No clear winner among osteoporosis drugs after hip fracture surgery

A systematic review and network meta-analysis found no consistent evidence that any one anti-osteoporosis medication is superior after surgery for a fragility hip fracture. The analysis combined 18 randomized and non-randomized studies involving 2,414 patients and compared re-fracture, hip bone mineral density, Harris Hip Score and pain. Zoledronic acid, denosumab and alendronate produced relatively favorable signals in some early re-fracture comparisons, while teriparatide showed a more favorable pattern for longer-term bone-mass restoration. None of these patterns was consistent across outcomes, and the investigators rated the certainty of evidence as limited, making the rankings contextual rather than a treatment hierarchy.

The review specifically addressed patients who had undergone surgery for a fragility hip fracture, a group that remains vulnerable to subsequent fractures, persistent pain and incomplete functional recovery even after the fracture has been stabilized. The authors searched PubMed, Embase, Web of Science and the Cochrane Library for studies published from January 2015 through April 15, 2026. Eligible interventions included zoledronic acid, denosumab, teriparatide, alendronate, risedronate, a sequence of pre-fracture alendronate followed by postoperative teriparatide, and control regimens based on calcium, vitamin D, placebo or a combination of these.

Seven randomized controlled trials and 11 non-randomized comparative studies met the criteria. The researchers used Bayesian random-effects consistency models to combine direct and indirect evidence, expressing dichotomous outcomes as odds ratios with 95% credible intervals and continuous outcomes as mean differences with the same interval type. Primary outcomes included subsequent hip fracture, fractures at any site and bone mineral density reported either in grams per square centimetre or as T-scores. Harris Hip Score and visual analog scale pain scores were secondary outcomes. Analyses restricted to randomized trials or to exactly 12 months of follow-up were conducted where the available networks permitted them.

For subsequent hip fracture within 12 months, five studies with 599 patients contributed data. Both zoledronic acid and denosumab showed trends toward lower risk than background therapy, and zoledronic acid also showed a trend toward lower risk than teriparatide. For fractures at any site within 12 months, six studies involving 725 patients produced favorable numerical trends for zoledronic acid, denosumab and alendronate against control, as well as several comparisons between active treatments. At 24 months, however, four studies involving 1,072 patients showed no clear differences among zoledronic acid, denosumab, teriparatide and control.

Those re-fracture findings came with substantial statistical and methodological uncertainty. Fractures were uncommon, several treatment comparisons contained no events, and some estimates were so extreme that they were sensitive to the priors used in the model. The credible intervals were correspondingly wide, and alternative prior specifications altered the magnitude of some results. Node-splitting analysis did not detect inconsistency between direct and indirect evidence for the 24-month network, and leave-one-out analyses produced broadly stable findings. Even so, the authors described the risk-reduction results as trends rather than definitive evidence of superiority.

Bone mineral density was likewise characterized by outcome-specific patterns rather than a stable medication advantage. Four randomized studies contributing 301 patients supplied areal density data in grams per square centimetre, while four studies with 368 patients supplied T-score data. Zoledronic acid and teriparatide had relatively favorable numerical rankings in the areal-density analysis, whereas alendronate and teriparatide ranked more favorably by T-score. Neither network showed clear between-treatment differences. The apparent divergence also reflected differences in baseline density, anatomical site, laterality, measurement devices and follow-up periods, which could not be resolved with reliable site-specific analyses.

No clear differences emerged for hip function or pain. Eight studies with 684 patients contributed Harris Hip Score data, and eight studies with 1,074 patients contributed visual analog scale data. The Harris Hip Score analysis showed very high heterogeneity, while heterogeneity for pain scores was also very high. Alendronate had a favorable numerical pattern for Harris Hip Score, and zoledronic acid and denosumab showed favorable patterns for pain, but no comparisons clearly distinguished the treatments. Randomized-only and exact-12-month sensitivity analyses were generally consistent with the primary models. The authors cautioned that these outcomes capture the combined effects of surgery, rehabilitation, analgesia, fracture characteristics and baseline health rather than the isolated action of an osteoporosis drug.

Risk-of-bias assessments reinforced the need for caution. All 11 non-randomized studies were judged to have a high overall risk of bias, with concerns involving participant selection, intervention classification, departures from intended treatment, outcome measurement and selective reporting. Although the non-randomized studies received moderate-to-good scores on a supplementary methodological-quality scale, the randomized trials also had unclear or high risk in some areas of sequence generation, allocation concealment and blinding. The GRADE assessment indicated limited certainty across the outcomes, while publication bias could not be assessed reliably because the networks were small and comparison-adjusted funnel plots were not used.

Treatment timing was another unresolved influence. The interval between fracture or surgery and the start of medication could affect early skeletal recovery and the time available for bone-density gains, particularly when antiresorptive and anabolic therapies are compared. Reporting was too inconsistent to form comparable groups, and the evidence could not support reliable subgroup or network meta-regression analyses. The synthesis also did not systematically evaluate adverse events, treatment discontinuation, adherence, renal considerations or hypocalcemia. As a result, it cannot establish comparative benefit-risk profiles, and the relatively favorable signals for individual drugs should not be read as prescribing advice or as evidence that one treatment should be selected over another.

The central message is that the available evidence does not support a universal ranking of osteoporosis medications after fragility hip fracture surgery. Favorable early re-fracture signals for zoledronic acid, denosumab and alendronate were outcome- and time-specific, whereas teriparatide’s relative pattern for bone-mass restoration emerged over longer follow-up. None of these signals was accompanied by consistent advantages across fracture, density, function or pain outcomes. More rigorous head-to-head randomized trials, standardized outcome measurement, clearly reported treatment timing and systematic assessment of safety and adherence are needed before comparative claims can become more reliable.

Subject of Research: Comparative effects of anti-osteoporosis medications after surgery for fragility hip fracture

Article Title: Effects of different anti-osteoporosis medications on re-fracture risk, bone mineral density, and functional recovery following hip fragility fracture surgery: a systematic review and network meta-analysis

Article References: Tian, J., Zhang, H., Lu, Y., Wu, H., Lu, Y., Yu, D., Yu, L., & Luo, Z. (2026). Effects of different anti-osteoporosis medications on re-fracture risk, bone mineral density, and functional recovery following hip fragility fracture surgery: a systematic review and network meta-analysis. Frontiers in Endocrinology, 17, Article 1949781. https://doi.org/10.3389/fendo.2026.1949781

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1949781

Keywords: fragility hip fracture, osteoporosis, network meta-analysis, anti-osteoporosis drugs, re-fracture prevention, bone mineral density, hip function, postoperative pain, evidence certainty, Effects, different, anti-osteoporosis