Denosumab and Male Infertility: a Randomized Controlled Double-blinded Intervention Study

INTRODUCTION

Infertility is a serious problem estimated to affect 7-26% of all couples globally (1;2). Approximately 9% of all newborns were conceived by assisted reproductive techniques in 2013 in Denmark (Danish Fertility Society). Impaired semen quality is the causal or contributing factor in almost 50% of all cases of infertility (3;4). Today, there exist no treatments that can improve semen quality of most infertile men. Instead, the vast majority of infertile couples are treated with assisted reproductive techniques (ART) independently of the aetiology (maternal/paternal) causing the infertility (3;5-8). The treatment choice ranges from mild intrauterine inseminations (IUI) to more invasive in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). ART is successful for more than 70% of all couples. However, ART is very expensive and associated with maternal side effects due to the invasive methodology and the need for hormonal treatment, often for several months (9-11). Infertility is also a financial burden to society due to the costs of ART to maintain an acceptable annual birth rate.

Fertility potential determined by semen quality is established already as a fetus (12). In case the testes don't develop normally, reduced semen quality in adulthood will be the result as a result of impaired Sertoli cell function. Up until today it has barely been investigated whether intervention during adulthood can improve semen quality.

Our recent studies using both human testis and Vitamin D receptor knock-out mice revealed that the vitamin D regulated bone factor RANKL is expressed in the testis (13;14). This is a novel finding, because up until now RANKL has only been known to affect bone homeostasis and to some extend influence the immune system, inflammation and lactation (15;16). In the skeleton RANKL is expressed in osteoblasts and binds to its specific receptor RANK in osteoclasts to induce osteoclastogenesis and bone resorption (17). This activation is controlled by osteoprotegerin (OPG), which binds to the ligand domain of RANKL and thus inhibits RANK activation and osteoclastogenesis, ultimately reducing bone resorption (18). This knowledge has been utilized into development of an OPG-analogue drug, a recombinant human monoclonal IGg2 antibody Denosumab (Prolia by Amgen), which inhibits RANKL and thereby bone resorption and is indicated for use in both osteoporosis and bone metastases (19;20). Prolia has in several clinical studies shown to be safe and is approved as treatment for osteoporosis in both men and women (21-24). Newer data indicate that RANKL/OPG may be involved in regulation of pancreatic function, insulin and glucagon production which support a possible indirect effect on reproduction through bone-pancreatic-gonadal axis.

AIM OF STUDY