Bisphosphonates for Secondary Prevention of Osteoporotic Fractures: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.

To investigate the comparative efficacies of the five most commonly used bisphosphonates for the secondary prevention of osteoporotic fractures in a Bayesian network meta-analysis. Five databases and the reference lists of all acquired articles from inception to July 2017 were searched. A Bayesian random-effects model was employed, and vertebral, hip and nonvertebral nonhip fractures were assessed by odds ratios (ORs) and 95%credible intervals. Furthermore, with respect to each endpoint, rank probabilities for each bisphosphonate were evaluated using the surface under the cumulative ranking curve (SUCRA) value. Thirteen eligible studies were identified involving 11,822 patients with osteoporotic fractures. Overall in the pairwise meta-analyses, bisphosphonate use significantly reduced the risk of new vertebral, hip, and nonvertebral nonhip fractures, with ORs and 95% confidence intervals of 0.56 (0.49-0.64), 0.69 (0.48-0.98), and 0.82 (0.70-0.97), respectively. In network meta-analyses, significant differences were found between placebo and any one of the five bisphosphonates for new vertebral fractures. The rank probability plot and the SUCRA calculation results suggested that alendronate was the best intervention (14.6%) for secondary prevention of vertebral fractures, followed by zoledronate (15.3%) and etidronate (22.1%). In terms of the incidence of new hip fractures, alendronate was associated with the lowest incidence (18.5%), followed by zoledronate (43.1%) and risedronate (52.5%). However, zoledronate ranked lowest (16.6%) regarding the incidence of new nonvertebral nonhip fractures, followed by risedronate (23.8%) and alendronate (44.1%). Bisphosphonates show significant efficacy for secondary prevention of new vertebral fractures, and alendronate is most likely to be successful at secondary prevention of vertebral and hip fractures compared with the other four bisphosphonates.

Shi L ，Min N ，Wang F ，Xue QY ... -  《-》

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》

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》

Etidronate 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. 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). 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. 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. 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. 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. 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. 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.

Wells GA ，Hsieh SC ，Peterson J ，Zheng C ，Kelly SE ，Shea B ，Tugwell P ... -  《Cochrane Database of Systematic Reviews》

Bisphosphonates for steroid-induced osteoporosis.

Allen CS ，Yeung JH ，Vandermeer B ，Homik J ... -  《Cochrane Database of Systematic Reviews》