42 CLINICAL FOCUS
42 CLINICAL FOCUS
20 JUNE 2025 ausdoc. com. au
Therapy Update
Bisphosphonate‘ treatment breaks’
Although bisphosphonates are safe overall in treating osteoporosis, treatment breaks are important to minimise the possible side-effects.
Adapted from Adler, 2016.
Endocrinology
BISPHOSPHONATES are the most common class of antiresorptive medications used in the treatment of osteoporosis, with proven efficacy in improving bone mineral density( BMD) and reducing fracture risk. 4
Bisphosphonates bind to active sites of the bone surface and impair the action of osteoclasts, the primary cell driving bone resorption. 5-7 These agents accumulate in bone, leading to continued release from bone long after stopping treatment and recirculation in active resorption pits. 8
Zoledronic acid is the most strongly bound to bone, followed by alendronate and risedronate. 7, 9 Clinically, this may account for differences between bisphosphonate agents in durability of anti-fracture effect once treatment is ceased.
Why consider treatment breaks?
Bisphosphonates are very safe treatments overall, even in the long term. However, rare skeletal side-effects can occur due to prolonged suppression of bone turnover and inhibited repair of microfractures.
The risk of atypical femoral fractures( AFF) increases with duration of bisphosphonate use. While the risk overall is very low with less than five years of treatment( less than 1 / 1000), this risk rises to around 1 in 250 in Caucasian women and as high as 1 in 50 in Asian women after 10 years of treatment. 10 Reassuringly, the risk of AFF rapidly reverses to pre-treatment risk within a few years of stopping treatment. 10
Figure 1. Determining suitability of a bisphosphonate treatment break.
Dr Mawson Wang is a consultant endocrinologist in the department of diabetes and endocrinology at Concord Repatriation General Hospital, an honorary medical officer at Westmead Hospital, Sydney, and PhD candidate in the faculty of medicine and health, University of Sydney. Dr Shejil Kumar is an endocrinology fellow and PhD candidate in the department of endocrinology at Westmead and Royal North Shore Hospitals, Sydney, and clinical lecturer in the faculty of medicine and health, University of Sydney. Dr Wang and Dr Kumar are equal first authors of this article.
Associate Professor Christian Girgis is a senior staff specialist in endocrinology at Westmead Hospital, Sydney, and associate professor in the faculty of medicine and health, University of Sydney.
Medication-related osteonecrosis of the jaw( MRONJ) is associated with cumulative high doses of bisphosphonates, mostly in the setting of invasive dental procedures( eg, extractions, implants). MRONJ is typically observed in oncology patients receiving higher-dose bisphosphonate regimens. 11
The incidence of MRONJ in patients receiving bisphosphonates for osteoporosis is quoted at less than 1 in 10,000 to 1 in 100,000 and is influenced by other risk factors, including glucocorticoid use, cancer therapy, alcohol / tobacco use and pre-existing dental disease.
12, 13
Thus, patients undergoing invasive dental procedures while receiving bisphosphonates should be managed under close dental supervision, but they can largely be reassured that their risk of MRONJ is low.
When treatment breaks are no-go
Denosumab is a six-monthly injectable treatment which inhibits molecular signals that drive osteoclast formation and survival. 14 Denosumab does not bind to the bone surface and is rapidly cleared from the circulation. Hence, unlike bisphosphonates, its effects are rapidly reversible after discontinuation.
Stopping or delaying denosumab doses results in a‘ rebound effect’ characterised by increased bone turn over, BMD loss back to pre-treatment levels and, in some cases, can precipitate spontaneous and / or multiple vertebral fractures. This means treatment breaks are not appropriate in
* Extension of pivotal studies indicate that a‘ treatment break’ after six years of IV zoledronic acid and 10 years of alendronate is safe in patients whose vertebral fracture predates treatment and BMD is no longer in the osteoporotic range. denosumab-users. In cases where denosumab is being ceased, the optimal strategy for‘ bridging’ patients off denosumab to an alternative treatment, such as a bisphosphonate, to minimise rebound bone loss is under investigation. Such complex cases warrant referral to an osteoporosis specialist.
Bisphosphonate break: the right patient at the right time
A common misconception in both clinicians and patients is that treatment breaks should be initiated in all patients after 3-5 years of continuous bisphosphonate use. 2
Clinical data suggests that a more nuanced approach is required, and that these decisions should be made according to best evidence on a case-by-case basis after individualised risk stratification. When deciding whether a bisphosphonate treatment break is suitable, it is important to weigh up the risks of interrupting treatment against the risks of continuing treatment. 3 Does the patient have any risk factors for a fragility fracture if treatment is stopped, such as fracture before or during treatment, low hip BMD at the end of treatment, or older age( see figure 1)?
If the patient has low risk of fragility fracture, then a supervised treatment break with reassessment every two years could be undertaken. In patients in whom the risk of fragility fracture remains high despite treatment, consider continuing treatment and reassessment of their risk profile with ongoing reviews.
If there are risk factors for AFF or MRONJ( such as prolonged treatment for greater than eight years, or planned invasive dental procedures), then a treatment break may be considered, particularly if the risk of fragility fracture has decreased with treatment.
Bisphosphonate treatment breaks or‘ drug holidays’ have become an important and popular tool in judicious treatment of osteoporosis to maximise the benefit / risk ratio of long-term use. It is important to recognise that the word‘ break’ implies that treatment may need to be restarted at a later stage, as osteoporosis is a chronic disorder with no established cure that requires long-term management.
Treatment breaks should also be supervised, such that patients have a monitoring plan in place at the time of interrupting treatment. This helps ensure that treatment may be promptly recommenced if there is significant BMD decline or new fracture.
Evidence-based decisions
Extension studies of pivotal RCTs and
NEED TO KNOW
Bisphosphonates are effective drugs in the treatment of osteoporosis and reduce the risk of fragility fracture by up to 70 %.
Prolonged treatment with bisphosphonates results in chronic suppression of bone turnover. In susceptible individuals, long-term bisphosphonate use is associated with skeletal adverse events, including atypical femoral fractures( AFF) and medication-related osteonecrosis of the jaw( MRONJ).
Bisphosphonate treatment breaks may reduce the risk of skeletal adverse events while maintaining anti-fracture efficacy beyond the period of use. The decision to embark on a treatment break is individualised and weighs up the risk of sustaining a fragility fracture once treatment is paused. A patient’ s risk / benefit profile should be carefully considered before deciding to undergo a treatment break.
Treatment breaks or‘ drug holidays’ are not permanent and should be supervised. An individual’ s fracture risk will increase with a longer gap in treatment, and ongoing bone mineral density( BMD) monitoring is recommended to advise treatment reinitiation at a later stage.
Unlike bisphosphonates, the effects of denosumab are rapidly reversible upon discontinuation. A treatment break is not recommended for patients receiving denosumab.‘ Bridging’ treatment onto an alternative agent, to facilitate cessation, may be considered, but should be guided by an osteoporosis specialist.
real-world studies have shed light on clinical factors which predict suitable and safe treatment breaks. Zoledronic acid and alendronate appear to have the most durable BMD-lowering and fracture-risk-reducing efficacy during a treatment break, compared to risedronate.
It is important to note, however, these studies still highlight that BMD losses and fracture risk start to increase after several years off treatment. A limitation of these studies is that they predominantly include postmenopausal women. This means there is less evidence guiding treatment decisions in other at-risk populations such as older men with osteoporosis.
After three years of IV zoledronic acid, a three-year treatment break led to declines in hip BMD but preserved lumbar spine BMD, whereas six years of zoledronic acid followed by a three-year break led to preserved hip BMD. 15, 16 A five-year treatment break after five years of oral alendronate led to total hip BMD return to baseline levels. 17 Similarly, total hip BMD gained after seven years of oral risedronate returned to baseline levels after only a one-year break. 18 There were more consistent trends in declines in hip BMD during treatment breaks compared to lumbar spine BMD, which may be related to artefactual increases with degenerative change.
In zoledronic acid and alendronate studies, risk factors for a fracture during a treatment break include older age, lower hip BMD( T-score ≤ −2.5 SD) at the end of treatment, previous fracture before or during treatment, and low medication adherence. These patients are at ongoing high fracture risk and may benefit from ongoing treatment.