Denosumab and Osteoporosis - A JAMA Review Save

An overview of denosumab use in osteoporosis (OP)  by Bauer and Ensrud was published in JAMA. 

Denosumab plays an important role in OP guidelines, often secondary to antiresorptive agents such as bisphosphonates (usual first-line therapy).  Yet, denosumab is recommended as it is more convenient, has fewer gastrointestinal adverse effects, and its use is increasing while bisphosphonate use remains constant.  3-year persistence with denosumab and bisphosphonates are similar (approximately 50%).  The authors review the current available evidence on Denosumab for Treatment for Fracture Prevention in Primary Care Practice. 

Initiation of Osteoporosis Drug Treatment

• Bisphosphonates remain first-line pharmacologic treatment 
  • patients at very high fracture risk - consider anabolic therapy with PTH analogs or romosozumab
• Intravenous bisphosphonates may be used if there are concerns about oral bisphosphonate 
• Refer patients with advanced CKD to a specialist with expertise in CKD and metabolic bone disease.

Prior to Denosumab Use for Any Reason

• Patients must be informed of the planned treatment duration and need for bisphosphonate treatment after denosumab discontinuation.
• Patients must be carefully counseled about not delaying or discontinuing injections without medical guidance.

Duration of Denosumab Treatment

• The antifracture efficacy and safety of denosumab treatment beyond 3 years of use have not been established in placebo-controlled trials.
• Despite the lack of evidence, some clinicians prescribe denosumab for 10 years or longer.

Switching From Bisphosphonate to Denosumab Treatment

• In patients who remain at high fracture risk after 3-5 years of bisphosphonates or experience multiple fractures while adherent to bisphosphonates, it is uncertain whether switching to denosumab will reduce fracture risk or prevent AFF or ONJ.^b
• Prior to changing therapy, evaluate patients remaining at high fracture risk for adherence to bisphosphonate treatment and consider consultation with osteoporosis specialist to rule out secondary causes of osteoporosis.

Denosumab Discontinuation

• Discontinuation of denosumab is associated with an increased fracture risk, especially multiple vertebral fractures.
• Unless contraindicated, intravenous zoledronate should be administered 6 months after last denosumab injection.
• Patients receiving >2 years of denosumab treatment or with a history of vertebral fracture should be referred to a specialist in metabolic bone disease prior to discontinuation.

Bisphosphonates have a long half-life in bone. But the discontinuation or delayed administration of denosumab after more than 4 injections (or more than 2 years of treatment) leads to a rapid reversal of denosumab’s effect, with accelerated bone loss and an increased risk for rebound fractures (especially multiple vertebral fractures). 

Unlike bisphosphonates, denosumab is not cleared by the kidney. Nearly all patients with stage 4 and 5 CKD have disorders in mineral and bone metabolism (CKD-MBD) manifesting in disturbances in mineral metabolism, vascular calcification, and bone fragility.⁹ However, the pathophysiology of bone fragility and increased fracture risk in CKD-MBD is complex and the diagnosis of osteoporosis can be difficult and cannot be made based on biochemical or bone density testing alone.  No clinical trials with fracture end points have evaluated efficacy and safety of osteoporosis drug treatment in patients with advanced chronic kidney disease (CKD), but some clinicians have assumed that denosumab is the preferred treatment for osteoporosis in this patient population.  A black box warning for severe hypocalcemia in patients with advanced CKD treated with denosumab was issued by the FDA in January 2024. Denosumab treatment in patients with late-stage CKD should only be considered in consultation with a nephrologist with expertise in the diagnosis and management of CKD-MBD.