REVIEW NSAID Exposure and Risk of Nonunion: A Meta-Analysis of Case–Control and Cohort Studies Emily R. Dodwell • Julius Gene Latorre • Emilio Parisini • Elisabeth Zwettler • Divay Chandra • Kishore Mulpuri • Brian Snyder Received: 10 February 2010 / Accepted: 28 March 2010 / Published online: 15 June 2010 Ó Springer Science+Business Media, LLC 2010 Abstract Nonsteroidal anti-inflammatory drugs (NSA- IDs) are frequently used for postoperative pain control. However, concerns regarding the potential deleterious effects of NSAIDs on bone healing have compelled many physicians to avoid NSAIDs in patients with healing frac- tures, osteotomies, and fusions. We systematically reviewed and analyzed the best clinical evidence regarding the effects of NSAID exposure on bone healing. Medline, Embase, and Cochrane electronic databases were searched for prospec- tive and retrospective clinical studies of fracture, osteot- omy, and fusion studies of patients with NSAID exposure and nonunion as an outcome. Study quality was assessed using the Newcastle–Ottawa Scale. Data on study design, patient characteristics, and risk estimates were extracted. Pooled effect estimates were calculated. Subanalyses were performed by bone type and by NSAID dose, duration, and route of administration. In the initial analysis of 11 cohort and case-control studies, the pooled odds ratio for nonunion with NSAID exposure was 3.0 (95% confidence interval 1.6–5.6). A significant association between lower-quality studies and higher reported odds ratios for nonunion was observed. When only higher-quality studies were consid- ered, seven spine fusion studies were analyzed, and no statistically significant association between NSAID exposure and nonunion was identified (odds ratio = 2.2, 95% confidence interval 0.8–6.3). There was no increased risk of nonunion with NSAID exposure when only the highest-quality studies were assessed. Randomized con- trolled trials assessing NSAID exposure in fracture, fusion, and osteotomy populations are warranted to confirm or refute the findings of this meta-analysis of observational studies. Keywords Nonunion Á NSAIDs Á Meta-analysis Á Bone healing Most fractures heal without incident. However, when bone does not heal, the resulting nonunion is typically painful, difficult, and time-consuming to treat, costly to the health care system, and detrimental to the patient’s quality of life [1]. Many factors have been identified that may affect bone healing. These include patient age, sex, nutritional status, bone quality, diabetes and other endocrine disorders, muscle mass, smoking status, fracture location and pattern, associated injuries, infection, and exposure to radiation and Dodwell, Parisini, Zwettler and Latorre contributed equally to this work. The authors have stated that they have no conflict of interest. E. R. Dodwell Á J. G. Latorre Á E. Parisini Á E. Zwettler Á D. Chandra Harvard School of Public Health, Harvard University, Boston, MA, USA E. R. Dodwell (&) Á K. Mulpuri Department of Orthopaedic Surgery, University of British Columbia, 3114-910 West 10th Avenue, Vancouver, BC V5Z 4E3, Canada e-mail: emilydodwell@yahoo.com B. Snyder Harvard Medical School and Children’s Hospital, Harvard University, Boston, MA, USA E. Zwettler 4th Medical Department and LBI of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Vienna, Austria E. Parisini Center for Nano Science and Technology of ITT at PoliMI, Milan, Italy 123 Calcif Tissue Int (2010) 87:193–202 DOI 10.1007/s00223-010-9379-7