Fracture Healing and Commonly Co-Prescribed Medications: Orthopedic Implications in Multimorbid Patients: A Narrative Review

Fracture healing is a biologically complex process influenced not only by mechanical stability and patient-related factors but also by systemic medications commonly prescribed in orthopedic populations. In contemporary practice, many adults sustaining fractures are treated within a broader context of multimorbidity and polypharmacy, raising clinical questions about how commonly co-prescribed drug classes may intersect with biological pathways relevant to bone repair and recovery. However, evidence addressing these relationships remains dispersed across disciplines and is characterized by heterogeneity in study design, exposure definitions, and outcome measures. To contextualize current evidence, we conducted a narrative review of peer-reviewed literature identified primarily through PubMed/MEDLINE, supplemented by manual screening of reference lists from key articles and reviews. The review focused on adult fracture populations and perioperative orthopedic settings and synthesized findings from observational studies, randomized trials, systematic reviews, and meta-analyses examining associations between fracture-related outcomes and medication classes frequently encountered in routine practice. These medication classes were evaluated individually rather than as interacting polypharmacy regimens, while remaining situated within the broader clinical context of multimorbidity and cumulative medication burden. These included analgesics and nonsteroidal anti-inflammatory drugs, systemic corticosteroids, anticoagulants, psychotropic medications, proton pump inhibitors, antidiabetic therapies, and other bone-active agents. Across the literature, several medication classes have been associated with altered fracture-related or skeletal outcomes relevant to orthopedic recovery in specific clinical contexts, although findings were inconsistent and often highly context-dependent. Evidence linking nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and anticoagulant therapies to fracture healing outcomes varied according to drug class, timing and duration of exposure, comorbidity burden, and fracture characteristics. For other commonly prescribed agents, including psychotropic medications, acid-suppressive therapies, and certain antidiabetic drugs, available data largely address fracture risk or bone health rather than fracture union or time to healing, limiting direct inference regarding repair processes. While some mechanisms underlying fracture risk, such as altered bone turnover or impaired bone quality, may overlap with pathways involved in repair, these processes are not biologically equivalent to the coordinated inflammatory, reparative, and remodeling phases of fracture healing and, therefore, require cautious interpretation. Overall, current evidence suggests that fracture healing in adult orthopedic patients frequently occurs within a complex therapeutic landscape shaped by cumulative medication exposure and underlying metabolic and clinical factors. Rather than implicating polypharmacy as a single causal determinant of impaired union, these findings highlight the importance of individualized medication review and interdisciplinary care when managing fractures in patients with multimorbidity. Future research should prioritize prospective designs with standardized, fracture-healing-specific outcomes to better clarify medication-related risks and inform evidence-based orthopedic practice.