± 8.93 < 0.001 Month 6 49.41 ± 7.85 60.22 ± 8.93 < 0.001 Month 12 49.63 ± 8.16 59.84 ± 9.12 < 0.001 Diuretics, n (%) Baseline 16 (14.7) 11 (9.8) 0.270 Month 3 1 (0.9) 1 (0.9) 1.000 Month 6 5 (4.6) 2 (1.8) 0.274 Month 12 3 (2.8) 2 (1.8) 0.679 ACEis/ ARBs, n (%) Baseline 51 (46.8) 55 (49.1) 0.730 Month 3 0 3 (2.7) 0.247 Month 6 2 (1.8) 1 (0.9) 0.617 Month 12 3 (2.8) 1 (0.9) 0.363 NSAIDs, n (%) Baseline 4 (3.7) 12 (10.7) 0.043 Month 3 4 (3.7) 6 (5.3) 0.749 Month 6 2 (1.8) 6 (5.3) 0.281 Month 12 2 (1.8) 6 (5.3) 0.281 UTI, n (%) Baseline 0 0 1.000 Month 3 4 (3.7) 5 (4.4) 1.000 Month 6 2 (1.8) 1 (0.9) 0.617 Month 12 5 (4.6) 1 (0.9) 0.114 ACEis/ARBs - The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, NSAIDs - Nonsteroidal anti-inflammatory drugs, UTI – Urinary tract infection. The results from the secondary outcome on the incidence of specific renal function related adverse events at 12 months revealed a recalculated CrCl cutoff for bisphosphonate use. Receiver Operating Characteristic (ROC) curve analysis was performed to identify an optimal CrCl threshold predictive of renal-related adverse events at 12 months. The identified cut-off was ≤ 35.93 mL/min, which yielded a sensitivity of 92.9% and a specificity of 46.7%. The area under the curve (AUC) was 0.744 (95% CI: 0.680 to 0.801), indicating fair discriminatory power. The result was statistically significant (z = 3.565, p = 0.0004), suggesting that CrCl is a meaningful predictor of renal-related complications in this population. (Fig. 4 ). The overall incidence of adverse events was 19.3% in the CrCl < 35 group and 11.5% in the CrCl ≥ 35 group. Gastrointestinal adverse events, such as gastroesophageal reflux disease (GERD), peptic ulcer and esophageal ulcer, were observed but did not differ significantly between the groups. The incidences of renal replacement therapy (RRT) and urinary tract infection (UTI) were higher in the CrCl < 35 group; however, these differences were not statistically significant. The analysis was adjusted for factors influencing renal function outcomes including hypertension, diabetes mellitus, nonsteroidal anti-inflammatory drug (NSAIDs) use, angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), and urinary tract infection (Table 4 ). A review of medical records regarding renal function change events identified explanatory causes in 11 (30.6%) cases. These consisted of 5 cases of pre-renal acute kidney injury (AKI), 3 cases of urinary tract infections, and 3 cases of drug-induced AKI (Table 5 ). Table 5 Summary of gastrointestinal and renal-related adverse events during 12-Month follow up. CrCl < 35 group (n = 109) CrCl ≥ 35 group (n = 113) p-value All adverse events, n (%) 21 (19.3) 13 (11.5) Gastrointestinal symptoms-related adverse events, n (%) GERD* 5 (4.6) 1 (0.9) 0.114 Esophageal ulcer 1 (0.9) 0 0.491 Peptic ulcer 2 (1.8) 4 (3.5) 0.684 Duodenal ulcer 1 (0.9) 1 (0.9) 1.000 Osteonecrosis of jaw 0 0 NA Renal-related adverse events, n (%) RRT* 1 (0.9) 0 0.491 UTI* 11 (10.1) 7 (6.2) 0.332 *GERD: gastroesophageal reflux disease, RRT: renal replacement therapy, UTI: urinary tract infection. Statistically significant at the 0.05 level. Discussion This study provides important insights into the renal safety of bisphosphonates in older osteoporotic patients with impaired renal function. Over a 12-month follow-up period, no statistically significant differences in renal function changes —including serum creatinine, the estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (eGFR: CKD-EPI), Creatinine clearance (CrCl), calculated using the Cockcroft-Gault formula (CrCl: Cockcroft-Gault) —were observed between patients with CrCl < 35 mL/min and those with CrCl ≥ 35 mL/min. These findings are consistent with previous reports suggesting that bisphosphonate therapy does not necessarily result in clinically significant renal deterioration in selected populations with chronic kidney disease (CKD) stages 3–4[ 16 , 17 , 26 , 27 ]. A key strength of this study lies in its use of CrCl calculated by the Cockcroft-Gault equation as a reference for dose adjustment, particularly relevant in geriatric patients who often have low muscle mass and body weight. These findings revealed that nearly half of the participants with eGFR ≥ 35 mL/min/1.73m² had a CrCl < 35 mL/min, highlighting a critical discrepancy between the two measures. This is clinically relevant, as eGFR may overestimate renal function in frail older adults, leading to potential misclassification and inappropriate prescribing. This observation supports prior studies emphasizing the use of CrCl—especially calculated with actual body weight—as a more reliable marker for drug dosing in older adults. These findings are supported by Kilbride et al., who demonstrated that CKD-EPI often overestimates GFR in older adults patients compared to gold standard measures such as iohexol clearance[ 9 , 20 ]. Although the overall renal function remained stable, the CrCl < 35 group exhibited a higher incidence of renal-related adverse events at 6 and 12 months, suggesting that subclinical renal vulnerability may persist even in the absence of overt deterioration in biochemical parameters. These findings reinforce the need for close renal function surveillance during bisphosphonate therapy in this subgroup. Previous reports have raised concerns about bisphosphonate-induced nephrotoxicity[ 6 – 8 ], and our results add to the evidence supporting cautious use under appropriate monitoring[ 16 , 17 ]. Additionally, The ROC analysis yielded an AUC of 0.744 (95% CI: 0.680 to 0.801), suggesting fair accuracy in identifying patients at risk for renal-related adverse events. The optimal threshold of CrCl ≤ 35.93 mL/min demonstrated excellent sensitivity (92.9%) but modest specificity (46.7%), which is acceptable in the context of screening for high-risk patients in clinical practice. The result was statistically significant (p = 0.0004), reinforcing the predictive validity of this threshold. These data support the clinical relevance of this threshold in real-world prescribing and suggest that CrCl < 35 mL/min remains a practical and evidence-based cutoff. Furthermore, this study identified the 12-month timepoint as a critical window during which renal changes and adverse events became more pronounced. These results support the recommendation that clinicians prioritize renal function monitoring, particularly within the first year of bisphosphonate therapy, to ensure timely identification of complications and facilitate early intervention[ 28 ]. In many low- and middle-income countries, access to advanced anti-osteoporotic therapies remains limited. Our findings provide support for the continued use of bisphosphonates as a viable and generally safe treatment option in older adults with moderate renal impairment when careful selection and regular monitoring are applied. These results may also reduce hesitation among clinicians who remain concerned about complications such as osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Lastly, the study underscores the importance of choosing appropriate renal function estimation methods—favoring CrCl over eGFR—for guiding dosing decisions in geriatric practice. Conclusion This study reinforces the cautious use of bisphosphonates in older adults with impaired renal functions. While no significant overall changes in renal function were observed over 12 months, patients with CrCl < 35 mL/min experienced a higher incidence of renal-related adverse events, particularly at 6 and 12 months. These findings support the clinical importance of using CrCl calculated by the Cockcroft-Gault equation for treatment decision-making. The identified CrCl threshold of 35.93 mL/min aligns closely with current FDA guidelines and demonstrated fair predictive accuracy for adverse outcomes. In settings where access to newer osteoporosis medications is limited, bisphosphonates remain a viable option when used with appropriate monitoring. Routine assessment of renal function using CrCl is essential to guide therapy, ensure safety, and optimize outcomes in this vulnerable population. Strengths and limitations The strength of this study lies in its significant contribution to the existing literature through the application of a robust methodology, careful adjustment for key confounders, and its focus on a vulnerable population of older adults with impaired renal function. By stratifying patients based on CrCl and utilizing long-term follow-up data, this research offers a more detailed and nuanced understanding of renal safety in bisphosphonate therapy compared to prior studies. Furthermore, the study minimized potential inaccuracies associated with computerized data systems, such as incorrect ICD-10 coding, by conducting a thorough review of patient records. This included an in-depth analysis of outpatient records, comorbidities, medication history, and healthcare visits. Such an approach provided near-real-time and clinically relevant baseline data for CrCl calculations, ensuring a robust foundation for the study’s conclusions. However, there were limitations to this study. Firstly, as a retrospective cohort study, some crucial information - such as drug compliance - was inherently challenging to capture. To address this, researchers thoroughly reviewed medical charts and documented instances of poor compliance in case report forms. Although reports of poor compliance were rare, an indirect measure of adherence was derived from serum 25-OH vitamin D levels, which significantly increased in both groups compared to baseline. Since vitamin D2 supplements are typically administered weekly, similar to oral bisphosphonates, this finding suggests comparable medication adherence between the groups. Another limitation was the issue of missing data, particularly during the first three months of follow-up. During this period, physicians may have conducted less frequent blood tests for outpatient cases, leading to gaps in renal function data collection. This limitation underscores the need for standardized monitoring protocols to ensure that comprehensive data is captured in future studies. Declarations Acknowledgements The authors thank Ms. Pornchita Thanakorn for her contribution to the statistical analysis. We would also like to express our sincere gratitude to Ms. Supawadee Sainimnuan for her invaluable assistance as a research assistant. Her dedicated support in coordinating and managing various aspects of the study was instrumental to its successful completion. Clinical trial number Not applicable. Authors’ contributions US, AT and VS conceived the ideas or experimental design of the study, US and AT did the data analysis and interpretation, AT drafted the paper, US provided revisions to the scientific content of the manuscript. All authors have read and approved the manuscript. Funding This research project was supported by the Faculty of Medicine Siriraj Hospital, Mahidol University, Grant Number (IO) R016731046. The funding body played no role in the design of the study, the collection, analysis or interpretation of the data or the writing of this manuscript. Availability of data and materials The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable requests Ethics approval and consent to participate Approval of the research protocol was obtained from Siriraj Institutional Review Board (SIRB) (COA no. Si 116/2024). Providing this study was a low-risk study, the SIRB considered the protocol as an expedited category. Data retrieval from hospital databased was made anonymized and did not require consent, according to the policy at the hospital and SIRB. The SIRB is grounded in the foundational ethical principles embodied in the Declaration of Helsinki of 1964 and its subsequent revisions and the Belmont Report. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a WHO study group. Geneva: World Health Organization. 1994. WHO Technical Report Series, No. 843. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33(4):278–85. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014;25(10):2359–81. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003;9(32):2643–58. Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12(6):1164–72. Sauter M, Jülg B, Porubsky S, Cohen C, Fischereder M, Sitter T, et al. Nephrotic-range proteinuria following pamidronate therapy in a patient with metastatic breast cancer: mitochondrial toxicity as a pathogenetic concept? Am J Kidney Dis. 2006;47(6):1075–80. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf. 1999;21(5):389–406. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385–93. Reclast. [prescribing information]. Stein, Switzerland: Novartis Pharma Stein AG; 2011. Actonel, [prescribing information]. Puerto Rico: Warner Chilcott Puerto Rico LLC; 2011. Bonviva. [summary of product characteristics]. Welwyn Garden City, UK: Roche Products Ltd; 2011. Fosamax. [summary of product characteristics]. Hertfordshire, UK: Merck, Sharp and Dohme Limited;: Hoddesdon; 2011. Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the Fracture Intervention Trial. Osteoporos Int. 1993;3(Suppl 3):S29–39. Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995;333(22):1437–43. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344(5):333–40. Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Min Res. 2007;22(4):503–8. Fixen CW, Fixen DR. Renal safety of zoledronic acid for osteoporosis in adults 75 years and older. Osteoporos Int. 2022;33(11):2417–22. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737–49. Kilbride HS, Stevens PE, Eaglestone G, Knight S, Carter JL, Delaney MP, et al. Accuracy of the MDRD (Modification of Diet in Renal Disease) study and CKD-EPI (CKD Epidemiology Collaboration) equations for estimation of GFR in the elderly. Am J Kidney Dis. 2013;61(1):57–66. Pottel H, Delanaye P, Schaeffner E, Dubourg L, Eriksen BO, Melsom T, et al. Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Nephrol Dial Transpl. 2017;32(3):497–507. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021;99(3s):S1-s87. Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-, et al. 2020 UPDATE EXECUTIVE SUMMARY. Endocr Pract. 2020;26(5):564–70. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. Shigematsu T, Muraoka R, Sugimoto T, Nishizawa Y. Risedronate therapy in patients with mild-to-moderate chronic kidney disease with osteoporosis: post-hoc analysis of data from the risedronate phase III clinical trials. BMC Nephrol. 2017;18(1):66. Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Min Res. 2005;20(12):2105–15. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Min Res. 2012;27(2):243–54. Reid DM, Devogelaer JP, Saag K, Roux C, Lau CS, Reginster JY, et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet. 2009;373(9671):1253–63. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Dec, 2025 Read the published version in BMC Geriatrics → Version 1 posted Editorial decision: Revision requested 19 Sep, 2025 Reviews received at journal 17 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviews received at journal 15 Sep, 2025 Reviews received at journal 13 Sep, 2025 Reviewers agreed at journal 10 Sep, 2025 Reviews received at journal 10 Sep, 2025 Reviewers agreed at journal 09 Sep, 2025 Reviewers agreed at journal 07 Sep, 2025 Reviewers agreed at journal 06 Sep, 2025 Reviewers agreed at journal 06 Sep, 2025 Reviewers agreed at journal 05 Sep, 2025 Reviewers agreed at journal 31 Aug, 2025 Reviewers invited by journal 14 Jul, 2025 Editor assigned by journal 14 Jul, 2025 Submission checks completed at journal 14 Jul, 2025 First submitted to journal 01 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7024056","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":485182781,"identity":"0a7da046-f503-4fc2-b9db-9fc1e0141d19","order_by":0,"name":"Akarawin Tweekittikul","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"prefix":"","firstName":"Akarawin","middleName":"","lastName":"Tweekittikul","suffix":""},{"id":485182782,"identity":"c12e7434-132c-4265-83e3-ed8b85d599d5","order_by":1,"name":"Varalak Srinonprasert","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"prefix":"","firstName":"Varalak","middleName":"","lastName":"Srinonprasert","suffix":""},{"id":485182783,"identity":"95e6e398-4e9c-48ae-b4cb-4744129b09dd","order_by":2,"name":"Unchana Sura-amonrattana","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYBAC+wYILQciDjwgRovBAQhtDNaSQIqWRLBtxGm5ffjhY962O+nzww4/BNpiJ6fbQECLfV+asTFv27PcjbfTDIBako3NDhCyhYfBTDq37XDuxtkJIC0HErcR1sL+/TdQS7rh7PQPxGrhMWMGakmQl84h2haeYuk/5w4bbpDOKTiQYECUX9g3fpxRdlhefnb65g8fKuzkCGpB6AWrNCBWOQjIN5CiehSMglEwCkYUAABTCUYlfajqVAAAAABJRU5ErkJggg==","orcid":"","institution":"Mahidol University","correspondingAuthor":true,"prefix":"","firstName":"Unchana","middleName":"","lastName":"Sura-amonrattana","suffix":""}],"badges":[],"createdAt":"2025-07-02 01:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7024056/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7024056/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12877-025-06689-9","type":"published","date":"2025-12-23T15:58:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87036414,"identity":"cf7c60f5-52e5-43ca-b87b-78f4e8bc3456","added_by":"auto","created_at":"2025-07-18 13:20:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":203792,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eConsort flow diagram of the study.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7024056/v1/47e3c794bc97804d99dbebb9.jpg"},{"id":87035263,"identity":"f8c37ae8-44bb-4f15-bacd-c5f058bcfa7b","added_by":"auto","created_at":"2025-07-18 13:12:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63836,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean renal function at baseline and at 3, 6 and 12 months by CrCl group.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e \u003cstrong\u003eSerum creatinine, (B) eGFR, (C) Creatinine clearance.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7024056/v1/6cb507e9eac7c2e783106c56.jpg"},{"id":87035264,"identity":"038c0c49-9b63-45c5-9869-6c18746bd6e3","added_by":"auto","created_at":"2025-07-18 13:12:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":67645,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean change in renal function from baseline at 3, 6, and 12 months.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum Creatinine, (B) eGFR, (C) Creatinine Clearance.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7024056/v1/64e05d07b202f453cb8ec385.jpg"},{"id":87036415,"identity":"045a45d0-4b79-4e1a-ae90-01d13bce0f72","added_by":"auto","created_at":"2025-07-18 13:20:52","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":31572,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curve for optimal CrCl threshold predicting renal-related adverse events \u0026nbsp;at 12 months.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7024056/v1/1ef28b0f1b8e9eef0a5c5baa.jpg"},{"id":99172479,"identity":"680c9494-dc1c-49bc-9508-9c5538457de2","added_by":"auto","created_at":"2025-12-29 16:10:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1841704,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7024056/v1/647d3cd0-e123-45f6-aae8-0eadc8be013a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of Bisphosphonates on Kidney Function in Osteoporotic Geriatric Patients with Impaired Renal Function","fulltext":[{"header":"Key Points","content":"\u003cp\u003e\u0026bull; Bisphosphonates are common in older adults osteoporosis care, requiring renal assessment.\u003c/p\u003e\n\u003cp\u003e\u0026bull; FDA recommends using CrCl from the Cockcroft-Gault equation to guide bisphosphonate prescribing.\u003c/p\u003e\n\u003cp\u003e\u0026bull; eGFR from CKD-EPI equation may overestimate renal function in older adults.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Older adults with CrCl \u0026lt;35 mL/min who received bisphosphonates had a significantly higher risk of renal function change events at 6 and 12 months.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eOsteoporosis is a chronic and progressive skeletal disease marked by diminished bone strength, which includes both a reduction in bone density and a deterioration in bone quality[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These structural changes render bones fragile and susceptible to fractures. The primary cause of osteoporosis lies in an imbalance between bone formation and resorption, influenced by factors such as genetic predisposition, aging and hormonal changes, particularly estrogen deficiency. As individuals age, the prevalence of osteoporosis rises significantly. Despite its widespread nature, the condition often remains asymptomatic until a fragility fracture occurs, osteoporotic fractures are associated with significant morbidity, reduced quality of life and mortality in the older adults[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe cornerstone of osteoporosis management lies in reducing fracture risk and maintaining bone strength. Treatment strategies involve a combination of non-pharmacological and pharmacological approaches. Non-pharmacological measures include lifestyle modifications, such as regular weight-bearing exercises, fall prevention, and adequate intake of calcium and vitamin D through dietary supplementation. Among pharmacological options, bisphosphonates (BPs) are highly recommended due to their well-established safety and efficacy profiles. These medications work by inhibiting osteoclast-mediated bone resorption, effectively preserving bone mass and significantly reducing the risk of fractures[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite their proven benefits in osteoporosis management, bisphosphonates are associated with potential renal toxicity, posing a significant concern in certain patient populations. The mechanisms underlying acute kidney injury (AKI) are hypothesized to include mitochondrial dysfunction, inhibition of adenosine triphosphate (ATP) production, and disruption of the mevalonate pathway. These disturbances can lead to cellular dysfunction, apoptosis, and structural changes within renal cells, particularly in nephrons and podocytes[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, drug precipitation may exacerbate renal impairment, especially in individuals with pre-existing kidney dysfunction. Since bisphosphonates are primarily excreted via the kidneys, impaired renal function increases the risk of drug accumulation, potentially resulting in heightened toxicity[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBased on growing evidence of renal adverse effects, the United States Food and Drug Administration (FDA) advises against the use of bisphosphonates in patients with a creatinine clearance (CrCl) below 35 mL/min, as calculated by the Cockcroft-Gault formula[\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This precaution has led to the exclusion of patients with renal impairment from most clinical trials, thereby limiting available data on the safety and efficacy of bisphosphonates in this population[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, emerging studies in patients with chronic kidney disease have not shown significant worsening of renal function following bisphosphonate administration. These findings suggest that, with careful patient selection and monitoring, bisphosphonates may remain a viable option for managing osteoporosis in select individuals with compromised kidney function[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAccurate renal function assessment is essential to determine the suitability of bisphosphonate therapy. In clinical practice, the estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (eGFR: CKD-EPI), is frequently used. However, eGFR and creatinine clearance are not directly interchangeable. CrCl, calculated using the Cockcroft-Gault formula (CrCl: Cockcroft-Gault), incorporates body weight and is reported in mL/min, whereas eGFR: CKD-EPI is expressed in mL/min/1.73m\u0026sup2; and does not consider body weight[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This discrepancy may lead to misclassification of renal status, especially in older adults with reduced muscle mass, as studies have shown that CKD-EPI-derived eGFR may overestimate kidney function compared to measured GFR (mGFR), such as that obtained through iohexol clearance techniques[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis review aims to analyze historical data to identify older adults with osteoporosis who were prescribed bisphosphonates despite discrepancies between eGFR: CKD-EPI\u0026thinsp;\u0026ge;\u0026thinsp;35 mL/min/1.73m\u0026sup2; and CrCl: Cockcroft-Gault\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min. Additionally, it seeks to evaluate changes in renal function at 3, 6, and 12 months after initiating bisphosphonate therapy, while also assessing other potential adverse effects associated with bisphosphonate use. Moreover, the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines recommend that renal function estimates for drug dosing should rely on creatinine clearance, particularly in older adults, frail individuals, or those with abnormal body composition[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and data collection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study was a retrospective cohort conducted at a university hospital in Thailand, exporting the patients\u0026rsquo; characteristics from the hospital electronic database between January 2015 and December 2022. The study received ethical approval from the Siriraj Institutional Review Board.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy population and eligibility criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis research focused on patients aged 65 years or older who were diagnosed with osteoporosis with impaired renal function and had been undergoing bisphosphonate treatments, including alendronate, ibandronate, risedronate and zoledronic acid, either orally or intravenously, for more than one year. The identification of osteoporosis patients was conducted using the International Classification of Diseases and Related Health Problem 10th Revision (ICD-10) coding, combined with a review of medical histories to confirm that the patients met the diagnostic criteria for osteoporosis based on the American Association of Clinical Endocrinologists (AACE) 2020 guidelines[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Baseline kidney function was assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, with values between 35 and 60 mL/min/1.73m\u0026sup2; recorded within one month prior to the initiation of treatment.\u003c/p\u003e\u003cp\u003ePatients were excluded if they were prescribed bisphosphonates for non-osteoporotic conditions, such as hypercalcemia. Additionally, individuals who switched from bisphosphonates to alternative treatments within the first year of therapy or those with active kidney diseases requiring specific medical interventions, such as nephrotic syndrome, nephritis syndrome or autoimmune diseases, were excluded. Further exclusions applied to individuals with conditions interfering with serum creatinine-based kidney function assessments, such as severe malnutrition or rhabdomyolysis. Patients with fewer than three annual serum creatinine measurements or incomplete medical records, which precluded proper kidney function assessment, were also excluded.\u003c/p\u003e\u003cp\u003eEligible patients were categorized into two groups based on their kidney function prior to initiating bisphosphonate therapy:\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cb\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min group\u003c/b\u003e: Patients with an eGFR: CKD-EPI of at least 35 mL/min/1.73m\u0026sup2; but a CrCl: Cockcroft-Gault of less than 35 mL/min.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 mL/min group\u003c/b\u003e: Patients with an eGFR: CKD-EPI of at least 35 mL/min/1.73m\u0026sup2; and a CrCl: Cockcroft-Gault of at least 35 mL/min.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eData collection and measurements\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe reviewer sorted the records in reverse chronological order, starting from the most recent individual who received the medication within the requested timeframe. The process was conducted sequentially without skipping any cases, continuing until the required number of participants meeting the eligibility criteria for this study was obtained.\u003c/p\u003e\u003cp\u003eBaseline characteristics and laboratory data were collected by reviewing patient medical records and blood test results using the hospital information system. Data collection began on the day bisphosphonate therapy was initiated, with follow-up data recorded at 3 months, 6 months and 12 months post-treatment initiation. Data from each follow-up point was included in the analysis if recorded within 4 weeks, before or after the specified timeframe. If no data was available for the specified period, they were excluded from the analysis.\u003c/p\u003e\u003cp\u003eRenal function was assessed for all patients using serum creatinine, eGFR: CKD-EPI and CrCl: Cockcroft-Gault. The actual recorded weight of the patient during the specified timeframe was used in the analysis. The study also monitored significant renal function changes, including the incidence of acute kidney injury as defined by the Acute Kidney Injury Network (AKIN) criteria[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and the initiation of new renal replacement therapy (RRT).\u003c/p\u003e\u003cp\u003e\u003cb\u003eRenal Function Estimation Equations\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eCockcroft-Gault Formula[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eCKD-EPI Formula[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eeGFR [mL/min/1.73 m\u0026sup2;]\u0026thinsp;=\u0026thinsp;142 X min (S\u003csub\u003ecr\u003c/sub\u003e/K, 1)\u003csup\u003eα\u003c/sup\u003e X max (S\u003csub\u003ecr\u003c/sub\u003e/K, 1)\u003csup\u003e-1.200\u003c/sup\u003e X 0.9938\u003csup\u003eAge\u003c/sup\u003e X 1.012\u003c/p\u003e\u003cp\u003eK\u0026thinsp;=\u0026thinsp;0.7 (females) or 0.9 (males)\u003c/p\u003e\u003cp\u003eα = -0.241 (females) or -0.302 (males)\u003c/p\u003e\u003cp\u003emin\u0026thinsp;=\u0026thinsp;indicates the minimum of Scr/K or 1\u003c/p\u003e\u003cp\u003emax\u0026thinsp;=\u0026thinsp;indicates the maximum of Scr/K or 1\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePrimary outcome\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary outcome is to assess changes in renal function among older adults with osteoporosis who are treated with bisphosphonates, with comparisons made between patient groups at 3, 6, and 12 months after treatment initiation. Renal function outcomes were evaluated using changes in serum creatinine, estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCl) over the specified time points.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSecondary outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe secondary outcomes also monitored the incidence of significant renal function changes that consisted of worsening renal function; characterized by a notable decline in estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) values, new-onset acute kidney injury (AKI); diagnosed according to the Acute Kidney Injury Network (AKIN) criteria and initiation of renal replacement therapy; Indicating severe renal impairment requiring intervention. Moreover, this study focused on evaluating adverse effects and complications associated with bisphosphonate use in older adults with osteoporosis. These outcomes provide critical insights into the safety profile of bisphosphonate therapy, encompassing both gastrointestinal and renal-related events.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe sample size calculation was based on the study by Takashi Shigematsu et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], which evaluated 852 osteoporosis patients receiving risedronate. In their study, the change in renal function in patients with normal renal function showed a mean of -7.35 and a standard deviation (SD) of 15.9, while in patients with mildly impaired renal function, the mean change was \u0026minus;\u0026thinsp;1.35 with an SD of 10.92. The appropriate sample size formula for comparing the means of two independent groups was used, with a significant level of 5% and a power (1-β) of 90%. The calculation determined that at least 109 participants per group were required, resulting in a total sample size of 218 participants for both groups.\u003c/p\u003e\u003cp\u003eBaseline characteristics were summarized both overall and stratified by groups. Continuous variables were reported as mean and standard deviation (SD) for normally distributed data or as median with interquartile range (IQR) for non-normally distributed data. Categorical variables were presented as frequencies and percentages. Comparisons of baseline characteristics between groups were performed using the independent samples t-test for normally distributed continuous variables, the Mann-Whitney U test for non-normally distributed continuous variables, and the Chi-square test for categorical variables.\u003c/p\u003e\u003cp\u003eFor the primary outcome on changes in renal function, statistical analysis was performed using generalized estimating equations (GEE), adjusted for potential confounders including age, gender, body weight, hypertension, diabetes mellitus, urinary tract infections (UTI), non-steroidal anti-inflammatory drug (NSAID) use and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) use.\u003c/p\u003e\u003cp\u003eThe incidence of significant renal function changes over time was evaluated using relative risk (RR), adjusted for potential confounders including age and diabetes mellitus through log-binomial model. Sensitivity analysis was not performed; however, the wide confidence intervals observed in adjusted relative risks suggest that results regarding adverse events must be interpreted cautiously.\u003c/p\u003e\u003cp\u003eAll statistical analyses were conducted using IBM SPSS Statistics, version 29. Statistical tests were two-tailed, and p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered indicative of statistical significance\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 737 osteoporotic patients aged 65 years and older with impaired renal function who underwent bisphosphonate treatment between January 2015 and December 2022 were identified. After applying the exclusion criteria, 515 patients were excluded, resulting in 222 patients eligible for analysis. Among these, 109 patients (49.1%) were categorized in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min group, while 113 patients (50.9%) were categorized in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 mL/min group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePatients in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group were older, with a mean age of 82.39\u0026thinsp;\u0026plusmn;\u0026thinsp;6.11 years, compared to 77.68\u0026thinsp;\u0026plusmn;\u0026thinsp;6.11 years in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Additionally, a greater proportion of patients aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years was found in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group (71.6%) compared to the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (38.1%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Female patients predominated in both groups, but the proportion was significantly higher in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group (92.7%) than in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (78.8%) (p\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\u003cp\u003eSignificant differences were observed in body weight and body mass index (BMI) between the two groups. Patients in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group had a lower mean body weight (49.10\u0026thinsp;\u0026plusmn;\u0026thinsp;7.86 kg) compared to the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (60.95\u0026thinsp;\u0026plusmn;\u0026thinsp;8.93 kg) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, the BMI was lower in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group (22.22\u0026thinsp;\u0026plusmn;\u0026thinsp;3.39 kg/m\u0026sup2;) than in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (26.05\u0026thinsp;\u0026plusmn;\u0026thinsp;3.99 kg/m\u0026sup2;) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This finding strongly suggests that body weight is a critical parameter influencing CrCl values. Since creatinine clearance is partially dependent on muscle mass, which correlates with body weight, a lower body weight in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group reflects its importance in renal function assessment. Moreover, the significantly lower BMI in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group aligns with the hypothesis that patients with reduced renal function are more likely to exhibit frailty or nutritional deficiencies.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRenal function metrics demonstrated substantial differences. The CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group had higher serum creatinine levels (1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 mg/dL) than the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 mg/dL) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Estimated glomerular filtration rate (eGFR) and creatinine clearance were significantly lower in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group (43.09\u0026thinsp;\u0026plusmn;\u0026thinsp;8.65 mL/min/1.73m\u0026sup2; and 27.72\u0026thinsp;\u0026plusmn;\u0026thinsp;5.06 mL/min, respectively) compared to the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (51.32\u0026thinsp;\u0026plusmn;\u0026thinsp;6.57 mL/min/1.73m\u0026sup2; and 41.61\u0026thinsp;\u0026plusmn;\u0026thinsp;5.42 mL/min, respectively) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both).\u003c/p\u003e\u003cp\u003eThe prevalence of hypertension was high and consistent between the groups, with 90.7% in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group and 89.4% in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (p\u0026thinsp;=\u0026thinsp;0.736). No significant differences were observed in the prevalence of diabetes mellitus (39.5% in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group vs. 45.1% in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group; p\u0026thinsp;=\u0026thinsp;0.392) or dementia status (15.6% in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group vs. 14.2% in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group; p\u0026thinsp;=\u0026thinsp;0.763). The Charlson Comorbidity Index (CCI) was comparable between the groups, with a median value of 5 [IQR: 4\u0026ndash;7] in both groups and similar proportions of patients having a CCI score\u0026thinsp;\u0026ge;\u0026thinsp;5 (p\u0026thinsp;=\u0026thinsp;0.638).\u003c/p\u003e\u003cp\u003eBaseline medication use was largely similar across the groups. The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers (ACEis/ARBs) was comparable between the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group (46.8%) and the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (49.1%) (p\u0026thinsp;=\u0026thinsp;0.730). However, nonsteroidal anti-inflammatory drugs (NSAIDs) use was significantly higher in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group (10.71%) compared to the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group (3.7%) (p\u0026thinsp;=\u0026thinsp;0.043). No significant differences were observed in the use of bisphosphonates, including alendronate, zoledronic acid and others.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of patients stratified by creatinine clearance (CrCl)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;222)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;35\u003c/p\u003e\u003cp\u003egroup\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;113)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge, years, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e\u0026ge;\u0026thinsp;80 years, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80.00\u0026thinsp;\u0026plusmn;\u0026thinsp;6.54\u003c/p\u003e\u003cp\u003e121 (54.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82.39\u0026thinsp;\u0026plusmn;\u0026thinsp;6.11\u003c/p\u003e\u003cp\u003e78 (71.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77.68\u0026thinsp;\u0026plusmn;\u0026thinsp;6.11\u003c/p\u003e\u003cp\u003e43 (38.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFemale, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e190 (85.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e101 (92.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e89 (78.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBW*, kg., mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55.14\u0026thinsp;\u0026plusmn;\u0026thinsp;10.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.10\u0026thinsp;\u0026plusmn;\u0026thinsp;7.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.95\u0026thinsp;\u0026plusmn;\u0026thinsp;8.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI*, kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e, \u003cb\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.18\u0026thinsp;\u0026plusmn;\u0026thinsp;4.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.22\u0026thinsp;\u0026plusmn;\u0026thinsp;3.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26.05\u0026thinsp;\u0026plusmn;\u0026thinsp;3.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidity, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHypertension\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e199 (89.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98 (90.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e101 (89.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.736\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiabetes mellitus\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94 (42.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43 (39.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e51 (45.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.392\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDementia\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33 (14.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (14.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.763\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCCI*, Median [IQR]\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.856\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCCI\u0026thinsp;\u0026ge;\u0026thinsp;5, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e152 (68.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e73 (67.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e79 (69.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.638\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlbumin, g/dL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.971\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum creatinine, mg/dL\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eeGFR, mL/min/1.73m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47.28\u0026thinsp;\u0026plusmn;\u0026thinsp;8.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.09\u0026thinsp;\u0026plusmn;\u0026thinsp;8.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e51.32\u0026thinsp;\u0026plusmn;\u0026thinsp;6.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCrCl, mL/min, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34.79\u0026thinsp;\u0026plusmn;\u0026thinsp;8.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.72\u0026thinsp;\u0026plusmn;\u0026thinsp;5.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41.61\u0026thinsp;\u0026plusmn;\u0026thinsp;5.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum calcium, mg/dL\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.991\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum phosphate, mg/dL\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.240\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum PTH*, pg/mL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52.27\u0026thinsp;\u0026plusmn;\u0026thinsp;26.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53.67\u0026thinsp;\u0026plusmn;\u0026thinsp;32.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50.90\u0026thinsp;\u0026plusmn;\u0026thinsp;17.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.624\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum 25-(OH)D level, ng/mL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.54\u0026thinsp;\u0026plusmn;\u0026thinsp;11.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.00\u0026thinsp;\u0026plusmn;\u0026thinsp;10.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33.01\u0026thinsp;\u0026plusmn;\u0026thinsp;12.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.597\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBaseline medication use, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eACEis / ARBs*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e106 (47.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51 (46.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55 (49.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.730\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNSAIDs*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (7.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiuretics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (12.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.270\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBisphosphonates, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlendronate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68 (30.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36 (31.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.622\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlendronate\u0026thinsp;+\u0026thinsp;vitamin D3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100 (45.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54 (49.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e46 (40.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.177\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIbandronate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.363\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRisedronate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (12.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (14.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.354\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eZoledronic acid\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (8.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 (12.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.312\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBisphosphonates reported poor compliance, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e*BW \u0026ndash; Body weight, BMI - Body mass index, CCI - Charlson Comorbidity Index, PTH \u0026ndash; Parathyroid hormone, ACEis/ARBs - The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, NSAIDs - Nonsteroidal anti-inflammatory drugs\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFor the primary outcome, no significant differences in overall renal function changes were observed between the groups (Table\u0026nbsp;2, Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, In the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group, serum creatinine levels remained unchanged at 3 months (0 mg/dL; 95% CI: -0.06 to 0.06, p\u0026thinsp;=\u0026thinsp;1.000) but increased slightly at 6 months (+\u0026thinsp;0.03 mg/dL; 95% CI: -0.05 to 0.11, p\u0026thinsp;=\u0026thinsp;1.000) and at 12 months (+\u0026thinsp;0.06 mg/dL; 95% CI: -0.02 to 0.14, p\u0026thinsp;=\u0026thinsp;0.370). Similarly, the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group showed negligible changes at all time points. Moreover, serum creatinine levels showed a slight increase at 12 months (0.02 mg/dL; 95% CI: -0.03 to 0.06, p\u0026thinsp;=\u0026thinsp;1.000).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe estimated glomerular filtration rate (eGFR) in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group showed a slight, non-significant increase at 3 months (+\u0026thinsp;1.57 mL/min/1.73m\u0026sup2;; 95% CI: -0.51 to 3.64, p\u0026thinsp;=\u0026thinsp;0.278) and 6 months (+\u0026thinsp;1.00 mL/min/1.73m\u0026sup2;; 95% CI: -1.18 to 3.18, p\u0026thinsp;=\u0026thinsp;1.000), followed by a minor decrease at 12 months (-0.41 mL/min/1.73m\u0026sup2;; 95% CI: -2.79 to 1.97, p\u0026thinsp;=\u0026thinsp;1.000). The CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group demonstrated a significant increase at 3 months (+\u0026thinsp;2.42 mL/min/1.73m\u0026sup2;; 95% CI: 0.16 to 4.67, p\u0026thinsp;=\u0026thinsp;0.028) but non-significant increase at 6 months (+\u0026thinsp;1.91 mL/min/1.73m\u0026sup2;; 95% CI: -0.17 to 4.00, p\u0026thinsp;=\u0026thinsp;0.092) and 12 months (+\u0026thinsp;0.12 mL/min/1.73m\u0026sup2;; 95% CI: -2.40 to 2.64, p\u0026thinsp;=\u0026thinsp;1.000).\u003c/p\u003e\u003cp\u003eCreatinine clearance (CrCl) remained stable in both groups. In the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group, CrCl showed a slight increase at 3 months (+\u0026thinsp;0.84 mL/min; 95% CI: -0.32 to 2.00, p\u0026thinsp;=\u0026thinsp;0.338) and 6 months (0.79 mL/min; 95% CI: -0.75 to 2.34, p\u0026thinsp;=\u0026thinsp;1.000) but declined modestly at 12 months (-0.25 mL/min; 95% CI: -1.63 to 1.13, p\u0026thinsp;=\u0026thinsp;1.000). The CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group exhibited comparable stability, with a marginal increase at 6 months (+\u0026thinsp;0.64 mL/min; 95% CI: -0.93 to 2.21, p\u0026thinsp;=\u0026thinsp;1.000) and declined slightly at 12 months (-0.64 mL/min; 95% CI: -2.69 to 1.41, p\u0026thinsp;=\u0026thinsp;1.000).\u003c/p\u003e\u003cp\u003eWhen comparing changes in renal function from baseline between the two groups, no statistically significant differences were observed at any time point during the data collection period.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"16\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e\u003cp\u003eTable\u0026nbsp;2: Renal function changes over 12 months by CrCl group using generalized estimating equations (GEE) analysis.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-value\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.123\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.540\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.540\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.704\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.830\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.680\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e0.474\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c16\" morerows=\"8\" rowspan=\"9\"\u003e\u003cp\u003eAdjusted with age, gender, body weight, hypertension, diabetes mellitus, urinary tract infection, ACEis/ARBs - The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, NSAIDs - Nonsteroidal anti-inflammatory drugs.\u003c/p\u003e\u003cp\u003eThe mean difference from baseline is statistically significant at p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e p-value of within-group effect. \u003csup\u003eb\u003c/sup\u003e p-value of interaction effect (difference of difference from baseline between groups).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eCrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.795\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.092\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.498\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eMean difference from baseline (95%CI)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.02 (-0.06, 0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.02 (-0.05, 0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.02 (-0.03, 0.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2.42 (0.16, 4.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.91 (-0.17, 4.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.12 (-2.40, 2.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e1.19 (-0.62, 3.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.64 (-0.93, 2.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e-0.64 (-2.69, 1.41)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e56.94\u0026thinsp;\u0026plusmn;\u0026thinsp;15.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e59.36\u0026thinsp;\u0026plusmn;\u0026thinsp;17.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e58.86\u0026thinsp;\u0026plusmn;\u0026thinsp;16.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e57.07\u0026thinsp;\u0026plusmn;\u0026thinsp;17.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e43.09\u0026thinsp;\u0026plusmn;\u0026thinsp;12.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e44.27\u0026thinsp;\u0026plusmn;\u0026thinsp;14.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e43.72\u0026thinsp;\u0026plusmn;\u0026thinsp;13.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e42.44\u0026thinsp;\u0026plusmn;\u0026thinsp;14.52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.370\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eMean difference from baseline (95%CI)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.00 (-0.06, 0.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.03 (-0.05, 0.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.06 (-0.02, 0.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.57 (-0.51, 3.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.00 (-1.18, 3.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e-0.41 (-2.79, 1.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.84 (-0.32, 2.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.79 (-0.75, 2.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e-0.25 (-1.63, 1.13)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e45.27\u0026thinsp;\u0026plusmn;\u0026thinsp;15.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e46.83\u0026thinsp;\u0026plusmn;\u0026thinsp;18.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e46.27\u0026thinsp;\u0026plusmn;\u0026thinsp;18.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e44.86\u0026thinsp;\u0026plusmn;\u0026thinsp;18.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e30.64\u0026thinsp;\u0026plusmn;\u0026thinsp;11.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e31.48\u0026thinsp;\u0026plusmn;\u0026thinsp;12.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e31.43\u0026thinsp;\u0026plusmn;\u0026thinsp;12.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e30.39\u0026thinsp;\u0026plusmn;\u0026thinsp;12.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eVisit\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eVariable\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCreatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eeGFR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e(mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eCrCl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e(mL/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRenal-related adverse events were more frequent in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group compared to CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group, particularly at 6 and 12 months. At 6 months, specific renal-related adverse events occurred in 13.2% of the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group patients compared to 1.9% in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group, with an adjusted relative risk (RR) of 6.77 (95% CI: 1.53 to 29.88, p\u0026thinsp;=\u0026thinsp;0.012). By 12 months, these events were reported in 10.4% of the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group patients compared to 2.8% in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group, with an adjusted RR of 3.75 (95% CI: 1.04 to 13.50, p\u0026thinsp;=\u0026thinsp;0.043) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eIncidence and RR of renal-related adverse events by CrCl group over 12 months.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;35\u003c/p\u003e\u003cp\u003egroup\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;113)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCrude RR\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdjusted RR*\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAt month 3\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.26\u003c/p\u003e\u003cp\u003e(0.42, 12.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.340\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003cp\u003e(0.57, 17.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.187\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAt month 6\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (13.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.07\u003c/p\u003e\u003cp\u003e(1.65, 30.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6.77\u003c/p\u003e\u003cp\u003e(1.53, 29.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAt month 12\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.70\u003c/p\u003e\u003cp\u003e(1.06, 12.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.040\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003cp\u003e(1.04, 13.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e*Adjusted with age, diabetes mellitus. Statistically significant at the 0.05 level\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eConfounding factors that may affect kidney function were observed. Overall, body weight was lower in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min group compared to the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 mL/min group. At 12 months, body weight increased slightly in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group but decreased slightly in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group. For medications, both ACEIs/ARBs and diuretics were prescribed at similar rates in both groups from baseline to 12 months. However, NSAIDs use was consistently higher in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group compared to the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group at baseline and at 3, 6 and 12 months with significantly higher prescriptions at baseline. The incidence of UTI in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group was slightly higher than in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group at 6 and 12 months, however, the difference was not statistically significant. (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDistribution of potential confounding factors related to renal function over 12 months\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVisit\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eBody weight, kg.,\u003c/p\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.95\u0026thinsp;\u0026plusmn;\u0026thinsp;8.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.36\u0026thinsp;\u0026plusmn;\u0026thinsp;7.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e59.99\u0026thinsp;\u0026plusmn;\u0026thinsp;8.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.41\u0026thinsp;\u0026plusmn;\u0026thinsp;7.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.22\u0026thinsp;\u0026plusmn;\u0026thinsp;8.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.63\u0026thinsp;\u0026plusmn;\u0026thinsp;8.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e59.84\u0026thinsp;\u0026plusmn;\u0026thinsp;9.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eDiuretics, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.270\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.274\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.679\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eACEis/ ARBs, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51 (46.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55 (49.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.730\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (2.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.247\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.617\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.363\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eNSAIDs, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.749\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.281\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.281\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eUTI, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.617\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonth 12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.114\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eACEis/ARBs - The use of Angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, NSAIDs - Nonsteroidal anti-inflammatory drugs, UTI \u0026ndash; Urinary tract infection.\u003c/p\u003e\u003cp\u003eThe results from the secondary outcome on the incidence of specific renal function related adverse events at 12 months revealed a recalculated CrCl cutoff for bisphosphonate use. Receiver Operating Characteristic (ROC) curve analysis was performed to identify an optimal CrCl threshold predictive of renal-related adverse events at 12 months. The identified cut-off was \u0026le;\u0026thinsp;35.93 mL/min, which yielded a sensitivity of 92.9% and a specificity of 46.7%. The area under the curve (AUC) was 0.744 (95% CI: 0.680 to 0.801), indicating fair discriminatory power. The result was statistically significant (z\u0026thinsp;=\u0026thinsp;3.565, p\u0026thinsp;=\u0026thinsp;0.0004), suggesting that CrCl is a meaningful predictor of renal-related complications in this population. (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe overall incidence of adverse events was 19.3% in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group and 11.5% in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group. Gastrointestinal adverse events, such as gastroesophageal reflux disease (GERD), peptic ulcer and esophageal ulcer, were observed but did not differ significantly between the groups. The incidences of renal replacement therapy (RRT) and urinary tract infection (UTI) were higher in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group; however, these differences were not statistically significant. The analysis was adjusted for factors influencing renal function outcomes including hypertension, diabetes mellitus, nonsteroidal anti-inflammatory drug (NSAIDs) use, angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), and urinary tract infection (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). A review of medical records regarding renal function change events identified explanatory causes in 11 (30.6%) cases. These consisted of 5 cases of pre-renal acute kidney injury (AKI), 3 cases of urinary tract infections, and 3 cases of drug-induced AKI (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of gastrointestinal and renal-related adverse events during 12-Month follow up.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;113)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll adverse events, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (19.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (11.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGastrointestinal symptoms-related adverse events, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGERD*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.114\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEsophageal ulcer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.491\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeptic ulcer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.684\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuodenal ulcer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteonecrosis of jaw\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRenal-related adverse events, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRRT*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.491\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUTI*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (6.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.332\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e*GERD: gastroesophageal reflux disease, RRT: renal replacement therapy, UTI: urinary tract infection.\u003c/p\u003e\u003cp\u003eStatistically significant at the 0.05 level.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides important insights into the renal safety of bisphosphonates in older osteoporotic patients with impaired renal function. Over a 12-month follow-up period, no statistically significant differences in renal function changes \u0026mdash;including serum creatinine, the estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (eGFR: CKD-EPI), Creatinine clearance (CrCl), calculated using the Cockcroft-Gault formula (CrCl: Cockcroft-Gault) \u0026mdash;were observed between patients with CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min and those with CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 mL/min. These findings are consistent with previous reports suggesting that bisphosphonate therapy does not necessarily result in clinically significant renal deterioration in selected populations with chronic kidney disease (CKD) stages 3\u0026ndash;4[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA key strength of this study lies in its use of CrCl calculated by the Cockcroft-Gault equation as a reference for dose adjustment, particularly relevant in geriatric patients who often have low muscle mass and body weight. These findings revealed that nearly half of the participants with eGFR\u0026thinsp;\u0026ge;\u0026thinsp;35 mL/min/1.73m\u0026sup2; had a CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min, highlighting a critical discrepancy between the two measures. This is clinically relevant, as eGFR may overestimate renal function in frail older adults, leading to potential misclassification and inappropriate prescribing. This observation supports prior studies emphasizing the use of CrCl\u0026mdash;especially calculated with actual body weight\u0026mdash;as a more reliable marker for drug dosing in older adults. These findings are supported by Kilbride et al., who demonstrated that CKD-EPI often overestimates GFR in older adults patients compared to gold standard measures such as iohexol clearance[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough the overall renal function remained stable, the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group exhibited a higher incidence of renal-related adverse events at 6 and 12 months, suggesting that subclinical renal vulnerability may persist even in the absence of overt deterioration in biochemical parameters. These findings reinforce the need for close renal function surveillance during bisphosphonate therapy in this subgroup. Previous reports have raised concerns about bisphosphonate-induced nephrotoxicity[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and our results add to the evidence supporting cautious use under appropriate monitoring[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, The ROC analysis yielded an AUC of 0.744 (95% CI: 0.680 to 0.801), suggesting fair accuracy in identifying patients at risk for renal-related adverse events. The optimal threshold of CrCl\u0026thinsp;\u0026le;\u0026thinsp;35.93 mL/min demonstrated excellent sensitivity (92.9%) but modest specificity (46.7%), which is acceptable in the context of screening for high-risk patients in clinical practice. The result was statistically significant (p\u0026thinsp;=\u0026thinsp;0.0004), reinforcing the predictive validity of this threshold. These data support the clinical relevance of this threshold in real-world prescribing and suggest that CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min remains a practical and evidence-based cutoff.\u003c/p\u003e\u003cp\u003eFurthermore, this study identified the 12-month timepoint as a critical window during which renal changes and adverse events became more pronounced. These results support the recommendation that clinicians prioritize renal function monitoring, particularly within the first year of bisphosphonate therapy, to ensure timely identification of complications and facilitate early intervention[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn many low- and middle-income countries, access to advanced anti-osteoporotic therapies remains limited. Our findings provide support for the continued use of bisphosphonates as a viable and generally safe treatment option in older adults with moderate renal impairment when careful selection and regular monitoring are applied. These results may also reduce hesitation among clinicians who remain concerned about complications such as osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Lastly, the study underscores the importance of choosing appropriate renal function estimation methods\u0026mdash;favoring CrCl over eGFR\u0026mdash;for guiding dosing decisions in geriatric practice.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study reinforces the cautious use of bisphosphonates in older adults with impaired renal functions. While no significant overall changes in renal function were observed over 12 months, patients with CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 mL/min experienced a higher incidence of renal-related adverse events, particularly at 6 and 12 months. These findings support the clinical importance of using CrCl calculated by the Cockcroft-Gault equation for treatment decision-making. The identified CrCl threshold of 35.93 mL/min aligns closely with current FDA guidelines and demonstrated fair predictive accuracy for adverse outcomes. In settings where access to newer osteoporosis medications is limited, bisphosphonates remain a viable option when used with appropriate monitoring. Routine assessment of renal function using CrCl is essential to guide therapy, ensure safety, and optimize outcomes in this vulnerable population.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStrengths and limitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe strength of this study lies in its significant contribution to the existing literature through the application of a robust methodology, careful adjustment for key confounders, and its focus on a vulnerable population of older adults with impaired renal function. By stratifying patients based on CrCl and utilizing long-term follow-up data, this research offers a more detailed and nuanced understanding of renal safety in bisphosphonate therapy compared to prior studies. Furthermore, the study minimized potential inaccuracies associated with computerized data systems, such as incorrect ICD-10 coding, by conducting a thorough review of patient records. This included an in-depth analysis of outpatient records, comorbidities, medication history, and healthcare visits. Such an approach provided near-real-time and clinically relevant baseline data for CrCl calculations, ensuring a robust foundation for the study\u0026rsquo;s conclusions.\u003c/p\u003e\u003cp\u003eHowever, there were limitations to this study. Firstly, as a retrospective cohort study, some crucial information - such as drug compliance - was inherently challenging to capture. To address this, researchers thoroughly reviewed medical charts and documented instances of poor compliance in case report forms. Although reports of poor compliance were rare, an indirect measure of adherence was derived from serum 25-OH vitamin D levels, which significantly increased in both groups compared to baseline. Since vitamin D2 supplements are typically administered weekly, similar to oral bisphosphonates, this finding suggests comparable medication adherence between the groups. Another limitation was the issue of missing data, particularly during the first three months of follow-up. During this period, physicians may have conducted less frequent blood tests for outpatient cases, leading to gaps in renal function data collection. This limitation underscores the need for standardized monitoring protocols to ensure that comprehensive data is captured in future studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The authors thank Ms. Pornchita Thanakorn for her contribution to the statistical analysis. We would also like to express our sincere gratitude to Ms. Supawadee Sainimnuan for her invaluable assistance as a research assistant. Her dedicated support in coordinating and managing various aspects of the study was instrumental to its successful completion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; US, AT and VS conceived the ideas or experimental design of the study, US and AT did the data analysis and interpretation, AT drafted the paper, US provided revisions to the scientific content of the manuscript. All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; This research project was supported by the Faculty of Medicine Siriraj Hospital, Mahidol University, Grant Number (IO) R016731046. The funding body played no role in the design of the study, the collection, analysis or interpretation of the data or the writing of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed in the current study are available from the corresponding author on reasonable requests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval of the research protocol was obtained from Siriraj Institutional Review Board (SIRB) (COA no. Si 116/2024). Providing this study was a low-risk study, the SIRB considered the protocol as an expedited category. Data retrieval from hospital databased was made anonymized and did not require consent, according to the policy at the hospital and SIRB. The SIRB is grounded in the foundational ethical principles embodied in the Declaration of Helsinki of 1964 and its subsequent revisions and the Belmont Report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\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. Geneva: World Health Organization. 1994. WHO Technical Report Series, No. 843.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33(4):278\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014;25(10):2359\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003;9(32):2643\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarkowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12(6):1164\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSauter M, J\u0026uuml;lg B, Porubsky S, Cohen C, Fischereder M, Sitter T, et al. Nephrotic-range proteinuria following pamidronate therapy in a patient with metastatic breast cancer: mitochondrial toxicity as a pathogenetic concept? Am J Kidney Dis. 2006;47(6):1075\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf. 1999;21(5):389\u0026ndash;406.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePerazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReclast. [prescribing information]. Stein, Switzerland: Novartis Pharma Stein AG; 2011.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eActonel, [prescribing information]. Puerto Rico: Warner Chilcott Puerto Rico LLC; 2011.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBonviva. [summary of product characteristics]. Welwyn Garden City, UK: Roche Products Ltd; 2011.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFosamax. [summary of product characteristics]. Hertfordshire, UK: Merck, Sharp and Dohme Limited;: Hoddesdon; 2011.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBlack DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the Fracture Intervention Trial. Osteoporos Int. 1993;3(Suppl 3):S29\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiberman UA, Weiss SR, Br\u0026ouml;ll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995;333(22):1437\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344(5):333\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Min Res. 2007;22(4):503\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFixen CW, Fixen DR. Renal safety of zoledronic acid for osteoporosis in adults 75 years and older. Osteoporos Int. 2022;33(11):2417\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eInker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKilbride HS, Stevens PE, Eaglestone G, Knight S, Carter JL, Delaney MP, et al. Accuracy of the MDRD (Modification of Diet in Renal Disease) study and CKD-EPI (CKD Epidemiology Collaboration) equations for estimation of GFR in the elderly. Am J Kidney Dis. 2013;61(1):57\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePottel H, Delanaye P, Schaeffner E, Dubourg L, Eriksen BO, Melsom T, et al. Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Nephrol Dial Transpl. 2017;32(3):497\u0026ndash;507.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021;99(3s):S1-s87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCamacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-, et al. 2020 UPDATE EXECUTIVE SUMMARY. Endocr Pract. 2020;26(5):564\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShigematsu T, Muraoka R, Sugimoto T, Nishizawa Y. Risedronate therapy in patients with mild-to-moderate chronic kidney disease with osteoporosis: post-hoc analysis of data from the risedronate phase III clinical trials. BMC Nephrol. 2017;18(1):66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Min Res. 2005;20(12):2105\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBlack DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Min Res. 2012;27(2):243\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReid DM, Devogelaer JP, Saag K, Roux C, Lau CS, Reginster JY, et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet. 2009;373(9671):1253\u0026ndash;63.\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-geriatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bgtc","sideBox":"Learn more about [BMC Geriatrics](http://bmcgeriatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bgtc/default.aspx","title":"BMC Geriatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Osteoporosis, Bisphosphonate, Renal function, Creatinine clearance, Older adults","lastPublishedDoi":"10.21203/rs.3.rs-7024056/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7024056/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eBisphosphonates are the mainstay treatment for osteoporosis, with initiation guided by creatinine clearance (CrCl) from the Cockcroft-Gault equation. However, many clinicians use estimated glomerular filtration rate (eGFR) from the CKD-EPI equation, primarily for chronic kidney disease (CKD) staging.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eTo compare renal function assessments derived from the two equations and evaluate changes over a 12-month treatment.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective cohort study compared renal outcomes in osteoporotic geriatric patients with an eGFR ranging from 35 to 60 mL/min/1.73m\u0026sup2; who received bisphosphonate between January 2015 and December 2022. Patients were categorized based on CrCl: \u0026lt;35 mL/min and \u0026ge;\u0026thinsp;35 mL/min using the Cockcroft-Gault equation\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 222 patients (190 [85.6%] female; mean age 80\u0026thinsp;\u0026plusmn;\u0026thinsp;6.54 years) were analyzed, with 109 (49.1%) in the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group and 113 (50.9%) in the CrCl\u0026thinsp;\u0026ge;\u0026thinsp;35 group. No significant differences in overall renal function changes were observed. The CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group had higher relative risk (RR) of renal function change events with an adjusted RR of 6.77 (95% CI: 1.53 to 29.88; p\u0026thinsp;=\u0026thinsp;0.012) at 6 months and an adjusted RR of 3.75 (95% CI: 1.04 to 13.50; p\u0026thinsp;=\u0026thinsp;0.043) at 12 months.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eCalculating CrCl using the Cockcroft-Gault equation is crucial in older patients before bisphosphonate therapy. Although no significant differences in overall renal function changes were observed, the CrCl\u0026thinsp;\u0026lt;\u0026thinsp;35 group demonstrated trends of renal function decline and higher relative risk of renal function change events at months 6 and 12.\u003c/p\u003e","manuscriptTitle":"The Effect of Bisphosphonates on Kidney Function in Osteoporotic Geriatric Patients with Impaired Renal Function","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 13:12:47","doi":"10.21203/rs.3.rs-7024056/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-19T10:47:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-17T06:14:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-17T02:55:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-15T09:32:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-13T13:01:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"199782215541903477874869236516930386844","date":"2025-09-11T00:17:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-10T16:05:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219769454724568840870160686608282652948","date":"2025-09-09T07:10:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284920556629845719679193713943028184257","date":"2025-09-07T07:47:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"108542988003226325643631898821387275203","date":"2025-09-06T18:56:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"200675747223757915400736899634943094808","date":"2025-09-06T06:03:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87141577115631112175253092557422789517","date":"2025-09-06T03:13:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"212966775371989977144333328737020516059","date":"2025-09-01T01:24:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-14T08:27:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-14T06:52:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-14T06:50:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Geriatrics","date":"2025-07-02T01:16:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-geriatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bgtc","sideBox":"Learn more about [BMC Geriatrics](http://bmcgeriatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bgtc/default.aspx","title":"BMC Geriatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"da4679bf-9d0b-4e21-91c5-2b8bf6ca7e0a","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T16:05:33+00:00","versionOfRecord":{"articleIdentity":"rs-7024056","link":"https://doi.org/10.1186/s12877-025-06689-9","journal":{"identity":"bmc-geriatrics","isVorOnly":false,"title":"BMC Geriatrics"},"publishedOn":"2025-12-23 15:58:04","publishedOnDateReadable":"December 23rd, 2025"},"versionCreatedAt":"2025-07-18 13:12:47","video":"","vorDoi":"10.1186/s12877-025-06689-9","vorDoiUrl":"https://doi.org/10.1186/s12877-025-06689-9","workflowStages":[]},"version":"v1","identity":"rs-7024056","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7024056","identity":"rs-7024056","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}