Does denosumab (Prolia) lose its effectiveness after 10 years of treatment for osteoporosis?

From the Guidelines

Denosumab (Prolia) does not lose its effectiveness after 10 years of treatment for osteoporosis, and its benefits in maintaining bone mineral density (BMD) and reducing fracture risk can persist with long-term continuous treatment. The FREEDOM study and its open-label extension, as reported by Ferrari et al 1, demonstrated that denosumab therapy for up to 7 years resulted in a further reduction in the nonvertebral fracture rate, indicating sustained efficacy. Although the provided evidence does not directly address the 10-year mark, the available data suggest that denosumab's mechanism of action, which involves inhibiting RANK ligand to reduce osteoclast formation and activity, thereby decreasing bone resorption and increasing bone density, remains effective with long-term use 1.

Key points to consider in the management of patients on long-term denosumab include:

• The importance of regular monitoring with DEXA scans every 1-2 years to assess ongoing treatment effectiveness 1.
• The potential for a rapid decrease in BMD and increased risk of multiple vertebral fractures if denosumab is discontinued without transitioning to another therapy 1.
• The need for individualized decision-making based on the patient's current fracture risk, BMD measurements, history of fractures, and other medical conditions when considering alternatives to denosumab 1.
• Options for patients who have been on denosumab for 10 years and are considering alternatives, including continuing denosumab, switching to a bisphosphonate like alendronate or zoledronic acid, or considering anabolic agents like teriparatide or romosozumab if there's evidence of very high fracture risk 1.

It is crucial to weigh the benefits and risks of long-term denosumab treatment and to consider the patient's overall clinical context, including their osteoporosis risk factors and history of fractures, when making decisions about continuing or altering therapy 1.

From the Research

Denosumab Effectiveness Over 10 Years

• Denosumab (Prolia) has been shown to maintain its benefits in reducing the risk of vertebral, nonvertebral, and hip fractures and increasing bone mineral density (BMD) across skeletal sites for up to 10 years of therapy 2.
• The FREEDOM trial and its 7-year open-label extension demonstrated that denosumab reduced the risk of fractures and increased BMD, with these benefits maintained over up to 10 years of therapy 2.

Discontinuation of Denosumab

• Discontinuation of denosumab can lead to a rebound of bone turnover markers and loss of accrued bone mineral density, resulting in an increased risk of fractures, particularly multiple vertebral fractures 3, 4.
• Studies have investigated the optimal treatment for patients who have sustained rebound-associated vertebral fractures after denosumab discontinuation, with results suggesting that antiresorptive and anabolic treatments can be effective in preserving BMD 5.

Treatment Duration and Discontinuation

• There is ongoing debate about the optimal duration of denosumab treatment, with some studies suggesting that treatment should be continued indefinitely for many patients 4.
• However, discontinuation of denosumab may be necessary due to non-adherence, lack of efficacy, or concerns about side effects, and sequential osteoporosis therapy may be necessary to reduce the risk of multiple vertebral fractures 4.
• Treatment with zoledronate after denosumab discontinuation has been investigated, with results showing that it may not fully prevent loss of BMD, regardless of the timing of the zoledronate infusion 6.