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)

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in treatment of hypercalcemia of malignancy have been completed, as have Phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.
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PMID:Optimising treatment of bone metastases by Aredia(TM) and Zometa(TM). 1111 66

This report summarizes results of the clinical development program evaluating zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) in the treatment of hypercalcemia of malignancy (HCM). In addition to a phase I dose escalation trial, two randomized, double-blind, double-dummy studies were conducted in parallel to investigate the clinical efficacy and safety of 4 mg and 8 mg zoledronic acid in patients with moderate to severe HCM. Patients were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or a control treatment, 90 mg pamidronate via 2-hour infusion. Patients who relapsed or had refractory HCM after initial treatment could be re-treated with 8 mg zoledronic acid. End points included rate of complete response, defined as normalization of corrected serum calcium by day 10, change in corrected serum calcium, time to relapse, duration of response, and bone biochemical markers. Doses of > or =0.02 mg/kg were effective and nontoxic in the phase I study. In the controlled studies, 287 patients were randomized and evaluated for safety and 275 patients were evaluable for efficacy. The proportions of patients with a complete response by day 10 were 88.4% and 86.7% in the 4 mg and 8 mg zoledronic acid groups, respectively, compared with 69.7% in the 90 mg pamidronate group. Corrected serum calcium normalization occurred by day 4 in 45.3% of patients treated with 4 mg zoledronic acid, 55.6% of patients treated with 8 mg zoledronic acid, and 33.3% of patients treated with pamidronate. Mean change from baseline in corrected serum calcium also was greater with zoledronic acid than with pamidronate. Median times to relapse were significantly longer in both the zoledronic acid 4 mg and 8 mg groups compared with the pamidronate group. There were no significant differences in efficacy between the 4 mg and 8 mg zoledronic acid doses. Retreatment in 69 patients with relapsing or refractory hypercalcemia with 8 mg zoledronic acid resulted in a 52% complete response rate. Fever, hypophosphatemia, and asymptomatic hypocalcemia were the most common drug-related adverse events. These studies have shown that a short single intravenous dose of 4 mg or 8 mg zoledronic acid is effective in treating moderate to severe HCM. Zoledronic acid produced a higher rate of calcium normalization, faster onset of action, and longer time to relapse than pamidronate, while maintaining an excellent safety profile. The lower dose of 4 mg is recommended as initial therapy, with the 8 mg dose reserved for patients requiring retreatment.
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PMID:Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program. 1134 61

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment.
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PMID:Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. 1134 63

Zoledronic acid (zoledronate) is a new generation bisphosphonate that inhibits osteoclast bone resorption. It was much more potent than other bisphosphonates at inhibiting 1,25-dihydroxyvitamin D3-induced hypercalcaemia in a rat model and calcium release in vitro. A single 5-minute intravenous infusion of zoledronic acid (4 or 8 mg) was significantly more effective than a 2-hour infusion of pamidronic acid (pamidronic acid disodium, pamidronate disodium) [90 mg] in normalising serum calcium levels in patients with hypercalcaemia of malignancy and resulted in a significantly longer median time to relapse (pooled analysis from 2 randomised, double-blind, parallel-group trials). There were no differences in tolerability between zoledronic acid and pamidronic acid in comparative trials; the most common events in pivotal trials were fever, anaemia, nausea, constipation and dyspnoea. Fever, hypophosphataemia and hypocalcaemia were the most common events in a small phase I trial.
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PMID:Zoledronic acid. 1139 11

Tumour-induced hypercalcaemia (TIH) is the most common metabolic disorder associated with cancer, and if left untreated is associated with a low survival rate. Bisphosphonates are potent inhibitors of bone resorption. They have emerged as the standard method of treatment for TIH and a new form of medical therapy for bone metastases in addition to current treatments. Newer forms of bisphosphonates are 100-1000 times more potent than pamidronate, the current gold standard. One of these third generation bisphosphonates, zoledronic acid (Zometa, Novartis Pharmaceuticals) has already been shown to provide more effective treatment of TIH than pamidronate. Ongoing research is aimed at choosing the optimum route, type of bisphosphonate and combination therapy to inhibit the development of bone metastases and TIH.
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PMID:Metastatic bone disease and tumour-induced hypercalcaemia: the role of bisphosphonates. 1206 26

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

Bone disease characterised by osteolytic lesions, pathological fractures and hypercalcaemia is an important clinical feature in multiple myeloma. Pain, decreased performance status, and the need for palliative radiotherapy and surgical interventions are common sequelae. Bisphosphonates act primarily on osteoclasts to inhibit excessive bone resorption, and have therefore been investigated in myeloma patients to ameliorate the clinical consequences of the bone disease. Bisphosphonates are currently the therapy of choice in myeloma patients with hypercalcaemia. In long-term management, both oral clodronate and intravenous pamidronate are effective in reducing skeletal-related events. Zoledronic acid seems to be as effective as pamidronate. Whether bisphosphonates have antimyeloma activity is currently unknown. Cost-benefit analyses have shown reasonable efficacy with acceptable costs. Bisphosphonate therapy is now accepted as an important part of care in myeloma patients, although much still has to be learned in order to optimise this therapy in multiple myeloma.
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PMID:Bisphosphonate therapy in multiple myeloma: past, present, future. 1293 Mar 27

The two main therapeutic applications of bisphosphonates are tumour bone disease and osteoporosis. They constitute the standard treatment for cancer hypercalcaemia, and placebo-controlled trials have shown that the prolonged administration of bisphosphonates, such as pamidronate or clodronate, can reduce the frequency of complications from tumour bone disease due to metastatic breast cancer or myeloma by a quarter to one-half. The results obtained with the intravenous route appear to be more impressive and more rapidly obtained than with oral compounds. Both agents can reduce the risk of vertebral, wrist and hip fractures by 30 - 50%, whereas other antiresorptive agents, such as raloxifene (Eli Lilly & Co.) or calcitonin (Unigene Laboratories Inc.), have only been demonstrated to reduce the incidence of vertebral fractures. The short infusion time (4 mg over 15 min) offers a convenient therapy and constitutes the most evident advantage of zoledronic acid, which will improve patients' quality of life. Zoledronic acid has the potential to change the treatment of osteoporosis dramatically.
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PMID:Zoledronic acid: an advance in tumour bone disease therapy and a new hope for osteoporosis. 1266 19

Less than 25 years ago, tumor-induced hypercalcemia was often a lethal complication of cancer. Nowadays, it can be successfully and easily treated in at least 90% of the cases by rehydration and potent antiosteoclastic bisphosphonates. The standard therapy consists of the administration of 90 mg of pamidronate (Aredia Dry Powder) or more recently, 4 mg of zoledronic acid (Zometa)], which is even more efficient, at least in patients without bone metastases. Recurrent hypercalcemia is nevertheless difficult to control and antibodies against parathyroid-hormone-related protein may prove to be a useful treatment.
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PMID:Treatment of tumor-induced hypercalcemia: a solved problem? 1272 83

Zoledronic acid is a potent, third generation, nitrogen-containing bisphosphonate, licensed for the management of skeletal metastases and hypercalcaemia of malignancy, both of which cause considerable morbidity. In the preclinical setting, zoledronic acid has demonstrated superior potency regarding inhibition of osteolysis and reduction of hypercalcaemia as compared with other bisphosphonates. Clinical trials have indicated that zoledronic acid is superior to pamidronate in suppressing osteolysis and in reducing hypercalcaemia of malignancy. Its main mechanism of action is induction of osteoclast apoptosis through inhibition of the mevalonate pathway. Zoledronic acid has also demonstrated direct anti-tumour activity both in vitro and in animal models, suggesting it may be of benefit in preventing the formation of bone metastases. Clinical trials are in progress, assessing the benefit of zoledronic acid in the adjuvant setting in both breast and prostate cancer.
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PMID:The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. 1452 88


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