Comparative efficacy of teriparatide and bisphosphonates or denosumab vs. teriparatide monotherapy in osteoporosis: a meta-analysis

Abstract

Introduction: Teriparatide (TPTD), a widely used bone-promoting drug in osteoporosis (OP) treatment, may cause compensatory bone resorption with long-term monotherapy (>6 months). Combining TPTD with anti-bone resorption drugs (e.g., bisphosphonates and denosumab) could reduce bone loss, yet existing randomised controlled trials (RCTs) remain inconclusive regarding their effects on bone mineral density (BMD) and bone turnover markers (BTMs). This study aimed to systematically evaluate the effect of TPTD combined with bisphosphonates or denosumab on BMD and fracture risk in OP patients, compared with TPTD monotherapy.

Methods: PubMed, Embase, Cochrane Library, and Web of Science databases (until March 2025) were searched for RCTs comparing TPTD monotherapy with combination therapy. Primary outcomes included vertebral/non-vertebral fracture risk reduction and BMD changes (lumbar spine, femoral neck, hip); secondary outcomes covered BTM variations and adverse events.

Results: Eight RCTs (n = 787) were meta-analysed using Review Manager 5.4. Results showed: ① No significant differences in vertebral (OR = 0.93, 95%CI 0.12-6.93) or non-vertebral fractures (OR = 0.68, 0.31-1.46) between groups. ② TPTD combined with denosumab significantly increased lumbar spine (+3.40%, 0.44-6.36), femoral neck (+4.00%, 1.96-6.04), and hip BMD (+4.25%, 3.20-5.29). Bisphosphonate combinations improved hip BMD in the short term (<24 months: +1.81%, 0.65-2.97) but not long-term (≥24 months).③ Combination therapies regulated BTMs bidirectionally: bisphosphonates suppressed P1NP (40%-80% reduction vs. monotherapy), while denosumab preserved OC levels (-8-16% vs. monotherapy).④ Safety profiles were comparable: hypercalcemia incidence (16.3% vs. 14.7%, OR = 1.22, 0.55-2.69), musculoskeletal pain (9.8% overall), with no osteonecrosis cases reported.

Conclusion: TPTD-denosumab combination is clinically preferable for BMD enhancement, though its long-term (>24 months) fracture risk reduction requires further validation.

Keywords: bisphosphonates; bone mineral density; bone turnover markers; denosumab; meta-analysis; osteoporosis; teriparatide monotherapy; vertebral fractures.

FIGURE 1

Document extraction and risk assessment map. (A) Literature screening flow chart; (B) Integrated migration map for quality assessment of included studies, “+” low-risk, “?” Unknown-risk, “-” high-risk; (C) Included study quality evaluation bias risk bar chat.

FIGURE 2

Forest map of fracture occurrence and growth rate of lumbar spine. (A) Forest map of vertebral fracture incidence (values <1 favor experimental group), (B) Forest map of non-vertebral fracture incidences (values <1 favor experimental group), (C) Forest map of lumbar spine bone mineral density (BMD) growth rate. Directionality note: Positive values indicate higher BMD gain in experimental group compared to control; The diamond/square position reflects the magnitude of BMD growth rate (left side represents smaller growth, right side represents larger growth).

FIGURE 3

Forest map of BMD growth rate subgroup analysis in lumbar spine. (A) Subgroup analyses according to treatment duration, (B) Subgroup analysis based on antiresorptive drug types. Directionality note: Positive values indicate experimental group superiority; Marker position corresponds to growth magnitude (left = smaller, right = larger).

FIGURE 4

Forest map of BMD growth rate subgroup analysis in the neck of femur. (A) Forest map of BMD growth rate in the neck of femur, (B) Sensitivity analysis of forest map after removing Finkelstein JS’s study, (C) Subgroup analyses according to treatment duration. Directionality annotation: Rightward values denote greater BMD improvement in experimental group; Plot position indicates effect size magnitude.

FIGURE 5

Forest plot of femoral neck BMD growth rate subgroup analysis and hip BMD growth rate. (A) Subgroup analysis of femoral neck BMD based on the type of antiresorptive drugs, (B) Forest map of the growth rate of neck of femur BMD, (C) Subgroup analysis of hip BMD based on treatment duration. Interpretation guidance: Positive standardized mean differences favor experimental intervention; Left-side positioning of markers indicates relatively smaller growth effects.

FIGURE 6

Forest plot of hip BMD subgroup analysis and sensitivity analysis. (A) Subgroup analysis of hip BMD based on the type of antiresorptive drugs, (B) Sensitivity analysis after removing Muschitz C’s study, (C) Sensitivity analysis after removing Finkelstein JS’s study. Directional reference: Right of unity line = experimental group advantage; Horizontal marker placement reflects effect size gradation.

FIGURE 7

Adverse events. (A) Forest map of adverse events (values <1 favor experimental group), (B) Subgroup analysis of hypercalcemia, (C) Inverted funnel diagram of adverse event statistics.