The aim of this commentary is to discuss the Cochrane Review “Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women” 1 by Wells et al.,a published in the Cochrane Library. This Cochrane Corner is produced in agreement with International Journal of Rheumatic Diseases by Cochrane Rehabilitation with viewsb of the review summary author in the “implications for practice” section. Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration, leading to increased bone fragility and a higher risk of fractures 2. Postmenopausal women are particularly vulnerable due to the rapid decline in estrogen levels, which accelerates bone loss 3. Osteoporotic fractures, especially those of the hip, spine, and wrist, are associated with significant morbidity, mortality, reduced quality of life, and increased healthcare costs 4. Bisphosphonates such as alendronate are potent inhibitors of osteoclast-mediated bone resorption and are widely considered first-line agents for the prevention and treatment of osteoporosis, as they effectively reduce bone loss and the risk of fragility fractures 5. This Cochrane systematic review 1 aimed to evaluate the efficacy and safety of alendronate for the prevention of osteoporotic fractures in postmenopausal women categorized into primary or secondary prevention groups based on baseline osteoporosis severity and fracture risk. (Wells GA, Hsieh SC, Peterson J, Zheng C, Kelly SE, Shea B, Tugwell P. 2025). The aim of this Cochrane Review 1 was to assess and update the current evidence regarding the efficacy and safety of alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture. The population of interest in this review 1 included postmenopausal women without significant underlying diseases, who were at an increased (low or high) risk of osteoporotic fractures and received at least one year of treatment with alendronate, placebo, or other anti-osteoporotic medications. Eligibility criteria for primary or secondary prevention were based on the presence of a clinical diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density (T score ≤ −2.5), or being aged ≥ 75 years. Participants with lower fracture risk were classified under primary prevention, while those with higher fracture risk were considered under secondary prevention. The major outcomes assessed were clinical vertebral fractures, nonvertebral fractures, hip fractures, wrist fractures, withdrawals due to adverse events, and serious adverse events. The Cochrane review 1 searched for studies published up to February 2023 using a comprehensive strategy that included CENTRAL, MEDLINE, Embase, clinical trial registries (ClinicalTrials.gov, WHO ICTRP), and regulatory agency websites (FDA, EMA, Health Canada), without applying any restrictions on language, date, publication format, or reported outcomes. The Cochrane review included a total of 119 randomized controlled trials, of which 102 contributed data to the quantitative synthesis. Among these, 34 studies (15 188 participants) focused on primary prevention and 68 studies (29 577 participants) on secondary prevention of osteoporotic fractures in postmenopausal women. Methodological concerns were common; only 20 studies (19%) adequately reported both sequence generation and allocation concealment, and just 8 studies (8%) were assessed as low risk of bias across all seven domains. The Cochrane review included a total of 34 studies on primary prevention and 68 on secondary prevention. However, the primary analyses were based on a subset of 16 primary prevention studies (10 057 participants, 1–5 years in duration) and 20 secondary prevention studies (7375 participants, 1–3 years in duration). These studies were selected because they provided placebo-controlled data using the standard dose of alendronate (10 mg/day or 70 mg/week), with sufficient follow-up and outcomes appropriate for meta-analysis. Limitations such as indirectness, imprecision, and risk of bias contributed to downgrading the certainty of the evidence across most outcomes. Alendronate probably results in a clinically important reduction in clinical vertebral fractures (24 events in 1114 women in the alendronate group versus 51 events in 1055 women in the control group). (Risk Ratio (RR) 0.45, 95% Confidence Interval (CI) 0.28 to 0.73; Absolute Risk Reduction (ARR) 2.7% fewer, 95% CI 3.5% fewer to 1.3% fewer; moderate-certainty evidence). Alendronate may reduce nonvertebral fracture risk (RR 0.80, 95% CI 0.64 to 0.99; ARR 2.8% fewer, 95% CI 5.1% fewer to 0.1% fewer; low-certainty evidence). Alendronate may reduce hip fracture risk (RR 0.49, 95% CI 0.25 to 0.96), corresponding to 1 fewer hip fracture per 100 women (ARR 1.0% fewer, 95% CI 1.5% fewer to 0.1% fewer; low-certainty evidence). Alendronate may reduce wrist fracture risk (RR 0.54, 95% CI 0.33 to 0.90; ARR 1.8% fewer, 95% CI 2.6% fewer to 0.4% fewer; low-certainty evidence). Alendronate may reduce serious adverse events (RR 0.75, 95% CI 0.59 to 0.96; ARR 3.5% fewer, 95% CI 5.8% fewer to 0.6% fewer; low-certainty evidence). The effect of alendronate on treatment discontinuation due to adverse events is very uncertain. (RR 0.95, 95% CI 0.78 to 1.16; ARR 0.4% fewer, 95% CI 1.7% fewer to 1.3% more; very low-certainty evidence). Alendronate may reduce clinical vertebral fracture risk (16 events in 1190 women in the alendronate group versus 24 events in 926 women in the control group), with a 55% relative risk reduction (RR 0.45, 95% CI 0.25 to 0.84; ARR 1.4% fewer, 95% CI 1.9% fewer to 0.4% fewer; low-certainty evidence). Alendronate may reduce nonvertebral fracture risk (RR 0.83, 95% CI 0.72 to 0.97; ARR 1.6% fewer, 95% CI 2.6% fewer to 0.3% fewer; low-certainty evidence). The effect of alendronate on hip fractures is uncertain (RR 0.76, 95% CI 0.43 to 1.32; ARR 0.2% fewer, 95% CI 0.4% fewer to 0.2% more; low-certainty evidence). The effect of alendronate on wrist fractures is uncertain (RR 1.12, 95% CI 0.84 to 1.49; ARR 0.3% more, 95% CI 0.4% fewer to 1.1% more; low-certainty evidence). Alendronate may have little to no effect on serious adverse events (RR 1.08, 95% CI 0.82 to 1.43; ARR 0.5% more, 95% CI 1.2% fewer to 2.8% more; low-certainty evidence). Alendronate may have little to no effect on treatment discontinuation due to adverse events (RR 1.03, 95% CI 0.89 to 1.18; ARR 0.2% more, 95% CI 0.9% fewer to 1.5% more; low-certainty evidence). In this Cochrane review 1, the authors concluded that alendronate 10 mg/day probably results in a clinically important reduction in clinical vertebral fractures in postmenopausal women undergoing secondary prevention. It may also reduce nonvertebral, hip, and wrist fractures, as well as serious adverse events, although the certainty of this evidence is low. However, the effect of alendronate on withdrawals due to adverse events is very uncertain. For primary prevention, alendronate 10 mg/day may reduce clinical vertebral and nonvertebral fractures, but its effects on hip and wrist fractures, serious adverse events, and treatment discontinuation are likely minimal or uncertain, with wide CIs and low-certainty evidence. The authors emphasized that indirectness, imprecision, and risk of bias in the included studies contributed to downgrading the certainty of the evidence across most outcomes. Osteoporotic fractures, particularly those involving the hip and spine, are associated with substantial morbidity, increased mortality, and a significant decline in quality of life. Notably, a significant proportion of these fragility fractures occur in postmenopausal women with osteopenia—defined by reduced bone mineral density that does not reach the diagnostic threshold for osteoporosis. Additionally, the occurrence of a prior osteoporotic fracture significantly elevates the risk of subsequent fractures, with the highest risk observed within the first 2 years following the initial event. These considerations highlight the critical importance of implementing effective strategies to prevent further bone loss and mitigate fracture risk in postmenopausal women 6, 7. The current Cochrane review assessed alendronate 10 mg/day for fracture prevention in postmenopausal women. In secondary prevention, alendronate likely reduces clinical vertebral fracture risk and also of nonvertebral, hip, and wrist fractures. In primary prevention, it may reduce risk of vertebral and nonvertebral fractures, though effects on hip and wrist fractures remain uncertain. Serious adverse events did not differ significantly from placebo, and no cases of osteonecrosis of the jaw or atypical femoral fractures were reported 1. Current clinical guidelines recommend bisphosphonates, including alendronate, as first-line therapy for the management of postmenopausal osteoporosis. The National Osteoporosis Guideline Group (NOGG) 2024 advises prescribing oral alendronate (70 mg weekly or 10 mg daily) for at least 5 years, followed by reassessment of fracture risk, with longer treatment durations recommended in women over 70 years or those with prior fragility fractures, ongoing glucocorticoid therapy, or new fractures during treatment 6. The Bone Health and Osteoporosis Foundation (BHOF) 2022 similarly recommends alendronate as a front-line agent, citing its ability to reduce spine and hip fracture risk by about 50% over 3 years in patients with prior fractures 7. Meanwhile, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), in collaboration with the International Osteoporosis Foundation (IOF), considers alendronate among the preferred agents for women at high fracture risk, particularly those with a recent fragility fracture, and supports its use in sequential regimens following anabolic therapy 8. From a rehabilitation perspective, these findings underscore the importance of integrating pharmacological interventions like alendronate into comprehensive management plans for postmenopausal women at risk of osteoporotic fractures. Preventing initial and subsequent fractures is crucial to maintaining functional independence and reducing the burden on rehabilitation services. However, the modest benefits observed in primary prevention highlight the need for individualized risk assessment, considering factors such as bone mineral density, age, prior fracture history, and fall risk 1, 6-8. In addition to pharmacotherapy, nonpharmacological strategies are integral to osteoporosis management and rehabilitation. Exercise programs focusing on weight-bearing and resistance training can improve bone density and reduce fall risk 9. Fall prevention measures, including home safety assessments and balance training, are essential components of a holistic approach. Nutritional support, ensuring adequate calcium and vitamin D intake, further complements these interventions 6, 7, 10-12. It has been confirmed that the author is solely responsible for the preparation of this article. The author thanks Cochrane Rehabilitation and Dr. Silvia Minozzi for reviewing the contents of the Cochrane Corner. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Sina Arman (Sun,) studied this question.