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Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0·09). Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Amgen.

In this trial, women between the ages of 60 and 90 with low bone mineral density received twice-yearly subcutaneous injections of denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, which inhibits the development and activity of osteoclasts, or placebo. Denosumab was associated with a reduced risk of vertebral, nonvertebral, and hip fractures. Women between the ages of 60 and 90 with low bone mineral density received twice-yearly subcutaneous injections of denosumab, which inhibits the development and activity of osteoclasts, or placebo. Denosumab was associated with a reduced risk of vertebral, nonvertebral, and hip fractures. Fractures are a major cause of disability and health care costs. 1 , 2 The use of denosumab is a novel approach to fracture prevention. It is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), a cytokine that is essential for the formation, function, and survival of osteoclasts. 3 By binding RANKL, denosumab prevents the interaction of RANKL with its receptor, RANK, on osteoclasts and osteoclast precursors and reversibly inhibits osteoclast-mediated bone resorption. 4 In previous trials, the subcutaneous administration of 60 mg of denosumab every 6 months reduced bone turnover and increased bone mineral density. 5 – 8 We . . .

Men receiving androgen-deprivation therapy for nonmetastatic prostate cancer are at high risk for bone loss and fractures. This placebo-controlled study investigated the effects of denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, on bone mineral density and fractures in such men. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures. This study investigated the effects of denosumab on bone mineral density and fractures in men receiving androgen-deprivation therapy for prostate cancer. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures. Prostate cancer is the most common newly diagnosed cancer in men worldwide. 1 In the United States, prostate cancer accounts for approximately 25% of all new cancer diagnoses and 10% of all deaths from cancer. 2 Androgen-deprivation therapy, through bilateral orchiectomy or treatment with gonadotropin-releasing hormone (GnRH) agonists, is the standard first-line therapy for metastatic prostate cancer. 3 , 4 GnRH agonists are also frequently used to treat men with nonmetastatic prostate cancer. 5 Androgen-deprivation therapy improves disease-free and overall survival in various clinical settings, such as when used as adjuvant treatment in men with locally advanced prostate cancer who are undergoing radiation therapy 6 , . . .

Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.

Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings.Long-term treatment with the anti-resorptive drug denosumab results in a continuous gain in bone mineral density, whereas denosumab withdrawal results in a transient overshoot in bone turnover, with rapid bone loss. This Perspective explores the potential mechanisms underlying these effects.

Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity. GCT is rich in osteoclast-like giant cells and contains mononuclear (stromal) cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. We investigated the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT. In this open-label, single-group study, 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous denosumab 120 mg monthly (every 28 days), with loading doses on days 8 and 15 of month 1. The primary endpoint was tumour response, defined as elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25. Study recruitment is closed; patient treatment and follow-up are ongoing. The study is registered with Clinical Trials.gov, NCT00396279. Two patients had insufficient histology or radiology data for efficacy assessment. 30 of 35 (86%; 95% CI 70–95) of evaluable patients had a tumour response: 20 of 20 assessed by histology and 10 of 15 assessed by radiology. Adverse events were reported in 33 of 37 patients; the most common being pain in an extremity (n=7), back pain (n=4), and headache (n=4). Five patients had grade 3–5 adverse events, only one of which (grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy) was deemed to be possibly treatment related. Five serious adverse events were reported although none were deemed treatment related. Further investigation of denosumab as a therapy for GCT is warranted. Amgen, Inc.

Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology.

A variety of osteolytic factors have been identified from breast cancer cells leading to osteolysis, but less is known about which factor plays an essential role in the initiation process prior to the overt vicious osteolytic cycle. Here, we present in vitro and in vivo evidences to clarify the role of interleukin-11 (IL-11) as an essential contributor to breast cancer bone metastasis mediated osteolysis. Animal studies showed that bone specific metastatic BoM-1833 cells induce earlier onset of osteolysis and faster tumor growth compared with MCF7 and parental MDA-MB-231 cells in BALB/c-nu/nu nude mice. IL-11 was further screened and identified as the indispensable factor secreted by BoM-1833 cells inducing osteoclastogenesis independently of receptor activator of nuclear factor κB ligand (RANKL). Mechanistic investigation revealed that the JAK1/STAT3 signaling pathway as a downstream effector of IL-11, STAT3 activation further induces the expression of c-Myc, a necessary factor required for osteoclastogenesis. By inhibiting STAT3 phosphorylation, AG-490 was shown effective in reducing osteolysis and tumor growth in the metastatic niche. Overall, our results revealed the essential role and the underlying molecular mechanism of IL-11 in breast cancer bone metastasis mediated osteolysis. STAT3 targeting through AG-490 is a potential therapeutic strategy for mitigating osteolysis and tumor growth of bone metastatic breast cancer.

Summary Denosumab is an injectable drug that reduces the risk of fractures. The objective was to estimate the cost-effectiveness of denosumab in a Swedish setting, also accounting for poor adherence to treatment. Denosumab is cost-effective, particularly for patients at high risk of fracture and low adherence to oral treatments. Introduction Denosumab is a novel biologic agent developed for the treatment of osteoporosis and osteoporotic fractures that has been shown to reduce the risk of fractures in a phase III trial. The objective of this study was to estimate the cost-effectiveness of denosumab from a societal perspective compared with generic alendronate, branded risedronate, strontium ranelate, and no treatment in a Swedish setting. Methods A Markov cohort model was used to estimate the cost-effectiveness of denosumab given for up to 5 years to a typical Swedish patient population (women aged 71 years, T-score ≤ −2.5 SD and a prevalence of morphometric vertebral fractures of 34%). The model included treatment persistence and residual effect after discontinuation assumed to be equal to the time on treatment. Persistence with the comparator treatments and with denosumab was derived from prescription data and a persistence study, respectively. Results The base-case incremental cost-effectiveness ratios were estimated at €27,000, €12,000, €5,000, and €14,000, for denosumab compared with generic alendronate, risedronate, strontium ranelate, and no treatment, respectively. Sub-optimal persistence had the greatest impact in the comparison with generic alendronate, where the difference in drug cost was large. Conclusion Improving persistence with osteoporosis treatment impacts positively on cost-effectiveness with a larger number of fractures avoided in the population targeted for treatment. Denosumab is a cost-effective alternative to oral osteoporosis treatments, particularly for patients at high risk of fracture and low expected adherence to oral treatments.

Bone disease in multiple myeloma (MM) is characterized by lytic bone lesions, which can cause severe bone pain, pathologic fractures and hypercalcemia. However, the lytic bone disease in MM differs from that in other cancer patients who have lytic bone metastases. Although increased osteoclastic bone destruction is involved in MM and other tumors involving bone, in contrast to other tumors, once the MM tumor burden exceeds 50% in a local area, osteoblast activity is either suppressed or absent. 1 The basis for this severe imbalance between increased osteoclastic bone resorption and decreased bone formation has been a topic of intensive investigation over the last several years and will be reviewed in this article.