Fracture Healing Appears Unaffected by Denosumab

Troy Brown

December 10, 2012

Denosumab (Prolia, Amgen, Inc) does not appear to delay fracture healing or cause other complications when given at or near the time of fracture in postmenopausal women with osteoporosis, according to a study published in the December issue of the Journal of Bone & Joint Surgery.

Silvano Adami, MD, PhD, head of the Rheumatologic Rehabilitation Unit at the University of Verona in Italy, and colleagues analyzed data from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial, a previously published 3-year, international, randomized, double-blind, placebo-controlled study of the effect of denosumab on the risk for fracture in postmenopausal women with osteoporosis. Women were included in the current study if they sustained a nonvertebral fracture during the FREEDOM study.

Denosumab is a fully human monoclonal antibody that reduces bone resorption by inhibiting the formation, function, and survival of osteoclasts.

Participants were randomly assigned to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every 6 months for 3 years. The researchers compared complications associated with all nonvertebral fractures that were sustained during the study.

At least a single dose of study treatment was given to 7762 participants (3886 in the denosumab group and 3876 in the placebo group). A total of 667 participants (303 in the denosumab group and 364 in the placebo group) experienced a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group).

Among those who experienced nonvertebral fractures, 58 (23 in the denosumab group and 35 in the placebo group) experienced at least 2 nonvertebral fractures in different clinical events.

No specific pattern was observed for the occurrence of nonvertebral fractures in the treatment group with regard to the timing of denosumab administration.

Nonvertebral fractures occurred within 6 weeks before or after denosumab administration in 123 participants (146 fractures) or 38% in the denosumab group. Of those fractures, 25 occurred within 1 week before or after denosumab administration, with 4 taking place 1 day before or after administration.

Two participants in the denosumab group and 5 in the placebo group experienced delayed healing, defined as incomplete fracture healing 6 months after the fracture. In 1 of the 2 patients in the denosumab group who experienced delayed fracture healing, the fracture occurred 7 weeks after denosumab administration, and in the other patient, the fracture occurred 16 weeks after administration. In the group that received placebo, delayed fracture healing occurred between 13 and 19 weeks after receiving placebo.

Nonunion was found in no participants in the treatment group and 1 participant in the placebo group.

The nonunion was found during additional follow-up of a humeral fracture.

Fracture-Associated Complications

Overall, fewer fractures occurred in the denosumab group than in the placebo group. In the denosumab group, the most commonly fractured sites were the wrist (127 fractures), humerus (42 fractures), rib (41 fractures), foot (36 fractures), and hip (29 fractures). In the placebo group, fractures happened most often in the wrist (152 fractures), humerus (49 fractures), hip (45 fractures), foot (42 fractures), and rib (35 fractures).

Surgery was performed on 79 fractures (in 65 participants) in the denosumab group and 120 fractures (in 100 participants) in the placebo group, with most surgeries performed on fractures of the wrist, hip, and humerus.

Among those who experienced a nonvertebral fracture during the study, 5 (2%) in the denosumab group and 20 (5%) in the placebo group experienced a complication related to the fracture or its treatment (P = .009). The complication types and incidence rates were typical of those observed in clinical practice, and incidences were similar between the 2 groups. None of these 25 participants experienced more than a single nonvertebral fracture during the study.

Complications from infection occurred in 2 (0.7%) participants in the denosumab group and 4 (1.1%) participants in the placebo group.

Steven J. Morgan, MD, an orthopedic surgeon at Mountain Orthopaedic Trauma Surgeons at Swedish in Englewood, Colorado who was not involved in the research, commented on the study in an email interview with Medscape Medical News.

This study provides a potential opportunity to start osteoporosis care in postmenopausal women at the time of fracture treatment, with the potential for immediate effect on the prevention of future osteoporosis-related fractures, Dr. Morgan explained.

"Not only can the patient's acute fracture be cared for immediately, the patient can potentially be administered a medication without fear that it will inhibit healing of the new fracture and potentially diminish the risk of another fracture in [the] future," Dr. Morgan noted.

He also said that studies that examine ways of preventing or diminishing fractures in patients with osteoporosis or patients at risk for osteoporosis are important.

"The study suggests for patients already being treated with this drug...nonvertebral fractures are not at increased risk for complications of healing. It further suggests that treatment for osteoporosis can be initiated early in this population [to] potentially prevent future fractures. This can significantly impact quality of life for these patients and diminish potential future healthcare costs," Dr. Morgan stated.

Dr. Adami has received a consulting fee or honorarium from Amgen and Merck Sharp & Dohme and has received other financial support from Amgen, Merck Sharp & Dohme, Roche, and Eli Lilly. Full conflict-of-interest information is available on the journal's Web site. Dr. Morgan has disclosed no relevant financial relationships.

J Bone Joint Surg Am. 2012;94:2113-2119. Abstract

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