Background: Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this preplanned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture.
Methods: Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture.
Results: Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups, respectively (p = 0.009).
Conclusions: Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.
Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
1Faculty of Medicine & Surgery, University of Verona, P. le Scuro 10, 37134, Verona, Italy
2Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320
3Bone Research Unit, Department of Experimental Medicine, Leuven University, Herestraat 49, B-3000 Leuven, Belgium
4San Francisco Coordinating Center, California Pacific Medical Center Research Institute and University of California, 158 Berry Street, San Francisco, CA 94107
5Department of Medicine, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032
6Department of Orthopedic Surgery, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: Lanej@HSS.edu
* The data and manuscript were discussed and reviewed throughout by the whole FREEDOM fracture-healing writing group. The listed authors were those who contributed most to the analysis of the data and preparation of the manuscript. FREEDOM fracture-healing writing group: Jonathan D. Adachi, Mohit Bhandari (McMaster University, Hamilton, Ontario, Canada); Silvano Adami (University of Verona, Verona, Italy); Steven Boonen (Bone Research Unit, Department of Experimental Medicine, Leuven University, Leuven, Belgium); Steven R. Cummings (San Francisco Coordinating Center, California Pacific Medical Center Research Institute and University of California, San Francisco, San Francisco, California); Luiz de Gregorio (Center for Clinical and Basic Research, Rio de Janeiro, Brazil); Nigel Gilchrist (Health Care of Elderly, The Princess Margaret Hospital, Christchurch, New Zealand); Pei-Ran Ho, Cesar Libanati, Andrea Wang (Amgen, Thousand Oaks, California); Joseph Lane (Hospital for Special Surgery, New York, NY); George Lyritis (Laboratory for the Study of Musculoskeletal System, Athens, Greece); Gerd Möller (Amgen [Europe] GmbH, Zug, Switzerland); Santiago Palacios (Instituto Palacios, Salud y Medicina de la Mujer, Madrid, Spain); Karel Pavelka (Institute of Rheumatology, Charles University Prague, Prague, Czech Republic); Heinrich Resch (St. Vincent Hospital Vienna, Medical University of Vienna, Vienna, Austria); Christian Roux (Paris Descartes University, Paris, France); Ethel Siris (Department of Medicine, Columbia University Medical Center, New York, NY); and Daniel Uebelhart (Valmont, Private Rehabilitation Clinic, Glion-sur-Montreux, Switzerland).