Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisphosphonates are stable analogues of pyrophosphate (PPi), an endogenous regulator of bone mineralisation. A number of placebo-controlled trials have demonstrated their positive impact on skeletal-related events (SRE) that occur as a consequence of metastatic or myelomatous bone disease. Based upon their chemical structure bisphosphonates can be classified into nitrogen-containing bisphosphonates, (N-bisphosphonates) (for example zoledronate and pamidronate) and non-nitrogen containing (for example, clodronate and etidronate), which more closely resemble PPi. Clinical trials investigating bisphosphonates in the preventative setting have shown bisphosphonates to not only delay occurrence of bone metastases in certain cancers, but in one trial, occurrence of non-osseous lesions was delayed, and survival was prolonged. Other trials however have shown the opposite. Likewise, in animal models of cancer and metastases, conflicting results have been obtained. In vitro work has concentrated on bisphosphonates direct action upon tumour cells and has found a variety of anti-tumour effects such as apoptosis induction, inhibition of cell growth, inhibition of invasive behaviour and inhibition of angiogenic factors. Furthermore it would appear that bisphosphonates have the potential to enhance anti-tumour activity of known cytotoxic drugs. Ongoing research aims to assess this further, in addition to determining more precisely the role of adjuvant bisphosphonates in cancers such as breast and prostate cancer.
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PMID:The anti-tumour activity of bisphosphonates. 1247 Sep 81

Bone metastases are a common feature of a variety of solid tumors and are associated with substantial skeletal morbidity, including severe bone pain and pathologic fractures. Treatment with bisphosphonates, primarily pamidronate, is the current standard of care for patients with breast cancer and multiple myeloma who have predominantly osteolytic lesions. However, until recently no bisphosphonate had demonstrated efficacy in patients with osteoblastic lesions, which are common during the progression of prostate cancer and other solid tumors. Zoledronic acid, a potent, new-generation, nitrogen-containing bisphosphonate, has demonstrated significant benefits for patients with bone metastases resulting from a broad range of primary tumors, including multiple myeloma and breast, lung, kidney, and prostate cancers, and other solid tumors. Benefits include a decreased incidence of pathologic fractures and longer time to the first skeletal complication. Zoledronic acid is the first and only bisphosphonate to be proved effective in patients with all types of bone lesions, from osteolytic to osteoblastic, and therefore represents an important therapeutic advancement in the treatment of bone metastases.
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PMID:Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors. 1256 47

Preclinical studies are providing a growing body of evidence that bisphosphonates, particularly nitrogen-containing bisphosphonates, have antitumor activity. Bisphosphonates induce tumor cell apoptosis and reduce skeletal tumor burden in tumor xenograft models. Clinical studies with daily oral clodronate suggest that bisphosphonates can prevent bone metastases when used in the adjuvant setting, but the effect on overall survival is less certain. The more potent nitrogen-containing bisphosphonates, i.e., pamidronate and zoledronic acid, have demonstrated antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro. A number of important unanswered questions must be addressed regarding the optimal use of bisphosphonates for prevention of bone metastases. For example, when should treatment begin, how long must treatment be continued, and what are the optimal dose and schedule to achieve clinically meaningful antitumor effects? Adjuvant studies of zoledronic acid in patients with breast and prostate cancer are under development, and the results are eagerly anticipated.
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PMID:Future directions in the treatment and prevention of bone metastases. 1256 49

The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates with ever-increasing potency. Recent studies have begun to shed light on the unique mechanism of action and pharmacologic properties of these compounds. On the basis of in vitro studies and animal models of osteoclast-mediated bone resorption, zoledronic acid is the most potent bisphosphonate among a large number of compounds tested, including pamidronate and most other commercially available bisphosphonates. Zoledronic acid maintains bone mass in estrogen-deficient animals without adversely affecting bone mineralization. Moreover, the high potency of zoledronic acid translates into dramatic suppression of bone resorption markers at very low doses in patients with bone metastases, and zoledronic acid has shown efficacy across a broad range of tumor types. Preclinical studies have also shown the potential of bisphosphonates to inhibit tumor cell growth and colonization of the bone and to reduce skeletal tumor burden in animal models. A variety of mechanisms have been proposed to explain these observations and continue to be investigated in animal models. Studies are ongoing to determine if the antitumor potential of bisphosphonates can be exploited in the clinical setting.
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PMID:Preclinical pharmacology of zoledronic acid. 1258 89

Advanced solid tumors are often aggressive and recurrent, and overall survival remains relatively poor despite contemporary therapeutic interventions. Bone metastases are common in these patients, and skeletal-related events, including bone pain, pathologic fractures, and potentially life-threatening hypercalcemia of malignancy, undermine the quality of patient survival. Bisphosphonates are widely used in the treatment of bone metastases associated with breast cancer and multiple myeloma, but have not been extensively investigated in the treatment of patients with solid tumors other than breast or prostate cancer. However, a new-generation nitrogen-containing bisphosphonate, zoledronic acid, has shown significant clinical benefits in indications in which other bisphosphonates have failed. In a phase III clinical trial in patients with bone metastases from solid tumors other than breast or prostate cancer, treatment with zoledronic acid (4 mg via 15-minute infusion) was well tolerated and significantly decreased the incidence of skeletal-related events and increased the time to first skeletal-related event compared with placebo-treated patients. This was the first demonstration of palliative efficacy for bisphosphonate therapy in patients with bone metastases from a wide variety of solid tumors.
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PMID:Efficacy and safety of zoledronic acid in the treatment of bone metastases associated with lung cancer and other solid tumors. 1258 92

Preclinical studies have provided evidence that bisphosphonates have antitumor activity. Bisphosphonates have been shown to induce tumor cell apoptosis in vitro and reduce skeletal tumor burden in tumor xenograft models. Indirect evidence of bisphosphonate antitumor activity has been acquired from studies of clodronate, pamidronate, and zoledronic acid in patients with established bone metastases. Furthermore, clinical studies of daily oral clodronate adjuvant therapy suggest that bisphosphonates can prevent bone metastases, but their effect on overall survival is less certain. Pamidronate and zoledronic acid, potent nitrogen-containing bisphosphonates, have shown antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro and may hold promise for the prevention of bone metastases. However, before the clinical application of bisphosphonates for the prevention of bone metastases can be initiated, clinical trials must assess the optimal stage of disease at which to initiate treatment, the duration of therapy, and the optimal dose and schedule to achieve clinically meaningful antitumor effects. Adjuvant studies of zoledronic acid in patients with breast cancer are in development and should further clarify the role of zoledronic acid in the prevention of bone metastases.
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PMID:Bisphosphonates for the prevention of bone metastases. 1258 94

The knowledge and training of nursing staff is essential for the safety and comfort of patients receiving i.v. therapies. The use of i.v. bisphosphonates as an adjunct to standard antineoplastic therapies in patients with advanced cancer is becoming widespread. Zoledronic acid and pamidronate (Zometa and Aredia, Novartis Pharmaceuticals Corporation, East Hanover, NJ) are nitrogen-containing bisphosphonates. Pamidronate has been the standard of care for patients with osteolytic bone lesions from breast cancer or multiple myeloma. However, zoledronic acid, which has demonstrated increased potency and a broad clinical utility, is emerging as the new standard of care. In addition to treating hypercalcemia of malignancy, zoledronic acid is approved for treating patients with bone metastases (osteolytic or osteoblastic) from a wide range of solid tumors, including breast, prostate, and lung cancers, or osteolytic bone lesions from multiple myeloma. Zoledronic acid (4 mg via a 15-minute infusion) has a safety profile comparable with pamidronate (90 mg via a two-hour infusion) and has demonstrated comparable or superior efficacy to that of pamidronate in every patient population tested. The shorter infusion time of zoledronic acid compared with that of pamidronate may provide added convenience, but safety guidelines should be followed for all i.v. bisphosphonate therapies. These guidelines and nursing care of patients receiving i.v. bisphosphonates are reviewed.
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PMID:Advances in supportive care of patients with cancer and bone metastases: nursing implications of zoledronic acid. 1292 73

Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (HUVEC) adhesion, migration, and survival, three events essential for angiogenesis. Zoledronate inhibited HUVEC adhesion mediated by integrin alphaVbeta3, but not alpha5beta1, blocked migration and disrupted established focal adhesions and actin stress fibers without modifying cell surface integrin expression level or affinity. Zoledronate treatment slightly decreased HUVEC viability and strongly enhanced tumor necrosis factor (TNF)-induced cell death. HUVEC treated with zoledronate and TNF died without evidence of enhanced annexin-V binding, chromatin condensation, or nuclear fragmentation and caspase dependence. Zoledronate inhibited sustained phosphorylation of focal adhesion kinase (FAK) and in combination with TNF, with and without interferon (IFN) gamma, of protein kinase B (PKB/Akt). Constitutive active PKB/Akt protected HUVEC from death induced by zoledronate and TNF/IFNgamma. Phosphorylation of c-Src and activation of NF-kappaB were not affected by zoledronate. Clodronate had no effect on HUVEC adhesion, migration, and survival nor did it enhanced TNF cytotoxicity. Taken together these data demonstrate that zoledronate sensitizes endothelial cells to TNF-induced, caspase-independent programmed cell death and point to the FAK-PKB/Akt pathway as a novel zoledronate target. These results have potential implications to the clinical use of zoledronate as an anti-angiogenic or anti-cancer agent.
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PMID:Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. 1293 98

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

Over the past 15 years, bisphosphonates have been demonstrated as effective therapy for the treatment of osteoporosis based on their ability to suppress bone turnover resulting in increased bone mineral content and increased bone strength. The mechanism of action at the cellular level has been identified, and the more potent nitrogen-containing bisphosphonates clearly have reduced the risk of vertebral and nonvertebral fractures in patients with osteoporosis. Future use of these therapies is evolving to less frequent administration, and the interaction with anabolic therapies is presently being defined. Data to date support long-term safety with bisphosphonates in small numbers of patients treated for 5 to 10 years, and continued vigilant follow-up of the post-marketing experience will be necessary to determine if sustained bone turnover suppression is associated with rare musculoskeletal adverse events. Further development of bisphosphonates as adjunctive therapy to reduce bone metastases is in progress, and trials evaluating bisphosphonates as a structure modifying agent in osteoarthritis are nearing completion.
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PMID:An update on bisphosphonates. 1471 3


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