Bisphosphonates have been the mainstay of osteoporosis therapy for over 2 decades and have been in clinical use for nearly 50 years. The advent of oral formulations of the more potent nitrogen-containing bisphosphonates in the 1990s, following pivotal trials demonstrating antifracture efficacy coupled with safety profile, heralded their highly prevalent prescribing across all clinical disciplines, most especially in primary care. This widespread use has most likely accounted for the decline in age-standardized rates of hip fracture and other fragility fractures . A more recent addition to the therapeutic options over the past decade is denosumab. Since osteoporosis therapy is often a long-term proposition, there is much debate on duration of therapy and about the need for drug holidays.
Pharmacology of bisphosphonates
Bisphosphonates are potent agents that diminish osteoclastic bone resorption, such that they are classified as antiresorptive agents . This is a reductive description because any decrease in bone resorption is followed by a decline in bone formation. As bisphosphonates bind to the mineral phase of bone, hydroxyapatite, to various degrees, they have a sustained effect after withdrawal of bisphosphonate therapy.
Risks of long-term bisphosphonate therapy
The adverse effects of long-term bisphosphonates are twofold. Osteonecrosis of the jaw due to bisphosphonate therapy principally occurs as a consequence of oncologic dose regimens for metastatic bone disease , and will not be discussed further. Atypical femur fracture (AFF) as a consequence of long-term bisphosphonate therapy, unlike osteonecrosis of the jaw, has had a major impact on prescribing practice.
Atypical femur fracture
Although a case series in 2005 warned about a spectrum of stress fractures with long-term bisphosphonate therapy , concern about a particular type of femur fracture (since termed AFF) emerged in the orthopedic literature in 2007, with the first report coming from Singapore . It quickly transpired that these AFFs had been occurring for some time. The response by the bone and mineral community was rapid and extensive, with two Task Force Reports in quick succession from the American Society of Bone and Mineral Research (ASBMR) [6,7]. The correlation between bisphosphonate use and AFF was substantive; the time order of their recognition coupled with non-spuriousness supported a causal relationship. Regardless of the debate about causation, the impact on clinician prescribing and patient adherence was considerable . The response to this crisis and sequence of events spawned the notion of a “drug holiday” from bisphosphonates.
Rationale for bisphosphonate drug holiday
The rationale for a drug holiday from bisphosphonates lies deeper than just the avoidance of AFF; it is founded in the noncongruence between the short duration of the bone remodeling cycle and the prolonged effect of bisphosphonate therapy. Extension trials of oral alendronate  and intravenous zoledronate [9,10] have shown that a plateau phase in the bone mineral density (BMD) response is established at about 5 years of treatment, with little or no increase in BMD thereafter. In addition, discontinuation of bisphosphonates has a slow offset effect; there is only a minimal decrease in BMD over the next few years, and antifracture efficacy persists after discontinuation [8–10]. Thus, ceasing bisphosphonate therapy for approximately 2 years – a drug holiday – has taken hold in clinical practice.
When to initiate a bisphosphonate drug holiday
The challenge that arises is to identify those who should have a drug holiday, and to maintain confidence in the long-term use of bisphosphonates, even if on an intermittent basis, to ensure that the prevention of fragility fractures is prioritized. To this end, the ASBMR published a Task Force Report on long-term use of bisphosphonates in which they offered guidelines for either embarking on a drug holiday or continuing with bisphosphonate therapy . The Task Force suggested that a risk assessment be made after 5 years of oral bisphosphonate therapy. They deemed that women at high risk for fragility fracture (those with a low hip T-score of ≤-2.5 or high fracture risk score, and those with prior hip or vertebral fracture) should continue treatment for up to 10 years of oral bisphosphonate therapy. They argued that while the risk for AFF clearly increases with bisphosphonate therapy duration, such rare events are outweighed by vertebral fracture risk reduction. Beyond 10 years of therapy, there is no evidence to guide clinicians on the best treatment option, and referral to an osteoporosis expert should be considered.
Embarking on a bisphosphonate drug holiday
If the clinician advocates a drug holiday, then it would seem reasonable to review BMD at approximately 2-year intervals, followed by clinical decision making regarding renewing bisphosphonate therapy. Discontinuation of bisphosphonate does not seem to be associated with increased fracture risk, but is certainly associated with reduced AFF risk .
Continuing with bisphosphonate therapy
Should the clinician advise continuation of bisphosphonate therapy beyond 5 years, then they should consider a strategy for early detection of AFF in its incomplete form. Using dual-energy X-ray absorptiometry systems to image the femur at the time of routine BMD testing is a means to the early recognition of incomplete AFF, particularly if the patient has prodromal symptoms of pain [13,14].
Comparison with denosumab (Table 1)
Denosumab therapy should not be followed by a drug holiday . Denosumab is a more potent agent than bisphosphonates, classified as having an antiresorptive action that also diminishes bone formation and bone turnover . It is frequently termed as a “dynamic” antiresorptive agent. While the end result is like that of bisphosphonates, the mechanism of action is different. Being a biologic agent, denosumab acts by blocking the action of receptor activator of nuclear factor κB ligand, curtailing the formation, function, and survival of osteoclasts . Once the effect of denosumab wanes, there is a short offset effect. Bone remodeling activity starts to recover rapidly about 6 months after each injection. A beneficial consequence of this short offset effect is the pattern in BMD change that is observed with long-term therapy: bone gain continues without an appreciable plateau phase .
If denosumab therapy is stopped, then bone remodeling overshoots. This has several consequences. BMD declines rapidly after cessation, such that nearly all the previous gains at spine and femur are lost within 12 months [18,19]. Antifracture efficacy is not maintained. Indeed, there is concern about an increase in the risk for vertebral fracture, particularly multiple vertebral fractures after denosumab discontinuation . Transient hypercalcemia has been recorded with suppressed parathyroid function; this nonparathyroid hypercalcemia seems to be more apt to occur with long-term denosumab therapy . Given that the summary of product characteristics advises estimation of calcium concentration every time prior to administration of denosumab (to identify patients at risk for hypocalcemia), it is possible that cases of transient mild hypercalcemia will be identified with unnecessary concern and unwarranted investigations. Although the evidence about benefit is lacking, it is suggested that cessation of denosumab therapy should be followed by bisphosphonate therapy .
Bone remodeling activity
Cessation of therapy
Slow offset effect
Ongoing antifracture efficacy
Rapid offset effect
Loss of antifracture efficacy
Risk for multiple fractures
Consider after 5 years
Avoid holiday, and consider switch to bisphosphonates
Atypical femur fracture
Rare, but increased risk with long-term use
Rare, but increased risk with long-term use
Osteoporosis of the jaw
Rare, but caution with dental implant surgery
BMD= bone mineral density; *refers to doses of bisphosphonates used to treat osteoporosis
Clinicians should review the need for ongoing bone medication in their patients when they have been taking oral bisphosphonates in excess of 5 years. A drug holiday for up to 2 years is a reasonable option. If the patient is deemed to be at high risk for fragility fracture and the clinician opts to prolong bisphosphonate therapy, then a surveillance strategy for early detection of AFF should be advised. On the contrary, patients on denosumab should not have a drug holiday without a plan to prescribe bisphosphonate therapy about 6 months after the last administration of denosumab as its effects begin to wane.
About the author