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PubMed2001

New advances in the biology and treatment of myeloma bone disease.

The bisphosphonates provide effective therapy for the skeletal complications of multiple myeloma (MM). Although the earliest bisphosphonates had poor bioavailability and relatively low potency, newer compounds such as pamidronate and zoledronic acid have greater potency. Bisphosphonates block the development of monocytes into osteoclasts and are thought to promote apoptosis of osteoclasts. These agents prevent osteoclasts from moving to the bone surface and seem to inhibit the production of bone-resorbing cytokines such as interleukin-6 (IL-6) by bone marrow stromal cells. In addition, bisphosphonates seem to have a direct antimyeloma effect by inducing apoptosis of malignant plasma cells. The beneficial effects of pamidronate have been demonstrated in a clinical trial setting. Patients who failed to respond to chemotherapy had a slight prolongation of survival and better performance status and quality of life. Ongoing clinical trials with ibandronate and zoledronic acid indicate the latter is 100 to 1,000 times more potent than pamidronate. Biochemical effects of zoledronic acid continue for as long as 8 weeks after a single administration. In a new trial comparing pamidronate and zoledronic acid, 90% of the patients who received zoledronic acid were normocalcemic, compared with 69% of those who received pamidronate at 10 days. In addition, the time to relapse or development of hypercalcemia was shorter for patients receiving pamidronate compared with zoledronic acid.

Bone Diseases↗
PubMed2005

Efficacy and safety of intravenous bisphosphonates for patients with breast cancer metastatic to bone: a review of randomized, double-blind, phase III trials.

Intravenous bisphosphonates are the preferred treatment to prevent skeletal complications for patients with breast cancer and bone metastases. Pamidronate, a single-nitrogen bisphosphonate, was the early standard of care for such patients based on 2 large, placebo-controlled trials involving 754 patients. Zoledronic acid, a new-generation bisphosphonate containing 2 nitrogens, was evaluated in 1130 patients with breast cancer in a large, randomized, comparative, phase III trial with pamidronate. At 25 months, zoledronic acid (4 mg) significantly reduced the overall risk of developing a skeletal-related event (SRE) by an additional 20% versus 90 mg pamidronate by multiple-event analysis. Furthermore, zoledronic acid was at least as effective as pamidronate in reducing the proportion of patients with > or = 1 SRE and in delaying the onset of SREs. Moreover, a retrospective subset analysis of 352 patients with > or = 1 osteolytic lesion proved zoledronic acid more effective than pamidronate in reducing the risk and delaying the onset of SREs. Intravenous ibandronate (6 mg via 1-2-hour infusion) was evaluated in a placebo-controlled, phase III trial of 466 patients and was significantly more effective than placebo in reducing the number of 12-week treatment periods in which an SRE occurred. The safety profiles among all intravenous bisphosphonates were similar; patients treated with intravenous bisphosphonates reported notably less bone pain but a higher incidence of mild to moderate transient infusion-related adverse events (eg, nausea, vomiting, myalgia, and anorexia) compared with placebo. In summary, intravenous bisphosphonates are effective for the treatment of bone metastases in patients with breast cancer and have similar safety profiles, but the shorter infusion time and greater efficacy of zoledronic acid in reducing overall skeletal morbidity provide advantages over other available agents.

Bone Neoplasms↗
PubMed2004

Toward new horizons: the future of bisphosphonate therapy.

Bisphosphonate therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer-treatment-induced bone loss (CTIBL) and the development of malignant bone disease in patients with early-stage cancer. Patients who receive adjuvant hormonal therapy for breast cancer or androgen-deprivation therapy for prostate cancer are at an especially high risk for CTIBL because of reduced estrogenic signaling. Oral clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), oral risedronate (Actonel; Proctor and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and i.v. zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) have all demonstrated promise in preventing CTIBL in patients receiving hormonal therapy for breast cancer. Zoledronic acid has demonstrated efficacy with the longest between-treatment interval (3-6 months) and is currently being investigated in the Zometa/Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the United States and Europe, respectively). In patients receiving androgen-deprivation therapy for prostate cancer, i.v. pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and i.v. zoledronic acid both have demonstrated significant benefits over placebo, but only zoledronic acid produced significant increases in bone mineral density compared with baseline values. Additionally, bisphosphonates have demonstrated antitumor activities in preclinical models, and clinical trials with oral clodronate suggest that bisphosphonates might prevent or delay bone metastasis in patients with early-stage breast cancer. Clinical trials are investigating the effect of zoledronic acid on disease progression in patients with breast cancer, prostate cancer, and non-small cell lung cancer. The results of these clinical trials should further define the clinical benefit of bisphosphonates in the oncology setting.

Bone Neoplasms↗
PubMed2005

The Otto Aufranc Award: bone augmentation around and within porous implants by local bisphosphonate elution.

The bisphosphonate zoledronic acid chemically and physically was bound to hydroxyapatite-coated porous tantalum implants. The zoledronic acid elution characteristics in saline were determined as a function of time and the in vivo effects of elution were quantified at 12 weeks in a canine ulnar implant model. Intramedullary implants surgically were implanted bilaterally into the ulnae of a control group of five dogs and a zoledronic acid-dosed (0.05 mg zoledronic acid) group of four dogs. Computerized image analysis of undecalcified histologic sections was used to quantify the amount of peri-implant bone within the intramedullary canal, the percentage of available pore space filled with new bone, and the number and size of the individual bone islands within the implant pores. The data were analyzed using a hierarchical analysis of variance with 95% confidence intervals. The peri-implant bone occupied a mean of 13.8% of the canal space in controls and 32.2% of the canal space in zoledronic acid-dosed dogs, a relative difference of 134% (2.34-fold) that was significant. The mean extent of bone ingrowth was 12.5% for the control implants and 19.8% for the zoledronic acid-dosed dogs, a relative difference of 58% that was statistically significant. Individual islands of new bone formation with the implant pores were similar in number in both implant groups but were 71% larger on average in the ZA-dosed group. We are the first authors to show that local elution of a bisphosphonate can cause substantial bone augmentation around and within porous orthopaedic implants. The concept represents a potential tool for restoration of bone stock and enhancement of implant fixation in primary and revision cementless joint arthroplasty surgeries in the face of compromised or deficient bone.

Animals↗
PubMed2003

Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells.

PURPOSE: Metastasis to bone is an important cause of morbidity in advanced prostate cancer. Despite the typically sclerotic nature of prostatic bone metastases osteolysis has a significant role in the pathogenesis of this disease. The nitrogen containing bisphosphonates (N-BPs), such as pamidronate and zoledronic acid, have greatly enhanced potency for inhibiting bone resorption and inducing apoptosis in osteoclasts. We investigated the effects of N-BPs on prostate cancer cells. MATERIALS AND METHODS: Cell viability was determined with an MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymeyhoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) dye reduction assay. Cell cycle analysis, DNA fragmentation and caspase 3 activity were assessed using flow cytometry. Ras, Bcl-2 and Bax were quantified by Western blotting. RESULTS: Pamidronate and zoledronic acid decreased cell viability in the 3 human cell lines DU145, PC3 and LNCaP. These effects were associated with changes in cell cycle distribution, induction of DNA fragmentation and a decrease in the Bcl-2-to-Bax ratio, which are features of apoptotic cell death. Pre-incubation with caspase inhibitors attenuated the effects of zoledronic acid and caspase 3 activity was demonstrated in treated DU145 cells. Zoledronic acid induced loss of cell viability in DU145 cells was prevented by co-treatment with farnesol, suggesting that N-BPs cause inhibition of the mevalonate pathway and Ras prenylation. A decrease in active, membrane bound Ras in zoledronic acid treated DU145 cells was shown by Western blot analysis. CONCLUSIONS: N-BPs induce apoptosis in prostate cancer via a caspase dependent mechanism. They have effects on protein prenylation via inhibition of the mevalonate pathway and impair membrane localization of Ras in prostate cancer cells.

Antineoplastic Agents↗
PubMed2002

Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats.

Bisphosphonates (BPs) are used currently in the treatment of patients with bone metastases because these compounds inhibit bone resorption. We examined here the effects of BPs on inhibition of endothelial cell functions in vitro and in vivo. Treatment of endothelial cells with BPs (clodronate, risedronate, ibandronate, and zoledronic acid) reduced proliferation, induced apoptosis, and decreased capillary-like tube formation in vitro. Quantification of blood vessels in bone biopsy specimens from patients with Paget's disease before and after clodronate treatment showed a 40% reduction of the vascularization after BP treatment. However, such a decreased vascularity could be secondary to a reduction of bone resorption. Therefore, the tissue distribution of [14C]BPs in male rats was examined to develop an angiogenesis model in a noncalcified tissue where BPs could accumulate. [14C]BPs (zoledronic acid, ibandronate, and clodronate) not only accumulated in bone but also transiently accumulated in the prostate. The effects of BPs on testosterone-induced revascularization of the prostate gland in castrated rats were then studied. Testosterone in combination with ibandronate or zoledronic acid induced a 17-35% reduction of the prostate weight compared with castrated rats treated with testosterone alone. Blood vessel immunostaining on prostate tissue sections revealed that both ibandronate and zoledronic acid induced a 50% reduction of the revascularization of the prostate gland. Moreover, zoledronic acid did not alter testosterone-induced activity of a luciferase gene reporter construct transfected in androgen-dependent prostatic cells, indicating that this BP did not directly interfere with testosterone. In conclusion, BPs have in vivo antiangiogenic properties, which could be of relevance to improve therapy and prevention of bone metastasis. In addition, our results extend the potential clinical use of BPs to patients with early prostate cancer.

Angiogenesis Inhibitors↗
PubMed2006

Pharmacological therapy of Paget's and other metabolic bone diseases.

Paget's disease is a relatively common high-turnover metabolic bone disease that can serve as a model for osteoporosis and other metabolic bone diseases in investigation of therapeutic strategies to normalize bone turnover. Aims of treatment include rapid normalization of bone formation and resorption to prevent loss of mechanical integrity. Treatment will also reduce pain, while long-term maintenance of normal turnover may prevent long-term complications. Newer bisphosphonates have high antiresorptive potency and increased retention in bone, permitting a strategy of intermittent intravenous (IV) administration in achieving and maintaining normal bone turnover. In pivotal zoledronic acid Paget's disease trials, patients received a single 15-min IV infusion of zoledronic acid 5 mg (ZOL 5 mg) or risedronate 30 mg/day orally for 2 months. Treatment with ZOL 5 mg was associated with significant improvement in serum alkaline phosphatase, normalization in both the short and long term, and significant prolongation of biochemical therapeutic response in long-term follow-up. No changes in serum creatinine levels were observed with either treatment, and no clinically significant renal abnormalities were reported. Intermittent IV administration of potent bisphosphonates constitutes an intriguing strategy for treatment of Paget's disease and other metabolic bone diseases.

Bone Density Conservation Agents↗
PubMed2003

Breakthroughs in the management of multiple myeloma.

Although multiple myeloma remains a terminal illness, the past four decades have seen a dramatic change in the outlook for a newly diagnosed patient in terms of therapies available, supportive care and insight into the pathogenesis of this disease. Among the newer agents available for treatment, thalidomide has been resurrected and discovered to be a valuable therapy for myeloma. Thalidomide appears to work, at least in part, through its anti-angiogenic properties, but much remains to be learned about its mechanism of action as well as optimal administration regimens. With the development of increasingly more potent bisphosphonates it has become possible to diminish the painful skeletal complications of myeloma, one of the most devastating problems of this disease. The most recent generation of bisphosphonates, pamidronic acid and zoledronic acid, have provided a statistically significant decrease in the skeletal complications of myeloma when used in a prophylactic manner. These agents appear to work by inhibiting osteoclast function. Progressive improvement in cytogenetic techniques has now demonstrated that almost all patients with myeloma have chromosomal abnormalities, some of which appear to confer varying degrees of prognostic significance. In particular, the changes in chromosome 13 are associated with an unusually poor outcome. These findings are serving as a guide toward learning more about the pathogenesis of myeloma as well as in identifying potential targets for therapy. Stem cell transplantation has emerged as the standard treatment for the large majority of patients with myeloma following the demonstration of superior complete remission and survival, both disease-free and overall, in a French randomised trial. Unfortunately, virtually all patients will eventually relapse following autologous stem cell transplantation, prompting continuing efforts such as tandem transplants, CD34+ selection, as well as modifications in the conditioning regimen to improve outcomes. Allogeneic bone marrow transplants appear to offer a better chance for a possible cure of myeloma but have been associated with an unusually high mortality. However, this approach is being revived with the advent of the less toxic non-myeloablative transplant that has provided an 81% short-term survival in a trial combining this approach with an initial conventional autologous bone marrow transplant. Immunotherapy with dendritic cells appears now to be a feasible way to enhance innate or acquired immunity to help eliminate minimal residual disease following autologous bone marrow transplant. Unfortunately, a cure for myeloma remains elusive but the continuing advances in management may significantly prolong survival in affected patients.

Bone Marrow Transplantation↗
PubMed2004

Bisphosphonates: clinical experience.

Bone is a preferred site of metastasis for many solid tumors, and the complications associated with bone metastases can result in significant skeletal morbidity including severe bone pain, pathologic fracture, spinal cord compression, and hypercalcemia of malignancy (HCM). 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 HCM. Bisphosphonates have been shown to significantly reduce the incidence of these events in patients with bone metastases. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ), pamidronate (Aredia; Novartis Pharmaceuticals Corp.), clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), and ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) all have demonstrated efficacy superior to that of placebo in patients with breast cancer. Zoledronic acid is the only bisphosphonate that has been compared directly with pamidronate, and it was shown by multiple event analysis to be significantly more effective at reducing the risk of an SRE. In patients with prostate cancer, clodronate, etidronate (Didronel; Procter and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and pamidronate have demonstrated transient palliation of bone pain. However, zoledronic acid is the only bisphosphonate to demonstrate both significant and sustained pain reduction and a significantly lower incidence and longer time to onset of SREs compared with placebo. Zoledronic acid is also the only bisphosphonate to demonstrate efficacy in patients with bone metastases from a variety of other solid tumors, including lung cancer and renal cell carcinoma. In conclusion, bisphosphonates effectively reduce skeletal complications in patients with bone metastases from breast cancer, and zoledronic acid has demonstrated the broadest clinical activity in patients with a wide variety of tumor types.

Bone Neoplasms↗
PubMed2004

Optimizing bisphosphonate therapy in patients with breast cancer on endocrine therapy.

Deterioration of bone health is a major concern during progression and treatment of patients with breast cancer, especially in postmenopausal women. Disease- and treatment-associated skeletal-related events include fractures, spinal compression, bone pain, and hypercalcemia of malignancy. Bisphosphonates, which inhibit osteoclastic bone resorption, are important new agents in the management of skeletal-related events, and their impact on breast cancer-related bone metastases and on bone loss during long-term estrogen deprivation therapies such as aromatase inhibitors is reviewed. Intravenous pamidronate has become the standard bisphosphonate to reduce or delay skeletal complications of advanced breast cancer bone metastases, but the more potent agent, zoledronic acid, appears to be at least as effective. Another agent, ibandronate, is also active but has not been investigated in comparison with the other intravenous bisphosphonates. Zoledronic acid is the most convenient to administer, requiring only a short infusion. The effects of bisphosphonates on bone health in women with early breast cancer are also being investigated. A single yearly infusion of zoledronic acid has been shown to significantly increase bone mineral density in osteoporotic postmenopausal women and to reduce biochemical markers of bone turnover. The possibility of such treatment-reversing aromatase inhibitor-associated bone loss during adjuvant therapy of breast cancer is being evaluated in a trial of letrozole, with zoledronic acid added initially or after the onset of bone loss or fracture.

Antineoplastic Agents↗
PubMedDate not supplied

Bone loss and the evolving role of bisphosphonate therapy in prostate cancer.

Androgen deprivation therapy (ADT) can result in significant loss of bone mineral density (BMD) but to date, there are no prospective studies that document the true severity of bone loss and resulting fracture rates. In the general population, however, the incidence of low BMD is increasing in elderly men. Men suffer more morbidity and mortality from fractures associated with low BMD than women. Problems of underdiagnosis and undertreatment in men can be addressed with enhanced awareness of the risk factors for bone loss in men and the available treatment options. Guidelines for diagnosis of low BMD in women can probably be applied to men. Treatment options have not been studied as extensively in men. For men treated with ADT for prostate cancer, however, use of intravenous zoledronic acid at the initiation of ADT has been shown to prevent and even reverse bone loss. Although the routine use of bisphosphonates to prevent bone loss is not yet recommended, zoledronic acid is a logical choice of therapy in men who have low BMD at baseline or who develop bone loss during the course of therapy. In addition to its effects on BMD, zoledronic acid has also been shown to decrease skeletal morbidity in men with metastatic hormone-refractory prostate cancer. Whether zoledronic acid or other bisphosphonates might actually prevent or delay the development of bone metastases remains to be studied in randomized clinical trials.

Age Factors↗
PubMed2006

Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients.

The incidence, characteristics and risk factors for the development of osteonecrosis of the jaw (ONJ) were evaluated among 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Zoledronic acid produced 9.5-fold greater risk for developing ONJ than pamidronate alone (P = 0.042) and 4.5-fold greater risk than subsequent use of pamidronate + zoledronic acid (P = 0.018). Use of thalidomide and number of bisphosphonate infusions also increased the risk for ONJ by 2.4-fold (P = 0.043), and 4.9-fold respectively (P = 0.012). ONJ developed earlier among patients receiving zoledronic acid. Our data indicates that administration of zoledronic acid for more than 2 years or in combination with thalidomide requires caution in myeloma.

Aged↗
PubMed2005

The role of bisphosphonates in hormone-refractory prostate cancer.

Men with advanced prostate cancer are at high risk for developing bone metastases, which result in clinically significant skeletal morbidity. Treatments that prevent skeletal complications in these patients could considerably improve their quality of life. Therefore, this paper reviews the role of bisphosphonates in the treatment of hormone-refractory prostate cancer (HRPC). Published studies were identified through MEDLINE searches, review of bibliographies of relevant articles, and review of abstracts from scientific meetings. Metastatic bone disease in men with HRPC results in skeletal complications such as pathologic fractures, spinal cord compression, and debilitating bone pain. First- and second-generation bisphosphonates, clodronate and pamidronate, had transient palliative effects that were not durable and did not prevent skeletal events in these patients. A small open-label study of ibandronate demonstrated significant reductions in pain, but these results have not been confirmed in a larger, randomized, controlled trial. To date, zoledronic acid is the only bisphosphonate that has demonstrated a statistically significant reduction in skeletal morbidity in this patient population. In a large, multicenter, randomized, placebo-controlled trial, treatment of men with HRPC and bone metastases with zoledronic acid significantly reduced skeletal-related events and provided a durable reduction of bone pain over 24 months compared with placebo. Zoledronic acid is the only bisphosphonate that has demonstrated efficacy for preventing skeletal complications in patients with HRPC and bone metastases. Therefore, initiation of zoledronic acid therapy should be considered to prevent skeletal morbidity and improve the quality of life of these patients.

Antineoplastic Agents↗
PubMed2004

The role of bisphosphonates in breast and prostate cancers.

Bisphosphonate drugs are a group of pyrophosphate analogues which bind avidly to hydroxyapatite bone mineral surfaces and their major action is to inhibit osteoclast activity and thus bone resorption. In oncology, their role in metastatic bone disease is well established, but there is increasing interest in their potential role in preventing and treating cancer-induced bone loss and their possible anti-tumour effects. Metastatic bone disease is associated with a variety of skeletal complications, including pathologic fractures, bone pain, impaired mobility, spinal cord compression and hypercalcaemia. Intravenous bisphosphonates, particularly zoledronic acid, in conjunction with rehydration, are now established as the treatment of choice for hypercalcaemia. For treatment of bone pain, it has also been shown that bisphosphonates can be an effective supplementary approach to radiotherapy. In breast cancer and myeloma, bisphosphonates have now become part of standard therapy to treat and prevent skeletal-related events (SRE) and, until recently, treatment was largely with intravenous pamidronate or oral clodronate. However, large, randomised, multicentre trials using intravenous administration of the highly potent bisphosphonate zoledronic acid every 3-4 weeks have recently demonstrated a reduction of 20% in the risk of developing an SRE compared with pamidronate for patients with breast cancer. Moreover, these trials have demonstrated, for the first time, that a bisphosphonate significantly reduces the occurrence of skeletal events in hormone-refractory prostate cancer and in non-small cell lung cancer and a range of other solid tumours. Investigations into the potential of the relatively low potency bisphosphonate, clodronate, for the prevention of bone metastases in breast cancer have produced conflicting data. Further large, randomised studies with clodronate and zoledronic acid are planned and until the results are available it is not possible to identify a definite adjuvant role for bisphosphonates. Evidence is accumulating in vitro that bisphosphonates are also able to directly affect tumour cells, in addition to their effects on osteoclasts, with zoledronic acid being particularly potent. Over recent decades there has been a significant improvement in cure rates and survival times in certain cancers and the use of chemotherapy and hormone therapy has expanded greatly, leading to increasing numbers of long-term survivors who have received these treatments. Management of treatment-induced bone loss is therefore assuming a greater importance and bisphosphonates represent an attractive treatment option in such patients. Several placebo-controlled trials using oral clodronate, oral risedronate, intravenous pamidronate and intravenous zoledronic acid have all now demonstrated benefits in reducing the loss in bone mineral density.

Antineoplastic Agents↗
PubMed2001

Chemical and biological prerequisites for novel bisphosphonate molecules: results of comparative preclinical studies.

While all bisphosphonates have a common basic structure, differences in substituents strongly influence the pharmacologic properties of these compounds. A large number of bisphosphonate analogs were evaluated in an effort to identify a new, high-potency, bisphosphonate that would meet the chemical and biological requirements for a potentially effective and safe antiresorptive treatment. Important parameters that were evaluated included inhibition of bone resorption, lack of effect on bone mineralization, tolerability (particularly renal), molecular mechanism of action, and the ability to prevent bone changes associated with estrogen deficiency. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a bisphosphonate characterized by an imidazole substituent, was selected for further development based on its potent antiresorptive effects in vitro and in vivo, minimal inhibition of bone mineralization, and improved therapeutic ratio (antiresorptive effects v renal tolerability). Zoledronic acid was 2 to 3 orders of magnitude more potent than pamidronate in bone resorption assays, but showed a 3-fold greater renal tolerability than pamidronate. Like other nitrogen-containing bisphosphonates, zoledronic acid inhibits protein prenylation in osteoclasts, confirming a molecular basis for its pharmacologic activity. In long-term animal studies in ovariectomized rats and monkeys, zoledronic acid was able to prevent all the bone changes associated with estrogen deficiency. These studies provided support for further clinical development of this compound in both benign and malignant diseases characterized by excessive bone resorption.

Animals↗
PubMed2006

Tolerability of different dosing regimens of bisphosphonates for the treatment of osteoporosis and malignant bone disease.

Bisphosphonates are the primary pharmacological agents used for the management of osteoporosis and hypercalcaemia of malignant bone disease. The efficacy of these agents in these two conditions has been demonstrated in many well designed trials published over the past 2 decades. The variety of bisphosphonates currently available to us provides a wide range of tolerability and dosing profiles thus necessitating a thorough comparison of the most recent oral and intravenous bisphosphonates to differentiate the clinical context in which they should be used. Despite the fact that bisphosphonates are generally well accepted, their tolerability is dependent on complications which encompass gastrointestinal (GI) and renal toxicity. Other adverse events include osteonecrosis of the jaw, arthralgias, flu-like symptoms and uveitis. Studies have shown that various dosing regimens are able to modulate these rates of toxicity. To maximise tolerability, the direction of future therapy will likely fall into a pattern of decreasing the frequency of administration of bisphosphonates, whether it is oral or intravenous formulations, thus improving patient adherence. To review the literature on different dosing regimens of various bisphosphonates and their associated tolerability, we searched MEDLINE for articles from 1975 to 2006. Oral bisphosphonates, in particular alendronate and risedronate, have been systematically evaluated with regards to GI toxicity. Overall tolerability with these oral formulations has found GI toxicity to be the primary adverse event of interest. Both alendronate and risedronate have been found to have similar rates of GI toxicity when compared with placebo. Mounting evidence has developed validating the use of intravenous ibandronate and zoledronic acid for the purpose of treating hypercalcaemia secondary to malignancy. Unique to all other bisphosphonates, ibandronate also has an oral form which has a similar GI-toxicity profile to placebo. In addition, no significant differences in renal toxicity have been observed between those receiving intravenous ibandronate compared with placebo. Because of its potency and mode of administration, zoledronic acid has been widely accepted for the treatment of hypercalcaemia secondary to malignancy. However, a decrease in renal function, albeit rare, remains a significant complication of zoledronic acid; therefore, regular renal monitoring is recommended.

Alendronate↗
PubMed2004

Cytostatic and apoptotic effects of bisphosphonates on prostate cancer cells.

BACKGROUND: Bisphosphonates are potent inhibitors of bone resorption frequently used for breast cancer and myeloma-induced bone disease. Zoledronic acid has been recently shown to also reduce skeletal morbidity from prostate cancer. METHODS: We have investigated the biological effects of bisphosphonates on PC-3 cell survival (MTT assay and DNA content). We compared four bisphosphonates at doses ranging from 10(-6) to 10(-4) M: clodronate, pamidronate, ibandronate and zoledronic acid. We analyzed cell cycle phases and assessed apoptotic effects of bisphosphonates by three different methods. RESULTS: Clodronate exhibited only a slight inhibitory effect on cell growth. In contrast, aminobisphosphonates markedly decreased cell growth in a time- and dose-dependent manner exerting cytostatic and apoptotic effects. The largest effects were observed after six days of exposure to 10(-4) M bisphosphonates. Cytostatic effects were observed with all three aminobisphosphonates whereas apoptotic effects were especially evident after zoledronic acid incubation. CONCLUSIONS: Aminobisphosphonates, especially zoledronic acid, markedly inhibited PC-3 cancer cell growth, through a variable combination of cytostatic and apoptotic effects. This activity could potentially contribute to the beneficial effects of bisphosphonates in prostate cancer patients with bone metastases.

Antineoplastic Agents↗
PubMed2002

Bisphosphonates for the prevention of bone metastases.

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.

Animals↗