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Michael S Ominsky, Steven K Boyd, Aurore Varela, Jacquelin Jolette, Melanie Felx, Nancy Doyle, Nacera Mellal, Susan Y Smith, Kathrin Locher, Sabina Buntich, Ian Pyrah, Rogely W Boyce
Romosozumab (Romo), a humanized sclerostin antibody, is a bone-forming agent under development for treatment of osteoporosis. To examine the effects of Romo on bone quality, mature cynomolgus monkeys (cynos) were treated 4 months post-ovariectomy (OVX) with vehicle, 3, or 30 mg/kg Romo for 12 months, or with 30 mg/kg Romo for 6 months followed by vehicle for 6 months (30/0). Serum bone formation markers were increased by Romo during the first 6 months, corresponding to increased cancellous, endocortical, and periosteal bone formation in rib and iliac biopsies at months 3 and 6...
November 10, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Socrates E Papapoulos
No abstract text is available yet for this article.
November 4, 2016: Nature Reviews. Endocrinology
Felicia Cosman, Daria B Crittenden, Jonathan D Adachi, Neil Binkley, Edward Czerwinski, Serge Ferrari, Lorenz C Hofbauer, Edith Lau, E Michael Lewiecki, Akimitsu Miyauchi, Cristiano A F Zerbini, Cassandra E Milmont, Li Chen, Judy Maddox, Paul D Meisner, Cesar Libanati, Andreas Grauer
Background Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. Methods We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months...
October 20, 2016: New England Journal of Medicine
Luc Chouinard, Melanie Felx, Nacera Mellal, Aurora Varela, Peter Mann, Jacquelin Jolette, Rana Samadfam, Susan Y Smith, Kathrin Locher, Sabina Buntich, Michael S Ominsky, Ian Pyrah, Rogely Waite Boyce
Romosozumab is a humanized immunoglobulin G2 monoclonal antibody that binds and blocks the action of sclerostin, a protein secreted by the osteocyte and an extracellular inhibitor of canonical Wnt signaling. Blockade of sclerostin binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) allows Wnt ligands to activate canonical Wnt signaling in bone, increasing bone formation and decreasing bone resorption, making sclerostin an attractive target for osteoporosis therapy. Because romosozumab is a bone-forming agent and an activator of canonical Wnt signaling, questions have arisen regarding a potential carcinogenic risk...
November 2016: Regulatory Toxicology and Pharmacology: RTP
Frances Milat, Peter R Ebeling
Osteoporosis affects 1.2 million Australians and, in 2012, fractures due to osteoporosis and osteopenia in Australians aged over 50 years cost $2.75 billion. Even minor minimal trauma fractures are associated with increased morbidity and mortality. Despite increasing therapeutic options for managing osteoporosis, fewer than 20% of patients with a minimal trauma fracture are treated or investigated for osteoporosis, so under-treatment is extremely common. Fracture risk assessment is important for selecting patients who require specific anti-osteoporosis therapy...
August 15, 2016: Medical Journal of Australia
H K Genant, K Engelke, M A Bolognese, C Mautalen, J P Brown, C Recknor, S Goemaere, T Fuerst, Y-C Yang, A Grauer, C Libanati
Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s...
August 3, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Torben Harsløf, Bente L Langdahl
Efficient therapies are available for the treatment of osteoporosis, however, there are still unmet needs. Anti-resorptive therapies only increase bone mineral density to a certain extent and reduce the risk of non-vertebral fractures by 20%, only one anabolic option is available-the effect of which levels off over time, and the evidence for combination therapy targeting both resorption and formation is limited. The current review will focus on emerging treatments of osteoporosis with the potential of enhanced anabolic effects (romosozumab and abaloparatide) or uncoupling of resorption and formation (odanacatib and romosozumab) as well as the effect of combination therapy...
June 2016: Current Opinion in Pharmacology
Brigitte Uebelhart, René Rizzoli
Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw...
January 13, 2016: Revue Médicale Suisse
Sune Larsson
Several decades ago, a clinical condition that included severe bone overgrowth was described in a few patients in South Africa. The autosomal-recessive disease that later was named sclerosteosis was found to be caused by a mutation in the SOTS gene causing a lack of the protein sclerostin. This protein is produced by osteocytes and exerts its effect as an inhibitor of bone formation by blocking the Wnt signaling pathway. By the use of a monoclonal antibody that can block sclerostin a novel therapeutic pathway for rebuilding bone has been described...
January 2016: Injury
Janice M Reichert
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent®), evolocumab (Repatha®), daratumumab (Darzalex®), dinutuximab (Unituxin®), idarucizumab (Praxbind®), mepolizumab (Nucala®)) granted first approvals as of mid-November*. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016...
2016: MAbs
Piet Geusens
For the prevention of fractures, antiresorptive drugs (bisphosphonates and denosumab) that decrease high bone resorption and, secondarily, also bone formation, are the mainstream of therapy. Osteoanabolic drugs, such as teriparatide, increase bone formation more than bone resorption, and are used in severe osteoporosis, including patients treated with antiresorptive drugs who still lose bone and have recurrent fractures. New potential drugs for fracture prevention that uncouple bone resorption from bone formation include odanacatib, a specific inhibitor of cathepsin-K, the enzyme that degrades bone collagen type I, that inhibits bone resorption and only temporarily bone formation, and monoclonal antibodies against sclerostin (romosozumab, blosozumab), that stimulate bone formation and decrease bone resorption...
2015: RMD Open
Toshio Matsumoto
Bone is constantly remodeled to maintain its volume, structural integrity and strength Currently available bone anabolic agent is teriparatide. Teriparatide increases bone mass and strength via both remodeling-dependent and -independent mechanisms, although remodeling-dependent mechanism overweighs the other. Canonical Wnt signal plays an important role in enhancing osteoblast differentiation and bone formation, and its osteocyte-derived inhibitor, sclerostin, regulates bone formation via the regulation of Wnt signaling...
October 2015: Nihon Rinsho. Japanese Journal of Clinical Medicine
R J Eudy, M R Gastonguay, K T Baron, M M Riggs
The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed...
September 2015: CPT: Pharmacometrics & Systems Pharmacology
Polyzois Makras, Sideris Delaroudis, Athanasios D Anastasilakis
Since the identification of osteoporosis as a major health issue in aging populations and the subsequent development of the first treatment modalities for its management, considerable progress has been made in our understanding of the mechanisms controlling bone turnover and disease pathophysiology, thus enabling the pinpointing of new targets for intervention. This progress, along with advances in biotechnology, has rendered possible the development of ever more sophisticated treatments employing novel mechanisms of action...
October 2015: Metabolism: Clinical and Experimental
Christian Graeff, Graeme M Campbell, Jaime Peña, Jan Borggrefe, Desmond Padhi, Allegra Kaufman, Sung Chang, Cesar Libanati, Claus-Christian Glüer
Romosozumab inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. This dual effect of romosozumab leads to rapid and substantial increases in areal bone mineral density (aBMD) as measured by dual-energy X-ray absorptiometry (DXA). In a phase 1b, randomized, double-blind, placebo-controlled study, romosozumab or placebo was administered to 32 women and 16 men with low aBMD for 3 months, with a further 3-month follow-up: women received six doses of 1 or 2mg/kg every 2 weeks (Q2W) or three doses of 2 or 3mg/kg every 4 weeks (Q4W); men received 1mg/kg Q2W or 3mg/kg Q4W...
December 2015: Bone
Arti D Shah, Dolores Shoback, E Michael Lewiecki
Osteoporosis and osteoporosis-related fractures are growing problems with the aging population and are associated with significant morbidity and mortality. At this time, other than parathyroid hormone analogs, all therapies for osteoporosis are antiresorptive. Therefore, researchers have focused efforts on development of more anabolic therapies. Understanding of the Wnt signaling pathway, which is critical for skeletal development, and the role of sclerostin in inhibition of Wnt signaling has led to the discovery of a novel therapeutic approach in the treatment of osteoporosis - sclerostin inhibition...
2015: International Journal of Women's Health
Toshihiro Sugiyama, Tetsuya Torio, Tsuyoshi Miyajima, Yoon Taek Kim, Hiromi Oda
No abstract text is available yet for this article.
2015: Frontiers in Endocrinology
Robert Brommage
During the past two decades effective drugs for treating osteoporosis have been developed, including anti-resorptives inhibiting bone resorption (estrogens, the SERM raloxifene, four bisphosphonates, RANKL inhibitor denosumab) and the anabolic bone forming daily injectable peptide teriparatide. Two potential drugs (odanacatib and romosozumab) are in late stage clinical development. The most pressing unmet need is for orally active anabolic drugs. This review describes the basic biological studies involved in developing these drugs, including the animal models employed for osteoporosis drug development...
October 2015: Journal of Cellular Biochemistry
Brigitte Uebelhart, René Rizzoli
Bone events related to bariatric surgery remain controversial. Denosumab, used in osteoporosis treatment, is safe and efficient. Romosozumab, an antibody raised against sclerostin, is a promising bone anabolic agent. Odanacatib, a cathepsin-K inhibitor, decreases bone resorption and reduces osteoporotic fracture risk. Denosumab, as bone resorption inhibitor, and Teriparatide, as anabolic agent, have been tested together in patients with osteoporosis. Calcium supplements and cardiovascular risk are still debated...
January 14, 2015: Revue Médicale Suisse
Sian Yik Lim, Marcy B Bolster
PURPOSE OF REVIEW: Osteoporosis is a skeletal disorder in which bone strength is decreased leading to an increased risk of fracture. In line with advances in knowledge of bone biology, the past several years have held major therapeutic advances in osteoporosis treatment. In this article, we review the current approaches to osteoporosis treatment with a focus on issues of interest to the practicing rheumatologist. RECENT FINDINGS: In addition to the bisphosphonates, the introduction of denosumab, teriparatide and selective oestrogen-receptor modulators, as well as the development of new therapeutic agents (romosozumab and odanacatib) has opened the door to new approaches, including individualization of treatment in different clinical circumstances based on patient comorbidities and preference; combination therapy to optimize treatment effect; and consideration of goal-based treatment...
May 2015: Current Opinion in Rheumatology
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