Who’s in need of a (bisphosphonate) holiday?

Hands up, who needs a holiday? (Me! Me!). It’s been an exhausting 6 months in General Practice, and many of us will be eyeing up July and August with a sense of relief that a well earned holiday is not too far away. Demand and expectation seem to have gone through the roof since March leaving us ratty, our patients ratty, and a sense that the well of empathy is running dry.

However, one consultation that rarely disappoints both clinician and patient alike is when you suggest they stop taking (at least temporarily) a medication that is giving them no day-to-day symptomatic benefit and maybe giving them some niggling side effects. Step forward exhibit A) - the bisphosphonate. They’ve been around for donkey's years but for a drug that has been around so long it is extraordinary that we still don’t really know what the optimum duration of treatment is, or when/if we can safely give patients a break from these drugs for a period of time - the so-called ‘drug holiday’. But this is the question that Wendy has come to you with - after 6 years of her alendronate can she safely stop this medication, even temporarily, as she could seriously do with a break from the reflux? 

In 2019 a systematic review found very little convincing evidence of benefit beyond 4-6 years of treatment, and almost no evidence on the effects of drug holidays, with the authors concluding that ‘To guide future decisions about osteoporosis treatment, considerable new research is warranted’. In principle giving people a break off bisphosphonates has always appealed, but the uncertainty about how to do it has always made me nervous and put me off. 

But the Drugs and Therapeutics Bulletin came to the rescue a few months back with an article on bisphosphonate holidays (Drug and Therapeutics Bulletin 2021;59:35-36). First, here’s the science ‘bit’….Bisphosphonates are complex phosphate salts that bind strongly to bone surface and impair osteoclastic activity, thereby reducing bone resorption, increasing (modestly) bone density and reducing fracture risk. Due to long half-lives the benefits of these drugs wear off slowly (over months-years), depending on the potency of the drug and how strongly it binds to bone e.g. risedronate and Ibandronate wear off more quickly vs alendronate, with zolendronate the most durable.

Aside from the dyspeptic side effects many people get with these drugs, the main concern over the years has been the increased incidence of atypical femoral fractures (AFFs). AFFs are thought to develop after non-traumatic stress fractures to the femoral cortex, usually then developing into femoral shaft fractures, occasionally bilaterally. Although rare (0.6-13/10,000 person-years depending on length of use), AFFs are particularly problematic with a review in 2018 concluding that ‘surgical treatment of AFF is more complex than that of typical femoral fractures, healing time is prolonged and reduction and surgical technique is more demanding’. The rate of AFF associated with bisphosphonate use goes up exponentially the longer you are on the drug, but drops quickly on stopping. Hence a drug holiday can quickly reduce AFF risk while maintaining the more durable benefits of the drugs on osteoporotic fracture. It’s important to highlight that the idea of drug holidays does NOT apply to denosumab - this drug has a very short half-life relatively, and as highlighted by the MHRA in August 2020, cessation of this drug can lead to a significant increased risk of vertebral fractures (occasionally multiple). 

So enough theory, what’s the bottom line Bob? This review suggests that after ~5 years of bisphosphonate use we can consider a 6 month break for risedronate and a 12-24 month break for alendronate, with holidays being more beneficial for those at low/moderate osteoporotic fracture risk, especially women of Asian origin (whose AFF risks are higher with lower osteoporotic fracture risks). The review reminds us that this is usually a drug ‘holiday’, not a drug ‘retirement’, with those people at higher osteoporotic fracture risk likely to need longer term treatment, albeit with intermittent breaks. However, this still feels like a win all round, even if temporary - a happy Wendy with reduced drug burden and side effects, fewer prescriptions for us to process, and cost saving for the drugs budget. I do love a good holiday.