Bisphosphonates and the RANK ligand inhibitor denosumab have profound effects on bone resorption, and there is an ongoing theoretical concern that antiresorptive agents potentially impair fracture-healing. In the report by Adami et al., complications of nonvertebral fracture-healing among women in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every Six Months) trial were evaluated with the intention to address the risk of delayed fracture-healing in patients receiving denosumab.
In this study, delayed fracture-healing was defined prospectively as incomplete healing by six months after the fracture. Thirty-eight percent of the 386 nonvertebral fractures in the denosumab group occurred within six weeks before or after administration of a scheduled denosumab dose. Among the fracture cases occurring during this twelve-week period, twenty-five occurred within one week before or after a denosumab dose. Delayed fracture-healing was reported in seven cases, two in the denosumab group and five in the placebo group. Notwithstanding the definition of delayed fracture-healing used in this study, the exact length of time required for healing was not determined, and thus the effect of denosumab versus the placebo within the six-month window is unknown. Nevertheless, the data presented do not suggest an increased risk of delayed fracture-healing with denosumab.
Orthopaedic surgeons have an ideal opportunity to address underlying osteoporosis in patients with nonvertebral fractures. This study suggests that those patients receiving denosumab within six weeks prior to the fracture are not at increased risk for impaired fracture-healing, and that denosumab can likely be continued, unless for other reasons the incident fracture is considered to be a treatment failure. For treatment-naïve patients, denosumab could be considered for timely treatment soon after the fracture. However, the ability to use denosumab (or another agent) with apparent impunity early after a fracture does not obviate the requirement for evaluation of underlying metabolic bone disease with priority given first to treatment of secondary medical problems. Early administration of denosumab (or another agent) should be accompanied by modification of dietary and behavioral contributors to bone loss, weaning the patient off of or substitution of bone-wasting medications if possible, as well as investigation of the underlying mechanism(s) of injury. These recommendations are consistent with performance measures suggested by medical organizations, including the American Orthopaedic Association1.
Growing evidence from clinical studies suggests that other available agents for the treatment of osteoporosis have negligible or neutral effects on fracture-healing. Early initiation of bisphosphonate treatment after a fracture appears not to influence clinical or radiographic outcomes2,3. The anabolic agent teriparatide similarly has no deleterious effects on fracture-healing and may in fact promote fracture-healing4,5.
In summary, available evidence indicates that clinical action with use of pharmacologic interventions for osteoporosis in the setting of an acute fracture should not be delayed on the basis of uncertainty regarding impaired fracture-healing. However, the convenience of administering a medication for osteoporosis as soon as possible after a fracture should not be substituted for a prior work-up for underlying contributors of metabolic bone disease and mechanisms of injury.
Disclosure: The author received no payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. Neither the author nor his institution has had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, the author has not had any other relationships, or engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.