Denosumab

Additional information

Female sex is one of the risk factors for osteoporosis fragility fractures. The same type of fractures occurs in men and women with osteoporosis. Women are more prone to spinal fractures, due to a relatively abrupt bone density loss after menopause. Men have a higher peak bone mass (in general), and the bone density deteriorates more successively from the age of 40 [1].

Osteoporosis in men is largely underdiagnosed and undertreated. Also, in those men with a history of fractures and a high risk of new fractures. Although there are differences between men and women in the pathophysiology of osteoporosis, such as in the pattern of bone loss, similarities like clinical risk factors predominate. Drug approval for osteoporosis treatment in men has generally been based on small-scale bridging trials with bone mineral density (BMD) endpoint for substances previously shown to reduce fracture risk in postmenopausal osteoporosis [2, 3].

Pharmacokinetics and dosing

According to the original manufacturer, denosumab pharmacokinetics is similar in men and women [4]. No studies with a clinically relevant sex analysis regarding the dosing of denosumab have been found.

Effects

Well-powered trials evaluating clinical fracture risk reduction in male osteoporosis are lacking. To estimate the anti-fracture efficacy of denosumab in men, trials have used assumptions concerning drug efficacy derived from trials in postmenopausal women [5]. For instance, percentage change from baseline to month 12 in lumbar spine BMD in women in the FREEDOM trial (placebo 0.7 vs. denosumab 4.8) was comparable to men in the ADAMO trial (placebo 1.0 vs. denosumab 4.8) [5-7].

Dose exposure-response relationship for denosumab was determined in patients with bone metastases from solid tumors. Patients (92 men, 281 women) received denosumab as single or multiple subcutaneous doses ranging from 30-180 mg administrated every 4 or 12 weeks for up to 3 years. Denosumab efficacy and potency did not differ between men and women [8].

Adverse effects

Denosumab-associated hypocalcemia (DAH) was associated with male sex (OR 4,30) in a retrospective cohort study in patients with osteoporosis or metastatic bone disease (41 men, 114 women) [9]. However, in another retrospective analysis based on medical records in osteoporotic community-dwelling patients treated with denosumab (134 men, 1871 women), a patient’s sex was not predictive of DAH [10].

Reproductive health issues

Denosumab may cause fetal harm when a man treated with denosumab has unprotected sexual intercourse with a pregnant partner [11]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish Janusmed fosterpåverkan).

Other information

In a Spanish population-based cohort study trends of use of anti-osteoporosis drugs were analyzed. Out of 1.5 million participants, 135,410 received anti-osteoporosis drug treatment during 2001–2013. Prevalence was higher in women (6.1%) compared to men (1.1%). The incidence rate (IR) was 24.90 in women and 2.77 in men. IRs for denosumab from marketing in 2011 were 0.03–2.64 and 0.09–0.15 in women and men respectively [12].