Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The osteoclast is a bone-degrading polykaryon. Recent studies have clarified the differentiation of this cell and the biochemical mechanisms it uses to resorb bone. The osteoclast derives from a monocyte/macrophage precursor. Osteoclast formation requires permissive concentrations of M-CSF and is driven by contact with mesenchymal cells in bone that bear the TNF-family ligand RANKL. Osteoclast precursors express RANK, and the interaction between RANKL and RANK (which is inhibited by OPG) is the major determinant of osteoclast formation. Hormones, such as PTH/PTHrP, glucocorticoids and 1,25(OH)2D3, and humoral factors, including TNFalpha, interleukin-1, TGFss and prostaglandins, influence osteoclast formation by altering expression of these molecular factors. TNFalpha, IL-6 and IL-11 have also been shown to promote osteoclast formation by RANKL-independent processes. RANKL-dependent/independent osteoclast formation is likely to play an important role in conditions where there is pathological bone resorption such as inflammatory arthritis and malignant bone resorption. Osteoclast functional defects cause sclerotic bone disorders, many of which have recently been identified as specific genetic defects. Osteoclasts express specialized proteins including a vacuolar-type H+-ATPase that drives HCl secretion for dissolution of bone mineral. One v-ATPase component, the 116 kD V0 subunit, has several isoforms. Only one isoform, TCIRG1, is up-regulated in osteoclasts. Defects in TCIRG1 are common causes of osteopetrosis. HCl secretion is dependent on chloride channels; a chloride channel homologue, CLCN7, is another common defect in osteopetrosis. Humans who are deficient in carbonic anhydrase II or who have defects in phagocytosis also have variable defects in bone remodelling. Organic bone matrix is degraded by thiol proteinases, principally cathepsin K, and abnormalities in cathepsin K cause another sclerotic bone disorder, pycnodysostosis. Thus, bone turnover in normal subjects depends on relative expression of key cytokines, and defects in osteoclastic turnover usually reflect defects in specific ion transporters or enzymes that play essential roles in bone degradation.
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PMID:Recent advances in osteoclast biology and pathological bone resorption. 1470 87

Hyperparathyroidism (HPT) is a significant clinical concern for patients with a variety of diseases, notably the secondary HPT associated with chronic kidney disease requiring dialysis. Secondary HPT is associated with elevated para-thyroid hormone (PTH) levels, decreased levels of 1,25 dihydroxyvitamin D, and disordered mineral levels (usually high calcium and phosphorus). If not controlled, secondary HPT can result in bone disease, vascular calcification, and ultimately, patient mortality. Established, conventional therapies, such as 1,25dihydroxyvitamin D analogues (vitamin D analogues) and phosphate binders, have proven to be inadequate in enabling patients to meet the National Kidney Foundation's-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) treatment goals for PTH, calcium and phosphorus levels. A novel therapeutic, cinacalcet HCl (formerly AMG 073; Sensipar in the US and Mimpara in Europe; Amgen, Inc.), binds directly to the calcium-sensing receptor (CaR) on the cells of the parathyroid gland, increasing the receptor's sensitivity to calcium and reducing PTH, serum calcium and phosphorus levels. Treatment with cinacalcet in clinical trials has safely and effectively improved achievement of the NKF-K/DOQI goals. Cinacalcet has also reduced serum calcium levels in patients with primary HPT, including parathyroid carcinoma, in the clinical trial setting. Evidence suggesting the utility of cinacalcet in these diseases and the potential for additional therapeutic applications will be discussed.
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PMID:Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. 1579 35

Hyperphosphatemia is considered as an independent risk factor for surrogate clinical endpoints like vascular calcification (VC) and bone disease, or hard clinical outcomes like cardiovascular events. To date, various treatment options for phosphate removal or reduction are available. The great expectations put into calcium-based phosphate binders were mitigated because of their possible contribution to progressive VC, particularly in patients treated simultaneously with active vitamin D derivatives. Thus, a paradigm change occurred whereby the main clinical concern shifted from the avoidance of hypocalcemia to that of the consequences of inducting a positive calcium balance. Sevelamer-HCl treatment allowed a comparable control of hyperphosphatemia with a lower risk of hypercalcemia than calcium-based phosphate binders, and a slower progression of VC; however, convincing evidence of improved clinical outcomes in dialysis patients is lacking. Although data on the safety and efficacy of lanthanum carbonate in the treatment of hyperphosphatemia have been provided in long-term clinical studies, there is still an ongoing scientific debate about its possible long-term toxicity. Moreover, there are no data from randomized clinical trials demonstrating beneficial effects of La carbonate treatment on VC or cardiovascular outcomes. In the absence of convincing clinical trials testing the effects of non-metal-based phosphate binders on cardiovascular and global outcomes it appears reasonable to maintain bone health and mineral homeostasis by mainly relying on adaptations of standard therapies. Noncalcium, non-aluminum-based binders might be reserved for patients with major mineral metabolism abnormalities and a high risk of VC.
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PMID:Phosphate metabolism in chronic kidney disease: from pathophysiology to clinical management. 1970 81

In end-stage renal disease patients, various abnormalities of bone mineral metabolism adversely affect mortality. Hyperphosphatemia is known to adversely affect mortality and quality of life in chronic kidney disease patients and has been shown to be involved not only in the onset and progression of secondary hyperparathyroidism but also in vascular calcification. Thus, hyperphosphatemia is the main treatment target indicated in several guidelines for chronic kidney disease-mineral and bone disorder treatment. Phosphate binders are typically required for the management of hyperphosphatemia because dietary phosphorus restriction and phosphorus removal by hemodialysis alone are insufficient. We are able to prescribe five phosphate binders (calcium carbonate, sevelamer HCl, lanthanum carbonate (LaC), bixalomer, and ferric citrate) to Japanese hemodialysis patients. LaC is the most powerful noncalcium-containing phosphate binder for the treatment of hyperphosphatemia. In this chapter, we discuss the efficacy and safety of LaC, the safety of which has been under debate. In particular, we consider its toxic effects on the skeletal system. LaC is effective for hyperphosphatemia treatment in end-stage renal failure patients. It has been shown to be able to decrease serum fibroblast growth factor-23 levels. This result suggests that it may have beneficial effects on the cardiovascular system in patients undergoing renal replacement therapy. However, the effects of LaC remain obscure. Further investigations are required. No negative effects of LaC on bone metabolism or bone morphometry have been reported, but long-term clinical data are needed.
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PMID:Safety and efficacy evaluation of lanthanum carbonate for hyperphosphatemia in end-stage renal disease patients. 2602 14