Management of glucocorticoids-induced osteoporosis: role of teriparatide

Glucocorticoids (GC)-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis, which leads to an increased fracture risk in patients. The normal bone turnover depends on a balance between osteoblasts and osteoclasts activity and GC can cause a rapid bone loss, decreasing bone formation and increasing bone resorption. The decreased bone formation is mainly due to the GC-induced apoptosis of both osteoblasts and osteocytes, while the increased bone resorption is due to the increased life-span of pre-existing osteoclasts. Bisphosphonates are clearly effective in preventing and treating GIOP but anabolic therapeutic strategies are the new promising therapeutic alternative. Experimental and clinical studies indicate that teriparatide, the active (1–34) parathyroid hormone (PTH) molecule, is efficacious for the treatment of GIOP, being able to induce an increase in bone mass in these patients. Intermittent administration of human PTH (1–34) stimulates bone formation by increasing osteoblast number. Additionally, human PTH (1–34) modulates the level and/or activity of locally produced growth factors and cytokines. Teriparatide has been demonstrated in several clinical studies to significantly decrease the incidence of fractures in patients affected by GIOP. It has recently received an indication for GIOP and its label indication has also been expanded

Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing?

BACKGROUND: With advancing age, thymic efficiency shows progressive decline due to thymic involution allowing impaired cell-mediated immunity and the appearance of age-related diseases. The intrinsic cause of thymic involution is still undefined. Chronic inflammation and high glucocorticoids (GCs) may be involved. However, transgenic mice, with increased GC sensitivity and over expression of GC receptors, display delayed age-associated thymic involution. This fact suggests that other substances may affect thymic involution. Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. Enhanced MTs in ageing allows constant sequester of zinc ions and no subsequent zinc release leading to low zinc ion bioavailability for thymic efficiency. This sequester is very limited in very old age. Thus, we have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice. METHODS: MTmRNA and IL-6mRNA (RT-PCR) in the thymus from different donors were tested. Concomitantly, TECs proliferation, zinc ion bioavailability (ratio total thymulin/active thymulin), thymulin activity and corticosterone were tested from different donors. RESULTS: Both isoforms of MTmRNA and IL-6mRNA increase in old thymus coupled with low zinc ion bioavailability, reduced TECs proliferation, impaired thymulin activity and enhanced plasma corticosterone in comparison with young. Conversely, although the thymus is involuted in very old mice because of no changes in thymus weight in comparison to old mice, reduced MTmRNA, especially MT-I+II isoforms, and low IL6mRNA occur. Concomitantly, good zinc ion bioavailability, maintained TECs proliferation, satisfactory thymulin activity and reduced corticosterone are observed in very old mice. CONCLUSIONS: The concomitant increments by high IL-6 of both MT isoforms in the thymus from old mice may be involved in thymic involution because provoking low zinc ion bioavailability, which is relevant for thymic efficiency. By contrast, the limited increments of MTs by low IL-6 induce good zinc ion bioavailability and satisfactory thymic efficiency in very old mice. Therefore, abnormal increased MTs may provoke complete thymic involution during ageing and the possible appearance of age-related diseases. If their increments are instead limited by low inflammation, healthy ageing and longevity may be reached

The Impact of an Adapted Physical Activity Program on Bone Turnover, Physical Performance and Fear of Falling in Osteoporotic Women with Vertebral Fractures: A Quasi-Experimental Pilot Study

Physical activity has been indicated as a potential strategy to counteract osteoporosis (OP). This study of post-menopausal women with osteoporotic vertebral fractures investigated the effect of an adapted physical activity (APA) program on two serum bone turnover biomarkers (Bone Alkaline Phosphatase, B-ALP and C-terminal telopeptide of type 1 collagen, CTX-1), functional capacity (6-Minutes Walking Test, 6MWT), and risk and fear of falls (Tinetti and Falls Efficacy scale). The APA group (n = 12) performed a 1-h group session twice per week for 6 months whereas the control group (n = 9) was asked to maintain their current lifestyle. The exercise program did not affect the serum concentrations of B-ALP and CTX-1 biomarkers measured at the baseline and after 6 months in women of the APA group. Moreover, at the end of intervention no significant differences in serum concentrations for either biomarker was observed between the two study groups. Interestingly, when compared to the control group, women in the APA group showed significant improvement in the functional capacity measures by 6MWT (p = 0.037) and a decrease of the risk and fear of falls as indicated by the Tinetti test (p = 0.043). Based on these findings, exercise could provide new perspectives for the care and management of OP

Clodronate in the management of different musculoskeletal conditions

INTRODUCTION: Clodronic acid is a non-nitrogen-containing bisphosphonate largely used from some decades in the prevention and treatment of postmenopausal and secondary osteoporosis. in addition to antiresorptive activity, clodronate has shown anti-inflammatory and analgesic properties, and modulatory effects on bone and cartilage metabolism. EVIDENCE ACQUISITION: A literature review has been conducted to characterize the mechanism of action of clodronate and to retrieve available evidence about the use of clodronate in primary and secondary osteoporosis, and its potential role in other musculoskeletal conditions and orthopedic surgery. EVIDENCE SYNTHESIS: The efficacy and safety of the available clodronate formulations (oral, intravenous and intramuscular) in the prevention and treatment of postmenopausal and secondary osteoporosis, including corticosteroid-induced osteoporosis and bone mass loss secondary to endocrine, gastrointestinal and neoplastic diseases, have been demonstrated in a variety of clinical trials. The analgesic, anti-inflammatory, bone- and chondro-modulating properties of clodronate have allowed to expand its use in other musculoskeletal conditions to those currently approved. clodronate has proven to be beneficial in the treatment of osteoarthritis of the knee and of the hand, in the management of complex regional pain syndrome, and in the peri- and postoperative phase in subjects undergoing arthroplasty. CONCLUSIONS: The analysis of the available literature has shown that clodronate has relevant musculoskeletal effects beyond the antiresorptive activity. Further research is needed to better position clodronate therapy in the management of these conditions and to define the optimal formulation and dose regimen in any of the tested new indications

Personal non-commercial use only. The Journal of Rheumatology 1552

ABSTRACT. Objective. Vertebral fractures are a common complication of osteoporosis and may have a negative effect on health-related quality of life (HRQOL). We investigated the effect of prevalent vertebral fractures on HRQOL in patients with osteoporosis. Methods. A cross-sectional multicenter study was carried out among postmenopausal women with primary osteoporosis attending primary care centers and hospital outpatient clinics: 234 women with vertebral fractures and 244 asymptomatic women. Women with secondary osteoporosis or taking medications that affect bone metabolism were excluded. All patients were questioned using the miniOsteoporosis Quality of Life Questionnaire (mini-OQLQ), Medical Outcomes Study Short , and the EuroQuol-5D, after assessment of all clinical variables and anthropometric data. To assess comorbidity we used the Self-Administered Comorbidity Questionnaire (SCQ). Diagnosis of osteoporosis was confirmed in all patients by bone mineral density using dual energy x-ray absorptiometry. Radiographic evaluation was performed by a musculoskeletal radiologist. A total of 483 postmenopausal women, randomly matched for age out of 1579 healthy controls, were chosen to compare the SF-36 scores with respect to patients with and without vertebral fractures due to osteoporosis. A multivariable regression analysis was conducted to identify the strongest determinant for low HRQOL, adjusted for potential confounding variables such as comorbid conditions, education level, and psychosocial status. Results. The vertebral fracture group had significantly lower scores than patients without fractures and controls in all domains of the generic and specific questionnaires. Women with only 1 prevalent fracture had statistically significantly lower HRQOL scores than those without fractures on SF-36 measures of bodily pain, physical functioning, and role function physical (all p < 0.01). HRQOL scores were lower in women with lumbar fractures compared with women with thoracic fractures only when the physical functioning and bodily pain dimensions approached statistical significance. Based on the multivariate analysis, the strongest determinant for low HRQOL was physical functioning (explained by number of vertebral fractures) followed by comorbidity score and age. Adjusted R 2 in the final model was 35.9%. Using the SF-36 summary scales, comorbid conditions predominantly affected either mental or physical health (p < 0.0001). A significant correlation (p < 0.0001) was found between total score on the mini-OQLQ and the mean SCQ comorbidity score. Conclusion MATERIALS AND METHODS Recruitment of patients. In this cross-sectional multicenter study we investigated 478 postmenopausal women (mean age 68.5 yrs, range 48-89 yrs) with primary clinically stable osteoporosis (no change in treatment and no new clinical deformities in the last 12 mo) attending primary care centers and hospital outpatient clinics. The patient group included 234 women (mean age 69 yrs, range 48-89) who had vertebral fractures due to osteoporosis, and a group of 244 asymptomatic osteoporotic women matched for age with the patients with vertebral fractures. The women were screened in 5 rheumatology centers in Northern and Central Italy. A simple algorithm, the OPERA 23 , based on age, weight, history of previous low impact fracture, early menopause, and corticosteroid therapy, was used as a prescreening tool to help clinicians identify which women are at increased risk for osteoporosis. Diagnosis of osteoporosis was confirmed by bone mineral density (BMD) using dual-energy x-ray absorptiometry (DEXA). Osteoporosis was defined as a T score lower than -2.5 (the difference between the measured BMD and the mean value of young adults, expressed in standard deviations), according to the World Health Organization Study Group definition 24 . All measurements at the left femoral neck and lumbar spine (L1-L4), in the anteroposterior position, were obtained using the Hologic scanner (Hologic QDR 4500; Hologic, Bedford, MA, USA). One of the inevitable limitations of the study was the use of different densitometry machines, yielding noncomparable BMD data. Thus, machines at each participating center were cross-calibrated at the beginning of the study using the same spine phantom (supplied by the manufacturer). Each phantom was scanned 10 times at each study center. Quality control procedures were followed according to the manufacturer's recommendations. T scores were based on a large European and US reference database for BMD 25 . Radiographic evaluation was performed centrally (at the Department of Radiology of the Università Politecnica delle Marche) by an experienced musculoskeletal radiologist. Total spine radiographs in lateral standing views in neutral/flexion/extension and in the lateral decubitus position in flexion/extension were taken with a film-tube distance of 1.8 m. The anterior, central, and posterior heights of each of the vertebral bodies from T4 to L5 in a neutral standing radiograph were measured using calipers. Vertebral fracture was considered present if at least one of 3 height measurements (anterior, middle, posterior) of one vertebra had decreased by more than 20% compared with the height of the nearest uncompressed vertebral body Further, 483 postmenopausal women (mean age 69.1 yrs, range 50-87) randomly matched for age out of 1579 healthy controls were chosen for comparison of SF-36 scores of patients with and without vertebral fractures due to osteoporosis. Subjects with fibromyalgia, chronic back pain, and vertebral or other fractures were excluded. As acquisition of radiographs in the control group study was considered unethical in the context of the study, inclusion in this group depended on oral confirmation that the individual had never 1552 The received a clinical diagnosis of vertebral or other fracture. This sample was selected from a previous cross-sectional population-based study, the MAP-PING (MArche Pain Prevalence INvestigation Group) study Background and illness-related variables. Demographic and socioeconomic information was assessed from patient interviews. Education level was separated into 3 categories based on the Italian school system: 1 = primary school, 2 = secondary school, and 3 = high school or university. The body mass index (BMI, body weight/height 2 ) was used to assess overweight. In all patients the presence of comorbidities was also assessed through patient self-reports using the Self-Administered Comorbidity Questionnaire (SCQ) 28 , a modification of the widely used Charlson Index 29 . The SCQ uses patient interview or questionnaire responses rather than chart abstraction for assessment of comorbidity and is in excellent agreement with the chart-based Charlson Index 28 . We evaluated the rate of endorsement of each of 12 specific conditions as well as the number of conditions endorsed. We also calculated a score with 1 point if the condition was endorsed and additional points if the subject reported currently receiving treatment for it, or if it limited activities. Each condition could, therefore, contribute 0 to 3 points for a maximum of 36 points

Morphology of the toe flexor muscles in older people with toe deformities

Objective: Despite suggestions that atrophied, or weak toe flexor muscles are associated with the formation of toe deformities, there has been little evidence to support this theory. This study aimed to determine whether the size of the toe flexor muscles differed in older people with and without toe deformities. Methods: Forty-four older adults (>60 years) were recruited for the study. Each participant had their feet assessed for the presence of hallux valgus or lesser toe deformities. Intrinsic and extrinsic toe flexor muscles were imaged with an ultrasound system using a standardised protocol. Assessor blinded muscle thickness and cross-sectional area was measured using Image J software. Results: Participants with lesser toe deformities (n=20) were found to have significantly smaller quadratus plantae (p=0.003), flexor digitorum brevis (p=0.013), abductor halluces (p=0.004) and flexor halluces brevis (p=0.005) muscles than the participants without any toe deformities (n=19). Female participants with hallux valgus (n=10) were found to have significantly smaller abductor hallucis (p=0.048) and flexor halluces brevis (p=0.013) muscles than the female participants without any toe deformities (n=10; p<0.05). Conclusion: This is the first study to use ultrasound to investigate the size of the toe flexor muscles in older people with hallux valgus and lesser toe deformities compared to otherwise healthy older adults. The size of the abductor hallucis and flexor hallucis brevis muscles were decreased in participants with hallux valgus whereas the quadratus plantae, flexor digitorum brevis, abductor hallucis and flexor halluces brevis muscles were smaller in those participants with lesser toe deformities

Zinc-bound metallothioneins and immune plasticity: lessons from very old mice and humans

The capacity of the remodelling immune responses during stress (named immune plasticity) is fundamental to reach successful ageing. We herein report two pivotal experimental models in order to demonstrate the relevance of the immune plasticity in ageing and successful ageing. These two experimental models will be compared with the capacity in remodelling the immune response in human centenarians. With regard to experimental models, one model is represented by the circadian rhythms of immune responses, the other one is the immune responses during partial hepatectomy/liver regeneration (pHx). The latter is suggestive because it mimics the immunosenescence and chronic inflammation 48 h after partial hepatectomy in the young through the continuous production of IL-6, which is the main cause of immune plasticity lack in ageing. The constant production of IL-6 leads to abnormal increments of zinc-bound Metallothionein (MT), which is in turn unable in zinc release in ageing. As a consequence, low zinc ion bioavailability appears for thymic and extrathymic immune efficiency, in particular of liver NKT cells bearing TCR γδ. The remodelling during the circadian cycle and during pHx of zinc-bound MT confers the immune plasticity of liver NKT γδ cells and NK cells in young and very old mice, not in old mice. With regard to human centenarians and their capacity in remodelling the immune response with respect to elderly, these exceptional individuals display low zinc-bound MT associated with: a) satisfactory intracellular zinc ion availability, b) more capacity in zinc release by MT, c) less inflammation due to low gene expression of IL-6 receptor (gp130), d) increased levels of IFN-gamma and number of NKT cell bearing TCR γδ. Moreover, some polymorphisms for MT tested in PBMCs from human donors are related to successful ageing. In conclusion, zinc-bound MT homeostasis is fundamental to confer the immune plasticity that is a condition "sine qua non" to achieve healthy ageing and longevity

ANNALS EXPRESS: Predictive Role of Tear Protein Expression in The Early Diagnosis of Sj\uf6gren's Syndrome

Background: The contribution of tear protein expression in patients with presumed diagnosis of Sjogren syndrome is underestimated. We aimed to evaluate the role of tear proteins in the Sjogren syndrome early diagnosis. Methods: Charts from 110 patients suspected of Sjogren syndrome were analysed and the subsequent diagnosis retrieved. Subjective symptoms (ocular surface disease index, OSDI), tear film break-up time (TFBUT), Schirmer test, Jones test, tear clearance (TC), corneal (NEI score) and conjunctival staining (van Bjerstelveldt score), esthesiometry, cytology, tear protein analysis (total protein [TP] content, lysozyme-C [LYS-C], lactoferrin [LACTO], lipocalin-I [LIPOC-I] and albumin [ALB]) were analysed. The diagnostic performance with area under the curve (AUC) and odds ratio (OR) for each parameter were calculated. Results: Thirty-five patients (31.8%) had been diagnosed as affected by Sjogren syndrome. Clinical tests showed lower diagnostic performance (OSDI > 44 [AUC 0.57], Schirmer 1/16 [0.68], Jones 2 [0.51], conjunctival staining > 2 [0.78]) compared with tear proteins (LYS-C = 15% [0.79]). LYS-C, LACTO, LIPOC-1 and ALB showed a significant association in predicting Sjogren syndrome vs. not-Sjogren syndrome dry eye (OR, respectively, 4.9, 5.5, 7.2, 6.7). Conclusions: Tear proteins' concentrations showed a significant higher accuracy compared with the traditional ocular clinical tests for reaching Sjogren syndrome's diagnosis. In particular, LACTO and LIPOC- I provided an excellent diagnostic performance and thus could likely be considered promising biomarkers of Sjogren syndrome