Individualized therapy decisions in osteoporosis

The chronic metabolic disease osteoporosis is particularly prevalent among postmenopausal women and can lead to severe health complications [1]. Judith Everts-Graber, MD, and Prof. Serge Ferrari discuss in a video interview the optimal therapy strategy to keep the fracture risk low in the long term.

Already at the annual congress of the Swiss Association against Osteoporosis (SVGO) in May 2022, Prof. Serge Ferrari, University Hospital Geneva, and Judith Everts-Graber, MD, OsteoRheuma Bern, debated the pros and cons of long-term treatment of osteoporosis in postmenopausal women with the human anti-RANKL monoclonal antibody denosumab (Prolia®) [2]. Their joint conclusion: The optimal therapy strategy depends on the individual conditions and needs of each patient.

Based on this, the expert gets to the bottom of the following questions, among others, in this video interview:

Which patients can benefit from treatment with denosumab?
What criteria should be met for a change in therapy to bisphosphonates?
When is long-term treatment with denosumab the optimal option for a patient?

Background information on denosumab

Denosumab may reduce fracture risk in postmenopausal women in the long term [3]

Six-monthly administration of denosumab significantly reduced the risk of vertebral fractures, nonvertebral fractures, and hip fractures in postmenopausal women after only three years compared with placebo in the randomized phase III FREEDOM trial and also increased bone mineral density (BMD) [4]. In the seven-year FREEDOM open-label extension study, BMD even increased in the long term under denosumab and fracture risk remained permanently low [3]. Compared with the first three years of treatment, denosumab showed an additional 26% (P = 0.008) and 28% (P < 0.001) reduction in the rate of nonvertebral fractures after a total of four to 10 and four to seven years, respectively, despite an aging study population. These observations support the notion that continuously increasing BMD under long-term denosumab treatment is associated with a further decrease in the risk of nonvertebral fractures [5].

Denosumab shows positive benefit-risk ratio over 10 years [5]

In the FREEDOM open-label extension study, a favorable safety profile was observed with long-term denosumab treatment, in addition to increasing efficacy. The annual exposure-adjusted incidence of adverse events with denosumab decreased from 165.3 to 95.9 events per 100 patient-years over 10 years, with the incidence of serious adverse events remaining similar over time [3]. Atypical femur fractures and osteonecrosis of the jaw occurred one and five times, respectively, per 10,000 patient-years. The risk-benefit ratio of long-term treatment with denosumab can therefore be considered positive overall [5].

Denosumab in the current SVGO recommendations [6]

The SVGO’s current treatment recommendations are based on a person’s individual risk of sustaining a fracture. Denosumab is recommended as first-line therapy in the high-risk category and as follow-up therapy to time-limited anabolic treatment in the very-high- and imminent-risk category, among others [6]. To keep the fracture risk permanently low, denosumab should be used on a long-term basis. If a change in therapy is nevertheless considered, the reversibility of beneficial effects under denosumab must be taken into account and temporary bisphosphonate treatment must be initiated after discontinuation to counteract loss of bone density [7, 8].

Conclusion

Treatment with denosumab can significantly reduce fracture risk in postmenopausal women over the long term while demonstrating a favorable safety profile [5]. The optimal therapeutic strategy should be tailored to the individual patient, especially in the long term, concluded Judith Everts-Graber, MD, and Prof. Serge Ferrari.

Literature

Sözen T et al. An overview and management of osteoporosis. Eur J Rheumatol, 2017. 4(1): p. 46-56.
Current technical information Prolia® (denosumab). www.swissmedicinfo.ch.
Bone HG et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol, 2017. 5(7): p. 513-523.
Cummings SR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med, 2009. 361(8): p. 756-65.
Ferrari S et al. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab, 2019. 104(8): p. 3450-3461.
Ferrari S et al. 2020 recommendations for osteoporosis treatment according to fracture risk from the Swiss Association against Osteoporosis (SVGO). Swiss Med Wkly, 2020. 150: p. w20352.
Meier C et al. Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the Swiss Association against Osteoporosis (SVGO/ASCO). Swiss Med Wkly, 2017. 147:w14484.
Kendler DL et al. Denosumab in the Treatment of Osteoporosis: 10 Years Later: A Narrative Review. Adv Ther, 2022. 39(1): p. 58-74.