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PubMed2002

Treatment of hypercalcemia of malignancy with bisphosphonates.

Hypercalcemia of malignancy (HCM) is a potentially life-threatening complication of cancer resulting from increased bone resorption by osteoclasts. Clinical management of HCM primarily consists of intravenous rehydration therapy combined with pharmaceutical agents that decrease osteoclast activity. Several generations of drugs designed to combat HCM have evolved, the latest being intravenous bisphosphonate therapy. Bisphosphonates safely and effectively decrease serum calcium levels by interfering with osteoclast activity and stimulating osteoclast apoptosis. Zoledronic acid is the most recent bisphosphonate approved by the US Food and Drug Administration for treatment of HCM and is significantly more effective in reducing serum calcium levels than previously used bisphosphonates. Furthermore, zoledronic acid has a safety profile similar to that of pamidronate and other intravenous bisphosphonates. Thus, zoledronic acid represents a significant therapeutic advance in the clinical management of HCM.

Bone Resorption↗
PubMed2006

Medical management of Paget's disease of bone: indications for treatment and review of current therapies.

Treatment with a potent bisphosphonate is indicated in patients with Paget's disease who have symptoms likely to respond to reduced bone turnover at pagetic sites. In asymptomatic patients with active disease at sites susceptible to local progression and late complications, treatment is also recommended. Biochemical remission is achievable in a majority of patients with pamidronate, alendronate, risedronate, or zoledronic acid. Indications for medical treatment of active Paget's disease of bone include symptoms referable to sites of the disease such as bone pain, joint pain, and neurological complications; elective surgery at an active pagetic site to reduce intraoperative blood loss from highly vascular bone; management of rare instances of immobilization hypercalcemia with polyostotic disease; and presence of disease activity in asymptomatic patients at sites at risk for future complications to limit progression and possibly lower that risk. The treatment of choice is a potent nitrogen-containing bisphosphonate, including oral alendronate or risedronate or intravenous pamidronate or zoledronic acid. Etidronate and tiludronate are less potent and are second-line choices. Recent data with zoledronic acid indicate that a single infusion of 5 mg is associated with normalization of serum alkaline phosphatase in 89% of patients and a prolonged biochemical remission, making it the most effective therapy available to date. Side effect profiles with alendronate and risedronate include esophageal irritation in a minority of patients. Intravenous pamidronate and zoledronic acid may induce an acute phase reaction with fever and flu-like symptoms with the first dose, primarily in patients who are treatment naïve to nitrogen-containing bisphosphonates. Calcium and vitamin D repletion are mandatory with these potent anti-osteoclast therapies to avoid hypocalcemia. Acquired resistance to etidronate and pamidronate has been reported in some patients, leading to lesser reductions in bone turnover and shorter periods of remission, but substitution with a different bisphosphonate provides a more robust response. It is not known whether resistance to other bisphosphonates in Paget's disease occurs.

Diphosphonates↗
PubMed2003

Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone lesions.

Various primary malignancies develop bone metastases, and the resultant skeletal complications cause significant morbidity/mortality in advanced cancer patients. Bone lesions associated with metastases are traditionally classified radiologically as either osteolytic or osteoblastic, and both types of lesions are associated with elevated levels of specific bone resorption markers. Some common aspects in the pathophysiology of bone lesions have prompted speculation that treatments for osteolytic metastases might also be effective for predominantly osteoblastic metastases, such as in prostate cancer. Potent osteoclast activity inhibitors, bisphosphonates have been successful in the treatment of osteolytic tumor bone disease. Zoledronic acid is the first bisphosphonate shown to have a direct clinical benefit in the treatment of osteoblastic bone metastases, reducing the number and rate of skeletal events in prostate cancer patients with metastatic bone disease. Moreover, the shorter, more convenient infusion time and similar safety profile of 4 mg zoledronic acid compared with 90 mg pamidronate presently make zoledronic acid the preferred therapy for treatment of bone metastases in patients with all types of advanced malignancy.

Bone Neoplasms↗
PubMed2001

Safety and efficacy of bisphosphonates beyond 24 months in cancer patients.

PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. CONCLUSION: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.

Bone Neoplasms↗
PubMed2005

Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.

PURPOSE: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. PATIENTS AND METHODS: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. RESULTS: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. CONCLUSION: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.

Adult↗
PubMedDate not supplied

Multimodal imaging analysis of tumor progression and bone resorption in a murine cancer model.

OBJECTIVE: This study evaluates the use of multimodal imaging to qualitatively and quantitatively measure tumor progression and bone resorption in a xenotransplanted tumor model of human neuroblastoma. METHODS: Human neuroblastoma cells expressing a luciferase reporter gene were injected into the femur of nu/nu mice. Tumor progression with and without zoledronic acid treatment was monitored using radiographs, D-luciferin-induced luminescence, micro-computer tomography (CT) and micro-magnetic resonance imaging (MRI). RESULTS: We observed a gradual increase in D-luciferin-based bioluminescence concomitant with detectable osteolytic lesions. Tumor growth was inhibited (P=0.003-0.07) with zoledronic acid treatment. Micro-CT analysis in vivo provided a method to quantify bone loss, and its prevention by zoledronic acid. High-resolution MRI images allowed the observation of tumor cells within the bone marrow cavity, as well as distant metastasis. CONCLUSION: Multimodal imaging allows to measure tumor growth and bone resorption simultaneously in vivo and also proved useful in the detection distant metastasis.

Animals↗
PubMed2006

Biphosphonates in advanced prostate and renal cell cancer--current status and potential applications.

OBJECTIVE: This review summarizes recent findings on the therapeutic benefits of biphosphonates in patients with advanced prostate or renal cell carcinoma (RCC). The role of biphosphonates in ADT-induced osteoporosis and delay of skeletal-related events (SREs) in metastatic bone disease is discussed. A brief overview on the proposed modes of action is given. METHODS: Literature search of PubMed documented publications and abstracts from meetings. RESULTS: Among the biphosphonates currently available, zoledronic acid is the only one known to be capable of delaying SREs in RCC and prostate cancer patients. Zoledronic acid counteracts cancer treatment-induced osteoporosis in men with prostate malignancies. The antitumor activity of biphosphonates found in vitro and in vivo is intriguing and has to be further assessed in clinical studies. CONCLUSION: Due to its unique properties, zoledronic acid is a breakthrough in the management of metastatic bone disease in patients with advanced prostate cancer and RCC. It significantly improves the patients' quality of life, drastically prolongs time to first SRE, and showed a positive but not significant effect on survival.

Bone Neoplasms↗
PubMed2000

Myeloma--the therapeutic challenge.

BACKGROUND: Bone loss--the major clinical manifestation of multiple myeloma--often leads to pathologic fractures, spinal cord compression, hypercalcemia and bone pain. THERAPY AND RESULTS: Analgesics, surgery and radiotherapy may effectively palliate patients with complications from myeloma bone disease, but cannot slow the progressive bone loss. Chemotherapy may reduce tumor burden but has little impact on the underlying bone disease. A dramatic change was the demonstration that intravenous pamidronate could reduce skeletal complications. Importantly, because bisphosphonates lack significant bone marrow suppressive effects they can be administered to other cytotoxic therapy. Laboratory studies show the improved potency of the 3rd-generation bisphosphonate zoledronic acid in its anti-bone resorptive as well as anti-myeloma effects. Phase-I and -II studies evaluating zoledronic acid in myeloma patients show marked and sustained inhibition of bone resorption markers. CONCLUSION: The randomized studies evaluating zoledronic acid have demonstrated its superiority to pamidronate in overcoming tumor-induced hypercalcemia. Results of ongoing phase-III studies will determine its relative safety and efficacy compared to pamidronate.

Antineoplastic Agents↗
PubMed2002

Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma.

Anti-resorptive bisphosphonates, such as pamidronate, are an effective treatment for osteolytic disease and hypercalcaemia in patients with multiple myeloma, but have also been shown to cause apoptosis of myeloma cell lines in vitro. In this study, we found that a single infusion of pamidronate, in 16 newly diagnosed patients with multiple myeloma, caused a marked increase in apoptosis of plasma cells in vivo in 10 patients and a minimal increase in four patients (P < 0.05). The nitrogen-containing bisphosphonates pamidronate and zoledronic acid also induced apoptosis of authentic, human bone marrow-derived plasma cells in vitro. Apoptosis of plasma cells in vitro was probably caused by inhibition of the mevalonate pathway and loss of prenylated small GTPases, as even low concentrations (>or= 1 micro mol/l) of zoledronic acid caused accumulation of unprenylated Rap1A in cultures of bone marrow mononuclear cells in vitro. GGTI-298, a specific inhibitor of geranylgeranyl transferase I, also induced apoptosis in human plasma cells in vitro, suggesting that geranylgeranylated proteins play a role in signalling pathways that prevent plasma cell death. Our results suggest that pamidronate may have direct and/or indirect anti-tumour effects in patients with multiple myeloma, which has important implications for the further development of the more potent nitrogen-containing bisphosphonates, such as zoledronic acid, in the treatment of myeloma.

Aged↗
PubMed2004

Bisphosphonates: preclinical review.

Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate alpha(v)beta(3) and alpha(v)beta(5) integrins. In addition, zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel trade mark and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.

Animals↗
PubMed2001

Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.

It has long been known that small changes to the structure of the R(2) side chain of nitrogen-containing bisphosphonates can dramatically affect their potency for inhibiting bone resorption in vitro and in vivo, although the reason for these differences in antiresorptive potency have not been explained at the level of a pharmacological target. Recently, several nitrogen-containing bisphosphonates were found to inhibit osteoclast-mediated bone resorption in vitro by inhibiting farnesyl diphosphate synthase, thereby preventing protein prenylation in osteoclasts. In this study, we examined the potency of a wider range of nitrogen-containing bisphosphonates, including the highly potent, heterocycle-containing zoledronic acid and minodronate (YM-529). We found a clear correlation between the ability to inhibit farnesyl diphosphate synthase in vitro, to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro, and to inhibit bone resorption in vivo. The activity of recombinant human farnesyl diphosphate synthase was inhibited at concentrations > or = 1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximately equal to minodronate > risedronate > ibandronate > incadronate > alendronate > pamidronate) closely matching the order of antiresorptive potency. Furthermore, minor changes to the structure of the R(2) side chain of heterocycle-containing bisphosphonates, giving rise to less potent inhibitors of bone resorption in vivo, also caused a reduction in potency up to approximately 300-fold for inhibition of farnesyl diphosphate synthase in vitro. These data indicate that farnesyl diphosphate synthase is the major pharmacological target of these drugs in vivo, and that small changes to the structure of the R(2) side chain alter antiresorptive potency by affecting the ability to inhibit farnesyl diphosphate synthase.

Alkyl and Aryl Transferases↗
PubMed2004

New generation of bisphosphonates: broad clinical utility in breast and prostate cancer.

Cancer treatment-induced bone loss is an emerging problem for patients with breast and prostate cancer, who are often treated with cancer therapies earlier in the disease process. Bone loss associated with cancer therapy can also progress rapidly and may cause significant morbidity in these patients. Many patients with metastatic prostate or breast cancer develop bone metastases and subsequent skeletal-related events. Studies suggest that bisphosphonates can maintain bone health when introduced early in the continuum of cancer care. They have shown efficacy in the prevention of bone loss and the more potent i.v. bisphosphonate, zoledronic acid, has prevented bone loss in addition to increasing BMD in prostate cancer patients with cancer treatment-induced bone loss. Intravenous zoledronic acid or pamidronate can be considered the standard of care for the treatment of osteolytic bone metastases in breast cancer. Clinical trials addressing the treatment of bone metastases related to prostate cancer have shown zoledronic acid to be the only bisphosphonate to have a significant positive effect on skeletal-related events.

Bone Density↗
PubMed2006

Breast cancer: bisphosphonate therapy for metastatic bone disease.

The indications of bisphosphonate therapy in breast cancer patients go from the correction of hypercalcemia to the prevention of cancer treatment-induced bone loss. Bisphosphonates are part of our therapeutic armamentarium against metastatic bone pain, and at least 50% of the patients benefit from a clinically relevant analgesic effect. Placebo-controlled trials with oral or i.v. bisphosphonates have shown that prolonged administration can reduce the frequency of skeletal-related events by 30% to 40%. The superiority of zoledronic acid compared with pamidronate has been shown by a multiple-event analysis in a large randomized trial. The short infusion time of zoledronic acid also constitutes a convenient therapy. Where available, oral ibandronate offers an interesting alternative, especially for patients receiving hormone therapy. There are some toxicity concerns with the prolonged use of bisphosphonates. The occasional renal toxicity of zoledronic acid has led to the recommendation to monitor renal function before each infusion and to adjust the dose according to creatinine clearance. Osteonecrosis of the jaw could occur in up to 2.5% of breast cancer patients during long-term bisphosphonate therapy. It is often a significant complication that seems to be linked with the duration of therapy.

Bone Density Conservation Agents↗
PubMed2004

Long-term implications of bone loss in breast cancer.

Cancer treatment-induced bone loss (CTIBL) is an emerging problem during long-term adjuvant therapy with aromatase inhibitors or ovarian-ablative therapy. CTIBL increases the risk of skeletal complications. Patients receiving adjuvant therapy for breast cancer should receive periodic bone mineral density (BMD) assessments, and those with clinically significant bone loss should be treated with bisphosphonates. Intravenous (i.v.) bisphosphonates (e.g., zoledronic acid) appear to be a very effective treatment for CTIBL. Recently, the Austrian Breast and Colorectal Cancer Study Group 012 trial reported that i.v. zoledronic acid (4 mg every 6 months) maintained BMD in premenopausal women receiving goserelin with either tamoxifen or anastrozole. The Z-FAST and ZO-FAST trials are comparing i.v. zoledronic acid (4 mg every 6 months) up front with letrozole versus initiation when patients exhibit lumbar-spine BMD T-scores > or =2 standard deviations below normal (i.e., T-score < or =-2.0). These studies will provide important insight into the management of CTIBL.

Aromatase Inhibitors↗
PubMed2004

Understanding treatments for bone loss and bone metastases in patients with prostate cancer: a practical review and guide for the clinician.

Prostate cancer patients are at risk for developing bone loss and bone metastases. Clinicians prescribing ADT should appreciate the potential effects of ADT on BMD as well as the morbidity and mortality that can result from osteoporotic fractures. Measures to address the evaluation of patients and when to treat patients with significant bone loss have been discussed. Bisphosphonates effectively prevent loss of BMD in prostate cancer patients. Treatment of prostate cancer patients with established bone metastases with zoledronic acid should be considered strongly based on the results of the Saad study and other studies of patients with bone metastases with other malignancies. Zoledronic acid is approved by the US FDA for use in men with metastatic hormone-refractory prostate cancer and in the European Union for any patient with bone metastases, including prostate cancer patients,because of the beneficial impact of zoledronic acid on skeletal-related events. There is no validated method to determine which patients might benefit most from bisphosphonate therapy in this setting. Many questions about the use of bisphosphonate therapy in men with prostate cancer must be addressed, both in terms of the use in bone loss and bone metastases. These questions include: What is the optimal timing of therapy? Which bisphosphonate is best? What is the best dose and dose schedule? Do bisphosphonates effectively decrease skeletal fracture rates in patients with osteoporosis? How long should patients receive therapy? Are bisphosphonate "holidays" warranted? What are the long-term skeletal and renal toxicities? Is there a role for sequencing bisphosphonate therapy either before or after chemotherapy? Is bisphosphonate therapy synergistic with certain chemotherapy or other bone-targeted therapies? Which patients are the most likely to benefit from bisphosphonate therapy? What are clinically significant endpoints of bisphosphonate trials in patients with metastatic disease? Does inhibiting bone turnover also inhibit formation of bone metastases? Preliminary work in these areas has been completed, but more questions than answers are available. Given the rising costs of health care, it is imperative that these questions be addressed to best use the health care dollar while offering high-risk patients the best available therapy. At present, no data suggest that bisphosphonates should be used routinely to prevent BMD loss in men with normal BMD or to prevent the development of bone metastases in men with biochemical relapse. Continuing trials may give us guidance in the future.

Age Distribution↗
PubMed2005

Bisphosphonates in breast cancer.

Breast cancer is the leading type of cancer among women, and bone metastases are common in patients with breast cancer, affecting more than half of all patients with advanced disease. Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcaemia of malignancy. Bisphosphonates significantly reduced the incidence of these events. Zoledronic acid, pamidronate, clodronate and ibandronate have demonstrated efficacy compared with placebo. Zoledronic acid has also been compared with another active bisphosphonate (i.e. pamidronate) and shown by multiple event analysis to be significantly more effective at reducing the risk of SREs. Bisphosphonates effectively reduce and prevent skeletal complications in patients with bone metastases from breast cancer. Preclinical data suggest that bisphosphonates have antitumour effects. Bisphosphonates may also be of use in the adjuvant setting.

Administration, Oral↗
PubMed2003

Bone metastases in breast cancer.

Patients with advanced breast cancer who develop bone metastases suffer from long-term skeletal morbidity. Complications of bone metastases include pain, pathologic fractures, and spinal cord compression, which have a significant impact on the quality of life of patients. Treatment options for patients with bone metastases include surgery, radiation, and analgesics to reduce bone pain and to prevent or repair fractures. Intravenous bisphosphonates can delay the onset of bone metastasis and reduce the percentage of patients who experience skeletal complications of bone metastasis, thus reducing skeletal morbidity. For the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous infusion) has been the treatment of choice for the prevention of skeletal complications of bone metastases in patients with breast cancer. However, a more potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute intravenous infusion), was approved for use and has improved efficacy in patients with bone metastases. Because of the increased efficacy and more convenient infusion time, zoledronic acid may become the new standard of care for the treatment and prevention of skeletal complications secondary to bone metastases in patients with breast cancer. Phase III clinical trials have shown that patients with an existing skeletal complication are more likely to develop subsequent complications compared with patients who have not experienced a complication. Therefore, zoledronic acid therapy should be initiated when the patient is diagnosed with bone metastasis.

Antineoplastic Agents↗