NSAID Use and Bone Healing: An Umbrella Review with a Reconstructed Meta-Analysis.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for perioperative analgesia, but effect on bone healing remains controversial. This umbrella review and reconstructed meta-analysis assessed whether NSAIDs impair bone healing and how risk varies by population, fracture type, dose, and duration. We conducted an umbrella review of systematic reviews/meta-analyses and a reconstructed meta-analysis of primary studies (PRIOR/PRISMA-compliant; PubMed, EMBASE, Web of Science, and Scopus to 9 November 2025). Two reviewers independently screened, extracted, and assessed quality (AMSTAR-2) and risk of bias. Overlapping cohorts were removed, and random-effects models were applied. Prespecified subgroups included age, clinical context (traumatic vs elective procedures), bone type (long bones vs spine), dose, and exposure duration (≤14 days). Sixteen reviews (10 meta-analyses, six systematic reviews) were included; most suggested that NSAIDs increase impaired bone healing risk, particularly with higher doses or prolonged use, with minimal signal for short, low-dose perioperative regimens, especially in spinal fusion. Quality was low/critically low. The meta-analysis pooled 38 primary studies. NSAID exposure was associated with higher nonunion risk (OR, 1.56, 95% CI, 1.18 to 2.11), but not clearly with delayed union (OR, 1.58, 95% CI, 0.65 to 3.67). Risk increased in adults (OR, 1.67, 95% CI, 1.25 to 2.47) but not in pediatric patients (OR 0.77, 95% CI 0.58 to 1.02), was higher in long-bone fractures than in spinal fusion, trended upward with higher doses, and was not elevated with short-term (≤14 days) use. Risk also differed by clinical context, higher in traumatic versus elective procedures. NSAID-related impairment of bone healing seems dose and context-dependent, with clinically important risk particularly in adults, long-bone fractures, and higher dose regimens. Short-term use (≤14 days) was not associated with increased nonunion risk. Risk seemed higher in traumatic fractures than in elective procedures. These findings support caution in higher risk scenarios, suggesting that short-duration NSAID use may be safe when avoiding higher dose exposure.