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Background: Bisphosphonates are potent inhibitors of bone resorption frequently used for breast cancer and myeloma-induced bone disease. Zoledronic acid has been recently shown to also reduce skeletal morbidity from prostate cancer., Methods: We have investigated the biological effects of bisphosphonates on PC-3 cell survival (MTT assay and DNA content). We compared four bisphosphonates at doses ranging from 10(-6) to 10(-4) M: clodronate, pamidronate, ibandronate and zoledronic acid. We analyzed cell cycle phases and assessed apoptotic effects of bisphosphonates by three different methods., Results: Clodronate exhibited only a slight inhibitory effect on cell growth. In contrast, aminobisphosphonates markedly decreased cell growth in a time- and dose-dependent manner exerting cytostatic and apoptotic effects. The largest effects were observed after six days of exposure to 10(-4) M bisphosphonates. Cytostatic effects were observed with all three aminobisphosphonates whereas apoptotic effects were especially evident after zoledronic acid incubation., Conclusions: Aminobisphosphonates, especially zoledronic acid, markedly inhibited PC-3 cancer cell growth, through a variable combination of cytostatic and apoptotic effects. This activity could potentially contribute to the beneficial effects of bisphosphonates in prostate cancer patients with bone metastases.

Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P=0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47 vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.

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.

Cancer hypercalcemia can now be easily and successfully treated in at least 90% of the cases. Standard therapy consists in rehydration and administration of bisphosphonates, namely pamidronate (90 mg), or more recently zoledronic acid (4 mg) which is more potent. When available, ibandronate constitutes an interesting alternative especially that this compound is apparently less nephrotoxic. Recurrent hypercalcemia remains difficult to control but often occurs in quite advanced stages of the neoplastic disease. In the future, antibodies against PTHrP could be useful in well selected patients. Prevention of cancer hypercalcemia is one of the objectives of long-term therapy with bisphosphonates in patients with bone metastases. They reduce the incidence of all complications of metastatic bone disease, including cancer hypercalcemia.

Background: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer., Patients and Methods: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated., Conclusions: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.

Various primary malignancies develop bone metastases, and the resultant skeletal complications cause significant morbidity/mortality in advanced cancer patients. Bone lesions associated with metastases are traditionally classified radiologically as either osteolytic or osteoblastic, and both types of lesions are associated with elevated levels of specific bone resorption markers. Some common aspects in the pathophysiology of bone lesions have prompted speculation that treatments for osteolytic metastases might also be effective for predominantly osteoblastic metastases, such as in prostate cancer. Potent osteoclast activity inhibitors, bisphosphonates have been successful in the treatment of osteolytic tumor bone disease. Zoledronic acid is the first bisphosphonate shown to have a direct clinical benefit in the treatment of osteoblastic bone metastases, reducing the number and rate of skeletal events in prostate cancer patients with metastatic bone disease. Moreover, the shorter, more convenient infusion time and similar safety profile of 4 mg zoledronic acid compared with 90 mg pamidronate presently make zoledronic acid the preferred therapy for treatment of bone metastases in patients with all types of advanced malignancy.

Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone-derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.

Less than 25 years ago, tumor-induced hypercalcemia was often a lethal complication of cancer. Nowadays, it can be successfully and easily treated in at least 90% of the cases by rehydration and potent antiosteoclastic bisphosphonates. The standard therapy consists of the administration of 90 mg of pamidronate (Aredia Dry Powder) or more recently, 4 mg of zoledronic acid (Zometa)], which is even more efficient, at least in patients without bone metastases. Recurrent hypercalcemia is nevertheless difficult to control and antibodies against parathyroid-hormone-related protein may prove to be a useful treatment.

The two main therapeutic applications of bisphosphonates are tumour bone disease and osteoporosis. They constitute the standard treatment for cancer hypercalcaemia, and placebo-controlled trials have shown that the prolonged administration of bisphosphonates, such as pamidronate or clodronate, can reduce the frequency of complications from tumour bone disease due to metastatic breast cancer or myeloma by a quarter to one-half. The results obtained with the intravenous route appear to be more impressive and more rapidly obtained than with oral compounds. Both agents can reduce the risk of vertebral, wrist and hip fractures by 30 - 50%, whereas other antiresorptive agents, such as raloxifene (Eli Lilly & Co.) or calcitonin (Unigene Laboratories Inc.), have only been demonstrated to reduce the incidence of vertebral fractures. The short infusion time (4 mg over 15 min) offers a convenient therapy and constitutes the most evident advantage of zoledronic acid, which will improve patients' quality of life. Zoledronic acid has the potential to change the treatment of osteoporosis dramatically.

Introduction: Different bisphosphonates have been shown to increase bone mineral density (BMD) and reduce the risk of fracture in osteoporotic patients. It is unclear how shifting from a treatment with one bisphosphonate to another will influence the evolution of BMD and bone turnover., Methods: In the present study, we followed BMD (DXA, Hologic QDR1000) of the lumbar spine (BMDL) and of the total hip (BMDH), bone alkaline phosphatase (Ostase, Hibritech), and urinary collagen cross links (pyridinoline, deoxypyridinoline, Biorad) in 39 patients treated with IV pamidronate (60 mg/3 months) since at least 2 years and who were shifted to oral alendronate (10 mg/day, n=18) or left to IV pamidronate (n=21) for 2 more years., Results: BMD increased similarly and significantly in both groups after 2 additional years of treatment as compared to baseline (P<0.05, sign test). BMDL: +3.8% in the alendronate group vs +4.1% in the pamidronate group; BMDH: +4.3% in alendronate group vs +3.6% in pamidronate group, There was no significant change in the biological parameters of bone turnover in any group., Conclusion: The increase of BMD with both bisphosphonates in these previously treated patients was as expected after a 2 more years of treatment. Alendronate administration did not induce a larger gain in BMD as compared to cyclic pamidronate. Bone turnover was no longer affected by switching the bisphosphonate treatment.

Background: Tumor-induced osteolysis due to breast carcinoma and myeloma is responsible for a considerable morbidity that severely impairs patients'quality of life. Osteoclast-mediated bone resorption is reported to be increased markedly in patients with tumor bone disease and can be inhibited by bisphosphonate therapy., Methods: The incidence of skeletal complications and the effectiveness of bisphosphonate therapy in patients with breast carcinoma metastatic to bone or in those with myeloma were derived from large-scale, long-term, placebo-controlled trials with clodronate or pamidronate. To the authors' knowledge, there are few studies published to date evaluating the cost-effectiveness of bisphosphonate therapy, and the majority that do exist often are based on models and are applicable only to a particular health care system., Results: From the placebo groups of the above-mentioned trials, one can estimate that approximately 25-40% of the patients with breast carcinoma metastatic to bone will require radiotherapy for bone pain and approximately 17-50% will sustain incident vertebral fractures yearly. The incidence of complications is reported to be lower in myeloma patients. The prolonged administration of bisphosphonates reportedly can reduce the frequency of skeletal-related events by approximately 25-50%. Maximal efficacy appears to have been achieved with the current therapeutic schemes based on monthly intravenous infusions. Beneficial effects appear to be obtained more readily using the intravenous route rather than the oral route. The costs of bisphosphonate therapy appear to be higher than the cost savings from the prevention of skeletal-related events. The costs per quality of life-adjusted year have been estimated to be > $100,000, but more research is needed. Limited data suggest that zoledronic acid will not reduce treatment costs but the short infusion time will lead to substantial time savings for patients and for outpatient oncology facilities., Conclusions: As is the case for many agents used in oncology, bisphosphonates remain a relatively expensive therapy. More studies are needed to evaluate their cost-effectiveness ratio correctly. A ceiling effect has been reached with current therapeutic schemes and tailoring therapy to the individual patient needs to be evaluated correctly to increase therapeutic effectiveness and improve quality of life further without increasing treatment costs., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11139)

Background: Osteoprotegerin (OPG) is a decoy receptor for OPG ligand (OPGL), or receptor activator of NF-kappaB ligand (RANKL). RANKL/RANK interaction is important in terminal differentiation and activation of osteoclasts. In binding to RANKL, OPG blocks differentiation and activation of osteoclasts. AMGN-0007 is a recombinant OPG construct developed as a potential therapeutic agent in the treatment of bone disease., Methods: A randomized, double-blind, double-dummy, active-controlled, single-dose, dose escalation study was conducted to determine the safety and effect on bone resorption of AMGN-0007 in patients with multiple myeloma (n = 28) or breast carcinoma (n = 26) with radiologically confirmed lytic bone lesions. Patients were randomized (3:1 ratio) to receive a single dose of either AMGN-0007 (subcutaneously [SC]) or pamidronate (90 mg intravenously) and were followed for 56 days. Medications or other diseases affecting bone metabolism and chemotherapy within 28 days of dosing were exclusion criteria. Biologic activity of AMGN-0007 was assessed by measurement of the surrogate marker of bone resorption, urinary N-telopeptide of collagen (NTX)., Results: AMGN-0007 caused a rapid, sustained, dose-dependent decrease in NTX/creatinine levels, which was at least comparable to the profile observed with pamidronate. Four serious adverse events were reported, three in breast carcinoma patients: a fracture in the left femur (pamidronate, considered unrelated), extreme fatigue (0.3 mg/kg AMGN-0007, considered unrelated), and congestive heart failure (1.0 mg/kg AMGN-0007, considered by the investigator to be probably related to doxorubicin and radiation therapy); one event occurred in a multiple myeloma patient: Herpes zoster (pamidronate, considered unrelated). Two multiple myeloma patients (1.0 mg/kg AMGN-0007) had albumin-adjusted serum calcium levels of 1.9 mmol/L on Day 8 but without clinical symptoms., Conclusions: A single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid, sustained, and profound decrease of urinary NTX/creatinine in multiple myeloma and breast carcinoma patients. Changes were comparable to those with pamidronate. AMGN-0007 was well tolerated., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11138)

Background: Fragments of collagen type I containing the epitope AHDGGR (CTX) are generated during bone resorption. The aspartyl-glycine (DG) site within CTX is synthesised in the L-aspartyl peptide (alphaL) form, but converts to the age-modified forms L-isoaspartyl peptide (betaL) and D-aspartyl peptide (alphaD) over time. The purpose of the present study was to test the ability of the various CTX forms to identify breast cancer patients with bone metastases and to investigate whether such patients had an altered CTX excretion pattern., Methods: In this cross-sectional study we compared CTX excretion in healthy premenopausal and postmenopausal women with CTX levels in patients with breast cancer. The breast cancer cohort comprised eight hypercalcemic patients with bone metastases (HC+), 100 normocalcemic patients with bone metastases (NC+) and 15 normocalcemic patients without bone metastases (NC-)., Results: In HC+ patients and NC+ patients, the excretion of alphaL CTX was highly increased compared with NC- patients (P < 0.01), with Z scores of 3.4 and 2.0, respectively. The excretion of the age-modified forms (betaL and alphaD CTX) was less increased in HC+ patients and in NC+ patients as compared with NC- patients, with Z scores of 2.2 and 1.0, respectively, for betaL CTX, and of 1.6 and 0.8, respectively, for alphaD CTX., Conclusion: Assays for the various isoforms of CTX have different sensitivities to identify patients affected by bone metastases. The alphaL CTX isoform reflecting resorption of young bone appeared to provide the best differentiation of patients affected by breast cancer-induced bone metastases. In conclusion, patients affected by metastatic bone disease present an altered excretion pattern of CTX isoforms.

In the collagen type I C-telopeptide an aspartyl-glycine site within the sequence AHDGGR is susceptible to molecular rearrangement. In newly synthesized collagen this site is in the native form, denoted alpha L. During aging a spontaneous reaction occurs resulting in three age-modified forms: an isomerized form (beta L) a racemized form (alpha D), and an isomerized/racemized form (beta D). In this study, we measured the urinary excretion of the four forms of C-telopeptides (CTX) in healthy adults and in patients with bone diseases. Levels of all CTX forms were higher in healthy postmenopausal women (P<0.001) compared with premenopausal controls. Levels decreased within 3 days of bisphosphonate treatment indicating that all CTX forms reflect bone resorption. In hyperthyroidism, characterized by a generalized increased bone turnover, native (alpha L) and age-modified (beta L, alpha D and beta D) forms increased to a similar extent compared to controls, resulting in normal ratios between the alpha L and age-modified forms of CTX. Conversely, in Paget's disease and prostate cancer-induced bone metastases, conditions characterized by focal increased bone turnover, alpha L CTX levels were more elevated than those of age-related CTX forms, resulting in increased ratios between native and age-modified CTX. For example, the ratio alpha L/alpha D was increased 7-fold in Paget's disease (P<0.001) and 2-fold in prostate cancer-induced bone metastases (P<0.002). In conclusion, the study suggests that in conditions with a localized alteration in bone turnover the ratio between alpha L CTX and the age-modified forms is significantly elevated. This may provide a new diagnostic and monitoring tool for diseases such as metastatic bone cancer and Paget's disease.

Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.

Although there is a great need for better therapeutic approaches to the patient who presents with a fracture, osteoporotic fractures will remain a condition that is more amenable to prevention than treatment. Hormone replacement therapy (HRT) is still considered by many the mainstay for the prevention and the treatment of posrmenopausal osteoporosis. However, there are several controversies regarding HRT, especially the duration of treatment and the risks/benefits ratio. Recent studies have challenged the assumption that HRT conveys real long-term beneficial effects. Raloxifene or other "selective estrogen receptor modulators" (SERMs) should progressively replace HRT in elderly women. Bisphosphonates have demonstrated a clearcut efficacy in the treatment of osteoporosis. Alendronate and risedronate have been the most extensively studied bisphosphonates under randomized controlled trials conditions. Both agents can reduce the risk of vertebral and hip fractures by one-fourth to one-half. However, oral bisphosphonates are not without gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Intermittent treatments are already in use. Weekly alendronate is as efficient as daily therapy and improves treatment compliance. Newer more potent bisphosphonates, such as oral ibandronate or intravenous zoledronic acid, will allow much less frequent administration. The anti-fracture efficacy of yearly zoledronic acid infusions is thus currently tested. On the other hand, bone-forming agents, such as daily subcutaneous injections of teriparatide (rhPTH 1-34) offer exciting perspectives for the treatment of severe osteoporosis despite the complexity of such therapy.

Bisphosphonates (BPs) are potent inhibitors of osteoclast-mediated bone resorption, and it is well accepted that tumor cells in bone, especially breast cancer and myeloma cells, can stimulate osteoclast formation and activity leading to the release of growth factors or cytokines, which will further stimulate cancer cells' growth and their secretion of osteolytic factors. BPs are now the standard treatment for cancer hypercalcemia, for which a dose of 90 mg of pamidronate or 1500 mg of clodronate is recommended; the former compound is more potent and has a longer lasting effect. Repeated pamidronate infusions exert clinically relevant analgesic effects in more than half of patients with metastatic bone pain. Recent data suggest that non-responding patients should perhaps be treated with higher doses. The optimal dose actually remains to be defined, especially as it is thought that it is probably a function of the disease stage. Regular pamidronate infusions can also achieve a partial objective response according to conventional UICC criteria and they can almost double the objective response rate to chemotherapy. Lifelong administration of oral clodronate to patients with breast cancer metastatic to bone reduces the frequency of morbid skeletal events by more than one-fourth. Two double-blind randomized placebo-controlled trials comparing monthly 90 mg pamidronate infusions to placebo infusions for 1-2 years in addition to hormone or chemotherapy in patients with at least one lytic bone metastasis have shown that the mean skeletal morbidity rate could be reduced by 30-40%. The results obtained with intravenous BPs are generally viewed as better than those obtained with oral clodronate. However, preference can be given to the oral route when BPs are started early in the process of metastatic bone disease in a patient receiving hormone therapy. According to the recently published ASCO guidelines, pamidronate 90 mg i.v. delivered over 2 h every 3-4 weeks can be recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. Furthermore, the ASCO Panel considered it "reasonable" to start i.v. BPs in women with localized pain whose bone scans were abnormal and plain radiographs normal, but not when an abnormal bone scan is asymptomatic. The pertinence of these criteria is discussed below. Because BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. However, criteria to determine whether and for how long an individual patient benefits from their administration are lacking. New biochemical markers of bone resorption might help identify those patients continuing to benefit from therapy. Even better results have been achieved in patients with multiple myeloma, and the general consensus is that BPs should be started as soon as the diagnosis of lytic disease is made in myeloma patients. On the other hand, data are scanty in prostate cancer, but large-scale trials with potent BPs are ongoing or planned in such patients. Similar results to those achieved with pamidronate have been obtained with monthly 6-mg infusions of the newer BP ibandronate in patients with breast cancer metastatic to bone. The tolerance of ibandronate could be better, and the drug has the potential to be administered as a 15- to 30-min infusion. Zoledronate can also be administered safely as a 15-min 4-mg infusion, and large scale phase III trials have just been completed. These newer BPs will simplify the current therapeutic schemes and improve the cost-effectiveness ratio; they also have the potential to improve the therapeutic efficacy, at least in patients with an aggressive osteolytic disease or when given as adjuvant therapy. For that matter, initial data with clodronate indicate that they have the potential to prevent the development of bone metastases, but the use of BPs in the adjuvant setting must still be viewed as experimental.

The key pharmacological action for the clinical use of bisphosphonates lies in the inhibition of osteoclast-mediated bone resorption. Osteoblasts could be other target cells for bisphosphonates. We studied the effects of bisphosphonates on the proliferation and the differentiation of normal human bone trabecular osteoblastic cells (hOB). We tested 4 different compounds: clodronate, pamidronate and 2 newer compounds: ibandronate, a nitrogen-containing bisphosphonate and zoledronate, which is a heterocyclic imidazole compound. Ibandronate and zoledronate stimulated hOB cell proliferation by up to 30% (p<0.05) after 72 h for concentrations ranging from 10(-8) M to 10(-5) M. Clodronate transiently enhanced hOB cell survival after only 24 h (+60%, p<0.001) whereas pamidronate had no effect. Longer time course studies, in presence of fetal calf serum, revealed that cell growth was finally reduced by all 4 bisphosphonates (40% after 7 days). Type I collagen synthesis was transiently increased by all 4 bisphosphonates after only 48 h incubation (+17% to +67%, p<0.05). Clodronate increased ALP activity by up to 1.7-fold after 4 days of culture (p<0.05) whereas ibandronate or zoledronate exhibited lesser stimulatory effects (+17 to +30%), and pamidronate had no significant effect. In conclusion, we found that different bisphosphonates, currently used or tested in various clinical conditions, transiently stimulated the growth of preosteoblastic cells and thereafter increased their differentiation according to sequential events (type I collagen synthesis first, then ALP activity to a lesser extent). Our data suggest that the beneficial effects of bisphosphonate treatment on bone mass and integrity could be partly mediated through a direct action on osteoblasts.

Calcitonin is a powerful inhibitor of osteoclast activity that exerts a rapid, transient, and reversible inhibition of bone resorption. Prolonged administration of parenteral calcitonin, by injections of 100 IU every 1 or 2 days, can prevent postmenopausal or postovariectomy bone loss, and is also able to increase trabecular bone mass among patients presenting an established osteoporosis. Prolonged treatment with calcitonin injections is, however, difficult to maintain over the long run. In addition to the ease of administration compared with the injectable forms, nasal calcitonin is much better tolerated, the side effects being rare and generally negligible. A prolonged administration of 200 IU intranasal calcitonin acutely inhibits parameters of bone resorption and can increase lumbar spine bone mineral density (BMD) by 1.7%-3.3% after 1 year. Lower doses also appear to be efficient to prevent early postmenopausal bone loss, but the data are conflictual. The results are more consistent in patients who already suffer from established osteoporosis. The increase in lumbar spine BMD is in the order of 1%-2% after 1 year with 200 IU daily. A therapeutic benefit of calcitonin at the level of the cortical bone has been less well demonstrated than for the trabecular bone. As for other antiosteoporotic therapies, the effect of calcitonin on the reduction of fracture risk has been examined less than the beneficial effect on trabecular bone mass. Currently, there is still no prospective, placebo-controlled study with a sufficient number of patients that demonstrates that long-term parenteral calcitonin administration reduces the risk of osteoporotic fractures. The efficacy of nasal calcitonin treatment to reduce vertebral fracture rate has been best examined in the PROOF (Prevent Recurrence of Osteoporotic Fractures) study. This was a prospective 5-year, placebo-controlled, dose-response study of nasal calcitonin (100, 200, or 400 IU daily). The increase in lumbar spine BMD was modest but significant and not clearly dose dependent, as was the reduction in bone turnover. The relative risk of developing new vertebral fractures was reduced by 33% at the end of the study in the 200-IU dose group (relative risk = 0.67, 95% CI 0.47-0.97, p = 0.03). There was also a nonsignificant reduction in the risk of hip fracture in this dose group. The doses of 100 and 400 IU of calcitonin also reduced the vertebral fracture risk, but the difference did not reach the classical level of statistical significance. A possible effect of calcitonin to enhance bone quality, which cannot be assessed by routinely available methods, is currently being investigated in a prospective placebo-controlled trial that could provide a rational explanation for these effects of calcitonin on the reduction in the vertebral fracture rate without much increase in bone mass or a marked reduction in bone turnover.

The concept of rehabilitation of cancer patients is based on the relatively recent awareness of the strong interrelations existing between physical, psychological and social aspects of human life. Cancer potentially disrupts all of these primary components of quality of life. The aim of rehabilitation is to promote global physical and psychosocial adjustment by acting at all modifiable levels, namely strengthening individual coping resources through psychotherapy, improving quantity and quality of familial and social support, and restoring optimal physical functioning.

Background: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored., Methods: We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point., Results: There were similar increases in bone mineral density in all the zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent higher than those in the placebo group (P<0.001) and values for the femoral neck that were 3.1 to 3.5 percent higher than those in the placebo group (P<0.001). Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. Myalgia and pyrexia occurred more commonly in the zoledronic acid groups, but treatment-related dropout rates were similar to that in the placebo group., Conclusions: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

The Supportive and Palliative Care Unit of the Institut Jules Bordet officially started its activities in February 1999. Our Unit comprises eight beds (four rooms with one bed each and two rooms with two beds each). We admit advanced cancer patients presenting with severe symptoms whose control is going to require all the expertise of a multidisciplinary team. Whilst these eight beds are identified geographically in the hospital, the team's mobility assures continuity of care for patients who wish to stay in another department. The infrastructure of the Unit and its rooms allow close family members who wish to sleep close to the patients to do so. Otherwise, visits are allowed round the clock, though always with due consideration for patients' comfort. Patients are referred either by a physician working in our Institution (medical oncologist, surgeon, or radiotherapist) or by their family physicians. Less frequently, patients themselves specifically ask to be admitted to our Unit. The activity of the Unit itself during its first year of functioning can be summarized as follows. We admitted 155 advanced cancer patients, for a total number of 210 hospitalizations. Patients were admitted a median of 35 months after their diagnosis and a median of 20 days before death. Stays were generally short (median 11 days). We systematically used quantitative assessment tools (MMSQ, MDAS,EFAT and various VAS) to detect and monitor their symptoms and any complications. The main symptoms on admission were pain, anorexia, asthenia, dyspnea and anxiety/depression. Pain, nausea/vomiting, constipation and cough were controlled in almost all patients, whereas control of asthenia and anorexia was most often insufficient. In 51% of our cases the patients could be discharged home; 40% died in the unit; 4% were transferred to long-term palliative care units and 1% to other units within our Institution (4% were still hospitalized at the time of this analysis).

Tumour-induced hypercalcaemia (TIH) is a frequent complication of advanced cancer but has been rarely reported in patients with malignant melanoma, and its pathogenesis remains unexplored. We studied eight patients with TIH and melanoma. We determined the incidence and pathogenesis of this complication and the effects of bisphosphonate therapy. The incidence of TIH in 751 patients with melanoma was 1.1%. All patients had liver and bone metastases at the time of hypercalcaemia. All patients had osteolytic lesions, most often multiple. The median survival was 30 days (range 4-136 days). After rehydration, the mean (+/- SEM) corrected calcium was 3.42 +/- 0.17 mmol/l. Parathyroid hormone levels were adequately suppressed and vitamin D concentrations were normal. Serum osteocalcin, a marker of bone formation, was low, except in the two patients with renal insufficiency, whereas fasting urinary calcium and hydroxyproline were increased, indicating inhibition of bone formation and stimulation of bone resorption. Increased parathyroid hormone-related protein secretion was noted in only one patient. Three of four patients became normocalcaemic after bisphosphonate therapy for a median duration of 2 weeks. In conclusion, hypercalcaemia is a rare complication of melanoma. It occurs in the context of far advanced disease and is essentially due to aggressive lytic bone metastases with an uncoupling in bone turnover. Bisphosphonates can offer short-term palliation.

The skeleton is the most common site of metastatic disease in breast cancer and the most common site of first distant relapse. Bone metastases in breast cancer are the source of considerable morbidity, including severe pain, pathological fractures, need for radiotherapy or surgery, and hypercalcemia. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and it is well known that breast cancer cells in bone can stimulate osteoclast formation and activity leading to the release of growth factors and cytokines, which will further stimulate cancer cell growth and their secretion of osteolytic factors. We are thus typically dealing with a vicious cycle, as the bone resorption-induced release of growth factors from the bone matrix will stimulate breast cancer cell growth (probably mainly by IGFs) and the production of the osteolytic factor PTHrP (probably mainly by TGF-beta but also by extracellular calcium). Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for osteoclasts. Nitrogen-containing bisphosphonates, such as pamidronate, ibandronate, and zoledronate, interfere with the mevalonate pathway that is crucial to maintain cell membrane integrity. The net result, regardless of the mechanism, is osteoclast apoptosis, notably through the induction of caspase-3. Bisphosphonates are now the standard treatment for cancer hypercalcemia. Repeated bisphosphonate infusions also exert clinically relevant analgesic effects in at least one half of the patients with metastatic bone pain. Most importantly, prolonged administration of bisphosphonates (for at least 1 year) reduces the frequency of morbid skeletal events by 30-40% in breast cancer metastatic to bone and in up to 50% in patients with multiple myeloma. Newer bisphosphonates, such as ibandronate and zoledronate, will simplify the current therapeutic schemes and improve the cost-effectiveness ratio, and they have the potential to improve the therapeutic efficacy, at least in patients with aggressive osteolytic disease or in the adjuvant setting.

Breast cancer is associated frequently with skeletal metastases, which cause significant morbidity. The main mechanism is an increase in osteoclast-mediated bone resorption. We postulated that osteoblasts could be other essential target cells and previously showed that conditioned medium (CM) of breast cancer cells (BCCs) inhibits the proliferation of osteoblast-like cells. In this study, we investigated the effects of BCC-secreted products on osteoprogenitor cells using a clonal fetal human bone marrow stromal preosteoblastic cell line (FHSO-6) that expresses alkaline phosphatase (ALP) activity, type I collagen (COLI), and increased osteocalcin (OC) and osteopontin under treatment with dexamethasone (Dex), 1,25-dihydroxyvitamin D [1,25(OH)2D], or recombinant human bone morphogenetic protein 2 (rhBMP-2). Treatment with MCF-7 CM inhibited FHSO-6 cell survival in a dose-dependent and irreversible manner. Morphological investigation indicated that MCF-7 CM increased both apoptotic and necrotic cell number. MCF-7 CM increased caspases activity and a broad inhibitor of caspase activity (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone [z-VAD-fmk]) partly reversed the CM-induced inhibition of FHSO-6 cell survival. Western blot analyses revealed an increased bax/bcl-2 ratio in MCF-7 CM-treated FHSO-6 cells. MCF-7 cells exhibit FasLigand as membrane-bound protein and as a soluble cytokine in the CM. Deprivation of MCF-7 CM from active FasLigand by saturation with a soluble Fas molecule suppressed the induction of FHSO-6 apoptosis, whereas fibroblast CM, which did not contain FasLigand, only weakly modified FHSO-6 cell survival because of increased cell necrosis. These data indicate that FasLigand secreted by BCCs induces apoptosis and necrosis of human preosteoblastic stromal cells through caspase cascade modulated by the bax and bcl-2 protein level. The induction of apoptosis in human bone marrow stromal cells by BCCs may contribute to the inappropriately low osteoblast reaction and bone formation during tumor-induced osteolysis in bone metastases.

Breast cancers frequently metastasize to bone where they often cause extensive tumor-induced osteoclast-mediated osteolysis. Interleukin-6 (IL-6) and IL-11 are two cytokines exhibiting osteolytic properties through their potent stimulation of osteoclast formation. We investigated the expression of IL-6 and IL-11 in 99 invasive primary breast tumors by immunohistochemistry and in situ hybridization, respectively. We examined their potential as predictive factors for further development of bone metastases. 52/90 (57%) of tumor samples showed IL-6 cytoplasmic immunostaining. There was no significant association between IL-6 status and any of the classical prognostic factors. 15/89 (17%) of the tumor samples expressed IL-11 mRNA. A positive IL-11 mRNA status was associated with a low tumor grade (P=0.05). Tumors expressing IL-11 mRNA had a statistically significant (P=0.002) higher rate of bone metastases occurrence (12/15, 80%) than IL-11 negative tumors (27/74, 37%). Such association was not found for IL-6. Our findings demonstrate for the first time IL-11 gene expression in some primary invasive breast tumors and suggest the potential of this cytokine as possible biological predictive factor for the development of bone metastases.

The bisphosphonates pamidronate and clodronate are most often used in oncology. Newer, more potent compounds under study are ibandronate and zoledronate. The main route of administration is by intravenous infusion (1-2 hours for pamidronate) but oral formulations are or soon will be available for some bisphosphonates (clodronate, ibandronate) and shorter infusion times are being studied (zoledronate, ibandronate). After oral administration of aminobisphosphonates, the main adverse event can be epigastric pain and esophagitis for which the current recommendations include swallowing 180 to 240 mL of water and remaining upright for 30 minutes after tablet ingestion. After intravenous administration, the main adverse events are injection site reaction and flu-like syndrome. Injection site reactions are seen in up to 6% of patients given pamidronate, and this figure is likely to be lower with ibandronate and zoledronate. Flu-like syndrome is seen in up to one third of patients given pamidronate, less with ibandronate, and no figure is yet available for zoledronate. Adverse effects on kidney function were only seen when using a high dose of zoledronate (8 mg over 5-15 minutes) and the current recommended dose is 4 mg given as a 15-minute infusion. Disadvantages of the oral route are poor absorption (<5%) and occasional digestive side effects. With protracted use the size and number of tablets required can reduce compliance. The advantage of oral administration is use on an outpatient basis and it may thus be the preferred route for patients on hormonal therapy and in the adjuvant setting. The main route of administration, however, is currently a 1- to 2-hour intravenous pamidronate infusion, often preferred for patients receiving chemotherapy. The disadvantage of the latter is the need for an appropriate hospital environment. Shorter infusion times are being studied with newer compounds. Intravenous administration is the preferred route for patients receiving chemotherapy. Equivalent intravenous doses to achieve similar success rates in normalizing serum calcium levels are approximately 90 mg, 4 mg, and 2 mg for pamidronate, ibandronate, and zoledronate, respectively. The expectation from the new, more potent compounds is for more convenient therapeutic schemes leading to increased patient compliance and improvements in the reduction of the skeletal morbidity rate and hopefully increase in survival rate., (Copyright 2001 by W.B. Saunders Company.)

We give an overview of the available medical solutions to help a patient with refractory symptoms at the end of his life. Patient "competence" must first be evaluated and, even if their diagnosis is difficult, organic mental disorders and depression must be diagnosed and adequately treated to allow a real, personal and honest dialog. Administration of high doses of morphine is frequently used at the end of life not only to fully relieve pain but also to accelerate death, even if this is not clearly stated. This technique is not devoid of hypocrisy and high doses of morphine can have quite unpleasant side effects. Treatment withdrawal or withholding is generally not sufficient to allow a correct end of life. The arrest of ventilation, dialysis, artificial nutrition and even more hydration must often be coupled with techniques inducing unconsciousness, which makes imprecise the limits between such a "passive" ending of life and "active" euthanasia. The technique of terminal sedation, frequently based on the use of midazolam, has been more recently introduced in some palliative care units. Such a "controlled sedation" is supposed to allow a "natural" death by inducing a profound sleep. In opposition with active euthanasia, which allows a quiet and rapid death at a moment chosen by the patient himself, this technique of "sedation" has an undetermined duration, has legal implications which could be viewed as quite similar as the ones of euthanasia, and, moreover, this prolonged agony can be extremely stressful and distressing for the family. Medical-assisted suicide is allowed in The Netherlands under the same conditions as euthanasia. Death is generally obtained after a few hours but the technique is not always successful and the process of death can sometimes be prolonged and uncomfortable. This technique can nevertheless be preferred by some physicians and patients. As compared to active euthanasia, the proportion of medically-assisted suicides (1/6) is low in The Netherlands. Euthanasia is the only technique able to induce a peaceful and rapid death. The proportion of various techniques to actively induce death is probably quite similar in our country than in The Netherlands but, most of the time, these interventions occur at the very end of life when the patient is no longer able to participate in the decision process and thus occur without his explicit request. We think that, as for all medical decisions, the use of one or the other of these various techniques should be selected after a quiet and free discussion between the patient and his physician, preferably in advance and not in a situation of emergency and panic.

Breast cancer frequently spreads to bone and is almost always associated with osteolysis. This tumor-induced osteolysis is caused by increased osteoclastic bone resorption. Bisphosphonates are used successfully to inhibit bone resorption in tumor bone disease and may prevent development of new osteolytic lesions. The classical view is that bisphosphonates only act on bone cells. We investigated their effects on breast cancer cells using three human cell lines, namely, MCF-7, T47D, and MDA.MB.231, and we tested four structurally different bisphosphonates: clodronate, pamidronate, ibandronate, and zoledronate. We performed time course studies for each bisphosphonate at various concentrations and found that all four compounds induced a nonreversible growth inhibition in both MCF-7 and T47D cell lines in a time- and dose-dependent manner. The MDA.MB.231 cell line was less responsive. Bisphosphonates induced apoptosis in MCF-7 and cell necrosis in T47D cells. The inhibition of MCF-7 cell proliferation could be reverted almost completely by the benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk) inhibitor of caspases, suggesting that the apoptotic process observed in the MCF-7 cell line is mediated, at least partly, by the caspase system. Caspase activity was little changed by bisphosphonates in T47D cells and the inhibitor of caspase did not modify bisphosphonates effects. In summary, we found that bisphosphonates inhibit breast cancer cell growth by inducing cell death in vitro. Such effects could contribute to the beneficial role of bisphosphonates in the treatment and the prevention of tumor-induced osteolysis.

Bisphosphonates are now the standard treatment for tumor-induced hypercalcemia (TIH), and pamidronate can normalize serum Ca in at least 90% of the patients treated for the first time. However, there are few data on the treatment of TIH when it recurs, and published results are contradictory. We studied 29 patients with solid tumors, 14 of whom had breast cancer and all of whom were naive to bisphosphonate therapy. They were retreated with pamidronate (median dose 1 mg/kg for both courses) for recurrence of TIH after a median interval of 78 (range 7-297) days. Fourteen of them, 7 of whom had breast cancer, were treated a third time 28 (range 5-79) days after the second course (median dose of pamidronate 1.5 mg/kg). Baseline Ca levels were not significantly different before each course, but the nadirs after each treatment progressively increased, 9.3 +/- 0.2 mg/dl, 10.5 +/- 0.3 mg/dl, and 12.3 +/- 0.4 mg/dl after the 1st, 2nd and 3rd administrations, respectively (P<0.05). The percentage of treatment failures also progressively increased: 10%, 31% and 85% (P< 0.05). This decreased hypocalcemic effect was essentially observed in patients without bone metastases or with tumors other than breast cancer. Thus, in patients without bone metastases, Ca levels did not decrease at all after the 3rd course, whereas the responses were not significantly different between the three courses in patients with bone metastases. Baseline urinary hydroxyproline, a marker of bone resorption, increased progressively from course to course, especially in patients with bone metastases or breast cancer, but this was not the case for parameters of bone formation. There was also a progressive increase in PTHrP levels accompanied by an increase in the number of patients with enhanced kidney reabsorption of Ca and a decrease in the threshold for Pi excretion, which was significant in patients without bone metastases. In conclusion, pamidronate was progressively less efficient when hypercalcemia recurred. This was observed mainly in patients with hypercalcemia of humoral origin. Tumor progression is accompanied by an enhanced release of osteolytic factors, notably PTHrP, that increase bone resorption and enhance kidney calcium reabsorption, especially in patients without bone metastases. When both phenomena occur, the response to bisphosphonates becomes minimal and the usefulness of therapy questionable.

The occurrence of undesirable side effects due to opioids (delirium, confusion, myoclonus, nausea, emesis) is one of the major complications in the management of pain, especially in chronic cancer pain states. Methadone, as an alternative to morphine, has been proposed in the control of opioid-induced toxicity. Methadone is a synthetic opioid, with mu and delta receptor activity, associated with the capacity to inhibit N-methyl-D-aspartate receptors. Questions have arisen concerning its equianalgesic ratio since its rediscovery over the past few years and are certainly related to its receptor interactions. Aspects of its pharmacology, indications, and switching modalities are discussed here. Opioid rotation is a new tool in the management of cancer pain, deserving more attention.

Background: Tumor-induced hypercalcemia (TIH) is essentially due to a marked stimulation of osteoclast-mediated bone resorption. An inhibition of bone formation and an enhanced tubular reabsorption of calcium play an important contributory role. These factors explain why serum calcium often rises rapidly in cancer patients and why high doses of bisphosphonates are needed to normalize bone resorption and to overcome the contributory role of the kidney., Methods: The author provides a short review of clinical trials in hypercalcemic cancer patients, with an emphasis on the most recent trials., Results: Rehydration and bisphosphonates now constitute the standard treatment of TIH. A single-day 1500-mg infusion of clodronate achieves normocalcemia in approximately 80% of the cases. Clodronate also can be given by subcutaneous infusion that can be particularly useful in the palliative setting. A dose of 90 mg of pamidronate achieves normocalcemia in more than 90% of the patients and has a longer-lasting effect than clodronate. Newer more potent bisphosphonates, such as ibandronate and zoledronate, may improve these results, and they certainly will simplify the therapeutic schemes. Ibandronate at the dose of 6 mg normalizes serum calcium in more than 75% of the patients with moderate or severe hypercalcemia. Of note, the same doses of pamidronate and ibandronate, repeated monthly for 1-2 years, have been shown to substantially reduce the skeletal morbidity rate in normocalcemic patients with tumor bone disease. Even lower doses of zoledronate, the most potent bisphosphonate tested so far, are able to correct TIH when administered as a 30-minute infusion., Conclusions: Bisphosphonates have become the standard treatment for cancer hypercalcemia. Success is achieved in more than 90% of the cases. Other classes of compounds are being tested for their antiosteoclastic activity, and animal studies suggest that osteoprotegerin could be as efficient and act faster than bisphosphonates.

The frequency of hyponatraemia varies from less than 1% to more than 40% in series reported from general hospitals. We performed a prospective study to evaluate its incidence and to determine the types of hyponatraemia in a dedicated cancer hospital. All patients admitted to the Department of Medicine were prospectively studied over 11 months. Hyponatraemia was defined as a serum Na level < or =130 mEq/l. Urine and blood samples were collected at baseline, and all consecutive hyponatraemic episodes were studied. One hundred and six patients developed 123 episodes of hyponatraemia. The observed incidence of hyponatraemia was 3.7%. Sodium depletion and syndrome of inappropriate antidiuretic hormone secretion (SIADH) each accounted for almost one third of all aetiologies. Serum urea and uric acid, urinary Na and fractional excretions of Na and urea were most useful for the differential diagnosis. The percentage of deaths observed in the hyponatraemic group, 19.5%, was higher than in the whole cancer population (6.3%) although no death was apparently due directly to hyponatraemia. Hyponatraemia is regularly diagnosed in cancer patients, but it was related to SIADH in only about one third of the cases. A higher mortality was observed in hyponatraemic patients than in normonatraemic patients.

Osteoporosis is now considered as a major public health issue and a serious threat for the quality of life of elderly women. Several new compounds are currently marketed for the prevention and treatment of involutional osteoporosis in women. Therefore, it is important to offer to the practitioners pragmatic solutions to be used for the rational management of this disorder. This article is the result of a national consensus offering practical guidelines for the management of osteoporotic patients, based on the current published data.

Breast cancer cells (BCC) frequently metastasize to bone where they may cause tumor-induced osteolysis (TIO). While the important eroding role of the osteoclasts in TIO is well admitted, the possibility that BCC and/or osteoblasts activated by tumoral factors could also directly degrade bone matrix in this pathology has been much less investigated. We show here that the net collagen amount produced in vitro by normal human osteoblasts and osteoblast-like cells was significantly reduced by culture medium conditioned by several BCC lines, including three newly isolated ones. There was no evidence for a decrease in collagen synthesis, as assessed by the production of the carboxyterminal propeptide of type I collagen. In contrast, the effect of BCC-derived medium on collagen amount was attenuated by inhibitors of matrix metalloproteinases (MMPs) as well as by tranexamic acid, an inhibitor of the plasminogen conversion to plasmin, while it was abolished in presence of the two kinds of proteinase inhibitors. This osteoblastic protein degradation activity appeared to be attributable to factors secreted by the osteoblasts as well as by BCC. These factors had molecular weights lower as well as higher than 10 kD. Our data suggest that besides the eroding action of osteoclasts, BCC- and osteoblast-derived MMPs and serine proteinases might play a direct role in bone collagen degradation in TIO.

The prevention of osteoporotic fractures in post-menopausal women must be viewed in the framework of the treatment of menopause. SERMs ("Selective Estrogen Receptor Modulators") derivative from steroid hormones have estrogenic and antiestrogenic properties according to the substance and the target tissue. Raloxifene is a second generation SERM. It increases bone mass by 1 to 3% according to the measured site and, after 3 years of therapy at the dose of 60 mg per day, it reduces the incidence of vertebral fractures by 30 to 50% if patients have or do not have vertebral fractures before therapy. This drug is approved for the prevention of vertebral fractures in post-menopausal women at increased risk of fractures. A significant reduction in the incidence of hip fractures has not been demonstrated. Raloxifene exerts favorable effects on cardiovascular risk factors but one has to wait for the results of controlled prospective trials before concluding that raloxifene reduces the risk of atherogeniec disease. Preliminary results indicate a substantial reduction of the risk of invasive breast cancer, still to be confirmed. The incidence of vaginal bleeding does not differ from placebo as raloxifene does not stimulate endometrial proliferation. The most serious adverse event, although infrequent, consists in an increase of the relative risk of thromboembolic disease by 3.1 as compared to placebo. Longer term studies are necessary to compare raloxifene with the estrogen replacement therapy and to determine the extra-bone effects.

The objective of this study was to determine the calcitonin (CT) hormone reserve in different severity of atrophic autoimmune thyroiditis (AAT). Forty-eight female patients with AAT were divided into four groups based on basal and peak thyrotropin (TSH) values (after oral thyrotropin-releasing hormone [TRH], free triiodothyronine (FT3) and free thyroxine (FT4) ranging from normal in group 1 to overt hypothyroidism in group 4. All had thyroid antibodies. The control group comprised euthyroid females of comparable age, without thyroid antibodies. Basal CT and CT response to calcium infusion (area under the curve) were investigated as parameters of CT reserve. Basal CT was lower in groups 2 to 4 of patients with AAT (compared to controls), but the difference was not significant. Stimulated CT levels were lower (p < 0.05) in all groups of patients compared to controls, with markedly reduced CT-secretory reserve in group 4. Thyroid antibody concentrations and, basal and postinfusion calcium levels were not significantly different among the various groups. In conclusion CT deficiency (especially stimulated values) occurs in AAT and is more severe in hypothyroid patients than in earlier stages of AAT.

The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca). To evaluate the prevalence of an increased renal tubular reabsorption of Ca index [tubular reabsorption of calcium index (TRCaI)] in cancer patients with hypercalcemia and of elevated circulating levels of PTH-related protein (PTHrP), which is recognized as a major mediator of this syndrome, we investigated 315 well rehydrated patients, aged 58.1 +/- 0.7 yr (mean +/- SEM), with hypercalcemia [albumin-corrected plasma Ca (pCa), >2.7 mmol/L] secondary to histologically proven malignancy. Changes in pCa and, therefore, various Ca filtered loads were obtained by different degrees of bone resorption inhibition achieved with a single infusion of the bisphosphonate ibandronate, given at various doses on a randomized, double blind basis. PTHrP was determined at baseline in 147 of the patients and 7 days after bisphosphonate therapy in 73. Before ibandronate therapy, pCa was 3.36 +/- 0.02 mmol/L, mean TRCaI was increased at 3.09 +/- 0.03 mmol/L glomerular filtration rate (GFR; normal, 2.40-2.90), and 65% of patients had TRCaI above 2.90 mmol/L GFR. Mean serum PTHrP levels were 4.9 +/- 0.5 pmol/L (normal, <2.5) and values above the normal range were found in 53% of the patients (76% in lung and upper respiratory tract malignancies). By 7 days after the infusion of ibandronate, a decrease in pCa of 0.69 +/- 0.03 mmol/L (20.0 +/- 0.7%; P < 0.001) and in bone resorption [mean change in fasting urinary Ca, 0.09 +/- 0.04 mmol/L GFR (47.6 +/- 8.6%; P < 0.001) and 14.4 +/- 1.7 nmol/mmol (27.6 +/- 10.6%; P < 0.01) in deoxypyridinoline] was observed. TRCaI was slightly lowered by 0.30 +/- 0.09 mmol/L GFR. Mean changes in PTHrP, 1,25-dihydroxyvitamin D3, and PTH were +0.7 +/- 0.4 (P = NS), +27.6 +/- 3.0 (P < 0.001), and +2.9 +/- 0.8 (P < 0.005) pmol/L, respectively. After ibandronate treatment, the relative risk of relapsing hypercalcemia was particularly increased (3.43-fold) in lung and upper respiratory tract malignancies. These results obtained in a large cohort of patients indicate a significant prevalence of an increased renal tubular reabsorption of calcium index in hypercalcemia of malignancy and a substantial proportion of patients with detectable PTHrP.

Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels >/=2.75 mmol/l). Based on estimates of potency, the starting dose was 0.002 mg/kg, and further tested doses were 0. 005, 0.01, 0.02, and 0.04 mg/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dose levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68-100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32-39 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0.04 mg/kg, i. e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.

Some epidemiological studies have suggested that aspirin could be a chemopreventive agent against breast cancer. We tested the effects of the aspirin metabolite salicylate (SA) on four (Hs578T, MCF-7, MDA-MB-231, and T-47D) breast cancer cell (BCC) lines in vitro. Two features were studied: the proliferation of BCC and their production of the osteolytic cytokines interleukins-6 (IL-6) and -11 (IL-11) since BCC frequently metastasize to bone and induce tumor-induced osteolysis. SA, from 0.5 to 5 mM, caused BCC growth inhibition by up to 70% (IC50 range 2.54 to 4.28 mM). At high concentrations, the drug induced apoptosis only (MDA-MB-231), or both apoptosis and primary necrosis (MCF-7). SA, as well as indomethacin (INDO), reduced the synthesis of IL-6 and -11, at both the protein and mRNA levels, in the two cell lines producing these cytokines (MDA-MB-231 and Hs578T). This latter effect seemed to be mediated by PGE2 since SA and INDO reduced PGE2 levels in MDA-MB-231 and Hs578T cells, PGE2 was not detected in MCF-7 and T-47D cells and exogenous PGE2 increased IL-6 and -11 expression by MDA-MB-231 cells. Collectively, our results suggest that SA could reduce the growth of breast tumors and inhibit to some extent the ability of BCC to induce osteoclast recruitment and osteolysis. These data indicate the need for further epidemiological and experimental studies.

Cancer anorexia/cachexia is a major clinical problem, especially in advanced cancer patients. Its pathogenesis is quite complex. Anorexia plays a central role, but cancer cachexia is more complex than pure chronic starvation. One of the key differences is the preferential mobilization of fat and the sparing of skeletal muscle in simple starvation compared with an equal mobilization of fat and skeletal muscle in cancer patients. An increase in basal energy expenditures seems to play a contributory role in many patients. Cytokines, essentially but not exclusively tumor necrosis factor alpha, play an essential role, and the syndrome can be compared with a low-grade chronic inflammatory state. As it is in most fields in medicine, prevention is more efficacious than treatment, and, to avoid the final and dramatic stages of cancer cachexia, adequate nutritional advice and support must be provided sufficiently early. Parenteral nutrition could facilitate the administration of complete doses of chemotherapy or radiotherapy, but no significant survival benefit or decrease in treatment-induced toxicity have ever been demonstrated in prospective randomized trials. The gut should always be used if at all possible. Percutaneous endoscopic gastrostomy is used increasingly in patients who cannot eat but who have functionally intact gastrointestinal tracts, especially in patients with head and neck cancer. Eight randomized, double-blind, placebo-controlled studies have demonstrated that progestational drugs can somewhat stimulate appetite, food intake, and energy level; increase weight in many patients; and often decrease nausea and vomiting severity; however, pharmacologic treatment of cancer cachexia remains disappointing, and more trials with anticytokine drugs should be conducted.

The pathogenesis of cancer anorexia/cachexia is still unclear, partly explaining why its treatment remains disappointing. Anorexia plays a central role but cancer cachexia is more complex than chronic starvation. One of the key differences is the preferential mobilization of fat and the sparing of skeletal muscle in simple starvation compared to an equal mobilization of fat and skeletal muscle in cancer patients. An increase in basal energy expenditure also appears to play a contributory role in many patients. Cytokines, essentially but not exclusively tumor necrosis factor-alpha, play an essential pathogenic role and the syndrome can be compared to a low grade chronic inflammatory state. Parenteral nutrition could facilitate the administration of complete doses of chemotherapy or radiotherapy but no significant survival benefit or decrease in treatment-induced toxicity have been demonstrated in prospective randomized trials. The gut should have the preference for nutritional support. Percutaneous endoscopic gastrostomy is used more and more often in patients with a functionally intact gastrointestinal tract, especially in patients with head and neck cancer. Progestational drugs can to some extent stimulate appetite, food intake, energy level, increase weight and decrease the severity of nausea and vomiting. However, pharmacological treatment of cancer cachexia remains disappointing and more trials with anticytokine drugs, anabolic agents or polyunsaturated fatty acids should be conducted.

Dyspnea, which has been defined as an "uncomfortable awareness of breathing," is a frequent and devastating symptom in advanced cancer patients. It has been reported to occur in 21-79% of patients evaluated a few days or weeks before death. In advanced cancer, the aim of effective management is to minimize the patient's perception of breathlessness, which depends in turn on a reliable assessment. Unfortunately, most of our knowledge and experience of dyspnea has been acquired through working with patients with chronic pulmonary disease, and there is a dearth of literature relating specifically to the assessment of dyspnea in advanced cancer. Dyspnea is a complex sensation including several dimensions, such as antecedents (physiological and psychological events or stimuli preceding the development of dyspnea), mediators (characteristics of individuals or their environment affecting the response), reactions to dyspnea, and consequences or outcomes that result once the individual has reacted to a stimulus. The literature gives us many tools to measure these aspects. For example, antecedents may be assessed by the British Medical Research Council Questionnaire, the American Thoracic Questionnaire (ATS-DLD-78) and the Dyspnea Interview Schedule. Mediators of dyspnea may be measured by the ATS-DLD-78, the Chronic Respiratory Questionnaire (CRQ), the Dyspnea Interview Schedule, the Pulmonary Functional Status Scale (PFSS) and the Therapy Impact Questionnaire (TIQ). Reactions to dyspnea may be assessed by the Dyspnea Visual Analogue Scale (DVAS), the TIQ and the Borg Scale, and the consequences of it by the TIQ, the Baseline Dyspnea Index (BDI), the Transition Dyspnea Index (TDI), and CRQ, and by the Oxygen Cost Diagram (OCD), the Dyspnea Interview Schedule and the Modified Medical Research Council Dyspnea Scale (MRC). No single assessment tool considers all the different components of dyspnea, and the final choice will depend on the purpose of the assessment, taking into account that the provision of quality of life is of paramount importance to patients who have limited time left to them and that the assessment should not therefore detract from the quality of life by being overlong, complicated or invasive.

Purpose: The purpose of this article is to review the recent data on bisphosphonate use in oncology and to provide some guidelines on the indications for their use in cancer patients., Design: The group consensus reached by experts on the rationale for the use of bisphosphonates in cancer patients and their current indications for the treatment of tumor-induced hypercalcemia and metastatic bone pain in advanced disease and for the prevention of the complications of multiple myeloma and of metastatic bone disease are reviewed., Results: Bisphosphonates are potent inhibitors of tumor-induced osteoclast-mediated bone resorption. They now constitute the standard treatment for cancer hypercalcemia, for which we recommend a dose of 1,500 mg of clodronate or 90 mg of pamidronate; the latter compound is more potent and has a longer lasting effect. Intravenous bisphosphonates exert clinically relevant analgesic effects in patients with metastatic bone pain. Regular pamidronate infusions can also achieve a partial objective response by conventional International Union Against Cancer criteria and enhance the objective response rate to chemotherapy. In breast cancer, the prolonged administration of oral clodronate 1,600 mg daily reduces the frequency of morbid skeletal events by more than one fourth, whereas monthly pamidronate infusions of 90 mg for only 1 year in addition to chemotherapy reduce by more than one third the frequency of all skeletal-related events. The use of bisphosphonates to prevent bone metastases remains experimental. Last, bisphosphonates in addition to chemotherapy are superior to chemotherapy alone in patients with stages II and III multiple myeloma and can reduce the skeletal morbidity rate by approximately one half., Conclusion: Bisphosphonate use is a major therapeutic advance in the management of the skeletal morbidity caused by metastatic breast cancer or multiple myeloma, although many questions remain unanswered, notably regarding the optimal selection of patients and the duration of treatment.