Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis

Aging results in deterioration of the immune system, which is associated with increased susceptibility to infection and impaired wound healing in the elderly. Phagocytosis is an essential process in both wound healing and immune defence. As such, age-related impairments in phagocytosis impact on the health of the elderly population. Phagocytic efficiency in peritoneal macrophages, bone marrow-derived macrophages and bone marrow monocytes from young and old mice was investigated. Aging significantly impaired phagocytosis by peritoneal macrophages, both in vitro and in vivo. However, bone marrow-derived macrophages and bone marrow monocytes did not exhibit age-related impairments in phagocytosis, suggesting no intrinsic defect in these cells. We sought to investigate underlying mechanisms in age-related impairments in phagocytosis by peritoneal macrophages. We hypothesized that microenvironmental factors in the peritoneum of old mice impaired macrophage phagocytosis. Indeed, macrophages from young mice injected into the peritoneum of old mice exhibited impaired phagocytosis. Proportions of peritoneal immune cells were characterized, and striking increases in numbers of T cells, B1 and B2 cells were observed in the peritoneum of old mice compared with young mice. In addition, B cell-derived IL-10 was increased in resting and LPS-activated peritoneal cell cultures from old mice. These data demonstrate that aging impairs phagocytosis by tissue-resident peritoneal macrophages, but not by bone marrow-derived macrophages/monocytes, and suggest that age-related defects in macrophage phagocytosis may be due to extrinsic factors in the tissue microenvironment. As such, defects may be reversible and macrophages could be targeted therapeutically in order to boost immune function in the elderly.

Age-related oral changes

Age-related oral changes are seen in the oral hard and soft tissues as well as in bone, the temporomandibular joints and the oral mucosa. As older patients retain their natural teeth for longer, the clinical picture consists of normal physiological age changes in combination with pathological and iatrogenic effects.

CLINICAL RELEVANCE: With an ageing population retaining more of its natural teeth for longer, dental professionals should expect to observe oral age changes more frequently.

Freshwater Reservoir Effect on Re-Dating of Eurasian Steppe Cultures: First Results for Eneolithic and Early Bronze Age North-East Kazakhstan

Freshwater reservoir effects (FRE) can cause a major problem with radiocarbon dating human skeletal material in the Eurasian steppe. We present the first results of research into the extent of the FRE in the sites of Borly 4 (Eneolithic), and Shauke 1 and 8b (Early Bronze Age), North-Eastern Kazakhstan. AMS 14C dating and stable isotope (δ13C, δ15N) analysis of associated groups of samples (32 samples, 11 groups in total) demonstrate that: a) the diet of the humans and fauna analysed was based on the C3 foodchain with no evidence of a C4 plant (such as millet) contribution; aquatic resources apparently were a continuous dietary feature for the humans; b) the first 14C dates obtained for the Upper and Middle Irtysh River region attribute the Eneolithic period of the area to the 34th-30th c. BC, and the Early Bronze Age – to the 25th-20th c. BC; there is a ca. 450 years hiatus between the two periods; c) the maximum fish-herbivore freshwater reservoir offset observed equals 301±47 14C yrs. As such, 14C dates from aquatic and human samples from the area need to be interpreted with caution as they are likely to be affected by the offset (i.e. appear older).
The paper also discusses the effect of a sodium hydroxide (NaOH) wash on δ13C, δ15N, C:Natomic levels and collagen yields of the bone samples. Our results indicate a minor but significant effect of NaOH treatment only on C:Natomic ratios of the samples.

Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling:results of a GITMO/EBMT randomized trial

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)

Successful bone marrow transplant for Fanconi anaemia in transformation

We present a patient who was diagnosed as suffering from Fanconi anaemia at the age of 36 years. At the time of diagnosis his bone marrow showed features of pre-leukaemic transformation. He received an allogeneic bone marrow transplant (BMT) from his HLA-identical sibling. The post-transplant course was unremarkable with evidence of trilineage engraftment at day +32 and no acute or chronic GVHD. He is well with sustained engraftment and no haematological evidence of Fanconi anaemia 18 months post-transplant.

The Middle Stone Age of Eastern Africa

The Middle Stone Age (MSA) covers the evolution, emergence, and dispersal of Homo sapiens. This article focuses on archaeological data and on published material from key stratified sites with some form of geochronological control from across eastern Africa. The MSA is often characterised by a shift from handaxe production towards discoidal and Levallois techniques. Although evidence for the controlled use of fire remains minimal, it seems likely that MSA hominins used it, as well as being highly skilled in working stone and probably bone and wood. MSA hominins appear to have exploited a range of different ecozones and many MSA sites are focused on ecotones, maximising access to resources. Over time, use of rockshelters and caves also seems to have increased. Although much work remains, the MSA is presently one of the most exciting and dynamic periods in the study of human evolution.

Age-period-cohort effects in the incidence of hip fractures: political and economic events are coincident with changes in risk

Introduction: Healthcare improvements have allowed prevention but have also increased life expectancy, resulting in more people being at risk. Our aim was to analyse the separate effects of age, period and cohort on incidence rates by sex in Portugal, 2000–2008. Methods: From the National Hospital Discharge Register, we selected admissions (aged ≥49 years) with hip fractures (ICD9-CM, codes 820.x) caused by low/moderate trauma (falls from standing height or less), readmissions and bone cancer cases. We calculated person-years at risk using population data from Statistics Portugal. To identify period and cohort effects for all ages, we used an age–period–cohort model (1-year intervals) followed by generalised additive models with a negative binomial distribution of the observed incidence rates of hip fractures. Results: There were 77,083 hospital admissions (77.4 % women). Incidence rates increased exponentially with age for both sexes (age effect). Incidence rates fell after 2004 for women and were random for men (period effect). There was a general cohort effect similar in both sexes; risk of hip fracture altered from an increasing trend for those born before 1930 to a decreasing trend following that year. Risk alterations (not statistically significant) coincident with major political and economic change in the history of Portugal were observed around birth cohorts 1920 (stable–increasing), 1940 (decreasing–increasing) and 1950 (increasing–decreasing only among women). Conclusions: Hip fracture risk was higher for those born during major economically/politically unstable periods. Although bone quality reflects lifetime exposure, conditions at birth may determine future risk for hip fractures.

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice.

A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

In postmenopausal women with osteoporosis, denosumab significantly improved trabecular bone score (TBS), an index of trabecular microarchitecture

Background/Purpose: The trabecular bone score (TBS), a novel graylevel texture index determined from lumbar spine DXA scans, correlates with 3D parameters of trabecular bone microarchitecture known to predict fracture. TBS may enhance the identification of patients at increased risk for vertebral fracture independently of bone mineral density (BMD) (Boutroy JBMR 2010; Hans JBMR 2011). Denosumab treatment for 36 months decreased bone turnover, increased BMD, and reduced new vertebral fractures in postmenopausal women with osteoporosis (Cummings NEJM 2009). We explored the effect of denosumab on TBS over 36 months and evaluated the association between TBS and lumbar spine BMD in women who had DXA scans obtained from eligible scanners for TBS evaluation in FREEDOM. Methods: FREEDOM was a 3-year, randomized, double-blind trial that enrolled postmenopausal women with a lumbar spine or total hip DXA T-score __2.5, but not __4.0 at both sites. Women received placebo or 60 mg denosumab every 6 months. A subset of women in FREEDOM participated in a DXA substudy where lumbar spine DXA scans were obtained at baseline and months 1, 6, 12, 24, and 36. We retrospectively applied, in a blinded-to-treatment manner, a novel software program (TBS iNsightR v1.9, Med-Imaps, Pessac, France) to the standard lumbar spine DXA scans obtained in these women to determine their TBS indices at baseline and months 12, 24, and 36. From previous studies, a TBS _1.35 is considered as normal microarchitecture, a TBS between 1.35 and _1.20 as partially deteriorated, and 1.20 reflects degraded microarchitecture. Results: There were 285 women (128 placebo, 157 denosumab) with a TBS value at baseline and _1 post-baseline visit. Their mean age was 73, their mean lumbar spine BMD T-score was _2.79, and their mean lumbar spine TBS was 1.20. In addition to the robust gains in DXA lumbar spine BMD observed with denosumab (9.8% at month 36), there were consistent, progressive, and significant increases in TBS compared with placebo and baseline (Table & Figure). BMD explained a very small fraction of the variance in TBS at baseline (r2_0.07). In addition, the variance in the TBS change was largely unrelated to BMD change, whether expressed in absolute or percentage changes, regardless of treatment, throughout the study (all r2_0.06); indicating that TBS provides distinct information, independently of BMD. Conclusion: In postmenopausal women with osteoporosis, denosumab significantly improved TBS, an index of lumbar spine trabecular microarchitecture, independently of BMD.

Trabecular bone score in type 1 diabetes--a cross-sectional study.

UNLABELLED: Trabecular bone score (TBS) seems to provide additive value on BMD to identify individuals with prevalent fractures in T1D. TBS did not significantly differ between T1D patients and healthy controls, but TBS and HbA1c were independently associated with prevalent fractures in T1D. A TBS cutoff <1.42 reflected prevalent fractures with 91.7 % sensitivity and 43.2 % specificity. INTRODUCTION: Type 1 diabetes (T1D) increases the risk of osteoporotic fractures. TBS was recently proposed as an indirect measure of bone microarchitecture. This study aimed at investigating the TBS in T1D patients and healthy controls. Associations with prevalent fractures were tested. METHODS: One hundred nineteen T1D patients (59 males, 60 premenopausal females; mean age 43.4 ± 8.9 years) and 68 healthy controls matched for gender, age, and body mass index (BMI) were analyzed. The TBS was calculated in the lumbar region, based on two-dimensional (2D) projections of DXA assessments. RESULTS: TBS was 1.357 ± 0.129 in T1D patients and 1.389 ± 0.085 in controls (p = 0.075). T1D patients with prevalent fractures (n = 24) had a significantly lower TBS than T1D patients without fractures (1.309 ± 0.125 versus 1.370 ± 0.127, p = 0.04). The presence of fractures in T1D was associated with lower TBS (odds ratio = 0.024, 95 % confidence interval (CI) = 0.001-0.875; p = 0.042) but not with age or BMI. TBS and HbA1c were independently associated with fractures. The area-under-the curve (AUC) of TBS was similar to that of total hip BMD in discriminating T1D patients with or without prevalent fractures. In this set-up, a TBS cutoff <1.42 discriminated the presence of fractures with a sensitivity of 91.7 % and a specificity of 43.2 %. CONCLUSIONS: TBS values are lower in T1D patients with prevalent fractures, suggesting an alteration of bone strength in this subgroup of patients. Reliable TBS cutoffs for the prediction of fracture risk in T1D need to be determined in larger prospective studies.

A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX.

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.

Effects of dietary restraint and oral contraceptives on bone strength and bone turnover in young women

ABSTRACT Introduction The purpose of this study was to assess specific osteoporosis-related health behaviours and physiological outcomes including daily calcium intake, physical activity levels, bone strength, as assessed by quantitative ultrasound, and bone turnover among women between the ages of 18 and 25. Respective differences on relevant study variables, based on dietary restraint and oral contraceptive use were also examined. Methods One hundred women (20.6 ± 0.2 years of age) volunteered to participate in the study. Informed written consent was obtained by all subjects prior to participation. The study and all related procedures were approved by the Brock University Research Ethics Board. Body mass, height, relative body fat, as well as chest, waist and hip circumferences were measured using standard procedures. The 10-item restrained eating subscale of the Dutch Eating Behaviour Questionnaire (DEBQ) was used to assess dietary restraint (van Strien et al., 1986). Daily calcium intake was assessed by the Rapid Assessment Method (RAM) (Hertzler & Frary 1994). Weekly physical activity was documented by the 4-item Godin Leisure-Time Exercise Questionnaire (Godin & Shephard 1985). Bone strength was determined from the speed of sound (SOS) as measured by QUS (Sunlight 7000S). SOS measurements (m/s) were taken of the dominant and non-dominant sides of the distal one third of the radius and the mid-shaft of the tibia. Resting blood samples were collected from all subjects between 9am and 12pm, in order to evaluate the impact of lifestyle factors on biochemical markers of bone turnover. Blood was collected during the early follicular phase of the menstrual cycle (approximately days 1-5) for all subjects. Samples were centrifliged and the serum or plasma was aliquoted into separate tubes and stored at -80°C until analysis. The bone formation markers measured were Osteocalcin (OC), bone specific alkaline phosphatase (BAP) and 25-OH vitamin D. The bone resorption markers measured were the carboxy (CTx) and amino (NTx) terminal telopeptides of type-I collagen crosslinks. All markers were assessed by ELISA. Subjects were divided into high (HDR) and low dietary restrainers (LDR) based on the median DEBQ score, and also into users (BC) and non-users (nBC) of oral contraceptives. A series of multiple one way ANOVA's were then conducted to identify differences between each set of groups for all relevant variables. A two-way ANOVA analysis was used to explore significant interactions between dietary restraint and use of oral contraceptives while a univariate follow-up analysis was also performed when appropriate. Pearson Product Moment Correlations were used to determine relationships among study variables. Results HDR had significantly higher BMI, %BF and circumference measures but lower daily calcium intake than LDR. There were no significant differences in physical activity levels between HDR and LDR. No significant differences were found between BC and nBC in body composition, calcium intake and physical activity. HDR had significantly lower tibial SOS scores than LDR in both the dominant and non-dominant sites. The post-hoc analysis showed that within the non-birth control group, the HDR had significantly lower tibial SOS scores of bone strength when compared to the LDR but Aere were no significant differences found between the two dietary restraint groups for those currently on birth control. HDR had significantly lower levels of OC than LDR and the BC group had lower levels of BAP than the nBC group. Consistently, the follow-up analysis revealed that within those not on birth control, subjects who were classified as HDR had significantly (f*<0.05) lower levels of OC when compared with LDR but no significant differences were observed in bone turnover between the two dietary restraint groups for those currently on birth control. Physical activity was not correlated with SOS scores and bone turnover markers possibly due to the low physical activity variability in this group of women. Conclusion This is the first study to examine the effects of dietary restraint on bone strength and turnover among this population of women. The most important finding of this study was that bone strength and turnover are negatively influenced by dietary restraint independent of relative body fat. In general, the results of the present thesis suggest that dietary restraint, oral contraceptive use, as well as low daily calcium intake and low physical activity levels were widespread behaviours among this population of college-aged women. The young women who were using dietary restraint as a strategy to lose weight, and thus were in the HDR group, despite their higher relative body fat and weight, had lower scores of bone strength and lower levels of markers of bone turnover compared to the low dietary restrainers. Additionally, bone turnover seemed to be negatively affected by oral contraceptives, while bone strength, as assessed by QUS, seemed unaffected by their use in this population of young women. Physical activity (weekly energy expenditure), on the other hand, was not associated with either bone strength or bone tiimover possibly due to the low variability of this variable in this population of young Canadian women.

Bone speed of sound in overweight and normal-weight girls and adolescents

Over the last two decades, the prevalence of obesity in the general population has been steadily increasing. Obesity is a major issue in scientific research because it is associated with many health problems, one of which is bone quality. In adult females, adiposity is associated with increased bone mineral density, suggesting that there is a protective effect of fat on bone. However, the association between adiposity and bone strength during childhood is not clear. Thus, the purpose of this study was to compare bone strength, as reflected by speed of sound (SOS), of overweight and obese girls and adolescents with normal-weight age-matched controls. Data from 75 females included normal-weight girls (G-NW; body fat:::; 25%; n = 21), overweight and obese girls (GOW; body fat ~ 28%; n = 19), normal-weight adolescents (A-NW, body fat:::; 25%; n = 13) and overweight and obese adolescents (A-OW; body fat ~ 28%; n = 22). Nutrition was assessed with a 24-hour recall questionnaire and habitual physical activity was measured for one week using accelerometry. Using quantitative ultrasound (QUS; Sunlight Omnisense™), bone SOS was measured at the distal radius and mid-tibia. No differences were found between groups in daily total energy, calcium or vitamin D intake. However, all groups were below the recommended daily calcium intake of 1300 mg (Osteoporosis Canada, 2008). Adolescents were significantly less active than girls (14.7 ± 0.6 vs. 6.3 ± 0.6% active for G and A, respectively). OW accumulated significantly less minutes of moderate-to-very vigorous physical activity per day (MVPA) than NW in both age groups (114 ± 6 vs. 57 ± 5 min/day for NW and OW, i respectively). Girls had significantly lower radial SOS (3794 ± 87 vs. 3964 ± 64 mls for G-NW and A-NW, respectively), and tibial SOS (3678 ± 86 vs. 3878 ± 52 mls for G-NW and A-NW, respectively) than adolescents. Radial SOS was similar in the two adiposity groups within each age group. However, tibial SOS was lower in the two overweight groups (3601 ± 75 mls vs. 3739 ± 134 mls for G-OW and A-OW, respectively) compared with the age-matched normal-weight controls. Body fat percentage negatively correlated with tibial SOS in the study sample as a whole (r = -0.30). However, when split into groups, percent bo~y fat correlated with tibial SOS only in the A-OW group (r = -0.53). MVPA correlated with tibial SOS (r = 0.40), once age was partialed out. In conclusion, in contrast withthe higher bone strength characteristic of obese adult women, overweight and obese girls and adolescents are characterized by low tibial bone strength, as assessed with QUS. The differences between adiposity groups in tibial SOS may be at least partially due to the reduced weight-bearing physical activity levels in the overweight girls and adolescents. However, other factors, such as hormonal influences associated with high body fat may also playa role in reducing bone strength in overweight girls. Further research is required to reveal the mechanisms causing low bone strength in overweight and obese children and adolescents.

The relationship between socioeconomic status, schools and bone health among adolescent females in Southern Ontario

We studied the association between socioeconomic status (SES), school attended and bone health measured by bone speed of sound (SOS) among adolescent females in Canada. 412 participants from six randomly selected schools in Southern Ontario were examined. Bone SOS was measured by quantitative ultrasound. Participant’s school and aggregate area-based census-derived (AABCD) SES were evaluated as predictors. Mean participant age was 15.7 (SD 1.0) years. Average median family income was $68,162 (SD $19,366). Median family income was non-linearly associated with bone SOS and restricted cubic splines described the relationship. Univariate regression, accounting for clustering of participants in schools, revealed a significant non-linear association between AABCD-median family income and non-dominant tibial SOS (LRT p = 0.031). Multivariable regression revealed school to have a significant impact (LRT p = 0.0001). High schools had a strong influence on the bone health of female students and this effect overrode the effect of SES.

Effect of a high fat maternal diet on body composition and bone development in male offspring

Direct high fat (HF) feeding has adverse effects on body composition and bone development in rodents. However, it is unclear whether maternal HF feeding has similar effects in male rat offspring. The objectives of this thesis were to determine if maternal HF feeding altered body composition, plasma hormones, bone development, and bone fatty acid composition in male offspring at weaning and 3 months of age. Maternal HF feeding increased bone mass and altered femur fatty acid composition at weaning, without differences in fat mass, lean mass, plasma hormones, or bone mass (femur or lumbar vertebrae). However, early differences did not persist at 3 months of age or contribute to lower bone strength – following consumption of a control diet post-weaning. These findings suggest that maternal HF feeding can alter body composition and bone development in weanling male offspring, without long-lasting effects if a healthy control diet is consumed post-weaning.