Vertebral fractures after denosumab discontinuation for dental procedures: a consequence of distorted perceptions of risk

Clinical record

A 68‐year‐old woman presented for a medical consultation. Her menopause was at age 40 years but there was no other significant medical history. She was taking no medications. Screening bone densitometry revealed osteoporosis — lumbar spine T‐score −3.4 and femoral neck T‐score −3.0. She had no prior fractures. No cause of secondary osteoporosis was identified. The calculated risk of fracture was 24% over the next 10 years.1 She started denosumab therapy 60 mg every 6 months.

After 5 years of denosumab therapy, the patient required teeth to be extracted. She was advised by the dentist to delay denosumab until the procedures were completed because of the risk of osteonecrosis of the jaw. Over the 5 months from the missed denosumab injection the patient sustained six vertebral fractures. These were managed with pain relief, and denosumab was restarted with no further fracture occurring.

Discussion

Both bisphosphonates and denosumab are effective for osteoporosis. Bisphosphonates bind to hydroxyapatite surfaces in bone, with a half‐life in bone of about 10 years, whereas denosumab acts as an osteoprotegerin analogue in the physiological RANKL (the receptor activator of nuclear factor‐κB ligand) pathway. Although bisphosphonates may be withdrawn after several years of therapy without loss of efficacy, regular administration of denosumab is essential to prevent rapid bone loss and fracture with treatment delay or withdrawal.2

Osteonecrosis of the jaw after tooth extraction was first recorded with long term bisphosphonate therapy in 20033 and, more recently and less commonly, with denosumab therapy.4 Concern about osteonecrosis of the jaw may lead to dental practitioners being wary of patients receiving antiresorptive therapy and sometimes asking them to delay therapy for dental treatment. This advice has entirely different consequences for the patient who stops bisphosphonates than for the patient who stops denosumab.

The International Task Force on Osteonecrosis of the Jaw reported that the frequency of osteonecrosis of the jaw in patients receiving bisphosphonate or denosumab in osteoporosis doses is estimated at 0.001–0.01%, marginally higher than in the general population (< 0.001%).4 The American Dental Association does not recommend interruption of either bisphosphonate or denosumab for dental extraction.5 Our patient’s future risk of fracture at presentation was estimated to be 24% over 10 years; therefore, it was disproportionately higher than her risk of osteonecrosis of the jaw, and considerably higher again with the rebound risk associated with cessation of the drug.

The long half‐life of bisphosphonates in bones makes any advice to stop these for dental extractions relatively safe but also futile.6 There is an apparent lack of appreciation of the rapid offset of denosumab action when a recommendation to stop that drug is given.2 Delaying denosumab therapy results in a reversal of the therapeutic effect as early as 9 months after the last dose.7 Several case series report multiple vertebral fractures in the setting of delayed administration in or cessation of the course of denosumab therapy.8

How should one prevent this adverse event? The key lies in education of the patient and communication with the dentist. One should emphasise to the patient from the first prescription of denosumab that they must not stop or delay denosumab therapy for any dental work. Providing the patient with a letter detailing the risks of stopping treatment for any reason reinforces this advice.9 The second important step is to establish a collaborative discussion with the treating dentist if they give advice to delay therapy. Provision of published recommendations, such as those from the Bone Health and Osteoporosis Foundation and, for the dentist, the American Dental Association, is helpful in this regard.5,9

In the rare event of osteonecrosis of the jaw during bisphosphonate therapy there is evidence for the effectiveness of teriparatide — 20 µg daily for 8 weeks — to promote healing.10 However, there has been only one case study reported where teriparatide has been used for osteonecrosis of the jaw after denosumab.11 The increase in bone turnover with this management may be beneficial for healing of osteonecrosis of the jaw but represents a risk for osteoporotic fracture. Combined denosumab and teriparatide may well be appropriate therapy if this situation arises but there are no published data on the use of this regimen for osteonecrosis of the jaw and it does not, at present, meet the Australian Pharmaceutical Benefits Scheme reimbursement guidelines.

This case highlights that a delay in denosumab therapy, often recommended for dental work, can result in a rebound of bone resorption and multiple vertebral fractures. Withholding antiresorptive agents for dental work has not been shown to alter the risk of developing osteonecrosis of the jaw.

Education of the patient about the risks of stopping denosumab and communication with the treating dentist are essential in averting this preventable adverse event.