Showing papers by "Jean-Jacques Body published in 2006"

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

Abstract: PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. EXPERIMENTAL DESIGN: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. RESULTS: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. CONCLUSIONS: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.

Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club.

Abstract: Glucocorticoids (GCs) are frequently prescribed for various inflammatory and/or life-threatening conditions concerning many systems in the body. However, they can provoke many aftereffects, of which osteoporosis (OP) is one of the most crippling complications, with its host of fractures. The dramatic increase in bone fragility is mainly attributable to the GC-induced rapid bone loss in all skeletal compartments. We have reviewed the meta-analyses and randomized controlled studies reporting medical therapeutic interventions currently registered in Belgium for the management of GC-OP comparatively with a placebo. Based on this research, an expert meeting developed a consensus on the prevention and therapy of GC-OP. The pathophysiology of GC-OP is complex. Several factors, acting separately or synergistically, have been described. Their great number could help to understand the rapidity of bone loss and of bone fragility occurrence, indicating that a rapid therapeutic intervention should be implemented to avoid complications. All patients on GCs are threatened with OP, so the prevention and/or therapy of GC-OP should be considered not only for postmenopausal females, but also for osteopenic premenopausal females and for males put on a daily dose of at least 7.5 mg equivalent prednisolone that is expected to last at least 3 months. Non-pharmacological interventions, such as exercise and avoidance of tobacco and alcohol, should be recommended, even if their role is not definitely settled in GC-OP prevention. Supplemental calcium and vitamin D should be considered as the first-line therapy because of the decrease in intestinal calcium absorption provoked by GCs. They also could be considered either as isolated therapy in patients taking less than 7.5 mg prednisolone daily and/or for a predicted period shorter than 3 months or as adjuvant therapy to other more potent drugs. Hormone replacement therapy could be considered in young postmenopausal females on GC, such as in postmenopausal OP, or in men with low androgen levels. Calcitonin appears to have a protective effect on trabecular bone in GC-OP, just as in postmenopausal OP. There is an increasing body of evidence supporting the antifracture efficacy of bisphosphonates, notably alendronate and risedronate. Preventative and curative therapy of GC-OP should be maintained as long as the patient is on GC treatment and could be stopped after weaning from GC, because there is more than circumstantial evidence of some recovery of BMD when GCs are stopped. There is no indication in GC-OP for any combination of two antiresorptive agents (except for calcium and vitamin D) or for an antiresorptive and an anabolic agent. There is indeed no proof that the increased costs of combined treatments will translate into increased therapeutic efficacy.

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

Abstract: 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.

Breast Cancer: Bisphosphonate Therapy for Metastatic Bone Disease

Abstract: The indications of bisphosphonate therapy in breast cancer patients go from the correction of hypercalcemia to the prevention of cancer treatment-induced bone loss Bisphosphonates are part of our therapeutic armamentarium against metastatic bone pain, and at least 50% of the patients benefit from a clinically relevant analgesic effect Placebo-controlled trials with oral or iv bisphosphonates have shown that prolonged administration can reduce the frequency of skeletal-related events by 30% to 40% The superiority of zoledronic acid compared with pamidronate has been shown by a multiple-event analysis in a large randomized trial The short infusion time of zoledronic acid also constitutes a convenient therapy Where available, oral ibandronate offers an interesting alternative, especially for patients receiving hormone therapy There are some toxicity concerns with the prolonged use of bisphosphonates The occasional renal toxicity of zoledronic acid has led to the recommendation to monitor renal function before each infusion and to adjust the dose according to creatinine clearance Osteonecrosis of the jaw could occur in up to 25% of breast cancer patients during long-term bisphosphonate therapy It is often a significant complication that seems to be linked with the duration of therapy

Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: phase III trial results.

Abstract: As patients with metastatic bone disease typically receive long-term treatment with bisphosphonates, and often antineoplastic compounds, drug-related safety is of considerable importance. Clinical trial data for intravenous (i.v.) ibandronate suggest that its nephrotoxic potential is comparable with placebo. We conducted a post hoc Kaplan-Meier analysis of time to serum creatinine increase with i.v. ibandronate throughout 2 years of treatment. After 96 weeks, 12% of patients in the placebo group and 6% in the ibandronate 6 mg group (ns, P = 0.22) had defined serum creatinine increases. After 12 treatment months (48 weeks), 4% of patients receiving placebo and 2% of patients receiving ibandronate 6 mg showed increased serum creatinine. These results suggest that there is no clinically relevant change in serum creatinine levels with i.v. ibandronate 6 mg infused every 3-4 weeks for 2 years. Comparative trials to examine the renal safety of ibandronate and other i.v. bisphosphonates are warranted.

Long-term safety of intravenous ibandronic acid for up to 4 years in metastatic breast cancer: an open-label trial.

Abstract: Background and objective: Despite their widespread use in metastatic bone disease, some bisphosphonate drugs are associated with adverse events (AEs), particularly renal toxicity, adding to treatment burdens and increasing healthcare costs. Ibandronic acid is a single-nitrogen bisphosphonate with high efficacy against bone events and metastatic bone pain, and a renal safety profile comparable to that of placebo. In this study, the safety of ibandronic acid was examined over a period of 4 years. Patients and methods: During an initial 96-week period, breast cancer patients with bone metastases were randomised in double-blind fashion to placebo or ibandronic acid 6mg administered by intravenous infusion over 1–2 hours every 3–4 weeks as part of a previously reported phase III trial (MF 4265 study). All patients completing the phase III trial were offered open-label active treatment for a further 96 weeks (extension phase). A total of 62 patients received ibandronic acid 6mg in this extension phase and were classified according to their initial treatment (placebo/ibandronic acid 6mg [placebo/6mg] and ibandronic acid 6mg/ ibandronic acid 6mg [6mg/6mg] groups). Safety was assessed by AE reports and clinical laboratory evaluations. Results: During the 4-year study, most patients experienced at least one AE, with malignancy progression being most commonly reported. However, fewer treatment-related AEs were reported in the extension phase (placebo/6mg: 6.3% [1/16]; 6mg/6mg: 13.0% [6/46]) than in the initial phase of the study (placebo: 56.3% [9/16]; 6mg: 67.4% [31/46]). Serious AEs were mainly due to malignancy progression. There were no clinically relevant renal AEs, and in both groups, serum creatinine levels were similar for up to 4 years. Conclusion: This 96-week open-label safety extension of a phase III, placebo-controlled trial demonstrates that long-term use of intravenous ibandronic acid is well tolerated.

Advances in Treating Metastatic Bone Cancer: Summary Statement for the First Cambridge Conference

Abstract: The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Sequence- and concentration-dependent effects of acute and long-term exposure to the bisphosphonate ibandronate in combination with single and multiple fractions of ionising radiation doses in human breast cancer cell lines

Abstract: Both bisphosphonates and radiotherapy are highly effective for the management of bone metastases. Our in vitro study examined the cytotoxic effects resulting from combinations of ibandronate and ionising radiations (RX) in various sequences on breast cancer cells. Single radiation doses were given before, at halftime of, or after acute ibandronate incubation (48 h). Single or fractionated radiation doses were applied at the end of chronic ibandronate incubation (5 weeks). Combination of acute ibandronate exposure and single radiation doses led to synergistic cytotoxic effects in MDA-MB-231 cell line, but only with low ibandronate concentrations in MCF-7 cell line. In both cell lines, synergy was more marked when ibandronate followed RX. After long-term ibandronate exposure, only high single radiation doses induced synergistic effects in MDA-MB-231 cell line. Synergy was only detected with low ibandronate concentrations in MCF-7 cell line. In both cell lines, fractionated radiation doses exerted similar effects. The combination of ibandronate with radiation can exert synergistic effects on the inhibition of breast cancer cells growth, depending on cell line, drug sequence and dosage. Our data might provide a rationale for associating bisphosphonates and radiotherapy for the treatment of bone metastases from breast cancer.

Individualization of bisphosphonate therapy

Abstract: According to the literature, 30-90% of patients with advanced cancer will develop skeletal metastases. Carcinomas of the breast (47-85%) and of the prostate (33-85%) are the tumors most commonly associated with bone metastases [31]. The skeleton is in fact the most common site of metastatic disease in breast cancer and the most common site of first distant relapse [21]. These patients have a longer survival after the diagnosis of bone metastases compared to patients with visceral metastases. Their median survival is usually beyond 20 months, and about 10% of them are still alive 5-10 years after the first diagnosis of skeletal dissemination [21]. Osteolytic bone disease is responsible for a considerable morbidity, and markedly decreases quality of life. The clinical consequences of cancer-mediated bone destruction are a source of misery for affected patients. Because of the long clinical course breast cancer may follow, morbidity due to tumor bone disease also makes major demands on resources for health-care provision. The term "skeletal-related events" (SREs) refers to the major complications of tumor bone disease, namely pathological fractures, need for radiotherapy, need for bone surgery, spinal-cord compression, and hypercalcemia. In addition to the complications of bone-marrow invasion, pain and functional disability occur in 45-95% of the cases [12, 31], whereas major complications will be observed in up to one-third of the patients whose first relapse is in bone [4, 21]. Hypercalcemia occurs in 10-15% of the cases and spinalcord compression in about 10%, and when long bones are invaded, fractures will occur in 10-20% of cases [3]. Pathological fractures are a dramatic consequence of tumor bone disease and they occur with a median onset of 11 months from the initial diagnosis of bone involvement [46]. Taken from data in placebo groups of randomized bisphosphonate trials, the mean skeletal morbidity rate (SMR; i.e., the mean number of SREs per year) varies between 2.2 and 4.0 [4, 8, 12, 21, 39, 46]. In a retrospective analysis of 859 patients at a single institution, it was shown that the frequency of SREs is dependent on the presence of other metastatic sites. As shown in Table 27.1, patients with bone metastases only have a much higher rate of SREs than patients with bone and visceral metastases (pleuropulmonary or liver). The frequency of SREs in patients with bone and soft-tissue metastases is intermediate [55]. That study also confirmed that survival from diagnosis of bone metastases was longest for patients with only bone metastases (median survival 24 months) and was least for patients with concomitant bone and liver metastases (median survival 5.5 months) [55]. (Table presented) The osteotropism associated with breast cancer remains incompletely understood. Various properties of cancer cells, such as the production of proteolytic enzymes and specific cell-adhesion molecules, can enhance their metastatic potential. More specifically, deposits into the skeleton can be due to the attraction of tumor cells by chemotactic factors released as a result of the normal remodeling of bone matrix. These factors include fragments of type I collagen and of osteocalcin, and several growth factors [5, 63]. The propensity of breast cancer cells to proliferate in bone is best explained by the "seed and soil" concept [43]. Breast cancer cells (the "seed") appear to secrete factors, such as parathyroid-hormone-related protein (PTHrP), potentiating the development of metastases in the skeleton, which constitutes a fertile "soil" that is rich in cytokines and growth factors, which stimulate the growth of breast cancer cells. Local production of PTHrP and of other osteolytic factors by cancer cells in bone stimulate osteoclastic bone resorption, essentially through the osteoblasts and probably also through the immune cells. Such factors induce osteoclast differentiation from hematopoietic stem cells and could also activate the mature osteoclasts already present in bone. PTHrP also alters the ratio between osteoprotegerin (OPG), the production of which is decreased, and receptor activator for Nf?B (RANK) ligand, the production of which is increased [38]. The net result of this imbalance in these key regulatory factors of osteoclast-mediated bone resorption is an increase in osteoclast proliferation and activity. Increased osteoclast number and activity then cause local foci of osteolysis, an enhanced release of growth factors, and a further stimulation of cancer cell proliferation [43, 64]. Bisphosphonates localize preferentially to sites of active bone remodeling. They act directly on mature osteoclasts, decreasing their bone resorption activity, notably by lowering H+ and Ca++ extrusion and modifying the activity of various enzymes [78]. However, the current view is that bisphosphonates essentially act by inducing osteoclast apoptosis. Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for macrophages and for osteoclasts. On the other hand, nitrogen-containing bisphosphonates, but not clodronate, in terfere with the mevalonate pathway, which is essential for the maintenance of cell membrane integrity. Aminobisphosphonates, such as pamidronate, zoledronate, or ibandronate, are nanomolar inhibitors of farnesyl-pyrophosphate synthase. This leads to an inhibition of posttranslational prenylation of proteins with farnesyl or geranylgeranyl isoprenoid groups. Various cellular proteins have to be anchored to the cell membrane by a prenyl group to become active. Most of these proteins are GTP-binding proteins, including the protein ras, and prenylated proteins are essential for osteoclast function, notably cell activity and attachment [49]. The net result, regardless of the mechanism (clodronate vs aminobisphosphonates), is osteoclast apoptosis, notably through the induction of caspase-3. It has also been found that bisphosphonates can directly inhibit the growth of breast cancer cells by a combination of necrotic and apoptotic processes, and inhibit the stimulatory effects of bonederived growth factors [29, 30]. The relevance of these in vitro observations to the clinical beneficial effects of bisphosphonates remains, however, to be demonstrated. The indications of bisphosphonate therapy, adapted to the individual patient, are reviewed in the following sections, from the correction of cancer hypercalcemia to the prevention of cancer-treatment-induced bone loss. © Springer-Verlag Berlin Heidelberg 2006.

Tumor bone disease.

Abstract: The propensity of breast cancer cells to metastasize in bone could notably be due to the rich supply of relevant growth factors present in the skeletal microenvironment, which increases breast cancer cell growth. Bone destruction is essentially mediated by osteoclast activation. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption that now constitute a standard non-cytotoxic treatment of bone metastases. They have become the optimal therapy for tumor-induced hypercalcemia, and at adequate doses (90 mg) the efficacy of pamidronate is not influenced significantly by the tumor type or the degree of metastatic bone involvement. Regular 90-mg pamidronate infusions can also relieve bone pain in about one-half of cases, and an objective sclerosis of osteolytic lesions can be seen in one-quarter of patients. Most importantly, the prolonged administration of oral or intravenous bisphosphonates can delay and reduce the frequency of morbid skeletal events in breast cancer metastatic to bone and in multiple myeloma by one-quarter to one-half. Intravenous bisphosphonates appear to produce larger and more rapid effects than available oral compounds. Newer, more potent bisphosphonates, such as ibandronate (6 mg) and zoledronate (4 mg), appear to produce similar results to pamidronate but are more convenient to administer. They could, nevertheless, be more potent in conditions characterized by severe osteolysis. Zoledronate has thus been shown to be superior to pamidronate in moderate to severe hypercalcemia. Therapy with bisphosphonates also has the advantage of preventing postmenopausal osteoporosis in women cured from breast cancer and for whom ERT is still considered to be contraindicated.