ABSTRACT
Osteoporosis, a metabolic bone disease characterized by low bone mass, microarchitectural deterioration of bone tissue, and increased susceptibility to fracture, now is recognized to be a disease of men and women. Based on bone mineral density measurements established by the World Health Organization, approximately 2 million men in the United States currently are affected. Information about the pathogenesis, diagnosis, and treatment of osteoporosis in men is accumulating. Estrogen now is known to be necessary for normal skeletal maturation and for maintenance of adult bone mass in men. As we will discuss, the age-related decline in bone mineral density in men seems to result from an age-related decline in the levels of bioavailable estrogen. Osteoporosis candidate genes have been discovered, and their polymorphisms may predispose men to a weakened, osteoporotic phenotype. Determining a bone mineral density standard to diagnose men with osteoporosis has proven challenging, often leaving diagnosis until a fragility fracture has occurred. General prevention strategies for osteoporosis in men are targeted at men most likely to sustain a fragility fracture. Specific medical therapies for osteoporosis in men, including bisphosphonates and intermittent parathyroid hormone, are proving promising.
Subject(s)
Aging/physiology , Men , Osteoporosis , Bone Density , Humans , Male , Osteoporosis/genetics , Osteoporosis/physiopathology , Osteoporosis/therapy , Risk FactorsABSTRACT
We describe the effects of the overexpression of noggin, a bone morphogenetic protein (BMP) inhibitor, on osteoblast differentiation and bone formation. Cells of the osteoblast and chondrocyte lineages, as well as bone marrow macrophages, showed intense beta-gal histo- or cytostaining in adult noggin+/- mice that had a LacZ transgene inserted at the site of noggin deletion. Despite identical BMP levels, however, osteoblasts of 20-month-old C57BL/6J and 4-month-old senescence-accelerated mice (SAM-P6 mice) had noggin expression levels that were approximately fourfold higher than those of 4-month-old C57BL/6J and SAM-R1 (control) mice, respectively. U-33 preosteoblastic cells overexpressing the noggin gene showed defective maturation and, in parallel, a decreased expression of Runx-2, bone sialoprotein, osteocalcin, and RANK-L. Noggin did not inhibit the ligandless signaling and pro-differentiation action of the constitutively activated BMP receptor type 1A, ca-ALK-3. Transgenic mice overexpressing noggin in mature osteocalcin-positive osteoblasts showed dramatic decreases in bone mineral density and bone formation rates with histological evidence of decreased trabecular bone and CFU-osteoblast colonies at 4 and 8 months. Together, the results provide compelling evidence that noggin, expressed in mature osteoblasts, inhibits osteoblast differentiation and bone formation. Thus, the overproduction of noggin during biological aging may result in impaired osteoblast formation and function and hence, net bone loss.
Subject(s)
Cell Differentiation/physiology , Neoplasm Proteins , Osteoblasts/physiology , Osteogenesis/physiology , Osteoporosis/metabolism , Proteins/metabolism , Aging/physiology , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Bone Morphogenetic Proteins/antagonists & inhibitors , Bone Morphogenetic Proteins/metabolism , Bone and Bones/cytology , Bone and Bones/metabolism , Carrier Proteins , Chondrocytes/metabolism , Core Binding Factor Alpha 1 Subunit , Core Binding Factor alpha Subunits , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Osteoblasts/cytology , Phenotype , Proteins/genetics , Transcription Factors/metabolism , TransgenesABSTRACT
Amgen Inc and Kirin Brewery Co Ltd, under license from NPS Pharmaceuticals Inc, are developing cinacalcet hydrochloride, the lead compound in a series of calcimimetics, for the potential treatment of primary and secondary hyperparathyroidism. Tecalcet hydrochloride was the first compound from this class to be extensively studied and most of the pharmacological data disclosed is for this compound. Cinacalcet hydrochloride was developed in an effort to improve on the poor pharmacokinetics and metabolism of tecalcet hydrochloride.
