Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clodronic acid is a non-aminate bisphosphonate capable of inhibiting bone resorption. Pharmacological and clinical trials have shown the efficacy of clodronic acid in the treatment of post-menopausal osteoporosis and in all conditions of excess bone resorption, such as Paget's disease, malignant tumoral hypercalcemia and osteolytic metastases. Clodronic acid is the only bisphosphonate currently on the market available for both oral and parenteral administration. Intramuscular therapy with clodronic acid at a dose of 100 mg/week has shown significant effects on bone mineral density after 6 months treatment in patients with postmenopausal osteoporosis and these effects were maintained 3 years after the start of treatment. Increased bone mass is associated with a reduced risk of the onset of vertebral fractures. In a recent three-year study a significant increase was observed in bone mineral density associated with a 46% reduction in the incidence of vertebral fractures. The reduction in bone pain after parenteral treatment with clodronic acid is an important added value in the use of this molecule in osteopenic pathologies. Moreover the costs of parenteral clodronic acid treatment is certainly competitive compared to other drugs. Oral and parenteral clodronic acid was well tolerated in clinical trials. Gastrointestinal adverse effects were described only with high oral doses. These effects were transient and generally resolved without interrupting the treatment. Clodronic acid is an effective and well tolerated drug able to inhibit bone resorption. The low incidence of undesired effects at a gastroenteric level, the possibility of formulas for parenteral administration, the antalgic effect and low costs make clodronic acid an extremely interesting molecule for the prevention and treatment of postmenopausal osteoporosis and all conditions of excessive bone resorption, such as Paget's disease, malignant tumoral hypercalcemia, osteolytic metastasis and hyperparathyroidism.
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PMID:[Use of clodronic acid in mineral metabolism conditions: state of the art in 2000]. 1153 69

One in three women and at least one in 12 men in the UK have osteoporosis, a condition which can lead to fractures, deformity, pain and disability, at a cost to the NHS of around 1.5 billion Pounds each year. Bisphosphonates offer a therapeutic option for preventing and treating osteoporosis. Here, we assess and compare the three bisphosphonates (alendronate, etidronate and risedronate) licensed for such use in the UK. We do not consider the four bisphosphonates (clodronate, pamidronate, tiludronate and zoledronate) that are licensed in the UK only for the treatment of Paget's disease of bone and/or hypercalcaemia of malignancy.
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PMID:Bisphosphonates for osteoporosis. 1158 3

Bisphosphonates, analogues of pyrophosphate, are potent inhibitors of osteoclast-mediated bone resorption. They are used in the treatment of Paget's disease of bone, hypercalcaemia and osteolytic bone disease of malignancy, primary and secondary hyperparathyroidism, and in osteoporosis. Bisphosphonate treatment causes an early reduction in bone resorption followed by a later reduction in bone formation. The early inhibition of bone resorption induces a reduction in serum calcium which leads to increased parathyroid hormone (PTH), and subsequently an increase in 1,25-dihydroxyvitamin D. The secondary hyperparathyroidism of bisphosphonate treatment also leads to urinary calcium conservation and phosphaturia, and a reduction in serum phosphate. The increase in the PTH following bisphosphonate therapy is a response to the change in serum calcium and can occur even when there is hypercalcaemia, and this can cause confusion in the interpretation of PTH results. The hypocalcaemic response to bisphosphonates is occasionally severe, especially in patients with hypoparathyroidism. The recent elucidation of bisphosphonate action at the cellular level on the mevalonate pathway has led to interest in its effects on lipoprotein metabolism, which may prove to be of clinical significance. Newer and more potent bisphosphonates are currently undergoing clinical trials in malignant bone disease and osteoporosis, and will lead to further advances in the optimal management of these conditions.
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PMID:Bisphosphonates: an overview with special reference to alendronate. 1173 44

Bisphosphonates are used for the treatment of bone resorption, hypercalcemia, osteoporosis and Paget's disease. Etidronate, pamidronate and clodronate also inhibit the development of experimental atherosclerosis without altering serum lipid profile. Bisphosphonates inhibit the arterial calcification, lipid accumulation and fibrosis. They accumulate extensively in arterial walls and suppress macrophages in atheromatous lesions. In macrophage cultures, bisphosphonates inhibit the cellular accumulation and degradation of atherogenic LDL-cholesterol and foam cell formation. Further, they inhibit various enzymes involved in cell signal transduction and cholesterol biosynthesis. Recently, etidronate has been shown to inhibit the thickening of carotid arterial wall even in man.
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PMID:Bisphosphonates and atherosclerosis. 1192 58

Calcitonin was discovered as a hypocalcemic principal that was initially thought to originate from the parathyroid gland. This view was corrected subsequently, and an origin from the thyroid C cells was documented. The purification and sequencing of various calcitonins soon followed. Calcitonin is a 32-amino-acid-long peptide with an N-terminal disulfide bridge and a C-terminal prolineamide residue. The peptide was shown to potently inhibit bone resorption; however, a direct osteoclastic action of the peptide was confirmed only in the early 1980s. Several osteoclast calcitonin receptors have subsequently been cloned and sequenced. Specific regions of the receptor necessary for ligand binding and intracellular signaling through cyclic AMP and calcium have been identified through systematic deletion mutagenesis and chimeric receptor studies. Calcitonin's potent antiresorptive effect has led to its use in treating Paget's disease of bone, osteoporosis, and hypercalcemia. This review retraces key aspects of the synthesis and structure of calcitonin, its cellular and molecular actions, and its therapeutic uses as they have emerged over the 40 years since its discovery. The review also examines the implications of these findings for future clinical applications as a tribute to early workers to whom credit must be given for creation of an important and expanding field. Notable are the new approaches currently being used to enhance calcitonin action, including novel allosteric activators of the calcitonin receptor, modulation of the release of endogenous calcitonin by calcimimetic agents, as well as the development of oral calcitonins.
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PMID:Forty years of calcitonin--where are we now? A tribute to the work of Iain Macintyre, FRS. 1199 1

Bisphosphonates are the most potent class of antiresorpitve drugs used in the treatment of bone diseases with enhanced resorption, like malignant osteolysis, osteoporosis and Paget's disease. Multiple myeloma is commonly associated with skeletal morbidity, including osteolysis, bone fractures, pain and hypercalcemia. These clinical complications result from increased osteoclast number and function which is due to release of osteoclast-stimulating factors by myeloma cells and the tumoral environment. By inhibition of osteoclast activity and inducing cell apoptosis, bisphosphonates can prevent development of bone destruction in myeloma patients. This article reviews efficacy of bisphosphonates in reducing skeletal events in patients with multiple myeloma and several in vitro studies which have shown that aminobisphosphonates may act as antimyeloma agents.
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PMID:[Bisphosphonates in the treatment of multiple myeloma]. 1210 45

Maturation of macrophages to osteoclasts requires the presence of marrow stromal cells or osteoblasts. Most calcitropic hormones act indirectly on osteoclasts through receptors on neighbouring osteoblasts. The discovery of osteoprotegerin (OPG), the receptor activator of nuclear factor-kappa b ligand (RANKL), and its receptor (RANK) has elucidated these phenomena. It appears that osteoclast differentiation, activity, and survival are regulated by the proportion of inhibiting OPG to stimulating RANKL. OPG and RANKL are produced by osteoblasts, whereas RANK is located to the osteoclasts. Treatment with OPG inhibits bone resorption in postmenopausal women. Mutations in the system may be responsible for focal skeletal disorders. The discovery opens up for new treatment opportunities in postmenopausal and steroid-induced osteoporosis, Paget's disease, hypercalcaemia, and rheumatoid arthritis.
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PMID:[Osteoclast function is regulated by neighbouring osteoblasts. Osteoprotegerin, RAND and RANK ligand constitute a unique regulatory system for bone resorption with important pathophysiological and therapeutic aspects]. 1211 80

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED(50) of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
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PMID:Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). 1216 45

Clodronate (CI2MBP) is a non-aminated bisphosphonate that inhibits bone resorption. Studies on the mechanisms of action of this molecule on bone metabolism have been limited and only recently has information on the molecular machinery that underlies its effects on the bone remodelling process become available. Pharmacological and clinical studies have demonstrated the effectiveness of clodronate in the treatment of postmenopausal osteoporosis and in all conditions of excessive bone resorption, such as Paget's disease, hypercalcaemia of malignancy and osteolytic metastases. Clodronate is the only bisphosphonate currently available on the market for both oral and parenteral administration. Treatment with clodronate via intramuscular administration of doses of 100 mg/week has shown significant effects on bone mineral density after 6 months in patients with postmenopausal osteoporosis and these effects are maintained 3 years after the start of the treatment. In a recent controlled clinical study, a significant increase in bone mineral density was observed, associated with a 46% reduction in the incidence of vertebral fractures. However, most relevant studies have been small, unblinded and short-term and have not systematically examined the effects of the dose and dosing intervals on bone mineral density and markers of bone turnover. Ongoing controlled clinical studies may offer answers regarding potential use of clodronate in osteoporosis and also about dosage of intermittent administration. This review summarises the accumulated knowledge in the mechanisms of action of clodronate on bone remodelling. Moreover, the clinical trials on the use of clodronate in metabolic bone diseases are described in-depth. We believe that this work will help to better focus on the need for more research on a compound which has potential applications in prevention and therapy of osteoporosis. However, studies that demonstrate an effect on the rate of fractures are needed before any recommendation can be made.
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PMID:Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders. 1243 97

The peptide hormone calcitonin is widely used therapeutically in the treatment of bone disorders such as Paget's disease, osteoporosis, and the hypercalcemia of some malignancies. However, emerging evidence suggests the actions of calcitonin via its G protein-coupled receptor, the calcitonin receptor, may not be limited to bone. Calcitonin receptors have also been identified in the central nervous system, testes, skeletal muscle, lymphocytes, and the placenta. We are now becoming aware that the complexity of the calcitonin response mediated by the calcitonin receptor can be influenced by accessory proteins, receptor isoforms, genetic polymorphisms, developmental and/or transcriptional regulation, feedback inhibition, and the specific cellular or tissue background. This article discusses what is known about the molecular and pharmacological actions of the calcitonin receptor and highlights areas of current research.
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PMID:Molecular pharmacology of the calcitonin receptor. 1252 40


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