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Our imminent model was less sensitive but more selective than FRAX® in the choice of treatment to prevent imminent fractures. This new model decreased NNT by 30%, which could reduce the treatment costs. In the Belgian FRISBEE cohort, the effect of recency further decreased the selectivity of FRAX®., Purpose: We analyzed the selection for treatment of patients at high risk of fracture by the Belgian FRISBEE imminent model and the FRAX® tool., Methods: We identified in the FRISBEE cohort subjects who sustained an incident MOF (mean age 76.5 ± 6.8 years). We calculated their estimated 10-year risk of fracture using FRAX® before and after adjustment for recency and the 2-year probability of fracture using the FRISBEE model., Results: After 6.8 years of follow-up, we validated 480 incident and 54 imminent MOFs. Of the subjects who had an imminent fracture, 94.0% had a fracture risk estimated above 20% by the FRAX® before correction for recency and 98.1% after adjustment, with a specificity of 20.2% and 5.9%, respectively. The sensitivity and specificity of the FRISBEE model at 2 years were 72.2% and 55.4%, respectively, for a threshold of 10%. For these thresholds, 47.3% of the patients were identified at high risk in both models before the correction, and 17.2% of them had an imminent MOF. The adjustment for recency did not change this selection. Before the correction, 34.2% of patients were selected for treatment by FRAX® only, and 18.8% would have had an imminent MOF. This percentage increased to 47% after the adjustment for recency, but only 6% of those would suffer a MOF within 2 years., Conclusion: In our Belgian FRISBEE cohort, the imminent model was less sensitive but more selective in the selection of subjects in whom an imminent fracture should be prevented, resulting in a lower NNT. The correction for recency in this elderly population further decreased the selectivity of FRAX®. These data should be validated in additional cohorts before using them in everyday practice., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

This study showed additional clinical risk factors for the occurrence of multiple fractures with regards to a single fracture, with often higher hazard ratios. It would be important to include the risk of the occurrence of multiple fractures in future prediction models., Purpose: To identify clinical risk factors (CRFs) which would specifically increase the risk of multiple fractures., Methods: Data of the 3560 postmenopausal women of the FRISBEE study were analysed. The CRFs and the fractures are collected annually. The cohort was divided into three groups: those who had no incident fracture, those who had a single incident fracture and those who had 2 two or more incident fractures (i.e. multiple fractures). Statistical analyses were performed using Cox proportional hazards models., Results: Among the 3560 subjects (followed for 9.1 (7.2-10.6) years), 261 subjects had two or more validated fractures during follow-up (146 were major osteoporotic fractures (MOFs)), 628 had one fracture (435 MOFs), 2671 had no fracture (2979 had no MOF); 157 subjects had two or more central fractures, 389 had only one and 3014 had none. The risk factors for those with multiple fractures at any site were age, history of fracture, history of fall, total hip bone mineral density (BMD), spine BMD and rheumatoid arthritis. For those with multiple MOFs, significant CRFs were age, history of fracture, parental hip fracture, total hip BMD and rheumatoid arthritis., Conclusion: We found in a prospective cohort study that there were more CRFs and higher hazard ratios for the occurrence of multiple fractures than for a single fracture., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Multiple factors increase the risk of an imminent fracture, including a recent fracture, older age, osteoporosis, comorbidities, and the fracture site. These findings could be a first step in the development of a model to predict an imminent fracture and select patients most at need of immediate treatment., Introduction: The risk of a recurrent fragility fracture is maximal during the first 2 years following an incident fracture. In this prospective cohort study, we looked at the incidence of recurrent fractures within 2 years after a first incident fracture and we assessed independent clinical risk factors (CRFs) increasing this imminent fracture risk., Methods: A total of 3560 postmenopausal women recruited from 2007 to 2013 were surveyed yearly for the occurrence of fragility fractures. We identified patients who sustained a fracture during the first 2 years following a first incident fragility fracture. We quantified the risk of a new fracture and assessed independent CRFs, associated with an imminent fracture at various sites., Results: A recent fracture was a significant CRF for an imminent fracture (OR (95% CI): 3.7 (2.4-5.7) [p < 0.0001]). The incidence of an imminent fracture was higher in subjects above 80 years (p < 0.001). Other CRFs highly predictive in a multivariate analysis were osteoporosis diagnosis (p < 0.01), a central fracture as the index fracture (p < 0.01), and the presence of comorbidities (p < 0.05), with likelihood ratios of 1.9, 1.9, and 2.2, respectively. An imminent fracture was better predicted by a central fracture (p < 0.01) than by a major osteoporotic fracture. The hazard ratio was the highest for a central fracture., Conclusion: In patients with a recent fracture, older age, osteoporosis, comorbidities, and fracture site were associated with an imminent fracture risk. These findings could be a first step in the development of a model to predict an imminent fracture and select patients most at need of immediate and most appropriate treatment.

FRAX ® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX ® -defined MOF compared with those treated with risedronate., Introduction: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX ® -defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures., Methods: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX ® -defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval., Results: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX ® -defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX ® -defined MOF sites. The largest difference in incidence rates of both FRAX ® -defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed., Conclusion: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX ® -defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment., Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Despite the availability of efficient drugs to prevent osteoporotic fractures, only a minority of women receives osteoporosis therapy after a fracture. The high treatment gap in our cohort consisted of unselected volunteer patients highlights the urgent need of additional education, especially for the medical profession, regarding the risk-benefit balance of treatment., Introduction: Despite the availability of efficient drugs to prevent osteoporotic fractures, only a minority of women receives osteoporosis therapy after a fracture, with a treatment gap around 80%. This can have dramatic consequences for patients and the healthcare systems., Methods: In this study based on longitudinal data from the FRISBEE (Fracture RIsk Brussels Epidemiological Enquiry) cohort of 3560 volunteer women aged 60 to 85 years, we evaluated the 1-year treatment gap after a first major incident fragility fracture., Results: There were 386 first validated fragility fractures, 285 major osteoporotic fractures (MOF) and 101 "other major" fractures. The rate of untreated patients was 85.0% (82.8% for MOF versus 91.0 % for "other major" fracture sites) (p = 0.04), with a lower rate for spine (70.5%) and hip (72.5%) versus shoulder (91.6%) and wrist (94.1%) (p < 0.0001). More specifically, the treatment gap for patients with osteoporosis, defined by a T-score < - 2.5 SD was 74.6% versus 76.5% for patients with osteoporosis defined by the presence of hip, shoulder, or spine fractures, independently of DXA results. When considering age groups, the rate of untreated women was 87.9% for women 60-70 years old, 88.2% between 70 and 80 years and 77.8% above 80 years (p = 0.03), with a greater difference between women who were younger or older than 80 years at inclusion: 88.1% versus 77.8% (p = 0.009). A diagnosis of osteoporosis (p = 0.01) and age (p = 0.03) were the only clinical risk factors (CRFs) significantly associated with treatment initiation., Conclusions: This study highlights the urgent need of additional education, especially for the medical profession, regarding the risk-benefit balance of treatment.

Introduction: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing., Objective: To review characteristics of ONJ in cancer patients receiving non-antiresorptives., Methods: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO., Results: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications., Conclusions: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for patients with some malignant and non-malignant hematological diseases. Advances in transplantation techniques and supportive care measures have substantially increased the number of long-term HSCT survivors. This has led to an increasing patient population suffering from the late effects of HSCT, of which, bone loss and its consequent fragility fractures lead to substantial morbidity. Altered bone health, with consequent fragility fractures, and chronic graft-versus-host disease (GVHD) are factors affecting long-term quality of life after HSCT. Hypogonadism, HSCT preparative regimens, nutritional factors, and glucocorticoids all contribute to accelerated bone loss and increased fracture risk. Management strategies should include bone mineral density examination, evaluation of clinical risk factors, and general dietary and physical activity measures. Evidence has accumulated permitting recommendations for more attentiveness to evaluation and monitoring of bone health, with appropriate application of osteoporosis pharmacotherapies to patients at increased risk of bone loss and fracture.

Purpose: Denosumab (administered via subcutaneous injection) demonstrated superior efficacy versus the intravenously administered zoledronic acid in the prevention of skeletal-related events in an integrated analysis of three head-to-head phase III trials in patients with bone metastases secondary to solid tumors. To date, no studies have evaluated treatment administration duration endpoints of these two agents., Methods: A multinational, multi-site, observational time and motion study conducted in 10 day oncology units (DOUs) across Belgium, Germany, and Italy. Observations of process time included task time and active healthcare professional (HCP) time for pre-defined tasks. Patient time measurements included entering/exiting the DOU, treatment room, and treatment chair or examination table., Results: A total of 189 patients were enrolled (82 received zoledronic acid and 107 received denosumab) and 238 observations were recorded (104 for zoledronic acid and 134 for denosumab). Mean total task time was reduced by 81% when denosumab was used versus zoledronic acid (8.4 versus 44.2 min; p < 0.0001; pooled analysis across all countries). Pooled estimates for active HCP time were 12.2 min for zoledronic acid and 6.9 min for denosumab (44% reduction; p < 0.0001)., Conclusions: In the countries studied, using denosumab compared with zoledronic acid reduced total task time and active HCP time. Thus, HCPs have more time to dedicate to other patients or care activities. An ability to increase the volume of appointments within DOUs could reduce waiting lists in sites operating at full capacity and increase overall productivity and efficiency in hospital processes.

Calcium Metabolism in Cancer and Hypercalcaemia of Malignancy: The balance between bone formation and resorption may be disrupted in patients with cancer, leading either to increased bone resorption, calcium release, and possibly hypercalcaemia, or to increased bone formation, sequestration of calcium, and possibly hypocalcaemia. In adults, hypercalcaemia of malignancy is most common in patients with tumours that produce factors that induce osteoclast activation and enhance bone resorption. Impaired renal function and increased renal tubular calcium resorption may further affect calcium levels., Treatment of Hypercalcaemia of Malignancy: Inhibitors of bone resorption, first the bisphosphonates and, later, denosumab, have been shown to be effective in hypercalcaemia treatment. Bisphosphonates (which are administered intravenously) are approved for hypercalcaemia of malignancy and are the current mainstay of treatment, whereas denosumab (which is administered subcutaneously) may offer an option for patients who do not respond to bisphosphonates or suffer from renal insufficiency., Hypocalcaemia: TREATMENT AND PREVENTION: Hypocalcaemia is most common in patients with prostate cancer and osteoblastic bone metastases, but can occur in patients with a variety of tumour types who are receiving inhibitors of bone resorption. While patients often respond to calcium and vitamin D supplementation, prevention should be the aim; at-risk patients should be identified before starting treatment with inhibitors of bone resorption, be closely monitored during at least the first few months of treatment, and receive concomitant calcium and vitamin D supplementation unless hypercalcaemia is present., Conclusion: Both hypercalcaemia and hypocalcaemia can be serious if left untreated. It is therefore important that patients with cancer are closely monitored and receive adequate prevention and treatment measures to maintain normal blood calcium levels.

The exact role of biochemical markers of bone turnover in the management of metabolic bone diseases remains a topic of controversy. In this consensus paper, the Belgian Bone Club aimed to provide a state of the art on the use of these biomarkers in different clinical or physiological situations like in postmenopausal women, osteoporosis in men, in elderly patients, in patients suffering from bone metastasis, in patients with chronic renal failure, in pregnant or lactating women, in intensive care patients, and in diabetics. We also gave our considerations on the analytical issues linked to the use of these biomarkers, on potential new emerging biomarkers, and on the use of bone turnover biomarkers in the follow-up of patients treated with new drugs for osteoporosis.

Purpose: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning., Methods: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm., Results: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function., Conclusions: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning.

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials., Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years., Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively., Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

Purpose: The aim of this study was to assess patients' preferences for efficacy, safety, and mode of administration in relation to available bone-targeted agents (BTA) for the prevention of skeletal-related events (SREs) associated with bone metastases in Europe., Methods: Adults in France (n = 159), Germany (n = 166), and the United Kingdom (UK; n = 159) with a self-reported physician diagnosis of bone metastases secondary to a solid tumour completed an online discrete- choice experiment survey of ten questions, choosing between pairs of hypothetical BTA profiles. Profiles were defined by five treatment attributes: delay of first SRE, delay of worsening of pain, annual risk of osteonecrosis of the jaw (ONJ), annual risk of renal impairment, and mode of administration. Profiles were generated using an experimental design with known statistical properties. A main-effects random parameters logit (RPL) model was applied to relate participants' choices to the characteristics of the BTA profiles., Results: The most important treatment attributes for patients across all three countries were time until first SRE, annual risk of renal complications and time until pain worsening. For these attributes, better levels of outcomes were significantly preferred to worse levels (p < 0.05). A 120-minutes infusion every 4 weeks was the least preferred mode of administration. Risk of ONJ was judged by patients in the UK and Germany to be the least important attribute., Conclusions: Patients consider delaying SREs, avoiding renal impairment and delaying pain worsening as the most important goals to consider when selecting treatment to prevent the bone complications commonly associated with bone metastases.

Purpose: This analysis evaluated patient-reported outcomes and analgesic use in patients with bone metastases from solid tumours across three comparative studies of denosumab and zoledronic acid., Methods: Pooled data were analysed from three identically designed double-blind phase III studies comparing subcutaneous denosumab 120 mg with intravenous zoledronic acid 4 mg monthly in patients with bone metastases from breast cancer (n = 2,046), castration-resistant prostate cancer (n = 1,901) or other solid tumours (n = 1,597). Pain severity, pain interference, health-related quality of life and analgesic use were quantified., Results: At baseline, approximately half of patients had no/mild pain (53 % [1,386/2,620] denosumab; 50 % [1,297/2,578] zoledronic acid). Denosumab delayed onset of moderate/severe pain by 1.8 months (median, 6.5 vs 4.7 months; hazard ratio, 0.83; 95 % CI, 0.76-0.92; p < 0.001; 17 % risk reduction) and clinically meaningful increases in overall pain interference by 2.6 months (median, 10.3 vs 7.7 months; hazard ratio, 0.83; 95 % CI, 0.75-0.92; p < 0.001; 17 % risk reduction) compared with zoledronic acid. Strong opioid use and worsening of health-related quality of life were less common with denosumab., Conclusions: Across three large studies of patients with advanced solid tumours and bone metastases, denosumab prevented progression of pain severity and pain interference more effectively than zoledronic acid.

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations., Competing Interests: René Rizzoli has received speaker or advisory board fees from Amgen, MSD, GSK, Servier, Danone and Takeda. Jean-Jacques Body has received speaker and consulting fees from Amgen and Novartis. Jorge B. Cannata-Andía has received research grants and speaker or advisory board fees from Amgen, Abbott, Servier and Shire. David Kendler has received honoraria for speaking, consulting and/or research grants from Amgen, Novartis, GSK, Eli Lily, Merck, Johnson&Johnson, Pfizer and Roche. Alexandra Papaioannou has been a consultant, or on a speaker’s bureau, or received unrestricted grants from Amgen, Eli Lilly, Merck Canada Inc., Novartis, Pfizer and Warner Chilcott. Tobias J de Villiers has received speaker or advisory board fees from Amgen, Merck, Adcock Ingram and Pfizer. Catherine Van Poznak has received research support from Amgen and Novartis. Ghada El-Hajj Fuleihan has received grants to support courses on osteoporosis from Novartis Pharmaceuticals and Les Laboratoires Servier. Abdellah El Maghraoui, Nicola Napoli, Dominique D Pierroz and Maria Rahme have no conflict of interest.

Background: Bone metastases occur frequently in patients with solid tumours such as those of the prostate, breast and lung, and are associated with an increased risk of skeletal-related events (SREs). This article reviews the personal, social and economic burdens of bone metastases and SREs, and approaches to treatment., Methods: PubMed searches were conducted using a broad range of search terms. Articles identified were refined by author review of abstracts. Additional material was identified by searching recent relevant congress abstracts., Results: Bone metastases often decrease quality of life, but quantitative data on the extent of this effect are limited. Data from the USA demonstrate a significant financial burden associated with bone metastases; similar trends are now being uncovered in Europe as the number of assessments of health economics and healthcare resource utilisation in the region increases. The bisphosphonate zoledronic acid reduces the incidence of SREs compared with placebo. Recent phase 3 studies have shown that therapy with the RANK ligand inhibitor denosumab is superior to zoledronic acid for preventing or delaying SREs in patients with bone metastases from solid tumours. Denosumab also has a comparable safety profile to bisphosphonates, with reduced risk of renal toxicity and acute phase reactions. Data from Europe suggest that denosumab is cost-effective for the prevention of SREs compared with zoledronic acid. Additionally, several new experimental bone-targeted agents show promise., Conclusion: Recent progress may help to reshape evidence-based guidelines to improve patient care and reduce the economic burden of bone metastases.

Purpose: Hypercalcemia is a frequent finding in cancer patients and can be observed in any type of cancer. The physician in charge of cancer patients often ignores non-malignant causes of hypercalcemia. Our objective was to review the causes of hypercalcemia in a large series of cancer patients., Methods: We have retrospectively studied in a Cancer Centre all consecutive hypercalcemic (Ca> 10.5 mg/dl) patients over an 8-year period. Of 699 evaluated patients, 642 were analyzed after exclusion of patients whose hypercalcemia resolved after rehydration or who had a normal Ca level after correction for protein concentrations. Clinical information was gathered on the type of cancer, its histology, whether the disease was active or in complete remission, and on the presence of bone metastases. Biochemical data included serum Ca, P(i), proteins in all patients, PTH in most patients, and PTHrP, 25OH-Vitamin D, 1,25(OH)(2)-Vitamin D, TSH, and T4 in selected cases., Results: By order of decreasing frequency, the main causes of hypercalcemia were cancer (69.0 %), primary hyperparathyroidism (24.6 %), hyperthyroidism (2.2 %), milk alkali syndrome (0.9 %), and sarcoidosis (0.45 %). In cancer-related causes, bone metastases accounted for 53.0 % of the cases, humoral hypercalcemia of malignancy (HHM) for 35.3 % while there were 11.7 % of cases apparently due to both HHM and bone metastases. Hypercalcemia was not due to cancer in 97 % (84/87) of the patients who were in complete remission. Even in patients with active neoplastic disease, the number of patients whose hypercalcemia was not due to cancer remained clinically relevant (115/555 = 20.5 %). In the 158 patients with primary hyperparathyroidism, 92 patients were in complete remission and 66 patients had active neoplastic disease., Conclusions: In this large series of hypercalcemia in cancer patients, the cause was not due to cancer in almost one third of the cases. Most patients considered to be in complete remission had hypercalcemia due to a benign condition. In that perspective, serum PTH determination is essential in the approach of hypercalcemic cancer patients since primary hyperparathyroidism is by far the first non-malignant cause of hypercalcemia.

Unlabelled: Aromatase inhibitors (AIs) are widely used in women with breast cancer, but they are known to increase bone loss and risk of fractures. Based on available evidence and recommendations, an ESCEO working group proposes specific guidance for the prevention of AIs-induced bone loss and fragility fractures., Introduction: Aromatase inhibitors (AIs) are now the standard treatment for hormone receptor-positive breast cancer. However, deleterious effects of AIs on bone health have been reported. An ESCEO working group proposes guidance for the prevention of bone loss and fragility fractures in post-menopausal women with breast cancer receiving AIs., Methods: A panel of experts addressed the issue of skeletal effects of AIs and effectiveness of antifracture therapies for the prevention of AI-induced bone loss and fractures. Recommendations by national and international organizations, and experts' opinions on this topic were evaluated., Results: All aromatase inhibitors are associated with negative effects on the skeleton, resulting in bone loss and increased risk of fragility fractures. Current guidelines suggest approaches that differ both in terms of drugs proposed for fracture prevention and duration of treatment., Conclusion: The ESCEO working group recommends that all AI-treated women should be evaluated for fracture risk. Besides general recommendations, zoledronic acid 4 mg i.v. every 6 months, denosumab s.c., or possibly oral bisphosphonates should be administered for the entire period of AI treatment to all osteoporotic women (T-score hip/spine <-2.5 or ≥ 1 prevalent fragility fracture), to women aged ≥ 75 irrespective of BMD, and to patients with T-score <-1.5 + ≥ 1 clinical risk factor or T-score <-1.0 + ≥ 2 clinical risk factors. Alternatively, therapy could be considered in patients with a FRAX-determined 10-year hip fracture probability ≥ 3%.

Unlabelled: Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection., Introduction: The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound., Methods: The present document is the result of a national consensus, based on a systematic and critical review of the literature., Results: Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed., Conclusion: Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices.

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies.

Background and Purpose: This study seeks to perform a survey of patterns of practice among the different physicians involved in the bone metastases management, with special focus on external beam radiotherapy (EBRT)., Methods and Materials: A questionnaire about bone metastases based on clinical cases and supplemented with general questions, including medical therapies, EBRT and metabolic radiotherapy strategies, surgery, and supportive care approaches, was sent to 4,706 French-speaking physicians in Belgium, France, Luxemburg, and Switzerland., Results: Overall, 644 questionnaires were analyzed. Twenty-eight percent concerned the radiotherapy approach and were judged adequate to respond to the part dedicated to EBRT. Sixty-nine percent of physicians used a total dose irradiation of 30 Gy delivered in ten fractions. A large majority (75%) used two opposed fields prescribed at mid-depth (30%), or with non-equally weighted fields (45%). Seventy percent irradiated also above and below the concerned vertebra. A dosimetry planning treatment was done in 85% and high-energy megavoltage photons were used in 42%. Moreover, 54% physicians used short course radiotherapy in routine., Conclusions: Radiotherapy remains the mainstay of treatment of bone metastases, but there is substantial heterogeneity in clinical practice. Guidelines and treatment protocols are required to improve the treatment quality.

Several drugs are available for the management of postmenopausal osteoporosis. This may, in daily practice, confuse the clinician. This manuscript offers an evidence-based update of previous treatment guidelines, with a critical assessment of the currently available efficacy data on all new chemical entities which were granted a marketing authorization. Osteoporosis is widely recognized as a major public health concern. The availability of new therapeutic agents makes clinical decision-making in osteoporosis more complex. Nation-specific guidelines are needed to take into consideration the specificities of each and every health care environment. The present manuscript is the result of a National Consensus, based on a systematic review and a critical appraisal of the currently available literature. It offers an evidence-based update of previous treatment guidelines, with the aim of providing clinicians with an unbiased assessment of osteoporosis treatment effect.

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

Cancer treatment-induced bone loss (CTIBL) is one of the most important side effects of adjuvant antineoplastic treatment in hormone-dependent neoplasms. Chemotherapy, GnRH analogs and tamoxifen can induce marked bone loss in premenopausal women with early breast cancer. Aromatase inhibitors (AIs) are replacing tamoxifen as the preferred treatment for postmenopausal women. As a class effect, steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs increase bone turnover and cause bone loss (4%-5% over 2 years). When compared to tamoxifen, the risk of getting a clinical fracture under AI treatment is increased by 35%-50%. In patients with prostate cancer, androgen deprivation therapy (ADT) increases bone turnover, reduces bone mass (4%-5% per year) and increases the fracture rate depending on the duration of therapy. Zoledronic acid can prevent accelerated bone loss induced by goserelin in premenopausal women, by letrozole in postmenopausal women and by ADT in men. More limited data indicate that weekly alendronate or risedronate could also be effective for preventing CTIBL. Initiation of therapy early, prior to the occurrence of severe osteoporosis, rather than after, may be more effective. Bisphosphonate treatment should be considered in osteoporotic but also in osteopenic patients if other risk factor(s) for fractures are present.

Unlabelled: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges., Introduction: After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis., Methods: In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed., Results: All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity., Conclusions: This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients.

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.

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.

Background: Ibandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy., Methods: A global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review., Results: Total cost, including drug acquisition, was pound 386 less per patient with oral ibandronate vs. i.v. zoledronic acid and pound 224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of pound 30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%., Conclusions: Oral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

Unlabelled: GOALS AND WORK: Despite medical awareness, intractable pain is a serious problem in cancer and occurs in up to 2% of advanced cancer patients. However, few data are available concerning the optimal treatment of such patients. The emergence of intractable pain may notably be due to the activation of N-methyl-D-aspartate (NMDA) receptors located in the central nervous system. NMDA antagonists might thus be an interesting approach in such pain syndromes., Patients and Methods: Twelve patients with intractable cancer pain received a test dose of 5-10 mg of ketamine, a strong NMDA antagonist, in order to determine their response and tolerance to the drug. Continuous intravenous infusions of ketamine associated with morphine were then administered., Main Results: The acute test dose was successful in all cases (VAS <3/10 after 5 min). The prolonged use of ketamine allowed us to reduce the total daily dose of morphine required (range: 200-1,200 mg) by 50% and allowed eight patients to go home with a portable pump with morphine and ketamine during a relatively long period of time (range: 7-350 days, median: 58 days). Side effects were moderate (dizziness) and they were limited to the test phase., Conclusion: Our data suggest the importance of NMDA receptors in the genesis of chronic cancer pain and indicate that NMDA antagonists should be further studied for the management of cancer pain and, in particular, intractable pain.

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 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.

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).

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 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.

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.

Tumor-induced hypercalcemia (TIH) and tumor-induced osteolysis (TIO) are essentially due to a marked increase in osteoclast-mediated bone resorption. Parathyroid-hormone-like protein plays an essential role in TIH, and maybe in TIO, but other substances, such as growth factors or cytokines, could contribute to the osteoclast activation and osteoblast inhibition secondary to the neoplastic infiltration of the skeleton. Treatment of TIH essentially consists of volume repletion and administration of potent anti-osteolytic drugs. Intravenous administration of the bisphosphonate clodronate or pamidronate is particularly useful for this. Pamidronate at a dose of 1.0-1.5 mg/kg as a single 4- to 24-h infusion can normalize serum calcium in about 90% of hypercalcemic cancer patients. The apparently low response rate of bone metastases to systemic antineoplastic therapy seems essentially to reflect the relative insensitivity of our current methods for assessing response in TIO. Quantitative evaluation of pain and of newly developed biochemical markers of bone turnover could be particularly useful for early assessment of response. Prolonged administration of oral pamidronate could reduce by almost one-half the complications of TIO, and iterative bisphosphonate infusions could induce a dramatic relief of bone pain in one-third and a sclerosis of lytic lesions in one-fourth of the cases. These data must, however, be confirmed in randomized blind trials and many questions remain unanswered concerning the optimal therapeutic schemes. Despite these limitations, medical therapy of TIO by non-cytotoxic means has already become a reality.