Skeletal adverse effects of drugs used for osteoporosis
Osteonecrosis of the jaw
Antiresorptive drugs (bisphosphonates and denosumab) are associated with a small increase in the incidence of osteonecrosis of the jaw, known as medication-related osteonecrosis of the jaw when associated with drug therapy. This is a rare complication that has mainly occurred in patients who had dental surgery during treatment with a high-dose intravenous bisphosphonate for multiple myeloma or metastatic cancer. The incidence of medication-related osteonecrosis of the jaw in patients taking an antiresorptive drug for osteoporosis ranges from fewer than 1 to 150 per 100 000 patient-years1. Although medication-related osteonecrosis of the jaw has significant consequences for the patient and can be difficult to treat, the benefit of antiresorptive therapy in preventing fractures far outweighs the low risk of medication-related osteonecrosis of the jaw in most patients.
The risk of medication-related osteonecrosis of the jaw is highest following dental extractions and dental implant insertion, and in periodontal disease. Advise patients starting an antiresorptive drug that ideally, they should have a dental review, and to notify the dentist that they are starting (or have recently started) antiresorptive therapy. Early dental assessment and initiation of dental treatment reduces the incidence of medication-related osteonecrosis of the jaw. Any necessary dental treatment should be completed before or shortly after starting antiresorptive therapy (eg within 6 months)—the risk of medication-related osteonecrosis of the jaw in osteoporotic patients remains low in the early stage of treatment.
To help prevent the need for an invasive dental procedure during antiresorptive treatment, advise patients to maintain good oral hygiene, have regular dental health reviews, and to seek early management of any oral or dental concerns. See also Maintaining optimal oral health for information about prevention of medication-related osteonecrosis of the jaw. Other factors that increase the risk of medication-related osteonecrosis of the jaw include smoking, glucocorticoid therapy, immune compromise, diabetes, anaemia, hyperthyroidism and dialysis. Bisphosphonate therapy for more than 4 years also increases the risk of medication-related osteonecrosis of the jaw.
If an invasive dental procedure is necessary, discuss the patient’s risk of medication-related osteonecrosis of the jaw, as well as the risk associated with the procedure, with the treating dentist. See Risk assessment for medication-related osteonecrosis of the jaw for a guide to stratifying the risk of medication-related osteonecrosis of the jaw. For a patient at higher risk of medication-related osteonecrosis of the jaw, referral to an oral maxillofacial surgeon for the procedure is appropriate.
Recommendations for patients taking an antiresorptive drug who require an invasive dental procedure vary among international and local guidelines2345. Interruption of antiresorptive therapy (a ‘drug holiday’), or timing of the procedure to coincide with a low serum drug concentration, have been suggested to reduce the risk of medication-related osteonecrosis of the jaw. These practices are based on extrapolation of the drug pharmacokinetics in the serum and on bone physiology; however, outcome data to support them are not available. Interruption is never appropriate for denosumab, as this leads to a rapid increase in bone turnover and loss of BMD, and increases the risk of spontaneous vertebral fracture (see Denosumab). See also Drug holidays and scheduling of procedures for more information.
Romosozumab has also been associated with an increased risk of osteonecrosis of the jaw, but at the time of writing the frequency is unknown.
Atypical fractures of the femur
Atypical subtrochanteric or diaphyseal femoral fractures are rare. Antiresorptive therapy increases the risk of atypical femoral fractures. The risk increases with duration of therapy, although the absolute incidence remains low (113 per 100 000 patient-years6 after 8 to 10 years of treatment). The risk appears to decline after stopping bisphosphonate therapy. The benefit of antiresorptive therapy in preventing fractures outweighs the low risk of atypical femoral fractures. About 7% of cases of atypical femoral fractures occur without exposure to either a bisphosphonate or denosumab.
A prodrome of thigh, groin or hip pain occurs in around 70% of patients with an atypical femoral fracture. Advise patients receiving prolonged bisphosphonate or denosumab therapy (more than 3 years) to report unexplained thigh or groin pain. If these symptoms develop, perform femoral shaft x-ray. An isotope bone scan or magnetic resonance imaging (MRI) may also be needed. Up to 40% of atypical femoral fractures are bilateral, so both femurs should be imaged. If an atypical femoral fracture is confirmed, stop the bisphosphonate or denosumab and urgently refer the patient to a specialist centre with bone and orthopaedic expertise.
At the time of writing, it is unclear at what frequency romosozumab causes atypical fractures of the femur.