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PubMed2005

Prostate cancer presenting with normal serum PSA levels and boney metastases treated with zoledronic acid.

Prostate specific antigen (PSA) is currently the most widely used tumor marker for diagnosing and monitoring prostate cancer. Serum PSA level greater than 10 ng/mL is considered a negative predictor for the presence of bone metastases and routine use of bone scans is therefore avoided. This report describes two cases of patients presenting with normal PSA levels (0-4 ng/ mL) and positive bone scans. The value of routine use of bone scintigraphy in the follow up of these cases is therefore questioned here. Moreover the addition of bisphosphonates to the androgen deprivation treatment, achieved not only pain relief and improvement in aspects of quality of life, but also provided radiographic evidence of management of metastatic bone disease.

Adenocarcinoma↗
PubMed2003

Bisphosphonates and metastatic breast carcinoma.

BACKGROUND: Metastasis to the skeleton occurs in approximately 75% of patients with advanced breast cancer. It is the cause of much morbidity and decreased quality of life in these patients. METHODS: Zoledronic acid (Zoledronate) is a new, potent third-generation bisphosphonate that has recently been approved by the U.S. Food and Drug Administration for the treatment of both osteolytic and osteoblastic bone metastases. A Phase 3 clinical trial comparing the efficacy of Zoledronic acid 4 and 8 mg compared with Pamidronate 90 mg every 3-4 weeks has been completed. RESULTS: A 15 minute infusion of 4 mg of zoledronic acid is at least as effective as 90 mg of pamidronate in preventing skeletal complications in patients with metastatic breast cancer. CONCLUSIONS: Bisphosphonate treatment can delay skeletal events in patients with breast carcinoma that is metastatic to bone. Future trials will build on the results achieved with bisphosphonate treatment.

Administration, Oral↗
PubMed2005

Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

Aged↗
PubMed2005

Zoledronic acid-induced severe hypocalcaemia in a prostate cancer patient with extensive osteoblastic bone metastases.

A 74-year old white man was undergoing treatment with palliative chemotherapy for Stage IV Prostate Adenocarcinoma with multiple osteoblastic metastases. He was started on intravenous Zoledronic acid for reduction of bone pain and prevention of skeletal complication from multiple bone metastases. Four days after intravenous Zoledronic acid, the patient presented to emergency room with complaints of carpopedal spasm and bronchospasm. On admission, serum calcium and albumin was 3.5 mg/dl and 3.7 g/dl respectively. QT interval was more than 500 m sec. The patient was started on intravenous calcium gluconate. He received 174 gm of intravenous calcium for total of 12 days. His serum calcium returned to a normal range in three months with Vitamin D and calcium supplement. Before starting Zoledronic acid therapy, the patient's serum calcium level was 6.9 mg/dl.

Adenocarcinoma↗
PubMed2005

Clinical pharmacology of potent new bisphosphonates for postmenopausal osteoporosis.

Bisphosphonates are potent inhibitors of bone resorption, used in most bone diseases associated with high bone resorption levels. Several bisphosphonates, developed to prevent and treat postmenopausal osteoporosis, increase bone mineral density and decrease biochemical markers of bone turnover, and more importantly, reduce fracture risk. Alendronate and risedronate have proven their efficacy to reduce vertebral and hip fracture risk among postmenopausal osteoporotic women, using daily regimens. Weekly intermittent schedules, however, are now most commonly prescribed, because they have shown pharmacologic equivalence to the daily regimen. Ibandronate has been the first bisphosphonate to demonstrate vertebral fracture risk reduction using an intermittent regimen. Studies using ibandronate as intravenous injections every 3 months are under way. Zoledronic acid may also be an attractive option for the treatment of postmenopausal osteoporosis if a large ongoing trial proves that a single annual injection of this compound allows osteoporotic fracture risk reduction.

Alendronate↗
PubMed2004

The role of bisphosphonates in breast cancer.

Patients with bone metastases from breast cancer are at high risk for debilitating skeletal complications. Bisphosphonates are effective inhibitors of tumour-induced bone resorption and significantly reduce the risk of skeletal complications in these patients. Several bisphosphonates have been investigated for the treatment of bone metastases in patients with breast cancer, including clodronate, pamidronate, ibandronate, and zoledronic acid. Among these agents, intravenous pamidronate and zoledronic acid have demonstrated the greatest clinical benefit based on conservative endpoints. Zoledronic acid is the only agent to be compared with another active bisphosphonate and has been shown to significantly reduce the risk of skeletal complications compared with pamidronate. On the basis of these results, zoledronic acid has rapidly become the new international standard of care for patients with bone metastases from breast cancer.

Bone Neoplasms↗
PubMed2005

Management of bone metastases in breast cancer.

Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.

Adult↗
PubMed2006

Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update.

The prevention of cancer-treatment-induced bone loss (CTIBL) in long-term adjuvant breast cancer therapy is a high priority. Postmenopausal women with cancer, already at increased risk of bone loss because of age-related estrogen deficiency, face accelerated bone loss with the use of estrogen-depleting therapies such as third-generation aromatase inhibitors (AIs). Although effective in reducing cancer recurrence rates in the adjuvant setting, AIs are associated with bone loss and an increased risk of fractures. Bisphosphonates, which act by inhibiting osteoclastic bone resorption, have been shown to increase bone mineral density (BMD) and reduce fracture risk in postmenopausal women with established osteoporosis. Furthermore, the potent bisphosphonate zoledronic acid has been shown to be efficacious in reducing bone loss in premenopausal women receiving combination adjuvant hormone therapy (goserelin, a gonadotropin-releasing hormone agonist, plus either an AI or tamoxifen). The use of zoledronic acid to prevent CTIBL in postmenopausal women receiving adjuvant AI therapy with letrozole is currently being investigated in the Zometa/Femara Adjuvant Synergy Trial (Z-FAST). Postmenopausal women with stage I-IIIa estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer starting letrozole are randomized to receive either upfront zoledronic acid or delayed zoledronic acid. At 6 months, assessable women in the upfront group showed a mean increase of 1.55% in lumbar spine (L1 - L4) BMD, compared with a mean decrease of 1.78% in women in the delayed group, resulting in a difference of 3.33% between groups; moreover, women in the former group showed a mean increase of 1.02% in total hip BMD, compared with a mean decrease of 1.40% in those in the latter group, resulting in a significant difference of 2.42% between groups (P <.001). Thus, the Z-FAST BMD results show that upfront zoledronic acid prevents CTIBL in postmenopausal women receiving adjuvant letrozole therapy for early breast cancer. Combining the anticancer efficacy of letrozole with the bone-protective effect of zoledronic acid may be a successful treatment in this setting.

Aromatase Inhibitors↗
PubMed2006

Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines.

PURPOSE: Bisphosphonates are established as a supportive therapy for a number of malignancies that metastasize to bone. Previous reports have also suggested potent antitumor and anti-angiogenic properties. We investigated the in vitro activity of the 2 aminobisphosphonates pamidronate (Faulding Pharmaceuticals, Paramus, New Jersey) and zoledronic acid (Novartis, Basel, Switzerland) on the growth and survival of the 3 renal cell carcinoma cell lines Caki-2, 769-P (American Type Culture Collection, Manassas, Virginia) and D69581. MATERIALS AND METHODS: Cell lines were exposed to bisphosphonates in vitro and evaluated by MTS (3-(4,5-dimethylahiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and cell cycle analysis. Mechanisms of apoptotic cell death were investigated by ApoDIRECT assay (BioVision, Mountain View, California) and Kinetworks analysis. RESULTS: Zoledronic acid was consistently more potent than pamidronate for inducing apoptotic cell death. Zoledronic acid was capable of overcoming resistance to pamidronate in 1 cell line. Although it was ultimately less potent, the inhibitory effects of pamidronate appeared earlier than those of zoledronic acid. The pro-apoptotic effect of zoledronic acid was achieved through nonmitochondrial pathways and it was associated with the activation of caspase 6 and 3, and poly adenosine diphosphate-ribosyltransferase polymerase cleavage. Furthermore, we observed a marked decrease in and intracellular distribution of MSH2, a protein involved in DNA mismatch repair, as well as evidence of a greater cellular response to zoledronic acid as increased expression of superoxide dismutase. CONCLUSIONS: These findings add further support to the clinical use of aminobisphosphonates, particularly zoledronic acid, in patients with renal cell carcinoma with disease metastatic to bone.

Antineoplastic Agents↗
PubMed2002

American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma.

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of lytic bone disease in multiple myeloma and to determine their respective role relative to other conventional therapies for this condition. METHODS: An expert multidisciplinary Panel reviewed pertinent information from the published literature through January 2002. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the Panel. Expert consensus was used if there were insufficient published data. The Panel addressed which patients to treat and when to treat them in the course of their disease. Additionally, specific drug delivery issues, duration of therapy, initiation of treatment and management of treatment of lytic bone disease was reviewed and compared with other forms of therapy for lytic bone lesions. Finally, the Panel discussed patient and physician expectations associated with this therapy for bony metastases, as well as public policy implications related to the use of bisphosphonates. The guidelines underwent external review by selected physicians, by the Health Services Research Committee members, and by the ASCO Board of Directors. RESULTS: The available evidence involving randomized controlled trials is modest but supports that oral clodronate, intravenous pamidronate, and intravenous zoledronic acid are superior to placebo in reducing skeletal complications. A reduction in vertebral fractures has consistently been seen across all studies. No agent has shown a definitive survival benefit. Intravenous zoledronic acid has recently been shown to be as effective as intravenous pamidronate. Because there are no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent cannot be definitively established. However, the panel recommends only intravenous pamidronate or zoledronic acid in light of the use of the time to first skeletal event as the primary end point and more complete assessment of bony complications in studies evaluating it. Additionally, clodronate is not available in the United States. The choice between pamidronate and zoledronic acid will depend on choosing between the higher drug cost of zoledronic acid, with its shorter, more convenient infusion time (15 minutes), versus the less expensive drug, pamidronate, with its longer infusion time (2 hours). CONCLUSION: Bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. However, further research on bisphosphonates is warranted, including the following: (1) when to start and stop therapy, (2) how to integrate their use with other treatments for lytic bone disease, (3) how to evaluate their role in myeloma patients without lytic bone involvement, (4) how to distinguish between symptomatic and asymptomatic bony events, and (5) how to better determine their cost-benefit consequence.

Clodronic Acid↗
PubMed2001

Bisphosphonates and nephrocalcinosis in a rabbit leg lengthening model: a histological and therapeutic comparison.

We performed a comparison of the effects of two bisphosphonates, pamidronate and zoledronic acid, on regenerate bone mineral content in distraction osteogenesis in an immature rabbit model. Single dose zoledronic acid was found to be 18 times more potent at producing an increase in bone mineral content than pamidronate per mg/kg of drug infused at surgery. Histological examination of all rabbit kidneys was performed at trial completion. Nephrocalcinosis was identified in 14 of 20 kidneys of rabbits infused with pamidronate, but was not detected in the 20 kidneys of those rabbits infused with zoledronic acid. A further 20 kidneys from rabbits given a second dose of zoledronic acid were also found to be free of signs of nephrocalcinosis. Three of 40 control kidneys exhibited signs of nephrocalcinosis. The increased potency of zoledronic acid allowed us to give one-tenth the dose of pamidronate, with increased therapeutic efficacy and no evidence of nephrocalcinosis.

Animals↗
PubMed2004

Role of bisphosphonates in prostate cancer.

OBJECTIVE(S): To investigate the role of bisphosphonates in the long-term supportive care of patients with prostate cancer, an emerging medical challenge. Although the success of current therapeutic options has extended the survival of patients with prostate cancer, they often develop skeletal morbidity from disease and treatment-related effects that undermine skeletal integrity. METHODS: Studies were identified through MEDLINE searches, review of bibliographies of relevant articles, and review of abstracts from scientific meetings. RESULTS: Low bone mass is prevalent in patients in early stages of prostate cancer, although the reasons for this correlation are unknown. Furthermore, androgen deprivation therapy (ADT) by either pharmaceutical (including hormonal) or surgical castration causes significant decreases in bone mineral density. Pamidronate has been shown to prevent bone loss, whereas zoledronic acid has been shown to increase bone mass in men undergoing ADT. Finally, zoledronic acid is the only bisphosphonate that has demonstrated efficacy in reducing objectively measurable skeletal complications in patients with bone metastases secondary to prostate cancer. CONCLUSION: Bisphosphonates, zoledronic acid in particular, have potent activities against osteoclasts, which affect bone integrity. Zoledronic acid has now become an additional option that can provide benefits to patients with prostate cancer throughout the course of their disease.

Androgen Antagonists↗
PubMed2006

Renal safety of 1-hour pamidronate infusion for breast cancer and multiple myeloma patients: comparison between clinical trials and population-based database.

PURPOSE: The American Society of Clinical Oncology recommends infusion of pamidronate over 2 hours to avoid renal deterioration, although there are data to suggest that 1-hour infusions may be safe. METHODS: Prevalence of renal deterioration with 1-hour pamidronate infusions from a population database was compared to renal deterioration with 2-hour pamidronate infusions, in randomised, controlled, trials. A cost-minimisation analysis, comparing the 1- and 2-hour pamidronate infusions, and the 15-minute infusion of zoledronic acid, was performed with a sensitivity analysis that varied the opportunity cost of time in the treatment room. RESULTS: Renal deterioration occurred in 7.7% of 169 patients with multiple myeloma and metastatic breast cancer. There is no evidence that this differs from the 10% reported in randomised, controlled, trials (one-tailed binomial test, P = 0.3874). A subgroup analysis showed that renal deterioration occurred in 15 and 1.1% of patients with multiple myeloma and metastatic breast cancer, respectively. The median increase in serum creatinine was 13 and 7% in the multiple myeloma and breast cancer groups, respectively. The respective costs/dose (drug/labour/supplies) of pamidronate and zoledronic acid are 325 dollars and 610 dollars. Cost neutrality occurs if the opportunity cost of chair time is 6.33 dollars/minute for pamidronate 1-hour versus zoledronic acid, and 2.71 dollars/minute for pamidronate 2-hour versus zoledronic acid. If a median 4 dollars/minute is used, the respective costs of pamidronate 1-hour, 2-hour, and zoledronic acid infusions are 685 dollars, 925 dollars, and 790 dollars/cycle. CONCLUSIONS: Prevalence of renal deterioration with 1-hour pamidronate infusions from a population database was not significantly different to 2-hour pamidronate infusions in clinical trials. Our findings suggest further support for the safety of 1-hour pamidronate infusions. Pamidronate via 1-hour infusion is less expensive than zoledronic acid.

Aged↗
PubMed2001

Advances in the biology and treatment of myeloma bone disease.

Potential antitumor effects of bisphosphonates are discussed, and trial results of zoledronic acid, a bisphosphonate that recently received FDA approval for the treatment of hypercalcemia of malignancy (HCM), are described. Substitution at two sites on the central carbon in the phosphate-carbon-phosphate backbone has resulted in bisphosphonates increasingly more potent than the first such drug, etidronate disodium. Besides having an antihypercalcemic effect, the nitrogen-containing bisphosphonates pamidronate disodium and zoledronic acid have been shown to have an antitumor effect. Possible mechanisms include inducing apoptosis in tumor cells, inhibiting angiogenesis, and reducing adherence of cancer cells to the bone matrix. Zoledronic acid 4 mg is superior to pamidronate disodium 90 mg in achieving a normal serum calcium concentration, without increased toxicity. Zoledronic acid has a higher response rate, faster onset, and longer duration of action, and is more convenient to administer. Doses of > or = 1.5 mg given every four weeks for three months resulted in sustained reductions in urinary markers of bone resorption. Clinical trial results suggest that zoledronic acid 4 mg is at least as effective as pamidronate disodium 90 mg in preventing skeletal complications of osteolytic disease. Zoledronic acid is superior to pamidronate disodium in treating HCM and more convenient to administer. More research to evaluate its safety and effectiveness at higher doses is needed before its full antitumor potential is realized.

Antineoplastic Agents↗
PubMed2005

Skeletal complications of prostate cancer: pathophysiology and therapeutic potential of bisphosphonates.

Patients with prostate cancer are at risk for skeletal complications resulting from treatment-induced bone loss and for bone metastases. The therapeutic potential of zoledronic acid for the treatment of prostate cancer has been demonstrated in both preclinical and clinical studies. In patients receiving androgen-deprivation therapy, zoledronic acid increases bone mineral density, and, in patients with bone metastases, it reduces the incidence of skeletal complications. Preclinical studies have also demonstrated the antitumor potential of bisphosphonates. Specifically, zoledronic acid inhibits proliferation and induces apoptosis of human prostate cancer cell lines in vitro and has enhanced antitumor activity when combined with taxanes. Animal models have further shown that bisphosphonates decrease tumor-induced osteolysis and reduce skeletal tumor burden. In a model of prostate cancer, zoledronic acid significantly inhibited growth of both osteolytic and osteoblastic tumors and reduced circulating levels of prostate-specific antigen. These studies suggest that zoledronic acid has the potential to inhibit bone metastasis and bone lesion progression in patients with prostate cancer.

Androgen Antagonists↗