In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).

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The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis.Introduction: RANKL is an essential osteoclastic differentiation and activation factor. Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebocontrolled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bonespecific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers. Results and Conclusions: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of Ϫ81% in the 3.0 mg/kg AMG 162 group compared with Ϫ10% in the placebo group; serum NTX changes were Ϫ56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to ϳ3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease Ͼ10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; =0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%;=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Objective. To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor ␣ agent etanercept and the anti-interleukin-1 agent anakinra.Methods. Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed.Results. Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P ‫؍‬ 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent.Conclusion. Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

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Purpose: Receptor activator of nuclear factor-nB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. Experimental Design: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. Results: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. Conclusions: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.The propensity of breast cancer cells to metastasize and proliferate in bone is currently explained by a ''seed and soil'' concept (1, 2). Once breast cancer cells colonize the bone marrow, they are attracted to bone surfaces by products of resorbing bone and destroy bone via osteoclast stimulation. The importance of direct osteolytic effects of metastatic cancer cells, including the effects of collagenases, remains uncertain. Breast cancer cells (the ''seed'') seem to secrete factors, such as parathyroid hormone-related protein, that potentiate the development of metastases in the skeleton, which constitutes a fertile ''soil'' rich in cytokines and growth factors that stimulate growth of breast cancer cells. Osteoclasts arise from precursor cells in the monocyte-macrophage lineage. Several osteoclastogenic factors have been implicated in the increased recruitment and activity of osteoclasts in myeloma (3). Active osteoclasts are found in proximity to tumor cells (4) and play a key role in bone lysis in patients with multiple myeloma or cancer-related bone metastases. Normal homeostatic mechanisms are unable to control osteoclastic bone resorption in this setting and the bone destruction often leads to dramatic complications, such as pathologic vertebral and long-bone fractures, pain requiring radiotherapy, spinal cord compression, and hypercalcemia (5).Desp...

The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162. a human monoclonal antibody to RANKI,, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis.Introduction: RANKL is an essential osteoclastic differentiation and activation factor. Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind. placebocontrolled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:l ratio). AMG 162 doses were 0.01,0.03, 0.1.0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-