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PubMed2003

Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma.

Osteoporosis is a complication of androgen deprivation therapy in men with prostate carcinoma. Androgen deprivation therapy, caused by either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone agonist, decreases bone mineral density and increases fracture risk. Other factors including diet and lifestyle may contribute to bone loss. There is limited information regarding the best strategy to prevent osteoporosis in men with prostate carcinoma. Lifestyle modification including smoking cessation, moderation of alcohol consumption, and regular weight-bearing exercise should be encouraged. Supplemental calcium and vitamin D are also recommended. Additional treatment may be warranted for men with osteoporosis, fractures, or high rates of bone loss during androgen deprivation therapy. Intravenous pamidronate, a second-generation bisphosphonate, prevents bone loss during androgen deprivation therapy. Zoledronic acid, a more potent third-generation bisphosphonate, not only prevents bone loss but also increases bone mineral density during androgen deprivation therapy. Other bisphosphonates may be effective although they have not been evaluated in this clinical setting. Treatment with estrogens or selective estrogen receptor modulators may also be effective. Monotherapy with bicalutamide or other antiandrogens may cause less bone loss than androgen deprivation therapy.

Absorptiometry, Photon↗
PubMed2004

Parathyroid hormone-related peptide as a cause of hypercalcemia in squamous cell carcinoma of the head and neck: a case presentation and subject review.

BACKGROUND: Serum levels of parathyroid hormone-related peptide (PTHrP) can be elevated with malignancy and cause hypercalcemia, which has been associated with a poor prognosis. METHODS: We present a case of supraglottic squamous cell carcinoma with elevated serum PTHrP and hypercalcemia. The patient was acutely managed with intravenous fluids, furosemide, and zoledronic acid and then underwent a total laryngectomy and modified radical neck dissection. RESULTS.: The patient remains disease free and normocalcemic. CONCLUSION: Curative treatment for patients with head and neck cancer should not be withheld solely on the basis of humoral hypecalcemia of malignancy.

Aged↗
PubMed2007

Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo.

Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease.

Animals↗
PubMed1997

Entamoeba histolytica: computer-assisted modeling of phosphofructokinase for the prediction of broad-spectrum antiparasitic agents.

Pyrophosphate-dependent phosphofructokinase (PPi-PFK) is the rate-limiting glycolytic enzyme found in the pathogenic protists Entamoeba histolytica, Giardia lamblia, Toxoplasma gondii, Trichomonas vaginalis, and Naegleria fowleri. The enzyme differs significantly from ATP-dependent phosphofructokinases found in humans and as such represents an important drug target. Current therapy for infections caused by these pathogens is inadequate, especially for children, pregnant women, and the immune compromised. The development of more selective, safer agents in imperative, as parasitic infections are currently a significant health threat worldwide and will likely become increasingly common agents of disease in the future. For the purpose of designing drugs to treat parasitic infections, we have constructed a model of PPi-PFK from E. histolytica based on the three-dimensional structure of the ATP-dependent PFK from Bacillus stearothermophilus. The model was used with the computer program Dock 3.5 (University of California, San Francisco) to predict the binding of pyrophosphate and selected bisphosphonates to the enzyme. The predicted drug-enzyme interactions suggested that two of these compounds would be competitive inhibitors of pyrophosphate. These drugs were tested against E. histolytica and inhibited the growth of amebae in vitro. This class of compounds may have broad-spectrum antiparasitic activity and, in the future, may facilitate the treatment of serious parasitic infections.

Amino Acid Sequence↗
PubMed2005

Noninvasive monitoring of changes in structural cancellous bone parameters with a novel prototype micro-CT.

Characterization of trabecular bone structures requires necropsy of animals followed by a labor-intense histomorphometric or ex vivo micro-CT analysis. We tested the novel vivaCT40 from Scanco Medical AG (Bassersdorf, Switzerland), which allows monitoring such changes repeatedly in anesthetized rats and mice. Postmenopausal osteoporosis: in 8-month-old ovariectomized (OVX) rats, the vivaCT40 was capable of picking up the decrease in trabecular bone volume and trabecular thinning as well as the decrease in the number of trabecular elements as a function of time. The bone anabolic effects of parathyroid hormone [hPTH(1-34)], which resulted in an increase in trabecular thickness but not their number, as well as the bone protective effect of the two antiresorptive agents zoledronic acid (ZA) and 17-alpha ethinylestradiol (aEE), were detected correctly with the vivaCT40. Adjuvans arthritis: the vivaCT40 allowed measuring trabecular bone loss caused by periarticular inflammation in a rat model of adjuvans arthritis and demonstrated the bone protective effect of dexamethasone (DM). In addition, it was possible to image the subtle erosive lesions in subchondral bone caused by the inflammatory processes. Tumor osteolysis: the vivaCT40 allowed monitoring of the progressive osteolytic response following the local administration of 4T1luc2000 tumor cells into the tibia metaphysis of nude mice. The potent protective effect of ZA on tumor osteolysis was demonstrated. In summary, the new vivaCT40 can monitor the effects of known agents and diseases such as osteoporosis, inflammatory arthritis, and tumor invasion on 3-D trabecular microarchitecture accurately, repeatedly, reliably, and quickly in anesthetized rats and mice. The scanner represents a breakthrough for noninvasive imaging and structural measurements in small rodents.

Animals↗
PubMed2005

[The study landscape for prostate cancer].

Current prostate cancer studies in Germany encompass the indications "adjuvant therapy", "rising PSA following radical prostatectomy", "metastasized, hormone sensitive prostate cancer", and "hormone refractory prostate cancer". In the adjuvant field, the potential of zoledronic acid for the prevention of bone metastases is being investigated in a large phase III trial. The activity of imatinib in low volume prostate cancer is being tested in patients with rising PSA following radical prostatectomy (phase II). The randomized phase III trial intermittent versus continuous hormone therapy in D1 and D2 patients has finished accrual and follow-up will be extended until the end of 2006. In hormone refractory prostate cancer(HRPC), the results of a recent phase II study (Association of Urological Oncology; AOU AP 33/02) were promising. This led to a currently activate phase III trial comparing intermittent with continuous chemotherapy in HRPC. The interdisciplinary study group of the AUO (Urology) and the ARO (Radio-oncology) has developed several new protocols which are currently under review by the German Cancer Aid (Deutsche Krebshilfe).

Antineoplastic Agents↗
PubMed2006

[Diagnostic work-up of bone metastases of genitourinary tumors and their treatment with bisphosphonates. Interdisciplinary consensus conference, Frankfurt, 2006].

The diagnostic algorithm in cases of suspected bone metastases of genitourinary tumors still starts with a scintigraphic examination. Osseous metastases of hormone-refractory prostate cancer require treatment with zoledronic acid. A potential indication is a hormone-sensitive status. Nephrotoxic substances should not be administered simultaneously. To avoid osteonecrosis of the jaw, prior dental examination, oral hygiene, and if necessary dental reconstruction are recommended. Bisphosphonates can be combined with radiation therapy and chemotherapy; additional administration of calcium and vitamin D is not mandatory. It is recommended that patients with bone metastases of renal cell cancer be treated with bisphosphonates approved for this indication. For urothelial carcinoma and other genitourinary tumors, the available data are not sufficient to give a recommendation.

Antineoplastic Agents↗
PubMed2006

Bisphosphonates for malignancy-related bone disease: current status, future developments.

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.

Antineoplastic Agents↗
PubMed2005

Should oral bisphosphonates be standard of care in women with early breast cancer?

There is increasing evidence that oral clodronate has important clinical benefits in early breast cancer. Longer-term follow-up data from two out of three randomized studies have shown that adjuvant clodronate improves survival. This article outlines the results of these studies and discusses the potential role for other bisphosphonates, such as ibandronate and zoledronic acid, in the adjuvant treatment of breast cancer.

Antimetabolites↗
PubMed2001

Bone disease in myeloma.

The major clinical manifestation of multiple myeloma results from osteolytic bone destruction. The only currently Food and Drug Administration-approved drug for the treatment of the bony complications of multiple myeloma is monthly intravenous pamidronate at a dose of 90 mg infused over 4 hours. Recent studies have shown the safety of 2-hour infusions. A randomized trial comparing pamidronate to placebo continued to show benefits throughout the 21-month trial. Although the duration of therapy has not been firmly determined, it is likely that discontinuation of this drug will be met by enhanced bone loss and an increased risk of bony complications for these patients. Thus, it is recommended that the drug be continued indefinitely. Support for this recommendation also comes from the reduced bone density observed in women with postmenopausal osteoporosis following the withdrawal of bisphosphonate treatment. Recent attempts to give higher doses, more frequent infusions (every 2 weeks or less), or more rapid infusions (1 hour or less) of pamidronate have occasionally been associated with albuminuria and azotemia. These modifications should therefore be avoided. Importantly, the drug can be safely administered at 90 mg monthly to patients with poor renal function. The use of pamidronate for myeloma patients without lytic bone involvement or with Durie-Salmon stages I or II disease has not been evaluated. However, it is recognized that most patients with earlier stages of disease or without lytic bone involvement also develop bony complications. There is no reason to believe that these patients would not benefit from monthly intravenous infusions of pamidronate. The potential antimyeloma effect of this agent is another reason to administer this drug in these types of patients. Thus, it is our practice to administer monthly pamidronate to myeloma patients regardless of stage or bone involvement. However, trials evaluating oral bisphosphonates have produced inconsistent clinical results, probably as a result of the erratic and scanty poor absorption as well as poor oral tolerability of these drugs. Although these oral agents may be useful in some patients, it is impossible to identify which myeloma patients will benefit from orally administered bisphosphonates. The more potent nitrogen-containing bisphosphonate zoledronic acid more effectively reverses hypercalcemia of malignancy than pamidronate, and it appears promising in reducing bone loss in cancer patients. However, its efficacy in preventing skeletal complications is still being evaluated. Many other types of new agents are in early clinical trials, but their efficacy remains unproven at the present time.

Antineoplastic Agents↗
PubMed2005

Myeloma bone disease.

The major clinical manifestation of multiple myeloma is related to the osteolytic bone destruction. The bone disease can lead to pathologic fractures, spinal cord compression, hypercalcemia, and pain. It is also a major cause of morbidity and mortality in these patients. These patients frequently require radiation therapy, surgery and analgesic medications. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in myeloma patients with bone disease during the past 15 years. Several large randomized trials have been conducted in myeloma patients also receiving chemotherapy. Orally administered bisphosphonates have shown little ability to slow the development of skeletal complications in these patients. In contrast, more potent intravenous monthly infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among these patients and are now a mainstay of myeloma therapy. A number of other types of new anti-bone-resorptive agents are also in early clinical development.

Antineoplastic Agents↗
PubMed2006

The extended adjuvant NCIC CTG MA.17 trials: initial and rerandomization studies.

Based upon the results of the NCIC CTG MA.17 trial, letrozole has become the only approved aromatase inhibitor (AI) in the extended adjuvant treatment setting following 5 years of tamoxifen therapy. In this trial, the AI letrozole decreased the overall risk of breast cancer recurrence by 42% compared with placebo in postmenopausal women completing 5 years of tamoxifen. The benefit of letrozole exceeded the expected difference after median follow-up of more than 2 years and led to the unblinding of the trial. The 30-month updated analyses found a 4.8%, 4-year disease-free survival improvement overall, an improvement in distant disease-free recurrence in both node-negative and node-positive patients, and a survival benefit for node-positive patients. Generally well tolerated, letrozole caused some adverse events including arthralgias and osteoporosis. However, results from the Zometa-Femara adjuvant synergy trial (Z-FAST) suggest that zoledronic acid, when used concomitantly with letrozole, is able to manage bone loss in postmenopausal women with early breast cancer.

Aromatase Inhibitors↗
PubMed2006

Simple analysis of four bisphosphonates simultaneously by reverse phase liquid chromatography using n-amylamine as volatile ion-pairing agent.

Volatile organic amine was used as the mobile phase addictive during the separation of four bisphosphonates (alendronate, pamidronate, zoledronic acid and etidronate). An isocratic liquid chromatography method with evaporative light-scattering detection (ELSD) was developed for these bisphosphonates which are not retained on non-polar column and lack chromophore for detection. The analytes have sufficiently separated from each other on a Phenomenex C18 column. The effects of mobile phase composition and instrumental parameters of ELSD were studied. This newly developed method enables direct measurement for analysis of bisphosphonates without the need of derivatization. This developed method provides high separation and specificity to bisphosphonate analysis. In quantitative analysis, the method showed satisfactory precision (less than 2.8%) and accuracy (higher than 94.4%), good linearity (r=0.9991-0.9997) and sufficient sensitivity (15-18 microg/ml). It can be easily and conveniently adopted for the routine quality control analysis.

Amines↗
PubMed2006

Update of current therapeutic options for the treatment of postmenopausal osteoporosis.

BACKGROUND: Osteoporosis is a common chronic condition in elderly women and is associated with decreased bone strength and an increased risk for fractures. As the incidence of osteoporotic fractures continues to rise, it is important to identify the most effective therapies for reducing patients' risk of fracture. OBJECTIVE: This article reviews the medication classes commonly used for treating osteoporosis and the efficacy, tolerability, and drug-interaction potential of specific medications. The evidence for the use of combination therapies is summarized, as are the agents under investigation. METHODS: Relevant articles were identified through a search of MEDLINE (August 1985-August 2005) using the terms osteoporosis, postmenopausal, fracture, and efficacy combined with drug therapy, calcium, vitamin D, estrogen, progesterone, selective estrogen modulators, calcitonin, strontium ranelate, bisphosphonates, alendronate, risedronate, ibandronate, pamidronate, parathyroid hormone, combination therapy, and zoledronic acid. The identified articles were reviewed for suitability, with priority given to meta-analyses. RESULTS: Among the therapeutic options for the treatment of osteoporosis, the bisphosphonates appear to provide the greatest antiresorptive efficacy, with some bisphosphonates providing 7% to 8% increases in bone mineral density and 60% to 70% decreases in markers of bone resorption. Bisphosphonates also may reduce the incidence of new vertebral fractures by 50% to 52%. CONCLUSIONS: Bisphosphonates are currently the first choice for the treatment of osteoporosis. Use of intermittent regimens of the newer bisphosphonates appears to be a promising alternative to administration of daily or weekly treatment.

Anabolic Agents↗
PubMed2006

Myeloma bone disease and treatment options.

Multiple myeloma (MM) is a B-cell malignancy characterized by enhanced bone loss commonly associated with a 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. Recent characterization of osteoclast-activating factors (OAFs), receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL)-osteoprotegerin-RANK system, and inhibitors of Wnt signaling have provided a better understanding of myeloma bone disease in molecular level. The development of minimally invasive surgical procedures such as kyphoplasty and vertebroplasty allows myeloma patients with vertebral compression fractures to have immediate improvement in quality of life and shorter hospital stays. Monthly intravenous infusion of either pamidronate or zoledronic acid have reduced the skeletal complications among MM patients 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 pre-clinical studies suggest nitrogen-containing bisphosphonates have potent anti-tumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible anti-tumor effects clinically. As our understanding of the pathophysiology of myeloma bone disease continues to increase, new target therapies will continue to emerge offering new and more advanced options for the management of myeloma bone disease.

Antineoplastic Agents↗
PubMed2007

Bone health in men receiving androgen deprivation therapy for prostate cancer.

PURPOSE: Patients with recurrent or metastatic prostate cancer generally receive androgen deprivation therapy, which can result in significant loss of bone mineral density. We explored androgen deprivation therapy related bone loss in prostate cancer, current treatments and emerging therapies. MATERIALS AND METHODS: Literature published on the pathogenesis and management of androgen deprivation therapy related bone loss was compiled and interpreted. Recent drug therapy findings were reviewed, including treatment guidelines. RESULTS: Men with prostate cancer often present with bone loss and the initiation of androgen deprivation therapy can trigger further rapid decreases. This results in an increased fracture risk, and greater morbidity and mortality. Early detection of osteoporosis through androgen deprivation therapy screening and prompt initiation of therapy are critical to prevent continued decreases. Lifestyle changes such as diet, supplementation and exercise can slow the rate of bone loss. Pharmacological therapy with oral and intravenous bisphosphonates has been demonstrated to prevent or decrease the bone loss associated with androgen deprivation therapy. However, important differences exist among various bisphosphonates with respect to efficacy, compliance and toxicity. Only zoledronic acid has been shown to increase bone mineral density above baseline and provide long-term benefit by decreasing the incidence of fracture and other skeletal related events in men with bone metastases. CONCLUSIONS: Androgen deprivation therapy associated bone loss adversely affects bone health, patient quality of life and survival in men with prostate cancer. Increased awareness of this issue, identification of risk factors, lifestyle modification and initiation of bisphosphonate therapy can improve outcomes. Education of patients and physicians regarding the importance of screening, prevention and treatment is essential.

Algorithms↗
PubMed2004

Calcium and vitamin D supplementation during bisphosphonate administration may increase osteoclastic activity in patients with bone metastasis.

Bone metastasis are a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. The consequences of bone metastasis are often devastating. Osteolytic metastasis can cause different kinds of skeletal related events including severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. These skeletal-related events are the result of the resorption of mineralized bone by osteoclasts. Bisphosphonates are synthetic analogues of naturally occurring pyrophosphate compounds that inhibit bone resorption. Potent bisphosphonates, pamidronate and, more importantly zoledronic acid may cause hypocalcemia, but mostly asymptomatic, mild, transient in most cases. Sufficient calcium and vitamin D intake needs to be ensured in patients with malignancy who have borderline or low levels of calcium when commencing treatment with bisphosphonates. Vitamin D itself induce the formation of osteoclasts by increasing the expression of RANKL on marrow stromal cells. Local calcium also promotes tumor growth and the production of parathyroid hormone-related peptide which in turn stimulates bone resorption. Vitamin D and calcium supplementation during bisphosphonate administration for the purpose of elimination of the side effects related to hypocalcemia in patients with bone metastasis may increase the bone resorption and decrease the efficacy of bisphosphonates. Therefore, vitamin D and calcium supplementation must not be routinely recommended during bisphosphonate administration.

Animals↗
PubMed2003

Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment.

Metastasis to bone is a common feature in advanced prostate cancer patients. Current treatments, while effective in suppressing tumour growth and relieving tumour associated bone pain, do not provide long term remission or 'cure' for the disease. A greater understanding of prostate cancer metastasis is required if new treatment strategies are to be developed. Growth of tumour foci in skeletal sites is a major cause of morbidity in advanced prostate cancer and has required the development of specialised approaches to treatment, including the use of bisphosphonates. These drugs inhibit tumour induced osteoclastic bone resorption, thereby preventing skeletal related events and treatment induced bone loss. Zoledronic acid is currently the only bisphosphonate with proven benefit in prostate cancer. Bisphosphonates may also modify the bone microenvironment so that it becomes less favourable for the growth and survival of metastases. The most recent developments in our understanding of the advantages for growth and survival gained by metastatic prostate cancer cells in the skeleton are reviewed, along with the clinical evidence supporting the use of bisphosphonates in advanced prostate cancer.

Bone Neoplasms↗