Understanding Bone Healing and Denosumab's Role
Fracture healing is a complex biological process that typically occurs in three overlapping phases: the inflammatory phase, the reparative phase, and the remodeling phase. It is the last phase, remodeling, where denosumab's primary effects are observed. As an anti-resorptive agent, denosumab works by binding to RANKL, a protein essential for the formation and function of osteoclasts, which are the cells responsible for breaking down bone tissue. By inhibiting osteoclast activity, denosumab effectively suppresses bone resorption.
Denosumab and the Normal Fracture Healing Process
The initial phases of fracture healing—inflammation and soft callus formation—rely heavily on anabolic processes rather than bone resorption, so denosumab has minimal impact here. The reparative phase involves the formation of a soft callus, which is then gradually converted into a hard, bony callus. Because denosumab's main action is to inhibit the bone resorption performed by osteoclasts, its effects are most pronounced during the final remodeling stage. By suppressing osteoclast activity, denosumab leads to an accumulation of bone mass, including a larger and denser fracture callus, while delaying the rate of its remodeling.
The FREEDOM Trial and Nonvertebral Fractures
The most substantial evidence regarding denosumab's effect on fracture healing comes from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. This landmark placebo-controlled study, involving over 7,800 postmenopausal women, specifically evaluated whether denosumab affected the healing of nonvertebral fractures that occurred during the trial.
- No Interference with Healing: The analysis found no evidence that denosumab delayed healing or contributed to complications related to nonvertebral fractures or their management.
- Low Rates of Complications: Complications associated with fractures were less frequent in the denosumab group compared to the placebo group.
- Early Administration Safe: The study also noted that initiating denosumab therapy near the time of a fracture did not appear to cause complications.
This evidence has helped to allay theoretical concerns that suppressing bone turnover could impede fracture repair in patients receiving denosumab for osteoporosis.
Comparative Effectiveness vs. Bisphosphonates
Recent clinical studies have compared denosumab directly with bisphosphonates regarding their effect on fracture healing, with findings suggesting that denosumab does not delay healing compared to these other standard-of-care medications. A January 2025 study comparing early denosumab versus ibandronate administration after femoral intertrochanteric fracture surgery found no statistically significant difference in radiological or clinical fracture healing times at three months.
| Feature | Denosumab (Prolia®) | Bisphosphonates (e.g., Alendronate) |
|---|---|---|
| Mechanism | Targets and inhibits RANKL, a protein crucial for osteoclast formation and function. | Inhibits osteoclast activity and induces apoptosis (cell death) of osteoclasts. |
| Effect on Remodeling | Potently suppresses osteoclast activity, which delays the remodeling phase. | Suppresses osteoclast activity, but some evidence suggests denosumab has a greater and more continuous effect on cortical bone over the long term. |
| Effect on Fracture Healing | Multiple studies show no delay in the early phases of healing; may increase callus volume and density. | Generally considered not to negatively influence fracture healing, especially for typical osteoporotic fractures. |
| Potential for Non-Union | Repurposed for non-union cases in higher doses (120mg), showing promising results in small case studies. | No evidence suggesting it can reverse non-union; has shown comparable healing rates to denosumab in some studies. |
| Long-Term Effects on Cortical Bone | Can lead to increased cortical thickness and density over longer treatment periods (up to 10 years). | Long-term use may cause the rate of BMD improvement to diminish over time. |
| Discontinuation Effect | Associated with a rapid rebound in bone turnover and increased risk of vertebral fractures if treatment is stopped. | No significant rebound effect on bone turnover upon discontinuation; effects persist longer than denosumab. |
Repurposing Denosumab for Impaired Healing
In rare cases of impaired fracture healing, especially recalcitrant non-unions, denosumab has been repurposed at higher doses (120 mg monthly for 3 months) to promote union. A case series of three patients showed that this off-label use was effective in increasing callus volume and density, bridging the fracture gap and leading to successful union. This application leverages denosumab's effect of inhibiting osteoclasts to allow bone-forming osteoblasts to dominate the local environment, thereby enhancing mineralization at the fracture site.
Conclusion
For most patients with osteoporosis, current clinical evidence indicates that standard doses of denosumab (60 mg every 6 months) do not delay the healing of new fractures, including those occurring during early treatment. Its potent anti-resorptive action affects the later remodeling phase of bone healing, often leading to a larger, denser fracture callus. In fact, this mechanism has shown promise in the successful treatment of recalcitrant non-union fractures when administered at higher doses in a supervised setting. Therefore, clinicians can initiate or continue denosumab therapy in patients with a new fracture without concern for inhibiting the healing process, allowing for effective treatment of the underlying osteoporosis.
Potential Risks and Considerations
While denosumab does not typically impede healing, it's essential to consider specific risks associated with its mechanism of action, particularly with long-term use. These include atypical femoral fractures and osteonecrosis of the jaw, though these occurrences are rare. Furthermore, the potent suppression of bone turnover requires careful management, as stopping denosumab can lead to a rapid rebound in bone resorption, significantly increasing the risk of new vertebral fractures. These considerations, combined with the lack of delay in fracture healing, reinforce the need for a comprehensive assessment by a healthcare provider when determining the appropriate treatment plan for an individual patient.
The Future of Denosumab and Fracture Healing
Further research is ongoing to explore the full potential of denosumab, particularly in the context of repurposing it for complex orthopedic cases. Larger, randomized controlled trials are needed to validate the promising results seen in small case studies involving fracture non-unions. A deeper understanding of how denosumab's effects on the RANKL pathway can be leveraged to accelerate or improve fracture repair in specific patient populations, such as those with risk factors for delayed healing, could revolutionize treatment paradigms in orthopedic medicine. The initial evidence is overwhelmingly positive, confirming that denosumab is a safe and effective option that does not jeopardize the natural healing process for most patients.
