Denosumab in the Treatment of Osteoporosis: 10 Years Later: A Narrative Review

Abstract

The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, 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. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis-10 Years Later (MP4 62727 KB).

Keywords: Bone density; Endocrinology; General medicine; Orthopedics; Osteoporosis; Therapeutics.

Fig. 1

Graphical summary of FREEDOM and FREEDOM Extension data. The primary endpoint of the 3-year FREEDOM trial in women with postmenopausal osteoporosis was the rate of new vertebral fractures over 3 years. All subjects who completed that trial without discontinuing treatment or missing more than one dose of either denosumab or placebo were eligible to enroll in the open-label, 7-year FREEDOM Extension, in which all participants received denosumab. Patients formerly in the placebo group were enrolled in the “crossover group,” whereas those who had received denosumab continued on denosumab as the “long-term group.” The primary objective of FREEDOM Extension was to evaluate the safety and tolerability of denosumab for up to 7 (crossover group) or 10 (long-term group) years of treatment

Fig. 2

Denosumab mechanism of action. A In response to pro-resorptive stimuli such as estrogen depletion after menopause, RANKL released from osteoblasts and osteocytes leads to osteoclast formation (②, ③) and activation (④, ⑤). Osteoclast activation results in release of enzymes involved in the degradation of collagens and other proteins, cavity formation, and a decrease in bone mass (⑥) [–22]. To physiologically suppress bone resorption, osteoclasts produce a soluble decoy protein called osteoprotegerin (OPG) that binds to and neutralizes RANKL (①), thereby preventing RANKL from binding to RANK on precursor cells and mature osteoclasts [21]. B Denosumab acts in a manner similar to that of OPG and thus inhibits development of osteoclasts from precursor cells (⑦) as well as the function and survival of differentiated osteoclasts (⑧) [23, 24]. This leads to a reduction in the release of protein-degrading enzymes, promotes refilling of resorption cavities by osteoblasts and leaves modeling-based bone formation unabated (⑨). Adapted from References [20] and [21]

Fig. 3

Effects of antiresorptive osteoporosis treatments on hip BMD. Data derived from long-term follow-up studies of the FLEX trial (alendronate, 5–10 mg peroral per day), the HORIZON trial (zoledronic acid, 5 mg intravenous infusion per year), and the FREEDOM trial (denosumab, 60 mg subcutaneous injection every 6 months) [18, 33, 34]. As data are derived from separate studies, formal comparisons between changes in BMD have not been made. Error bars indicate 95% confidence intervals. Adapted from Reference [35]

Fig. 4

Relationship between BMD T-score and fracture risk. An analysis of FREEDOM Extension data showed a clear relationship between hip BMD T-scores achieved in response to denosumab treatment and subsequent 1-year incidence of A nonvertebral or B vertebral fractures. Achievement of hip BMD T-scores > −1.5 did not further reduce the nonvertebral fracture incidence. Adapted from Reference [31]