Pamidronate is superior to ibandronate in decreasing bone resorption,interleukin-6 and beta 2-microglobulin in multiple myeloma

OBJECTIVES: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third-generation aminobisphosphonate, in bone turnover and disease activity in MM patients. METHODS: Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N-terminal cross-linking telopeptide of type-I collagen (NTX) and tartrate-resistant acid phosphatase type 5b (TRACP-5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, beta 2-microglobulin), and interleukin-6 (IL-6) were also studied. RESULTS: In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL-6, paraprotein, CRP, and beta 2-microglobulin from the second month of treatment, having no effect on bone formation. TRACP-5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL-6, and beta 2-microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP-5b, starting at the fourth month (P = 0.014), that being continued throughout the 10-month follow-up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP-5b, IL-6, and beta 2-microglobulin from the second month for patients of both groups. CONCLUSIONS: These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL-6, and possibly tumour burden in MM. TRACP-5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.     

Hypophosphatemic osteomalacia: a report of five cases and evaluation of bone markers

In this study, we analyzed the changes in biochemical markers of bone turnover in five patients with hypophosphatemic osteomalacia. The following bone markers were evaluated: among bone formation markers, total alkaline phosphatase (TAP), bone alkaline phosphatase (BAP), osteocalcin (bone Gla protein, BGP) and procollagen type I N propeptide (PINP); among bone resorption markers, serum C-terminal cross-linked telopeptide of type I collagen (s-CTx), urinary hydroxyproline (HYP), and N-terminal and and C-terminal cross-linked telopeptides of collagen (NTx and - and -CTx). In addition, the /-CTx ratio was evaluated. TAP and BAP were the markers with the highest increase in both frequency and magnitude. Conversely, BGP values were low in all patients. Collagen-related markers were slightly increased in nearly half of the patients. Among them, PINP showed the highest proportion of increased values. The /-CTx ratio was within normal values in all patients. In conclusion, TAP and BAP seem to be the best bone markers in the diagnostic evaluation of hypophosphatemic osteomalacia. In addition, their high values associated with low levels of BGP provide an even more reliable biochemical profile of this disorder, when associated with the classic mineral and skeletal homeostasis abnormalities.     

Early changes in urinary cross-linked N-terminal telopeptides of type I collagen level correlate with 1-year response of lumbar bone mineral density to alendronate in postmenopausal Japanese women with osteoporosis

The purpose of this study was to determine whether early changes in the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) during alendronate treatment would be correlated with the 1-year response of lumbar bone mineral density (BMD) in postmenopausal Japanese women with osteoporosis. One hundred five postmenopausal women with osteoporosis, aged 54–88 years, were treated with alendronate (5mg daily) for 12 months. The urinary NTX levels were measured by enzyme-linked immunosorbent assay at the baseline and at 3, 6, and 12 months, and lumbar (L1–L4) BMD was measured by dual-energy X-ray absorptiometry using the Hologic QDR 1500W equipment at the baseline and at 12 months. The mean percent reduction in urinary NTX level at 3, 6, and 12 months was 36.8%, 49.5%, and 49.0%, respectively, the extent of reduction at 6 and 12 months being greater than that at 3 months, and the mean percent increase of the lumbar BMD at 12 months was 8.2%. Single regression analysis showed a significant correlation between the percent reductions in the urinary NTX level at 3, 6, and 12 months of treatment and the percent increase of the lumbar BMD at 12 months (r = 0.200, P < 0.05; r = 0.341, P < 0.001; and r = 0.338, P < 0.001, respectively). Thirty percent of the patients were labeled as poor responders at 3 months, with the reduction in the urinary NTX level being less than the minimum significant change (MSC); 61% of these patients showed a greater reduction in the urinary NTX level, exceeding the MSC, at 6 months. These results suggest that the changes in the urinary NTX levels at 3 and 6 months after the start of alendronate treatment at the dose of 5mg daily may be correlated with the 1-year response of the lumbar BMD in postmenopausal Japanese women with osteoporosis. In other words, the greater the reduction of the urinary NTX level at 3 and 6 months after the start of alendronate treatment, the greater can be the expected increase of the lumbar BMD after 12 months of treatment. In this study, 70% of the patients were good responders, who showed a reduction of the urinary NTX level exceeding the MSC at 3 months. Among the remaining 30% poor responders, about 60% showed satisfactory reduction of the urinary NTX level, exceeding the MSC, at 6 months after the start of treatment with alendronate.     

纳曲酮长效缓释剂包埋术100例临床分析

目的：验证纳洛酮冲击疗法、纳曲酮冲击疗法的临床效果,探讨纳曲酮长效缓释剂包埋术的防复吸效能。方法：需脱毒者采用NTX冲击疗法或NLX冲击疗法快速脱毒,次日进行NTX长效缓释剂包埋术,观察冲击疗法临床效果,随访出院后稽延性戒断症状及防复吸效能。结果：100例中,已完成脱毒者7例,采用NTX冲击治疗者36例,采用NLX冲击治疗者57例,次日进行包埋术,无一例出现严重戒断症状,冲击成功率100%,出现无菌性炎症4例,稽延性戒断症均在1个月以内消除,半年操守率96.8%。结论：NLX或NTX冲击疗法具有时间短、脱毒快、彻底、成功率高的优点,经得起临床验证。NTX长效缓释剂有较好的防复吸效能,很有临床实用价值。     

High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature

Although systematic review and meta-analysis of randomized controlled trials (RCTs) have concluded that vitamin K is effective in preventing fractures, the effect of vitamin K on the skeleton remains a matter of controversy. The objective of the present review of the literature was to evaluate the effect of vitamin K supplementation on the skeleton of postmenopausal women. PubMed was used to search the reliable literature for RCTs by using the search terms “vitamin K₁ or vitamin K₂,” “bone,” and “postmenopausal women” and the following inclusion criteria: approximately 50 or more subjects per group and study period of 2 years or longer. Seven RCTs met the inclusion criteria. The results of these RCTs showed that vitamin K₁ and vitamin K₂ supplementation reduced serum undercarboxylated osteocalcin levels regardless of dose but that it had inconsistent effects on serum total osteocalcin levels and no effect on bone resorption. Despite the lack of a significant change or the occurrence of only a modest increase in bone mineral density, high-dose vitamin K₁ and vitamin K₂ supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures. The review of the reliable literature confirmed the effect of vitamin K₁ and vitamin K₂ supplementation on the skeleton of postmenopausal women mediated by mechanisms other than bone mineral density and bone turnover.     

Biochemical markers in oncology. Part I: molecular basis. Part II: clinical uses

The investigation of the molecular mechanisms involved in carcinogenesis and tumor progression has led to the development of numerous biochemical markers. Biochemical markers may serve for early prediction of tumor recurrence, progression and development of metastases including bone metastases and for prediction of response to therapy. Tumor antigens have been used for more than a decade and although they have shown promising clinical results, their sensitivity and specificity remain limited. A lot of knowledge on the key molecules which control cell cycle, apoptosis and angiogenesis has been acquired during recent years, but their clinical value remains uncertain. Molecular markers which are linked to malignant transformation may provide a non-surgical therapeutic approach by targeting these molecules through gene therapy or antisense molecules. Because of the complexity of the physiopathogical processes involved in tumorogenesis and metastases, we first provide a review on the molecular basis of the various tumor markers and then discuss their potential clinical utility for the major cancers. The review of the current literature indicates that at the exception of a few examples, such as the use of Her-2 to predict response of the targeted Herceptin therapy, no single marker is sensitive and specific enough to perform an accurate diagnosis, predict disease progression or response to treatment. A combination of different biochemical and imaging markers appears to be the most promising strategy to monitor patients with cancer.     

Therapeutic approaches to myeloma bone disease: an evolving story

Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross-talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1α/chemokine receptor for macrophage inflammatory protein-1α axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-β, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease.     

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid

BACKGROUND: For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear. METHODS: Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n = 578), hormone-refractory prostate cancer (HRPC; n = 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n = 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; <64 nmol/mmol creatinine) or elevated (E; > or =64 nmol/mmol creatinine). RESULTS: After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N. CONCLUSIONS: Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of skeletal complications and death.