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PubMed2005

Therapy Insight: osteoporosis during hormone therapy for prostate cancer.

The intended therapeutic effect of gonadotropin-releasing-hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Observations are consistent with this effect: GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Estrogens play a central role in homeostasis of the normal male skeleton and evidence suggests that estrogen deficiency is primarily responsible for the adverse skeletal effects of GnRH agonists. The mechanism of treatment-related bone loss involves acceleration of physiologic bone turnover. In small, randomized, controlled trials, bisphosphonates (pamidronate, zoledronic acid) and selective estrogen-receptor modulators (raloxifene, toremifene) increased bone mineral density in GnRH-agonist-treated men. Two ongoing large, randomized, placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG 162, toremifene) in GnRH-agonist-treated men.

Bone Density↗
PubMed2006

A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates.

1. Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess bone resorption. On the basis of their molecular mechanism of action, bisphosphonates can be divided into two pharmacological classes; nitrogen-containing (N-BPs) and non-nitrogen-containing bisphosphonates (non-N-BP). Both classes induce apoptosis but they evoke it differently; N-BPs by inhibiting the intracellular mevalonate pathway and protein isoprenylation, and non-N-BPs via cytotoxic ATP analog-type metabolites. N-BPs are not metabolized to ATP analogs, but we report here that these bisphosphonates can induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of the mevalonate pathway in cells. We also investigated whether ApppI is involved in the apoptosis induced by N-BPs. 2. Mass spectrometry and NMR were used to identify ApppI in N-BP treated osteoclasts, macrophages and glioma cells. The potency of different bisphosphonates to promote ApppI production was tested in J774 macrophages. The effects of ApppI on ADP/ATP translocase in isolated mitochondria and its capability to induce apoptosis in osteoclasts were also studied. 3. ApppI production correlated well with the capacity of N-BPs to inhibit mevalonate pathway. ApppI inhibited the mitochondrial ADP/ATP translocase and caused apoptosis in osteoclasts. 4. In conclusion, these findings provide the basis for a new mechanism of action for N-BPs. Some of these very potent bisphosphonates, such as zoledronic acid, represent a third class of bisphosphonates that can act both via the inhibition of the mevalonate pathway and by the blockade of mitochondrial ADP/ATP translocase, which is known to be involved in the induction of apoptosis.

Adenine Nucleotide Translocator 1↗
PubMed2005

The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio.

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.

Adult↗
PubMed2004

Patient management issues in metastatic bone disease.

The main goals of bisphosphonate therapy are to prevent and treat skeletal events, minimize disability, and relieve pain without increasing the overall burden that bone metastases (and their treatment) place on patients. The ease and convenience of treatment are important to patients, and there are data suggesting that patients prefer oral therapy over intravenous drugs to help them maintain a normal life. Intravenous therapy with zoledronic acid and pamidronate is currently time-consuming; preparation, renal monitoring, infusion, and follow-up use valuable health care resources. Intravenous ibandronate could help alleviate this burden because of its good renal safety profile. Although efficacious, oral clodronate has compliance problems because of multiple dosing, large tablet size, and gastrointestinal tolerability issues. Recent phase III trials of oral ibandronate have shown efficacy similar to that of intravenous ibandronate, with no compliance or tolerability concerns. Ibandronate appears to have several advantages over current therapies that could improve treatment acceptability and reduce the burden of disease on the health care system. Research continues into the efficacy, safety, and pharmacoeconomics of ibandronate.

Administration, Oral↗
PubMed2004

Profiling the safety and tolerability of bisphosphonates.

Because patients with metastatic bone disease suffer a significant burden from their illness and from anticancer treatments, it is therefore important to minimize the side effects of bisphosphonates. The intravenous bisphosphonates, zoledronic acid and pamidronate, have tolerability issues that include a flu-like syndrome, injection-site reactions, and occasional renal toxicity. Because of the potentially severe nature of the renal toxicity, renal monitoring is required before each dose, with drug withdrawal if the patients' renal function deteriorates. Oral clodronate often causes gastrointestinal disturbances, particularly diarrhea; compliance is often poor because of the large tablet size and multiple daily dosing. Long-term data have shown that the bisphosphonate ibandronate is well tolerated either intravenously or orally, with a renal safety profile similar to placebo and no evidence of cumulative renal damage. Studies investigating the effects of 15-minute infusions and intensive dosing indicate that intravenous ibandronate given rapidly or at high doses is also well tolerated with no renal safety concerns. Taken together, these results suggest that the favorable safety profile of ibandronate provides an important alternative to existing bisphosphonate options for metastatic bone disease. Using ibandronate could improve patient acceptability and simplify management, with reductions in the need for safety monitoring and management of adverse events.

Administration, Oral↗
PubMed2005

The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer.

BACKGROUND: We examined the clinical relevance of skeletal-related events (SREs) for health state preferences, pain and health-related quality of life in patients with advanced prostate cancer and a history of bone metastases. PATIENTS AND METHODS: Data were from a clinical trial of zoledronic acid versus placebo in the treatment of SREs associated with advanced prostate cancer metastatic to bone. Patients (n=248) were included if they experienced an SRE during the study. Outcome measures were assessed at fixed intervals. We used mixed-effects models to estimate changes in outcomes after each patient's first SRE. RESULTS: There were clinically meaningful and statistically significant declines in physical well-being after: radiation and pathologic fractures; functional well-being after radiation; and emotional well-being after radiation and pathologic fractures. There also were meaningful and significant declines in preference and utility scores after radiation and fracture. Pain intensity declined after radiation, but not after other SREs; no other pain measure changed substantively. CONCLUSIONS: SREs have important and significant effects on measures of health-related quality of life in men with prostate cancer. Treatments that prevent SREs may not demonstrate corresponding effects on outcomes if the effects of SREs occur between scheduled outcome assessments. Implications for trial design are discussed.

Aged↗
PubMed2005

Myeloma bone disease: pathophysiology and management.

Bone disease is a major feature of multiple myeloma. Myeloma-induced bone destruction is the result of an increased activity of osteoclasts, which is not accompanied by a comparable increase of osteoblast function. Recent studies have revealed that new molecules such as the receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL), osteoprotegerin (OPG), and macrophage inflammatory protein-1alpha are implicated in osteoclast activation and differentiation, while proteins such as dickkopf-1 inhibit osteoblastic bone formation. These new molecules seem to interfere not only with the biology of myeloma bone destruction but also with tumour growth and survival, creating novel targets for the development of new antimyeloma treatment. Currently, bisphosphonates play a major role in the management of myeloma bone disease. Clodronate, pamidronate and zoledronic acid are the most effective bisphosphonates in symptomatic myeloma patients. Biochemical markers of bone remodeling have been used in an attempt to identify patients more likely to benefit from early treatment with bisphosphonates. Furthermore, using microarray techniques, myeloma patients may be subdivided into molecular subgroups with certain clinical characteristics, such as propensity for lytic lesions that may need early prophylactic treatment. Recent phase I studies with recombinant OPG and monoclonal antibodies to RANKL appear promising.

Antineoplastic Agents↗
PubMed2006

Cost effectiveness of bisphosphonates in the management of breast cancer patients with bone metastases.

BACKGROUND: Bisphosphonates are recommended to prevent skeletal related events (SREs) in patients with breast cancer and bone metastases (BCBM). However, their clinical and economic profiles vary from one agent to the other. MATERIALS AND METHODS: Using modeling techniques, we simulated from the perspective of the UK's National Health Service (NHS) the cost and quality adjusted survival (QALY) associated with five commonly-used bisphosphonates or no therapy in this patient population. The simulation followed patients into several health states (i.e. alive or dead, experiencing an SRE or no SRE, and receiving first or second line therapy). Drugs costs, infusion costs, SREs costs, and utility values were estimated from published sources. Utilities were applied to time with and without SREs to capture the impact on quality of life. RESULTS: Compared to no therapy, all bisphosphonates are either cost saving or highly cost-effective (with a cost per QALY < or = 6126 pounds sterlings). Within this evaluation, zoledronic acid was more effective and less expensive than all other options. CONCLUSIONS: Based on our model, the use of bisphosphonates in breast cancer patients with bone metastases should lead to improved patient outcomes and cost savings to the NHS and possibly other similar entities.

Bone Diseases↗
PubMed2006

Bisphosphonates and osteonecrosis of the jaw: cause and effect or a post hoc fallacy?

BACKGROUND: An increasing amount of reports are being published suggesting a relationship between the use of bisphosphonates (BPs) and the development of osteonecrosis of the jaw (ONJ). We reviewed the currently available evidence and explore the potential mechanisms of action based on the known effects of the concerned BP. DESIGN: The MEDLine, Current Contents and Science Citation Index Expanded databases were queried and the results augmented by analyzing cited references and recent congress proceedings. RESULTS: 22 papers were included detailing 225 patients, all based on retrospective chart review without control groups. The prevalence of ONJ was estimated at 1.5%. The involved BPs were pamidronate, zoledronic acid, alendronate and risedronate, all potent nitrogen-containing agents. The most common symptom was pain (81.7%), although 12.2% of cases were asymptomatic. In 69.3% of patients ONJ was preceded by a dental extraction. At the time of diagnosis, 74.5% of patients were receiving chemotherapy and in 38.2% of cases corticosteroids were administered. Although various conservative and surgical treatment modalities were reported, residual sites of ONJ persisted in 72.5% of cases. CONCLUSION: Although not enough evidence is available to prove a causal link, it seems that under specific circumstances local defenses can become overwhelmed resulting in ONJ.

Bone Density Conservation Agents↗
PubMed2006

Combined ovarian ablation and aromatase inhibition as first-line therapy for hormone receptor-positive metastatic breast cancer in premenopausal women: report of three cases.

Aromatase inhibitors have become well established for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and for adjuvant hormonal therapy for primary breast cancer. Benefit of aromatase inhibition has not yet been extended to premenopausal women. Ovarian ablation by oophorectomy, ovarian radiation or hormonal suppression is the initial recommended treatment for hormone receptor-positive metastatic breast cancer in premenopausal women. The addition of tamoxifen improves the benefit of ovarian ablation/ovarian suppression. Addition of aromatase inhibitors to luteinizing hormone-releasing hormone analogs has been reported to significantly decrease circulating estrogens and produce tumor responses in only a very small number of patients over the last 15 years. We treated three premenopausal patients with hormone receptor-positive metastatic breast cancer with combined oophorectomy or ovarian irradiation and anastrozole. One patient remained free of progression for 4 years, while the other two remained free of progression for more than 5 and 3 years, respectively. We also note that monthly zoledronic acid for 4 years produced sclerosis of vertebral body metastasis. We conclude that combined ovarian ablation and aromatase inhibition is a feasible treatment modality that deserves more attention and further investigation for hormone receptor-positive metastatic breast cancer in premenopausal women.

Adult↗
PubMed2005

Review of treatment modalities for postmenopausal osteoporosis.

This review summarizes and updates data presented at recent annual Southern Medical Association conferences on postmenopausal osteoporosis. As part of any osteoporosis treatment program, it is important to maintain adequate calcium and 25-hydroxyvitamin D levels either through diet or supplementation. Among the available pharmacologic therapies, the bisphosphonates alendronate and risedronate have demonstrated the most robust fracture risk reductions-approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Ibandronate, a new bisphosphonate, has demonstrated efficacy in reducing vertebral fracture risk. Salmon calcitonin nasal spray and raloxifene demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include strontium ranelate, which has been shown to reduce vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

Alendronate↗
PubMed2006

Treatment for myeloma bone disease.

Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Consequently, patients with MM frequently require radiation therapy, surgery, and analgesic medications. The recent development of minimally invasive surgical procedures such as kyphoplasty allows patients with myeloma with vertebral compression fractures to have immediate improvement in their quality of life with shorter hospital stays. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in patients with MM with bone disease during the past 15 years. Monthly i.v. infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with MM and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although preclinical studies suggest that nitrogen-containing bisphosphonates have potent antitumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible antitumor effects clinically. Moreover, recent advances in the use of bone-seeking radiopharmaceuticals make these attractive therapeutic candidates to combine with bisphosphonates or radiosensitizing drugs (e.g., bortezomib) to achieve a synergistic effect. As our understanding of the pathophysiology of myeloma bone disease continues to grow, new target therapies will continue to emerge, offering new and more advanced options for the management of myeloma bone disease.

Animals↗
PubMed2006

Treatment-related osteoporosis in men with prostate cancer.

The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men. Consistent with this observation, GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk. Large claims-based analyses and other retrospective studies provide compelling evidence that GnRH agonists increase risk of clinical fractures. Estrogens play a central role in homeostasis of the normal male skeleton, and estrogen deficiency rather than testosterone deficiency seems to be primarily responsible for the adverse skeletal effects of GnRH agonists. In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist-treated men. Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment.

Antineoplastic Agents↗
PubMed2004

The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer.

PURPOSE: Patients with bone metastases from lung cancer often experience skeletal-related events (SREs) including pathological fracture, spinal cord compression, hypercalcemia or pain requiring surgery, radiotherapy or opioid analgesics. These complications result in impaired mobility and reduced quality of life and have a significant negative impact on survival. The economic consequences of SREs in patients with lung cancer have not been examined. METHODS: We conducted a retrospective analysis using a large US health insurance claims database to estimate the incidence and costs of treatment of SREs in patients with bone metastases of lung cancer treated in a naturalistic setting. Study subjects had >/=2 encounters with a diagnosis of primary lung cancer and >/=2 encounters with a diagnosis of metastases to bone. SREs were identified based on the occurrence on or after the date of first diagnosis of bone metastases, of (1) >/=1 encounter with a diagnosis of pathological fracture, spinal cord compression or hypercalcemia, (2) >/=1 bone surgery or radiotherapy procedure, or (3) the initiation of opioid analgesic therapy. Survival and costs of SRE-related care in patients with SREs were estimated using Kaplan-Meier methods. RESULTS: We identified 534 patients with lung cancer and bone metastases, including 295 (55%) with >/=1 SRE. Radiotherapy (68%) and fracture (35%) were the most common SREs. Median survival after the first identified SRE was 4.1 months (95% confidence interval: 3.6-5.5 months). The estimated lifetime SRE-related cost per patient was USD 11,979 (95% confidence interval: USD 10,193-13,766). Radiotherapy accounted for the greatest proportion of cost (61%) by SRE type. CONCLUSION: The economic burden of SREs in patients with bone metastases of lung cancer is substantial. Intravenous bisphosphonates, such as zoledronic acid, which have been shown to prevent these events, may reduce these costs.

Aged↗
PubMed2006

Unilateral diaphragm paralysis possibly due to cervical spine involvement in multiple myeloma.

OBJECTIVE: To describe a patient with unilateral diaphragmatic paralysis due to multiple myeloma (MM) involving the cervical spine and related structures. CASE PRESENTATION AND INTERVENTION: A 52-year-old female presented with dyspnea, low back and widespread bone pain. She was diagnosed as having MM with vertebral involvement and unilateral paralysis of the diaphragm. She received two cycles of a chemotherapeutic regimen consisting of vincristine-Adriamycin-dexamethasone. The bisphosphonate zoledronic acid was also initiated at the same time. During follow-up, the back pain disappeared and the complaint of dyspnea decreased, although the paralysis persisted. CONCLUSION: As part of the differential diagnosis of bone and back pain, we draw attention to MMand the rare complication of diaphragmatic paralysis due to phrenic nerve involvement.

Cervical Vertebrae↗
PubMed2006

Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease.

Renal dysfunction is a particularly problematic adverse event that requires additional management and can prohibit the use of certain medications. Due to their renal uptake and elimination, some bisphosphonates can cause nephrotoxicity when used for the treatment of skeletal-related events in patients with bone metastases. However, clinical studies and post-marketing experience indicate that renal effects do not appear to be the same for all bisphosphonates. Zoledronic acid and pamidronate appear to be associated with a greater risk of renal toxicity, especially when given in high doses or over short infusion times. In contrast, high loading doses of intravenous ibandronate (3 x 6 mg given on days 1-3) have shown no additional renal safety concerns, and intravenous ibandronate 6 mg appears to have a renal safety profile comparable to placebo. This paper reviews the renal safety of intravenously administered bisphosphonates and makes some suggestions, based on preclinical and clinical data, as to why renal safety profiles may differ.

Bone Density Conservation Agents↗
PubMed2007

High-dose therapy in patients with plasma cell dyscrasias and renal dysfunction.

Multiple mycloma causes a disproportionate amount of the malignancy-related renal insufficiency. Acute renal insufficiency in myeloma patients can occur due to dehydration, hypercalcemia, side effects of medications (NSAIDs) or tumor lysis syndrome in addition to cast nephropathy, amyloidosis and light chain deposition disease. Patients on hemodialysis have traditionally been excluded from antineoplastic therapy due to fear of side effects and lack of studies addressing benefit. Melphalan is the most effective chemotherapeutic agent in myeloma and its PK (pharmacokinetics) are not adversely affected by impaired renal function. Because of more pronounced toxicity of Melphalan 200 mg/m2 conditioning regimen, Melphalan 140 mg/m2 has become the standard of care. 24% of patients become dialysis-independent at a median of 4 months after autotransplantation. Favorable factors for becoming dialysis independent were duration of dialysis 10 ml/min. While no good data are available on the use of thalidomide in the presence of renal failure, it is our experience that severe neuropathy, constipation, lethargy and bradycardia are more frequent in patients with creatinine >or=3 mg/dl. It has become apparent that bisphosphanates-zoledronic acid more than pamidronate-cause renal dysfunction. If patients remain dialysis-dependent after autotransplantation, we recommend to delay considering a renal transplant until at least 3 years after the first transplant.

Antineoplastic Agents, Alkylating↗