Bone remodeling osteoporosis

The bone disease osteoporosis results when an imbalance occurs in the normal course of bone remodeling, a dynamic and highly regulated... 

Eriksen EF, Hodgson SF, Eastell R, Cedel SL, O Fallon WM, Riggs BL (1990) Cancellous bone remodeling in type I (postmenopausal) osteoporosis quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J Bone Miner Res 5 311-319... 

Research in humans has been mainly focused either in the prevention of osteoporosis in healthy postmenopausal women or in the treatment of already osteoporotic women. Some research programs have extensively used estimates of biochemical markers of bone remodeling, while others have mostly relied on evaluations of BMD, histomorphometry, and fracture incidence. 

Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E (2002) Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 87 985-992... 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

Markers of bone remodeling were very useful when used in clinical studies that were intended to learn and understand the pathogenesis of osteoporosis, and the... 

Looker AC, Bauer DC, Chestnut CH HI, Gundberg CM, Hochberg MC, EHee G, et al. Clinical uses of biochemical markers of bone remodeling current status and future directions. Osteoporosis Int 2000 11 467-80. 

Bone tissue is constantly being renewed by the concerted action of osteoblasts and osteoclasts. Bone remodeling has two main phases a resorption phase consisting in the removal of old bone by osteoclasts, and a later phase of new bone formation driven by osteoblasts [6], Thus, the activity of osteoblasts and osteoclasts determines bone mass, bone geometry, bone quality, and, subsequently, bone strength [7, 8]. Osteoporosis is a prevalent disorder consisting in decreased bone mass and/or abnormal bone microarchitecture that impairs bone strength and increases the risk of fracture. Therefore, patients with osteoporosis may suffer fractures as a result of minor trauma, or even in the absence of trauma. The most common osteoporotic fractures are those of the vertebral bodies, the hip, the wrist, the shoulder, and the pelvis. 

Vitamin D is a fat soluble vitamin related to cholesterol. In the skin, sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol. 7-Dehydrocholesterol spontaneously isomerizes to cholecalciferol (vitamin D3), which is oxidized in the liver to 25-hydroxy cholecalciferol and, under the influence of PTH in the kidney, to 1,25-dihy-droxy cholecalciferol (calcitriol), the active form of vitamin D. Vitamin D induces the expression of calcium ion transport proteins (calbindins) in intestinal epithelium, osteoclasts, and osteoblasts. Calbindins and transient receptor potential channels (TRPV) are responsible for the uptake of calcium from the diet. In children, the absence of sunlight provokes a deficiency of vitamin D, causing an absence of calbindins and inadequate blood calcium levels. Osteoid tissue cannot calcify, causing skeletal deformities (rickets). In the elderly, there is a loss of intestinal TRPV receptors and decreased calbindin expression by vitamin D. In both cases, the resultant low blood calcium levels cause poor mineralization during bone remodeling (osteomalacia). Rickets is the childhood expression of osteomalacia. Osteoclast activity is normal but the bone does not properly mineralize. In osteoporosis, the bone is properly mineralized but osteoclasts are overly active. 

An estimated 75 million people are affected by osteoporosis to some degree in the United States, Europe, and Japan. Osteoporosis is a systematic skeletal disease characterized by bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture. Operationally, osteoporosis can be defined as a certain level of bone mineral density. The definition of osteoporosis is somewhat arbitrary and is based on epidemiological data relating fracture incidence to bone mass. Uncertainty also is introduced due to variability in bone densitometry measurements. Other clinical measures to assess the skeleton include collagen cross-links (measure of bone resorption) and levels of bone-specific alkaline phosphatase and osteocalcin (bone formation). A list of biochemical markers of bone remodeling is provided in Table 37-3. Measurement of total serum alkaline phosphatase level and urinary hydroxyproline or calcium levels is of limited value. 

The ability of SARMs to increase both muscle and bone strength in animal models suggests that they may provide a unique dual approach to osteoporosis therapy [94, 95, 151]. The process of bone remodeling is ongoing throughout life, and involves the resorption and deposition of bone by osteoclasts and osteoblasts, respectively [245]. The resorption and deposition processes are promoted at the... 

Involutional (primary) osteoporosis is the manifestation of a metabolic bone disease in which the amount of normally mineralized bone matrix in affected patients has been reduced to a level below that of the normal population of the same age and sex. The disease is certainly of multifactorial origin, since genetic (Seeman etal. 1989), mechanical (e.g.. Frost 1988), nutritional (e.g., Hegsted 1986), and hormonal factors (e.g., Melton and Riggs 1988) can cause the severe impairment of the bone remodeling process (Eriksen etal. 1994) which underlies the observed reduction in bone mass and microarchitectural deterioration of bone tissue that lead to an increased risk of fractures at typical sites of the skeleton (for a definition, see Anonymous 1993)... 

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