Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high). OBJECTIVES: To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively. SEARCH METHODS: We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023. SELECTION CRITERIA: We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study. MAIN RESULTS: Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies. AUTHORS' CONCLUSIONS: This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.

Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation.

UNLABELLED: Association between warfarin use and fracture risk is unclear. We examined the association between long-term warfarin use and fracture risk at the hip, spine, and wrist in elders. No significant association was found between long-term warfarin use and fracture risk, despite biological plausibility. INTRODUCTION: Prior studies examining the association of warfarin use and osteoporotic fractures have been conflicting, potentially related to methodological limitations. Thus, we examined the association of long-term warfarin use with risk of hip, spine, and wrist fractures among older adults with atrial fibrillation, attempting to address prior methodologic challenges. METHODS: We included men and women ≥ 65 years of age with incident atrial fibrillation and without prior history of fractures from The Health Improvement Network followed between 2000 and 2010. Long-term warfarin use was defined in two ways: (1) warfarin use ≥ 1 year; (2) warfarin use ≥ 3 years. Propensity-score matched cohorts of warfarin users and nonusers were created to evaluate the association between long-term warfarin use and risk of hip, spine, and wrist fractures separately as well as combined, using Cox-proportional hazards regression models. RESULTS: Among >20,000 participants with incident atrial fibrillation, the hazard ratios (HR) for hip fracture with warfarin use ≥ 1 and ≥ 3 years, respectively, were 1.08 (95%CI 0.87, 1.35) and 1.13 (95% CI 0.84, 1.50). Similarly, no significant associations were observed between long-term warfarin use and risk of spine or wrist fracture. When risk of any fracture was assessed with warfarin use, no association was found [HR for warfarin use ≥ 1 year 0.92 (95%CI 0.77, 1.10); HR for warfarin use ≥ 3 years 1.12 (95%CI 0.88, 1.43)]. CONCLUSIONS: Long-term warfarin use among elders with atrial fibrillation was not associated with increased risk of osteoporotic fractures and therefore does not appear to necessitate additional surveillance or prophylaxis.

Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents.

BACKGROUND: Whereas tenofovir (TDF) exposure has been associated with decreased bone density, it remains unclear whether it is associated with increased risk of osteoporotic fractures. METHODS: Patients with any osteoporotic fracture (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by International Classification of Diseases - 9th Revision (ICD-9) code in the Veterans Affairs' Clinical Case Registry from 1988 to 2009. Osteoporotic fracture risk associated with cumulative exposure to TDF and other antiretrovirals was examined in univariate analysis and multivariate model 1 (MV1 - controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status) and model 2 (MV2 - controlling for MV1 variables + concomitant antiretroviral exposures). RESULTS: Among 56,660 patients evaluated, TDF exposure (total 46,062 person-years) was associated with an osteoporotic fracture hazard ratio of 1.080 [95% confidence interval (CI) 1.02-1.15, P < 0.001] in univariate analysis, 1.06 (0.99-1.12) in MV1 and 1.06 (0.99-1.14) in MV2. Among patients entering the cohort in the highly active antiretroviral therapy (HAART) era (n = 32,439), TDF exposure was associated with a yearly hazard ratio for osteoporotic fracture of 1.16 (95% CI 1.08-1.24, P < 0.001) in univariate model, 1.13 (1.05-1.21, P = 0.001) in MV1 and 1.12 (1.03-1.21, P = 0.011) in MV2. Boosted protease inhibitor exposure was associated with hazard ratio of 1.11 (1.05-1.18, P = 0.001) in univariate model, 1.08 (1.01-1.15, P = 0.026) in MV1 and 1.05 (0.97-1.13, P = 0.237) in MV2. Among protease inhibitors, lopinavir/ritonavir (LPV/RTV) had an osteoporotic fracture hazard ratio of 1.09 (CI 1.00-1.20, P = 0.051) in MV2. CONCLUSION: Cumulative exposure to TDF and, among protease inhibitors, LPV/RTV was independently predictive of increased risk of osteoporotic fracture in the HAART era.

Use of proton pump inhibitors and risk of osteoporosis-related fractures.

BACKGROUND: The use of proton pump inhibitors has been associated with an increased risk of hip fracture. We sought to further explore the relation between duration of exposure to proton pump inhibitors and osteoporosis-related fractures. METHODS: We used administrative claims data to identify patients with a fracture of the hip, vertebra or wrist between April 1996 and March 2004. Cases were each matched with 3 controls based on age, sex and comorbidities. We calculated adjusted odds ratios (OR) for the risk of hip fracture and all osteoporosis-related fractures for durations of proton pump inhibitor exposure ranging from 1 or more years to more than 7 years. RESULTS: We matched 15 792 cases of osteoporosis-related fractures with 47 289 controls. We did not detect a significant association between the overall risk of an osteoportic fracture and the use of proton pump inhibitors for durations of 6 years or less. However, exposure of 7 or more years was associated with increased risk of an osteoporosis-related fracture (adjusted OR 1.92, 95% confidence interval [CI] 1.16-3.18, p = 0.011). We also found an increased risk of hip fracture after 5 or more years of exposure (adjusted OR 1.62, 95% CI 1.02-2.58, p = 0.04), with even higher risk after 7 or more years exposure (adjusted OR 4.55, 95% CI 1.68-12.29, p = 0.002). INTERPRETATION: Use of proton pump inhibitors for 7 or more years is associated with a significantly increased risk of an osteoporosis-related fracture. There is an increased risk of hip fracture after 5 or more years exposure. Further study is required to determine the clinical importance of this finding and to determine the value of osteoprotective medications for patients with long-term use of proton pump inhibitors.

Assessing the risk of bone fracture among postmenopausal women who are receiving adjuvant hormonal therapy for breast cancer.

OBJECTIVE: To understand better the true impact of widespread adoption of adjuvant aromatase inhibitor (AI) therapy on postmenopausal breast cancer patients' risk of bone fracture. METHODS: Data from three different studies were used to estimate the relative risk of bone fracture for each of the following groups of women (i.e., versus a control group of healthy postmenopausal women): (a) healthy postmenopausal women receiving tamoxifen; (b) postmenopausal women who had received treatment for early breast cancer; (c) postmenopausal breast cancer patients on adjuvant tamoxifen therapy; (d) postmenopausal breast cancer patients on adjuvant anastrozole therapy. The results of these analyses were then used to estimate the likely incidence of clinical fracture among such populations in 'real-life' clinical practice. RESULTS: Breast cancer survivors were calculated to be at increased risk of clinical bone fracture (i.e., RR 1.15 vs. control group over 5 years). Breast cancer patients initiated on adjuvant anastrozole were also calculated to be at increased risk of bone fracture (RR = 1.36 vs. control group over 5 years), while the calculated risk of fracture among tamoxifen-treated breast cancer patients was similar to that observed in the control population (RR = 0.91). CONCLUSION: Breast cancer patients are at increased risk of clinical bone fracture (compared with the general postmenopausal population) and adjuvant anastrozole therapy slightly adds to this risk. Importantly, however, the absolute risk of bone fracture appears to remain low in each of the evaluated patient populations, suggesting that fear of fracture should not prevent the initiation of adjuvant aromatase inhibitor therapy.