Bisphosphonate Interruption Reduces Fragility Fracture Risk

Bisphosphonates are a cornerstone in the prevention of osteoporotic fractures, yet concerns persist regarding the optimal duration of therapy and the cumulative risk of rare but serious adverse events. Understanding the balance between sustained efficacy and the emergence of complications like atypical femoral fracture and osteonecrosis of the jaw is essential for guiding long-term treatment strategies.¹

What the study did

A nested case-control and cohort study, utilising primary and secondary care data from England, evaluated the association between fragility fracture and bisphosphonate interruption after three and five years of initial prescription.¹ The study also explored the incidence of atypical femoral fracture and osteonecrosis of the jaw after three and five years of continued bisphosphonate prescription.¹

The case-control component included 10,233 individuals with a fragility fracture and 102,330 matched controls.¹ The cohort study comprised 1,245,678 individuals for the 3-year analysis and 798,456 individuals for the 5-year analysis, all of whom had received at least one bisphosphonate prescription.¹ Data were collected from 2000 to 2020.¹

Key Findings

For the case-control study, bisphosphonate interruption after 3 years was associated with a reduced risk of fragility fracture, with an adjusted hazard ratio (aHR) of 0.84 (95% CI 0.79-0.89).¹ Similarly, interruption after 5 years showed an aHR of 0.82 (95% CI 0.77-0.87) for fragility fracture.¹ These findings indicate that planned interruptions may not increase the risk of fragility fractures and could potentially reduce it.¹

In the cohort study, the incidence of atypical femoral fracture (AFF) after 3 years of continued bisphosphonate prescription was 0.003% (95% CI 0.002-0.004).¹ After 5 years of continued prescription, the incidence of AFF increased to 0.006% (95% CI 0.005-0.007).¹ The incidence of osteonecrosis of the jaw (ONJ) after 3 years of continued bisphosphonate prescription was 0.002% (95% CI 0.001-0.003), rising to 0.004% (95% CI 0.003-0.005) after 5 years.¹ These data quantify the low but increasing risk of these specific adverse events with prolonged bisphosphonate use.¹

The study's strengths include its large sample size derived from real-world primary and secondary care data in England, providing robust estimates for both fracture risk and adverse event incidence.¹ A limitation is the observational nature of the study, which, despite extensive adjustment for confounders, cannot definitively establish causality.¹ Residual confounding from unmeasured factors, such as adherence to therapy or specific fracture risk profiles not fully captured in the data, may also exist.¹ Future research could involve randomised controlled trials to confirm these findings and further delineate optimal treatment durations for various patient subgroups.

Clinical Implications and Future Directions

The findings from this extensive UK-based study offer crucial insights for clinicians managing patients on long-term bisphosphonate therapy. The observed reduction in fragility fracture risk following bisphosphonate interruption after three and five years challenges the conventional assumption that continuous therapy is always superior for fracture prevention. This suggests that for many patients, a planned "drug holiday" may not only be safe but potentially beneficial, aligning with a more nuanced, personalised approach to osteoporosis management.

Specifically, the data on atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) underscore the importance of regular reassessment for patients on prolonged bisphosphonate regimens. While the absolute incidence of these adverse events remains low, their gradual increase with extended use necessitates careful consideration, particularly in individuals with lower baseline fracture risk or those who have achieved significant bone mineral density improvements. Clinicians should engage in shared decision-making with patients, weighing the ongoing benefits of bisphosphonate therapy against the accumulating, albeit small, risks of these serious complications.

Further research is warranted to identify specific patient profiles that would most benefit from bisphosphonate interruptions. This could involve investigating the impact of factors such as baseline fracture risk, bone mineral density response to initial therapy, and the presence of comorbidities. Additionally, studies exploring the optimal duration of drug holidays and the criteria for restarting therapy would be invaluable. The development of predictive models incorporating genetic and lifestyle factors could also help refine individualised treatment strategies, moving beyond a one-size-fits-all approach to osteoporosis prevention.