Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which 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.
To assess the benefits and harms of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively.
We searched Evidence-Based Medicine Reviews (which includes CENTRAL), MEDLINE, Embase, two trial registers, drug approval agency websites, and the bibliographies of relevant systematic reviews to identify the studies included in this review. The latest search date was 01 February 2023. We imposed no restrictions on language, date, form of publication, or reported outcomes.
We included only randomized controlled trials that assessed the effects of alendronate on postmenopausal women. Targeted participants must have received at least one year of alendronate. We classified a study as secondary prevention if its population met 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 lower), and 75 years old or older. If a study population met none of those criteria, we classified it as a primary prevention study.
Our major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events.
We used the Cochrane risk of bias 1 tool.
We used standard methodological procedures expected by Cochrane. Based on the previous review experience, in which the clinical and methodological characteristics in the primary and secondary prevention studies were homogeneous, we used a fixed-effect model for meta-analysis and estimated effects using the risk ratio (RR) for dichotomous outcomes. Our base case analyses included all eligible placebo-controlled studies with usable data. We selected the data available for the longest treatment period. We consider a relative change exceeding 15% as clinically important.
We included 119 studies, of which 102 studies provided data for quantitative synthesis. Of these, we classified 34 studies (15,188 participants) as primary prevention and 68 studies (29,577 participants) as secondary prevention. We had concerns about risks of bias in most studies. Selection bias was the most frequently overlooked domain, with only 20 studies (19%) describing appropriate methods for both sequence generation and allocation concealment. Eight studies (8%) were at low risk of bias in all seven domains.
The base case analyses included 16 primary prevention studies (one to five years in length; 10,057 women) and 20 secondary prevention studies (one to three years in length; 7375 women) which compared alendronate 10 mg/day (or 70 mg/week) to placebo, no treatment, or both. Indirectness, imprecision, and risk of bias emerged as the main factors contributing to the downgrading of the certainty of the evidence. For primary prevention, alendronate may lead to a clinically important reduction in clinical vertebral fractures (16/1190 in the alendronate group versus 24/926 in the placebo group; RR 0.45, 95% confidence interval [CI] 0.25 to 0.84; absolute risk reduction [ARR] 1.4% fewer, 95% CI 1.9% fewer to 0.4% fewer; low-certainty evidence) and non-vertebral fractures (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). However, clinically important differences were not observed for the following outcomes: hip fractures (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); wrist fractures (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); withdrawals 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); and 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). For secondary prevention, alendronate probably results in a clinically important reduction in clinical vertebral fractures (24/1114 in the alendronate group versus 51/1055 in the placebo group; RR 0.45, 95% CI 0.28 to 0.73; ARR 2.7% fewer, 95% CI 3.5% fewer to 1.3% fewer; moderate-certainty evidence). It may lead to a clinically important reduction in non-vertebral fractures (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); hip fractures (RR 0.49, 95% CI 0.25 to 0.96; ARR 1.0% fewer, 95% CI 1.5% fewer to 0.1% fewer; low-certainty evidence); wrist fractures (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); and 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). However, the effects of alendronate for withdrawals due to adverse events are 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). Furthermore, the updated evidence for the safety risks of alendronate suggests that, irrespective of participants' risk of fracture, alendronate may lead to little or no difference for gastrointestinal adverse events. Zero incidents of osteonecrosis of the jaw and atypical femoral fracture were observed.
For primary prevention, compared to placebo, alendronate 10 mg/day may reduce clinical vertebral and non-vertebral fractures, but it might make little or no difference to hip and wrist fractures, withdrawals due to adverse events, and serious adverse events. For secondary prevention, alendronate probably reduces clinical vertebral fractures, and may reduce non-vertebral, hip, and wrist fractures, and serious adverse events, compared to placebo. The evidence is very uncertain about the effect of alendronate on withdrawals due to adverse events.
This Cochrane review had no dedicated funding.
This review is an update of the previous review (DOI: 10.1002/14651858.CD001155).
Wells GA
，Hsieh SC
，Peterson J
，Zheng C
，Kelly SE
，Shea B
，Tugwell P
... -
《Cochrane Database of Systematic Reviews》
Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis.
Bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women.
To assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs).
We identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.
We included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases.
Two review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings.
Forty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options). Bone mineral density We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty). Quality of life No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined. Overall fracture rate We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty). Overall survival We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty). Osteonecrosis of the jaw We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty). Renal impairment We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty).
When considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.
Adams A
，Jakob T
，Huth A
，Monsef I
，Ernst M
，Kopp M
，Caro-Valenzuela J
，Wöckel A
，Skoetz N
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
