Effectiveness of anabolic and anti-resorptive agents for preventing postmenopausal osteoporosis fractures: a systematic review and network meta-analysis.

BACKGROUND

While anabolic agents are highly effective in stimulating bone formation, their benefits are transient and tend to plateau after prolonged use. This necessitates a transition to anti-resorptive therapies. We aimed to estimate anti-osteoporosis effect and compliance of different anabolic and anti-resorptive agents to explore the optimal cycling strategy.

METHODS

PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials comparing anabolic or anti-resorptive agents with placebo or each other in postmenopausal women with osteoporosis or osteopenia, reporting outcomes on bone mineral density (BMD) change, fracture incidence, or treatment discontinuation from inception to February 1, 2024. The frequentist random-effect model for network meta-analysis was performed to summarize the evidence, and the Grading of Recommendations Assessment, Development, and Evaluation frameworks was applied to rate the certainty of evidence.

RESULTS

A total of 16,231 citations were identified, and 227 trials with 140,230 participants met the inclusion criteria. The anti-sclerostin (AS) antibody was the most effective anabolic agent, significantly increasing BMD at the femoral neck (Mean difference (MD): 6.00; 95% confidence interval (CI): 3.34-8.66) and spine (MD: 13.30; 95% CI: 9.15-17.45), and reducing spine and hip fracture risk (OR: 0.27; 95% CI: 0.15-0.47) at 12 months without a significant increase in discontinuation (OR: 0.88; 95% CI: 0.57-1.35) compared to placebo. Among anti-resorptive agents, the anti-RANKL (AR) antibody showed the greatest efficacy, improving BMD at the femoral neck (12 m: MD: 2.50, 95% CI: 0.96 to 4.05; 24 m: MD: 3.58, 95% CI: 0.83 to 6.34; 36 m: MD: 5.67, 95% CI: 2.61 to 8.74) and spine (12 m: MD: 5.26, 95% CI: 4.00 to 6.53; 24 m: MD: 7.46, 95% CI: 4.89 to 10.04; 36 m: MD: 9.49, 95% CI: 6.60 to 12.38), while reducing fracture risk (12 m OR: 0.41; 24 m OR: 0.22; 36 m OR: 0.33), with no significant difference in discontinuation (OR: 1.13; 95% CI: 0.96-1.33) compared to placebo. Other agents such as bisphosphonates, parathyroid hormone analogues, and selective estrogen receptor modulators showed moderate benefits with varying tolerability profiles.

CONCLUSIONS

This study identified anti-sclerostin antibody as the most effective anabolic agent for rapid BMD gains and early fracture prevention, followed by anti-RANKL antibody as the most effective anti-resorptive agent for long-term maintenance. This sequential anabolic-to-anti-resorptive therapy may inform treatment guidelines for high-risk postmenopausal populations. Future research should focus on head-to-head trials comparing treatment sequences, long-term safety beyond 36 months, and outcomes in diverse racial or age subgroups. Limitations include potential heterogeneity in study populations and treatment protocols, and limited long-term safety data.

STUDY REGISTRATION: PROSPEROPROSPERO (CRD42023396110).