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PubMed2006

Management of the adverse effects associated with intravenous bisphosphonates.

Intravenous bisphosphonates are widely used to treat hypercalcemia and to reduce skeletal-related morbidity among cancer patients. However, serious complications, generally occurring in less than 2% of patients participated in phase III clinical trials, including acute systemic inflammatory reaction, ocular inflammation, renal failure, nephrotic syndrome, electrolyte imbalance, and osteonecrosis of the maxilla and mandible have all been increasingly reported. Yet, strategies to deal with these complications are becoming clear. Acute systemic inflammatory reaction is often self-limited and becomes less intense during subsequent treatments. For patients who develop ocular symptoms, prompt ophthalmologic evaluation is crucial to determine the safety of a subsequent bisphosphonate therapy. Patients who receive long-term pamidronate should be evaluated at intervals for early sign of nephritic syndrome as timely cessation of the agent may result in a full recovery. To reduce the risk of severe electrolyte abnormalities, particularly hypocalcemia, correcting any pre-treatment electrolyte abnormality and supplementing vitamin D and calcium may be helpful. Finally, to reduce the risk of osteonecrosis of the maxilla and mandible, obtaining a full dental evaluation before treatment and avoidance of invasive dental procedures is suggested. The three commonly used intravenous bisphosphonates (pamidronate, zoledronic acid, and ibandronate), are generally safe; ibandronate has to date been the least reported to be associated with renal side effects. As clinical indications of intravenous bisphosphonates continue to expand, prescribing clinicians should be familiar with these possible adverse effects and discuss them with patients before commencing or continuing on therapy.

Antineoplastic Agents↗
PubMed2005

Reversible metastatic visceral calcification detected by 99mTc-methylene diphosphonate bone scanning in breast cancer.

Diffuse metastatic visceral calcification is rare in breast cancer. We report on a 57-year-old woman with breast cancer and hypercalcemia who had diffuse metastatic visceral calcifications on lungs, myocardium, stomach, and thyroid on a (99m)Tc-methylene diphosphonate bone scan. Visceral calcifications were completely resolved 6 months after successful anticancer and zoledronic acid treatments. Bone scanning offers a useful diagnostic tool for both identifying visceral calcification and assessing the response to therapy in chemosensitive malignities with hypercalcemia such as breast cancer.

Antineoplastic Agents↗
PubMed2002

Novel approaches to the management of bone metastases in patients with breast cancer.

Bone metastases appear frequently in patients with advanced breast cancer. They are associated with substantial morbidity and occasionally produce life-threatening complications. Systemic anticancer therapies (chemotherapy and hormonal therapies) represent the treatment of choice for these and other distant metastases from breast cancer. Aggressive use of prophylactic and therapeutic orthopedic surgery is warranted, especially for lesions in weight-bearing areas. Judicious use of external radiotherapy and bone-seeking radionuclides contributes to the control of pain and local control of lesions in strategic locations. In recent years, the development of osteoclast-inhibitory therapy added a new dimension to symptom control and prevention of skeletal complications. The bisphosphonates, clodronate, pamidronate, and zoledronic acid, are potent osteoclast inhibitors with marked clinical effects. They represent the drugs of choice for control of hypercalcemia of malignancy, and they are critical adjuvants to systemic anticancer therapy of metastatic disease. More recently, the development of recombinant osteoprotegerin and an anti-parathyroid hormone-related protein monoclonal antibody represent promising new options for the treatment of patients with bone metastases.

Antineoplastic Agents↗
PubMed2006

Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment.

We present current knowledge of bisphosphonate-associated osteonecrosis, a new oral complication in oncology. It was first described in 2003, and hundreds of cases have been reported worldwide. The disorder affects patients with cancer on bisphosphonate treatment for multiple myeloma or bone metastasis from breast, prostate, or lung cancer. Bisphosphonate-associated osteonecrosis is characterised by the unexpected appearance of necrotic bone in the oral cavity. Osteonecrosis can develop spontaneously or after an invasive surgical procedure such as dental extraction. Patients might have severe pain or be asymptomatic. Symptoms can mimic routine dental problems such as decay or periodontal disease. Intravenous use of pamidronate and zoledronic acid is associated with most cases. Other risk factors include duration of bisphosphonate treatment (ie, 36 months and longer), old age in patients with multiple myeloma, and a history of recent dental extraction. We also discuss pathobiology, clinical features, management, and future directions for the disorder.

Antineoplastic Agents↗
PubMed2006

The role of bisphosphonates in the treatment of prostate cancer: recommendations from an expert panel.

In this study, we provide consensus guidelines for the use of bisphosphonates in men with prostate cancer. To this end, an expert panel composed of urologists, medical oncologists, radiation oncologists, and endocrinologists met to review current clinical evidence for the use of bisphosphonates in patients with different stages of prostate cancer to derive consensus recommendations. Physicians should be proactive in monitoring bone loss in patients receiving long-term androgen-deprivation therapy for prostate cancer. Further study is needed before recommending the routine use of bisphosphonates in men with nonmetastatic prostate cancer. However, if a patient has clinically significant bone loss, use of a bisphosphonate to prevent further compromise of bone integrity should be strongly considered, regardless of hormonal and metastatic status. Bone scans are the preferred method for the identification of bone metastases. In patients with hormone-refractory prostate cancer and bone metastases, zoledronic acid is the only bisphosphonate indicated for the prevention of skeletal complications. In conclusion, patients with prostate cancer are at high risk for skeletal morbidity. Bisphosphonates have been shown to prevent cancer treatment-induced bone loss in men receiving androgen-deprivation therapy as well as skeletal complications in men with bone metastases. However, further study of the use of bisphosphonates across the clinical spectrum of prostate cancer is needed.

Bone Density Conservation Agents↗
PubMed2004

Hypercalcemia of malignancy.

Less than 25 years ago tumor-induced hypercalcemia was often a lethal complication of cancer. Nowadays, it can be treated easily and successfully in at least 90% of cases by volume repletion in addition to the use of bisphosphonates that are potent anti-osteoclastic compounds. The standard therapy consists of the administration of 90 mg pamidronate or, more recently, 4 mg zoledronic acid, a more efficient bisphosphonate. When available, another alternative bisphosphonate is ibandronate. Recurrent hypercalcemia is nevertheless difficult to control and antibodies against parathyroid hormone-related protein could be useful for that matter in selected patients who are not in the terminal stage of their disease. Prevention of tumor-induced hypercalcemia is one of the objectives of long-term therapy with bisphosphonates in patients with tumor bone disease. The use of bisphosphonates in placebo-controlled trials has shown that the incidence of hypercalcemic episodes is reduced by more than one half.

Antineoplastic Agents↗
PubMed2005

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 2: Clinical studies and economic analyses.

Newer-generation intravenous bisphosphonates have resulted in the reduction of skeletal-related complications, i.e. skeletal-related events (SREs) such as pain, hypercalcemia, pathologic fractures and spinal cord and nerve compression, as well as improvements in the quality of life in patients with metastatic bone disease who are likely to have a prolonged clinical course. Highly potent, nitrogen-containing bisphosphonates such as zoledronic acid reduce SREs in patients with bone metastases from other solid tumors (including lung cancer). Part one of our review discussed the mechanisms of action by bisphosphonates as well as potential roles for bone markers and imaging in lung cancer. In this article, part two of our review, we examine the economic and clinical impact of bisphosphonates in lung cancer, with a focus on the potential role of newer-generation bisphosphonates in the management of advanced, metastatic bone disease of lung cancer.

Antineoplastic Agents↗
PubMed2006

Oral post-surgical complications following the administration of bisphosphonates given for osteopenia related to malignancy.

BACKGROUND: This case report seeks to illustrate the clinical consequences of the administration of bisphosphonate therapy to prevent osteopenia secondary to malignancy in one patient. METHODS: A 69-year-old white female with a history of breast cancer with metastasis presented with pain in the upper left quadrant and periodontal pocketing of at least 6 mm in each of the four quadrants of the oral cavity. One week following surgery on the lower right region, lingual bone exposure was noted, and several attempts at achieving healing over the course of 15 months proved unsuccessful. RESULTS: Upon referral to a surgeon at the Louisiana State University Medical Center, New Orleans, Louisiana, a potential causative factor was finally identified. The drug zoledronic acid, a bisphosphonate given for prevention of osteoclastic activity of bone metastasis, secondary to breast cancer, was identified as the possible cause of inhibition of healing, most likely from regional vascular insufficiency. The drug was immediately discontinued. The patient is healing very slowly with the aid of hyperbaric therapy; she has been unable to achieve smoking cessation, which is deterring thorough healing of the exposed bony area on the lower right lingual side. CONCLUSIONS: Physicians and dentists alike must become increasingly aware of impaired oral healing following the use of bisphosphonates given for malignancy-related osteopenia. A dental exam should be performed before bisphosphonate therapy, as recommended for radiation therapy related to malignancy.

Aged↗
PubMed2006

Improving bone health in patients with early breast cancer by adding bisphosphonates to letrozole: the Z-ZO-E-ZO-FAST program.

Women undergoing treatment for breast cancer often have a number of pre-existing risk factors for bone loss, including existing or induced postmenopausal status. Long-term anticancer treatments may further augment this risk, inducing further bone-loss, increasing the incidence of bone fractures, associated morbidity and mortality, and healthcare costs. Long-term treatment with third-generation antiaromatase agents (AAAs) is used more and more instead of or after the selective estrogen-receptor modulator tamoxifen for the adjuvant treatment of postmenopausal women with breast cancer. These AAAs include anastrozole, letrozole, and exemestane, and all are superior to tamoxifen in both efficacy and safety. In particular, they reduce the incidence of serious adverse events such as thromboembolism and endometrial cancer that are associated with tamoxifen treatment. On the other hand, the AAAs lead to profound estrogen depletion and appear to have a pronounced effect on bone mineral density (BMD), and a significantly higher incidence of osteoporosis/osteopenia and bone fracture has been reported in some trials. Bisphosphonate therapies, including zoledronic acid (ZA), have emerged as a promising means of reducing bone loss associated with antiaromatase therapy. Several large, randomized, multicenter trials are underway to determine whether upfront or delayed ZA therapy can decrease BMD losses in patients undergoing treatment with the antiaromatase agent letrozole (Z-FAST; ZO-FAST, and E-ZO-FAST), and early results from the Zometa-Femara adjuvant synergy trial (Z-FAST) trial indicate a significant benefit of upfront ZA therapy compared with delayed ZA therapy. Forthcoming results from all these trials should determine whether ZA could be used to improve bone heath in women undergoing adjuvant therapy with AAAs for breast cancer.

Aromatase Inhibitors↗
PubMed2007

Bisphosphonate-associated osteonecrosis of the jaws: a therapeutic dilemma.

OBJECTIVE: To describe our experience in prevention and treatment of mandibular and maxillary osteonecrosis, an emerging complication of long-term intravenous administration of bisphosphonates. STUDY DESIGN: Between February 2004 and February 2006, 10 patients who had received zoledronic acid intravenously because of multiple bone myelomas or bone metastases were treated for mandibular and maxillary osteonecrosis in the Departments of Otorhinolaryngology and Maxillofacial Surgery of our institution. RESULTS: All of the patients underwent surgical sequestrectomies. More extensive surgery was necessary in 3 cases. There were no major complications, and the majority of the patients are alive with no signs of infection or bone exposure. CONCLUSIONS: Our experience confirms that bisphosphonate therapy contributes to the pathogenesis of mandibular and maxillary osteonecrosis. Surgery seems to be necessary in the majority of the patients, although the most adequate procedure is far from being standardized and prevention seems to play a pivotal role.

Aged↗
PubMed2004

An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.

A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated cellular and molecular targets of ZA's actions: ZA suppressed MMP-9 expression by infiltrating macrophages and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an "unconventional" MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.

Angiogenesis Inhibitors↗
PubMed2006

Osteonecrosis of the jaws and bisphosphonate treatment in cancer patients.

PURPOSE: Osteonecrosis of the jaws is described as an intraoral complication after administration of intravenous nitrogen-containing bisphosphonates. In a retrospective study, patients with osteonecrosis of the jaws after bisphosphonate treatment were evaluated with regard to diagnostic investigations and therapeutic management. PATIENTS AND METHODS: Seventeen patients with osteonecrosis of the jaws after bisphosphonate treatment who were referred to our department between July 2004 and June 2005 were included in this study. Computer tomography, magnetic resonance imaging, scintigraphy, bacteriology and biopsy were used in diagnostic evaluation. All patients were treated surgically. RESULTS: The reasons for bisphosphonate treatment were multiple myeloma in 12 patients, breast cancer with bone metastasis in four patients and histiocytosis X in one patient. Five patients had received intravenous pamidronate and 12 patients zoledronic acid. The median number of treatment cycles for pamidronate was 36 times (range 4-100) in 38 months (range 4-100). Zolendric acid was given 23.5 times (range 5-39) in 26 months (range 5-39). Nine patients had a lesion in the mandible, eight in the maxilla. Clinical symptoms were exposed bone, pain and local inflammation of the mucosa. Computer tomography showed sclerotic areas in the osteonecrosis zone. The biopsy did not show a metastatic lesion. Sequestrectomy and decortication was adequate in the follow-up. CONCLUSION: Nitrogen-containing bisphosphonates appear to be associated with the risk of developing osteonecrosis of the jaws. To reduce this risk, patients should be evaluated by a dentist before beginning treatment with intravenous bisphosphonates.

Adult↗
PubMed2005

The decrease of particle-induced osteolysis after a single dose of bisphosphonate.

The most common cause of implant failure in joint replacement is aseptic loosening due to particle-induced osteolysis. Bisphosphonates have been shown to be effective against particle-induced osteolysis when administered daily. We investigated the effect of a single subcutaneous dose of a more potent third generation bisphosphonate on particle-induced osteolysis. We utilized the murine calvaria osteolysis model in C57BL/J6 mice. Bone resorption was measured as resorption within the midline suture using Giemsa staining. Twenty-eight mice were used, seven per group. Seven animals were treated with a single dose of zoledronic acid (ZA) directly after surgery and seven animals were treated four days postoperatively. For statistical analysis one-way ANOVA and a Student's t-test were used. Bone resorption was 0.26+/-0.09 mm(2) in animals with particle implantation, 0.14+/-0.05 mm(2) in animals with particle implantation and ZA treatment directly after surgery (p = 0.0047), and 0.15+/-0.05 mm(2) in animals with particle implantation and ZA treatment on the fourth postoperative day (p = 0.006). In conclusion, particle-induced bone resorption was markedly decreased by a single s.c. dose of a third generation bisphosphonate. This important new finding holds great promise, because single dose treatment of particle-induced osteolysis may reduce side effects compared to repeated application of bisphosphonates.

Animals↗
PubMed2006

Evaluation of human fetal bone implants in SCID mice as a model of prostate cancer bone metastasis.

The metastasis of prostate cancer cells to the bone marrow constitutes the major source of morbidity and mortality in prostate cancer. Studying this process has been hampered by the lack of preclinical models to evaluate novel therapeutics and to study the biology of the disease. One proposed model utilizes human fetal bone implants to serve as the target for prostate cancer cells injected via the tail vein. We employed this model to test the ability of zoledronic acid to prophylax and to treat bone metastases. To improve the rate of bone metastasis, we used two bone implants instead of one to evaluate the cell lines PC3 and PC3M, a more metastatic subline. For this purpose we generated the novel cell line PC3EGFPLuc, which can be used for luminescence and/or fluorescence imaging in vivo. We did not observe bone implant metastases in 52 mice, with 90 bone implants following tail vein injection of 1x10(6) PC3 or PC3M cells. Soft tissue lesions in the buttocks and hind limbs as well as cellular growth in the hindlimbs were observed via bioluminescence imaging. This evidence together with literature findings suggests that this model produces artifactual 'bone metastasis' lesions.

Animals↗
PubMed2006

Home infusions of biphosphonate in cancer patients: a prospective study.

The objective of the study was to determine outcome and satisfaction of cancer patients treated by home-infusions of biphosphonates. 107 patients entered the study and 97 of them chose to receive infusions of zoledronic acid (Z) in the home setting. Patient satisfaction and quality of care (QoC) were assessed by a 22-item questionnaire. Changes from baseline were determined for bone pain using a 0-10 cm visual analogue scale pain score (VAS). Patients expressed a high level of satisfaction specifically with regard to nursing care. Seventy patients experienced a significant decrease in the median pain score during the home-therapy phase not due to an increased use of analgesic therapy (P = 0.03). Z was well tolerated with no major adverse events. The authors conclude that home infusions of biphosphonates, on the condition that the supportive care team is well-organized, is a safe procedure that could be advantageous for patients by increasing satisfaction and compliance with treatment.

Bone Density Conservation Agents↗
PubMed2007

Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis.

Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus-induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction.

Animals↗
PubMed2000

Optimising treatment of bone metastases by Aredia(TM) and Zometa(TM).

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in treatment of hypercalcemia of malignancy have been completed, as have Phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.

Antineoplastic Agents↗
PubMed2005

Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.

PURPOSE: To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. PATIENTS AND METHODS: The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. RESULTS: At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. CONCLUSION: Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.

Aged↗