A number of case reports highlight the possibility of rebound vertebral fractures occurring soon after ceasing denosumab therapy. Denosumab is a monoclonal antibody that reduces bone resorption by inhibiting the formation and activity of osteoclasts. It is indicated for the treatment of postmenopausal osteoporosis, to increase bone mineral density (BMD) in men with osteopenia or osteoporosis, hypercalcaemia of malignancy, giant cell tumour of bone, and to prevent skeletal-related events due to bone metastases.

In contrast to bisphosphonates, denosumab is not incorporated into the bone. Therefore, while the effects of bisphosphonates are durable, the beneficial effects of denosumab on bone resorption stop after treatment is ceased. A recent post hoc analysis of the randomised placebo-controlled FREEDOM trial found that the rate of vertebral fractures after discontinuing denosumab increased to a rate that was similar to patients receiving placebo. Patients with a history of vertebral fractures were at particularly high risk.

The mechanism for this effect appears to be a rebound increase in bone resorption within the three months after a scheduled dose is missed. There is currently a lack of data describing this effect or appropriate measures to mitigate the risk. However, the study authors suggest that treatment with another antiresorptive agent should be considered for osteoporosis patients when discontinuing denosumab. The issue of “drug-holidays,” sometimes recommended for antiresorptive agents prior to invasive dental procedures, is not as well defined. The Therapeutic Guidelines propose that patients prescribed denosumab for osteoporosis should be managed in the same way as patients taking bisphosphonates. However, some sources go further to recommend that, instead of withholding therapy, non-urgent dental work should be scheduled for the three to four months after a denosumab dose. This allows time for healing to occur before the next planned dose.

References:

  1. Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JE, McClung M, 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): 190-8.
  2. Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. J Clin Endocr Metab. 2017; 102(2): 354-8.
  3. McClung MR. Cancel the denosumab holiday. Osteoporos Int. 2016; 27(5): 1677-82.
  4. Oral and Dental Expert Group. Dental Management of Patients with Medical Conditions. In: eTG Complete [Internet]. Melbourne: Therapeutic Guidelines; 2017.

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