What is the role of Denosumab (denosumab) in the management of osteoporotic (fragility) fractures?

From the Guidelines

Denosumab is a highly effective treatment for preventing osteoporotic fractures in postmenopausal women and men with osteoporosis, with a significant reduction in vertebral and nonvertebral fractures, as demonstrated in the FREEDOM trial 1. The standard dosage of denosumab is 60 mg administered as a subcutaneous injection every 6 months, which has been shown to increase bone mineral density and reduce fracture risk in various patient populations, including postmenopausal women and men receiving androgen deprivation therapy for nonmetastatic prostate cancer 1. Key benefits of denosumab include:

• Significant reduction in vertebral and nonvertebral fractures, with a relative risk of 0.32 for new radiographic vertebral fractures and 0.80 for nonvertebral fractures 1
• Increased bone mineral density at the lumbar spine, total hip, femoral neck, and distal third of the radius 1
• Particular value for patients with renal impairment, where bisphosphonates may be contraindicated 1 However, it's essential to note that:
• Discontinuation of denosumab can lead to rapid bone loss and increased fracture risk, so a transition to another antiresorptive agent should be considered if stopping treatment 1
• Common side effects include musculoskeletal pain, hypercholesterolemia, and skin infections, while rare but serious adverse effects include osteonecrosis of the jaw and atypical femur fractures, particularly with long-term use 1 Overall, denosumab is a valuable treatment option for preventing osteoporotic fractures, with a favorable risk-benefit profile when used appropriately and with careful monitoring.

From the FDA Drug Label

The efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled trial. Women were randomized to receive subcutaneous injections of either placebo (N = 3906) or Prolia 60 mg (N = 3902) once every 6 months. The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Prolia significantly reduced the incidence of new morphometric vertebral fractures at 1,2, and 3 years (p < 0.0001), as shown in Table 3. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Prolia-treated women. The absolute risk reduction was 4. 8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.

The role of Denosumab in the management of osteoporotic (fragility) fractures is to reduce the incidence of new vertebral fractures. Key points include:

• Significant reduction in the incidence of new morphometric vertebral fractures at 1,2, and 3 years
• Absolute risk reduction of 4.8% and relative risk reduction of 68% for new morphometric vertebral fractures at year 3
• Primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years 2

From the Research

Role of Denosumab in Osteoporotic Fracture Management

• Denosumab is a fully human monoclonal antibody that inhibits osteoclast-mediated bone resorption by neutralizing the receptor activator of nuclear factor kappa-Β ligand (RANKL) 3, 4.
• It has been shown to reduce the risk of new vertebral, non-vertebral, and hip fractures in women with postmenopausal osteoporosis 3.
• A post-hoc analysis of the FREEDOM trial found that denosumab significantly reduced the risk of secondary fragility fractures by 39% compared to placebo 3.

Efficacy of Denosumab in Preventing Fractures

• Denosumab has been found to reduce the risk of fragility fractures by 40% in the overall population, with similar results observed regardless of age or prior fracture site 3.
• The risk of vertebral fractures was also reduced by denosumab, with a hazard ratio of 0.31 (95% CI, 0.23 to 0.41) compared to placebo 3.
• However, delayed administration of subsequent denosumab doses by more than 16 weeks may be associated with an increased risk of vertebral fracture compared to on-time dosing 5.

Effect of Denosumab on Quality of Life and Disability

• Denosumab has been found to reduce back pain-related disability and improve health-related quality-of-life (HRQoL) in post-menopausal women with vertebral fractures 6.
• The Spine Pain Index (SPI) and SF-12 Physical Health Composite Score (PCS) were significantly improved after 12 months of denosumab treatment 6.
• Denosumab also improved the EuroQol-5D (EQ-5D-3L index and EQ-VAS) scores, indicating an improvement in overall quality of life 6.

Long-term Safety and Efficacy of Denosumab

• Denosumab has been found to be safe and effective for long-term treatment of osteoporosis, with a reversible reduction in bone turnover markers and a continuous increase in bone mineral density 4.
• The 10-year FREEDOM Extension study found that denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity 7.
• However, it is essential to transition to another anti-osteoporosis therapy after denosumab discontinuation to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs) 7.