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PubMed2006

Medical therapy in adults with fibrous dysplasia of bone.

UNLABELLED: In open studies, bisphosphonate therapy (pamidronate, alendronate) reduced bone pain associated with fibrous dysplasia of bone and was associated to some radiological improvement. Calcium, vitamin D, and phosphorus supplements may be useful in patients with deficiency. We are awaiting results from controlled trials testing bisphosphonates. INTRODUCTION: Fibrous dysplasia of bone (FD), a rare disease caused by osteoblastic lineage differentiation defects, is associated with bone pain, fracture, and bone deformity, but few therapeutic options are available. MATERIALS AND METHODS: We reviewed published data on the treatment of FD with bisphosphonates (pamidronate, alendronate), calcium, vitamin D, and phosphorus. We also present new results on FD therapy with a more potent bisphosphonate, zoledronic acid, given intravenously at the dose of 4 mg every 6 months. RESULTS: Pamidronate therapy, given intravenously every 6 months at a dose of 180 mg in adults, relieved bone pain, decreased bone resorption, and improved the radiological aspect (filling of lytic lesions and/or thickening of cortices) in approximately 50% of patients. BMD in affected sites was also significantly increased after pamidronate treatment. Those results have been obtained only in open studies, without controls, by several research groups. In a series of nine patients on long-term pamidronate treatment, but resisting to this medication and switched to intravenous zoledronic acid, no substantial improvement was observed. There is some biological rationale supporting the use of calcium and vitamin D in patients with deficiency to improve FD lesions by limiting secondary hyperparathyroidism. Phosphorus supplementation may prevent mineralization defects in those patients who have both FD and renal phosphate wasting. However, we are lacking clinical evidence for the efficacy of such supplements. CONCLUSIONS: Bisphosphonate treatment reduces increased osteoclastic activity in FD and probably improves bone pain, but their use should be better studied in randomized controlled trials.

Adolescent↗

PubMed2001

Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro.

Bisphosphonates inhibit osteoclast-mediated bone resorption by mechanisms that have only recently become clear. Whereas nitrogen-containing bisphosphonates affect osteoclast function by preventing protein prenylation (especially geranylgeranylation), non-nitrogen-containing bisphosphonates have a different molecular mechanism of action. In this study, we demonstrate that nitrogen-containing bisphosphonates (risedronate, alendronate, pamidronate, and zoledronic acid) and non-nitrogen-containing bisphosphonates (clodronate and etidronate) cause apoptosis of rabbit osteoclasts, human osteoclastoma-derived osteoclasts, and human osteoclast-like cells generated in cultures of bone marrow in vitro. Osteoclast apoptosis was shown to involve characteristic morphological changes, loss of mitochondrial membrane potential, and the activation of caspase-3-like proteases capable of cleaving peptide substrates with the sequence DEVD. Caspase-3-like activity could be visualized in unfixed, dying osteoclasts and osteoclast-like cells using a cell-permeable, fluorogenic substrate. Bisphosphonate-induced osteoclast apoptosis was dependent on caspase activation, because apoptosis resulting from alendronate, clodronate, or zoledronic acid treatment was suppressed by zVAD-fmk, a broad-range caspase inhibitor, or by SB-281277, a specific isatin sulfonamide inhibitor of caspase-3/-7. Furthermore, caspase-3 (but not caspase-6 or caspase-7) activity could be detected and quantitated in lysates from purified rabbit osteoclasts, whereas the p17 fragment of active caspase-3 could be detected in human osteoclast-like cells by immunofluorescence staining. Caspase-3, therefore, appears to be the major effector caspase activated in osteoclasts by bisphosphonate treatment. Caspase activation and apoptosis induced by nitrogen-containing bisphosphonates are likely to be the consequence of the loss of geranylgeranylated rather than farnesylated proteins, because the ability to cause apoptosis and caspase activation was mimicked by GGTI-298, a specific inhibitor of protein geranylgeranylation, whereas FTI-277, a specific inhibitor of protein farnesylation, had no effect on apoptosis or caspase activity.

Animals↗

PubMed2003

American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer.

PURPOSE: To update the 2000 ASCO guidelines on the role of bisphosphonates in women with breast cancer and address the subject of bone health in these women. RESULTS: For patients with plain radiographic evidence of bone destruction, intravenous pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence supporting the efficacy of one bisphosphonate over the other. Starting bisphosphonates in women who demonstrate bone destruction through imaging but who have normal plain radiographs is considered reasonable treatment. Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction is not recommended. The presence or absence of bone pain should not be a factor in initiating bisphosphonates. In patients with a serum creatinine less than 3.0 mg/dL (265 mumol/L), no change in dosage, infusion time, or interval is required. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. Creatinine should be monitored before each dose of either agent in accordance with US Food and Drug Administration (FDA) labeling. Oncology professionals, especially medical oncologists, need to take an expanded role in the routine and regular assessment of the osteoporosis risk in women with breast cancer. The panel recommends an algorithm for patient management to maintain bone health. CONCLUSION: Bisphosphonates provide a supportive, albeit expensive and non-life-prolonging, benefit to many patients with bone metastases. Current research is focusing on bisphosphonates as adjuvant therapy. Although new data addressing when to stop therapy, alternative doses or schedules for administration, and how to best coordinate bisphosphonates with other palliative therapies are needed, they are not currently being investigated.

Bone Density↗

PubMed2004

Bisphosphonates in the treatment of skeletal metastases.

Metastatic bone disease puts an enormous burden on patients and health care resources. Disruption of normal bone homeostasis by bone metastases leads to troublesome skeletal complications, such as bone pain, pathologic fractures, hypercalcemia of malignancy, and spinal cord compression. Bisphosphonates are an effective treatment for skeletal complications. These agents act primarily by initiating biochemical processes that ultimately result in apoptosis of osteoclasts, but they also have a number of other antitumor functions (eg, inhibition of angiogenesis). At present, the most widely used bisphosphonates are oral clodronate and intravenous pamidronate and zoledronic acid. Although these agents are effective in reducing skeletal complications, they are associated with varying safety and convenience issues. More recently, the availability of ibandronate as intravenous and oral formulations represents a new alternative for the treatment of metastatic bone disease. Further studies are necessary to establish the comparative benefits of bisphosphonates in metastatic bone disease.

Bone Neoplasms↗

PubMed2003

Bisphosphonate therapy in the oncology setting.

Patients with metastatic cancer and bone involvement are at chronic risk of skeletal complications, including bone pain, fractures, spinal cord compression and hypercalcaemia of malignancy. Therapies targeting the primary malignancy are often unable to prevent skeletal complications, which often require orthopaedic surgery, radiation therapy and analgesics. Intravenous bisphosphonates can reduce the risk of skeletal complications and the requirement for palliative radiation therapy. Since its broad regulatory approval, zoledronic acid (ZOMETA, Novartis Pharma AG/Novartis Pharmaceuticals Corporation) 4 mg by 15-minute intravenous infusion has become widely used to treat bone metastases from all solid tumours and is becoming the standard of care for advanced breast cancer and multiple myeloma. Additionally, cancer treatment-induced bone loss is an emerging problem in clinical oncology, and bisphosphonates -- particularly intravenous bisphosphonates -- may provide benefits even before bone lesions develop. Further investigations of bisphosphonates in these and other indications are ongoing.

Administration, Oral↗

PubMed2007

R115777 (Zarnestra)/Zoledronic acid (Zometa) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation.

Zoledronic acid (ZOL) has proved activity in bone metastases from prostate cancer through inhibition of mevalonate pathway and of prenylation of intracellular proteins. We have reported that ZOL synergizes with R115777 farnesyltransferase inhibitor (FTI, Zarnestra) in inducing apoptosis and growth inhibition on epidermoid cancer cells. Here, we have studied the effects of the combination of these agents in prostate adenocarcinoma models and, specifically, on androgen-independent (PC3 and DU145) and -dependent (LNCaP) prostate cancer cell lines. We have found that ZOL and R115777 were synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by disruption of Ras-->Erk and Akt survival pathways, consequent decreased phosphorylation of both mitochondrial bcl-2 and bad proteins, and caspase activation. Finally, ZOL/R115777 combination induced cooperative effects also in vivo on tumor growth inhibition of prostate cancer xenografts in nude mice with a significant survival increase. These effects were paralleled by enhanced apoptosis and inactivation of both Erk and Akt. In conclusions, the combination between ZOL and FTI leads to enhanced anti-tumor activity in human prostate adenocarcinoma cells likely through a more efficacious inhibition of ras-dependent survival pathways and consequent bcl-related proteins-dependent apoptosis.

Adenocarcinoma↗

PubMed2005

New therapeutic agents for the treatment of bone diseases.

Bisphosphonates have demonstrated important clinical benefits for patients with malignant bone disease, metabolic bone diseases, such as Paget's disease, and postmenopausal osteoporosis. The introduction of nitrogen-containing bisphosphonates with high affinity for hydroxyapatite in bone represents an important advancement. These agents are now a standard of care for osteoporosis, Paget's disease, osteogenesis imperfecta, primary bone lesions from multiple myeloma and bone metastases from breast cancer. Moreover, the recent clinical development of zoledronic acid (4 mg by 15-minute intravenous infusion) has expanded the benefits of bisphosphonate therapy to patients with bone metastases from any solid tumour. Bisphosphonates are also being investigated at present for the prevention of bone loss resulting from cancer therapy. In addition, a variety of novel biologic agents, receptor activator of nuclear factor-kappaB (RANK) ligand antibodies, osteoprotegerin and cathepsin K inhibitors are being investigated at present for the treatment of malignant bone disease. The management of bone health is an important area of active research, and the armamentarium and role of bone-specific therapies continue to expand.

Antineoplastic Agents↗

PubMedDate not supplied

Bisphosphonate therapy in multiple myeloma: past, present, future.

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.

Bone Diseases↗

PubMed2005

Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates?

INTRODUCTION: In the last decade, bisphosphonates were regularly used to treat osteoporosis and bone pain from diseases such as metastatic breast cancer, multiple myeloma and Paget's disease. Currently, the influence of bisphosphonates in development of avascular osteonecrosis of the jaws has been recognized by various authors. In many cancer patients chemotherapy and medications like steroids have also to be applied. Agreement exists that these drugs can initiate vascular endothelial cell damage and accelerate disturbances in the microcirculation of the jaws possibly resulting in thrombosis of nutrient end arteries. The role of bisphosphonates in cancer patients with previously treated jaws has yet to be elucidated. PATIENTS: Four case reports of 'cancer' patients are described in whom osteonecrosis of the jaws was found. In two patients, the nitrogen-containing bisphosphonate zoledronic acid was prescribed for additional therapy of malignancy for a period of 45 up to 70 months. In another case, supportive treatment of breast cancer was offered using ibandronate. The fourth patient suffered avascular necrosis of the mandible without ever having taken bisphosphonates. In any case, revisional, as well as extended surgery has to be performed for osteonecrosis because neither conservative debridement nor antibiotic therapy have shown long term success, with or without bisphosphonates. No withdrawal of bisphosphonates was performed in view of the information on the direct correlation of total dosage and duration of drug intake to systemic incorporation and the long time for drug release. CONCLUSION: According to our observations, withdrawal of bisphosphonates is not recommended when necrosis of the jaws has occurred.

Adult↗

PubMed2004

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications.

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.

Antineoplastic Agents↗

PubMed2002

Novel therapeutic options for osteoporosis.

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason, research continues in search of more effective and more tolerable agents. Arzoxifene and TSE-424 are investigational selective estrogen receptor modulators that have been shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for the prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. Although studies of the effect of isoflavones on bone mineral density have been encouraging, a large multicenter study in Europe recently showed no effect of isoflavones on fractures. The investigational bisphosphonates ibandronate and zoledronic acid may offer the advantage of less frequent dosing. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Finally, the issue of efficacy of statins in bone continues to be debated with no prospective, randomized studies yet to confirm the suggestion of benefit seen in epidemiologic studies.

Animals↗

PubMed2005

Evolving role of bisphosphonates in women undergoing treatment for localized and advanced breast cancer.

Breast cancer commonly metastasizes to bone, producing hypercalcemia, pathologic fractures, spinal compression, and pain that increase morbidity and affect the patient's mobility and quality of life. The use of bisphosphonates like pamidronate and zoledronic acid inhibits osteolytic activity caused by bone metastases. The use of bisphosphonates to prevent bone loss and preserve bone health in the adjuvant setting in women with breast cancer undergoing hormonal therapy with aromatase inhibitors or ovarian suppression is being actively investigated. Interestingly, clodronate, an oral bisphosphonate, has been shown in 2 trials to decrease the risk of recurrence in women with early-stage breast cancer, suggesting a direct or indirect antitumor effect of bisphosphonates. Trials to confirm the antitumor effects of bisphosphonates are currently ongoing. Prolonged intravenous bisphosphonate use has been associated with a rare risk of osteonecrosis of the jaw. Recommendations for management of this condition are discussed.

Antineoplastic Agents↗

PubMed2004

Advances in the use of bisphosphonates in the prostate cancer setting.

Prostate cancer incidence is rising, and represents a major public health issue. Bone is by far the most common site for metastases in this disease, accounting for considerable morbidity. Until recently, there have been few viable options for the treatment of patients with hormone-refractory metastatic disease. This review examines the pathophysiology underlying the development of bone metastases. It also summarises some of the clinical approaches for the management of this common condition, focusing on recent evidence supporting the use of zoledronic acid, a member of one of the most promising groups of pharmacological agents, the third-generation bisphosphonates.

Bone Neoplasms↗

PubMed2004

Zoledronate in a patient with pamidronate refractory hypercalcemia syndrome.

Hypercalcemia of malignancy remains a common metabolic complication of advanced cancer often resulting in considerable morbidity and diminishing life quality in the later stages of disease. Bisphosphonates, especially zoledronic acid, are potent inhibitors of bone resorption and are the most effective therapy for hypercalcemia of malignancy. We report on the course of disease in a 51-year-old woman who presented with metastatic breast cancer that had relapsed to the liver. The patient suffered from a pamidronate-refractory paraneoplastic hypercalcemia, which caused a confused mental status and compromised her already severely limited life quality. Only with the introduction of zoledronate could the patient's hypercalcemia be normalized with consecutive regain of an acceptable life quality.

Bone Resorption↗

PubMed2001

Metastatic bone disease and tumour-induced hypercalcaemia: the role of bisphosphonates.

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.

Bone Neoplasms↗

PubMed2005

Zometa in the treatment of diseminated prostate cancer.

Zoledronic acid is the first bisphosphonat that confirms the a efficacy in the treatment of bone metastases in prostate carcinoma. That is the most potent bisphosphonat up to date which safe and simple administration. Zometa is strong inhibitor of osteoclast activity.

Bone Density Conservation Agents↗

PubMed2006

[The effect of bisphosphonates on bone metastasis of hormone-refractory prostate cancer].

Approximately 70% of patients with advanced prostate cancer have bone metastases, which are associated with considerable skeletal morbidity, accompanied by severe bone pain that requires narcotics or palliative radiation therapy, pathological fractures, spinal cord compression and hypercalcemia of malignancy (HCM), which consequentiy lower the patient's quality of life. Bisphosphonates, potent inhibitors of osteoclast activity and survival, therefore inhibiting osteoclast-mediated bone absorption, transiently palliative bone pain and decrease analgesic usage in patients who have hormone-refractory prostate cancer (HRPC) with bone metastases. Recently, a randomized controlled trial showed that a third-generation bisphosphonate, zoledronic acid reduced bone pain and skeletal-related events (SREs). In this manuscript, we reviwed the efficacy of bisphosphonates in HRPC with bone metastases from several clinical studies and discuss treatment of advanced prostate cancer with bisphosphonates.

Antineoplastic Agents↗

PubMed2006

[Bisphosphonates for bone metastasis of malignant tumor].

Bone metastasis of a malignant tumor causes various skeletal related events (SREs) and often harms patients' QOL. Bisphosphonates is a standard treatment medicine for the patient with bone metastasis of a malignant tumor. It is possible that Bisphosphonates improve and also maintain their QOL because it restrains manifestation of SREs. Particularly zoledronic acid is recommended for bone metastasis of all malignant tumors in a guideline of American Society of Clinical Oncology (ASCO). Bisphosphonates should be used positively for profit of the patient.

Bone Neoplasms↗