N-Butyrylated Hyaluronic Acid Achieves Anti-Inflammatory Effects In Vitro and in Adjuvant-Induced Immune Activation in Rats.

Previously synthesized N-butyrylated hyaluronic acid (BHA) provides anti-inflammatory effects in rat models of acute gouty arthritis and hyperuricemia. However, the mechanism of action remains to be elucidated. Herein, the anti-inflammatory and antioxidative activities of BHA and the targeted signaling pathways were explored with LPS-induced RAW264.7 and an adjuvant-induced inflammation in a rat model. Results indicated that BHA inhibited the generation of pro-inflammatory cytokines TNFα, IL-1ß and IL-6, reduced ROS production and down-regulated JAK1-STAT1/3 signaling pathways in LPS-induced RAW264.7. In vivo, BHA alleviated paw and joint swelling, decreased inflammatory cell infiltration in paw tissues, suppressed gene expressions of p38 and p65, down-regulated the NF-κB and MAPK signaling pathways and reduced protein levels of TNFα, IL-1ß and IL-6 in joint tissues of arthritis rats. This study demonstrated the pivotal role of BHA in anti-inflammation and anti-oxidation, suggesting the potential clinical value of BHA in the prevention of inflammatory arthritis and is worthy for development as a new pharmacological treatment.

Secreted Phosphoprotein 24 is a Biomarker of Mineral Metabolism.

The 24 kD form of secreted phosphoprotein (SPP-24), a cytokine-binding bone matrix protein with various truncated C-terminal products, is primarily synthesized by the liver. SPP-24 shares homology with fetuin-A, a potent vascular and soft tissue calcification inhibitor and SPP-24 is one component of calciprotein particles (CPPs), a circulating fetuin-mineral complex. The limited molecular evidence to date suggests that SPP-24 may also function as an inhibitor of bone formation and ectopic vascular calcification, potentially through bone morphogenic protein 2 (BMP-2) and Wnt-signaling mediated actions. The C-terminal products of SPP-24 bind to BMP-2 and attenuate BMP-2-induced bone formation. The aim of this study was to assess circulating SPP-24 in relation to kidney function and in concert with markers of mineral metabolism in humans. SPP-24 was measured in the serum of total of 192 subjects using ELISA-based measurements. Subjects were participants of one of two cohorts: (1) mGFR Cohort (n = 80) was participants of a study of measured GFR (mGFR) using inulin urinary clearance, recruited mostly from a chronic kidney disease clinic with low-range kidney function (eGFR 38.7 ± 25.0 mL/min/1.73 m2) and (2) CaMOS Cohort (n = 112) was a subset of randomly selected, community-dwelling participants of year 10 of the Canadian Multicentre Osteoporosis Study with eGFR in the normal range of 75.0 ± 15.9 mL/min/1.73 m2. In the combined cohort, the mean SPP-24 was 167.7 ± 101.1 ng/mL (range 33.4-633.6 ng/mL). The mean age was 66.5 ± 11.3, 57.1% female and mean eGFR (CKD-EPI) was 59.9 ± 27.0 mL/min/1.73 m2 (range 8-122 mL/min/1.73 m2). There was a strong inverse correlation between SPP-24 and eGFR (R = - 0.58, p < 0.001) that remained after adjustment for age. Following adjustment for age, eGFR, and sex, SPP-24 was significantly associated with phosphate (R = - 0.199), PTH (R = 0.298), and the Wnt-signaling inhibitor Dickkopf-related protein 1 (R = - 0.156). The results of this study indicate that SPP-24 is significantly altered by kidney function and is the first human data linking levels of SPP-24 to other biomarkers involved in mineral metabolism. Whether there is a role for circulating SPP-24 in bone formation and ectopic mineralization requires further study.

A Low Molecular Weight Hyaluronic Acid Derivative Accelerates Excisional Wound Healing by Modulating Pro-Inflammation, Promoting Epithelialization and Neovascularization, and Remodeling Collagen.

Recent knowledge of the cellular and molecular mechanisms underlying cutaneous wound healing has advanced the development of medical products. However, patients still suffer from the failure of current treatments, due to the complexity of healing process and thus novel therapeutic approaches are urgently needed. Previously, our laboratories produced a range of low molecular weight hyaluronic acid (LMW-HA) fragments, where a proportion of the glucosamine moieties were chemically N-acyl substituted. Specifically, N-butyrylation results in anti-inflammatory properties in a macrophage system, and we demonstrate the importance of N-acyl substituents in modulating the inflammatory response of LMW-HA. We have set up an inter-institutional collaborative program to examine the biomedical applications of the N-butyrylated LMW-HA (BHA). In this study, the potentials of BHA for dermal healing are assessed in vitro and in vivo. Consequently, BHA significantly promotes dermal healing relative to a commercial wound care product. By contrast, the "parent" partially de-acetylated LMW-HA (DHA) and the re-acetylated DHA (AHA) significantly delays wound closure, demonstrating the specificity of this N-acylation of LMW-HA in wound healing. Mechanistic studies reveal that the BHA-mediated therapeutic effect is achieved by targeting three phases of wound healing (i.e., inflammation, proliferation and maturation), demonstrating the significant potential of BHA for clinical translation in cutaneous wound healing.

N-Butyrylated hyaluronic acid ameliorates gout and hyperuricemia in animal models.

Context: Hyaluronic acid (HA) plays critical roles in the structural skeleton, joint lubrication, renal function and cell signaling. We previously showed that partially N-butyrylated, low molecular weight, hyaluronic acid (BHA) exhibited an anti-inflammatory effect in cultured human macrophage, where inflammation was induced either by a TL-4 agonist or the low molecular weight HA itself, in dose-dependent fashion. Objectives: To investigate the anti-inflammatory, antioxidative, and antihyperuricemic effects of BHA using animal models of acute gouty arthritis and hyperuricemia. Materials and methods: The anti-inflammatory effect of articular BHA (10 and 50 µg) injections was evaluated by measuring joint swelling and the serum levels of inflammatory cytokines in a model of acute gouty arthritis induced by intra-articular injection of monosodium urate crystals in Wistar rats (n = 10/group), in comparison to the control group with saline injection. Antioxidative and antihyperuricemic activities were investigated using intraperitoneal injections of oteracil potassium and yeast extract hyperuricemic Balb/C mice, which were treated with intraperitoneal injection of BHA at day 6-8 in the model. Results: In the gouty arthritis rat model, BHA at a higher dosage (50 µg) demonstrated a strong anti-inflammatory effect by reducing the degree of articular swelling and the serum levels of IL-1ß, IL-8, IFN-γ, and MCP-1 by 5.56%, 6.55%, 15.58% and 33.18%. In the hyperuricemic mouse model, lower dosage BHA (10 µg) was sufficient to provide antioxidative activities by significantly decreasing the ROS levels in both serum and liver by 14.87% and 8.04%, while improving liver SOD by 12.77%. Intraperitoneal injection of BHA suppressed uric acid production through reducing liver XO activity by 19.78% and decreased the serum uric acid level in hyperuricemic mice by 30.41%. Conclusions: This study demonstrated for the first time that BHA exhibits anti-inflammatory, antioxidative and antihyperuricemic effects in vivo, suggesting a potential therapeutic application of BHA in gouty arthritis and hyperuricemia.

Human acetyl-CoA:glucosamine-6-phosphate N-acetyltransferase 1 has a relaxed donor specificity and transfers acyl groups up to four carbons in length.

Glucosamine-6-phosphate N-acetyltransferase1 (GNA1) catalyses the transfer of an acetyl group from acetyl coenzyme A (AcCoA) to glucosamine-6-phosphate (GlcN6P) to form N-acetylglucosamine-6-phosphate (GlcNAc6P), which is an essential intermediate in UDP-GlcNAc biosynthesis. An analog of GlcNAc, N-butyrylglucosamine (GlcNBu) has shown healing properties for bone and articular cartilage in animal models of arthritis. The goal of this work was to examine whether GNA1 has the ability to transfer a butyryl group from butyryl-CoA to GlcN6P to form GlcNBu6P, which can then be converted to GlcNBu. We developed fluorescent and radioactive assays and examined the donor specificity of human GNA1. Acetyl, propionyl, n-butyryl, and isobutyryl groups were all transferred to GlcN6P, but isovaleryl-CoA and decanoyl-CoA did not serve as donor substrates. Site-specific mutants were produced to examine the role of amino acids potentially affecting the size and properties of the AcCoA binding pocket. All of the wild type and mutant enzymes showed activities of both acetyl and butyryl transfer and can therefore be used for the enzymatic synthesis of GlcNBu for biomedical applications.

Chemically modified N-acylated hyaluronan fragments modulate proinflammatory cytokine production by stimulated human macrophages.

Low molecular mass hyaluronans are known to induce inflammation. To determine the role of the acetyl groups of low molecular mass hyaluronan in stimulating the production of proinflammatory cytokines, partial N-deacetylation was carried out by hydrazinolysis. This resulted in 19.7 ± 3.5% free NH2 functional groups, which were then acylated by reacting with an acyl anhydride, including acetic anhydride. Hydrazinolysis resulted in bond cleavage of the hyaluronan chain causing a reduction of the molecular mass to 30-214 kDa. The total NH2 and N-acetyl moieties in the reacetylated hyaluronan were 0% and 98.7 ± 1.5% respectively, whereas for butyrylated hyaluronan, the total NH2, N-acetyl, and N-butyryl moieties were 0, 82.2 ± 4.6, and 22.7 ± 3.8%, respectively, based on (1)H NMR. We studied the effect of these polymers on cytokine production by cultured human macrophages (THP-1 cells). The reacetylated hyaluronan stimulated proinflammatory cytokine production to levels similar to LPS, whereas partially deacetylated hyaluronan had no stimulatory effect, indicating the critical role of the N-acetyl groups in the stimulation of proinflammatory cytokine production. Butyrylated hyaluronan significantly reduced the stimulatory effect on cytokine production by the reacetylated hyaluronan or LPS but had no stimulatory effect of its own. The other partially N-acylated hyaluronan derivatives tested showed smaller stimulatory effects than reacetylated hyaluronan. Antibody and antagonist experiments suggest that the acetylated and partially butyrylated lower molecular mass hyaluronans exert their effects through the TLR-4 receptor system. Selectively N-butyrylated lower molecular mass hyaluronan shows promise as an example of a novel semisynthetic anti-inflammatory molecule.

Effect of Anticholinergic Medications on Falls, Fracture Risk, and Bone Mineral Density Over a 10-Year Period.

BACKGROUND: Many medications used in older adults have strong anticholinergic (ACH) properties, which may increase the risk of falls and fractures. Use of these medications was identified in a population-based Canadian cohort. OBJECTIVE: To identify the fall and fracture risk associated with ACH medication use. METHODS: Data collection and analysis were conducted at baseline, year 5, and year 10. Cross-sectional analyses were performed to examine associations between ACH medication use and falls. Time-dependent Cox regression was used to examine time to first nontraumatic fracture. Finally, change in bone mineral density (BMD) over 10 years was compared in ACH medication users versus nonusers. RESULTS: Strongly ACH medications were used by 618 of 7753 participants (8.0%) at study baseline, 592 (9.5%) at year 5, and 334 (7.7%) at year 10. Unadjusted ACH medication use was associated with falls at baseline (odds ratio = 1.50; 95% CI = 1.14-1.98; P = 0.004), but the association was no longer significant after covariate adjustment. Similar results occurred at years 5 and 10. ACH medication use was associated with increased incident fracture risk before (hazard ratio = 1.22; CI = 1.13-1.32; P < 0.001) but not after covariate adjustment. Mean (SD) change in femoral neck BMD T-score over 10 years, in those using ACH medications at both years 0 and 5, was -0.60 (0.63) in ACH users versus -0.49 (0.45) in nonusers (P = 0.041), but this was not significant after covariate adjustment. CONCLUSIONS: ACH medications were not found to be independently associated with an increased risk of falling, fractures, or BMD loss. Rather, factors associated with ACH medication use explained the apparent associations.

Prospectively measured 10-year changes in health-related quality of life and comparison with cross-sectional estimates in a population-based cohort of adult women and men.

PURPOSE: To prospectively assess changes in health-related quality of life (HRQOL) over 10 years, by age and sex, and to compare measured within-person change to estimates of change based on cross-sectional data. METHODS: Participants in the Canadian Multicentre Osteoporosis Study completed the 36-item short form (SF-36) in 1995/1997 and 2005/2007. Mean within-person changes for domain and summary components were calculated for men and women separately, stratified by 10-year age groups. Projected changes based on published age- and sex-stratified cross-sectional data were also calculated. Mean differences between the two methods were then estimated, along with the 95 % credible intervals of the differences. RESULTS: Data were available for 5,569/9,423 (59.1 %) of the original cohort. Prospectively collected 10-year changes suggested that the four physically oriented domains declined in all but the youngest group of men and women, with declines in the elderly men exceeding 25 points. The four mentally oriented domains tended to improve over time, only showing substantial declines in vitality and role emotional in older women, and all four domains in older men. Cross-sectional estimates identified a similar pattern of change but with a smaller magnitude, particularly in men. Correspondence between the two methods was generally high. CONCLUSIONS: Changes in HRQOL may be minimal over much of the life span, but physically oriented HRQOL can decline substantially after middle age. Although clinically relevant declines were more evident in prospectively collected data, differences in 10-year age increments of cross-sectional data may be a reasonable proxy for longitudinal changes, at least in those under 65 years of age. Results provide additional insight into the natural progression of HRQOL in the general population.

Choice of lumbar spine bone density reference database for fracture prediction in men and women: a population-based analysis.

The diagnosis of osteoporosis in men is controversial, although most studies demonstrate similar fracture rates for men and women with the same level of hip bone mineral density (BMD). Whether this applies to the lumbar spine is currently uncertain and has important implications with respect to choice of reference population for T-score calculation and osteoporosis diagnosis. This question was specifically addressed in the population-based Canadian Multicentre Osteoporosis Study cohort of 4745 women and 1887 men ages 50+ yr at the time of baseline lumbar spine dual energy x-ray absorptiometry. In up to 10 yr of observation, incident clinical major osteoporotic fractures occurred in 110 men (5.8%) vs 543 women (11.4%) (p < 0.001). Mean lumbar spine BMD in men was greater than in women, both among those with and those without incident major osteoporotic fracture (p < 0.001). Men were at slightly lower risk for incident major osteoporotic fracture than women for an equivalent lumbar spine BMD (age- and BMD-adjusted rate ratio 0.75, 95% confidence interval 0.60-0.93, p = 0.008) with similar findings after adjustment for the World Health Organization fracture risk assessment clinical risk factors or competing mortality. No significant sex difference in the BMD relationship was seen for vertebral fractures (clinical or radiographic) or for all fractures. In summary, this large population-based longitudinal cohort study found similar or lower fracture risk for men vs women after adjustment for absolute lumbar spine BMD and additional covariates. The least complicated model for describing fracture risk is therefore to use the same reference lumbar spine data for generating T-scores in men and women.

Immunoassay of low to moderately abundant anionic proteins utilizing selective immobilization to chitosan-coated plates.

The quantitation of low to moderately abundant serum proteins is a common problem encountered in biochemistry. A physical property of the antigen of interest needs to be exploited in the initial binding step of an immunoassay resulting in capture (purification). We describe a two-stage immunoassay utilizing chromogenic and chemiluminescent substrates which is applied to two serum anionic proteins. In this assay, anionic serum proteins are selectively bound to positively charged chitosan-coated polystyrene plates at pH 6.1, in the presence of detergent. The assay has a detection limit of 0.1 microg/mL and a 1000-fold range.

Dietary patterns in Canadian men and women ages 25 and older: relationship to demographics, body mass index, and bone mineral density.

BACKGROUND: Previous research has shown that underlying dietary patterns are related to the risk of many different adverse health outcomes, but the relationship of these underlying patterns to skeletal fragility is not well understood. The objective of the study was to determine whether dietary patterns in men (ages 25-49, 50+) and women (pre-menopause, post-menopause) are related to femoral neck bone mineral density (BMD) independently of other lifestyle variables, and whether this relationship is mediated by body mass index. METHODS: We performed an analysis of 1928 men and 4611 women participants in the Canadian Multicentre Osteoporosis Study, a randomly selected population-based longitudinal cohort. We determined dietary patterns based on the self-administered food frequency questionnaires in year 2 of the study (1997-99). Our primary outcome was BMD as measured by dual x-ray absorptiometry in year 5 of the study (2000-02). RESULTS: We identified two underlying dietary patterns using factor analysis and then derived factor scores. The first factor (nutrient dense) was most strongly associated with intake of fruits, vegetables, and whole grains. The second factor (energy dense) was most strongly associated with intake of soft drinks, potato chips and French fries, certain meats (hamburger, hot dog, lunch meat, bacon, and sausage), and certain desserts (doughnuts, chocolate, ice cream). The energy dense factor was associated with higher body mass index independent of other demographic and lifestyle factors, and body mass index was a strong independent predictor of BMD. Surprisingly, we did not find a similar positive association between diet and BMD. In fact, when adjusted for body mass index, each standard deviation increase in the energy dense score was associated with a BMD decrease of 0.009 (95% CI: 0.002, 0.016) g/cm(2) for men 50+ years old and 0.004 (95% CI: 0.000, 0.008) g/cm(2) for postmenopausal women. In contrast, for men 25-49 years old, each standard deviation increase in the nutrient dense score, adjusted for body mass index, was associated with a BMD increase of 0.012 (95% CI: 0.002, 0.022) g/cm(2). CONCLUSIONS: In summary, we found no consistent relationship between diet and BMD despite finding a positive association between a diet high in energy dense foods and higher body mass index and a strong correlation between body mass index and BMD. Our data suggest that some factor related to the energy dense dietary pattern may partially offset the advantages of higher body mass index with regard to bone health.

Post-Streptococcal Reactive Arthritis.

INTRODUCTION: Post-Streptococcal Reactive Arthritis (PSRA) is defined as inflammatory arthritis of ≥1 joint associated with a recent group A streptococcal infection in a patient who does not fulfill the Jones criteria for the diagnosis of Acute Rheumatic Fever (ARF). METHODS: In this narrative review, we conducted a systematic search on MEDLINE, EMBASE, Cochrane Library and Google Scholar using the words poststreptococcal reactive arthritis. The search covered the time period between 1982 and 2016. The purpose of this review is to summarize the current state of knowledge of PSRA with respect to the definition, epidemiology, clinical presentation and treatment. We also summarize the key differences between PSRA, reactive arthritis (ReA) and ARF. RESULTS: PSRA has a bimodal age distribution at ages 8-14 and 21-37 years with an almost equal male to female ratio. Clinically, it causes acute asymmetrical non-migratory polyarthritis, however, tenosynovitis and small joint arthritis may occur. This disease entity can be associated with extraarticular manifestations, including erythema nodosum, uveitis and glomerulonephritis. The frequency of HLA-B27 in PSRA does not differ from that of the normal population, which suggests that it is a separate entity from ReA. Involvement of the axial skeleton, including sacroiliitis, is uncommon in PSRA. PSRA tends to occur within 10 days of a group A streptococcal infection, as opposed to the 2 to 3 weeks delay for ARF. PSRA can be associated with prolonged or recurrent arthritis, in contrast to ARF, in which arthritis usually lasts a few days to 3 weeks. Treatment usually involves NSAIDs or corticosteroids. CONCLUSION: We summarize clinical features that help differentiate PSRA from ARF and ReA. First-line treatment options include NSAIDs and corticosteroids. Most cases resolve spontaneously within a few weeks, but some cases are recurrent or prolonged. There are no published randomized controlled trials of PSRA.

Is Rheumatoid Arthritis a Risk Factor for Fractures: A Systematic Review of Observational Studies.

AIM: The primary objective was to assess the risk of fractures in adults with RA compared with controls from the general population. The review also assessed an increased risk of fractures in RA patients when accounting for steroid use, RA disease severity or functional impairment. METHODS: Citations were screened from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and CINAHL. Included citations were written in English, including adult patients at least 18 years of age and compared fracture incidence or prevalence between RA patients and a control group. Case-control, cohort and cross-sectional studies were included. RESULTS: There were a total of 3451 citations; after application of the inclusion criteria, 17 studies were selected. In 14 of the 17 studies, there was an increase in the risk of fracture in RA patients compared to controls. In studies that evaluated for glucocorticoid use, four of 13 demonstrated an increased risk of fracture with glucocorticoid use, however, only two of these four studies specifically assessed glucocorticoid use amongst patients with RA. In studies that analyzed RA severity or functional impairment, two of seven demonstrated disease severity or impairment as a risk factor for fracture. There was marked study heterogeneity in terms of patient and fracture characteristics, which was a limitation of the analysis that impeded the ability to make direct comparisons. CONCLUSION: The risk of fracture in RA patients is elevated when compared to the general population, although the etiology of the increased risk remains to be elucidated.

Changes in vascular calcification and bone mineral density in calcium supplement users from the Canadian Multi-center Osteoporosis Study (CaMOS).

BACKGROUND AND AIMS: Calcium supplements have been associated with increased cardiovascular events. This study investigates the relationship between calcium supplement use and the 5 year progression of abdominal aorta calcification (AAC) in participants from one center of the Canadian Multi-Centre Osteoporosis Study (CaMOS). METHODS: Participants (n = 296; 217 women and 79 men) had lateral spine X-rays and DEXA bone mineral density (BMD) scans (femoral neck, lumbar spine and total hip) taken at two time points within a 5 year interval. AAC was assessed using the Framingham Method. Calcium supplement use was assessed by a facilitated health history questionnaire and medication inventory. RESULTS: AAC significantly increased over 5 years, AAC progression was significantly greater in calcium supplement users, as compared to non-users, overall and in females. The amount of calcium was positively correlated to AAC progression. A multi-variable linear regression model was generated for women only, as there were not enough men for multivariable modelling. Calcium supplement use and amount remained significantly associated with AAC progression after adjustment for age, hypertension, diabetes and smoking history. Change in AAC score was not associated with change in BMD T-Score. In univariate analyses of males, calcium supplement use was associated with a significantly greater BMD loss at the lumbar spine, hip, and femoral neck. CONCLUSIONS: Older female calcium supplement users had significantly higher AAC progression over 5 years, but did not have any significant BMD preservation. These results suggest that vascular calcification may contribute to the cardiovascular events observed in calcium supplement users.

Statin Use is Associated With Insulin Resistance in Participants of the Canadian Multicentre Osteoporosis Study.

CONTEXT: Statins have been linked to the development of diabetes and atherosclerotic plaque calcification in patients with cardiac disease. OBJECTIVE: To determine the association between statin use and statin characteristics and insulin resistance and abdominal aortic calcification (AAC) in participants of the Canadian Multicentre Osteoporosis Study (CaMos). DESIGN: Observational study. SETTING: General community. PARTICIPANTS: Nondiabetic participants of the Kingston CaMos site. INTERVENTION: Insulin resistance and AAC in statin users and nonstatin users were compared with and without the inclusion of a propensity score (PS) to be on a statin. The covariates of hypertension, sex, body mass index, smoking, kidney stones, and age that were included in the PS were selected based on clinical judgment confirmed by the statistical analysis of a difference between statin users and nonstatin users. MAIN OUTCOME MEASURES: Insulin resistance measured by the homeostasis model assessment (HOMA-IR) and AAC assessed on lateral spine radiographs using the Framingham methodology. RESULTS: Using a general linear model, statin use was associated with higher levels of HOMA-IR after stratified PS adjustment (ß = 1.52, [1.18-1.95], P < 0.01). Hydrophilic statin users (n = 9) and lipophilic statins users (n = 30) had higher HOMA-IR compared to nonstatin users (n = 125) ([ß = 2.29, (1.43-3.68), P < 0.001] and [ß = 1.36, (1.04-1.78), P < 0.05]), respectively, in general linear models after stratified PS adjustment. Statin use was associated with AAC without stratifying by PS in the Wilcoxon test, but was no longer significant when stratified by PS. CONCLUSIONS: Statins, widely prescribed drugs to lower cholesterol, may have unintended consequences related to glucose homeostasis that could be relevant in healthy aging.

Vertebral Fractures in Individuals With Type 2 Diabetes: More Than Skeletal Complications Alone.

OBJECTIVE: We aimed to assess whether individuals with type 2 diabetes (T2D) have increased risk of vertebral fractures (VFs) and to estimate nonvertebral fracture and mortality risk among individuals with both prevalent T2D and VFs. RESEARCH DESIGN AND METHODS: A systematic PubMed search was performed to identify studies that investigated the relationship between T2D and VFs. Cohorts providing individual participant data (IPD) were also included. Estimates from published summary data and IPD cohorts were pooled in a random-effects meta-analysis. Multivariate Cox regression models were used to estimate nonvertebral fracture and mortality risk among individuals with T2D and VFs. RESULTS: Across 15 studies comprising 852,705 men and women, individuals with T2D had lower risk of prevalent (odds ratio [OR] 0.84 [95% CI 0.74-0.95]; I 2 = 0.0%; P het = 0.54) but increased risk of incident VFs (OR 1.35 [95% CI 1.27-1.44]; I 2 = 0.6%; P het = 0.43). In the IPD cohorts (N = 19,820), risk of nonvertebral fractures was higher in those with both T2D and VFs compared with those without T2D or VFs (hazard ratio [HR] 2.42 [95% CI 1.86-3.15]) or with VFs (HR 1.73 [95% CI 1.32-2.27]) or T2D (HR 1.94 [95% CI 1.46-2.59]) alone. Individuals with both T2D and VFs had increased mortality compared with individuals without T2D and VFs (HR 2.11 [95% CI 1.72-2.59]) or with VFs alone (HR 1.84 [95% CI 1.49-2.28]) and borderline increased compared with individuals with T2D alone (HR 1.23 [95% CI 0.99-1.52]). CONCLUSIONS: Based on our findings, individuals with T2D should be systematically assessed for presence of VFs, and, as in individuals without T2D, their presence constitutes an indication to start osteoporosis treatment for the prevention of future fractures.

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study.

BACKGROUND: Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality. METHODS: A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and "other"). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death. RESULTS: Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1-6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4-7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1-12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2-8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0-8.7). INTERPRETATION: Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.

Health-related quality of life in Canadian adolescents and young adults: normative data using the SF-36.

OBJECTIVES: Normative data for the SF-36 measure of health-related quality of life (HRQOL) exist for those over 25 years of age, based on data from the population-based Canadian Multicentre Osteoporosis Study (CaMos). CaMos recently recruited a sample of young Canadians aged between 16 and 24 years. The purpose of this study was to develop normative SF-36 data for this age group. METHODS: After direct standardization to the Canadian population, means, standard deviations (SD), 95% confidence intervals and percentage at floor and ceiling were produced for the eight domain and two summary scores of the SF-36. Domains are scored from 0 (poor) to 100 (excellent). Summary scores are standardized to a mean of 50, with scores over 50 representing better than average and below 50 poorer than average function. Separate analyses were completed for men and women, and for those 16-19 years and 20-24 years. RESULTS: The 1,001 community-based participants consisted of 474 men and 527 women from nine CaMos centres across Canada. Mean Physical Component Summary scores were 53.9 (SD = 6.9) and 53.3 (SD = 5.7) for young men and women, respectively. The equivalent Mental Component Summary scores were 49.3 (SD = 9.7) and 48.8 (SD = 8.9). In general, men scored somewhat higher than women, and younger (16-19 years) women scored higher than older (20-24 years) women, although the differences were small. CONCLUSION: HRQOL is good in this cohort of young Canadians. Both men and women scored somewhat better on physically than mentally oriented domains. In general, Canadian scores were similar to those of the US, while a comparable Swedish sample scored higher than both countries on most domains. Results underscore the importance of taking country, age and gender into consideration when using normative data.

Chemical Modification of the N-Acetyl Moieties of Hyaluronic Acid from Streptococcus equi for Studies in Cytokine Production.

Partial N-deacetylation and certain N-reacylations of low-molecular-weight hyaluronic acid (hyaluronan) abate its proinflammatory properties in mammalian systems. Here, we describe the treatment of bacterial hyaluronic acid by hydrazine or NaOH to yield smaller partially deacetylated polymers. These N-deacetylated polymers can be reacylated with acyl anhydrides to yield substituted hyaluronic acid derivatives of equivalent size and equimolar N-acyl substitutions.

Frailty and Risk of Fractures in Patients With Type 2 Diabetes.

OBJECTIVE: We aimed to explore whether frailty was associated with fracture risk and whether frailty could modify the propensity of type 2 diabetes toward increased risk of fractures. RESEARCH DESIGN AND METHODS: Data were from a prospective cohort study. Our primary outcome was time to the first incident clinical fragility fracture; secondary outcomes included time to hip fracture and to clinical spine fracture. Frailty status was measured by a Frailty Index (FI) of deficit accumulation. The Cox model incorporating an interaction term (frailty × diabetes) was used for analyses. RESULTS: The analysis included 3,149 (70% women) participants; 138 (60% women) had diabetes. Higher bone mineral density and FI were observed in participants with diabetes compared with control subjects. A significant relationship between the FI and the risk of incident fragility fractures was found, with a hazard ratio (HR) of 1.02 (95% CI 1.01-1.03) and 1.19 (95% CI 1.10-1.33) for per-0.01 and per-0.10 FI increase, respectively. The interaction was also statistically significant (P = 0.018). The HR for per-0.1 increase in the FI was 1.33 for participants with diabetes and 1.19 for those without diabetes if combining the estimate for the FI itself with the estimate from the interaction term. No evidence of interaction between frailty and diabetes was found for risk of hip and clinical spine fractures. CONCLUSIONS: Participants with type 2 diabetes were significantly frailer than individuals without diabetes. Frailty increases the risk of fragility fracture and enhances the effect of diabetes on fragility fractures. Particular attention should be paid to diabetes as a risk factor for fragility fractures in those who are frail.