Showing papers by "Jean-Jacques Body published in 2008"

Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy.

Abstract: Purpose: Denosumab, a fully human monoclonal antibody to RANKL, suppresses bone resorption. This study evaluated the effects of denosumab in i.v. bisphosphonate (IV BP)–naive patients with breast cancer-related bone metastases. Experimental Design: Eligible women ( n = 255), stratified by type of antineoplastic therapy, were randomized to 1 of 5 blinded denosumab cohorts or an open-label IV BP cohort. Denosumab was administered s.c. every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg) through 21 weeks. Final efficacy results for up to 25 weeks are reported, including percentage change from baseline in urine N-telopeptide corrected for creatinine (uNTx/Cr) and incidence of skeletal-related events (SRE). Safety results are reported through the end of follow-up (up to 57 weeks). Results: At week 13 and 25, the median percent changes in uNTx/creatinine (Cr) among patients with measurable uNTx were −73% and −75% for the pooled denosumab groups and −79% and −71% for the IV BP group. Among patients with ≥1 postbaseline measurement of uNTx at week 25, 52% (109 of 208) of denosumab-treated patients and 46% (19 of 41) of IV BP–treated patients achieved >65% uNTx/Cr reduction. On-study SREs occurred in 12% (26 of 211) of denosumab-treated patients and 16% (7 of 43) of IV BP–treated patients. Overall rates of adverse events were 95% in denosumab and IV BP groups. No denosumab-related serious or fatal adverse events occurred. Conclusions: In IV BP–naive breast cancer patients with bone metastases, denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs, with a safety profile consistent with an advanced cancer population receiving systemic therapy.

Advancing Treatment for Metastatic Bone Cancer: Consensus Recommendations from the Second Cambridge Conference

Abstract: Purpose: Summarize current knowledge, critical gaps in knowledge, and recommendations to advance the field of metastatic bone cancer. Experimental Design: A multidisciplinary consensus conference was convened to review recent progress in basic and clinical research, assess critical gaps in current knowledge, and prioritize recommendations to advance research in the next 5 years. The program addressed three principal topics: biology of metastasis, preserving normal bone health, and optimizing bone-targeted therapies. Results: A variety of specific recommendations were identified as important to advance research and clinical care over the next 5 years. Conclusions : Priorities for research in bone biology include characterizing components of the stem cell niche in bone, developing oncogenic immunocompetent animal models of bone metastasis, and investigating the unique contribution of the bone microenvironment to tumor growth and dormancy. Priorities for research in preserving normal bone health include developing methods to measure and characterize disseminating tumor cells, assessing outcomes from the major prevention trials currently in progress, and improving methodologies to assess risks and benefits of treatment. Priorities for optimizing bone-targeted therapies include advancing studies of serum proteomics and genomics to reliably identify patients who will develop bone metastases, enhancing imaging for early detection of bone metastases and early response evaluation, and developing new tests to evaluate response to bone-directed treatments.

Management of patients with Paget’s disease: a consensus document of the Belgian Bone Club

Abstract: Paget's disease of bone (PDB) is a potentially crippling condition. Pain, fracture, spinal stenosis, nerve entrapment, vascular steal syndrome, secondary osteoarthritis, bone deformity, dental problems, deafness, excessive bleeding during orthopaedic surgery, rare sarcomatous degeneration, and hypercalcaemia constitute complications that may impair the quality of life. The therapeutic approach varies from symptomatic (analgesics, anti-inflammatory drugs) to more specific drugs such as increasingly potent bisphosphonates. Studies such as the PRISM study should in the future help to determine the superiority or not of aggressive treatment over symptomatic treatment in the prevention of complications. Various oral and/or intravenous (I.V.) bisphosphonates have been tested and are currently on the market. The most recently available nitrogen-containing bisphosphonate, I.V. zoledronic acid, is the most potent therapy available for the treatment of PDB. Its therapeutic efficacy, its long-term effect on biologic activity and its good tolerance currently supports its use as a first-line therapeutic option in patients suffering from PDB.

Extracellular calcium increases bisphosphonate-induced growth inhibition of breast cancer cells

Abstract: Bisphosphonates have become standard therapy for the treatment of skeletal complications related to breast cancer. Although their therapeutic effects mainly result from an inhibition of osteoclastic bone resorption, in vitro data indicate that they also act directly on breast cancer cells, inhibiting proliferation and inducing apoptosis. The present study examined the effects of calcium (from 0.6 to 2.0 mmol/l) on the antitumour activity of the bisphosphonate ibandronate (1 to 1,000 nmol/l) on MDA-MB-231 and MCF-7 breast cancer cells. Cell culture densities were determined using crystal violet staining assay. Apoptotic cell death was assessed by annexin V-phycoerythrin and 7-amino-actinomycin double staining. At low calcium concentration, 30 μmol/l ibandronate had no effect on MDA-MB-231 cells growth and only slightly inhibited MCF-7 cells growth. Higher calcium levels significantly increased growth inhibition as well as cell apoptosis induced by ibandronate. We observed similar effects with zoledronic acid. Of note, enhancement of ibandronate-induced growth inhibition was also observed in other breast cancer cell lines (T-47D, ZR-75, Hs-578T and BT-549 cells). The growth inhibitory effect of ibandronate in the presence of high concentrations of calcium was partly suppressed by the calcium chelator EGTA (ethylene glycol tetra-acetic acid). In addition, in the presence of calcium at high concentrations, cells accumulated more [14C]ibandronate than at low calcium concentrations. We obtained further evidence of enhancement of cellular ibandronate accumulation by calcium by demonstrating that high calcium levels increased the inhibition of protein prenylation induced by the bisphosphonate. Altogether, our data suggest that extracellular calcium, probably through its binding to ibandronate, markedly increased its cellular accumulation and its inhibitory activity on breast tumour cells. Thus, calcium released during the process of tumour-induced osteolysis might enhance the antitumour effects of bisphosphonates and contribute to their therapeutic efficacy.

Hormone therapy for breast cancer, with an emphasis on the pure antiestrogen fulvestrant: mode of action, antitumor efficacy and effects on bone health.

Abstract: Breast cancer is a major health problem in women of developed Western countries. Whereas estrogen receptor (ER) may be involved in many cases in breast carcinogenesis, its expression in breast tumors may predict a favorable response to hormone therapy. In this review, we report the role played by ER in breast cancer and compare the effects and mechanisms of action of partial (tamoxifen) and pure (fulvestrant) antiestrogens, as well as of aromatase inhibitors. Moreover, as ER also has a critical role in bone metabolism, we review the beneficial and adverse effects of breast cancer hormone therapy on bone health, with a particular emphasis on fulvestrant, the only pure antiestrogen recently approved by the FDA for Phase III clinical trials. We conclude that, because of its therapeutic efficacy and its seemingly minimal effect on bone integrity, fulvestrant represents a new option for the hormonal treatment of breast cancer that deserves further clinical evaluation.

Renal tolerability of intermittent intravenous ibandronate treatment for patients with postmenopausal osteoporosis: a review.

Abstract: While intravenous (IV) bisphosphonates are well established in managing metastatic bone disease and hypercalcemia of malignancy, oral bisphosphonates are the primary treatment for postmenopausal osteoporosis. The availability of a well-tolerated, effective, IV bisphosphonate regimen for postmenopausal osteoporosis would increase physicians' options, allowing treatment of patients who cannot tolerate oral therapy, for whom oral bisphosphonates should be avoided or patients who are unable to comply with the oral dosing recommendations. Ibandronate is a potent, nitrogen-containing bisphosphonate, with proven efficacy and good tolerability when administered intermittently either orally or intravenously. Preclinical experience in animal models with IV ibandronate indicated that it had good renal tolerability. These data are supported by clinical pharmacology studies. Prolonged follow-up of patients receiving intermittent IV 15-30 second injections of 0.5-3 mg IV ibandronate has demonstrated no clinical evidence of renal toxicity in patients with postmenopausal osteoporosis. What is seen in controlled studies is not always the case in uncontrolled studies, however, no reports of renal failure have been received in post-marketing surveillance of >500,000 patients receiving IV ibandronate infusions in various indications including metastatic breast and prostate cancer. The good renal tolerability of IV ibandronate in patients with osteoporosis with glomerular filtration rates >30 mL/minute and without renal co-morbid conditions is reassuring.

Hormone therapy for breast cancer, with an emphasis on the pure antiestrogen fulvestrant: mode of action, antitumor

Abstract: Breast cancer is a major health problem in women of developed Western countries. Whereas estrogen receptor (ER) may be involved in many cases in breast carcinogenesis, its expression in breast tumors may predict a favorable response to hormone therapy. In this review, we report the role played by ER in breast cancer and compare the effects and mechanisms of action of partial (tamoxifen) and pure (fulvestrant) antiestrogens, as well as of aromatase inhibitors. Moreover, as ER also has a critical role in bone metabolism, we review the beneficial and adverse effects of breast cancer hormone therapy on bone health, with a particular emphasis on fulvestrant, the only pure antiestrogen recently approved by the FDA for Phase III clinical trials. We conclude that, because of its therapeutic efficacy and its seemingly minimal effect on bone integrity, fulvestrant represents a new option for the hormonal treatment of breast cancer that deserves further clinical evaluation.

Denosumab in patients with bone metastases from prostate, breast, and other cancers and elevated urinary N-telopeptide (uNTx) during intravenous bisphosphonate (IV BP) therapy: Final results of a randomized, phase II study

Abstract: 3596 Background: Patients (pts) with elevated levels of uNTx, representing excessive bone resorption, are at high risk for skeletal- related events (SREs), disease progression, and death (Coleman, ...

Update on treatment of postmenopausal osteoporosis

Abstract: The most frequent sites of osteoporotic fractures are the vertebrae, the hip, the forearm and the proximal humerus. Drugs that inhibit bone resorption constitute the mainstay for the treatment of postmenopausal osteoporosis. A recent meta-analysis indicates that vitamin D can reduce the risk of hip fractures only if calcium supplements are also administered. The effect of hormone replacement therapy on the risk of non vertebral fractures is less clear than on vertebral fractures. Raloxifene (a SERM) reduces the rate of vertebral fractures and of breast cancer, but it does not protect against hip fracture. Bisphosphonates are the most commonly used compounds to treat postmenopausal osteoporosis. The level of evidence for currently used bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) to reduce vertebral fracture rate is maximal. Results of controlled clinical trials indicate a reduction in the risk of vertebral fractures of 40-50% and of 20-40% for non vertebral fractures, including hip fractures. However, their relative efficacy on hip fractures has been less well studied and remains more controversial. Long-term compliance of bisphosphonate therapy is improved by intermittent schemes. The most recent developpements concern the intravenous administration of ibandronate and even more of zoledronate (yearly infusions). The reduction in the rate of vertebral and hip fractures has been demonstrated in the main zoledronate trial and a prolongation of survival has been shown in the study including patients with a recent hip fracture. Whereas hyperparathyroidism is a cause of bone loss, the intermittent administration of parathyroid hormone or of its 1-34 fragment (teriparatide) exerts anabolic effects on the skeleton. The treatment is demanding and costly (daily sc injections during 18 months), requires some monitoring (serum and urinary calcium) but the results, at least for vertebral fractures, are quite favorable. Strontium ranelate is a less powerful stimulator of bone formation but it also reduces bone resorption. Its daily administration for 3 years reduces the risk of vertebral fractures and, to a lesser extent, of non vertebral fractures. Lastly, denosumab is a high affinity antibody against RANK Ligand that specifically blocks the formation and the activity of osteoclasts. The efficacy of this promising compound will soon be known.

Effects of denosumab on bone resorption in patients with solid tumors and bone metastases: Comparison of serum-C telopeptide levels from two randomized, active-controlled, phase II trials

Abstract: 9574 Background: Patients with bone metastases have a high risk of skeletal morbidity and high rates of bone remodeling, both mediated by RANKL-stimulated osteoclasts. Denosumab, a fully human mono...

Prédiction du risque fracturaire absolu par validation de facteurs de risque et dépistage de l'ostéoporose dans une cohorte bruxelloise suivie pendant 10 ans (étude FRISBEE*)

Abstract: Osteoporosis is a major public health problem. For the time being, the diagnosis of osteoporosis relies on densitometry (T-score 3 months), tabagism and excessive alcohol consumption. A WHO taskforce has combined these different factors in order to integrate them in a 10-years predictive risk model of fracture (FRAX**). This model should still be validated in different populations, especially in populations not included in its development, which is the case for Belgium. We are evaluating these different risk factors for fracture in a Brussels population of 5000 women (60-80 years) who will be followed each year during 10 years. We also assess the predictive value of other risk factors for fracture not included in the WHO model (tendency to fall, use of sleeping pills, early non substituted menopause, sedentarity, ...). In an interim analysis of the first 452 women included and with data yet available at the time of this writing, we could find a significant (P 70 years, a personal history of fracture after 50 years and a BMI < 20.