New and emerging concepts in the use of denosumab for the treatment of osteoporosis

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Abstract

<p class="first" id="d5177244e106">Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine expressed by cells of the osteoblast lineage that is a key regulator of osteoclastic bone resorption. By binding and neutralizing RANKL, denosumab inhibits osteoclast differentiation, activity, and survival. Clinical trials in postmenopausal women with osteoporosis have shown that it reduces the risk of vertebral fractures, nonvertebral fractures, and hip fractures, with a generally favorable safety profile. With a dose of 60 mg subcutaneously every 6 months, it is approved for: treatment of postmenopausal women and men with osteoporosis, and for women and men with glucocorticoid-induced osteoporosis who are at high risk for fracture; treatment to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer; and treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. Atypical femur fractures and osteonecrosis of the jaw have been reported in patients treated with denosumab. Discontinuation of denosumab is followed by rapidly rising bone turnover markers, decreasing bone density, and vertebral fracture risk that returns to baseline, with a possible increase in the risk of multiple vertebral fractures. Further study is needed to clarify this potential risk. After stopping long-term denosumab, patients should be switched to another antiresorptive agent to maintain the benefit achieved with denosumab. </p>

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Functions of RANKL/RANK/OPG in bone modeling and remodeling.

Brendan F Boyce, Lianping Xing (2008)

The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.

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Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.

Sundeep Khosla, David Burr, Jane Cauley … (2007)

ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.

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Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.

Dennis M. Black, Ann Schwartz, Kristine Ensrud … (2006)

The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. clinicaltrials.gov Identifier: NCT 00398931.