Role Of Bisphosphonates Research Articles

Use of bisphosphonates in prostate cancer: Current status

Bisphosphonates are a relatively newer class of drugs which have been used for the prevention of skeletal related complications of age related osteoporosis or metastatic disease from carcinoma breast or multiple myeloma. Their role in the management of prostate cancer is still under evolution. We hereby review the ongoing and some published randomized trials to define the role of bisphosphonates in various stages of prostate cancer.

Bisphosphonate Therapy for the Treatment of Skeletal Complications in Patients with Prostate Cancer

Osseous metastases and osteoporotic fractures are a serious problem in patients with prostate cancer. As androgen-deprivation therapy is being used earlier in the course of the disease, the risk of osteoporosis and insufficiency fractures is increasing. In this review, the contribution of androgen-deprivation therapy to osteoporosis and bone metastases will be discussed. The role of bisphosphonates in treating osteoporosis and bone metastases will also be reviewed. The review will conclude with a discussion of the toxicities associated with bisphosphonate use.

New Therapeutic Protocol in the Treatment of Avascular Necrosis of the Jaws

Osteonecrosis of the jaws is being increasingly reported in patients with bone metastasis from a variety of solid tumors and disseminated multiple myeloma receiving intravenous bisphosphonates. 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. The signs and symptoms that may occur before the appearance of evident osteonecrosis include changes in the health of periodontal tissues, nonhealing mucosal ulcers, loose teeth and unexplained soft tissue infection. A series of 30 periodontally involved patients showing osteonecrosis of the jaws that appeared following the intravenous use of bisphosphonates is reported. Clinical management of the avascular necrosis of the jaws in patients treated with bisphosphonates presents several problems. An analysis of the international medical literature shows that surgical treatment of the necrotic jaws in patients treated with bisphosphonates has proven to be ineffective in stopping the pathological process. The use of hyperbaric oxygen and antibiotics are not effective, either. The authors have developed a new protocol for the management of these lesions. Compared with other therapeutic choices, this protocol has introduced the use of ozone therapy as therapeutic support.

The Role of Bisphosphonates in Early Breast Cancer

Clinical trials are investigating the use of bisphosphonates in patients with early (nonmetastatic) breast cancer. Results from trials of clodronate are generally encouraging but somewhat contradictory. Of the three trials published to date, two reported that clodronate had beneficial effects on both bone metastases and survival. In contrast, the third trial reported that clodronate had no effect on metastases and a negative effect on survival. Small studies of adjuvant pamidronate and zoledronic acid also produced promising data, but these need to be reproduced in a large-scale, randomized trial setting before clinically meaningful conclusions can be drawn. A number of adjuvant trials are in progress to further evaluate the role of oral clodronate and i.v. zoledronic acid and to examine the effects of the newer bisphosphonate, ibandronate (oral formulation), in this setting. One of these trials is the joint Southwest Oncology Group/Intergroup/National Surgical Adjuvant Breast and Bowel Project trial, which is designed to compare the efficacy and safety of all three of these bisphosphonates in approximately 6,000 women with early breast cancer. Patient preference for oral or i.v. therapy will also be assessed.

Reports of Adverse Events From Bone Drugs Prompt Caution

IN 2003, CASE REPORTS OF A RARE BUT serious condition occurring in patients taking bisphosphonates to prevent breakdown of bone began surfacing. Since then, reports of more than 2000 cases of this adverse event, osteonecrosis of the jaw, have spurred letters of caution from the manufacturer to physicians and dentists, revisions to the labels of some of the products, and recommendations from the US Food and Drug Administration (FDA). Although most cases have occurred in patients receiving high-dose intravenous formulations of the drugs as part of cancer treatment, some have occurred in patients taking popular oral bisphosphonates to treat or prevent osteoporosis, suggesting that the problem may be a class effect. Scientists from the FDA have also recently identified another type of adverse event, severe bone, joint, or muscle pain associated with oral formulations. Some professional groups of physicians and dentists are taking steps to prevent osteonecrosis of the jaw in patients who take these drugs. But many unanswered questions remain about the role of bisphosphonates in these adverse events, how best to prevent such problems, as well as the degree of risk associated with the drugs.

The role of bisphosphonates and bone health issues in Japanese Breast Cancer patients: Efficacy of alendronate with aromatase inhibitors

10777 Background: Adjuvant hormonal therapy for postmenopausal breast cancer is now one of the most significant therapies in the world. From the results of the ATAC trial and the ITA trial, standard hormonal therapy for postmenopausal breast cancer has changed from tamoxifen to aromatase inhibitor. However concerning the rate of bone-relating complications including bone fracture, osteoporosis, a decrease in bone mineral density (BMD), aromatase inhibitor is reported higher than tamoxifen. According to the 2003 ASCO guidelines on the role of bisphosphonates in women with breast cancer, most women with newly diagnosed breast cancer are at risk of osteoporosis due to either their age or their breast cancer treatment. The Panel recommended an algorithm for patient management to maintain bone health. The purpose of the study is to investigate the efficacy of bisphosphonate for prevention from osteoporosis by aromatase inhibitor in Japanese women with breast cancer. Methods: From 2002 to 2004, we experienced 92 cases of postmenopausal Japanese women who underwent breast cancer operations and take aromatase inhibitor after operations in Tokyo Medical University hospital. We selected two medicines. One is Anastrozole (ArimidexR) as an aromatase inhibitor, and the other is Alendronate (BonalonR) as a bisphosphonate medicine.We investigated the change of BMD, calcium, bone absorption marker like NTX, I-CTP. Results: The value of NTX which patients take Alendronate with Anastrozole decreased about 40% than which patients take Anastrozole alone. Also the rate of bone-relating complications is lower.The mean value of BMD, % YAM, T-score, Z-score is 0.86, 81.0, −1.52, 1.47, respectively. Conclusions: The results suggest the efficacy of bisphosphonate for prevention from bone-relating complications osteoporosis by aromatase inhibitor in Japanese women with breast cancer. No significant financial relationships to disclose.

The role of bisphosphonates in the management of prostate cancer

Current therapies have extended the survival of patients with prostate cancer. However, these patients often develop skeletal morbidity from disease- and treatment-related effects that undermine skeletal integrity throughout the course of the disease. Low bone mineral density (BMD) is prevalent in patients with early-stage prostate cancer, and androgen-deprivation therapy by either pharmaceutical agent (including hormonal) or surgical castration causes significant decreases in BMD. Fractures can result in a loss of independence and have been associated with shorter survival in patients with prostate cancer. Zoledronic acid is the only bisphosphonate that has demonstrated objective and long-term benefits in reducing skeletal morbidity in patients with bone metastases due to prostate cancer, and it has produced long-term reductions in pain levels compared with placebo in this setting. Therefore, bisphosphonates, particularly zoledronic acid, may provide important benefits for preserving bone health during the course of prostate cancer progression.

Too Much, Too Little, Too Late to Start Again? Assessing the Efficacy of Bisphosphonates in Patients with Bone Metastases from Breast Cancer

The diagnosis of bone metastases can be a devastating occurrence for any woman with breast cancer. In this setting, bone metastases can result in skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, and hypercalcemia. Several trials have confirmed the ability of bisphosphonates to reduce or delay these skeletal complications, and they should now be considered standard care for these women. The analysis of SREs is the typical primary end point in bisphosphonate studies. While not undermining their importance, the definition of SREs does not include complications important to patients, such as pain and immobility. It is these symptoms that are most frequently reported by patients, and bone pain and quality of life (QoL) are often measured as secondary end points in these trials. Bone pain and QoL measures are not standardized and are difficult to compare among patient populations. We do not yet know the true efficacy of bisphosphonates as analgesics or how they impact QoL. This paper reviews the current efficacy measures used in recent bisphosphonate trials and discusses their benefits and limitations. It also explores the role of bone biomarkers and their potential use in monitoring treatment response.

Bone health in pediatric rheumatic disease

Children with chronic rheumatic disease have decreased bone mass. In adults, lowered bone mineral density is associated with increased fracture risk. This morbidity is undetermined in pediatric rheumatic disease as osteoporosis has not been well-defined in children. This review compares methods for determining bone mass in children, examines insights into molecular mechanisms of bone metabolism, and discusses the prevention and treatment of decreased bone mass in children. Peak bone mass, attained during adolescence and early adulthood, is critical in determining fracture risk. Studies of children with chronic rheumatic disease demonstrate decreased bone mineral density, and potentially lowered peak bone mass. Dual energy x-ray absorptiometry is the most commonly used technique for monitoring bone mineral density and should be interpreted utilizing age-appropriate Z-scores. Recent studies suggest quantitative ultrasound may be as reliable as dual energy x-ray absorptiometry and lacks radiation exposure. The molecular mechanisms by which inflammation alters bone mineral density involve receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin, tumor necrosis factor-alpha, and interleukin-1. Limited data on the use of bisphosphonates and calcitonin in children suggest they are safe and effective, but should be used cautiously. Children with chronic rheumatic disease should have bone mass monitored by dual energy x-ray absorptiometry Z-scores. Targeting the RANKL/osteoprotegerin pathway may lead to therapies that improve bone health in this population. More studies on the role of bisphosphonates and calcitonin must be pursued to establish guidelines for use in pediatric patients with chronic rheumatic disease. For now, supplemental calcium and vitamin D should be implemented in these children.

State of the Art of Biochemical Markers in Metastatic Bone Disease and the Role of Bisphosphonates as Therapeutic Agents

Metastatic spread of cancer to bone is a frequent complication in several types of malignancies. Normal bone metabolic process is affected and the imbalance between bone formation and resorption defines bone disease in cancer. The major causes of the secondary development of the disease is either the cancer cell itself (metastatic or non-metastatic) or cancer therapies. Early diagnosis of bone metastatic disease is very important for the survival of patients. The dominant disadvantage of imaging techniques used for detection of bone metastases is that they are based on direct anatomic visualization of the metastatic sites on the skeleton and, therefore, are not able to detect metastasis in early stages of the disease. Various biomarkers have been developed and used as indicators of bone formation or resorption. Substantially, these biochemical markers are products, released during the bone metabolic cycle and can be detected in biological samples. The levels of these markers in serum or urine can be correlated with the diagnosis of osseous metastases and the bulk of tumor burden and, in addition, may provide useful data for the patients follow-up, in order to evaluate the response to various treatments. The biochemical markers often used for monitoring bone formation involve total and bone-specific alkaline phosphatase, osteocalcin and procollagen type I extension propeptides, and those for bone resorption involve urinary calcium, hydroxyproline, hydroxylysine-glycosides, pyridinium crosslinks, crosslinked telopeptides of type I collagen, tartarate-resistant acid phosphatase and bone sialoprotein. For the treatment of bone disease, many therapies have been developed. Bisphosphonates, compounds based on a phosphorous-carbon-phosphorous spine similar to endogenous pyrophosphate, have been successfully used in the treatment of osteoporosis and hypercalcemia of malignancy. They have powerful anti-resorptive activity by suppressing the action of osteoclasts, resulting in the reduction of skeletal events. The analytical methods used for the determination of biomarkers in biological samples as well as the effect of bisphosphonates on the drift of metastatic bone disease are presented in this review. Keywords: metastatic bone disease, skeletal metastases, biochemical markers, bisphosphonates

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

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. 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. According to our observations, withdrawal of bisphosphonates is not recommended when necrosis of the jaws has occurred.

Molecular and Biological Mechanisms of Bone Metastasis

Metastatic disease is the cause of death in the majority of cancer patients. Bone marrow is a preferential site of metastasis in breast and prostate cancer, responsible for the majority of skeletal metastases. Micrometastases are often present in the bone marrow of cancer patients and may progress to overt metastases. The survival of these cells and the development of bone metastases depend on the growth support provided by the bone microenvironment and the ability of cancer cells to adapt to this environment, often mimicking the behaviour and gene expression of cells of the bone and bone marrow environment. Experimental evidence suggests that the growth support provided by the bone microenvironment is active during bone resorption. Increased bone turnover as it occurs with hormonal deprivation, therefore, might be a risk factor for developing bone metastases. Interference with bone turnover, however, offers a novel target for preventive and adjuvant therapies. In this review possible mechanisms and factors involved in the development and progression of bone metastases, as well as the molecular, biological and physiological processes of metastases, especially to the bone, are discussed. Furthermore the role of bisphosphonates in the prevention and treatment of bone metastases is reviewed.

The Bisphosphonate YM529 Inhibits Osteolytic and Osteoblastic Changes and CXCR-4–Induced Invasion in Prostate Cancer

Bisphosphonates are useful for the treatment of prostate cancer bone metastasis. However, the role of bisphosphonate on the development of the osteoblastic component of prostate cancer bone metastases is not defined. In the present study, the third-generation bisphosphonate, YM529 (minodoronate), was tested for its effects on the osteolytic PC-3 and novel osteoblastic LNCaP-SF cell lines. YM529 inhibited both osteolytic and osteoblastic changes in an intratibial tumor injection murine model. In vitro, YM529 inhibited both the proliferation and the invasion of both prostate cancer cell lines. The stromal cell-derived factor-1 (or CXCL12)/CXCR-4 pathway is believed to play an important role in the development of prostate cancer bone metastases. Thus, we determined if YM529 affected this pathway. YM529 suppressed CXCR-4 expression in PC-3 and LNCaP-SF in vitro and in vivo and this was associated with decreased in vitro invasion. These results suggest that YM529 may inhibit cancer cell invasion into the bone matrix by repressing the expression of CXCR-4 in bone metastasis lesions.

Bone Complications in Prostate Cancer: Current and Future Role of Bisphosphonates

During all disease stages, patients with prostate cancer may suffer from generalised bone loss or localised decreases in bone integrity (for example, at sites of metastatic bone lesions) [...]

Long-term safety and efficacy of bisphosphonate (BP) therapy for more than 24 months (M) in breast cancer (BC) patients (pts) with bone metastasis (BM)

816 Background: In BC pts, bone is the most frequent site of distant metastasis. BPs exhibit highly beneficial effects on lytic bone lesions in BC pts. ASCO guidelines on the role of BPs in women with BC suggest that intravenous BPs be continued until evidence of substantial decline in general performance status (PS). However, the safety of continuing BP therapy for a prolonged period has rarely been investigated. We studied the long-term safety and efficacy of BP therapy in BC pts with BM who received BP therapy for more than 24 M as long-term administration. Methods: Pamidronate (PMT) 45mg and incadronate (INC) 10mg were given over 60 min intravenous infusion to BC pts with BM. The dosing interval was every 2 weeks at the start. When an effective response was obtained, BP was given at the interval of every 4 weeks or longer. PMT was given to all pts at the start, then changed to INC when there was no response. All pts received systemic therapy. Laboratory tests were performed at every administration. Adverse events (AEs) were assessed using NIC-CTC. Results: Twenty-one pts received BPs for more than 24 M. Median duration of administration of BPs was 48 M (24∼87 M), and 10 pts received BPs for more than 50 M. Eight pts were changed from PMT to INC. During treatment, there were no pathological fractures observed. No radiation or surgical treatment of bone was performed. Hypercalcemia was detected in 1 pt (4.8%). Lytic bone lesions changed to sclerotic lesions in 13 pts (61.9%). Improvement of PS was detected in 7 pts (33.3%). Hypocalcemia was seen in 13 pts (61.9%) but was not symptomatic. Leukopenia, thrombocytopenia and anemia were not observed. The baseline serum creatinine level was maintained and G1 serum creatinine elevation was seen in 4.8% of pts. G1 fatigue (19.0%), fever (13.3%), headache (4.8%) and diarrhea (4.8%) were detected. Major AEs were mild and transient. Conclusions: Severe AEs of long-term BP therapy were not seen. We conclude that long-term BP therapy was very effective and well-tolerated in BC pts with BM. AEs in this study were fewer than in previous reports. The optimal dose, duration and dosing interval for long-term BP therapy should be determined. No significant financial relationships to disclose.

Approaches to managing bone metastases from breast cancer: The role of bisphosphonates

Conventional management of metastatic bone disease involves local and systemic therapies in various combinations, along with symptomatic management to provide optimal care. In recent years, it has become clear that adding bisphosphonates to these treatments reduces the incidence and severity of skeletal complications. Bisphosphonates can also relieve metastatic bone pain and improve quality of life, although the extent to which they have demonstrated these effects may differ between agents. While bisphosphonates are the standard of care for the treatment of bone metastases, clinical trials are investigating additional indications for these agents, including the use of intensive dosing regimens for the relief of severe or opioid-resistant metastatic bone pain and adjuvant treatment for the prevention of bone metastases and cancer treatment-induced bone loss. Current and future indications demand effective, well-tolerated and convenient bisphosphonates, and the benefits of different drugs must be balanced against their limitations. The cost-effectiveness of bisphosphonate treatment is also a consideration, given the high economic burden of metastatic bone disease from breast cancer.

Osteoporosis in renal failure: How accurate is the diagnosis and is there any role for bisphosphonates?

Patients with chronic renal failure (CRF) may be at a particularly increased risk for osteoporosis and its related fracturesgiven the high prevalence of some of the known risk factors for osteoporosis. The challenge is how to accurately make thediagnosis of osteoporosis in subjects with CRF since low bone mineral density and fractures could result from secondaryhyperparathyroidism, adynamic bone disease, osteomalacia, as well as osteoporosis. Helpful tests include bone turnovermarkers and double tetracycline-labeled bone biopsy. In patients with confirmed osteoporosis, preliminary data suggest thatbisphosphonates seem to be safe and effective down to glomerular filtration rates of 15 mL/min. Low to moderate doses ofvitamin D analogues are also helpful in such patients.

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.

Short-Term Zoledronic Acid Treatment Increases Bone Mineral Density and Marrow Clonogenic Fibroblast Progenitors after Allogeneic Stem Cell Transplantation

Although osteoporosis is a relatively common complication after allogeneic stem cell transplantation, the role of bisphosphonates in its management has not yet been completely established. Thirty-two patients who underwent allogeneic stem cell transplantation were prospectively evaluated for bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) after a median period of 12.2 months. Then, 15 of the patients with osteoporosis or rapidly progressing osteopenia (bone loss > 5%/yr) received three monthly doses of 4 mg zoledronic acid iv. Fifteen patients were followed up without treatment, and all 30 patients were reevaluated after 12 months for BMD and bone turnover markers. By using enriched mesenchymal stem cells in the colony-forming units fibroblast (CFU-F) assay, we evaluated the osteogenic stromal lineage. This procedure was performed in both groups of patients at study entry and after 12 months. The average BMD loss was 3.42% at LS and 3.8% at FN during a 1-yr longitudinal evaluation in 32 patients. Subsequently, BMD increased at both LS and FN (9.8 and 6.4%, respectively) in the zoledronic acid-treated cohort. Hydroxyproline excretion decreased, and serum bone-specific alkaline phosphatase increased significantly, whereas serum osteocalcin increase did not reach the limit of significance. A significant increase in CFU-F growth in vitro was induced by in vivo zoledronic acid administration. In the untreated group, no significant change was observed in bone turnover markers, LS BMD (-2.1%), FN BMD (-2.3%), and CFU-F colony number. In conclusion, short-term zoledronic acid treatment consistently improved both LS and FN BMD in transplanted patients who were at high risk for fast and/or persistent bone loss, partly by increasing the osteogenic progenitors in the stromal cell compartment.

Bisphosphonates and Cancer

Bisphosphonates form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption and pharma‐cokinetically by similar intestinal absorption, skeletal distribution, and renal elimination. Two groups of bisphosphonates exist chemically, non‐amino‐bisphosphates and amino‐bisphosphonates. The amino‐bisphosphonates have greater antiresorptive capabilities and represent a newer generation of bisphosphonates. The primary mechanism of action of bisphosphonates is inhibition of osteoclastic activity. Non‐amino‐bisphosphonates are incorporated into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to apoptosis. Amino‐bisphosphonates exert their effect on osteoclasts via their inhibition of the mevalonate pathways, resulting in disruption of intracellular signaling and induction of apoptosis. Bisphosphonates also inhibit cancer cell proliferation, induce apoptosis in in vitro cultures, inhibit angiogenesis, inhibit matrix metalloproteinase, have effects on cytokine and growth factors, and are immunomodulatory. Clinical applications in oncology could include therapy for hypercalcemia of malignancy, inhibition of bone metastasis, and therapy for bone pain. Although bisphosphonates are regarded as metabolically inert in the body, adverse effects do occur and include esophagitis, gastritis, suppression of bone repair, and allergic reactions. Little is published on the effects of bisphosphonates in dogs with cancer. Further research into the role of bisphosphonates in veterinary oncology is needed to identify clinical efficacy and safety of these potentially beneficial drugs.