In our ongoing attempt to identify pharmacologic interventions that improve fracture healing, the sclerostin inhibitor romosozumab is a logical candidate, as it has been shown to decrease bone resorption, improve bone healing in animal and human studies, and reduce the prevalence of some fragility fractures in postmenopausal women. In the August 19, 2020 issue of The Journal, Bhandari et al. present the results of a randomized trial comparing romosozumab to placebo in the healing of tibial diaphyseal fractures treated with intramedullary (IM) nails. Tibial shaft fractures are common in adults, but even after IM nail fixation there is a significant rate of healing failure and subpar functional outcomes with this fracture type.
The study by Bhandari et al. was very well designed and conducted with high-quality data collection. In terms of the primary outcome—median time to radiographic healing—there was no significant difference between the placebo group (n=100) and 9 romosozumab groups (n=293 total, testing 3 different dose levels and 3 different frequencies). Additionally, analysis revealed no differences between placebo and romosozumab groups in median time to clinical healing or in changes in physical function from baseline. (See related OrthoBuzz post about a recent randomized trial investigating romosozumab for hip fractures.)
Kudos to Amgen for funding the trial and for allowing the 66-center, international academic consortium that conducted it to publish the results, warts and all. Such negative findings appropriately inform decisions about which compounds to investigate and about study designs for retesting the same compounds. For example, Bhandari et al. encourage further study of romosozumab in tibial-fracture patients at high risk of poor fracture healing, such as those with diabetes or patients undergoing treatment with corticosteroids.
We are likely to see many such “failures” in the search for pharmacological adjuncts to improve fracture healing, but it seems our orthopaedic community has laid out a clear roadmap for studying this important question further.
Marc Swiontkowski, MD
We have all come to realize that promising results from lab studies or preclinical trials in animal models do not always translate into meaningful clinical benefits in humans. Yet it is vitally important to perform those human trials to ascertain that knowledge. This is demonstrated by Schemitsch et al. in the April 15, 2020 edition of The Journal. The authors performed a Level I, double-blinded, randomized controlled trial comparing varying doses of romosozumab to placebo in the treatment of older patients with a hip fracture.
Romosozumab is a sclerostin-inhibiting antibody that helps increase bone formation while decreasing resorption. It is indicated to treat osteoporosis in postmenopausal women, in whom the drug has been shown to increase bone mineral density and reduce the risk of fragility fractures. In multiple preclinical studies, romosozumab has increased bone mass and bone strength in rodent osteotomy models, suggesting it might possibly promote fracture healing in people.
In the current study, Schemitsch et al. randomized patients between 55 and 95 years old who had a low-energy hip fracture amenable to internal fixation to receive 3 postsurgical subcutaneous injections of romosozumab at doses of either 70 mg (60 patients), 140 mg (93 patients), or 210 mg (90 patients), or to receive 3 placebo injections (89 patients). The primary end point was the validated “timed Up and Go” (TUG) score. The authors also measured the Radiographic Union Scale for Hip (RUSH) score, and hip pain on a visual analog scale (VAS).
The authors enrolled 325 patients, with 263 (79.2%) reaching the 24-week follow up and 229 (69.0%) reaching the 52-week follow up. They found no statistically significant between-group differences in the TUG, with all patients improving and plateauing at week 20. Similarly, there were no differences between any of the treatment arms in time to radiographic healing, RUSH scores, or VAS. The safety profile of the medication was similar between the 3 romosozumab doses and the placebo.
Romosozumab may increase bone mineral density and reduce the risk of fragility fracture in patients with osteoporosis, but when it comes to helping heal hip fractures, it did not prove to be more advantageous than placebo. This shows, yet again, that what may glitter in animal studies may not necessarily shine like gold in clinical trials with people.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media