Influence of bisphosphonate pretreatment on bone mineral density gains and fracture outcomes with teriparatide: A systematic review and meta-analysis.

Abstract

Teriparatide is a potent anabolic therapy for osteoporosis and is frequently prescribed after prior bisphosphonate (BP) treatment in routine clinical practice. Whether such pretreatment alters teriparatide efficacy, particularly with respect to fracture outcomes, remains uncertain. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines (PROSPERO: CRD420251234859). PubMed/MEDLINE, Embase, and Scopus were searched from inception to November 30, 2025. Randomized trials, non-randomized trials, observational studies, and post hoc or subgroup analyses comparing teriparatide efficacy in BP-pretreated versus BP-naïve individuals were included. Outcomes included percentage change in areal bone mineral density (BMD) at the lumbar spine, hip, and femoral neck, and incident fractures. Random-effects models with Hartung-Knapp adjustment were used. Fifteen studies involving 8,763 BP-pretreated and 7,071 BP-naïve individuals were analysed. Prior BP exposure was associated with a significantly smaller increase in lumbar spine BMD following teriparatide (mean difference [MD] -2.21%; 95% CI -4.17,-0.25; p = 0.027). No significant differences were observed at the hip (MD -0.88%; 95% CI -1.98,0.19; p = 0.108) or femoral neck (MD -0.52%; 95% CI -1.36,0.33; p = 0.230). Pooling of absolute fracture events suggested a higher fracture risk in BP-pretreated patients (OR 1.43; 95% CI 1.09,1.88; p = 0.009), whereas pooled adjusted hazard ratios did not show a statistically significant difference (HR 1.35; 95% CI 0.99,1.83; p = 0.055). Prior bisphosphonate exposure is associated with modest, site-specific attenuation of lumbar spine BMD gains with teriparatide, without significant effects at non-spinal sites. Available fracture data remain inconclusive and adjusted analyses, albeit based on only two studies, do not indicate a clear attenuation of fracture protection. Prior bisphosphonate exposure may attenuate teriparatide response, but its clinical relevance is unclear. In this meta-analysis, lumbar spine BMD gains were modestly reduced, while hip/femoral neck BMD and adjusted fracture outcomes were not significantly affected. These findings support the continued use of teriparatide either before or after bisphosphonates when clinically indicated.