Menopausal hormone therapy combined with antiresorptive therapy for skeletal outcomes in postmenopausal women: a systematic review and network meta-analysis of randomized controlled trials.

Abstract

Importance: Postmenopausal bone loss is a major contributor to osteoporosis, fracture-related morbidity, loss of independence, and mortality. Although systemic menopausal hormone therapy (MHT), antiresorptive therapy, and combination regimens improve bone mineral density (BMD), their comparative skeletal benefits and safety profiles remain incompletely defined.

Objective: The study aims to compare the therapeutic and preventive skeletal effects of systemic MHT, antiresorptive therapy, and combined MHT plus antiresorptive therapy on site-specific BMD, fracture outcomes, and selected safety outcomes in postmenopausal women.

Evidence review: PubMed, Embase, Scopus, and the Cochrane Library were searched from database inception until April 14, 2026, for randomized controlled trials evaluating systemic MHT, bisphosphonate therapy, calcitonin therapy, or MHT combined with antiresorptive therapy in postmenopausal women. Eligible comparators included placebo, no active bone-specific therapy, or another eligible randomized treatment arm. Study selection and data extraction were performed using predefined eligibility criteria and standardized extraction forms. Treatment effects were synthesized using frequentist random-effects network meta-analysis.

Findings: Sixteen randomized controlled trials, including 2,861 postmenopausal women, were included. Compared with control, all active treatment nodes were associated with greater increases in lumbar spine BMD. The largest estimates were observed for MHT plus calcitonin therapy (mean difference [MD], 12.24%; 95% CI, 7.46-17.01) and MHT plus bisphosphonate therapy (MD, 9.71%; 95% CI, 6.99-12.42), although calcitonin-based estimates were informed by limited evidence. Across hip-region outcomes, MHT plus bisphosphonate therapy showed the most favorable BMD profile, including at the femoral neck (MD, 4.87%; 95% CI, 2.66-7.07) and femoral trochanter (MD, 6.65%; 95% CI, 5.12-8.17). MHT alone and MHT plus bisphosphonate therapy were associated with higher risks of mastalgia and vaginal spotting or bleeding. MHT plus bisphosphonate therapy was associated with a lower risk of any fracture compared with control (risk ratio, 0.51; 95% CI, 0.28-0.93), but fracture events were sparse and were often not prespecified efficacy outcomes.

Conclusions and relevance: In postmenopausal women, systemic MHT, bisphosphonate therapy, and their combination improved BMD compared with control. Combination MHT plus bisphosphonate therapy showed the most favorable hip-region BMD profile; however, current evidence is insufficient to establish superior fracture prevention or long-term safety.