Bone resorption, effect

Authors Cell model of bone resorption Effect of isoflavones... 

Yamaguchi and Gao, 1998 Rat femoral-metaphyseal tissues cultured for 48 h with bone resorbing factors PTH, PGE2 or EPS) +/- genistein measured bone calcium content, acid and alkaline phosphatases Genistein (10 Yi O M) inhibited bone resorption. Effect reversed by anti-estrogen, tamoxifen. 

Ahlen J, Andersson S, Mukohyama H, Roth C, Backman A, Conaway HH, Lerner UH (2002) Characterization of the bone-resorptive effect of interleukin-11 in cultured mouse calvarial bones. Bone 31 242-251... 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

Due to its anti-resorptive effects, calcitonin has been widely used to treat a variety of metabolic bone diseases, including osteoporosis. However, the availability of more potent drugs has lead to a decline in the clinical use of calcitonin. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Recombinant human DL-1 receptor antagonist (Anakinra, Kineret ) blocks the biological activity of interleukin-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. Thereby it reduces the pro-inflammatory activities of IL-1 including cartilage destiuction and bone resorption. Side effects include an increased risk of infections and neutropenia. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Studies have demonstrated that treatment with soy or phytoestrogen enriched diets is effective in conserving bone in rodent models of osteoporosis (Anderson and Gamer, 1998 Ishimi et al, 2000 Draper et al, 1997). The mechanism of action of phytoestrogens on bone health is unclear but several mechanisms including inhibition of bone resorption and stimulation of bone formation maybe involved (Fanti etal, 1998 Ishimi e/a/., 1999 Picherit eta/., 2000). Limited data from studies in postmenopausal women have indicated that phytoestrogen supplements have a small, beneficial effect on bone loss in the lumbar spine (Alekel et al, 2000 Potter et al, 1998 Somekawa et al, 2001). 

Morabito et al., 2002 European postmenopause placebo, n = 30 genistein, n = 30 HRT, n = 30 First randomized, double-blind placebo-controlled study. Compared to placebo control, genistein (54 mg/day) consumed for 1 year significantly reduced urinary excretion of bone resorption markers and increased bone formation markers at 6 and 12 months BMD was significantly increased at the femoral neck and lumbar spine plasma genistein concentration was around 1.5 pM. HRT showed similar effects to genistein for BMD. 

Table 6.5 Effect of isoflavones in cellular models of bone resorption...

YAMAGUCHI M and GAO Y H (1998) Inhibitory effect of genistein on bone resorption in tissue culture. Biochem Pharmacol 55, 71-6. 

An in vitro cell model resembles the remodeling process of osteoclastic bone resorption followed by osteoblastic bone formation investigate the influence of lead on the communication between these cells determine if lead in the medium (i.e. extracellular fluid) or in the matrix (i.e. in the bone) has different effects on osteoclasts and osteoblasts... 

Calcitonin. This hormone, which is also secreted from the thyroid gland, is synthesized by the parafollicular cells (C cells) located between the follicles. The primary effect of calcitonin is to decrease the blood levels of calcium and phosphate. The mechanism of action involves the direct inhibition of osteoclast activity, which decreases bone resorption. This results in less demineralization of the bone and therefore a decrease in the release of calcium and phosphate from the bone into the blood. Calcitonin has no direct effect on bone formation by osteoblasts. 

Parathyroid hormone stimulates bone resorption by increasing the number and activity of osteoclasts. This demineralization process in the bone releases calcium and phosphate into the blood. Although the action of PTH on the bone appears to increase blood phosphate, its action on the kidney, which increases phosphate excretion in the urine, more than compensates for this increase and the net effect is a decrease in serum phosphate. 

Calcium-phosphorus balance is mediated through a complex interplay of hormones and their effects on bone, GI tract, kidney, and parathyroid gland. As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy (ROD) (Fig. 76-7). 

Interleukin-6 (IL-6) is a member of the gpl30 cytokine family and is con-stitutively produced by several cells of bone microenvironment, particularly by osteoblasts and their precursors (Heymann et al. 2000). The main function in bone is on OCS and bone resorption, and its effects are connected to those of IL-1, TNF-a, and PTHrP. IL-6 induces osteoclastlike formation by inducing IL-1 synthesis, and the addition of anti-IL-1 inhibits osteoclast formation by IL-6 (Kurihara et al. 1990). Moreover, IL-6 mediates the effects of TNF-a and enhances PTHrP-induced hypercalcemia and bone resorption by increasing the osteoclast progenitor pool and differentiation into mature osteoclasts (Devlin et al. 1998). 

The most extensively used animal model to evaluate the action of SERMs on bone has been the ovariectomized (OVX) rat. In rats, tamoxifen antagonizes bone resorption and uterine growth (Turner et al. 1987,1988) and reduces the number and size of osteoclasts. The inhibitory effect on bone resorption of tamoxifen has also been reported in dogs and immobilized male rats (Wakley et al. 1988 Waters et al. 1991). As an antiresorptive agent, however, tamoxifen is less effective than 17/3-estradiol (17/9E2) (Williams et al. 1991) and has no effect when the endogenous production of estrogens is normal (Evans et al. 1994). 

Prevention of osteoporosis and fracture can be achieved through limiting the resorption-remodeling process. Four main families of products can be effective in controlling bone resorption estrogens, SERMs, bisphosphonates, and calcitonin. Large, prospective randomized trials have proven the effectiveness... 

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