In the long-term treatment of osteoporosis, the effects of most classes of antiresorptive therapies are not sustained after treatment is discontinued, and bone mineral density (BMD) typically returns to pretreatment levels.1 This is especially notable with the discontinuation of denosumab, which leads to rebound bone turnover activation that is substantially higher than pretreatment levels, rapid bone loss, and elevated risk for vertebral fractures.

With bisphosphonates, however, the antiresorptive effect is maintained because these agents “adhere very strongly to bone surfaces and therefore… remain in the bone for years after stopping taking the drug,” according to a review published in the European Journal of Endocrinology.1 For this reason, it has been proposed that some patients may benefit from periodic breaks from bisphosphonates, also referred to as drug holidays, to reduce unnecessary treatment along with the risk for adverse effects.

Atypical femur fractures are the adverse effect most supported by research, although the risk is very low. In a study that examined radiographs of patients with subtrochanteric femur fracture, they observed an absolute risk for bisphosphonate users of 11 per 10,000 person-years.2

Earlier concerns about an elevated risk for atrial fibrillation with bisphosphonates have not been confirmed. Another potential risk, osteonecrosis of the jaw, rarely occurs in patients treated with bisphosphonates, and when it does, it is usually “mild and self-limiting.”1

In addition to concerns about unnecessary exposure to risks with long-term bisphosphonate use, interest in the effects of treatment breaks also arose from the observation that patient compliance with these drugs is often low.

Because of their continued effects after treatment is stopped, it “can therefore be argued that a treatment break with bisphosphonates is not a treatment break, merely a discontinuation of administration of the drug, during which [their] anti-resorptive effect will weaken over time,” the review authors noted.1

To learn more about these drug holidays, Rheumatology Advisor interviewed Christine Peoples, MD, rheumatologist and clinical assistant professor of medicine at the University of Pittsburgh Medical Center in Pennsylvania; Abby G. Abelson, MD, chair of Cleveland Clinic’s Department of Rheumatic and Immunologic Disease in Ohio; and Mary Bridgeman, PharmD, BCPS, BCGP, clinical associate professor at the Ernest Mario School of Pharmacy at Rutgers University and internal medicine clinical pharmacist at the Robert Wood Johnson University Hospital in New Brunswick, New Jersey.

Rheumatology Advisor: What are the effects of long-term treatment with bisphosphonates?

Dr Peoples: Most of the information we know on this topic stems from 2 major fracture prevention trial extensions with alendronate and zoledronic acid.1 Even then, the data are less robust in the extension trials, and we do not have data beyond 10 years. Long-term treatment with bisphosphonates leads to increasing lumbar spine BMD and stable BMD at the hip. The risk for clinical vertebral fractures is less in patients who are receiving long-term treatment with bisphosphonates compared with those who stop bisphosphonates. Bisphosphonates inhibit osteoclastic bone resorption, which leads to an increase in bone mass; this effect is seen in both trabecular and cortical bone.

Dr Abelson: Adverse effects of the oral medications are rare, but can include gastric or esophageal ulcers and reflux, and during the last 10 years, concerns have been raised about even rarer but serious conditions of atypical femoral fractures and osteonecrosis of the jaw. 

Dr Bridgeman: Bisphosphonates are generally a safe and well-tolerated class of medications. With long-term use beyond 3 or more years, however, there have been some concerns raised for an association with [the adverse effects mentioned earlier]. 

Rheumatology Advisor: What are the potential benefits of treatment breaks from bisphosphonates?

Dr Peoples: Many patients are hesitant to continue treatment for a disease such as osteoporosis that has no symptoms. In addition, patient compliance with bisphosphate therapy often comes into question. For example, patients often admit to not taking their bisphosphonate for an extended period, or only occasionally due to one of several reasons – such as cost, concern about side effects, and a desire for natural treatment.

Patients are often made aware of the possibility of participating in a drug holiday in conversations with friends or family or in the news. Many patients are aware of the rare, yet significant, potential side effects such as osteonecrosis of the jaw, atrial fibrillation, and atypical femur fractures. Ongoing treatment with bisphosphonate therapy may not be needed to prevent future fractures in certain patients due to the sustained effect of the drug. In addition, treatment breaks reduce the risk for adverse events from the drug.

Dr Abelson: There has been some suggestion that periods of going off bisphosphonates or stopping the medications after 3 to 7 years might decrease the potential for adverse events. Several studies suggest that after 3 to 7 years of oral bisphosphonate or 3 to 5 years of intravenous bisphosphonates, a drug holiday can be safely considered in most patients with postmenopausal osteoporosis. However, the decision about the timing and duration of the holiday will depend on clinical judgment related to bone density and fracture risk.

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A recent study concluded that a bisphosphonate holiday group [comprised of women who took a break of ≥12 months after ≥3 years of use] were not at greater risk for fracture than patients who continued to receive therapy, and that “[bisphosphonate] holiday remains a viable strategy for balancing the risks and potential harms associated with long-term [bisphosphonate] use.”3

Dr Bridgeman: This has been an area of controversy for a number of years now, but it appears that discontinuation of this drug class for a period of time may reduce the potential risks with a residual antiresorptive effect, at least in the short term. 

Nonetheless, it is important to point out that not all patients are eligible for treatment breaks as part of the management of osteoporosis; an individualized approach must be taken with consideration for a patient’s specific clinical situation and medical and medication use history. For individuals at high risk for fracture, interruption of therapy may not be appropriate, and depending on fracture risk, utilizing an alternative agent during the break from bisphosphonate use may be appropriate. Further, the optimal duration of a drug holiday with regard to use of bisphosphonates has not been established. 

Ultimately, while an interruption in therapy may be appropriate for some patients, it is important for the clinician to reiterate to the patient that the drug may need to be restarted in the future, as the effects on the bone may diminish over time. 

Rheumatology Advisor: What are some approaches to decision making and monitoring of these drug holidays?

Dr Peoples: Specific and comprehensive guidelines for the duration and monitoring of bisphosphonate treatment breaks are lacking, and additional research is needed. The decision about taking a treatment break must be framed within an individualized patient approach. A discussion with the patient about fracture risk, BMD information or trend, recent major fractures, vertebral fractures, or previous hip fracture must be undertaken with a thorough approach. I recommend engaging patients in this decision, as this increases their understanding of the treatment of osteoporosis.

Patients should be monitored for fracture during a treatment break, along with evaluation of BMD every 2 to 3 years. Bone turnover markers represent another option for monitoring of treatment breaks; however, there is variation in the testing, and it can be difficult to accurately follow these markers over time.

Dr Abelson: During the holiday, it is important that the patient maintains adequate calcium and vitamin D intake and participates in appropriate weight-bearing exercise. Bone density testing with dual-energy x-ray absorptiometry should be done every 2 years. Some specialists follow bone resorption markers to monitor patients in this setting. 

Dr Bridgeman: There are guidelines set forth by the American Academy of Clinical Endocrinology and the American Society for Bone and Mineral Research task force that can be referenced by the clinician. Ultimately, duration of exposure to the bisphosphonate, risk for fracture vs risk for serious adverse event occurrence, and clinical patient-specific features (including risk for fracture and personal history of major osteoporotic fracture) must weigh into the consideration for eligibility for a drug holiday. 

Rheumatology Advisor: What are additional clinical recommendations or thoughts about future research needed in this area?

Dr Peoples: Again, specific guidelines for the duration and monitoring of bisphosphonate treatment breaks are lacking, and additional research is needed. I would recommend that the clinician approach the topic of treatment breaks in osteoporosis on a patient-by-patient basis. It is fundamental to have a discussion with the patient about several factors related to the treatment of osteoporosis. The clinician should not overlook the importance of lifestyle measures including adequate calcium and vitamin D intake, exercise, smoking status, fall prevention, and alcohol use.

Patients with osteoporosis who are currently being treated with a bisphosphonate or those patients who are considering bisphosphonate treatment often will broach the topic of a treatment break with their physician initially. Clinicians must be prepared to have this discussion, especially considering the potentially significant, although rare, adverse effects of bisphosphonate therapy. The patient’s comorbidities may also play a major role in the discussion.

Dr Abelson: It should be noted that drug holidays do not apply to denosumab. It is in the family of antiresorptives, but does not persist in bone like the bisphosphonates do. If it is discontinued, the gain in bone density is lost rapidly. For instance, after 7 years of treatment, bone density declines back to baseline within 7 years of stopping denosumab.

Dr Bridgeman: As mentioned, this is a clinical controversy: the efficacy of the bisphosphonates beyond 10 years really has not been established in clinical investigations, and with regard to drug holiday implementation, it is unclear how long is optimal for reducing adverse event risk while maintaining efficacy on markers of bone density. Clinicians need to remain abreast of emerging evidence and to consider their individual patient’s history in applying the most current evidence to reduce fracture risks and ensure optimization of bone health.

Interviews have been lightly edited for style.

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References

  1. Langdahl B. Management of endocrine disease: Treatment breaks in long-term management of osteoporosis. Eur J Endocrinol. 2018. doi:10.1530/EJE-18-028 [Published online ahead of print]
  2. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Full report of a nationwide study. Acta Orthop. 2015;86(1):100–107.
  3. Adams AL, Adams JL, Raebel MA, et al. Bisphosphonate drug holiday and fracture risk: a population-based cohort study. J Bone Miner Res. 2018;33(7):1252-1259.

This article originally appeared on Rheumatology Advisor