By Chad Deal, MD
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Note: This is an abridged version of an article originally published in the Cleveland Clinic Journal of Medicine. For the full article, please click here.
Physicians and patients have become accustomed to a drug holiday with osteoporosis therapy. The American Society for Bone and Mineral Research has published recommendations for long-term bisphosphonate treatment,1 in which they suggested that after five years of oral or three years of intravenous bisphosphonate treatment, one should consider reassessing fracture risk.
In women who have no factors that place them at high risk for fracture (hip T score less than −2.5, FRAX score indicating high fracture risk, previous fracture, or fracture on therapy), a holiday should be considered. For patients at high risk, continuing for up to 10 years of oral and six years of intravenous bisphosphonate should be considered.
But a holiday is not forever. Therapy often needs to be restarted, especially if bone density declines or a fracture occurs.
A holiday is suggested since long-term use of bisphosphonates has been associated with atypical femoral fractures, and higher doses and longer duration of use have been associated with osteonecrosis of the jaw.
However, in the case of bisphosphonates, a holiday is “administrative.” Although administration of the drug is stopped, these drugs have a long half-life in bone, and their pharmacologic effects continue for years after discontinuation, depending on the drug and duration of treatment.2 This prolonged effect after discontinuation is not the case with other therapies for osteoporosis, including the parathyroid hormone analogues abaloparatide and teriparatide, estrogens, estrogen agonists-antagonists (e.g., raloxifene), romosozumab and denosumab.
Rapid bone loss after denosumab is stopped
Romosozumab is a humanized monoclonal antibody against sclerostin, a cytokine in the Wnt signaling pathway that inhibits bone formation, and denosumab is a fully human monoclonal antibody against RANK-ligand, a cytokine necessary for osteoclast formation and function. Unlike bisphosphonates, which bind avidly to hydroxyapatite and have a long half-life in bone, the effect of these two monoclonal antibodies is transient.
In phase 2 trials of denosumab, the gain in bone mass with two years of treatment was completely lost after one year off therapy.3 Markers of bone resorption increased after denosumab discontinuation to levels higher than baseline, suggesting a hyperresorptive state. McClung et al.4 found that bone mineral density in the lumbar spine had increased 16.8% after eight years of denosumab therapy but declined 6.7% in the first year after stopping.
Some have described the dramatic decline in bone mass as if bone were a “spring,” (i.e., when pressure is released, the material wants to rebound to the pretreatment state). Finite element analysis, a measure of bone strength, was shown to increase with denosumab treatment in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial.5
If denosumab must be stopped
Since fracture risk increases rapidly after denosumab discontinuation and multiple vertebral fractures occur with greater frequency, it is important to track patients who miss their scheduled injections. Further, if patients must discontinue denosumab (e.g., because of adverse effects), another osteoporosis medication should be initiated to prevent bone loss and prevent fracture.
In the Denosumab Adherence Preference Satisfaction (DAPS) study, 115 of 126 patients randomized to denosumab for 12 months were transitioned to alendronate for 12 months; 15.9%, 7.6% and 21.7% lost bone mineral density in the lumbar spine, total hip and femoral neck, respectively.11
In six patients who discontinued denosumab after seven years and received one dose of zoledronate, bone mineral density declined in both the lumbar spine and hip at 18 to 23 months after infusion.12 Bone mineral density remained significantly higher than baseline in the lumbar spine but declined to pretreatment levels in the hip. The authors suggested that more than one dose of zoledronate might be more effective for preventing bone loss.
The timing of administration of zoledronate may be important. Data suggest that if bone turnover is very low, bisphosphonate binding to bone may be reduced, and this lessens its efficacy in preventing bone loss. The ZOLARMAB trial (Treatment With Zoledronic Acid Subsequent to Denosumab in Oteoporosis, clinicaltrials.gov identifier NCT03087851) has enrolled 60 patients in three arms, i.e., receiving a dose of zoledronate at either six or nine months after denosumab discontinuation, or when a marker of bone resorption rises above a prespecified level. A second dose of zoledronate is given in patients who have a decline in bone mineral density or an increase in a marker of bone resorption. Results are expected in 2020 or 2021.
Given the risks associated with discontinuation, should we continue to prescribe denosumab? The answer is that denosumab clearly has a place in therapy for patients at high risk of fracture. Bisphosphonates are not recommended if the glomerular filtration rate is less than 35 mL/min/1.73 m2. Since denosumab is excreted by the reticuloendothelial system and not the kidney, it is preferred in patients with chronic kidney disease.
Many patients do not tolerate oral bisphosphonates because of gastrointestinal adverse effects or bone pain. With bisphosphonate therapy, increases in bone mass occur in the first three years of therapy, after which no further increases occur. Denosumab is unique in that increases in bone mass continue through 10 years of treatment. Analysis of the FREEDOM extension showed that the incidence of nonvertebral fractures was lower with higher total hip T scores achieved with treatment.13 For these reasons denosumab will continue to have an important place in the treatment of patients with low bone mass. For those who must discontinue denosumab, a bisphosphonate is recommended. More information is needed on oral or intravenous bisphosphonate therapy and the appropriate timing of therapy after denosumab discontinuation.
Considerations during the COVID-19 pandemic
As a result of the current COVID-19 pandemic, there is a higher likelihood that patients will miss scheduled denosumab treatments. Many patients are appropriately wary about coming for an appointment, so it is incumbent on providers to make patients understand the risks of discontinuation.
Many assisted-living facilities and nursing homes do not want residents to go to “routine” heathcare visits. Whenever possible, we should encourage these facilities to administer denosumab to their residents and make financial considerations secondary. If a family member is a healthcare provider, an attempt should be made to have the drug administered at home, if possible.
We should go the extra mile to make sure our patients get appropriate treatment. If all else fails, an oral bisphosphonate should be started, and denosumab can be resumed at a later date.
- Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16–35.
- Fleisch H. Bisphosphonates in bone disease. 4th ed. San Diego, CA: Academic Press; 2000.
- Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96(4):972–980.
- McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM. Observations following discontinuation of long-term denosumab therapy. Osteoporos Int. 2017;28(5):1723–1732.
- Keaveny TM, McClung MR, Genant HK, et al. Femoral and vertebral strength improvements in postmenopausal women treated with denosumab. J Bone Miner Res. 2014;29(1):158–165.
- Dupont J, Laurent MR, Dedeyne L, Luyten FP, Gielen E, Dejaeger M. Vertebral fractures after denosumab cessation. Cleve Clin J Med. 2020;87(6):337–338.
- Brown JP, Roux C, Törring O, et al. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013;28(4):746–752.
- Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. 2017;32(6):1291–1296.
- Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190–198.
- Black DM, Bauer DC, Schwartz AV, Cummings SR, Rosen CJ. Continuing bisphosphonate treatment for osteoporosis—for whom and for how long? N Engl J Med. 2012;366(22):2051–2053.
- Freemantle N, Satram-Hoang S, Tang ET, et al; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012;23(1):317–326.
- Reid IR, Horne AM, Mihov B, Gamble GD. Bone loss after denosumab: only partial protection with zoledronate. Calcif Tissue Int. 2017;101(4):371–374.
- Ferrari S, Libanati C, Lin CJF, et al. Relationship between bone mineral density T-score and nonvertebral fracture risk over 10 years of denosumab treatment. J Bone Miner Res. 2019;34(6):1033–1040.