Southhampton, UK—Are drug holidays from antiosteoporosis treatments such as bisphosphonates or denosumab riskier than previously reported?

A study published in the journal Osteoporosis International suggests that might be the case.

University of Southampton–led researchers point out that the practice of recommending 1- to 2-year drug holidays became more common after concerns were raised that long-term use of bisphosphonates is associated with rare side effects, namely atypical femoral fractures and osteonecrosis of the jaw. For patients who are at high risk of fracture, the risk-benefit ratio supports treatment continuation, with approximately 100 new fragility fractures prevented for each of these adverse events, the authors advise.

“Our aim was to review the available literature to assess what evidence exists to inform decision making on drug holidays and to identify any indicators that might help clinicians decide whether to continue or discontinue therapy in individual patients,” explained lead author Elaine Dennison, MB, PhD, MSc.

The study notes that differing pharmacokinetics lead to varying outcomes on stopping therapy, but that prospective and retrospective analyses report that the risk of new clinical fractures was 20% to 40% higher in subjects who stopped bisphosphonate treatment and vertebral fracture risk was approximately doubled.

“Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%,” the researchers write. “Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g., prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture.”

The authors report that after stopping bisphosphonate treatment, the risk of new nonvertebral fractures was higher in women who had a total hip T-score below -2.5, and the risk of clinical vertebral fractures was approximately double.

“The view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence,” the researchers conclude. “Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.”

The authors note that many past studies did not consider increased fracture risk with long-term discontinuation and reported very low rates of adverse skeletal events such as atypical fractures.

“This review points to the need for a far more nuanced approach to drug holidays,” notes coauthor Serge Ferrari, MD, chair of the International Osteoporosis Foundation.

“Osteoporotic fractures can be life-threatening and have a devastating impact on quality of life. Doctors and patients must be aware that, particularly for individuals at high risk, the benefits of staying on treatment clearly outweighs the risk of rare side effects. Furthermore, it is important to understand that bisphosphonates and denosumab are fundamentally different types of treatment which require different approaches as discontinuation of denosumab results in rapid bone loss, at least in subjects not previously exposed to long-lasting bisphosphonates.”

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