Soluble cathepsin-L: a marker of bone resorption and bone density?

We sought to evaluate cathepsin L serum levels in the peripheral blood of patients with low bone density. Blood samples from 60 patients (32 osteoporotic, 28 osteopenic) and 16 healthy controls were taken and quantitative measurements of cathepsin L were performed with the use of a commercially available enzyme-linked immunosorbent assay. Dual x-ray absorptionometry measurements and serum levels of alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, parathyroid hormone, sexual hormones, and N -terminal crosslinks of type I collagen were examined. Group comparisons between patients with osteoporosis and controls showed significant differences with respect to cathepsin L ( t = -2.839; df = 29; P =.008). Osteoporosis treatment decreased the serum level of cathespsin L in a statistically significant fashion ( P =.002). These results suggest that the serum level of cathepsin L can serve as a marker of bone resorption and bone density.     

Changes in bone resorption markers among Japanese patients with postmenopausal osteoporosis treated with alendronate and risedronate

We compared the abilities of alendronate and risedronate to reduce levels of urinary cross-1inked N-telopeptides of type I collagen (NTX) in Japanese postmenopausal women. The patients were randomly divided into two groups (alendronate, 5 mg/day, n = 61; risedronate, 2.5 mg/day, n = 60). All patients had taken all medication prescribed for the first month and at least 90% of that prescribed for each of the following 6 months. Urinary NTX was measured at baseline, as well as at 1 and 6 months after starting treatment. According to the guidelines of the Japan Osteoporosis Society, the minimum significant change (MSC) for urinary NTX is defined as a 35% decrease from baseline and the cutoff level for a high risk of future fracture is 54.3 nmol bone collagen equivalent (BCE)/mmol·Cr. The NTX reduction rates at 1 and 6 months were greater with alendronate than with risedronate, but the difference was not significant. The rate of patients with a reduction in the MSC at 1 month was greater with alendronate than with risedronate, but the difference did not reach significance. Alendronate reduced NTX at 1 month significantly more in patients with a high risk of fracture than risedronate, but the difference was no longer significant at 6 months. The rate of MSC did not significantly differ between the two groups. In conclusion, alendronate decreases bone resorption markers more obviously and rapidly than risedronate, especially in high risk for fracture, but not significantly according to the guidelines of the Japan Osteoporosis Society.     

Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: evidence for multiple diverse hyperalgesic systems

Hyperalgesia following chronic morphine treatment is thought to be a response to opioid receptor activation and analgesia and contribute to the development of analgesic tolerance. Here, the relationship between these variables was studied in mice tested for nociceptive sensitivity on the tail-withdrawal test during chronic infusion of various morphine doses. Hyperalgesic onset was preceded by dose-dependent analgesia except for the lowest morphine dose, which caused hyperalgesia 6 h after the start of infusion. Morphine ED50 values obtained at various infusion intervals demonstrated both analgesic tolerance in the absence of hyperalgesia and hyperalgesia in the absence of tolerance. Continuous opioid receptor antagonism using naltrexone pellets abolished analgesia during continuous morphine administration, transiently potentiated hyperalgesia, and revealed differences in hyperalgesic onset between morphine infusion doses. Acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 attenuated hyperalgesia in naltrexone-treated mice, demonstrating a role for this receptor in morphine hyperalgesia unrelated to its effects upon morphine analgesia. In mice where hyperalgesia subsided after continuous infusion of the highest morphine dose (i.e., hyperalgesic adaptation), hyperalgesia was restored after infusing the lower but not higher morphine dose. In addition, acute injection of morphine-3beta-glucoronide (M3G) caused hyperalgesia that was cross-adaptive with the lower morphine dose only. The data demonstrate that morphine hyperalgesia is independent of prior or concurrent opioid receptor activity or analgesia and is unrelated to analgesic tolerance. Furthermore, the lack of hyperalgesic cross-adaptation between high and low morphine doses, and their differential cross-adaptation with M3G hyperalgesia, also suggests distinct morphine dose-dependent hyperalgesic systems.     

Unusual Association between Increased Bone Resorption and Presence of Paroxysmal Nocturnal Hemoglobinuria Phenotype in Multiple Myeloma

Paroxysmal nocturnal hemoglobinuria (PNH) clones deficient in glycosylphosphatidylinositol-anchored molecules, including CD55 and CD59, have been previously described in patients with multiple myeloma (MM). The aim of this study was to investigate the possible association between existence of the PNH phenotype and myeloma bone disease. Forty-three patients with newly diagnosed MM were the subjects of the study. Radiographic evaluation of the skeleton was performed in all patients at diagnosis. The following biochemical markers were measured: bone resorption markers (tartrate-resistant acid phosphatase isoform 5b [TRACP-5b]and N-terminal cross-linking telopeptide of type-I collagen [NTX]), bone formation markers (bone alkaline phosphatase [bALP] and osteocalcin [OC]), osteoprotegerin (OPG), soluble receptor activator of nuclear factor KB ligand (sRANKL), and interleukin 6 (IL-6). Detection of CD55- and/or CD59-deficient red cell populations was performed after diagnosis. Patients with MM had elevated mean baseline NTX, TRACP-5b, sRANKL, and IL-6 levels compared with controls, whereas the mean values of bALP, OC, and OPG were significantly decreased. Four patients had no osteolytic lesions, whereas 8 patients had 1 to 3 lytic lesions, and 31 patients had more than 3 lytic lesions and/or pathologic fractures in the skeletal survey. CD55- and/or CD59-deficient red cell populations were observed in 56% of patients with MM. There was a strong correlation between the presence of PNH-like erythrocytes and increased bone resorption, as measured by NTX, TRACP-5b, and sRANKL/OPG ratio (P < .03, P < .02, and P < .02, respectively). There was also a significant correlation between PNH phenotype and severe bone disease (P < .02). These results suggest that there is a possible link between PNH phenotype and increased osteoclastic activity in MM owing to a potential effect of myeloma microenvironment on a preexisting PNH clone. Further studies are required for clarifying this phenomenon and investigating possible mechanisms of this unusual association.     

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。     

Naltrexone (NTX) relieves inflammation in the collagen-induced- arthritis (CIA) rat models through regulating TLR4/NFκB signaling pathway

ObjectiveOur aim was to study the efficacy and mechanism by which NTX alleviate arthritis in CIA rat models in vivo.MethodsFemale Wistar rats were randomly divided into 6 groups, their weights were observed and the severity of arthritis and pathological changes were evaluated by HE staining. T lymphocyte subsets were detected by flow cytometry. The expression of cytokines was detected in peripheral serum by ELISA. Real time PCR, immunohistochemical staining and western blot analysis were utilized to detect the mRNA and protein expression of opioid receptors, TLR4, RANKL and /NF-κB in synovial tissue and the spleen.ResultsThe weight of the rats in the 10 mg/kg NTX group decreased the least, and had the least severe arthritis. CD4⁺ T cells, Th1 cells and Treg cells increased, and CD8⁺T cells, Th1 cells and Th17 cells decreased in the splenic lymphocytes. The expression of proinflammatory cytokines decreased, and the expression of anti-inflammatory cytokines increased. MOR and DOR were strongly expressed in the spleen, whereas KOR and DOR were strongly expressed in synovial tissue. The expression of TLR4, NF-κB and RANKL was reduced in the spleen and synovium in the NTX group.ConclusionsNTX relieved the severity of arthritis in the CIA rat models at a concentration of 10 mg/kg by regulating T lymphocyte subsets and the expression of cytokines. NTX affected opioid receptors to inhibit the TLR4/NF-κB signaling pathway, regulating the systemic immune response and decreasing osteoclast differentiation, thereby alleviating inflammation and the erosion of articular cartilage along with bone tissue.