Age-related Bone Loss Research Articles

Molecular structure, expression, and functional role of Clec11a in skeletal biology and cancers.

C-type lectin domain family 11 member A (Clec11a), also known as stem cell growth factor (SCGF), C-type lectin superfamily member 3 (CLECSF3), or osteolectin was initially identified as a growth factor for hematopoietic progenitor cells. The human Clec11a gene encodes a polypeptide of 323 amino acids with characteristics of a secreted glycoprotein encompassing two integrin-binding motifs, RGD (Arg-Gly-Asp) and LDT (Leu-Asp-Thr), a putative leucine zipperdomain, and a functional C-type lectin domain. It regulates hematopoietic differentiation and homeostasisand exhibits a protective effect against severe malarial anemia and lipotoxicity. Furthermore, Clec11a promotes the differentiation of mesenchymal progenitors into mature osteoblasts in vitro and plays an important role in the maintenance of adult skeleton age-related bone loss and fracture repair. Receptor ligand binding results in activation of downstream signaling cascades including glycogen synthase kinase 3 (GSK3), β-catenin, and Wnt, resulting in the expression of osteoblast-related gene transcripts including Alp, Runx2, Lef1, and Axin2. In addition, Clec11a is also associated with the development of several cancers, including leukemia, multiple myeloma, and gastrointestinal tract tumors. To date, however, the mechanisms governing transcription regulation of the Clec11a gene arenot known and remainto be uncovered. Understanding the function and mechanism of action of Clec11a will pave the way for the development of Clec11a as a novel therapeutic target for conditions such as cancer, anemia, and skeletal diseases.

Secular decline in limb bone strength among South African Africans during the 19th and 20th centuries.

South African Africans have been reported to have experienced negative or null secular trends in stature and other measures of skeletal structure across the 19th and 20th centuries, presumably due to poor living conditions during a time of intensifying racial discrimination. Here, we investigate whether any secular trend is apparent in limb bone strength during the same period. Cadaver-derived skeletons (n = 221) were analyzed from female and male South African Africans who were born between 1839 and 1970, lived in and around Johannesburg, and died between 1925 and 1991 when they were 17-90 years of age. For each skeleton, a humerus and femur were scanned using computed tomography, and mid-diaphyseal cross-sectional geometric properties were calculated and scaled according to body size. In general linear mixed models accounting for sex, age at death, and skeletal element, year of birth was a significant (p < .05) negative predictor of size-standardized mid-diaphyseal cortical area (a proxy for resistance to axial loading) and polar moment of area (a proxy for resistance to bending and torsion), indicating a temporal trend toward diminishing limb bone strength. No significant interactions were detected between year of birth and age at death, suggesting that the decline in limb bone strength was mainly due to changes in skeletal maturation rather than severity of age-related bone loss. Limb bone strength is thus potentially another feature of the skeletal biology of South African Africans that was compromised by poor living conditions during the 19th and 20th centuries.

Age-dependent role of SIRT6 in jawbone via regulating senescence and autophagy of bone marrow stromal cells.

Age-related jawbone loss directly impact the function of oral cavity resulted from tooth loss, implant failure, and jaw fracture. Numerous evidences show that age-related senescence of bone marrow stromal cells (BMSCs) play a critical role in bone loss, but little attention has been paid to jawbone. Here, we delineated the critical role of sirtuin family protein 6 (SIRT6) in senescence, autophagy, and osteogenesis of BMSCs from jawbones. Radiography analysis showed less jawbone quality in elderly than young people. We also showed that SIRT6 expression decreased in bone tissue and BMSCs from the elderly by immunochemical staining. BMSCs from the elderly exhibited decreased osteogenic differentiation and inclined senescence which these phenotypes could be simulated by SIRT6 knockdown. Furthermore, accompanied with the inhibition of SIRT6, the autophagy level and ostogenesis of BMSCs was also decreased. However, using rapamycin, an autophagy activator, could rescue these adverse effects of BMSCs caused by SIRT6 inhibition. Mechanistically, SIRT6 regulated the autophagy and osteogenesis of BMSCs by activating AKT-mTOR pathway, at least in part. Finally, a decreased jawbone quality was shown in SIRT6 haploinsufficiency mice by Wnt1 specific tissue knockdown (Wnt1-Cre;SIRT6fl/+) model. Taken together, our data revealed that SIRT6 adjusted senescence and osteogenesis of BMSCs via altering autophagy level, and associated with age-related bone loss. SIRT6 could be as a promising therapeutic target for age-related osteoporosis of jawbone.

Effect of vitamin D on bone strength in older African Americans: a randomized controlled trial.

The role of vitamin D in bone strength has not been investigated in the African American (AA) population. A 3-year randomized controlled trial was designed to examine the effect of vitamin D supplementation on physical performance, bone loss, and bone strength in healthy older AA women. A total of 260 postmenopausal AA women, ages ≥ 60years were randomized to a vitamin D3 or placebo arm. Vitamin D3 dose was adjusted to maintain serum 25OHD > 30ng/mL. Bone mineral density, femoral axis length, and femoral neck (FN) width were measured by dual-energy X-ray absorptiometry. Composite indices of FN strength [compression strength index (CSI), bending strength index (BSI), and impact strength index (ISI)] were computed. The mean age of participants was 68.2 ± 4.9years. Baseline characteristics between groups were similar. The average dose of vitamin D3 was 3490 ± 1465IU/day in the active group. The mean serum 25OHD was 46.8 ± 1.2ng/mL versus 20.7 ± 1.1ng/mL in the active versus placebo group. Serum 25OHD did not correlate with any composite indices. The longitudinal differences observed in FN width, CSI, BSI, and ISI in both groups were not statistically significant (all p values > 0.05). Further, there was no group × time interaction effect for any of the composite indices (all p values > 0.05). Maintaining serum 25OHD > 30ng/mL (75nmol/L) does not affect bone strength in older AA women. There is no evidence to support vitamin D intake greater than the recommended RDA by the Institute of Medicine in this population for bone strength.

Mechanosensitive Ca2+ signaling and coordination is diminished in osteocytes of aged mice during ex vivo tibial loading

ABSTRACTPurpose: The osteocyte is considered the major mechanosensor in bone, capable of detecting forces at a cellular level to coordinate bone formation and resorption. The pathology of age-related bone loss, a hallmark of osteoporosis, is attributed in part to impaired osteocyte mechanosensing. However, real-time evidence of the effect of aging on osteocyte responses to mechanical load is lacking. Intracellular calcium (Ca2+) oscillations have been characterized as an early mechanosensitive response in osteocytes in systems of multiple scales and thus can serve as a real-time measure of osteocyte mechanosensitivity. Our objective was to utilize an ex vivo model to investigate potentially altered mechanosensing in the osteocyte network with aging.Methods: Tibiae were explanted from young-adult (5 mo) and aged (22 mo) female mice and incubated with Fluo-8 AM to visualize osteocyte intracellular Ca2+. Whole tibiae were cyclically loaded while in situ osteocyte Ca2+ dynamics were simultaneously imaged with confocal microscopy. Responsive osteocyte percentage and Ca2+ peak characteristics were quantified, as well as signaling synchrony between paired cells in the field of view.Results: Fewer osteocytes responded to mechanical loading in aged mice compared to young-adult and did so in a delayed manner. Osteocytes from aged mice also lacked the well-correlated relationship between Ca2+ signaling synchrony and cell-cell distance exhibited by young-adult osteocytes.Conclusions: We have demonstrated, for the first time, real-time evidence of the diminished mechanosensing and lack of signaling coordination in aged osteocyte networks in tibial explants, which may contribute to pathology of age-induced bone loss.

Sex differences in the patterning of age-related bone loss in the human hallucal metatarsal in rural and urban populations.

Age-degenerative features of the metatarsals are poorly known despite the importance of metatarsal bone properties for investigating mobility patterns. We assessed the role of habitual activity in shaping the patterning and magnitude of sexual dimorphism in age-related bone loss in the hallucal metatarsal. Cross-sections were extracted at midshaft from micro-computed tomography scan models of individuals from medieval rural (Abingdon Vineyard) and early industrial urban (Spitalfields) settings (n = 71). A suite of cross-sectional geometry dimensions and biomechanical properties were compared between populations. The rural group display generally stronger and larger metatarsals that show a greater capacity to resist torsion and that have comparatively greater bending strength along the medio-lateral plane. Men in both groups show greater values of cortical area than women, but only in the urban group do men show lower magnitudes of age-related decline compared to females. Women in rural and urban populations show different patterns of age-related decline in bone mass, particularly old women in the urban group show a marked decline in cortical area that is absent for women in the rural group. Lifetime exposure to hard, physical activity in an agricultural setting has contributed to the attainment of greater bone mass and stronger bones in young adults. Furthermore, over the life-course, less of this greater amount of bone is lost, such that sustained activity levels may have acted to buffer against age-related decline, and this is most pronounced for women, who are expected to experience greater bone loss later in life than men.

1,25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel VDR-Ezh2-p16 signal axis.

To determine whether 1,25‐dihydroxyvitamin D (1,25(OH)2D) can exert an anti‐osteoporosis role through anti‐aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)2D deficiency due to deletion of the enzyme, 25‐hydroxyvitamin D 1α‐hydroxylase, while on a rescue diet. 1,25(OH)2D deficiency accelerated age‐related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence‐associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)2D3 corrected the osteoporotic phenotype caused by 1,25(OH)2D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH)2D3 deficiency, whereas 1,25(OH)2D3 could up‐regulate the enzyme Ezh2 via VDR‐mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH)2D3 improved the osteogenic defects of human BM‐MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR‐Ezh2‐p16 axis. The results of this study therefore indicate that 1,25(OH)2D3 plays a role in preventing age‐related osteoporosis by up‐regulating Ezh2 via VDR‐mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM‐MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.

Effect of Aerobic or Resistance Exercise, or Both, on Bone Mineral Density and Bone Metabolism in Obese Older Adults While Dieting: A Randomized Controlled Trial.

Weight loss therapy of older adults with obesity is limited by weight loss-induced decrease in bone mineral density (BMD), which could exacerbate ongoing age-related bone loss and increase the risk for fractures. Therefore, it is recommended that weight loss therapy of older adults with obesity should include an intervention such as regular exercise to reduce the concomitant bone loss. However, the most appropriate exercise types to combine with weight loss therapy in this older population is unknown. In a randomized controlled trial, we performed a head-to-head comparison of aerobic or resistance exercise, or both, during matched ~10% weight loss in 160 older adults with obesity. We measured changes in BMD (total hip, femoral neck, trochanter, intertrochanter, one-third radius, lumbar spine) and bone markers. Changes between groups were analyzed using mixed-model repeated measures analyses of variance. After 6 months of intensive lifestyle interventions, BMD decreased less in the resistance group (-0.006 g/cm2 [-0.7%]) and combination group (-0.012 g/cm2 [-1.1%]) than in the aerobic group (-0.027 g/cm2 [-2.6%]) (p = 0.001 for between-group comparisons). Serum C-telopeptide, procollagen type 1 N-propeptide, and osteocalcin concentrations increased more in the aerobic group (33%, 16%, and 16%, respectively) than in the resistance group (7%, 2%, and 0%, respectively) and combination group (11%, 2%, and 5%, respectively) (p = 0.004 to 0.048 for between-group comparisons). Multiple regression analyses revealed that the decline in whole body mass and serum leptin were the independent predictors of the decline in hip BMD (multiple R = 0.45 [p < .001]). These findings indicate that compared with aerobic exercise, resistance and combined aerobic and resistance exercise are associated with less weight loss-induced decrease in hip BMD and less weight loss-induced increase in bone turnover. Therefore, both resistance and combined aerobic and resistance exercise can be recommended to protect against bone loss during weight loss therapy of older adults with obesity. (LITOE ClinicalTrials.gov number NCT01065636.) © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

MiR-219a-5p Regulates Rorβ During Osteoblast Differentiation and in Age-related Bone Loss.

Developing novel approaches to treat skeletal disorders requires an understanding of how critical molecular factors regulate osteoblast differentiation and bone remodeling. We have reported that (1) retinoic acid receptor-related orphan receptor beta (Rorβ) is upregulated in bone samples isolated from aged mice and humans in vivo; (2) Rorβ expression is inhibited during osteoblastic differentiation in vitro; and (3) genetic deletion of Rorβ in mice results in preservation of bone mass during aging. These data establish that Rorβ inhibits osteogenesis and that strict control of Rorβ expression is essential for bone homeostasis. Because microRNAs (miRNAs) are known to play important roles in the regulation of gene expression in bone, we explored whether a predicted subset of nine miRNAs regulates Rorβ expression during both osteoblast differentiation and aging. Mouse osteoblastic cells were differentiated in vitro and assayed for Rorβ and miRNA expression. As Rorβ levels declined with differentiation, the expression of many of these miRNAs, including miR-219a-5p, was increased. We further demonstrated that miR-219a-5p was decreased in bone samples from old (24-month) mice, as compared with young (6-month) mice, concomitant with increased Rorβ expression. Importantly, we also found that miR-219a-5p expression was decreased in aged human bone biopsies compared with young controls, demonstrating that this phenomenon also occurs in aging bone in humans. Inhibition of miR-219a-5p in mouse calvarial osteoblasts led to increased Rorβ expression and decreased alkaline phosphatase expression and activity, whereas a miR-219a-5p mimic decreased Rorβ expression and increased osteogenic activity. Finally, we demonstrated that miR-219a-5p physically interacts with Rorβ mRNA in osteoblasts, defining Rorβ as a true molecular target of miR-219a-5p. Overall, our findings demonstrate that miR-219a-5p is involved in the regulation of Rorβ in both mouse and human bone. © 2018 American Society for Bone and Mineral Research.

Targeting Bortezomib to Bone Increases Its Bone Anabolic Activity and Reduces Systemic Adverse Effects in Mice.

Bortezomib (Btz) is a proteasome inhibitor approved by the FDA to treat multiple myeloma. It also increases bone volume by promoting osteoblast differentiation and inhibiting osteoclastogenesis in mice. However, Btz has severe systemic adverse effects, which would limit its use as a bone anabolic agent. Here, we designed and synthesized a bone-targeted form of Btz by conjugating it to a bisphosphonate (BP) with no antiresorptive activity. We report that BP-Btz inhibited osteoclast formation and bone resorption and stimulated osteoblast differentiation in vitro similar to Btz. In vivo, BP-Btz increased bone volume more effectively than Btz in three mouse models: untreated wild-type mice, mice with ovariectomy, and aged mice with tibial factures. Importantly, BP-Btz had significantly less systemic side effects than Btz, including less thymic cell death, sympathetic nerve damage, and thrombocytopenia, and it improved survival rates in aged mice. Thus, BP-Btz represents a novel anabolic agent to treat conditions, such as postmenopausal and age-related bone loss. Bone targeting is an attractive approach to repurpose approved drugs to treat skeletal diseases. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Ixazomib Modulates Bone Remodeling and Actives Sonic Hedgehog Pathways

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Osteolytic bone disease is a common manifestation of MM that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. Pathogenetic mechanisms of MM bone destruction are closely linked to MM PC and osteoclasts (OCs) hyperactivity coupled with defective osteoblast (OB) function unable to counteract bone resorption. We recently demonstrated that the proteasome inhibitor (PI) Bortezomib, commonly used to treat MM, was capable to inhibit osteoclastic differentiation modulating chitinase family genes. In this work we investigated the effect of Ixazomib (IXA), a third generation PI, on osteoclastogenesis and osteogenic differentiation. Human monocytes were differentiated in OCs in presence of OC medium (supplemented with RANKL and M-CSF), and/or 10nM IXA. We observed that IXA was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP, and MMP9 when added in OC medium in respect to OC medium alone (p&lt;0.001). In addition, IXA treatment reduced CHIT1 enzymatic activity and downregulated CHIT1 and YKL40 (both mRNA and proteins). Immunofluorescence evaluation confirmed that IXA inhibited the mature OCs formation with five or more nuclei. Moreover, IXA was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs). After 21 days of treatment, IXA alone or added to osteogenic medium increased the osteogenic markers genes (BMP2, RUNX2, Osteocalcin and Osteonectin). Immunofluorescence assay confirmed the increase of BMP2 after IXA treatment alone or in combination with osteogenic medium. Sonic Hedgehog (Shh) is one of the intricate signal transduction mechanisms that govern the precisely regulated developmental processes of multicellular organisms. Its signaling cascade plays an important role in bone homeostasis, and reducing Shh pathway protects against age-related bone loss. In this work we observed that IXA, but not Bortezomib, was able to bind the Smoothened (Smo) receptor which is the transducing molecule of the extracellular signal of Shh. Interestingly, using cellular thermal shift assay (CETSA), we demonstrated that IXA was able to bind directly Smo receptor activating the Shh cascade that leads to the nuclear translocation of Gli1 an effector of this pathway. Inhibiting Shh signaling by using an inhibitor of Smo activation (Cyclopamine), IXA-activated ostegenic differentiation-related genes were down-regulated. In conclusion, our data demonstrated that IXA regulates bone remodeling decreasing osteoclastogenesis and promoting osteogenic differentiation and therefore represents a good therapeutic option to improve the complex pathological condition of patients with MM. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Hospira: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding.

33Can anti-hypertensive thiazide diuretics also reduce fragility fracture risk?

Abstract Introduction A great deal of fractures are related to osteoporosis. Thiazide diuretics have been associated with reduced age-related bone loss, by decreasing urinary calcium excretion. On the other hand, they can also induce hyponatremia, which is a risk factor for fracture occurrence, potentially jeopardizing hypocalciuric protective effects. Recently, a secondary analysis of the ALLHAT trial found that chlorthalidone may reduce hip and pelvic fractures, when compared to lisinopril. Purpose To compare fracture outcomes of hypertensive thiazide users with those of hypertensive patients not treated with thiazides. Methods MEDLINE, EMBASE, Cochrane and SCOPUS databases were comprehensively searched, from inception to the first of February of 2019, for cohort studies mentioning thiazide diuretic usage and fracture rates. Literature search, study eligibility, including methodological quality assessment, and data extraction were independently conducted by two investigators. Meta-analysis was performed using generic inverse variance outcome and, due to heterogeneity of the original studies, a random effects model. Confounder-adjusted relative risk (RR) was pooled. Primary outcome was total fracture rate, whereas hip and women-specific fracture risk were regarded as secondary endpoints. Results Fourteen eligible studies were identified. Overall, 3,601,779 patients were included and 290,885 incidental fractures were recorded. Prototype patient was middle-aged to old and three studies only enrolled females. Clinical follow-up was documented at a median of five years. Thiazide diuretic users, as compared with non-users, had a significant 11% reduction in total fractures (RR=0.86, 95% confidence interval [CI]=0.82–0.97, p=0.008, i2=77%). Seven studies, encompassing 553,614 patients and 5,005 cases, allowed for estimation of hip fracture risk, with thiazides demonstrating an even larger effect (RR=0.78, 95% CI=0.68–0.89, p=0.0004, i2=45%). Likewise, four studies, incorporating 149,024 patients and 150.998 cases, were able to provide insight into women fracture risk, in whom thiazides seem to exert no significant protective effect (RR=1.00, 95% CI=0.78–1.27, p=0.98, i2=77%). Conclusion Thiazide diuretics may convey a decreased risk of fracture, particularly in the potentially lethal hip location. This protective secondary effect of thiazides should be considered in hypertension clinic, with osteoporotic men seeming the best candidates for this therapy.

SIRT2 deficiency prevents age-related bone loss in rats by inhibiting osteoclastogenesis

Sirtuin 2 (SIRT2) is a deacetylase that belongs to class III family of histone deacetylases (HDACs). Although it is the most abundantly expressed member of HDAC-III in human bone tissues, it is unclear whether SIRT2 plays a role in bone metabolism. In this study, the role of SIRT2 in bone metabolism, and the underlying mechanism were investigated. In in vivo experiments, micro-CT analysis revealed that there were no differences in bone microstructures between SIRT2-KO and WT rats at 12 weeks of age. However, in 36-week-old rats, increased Tb. BMD, bone volume fraction (BV/TV) and trabecular number (Tb. N) of distal femurs were observed in SIRT2-KO rats, when compared with those of WT rats. Moreover, reduced serum β-CTX was identified in the 36-week old rats. In in vitro studies, inhibition of SIRT2 with its specific inhibitor, AGK2, suppressed the differentiation of bone marrow-derived mononuclear cells (BMMs) into osteoclasts via reduction of the expressions of c-Fos and NFATc1. These results suggest that SIRT2 plays a role in age-related bone loss, probably by regulating osteoclastogenesis.

The effects of dietary fatty acids on bone, hematopoietic marrow and marrow adipose tissue in a murine model of senile osteoporosis

Purpose: Marrow adipose tissue (MAT) expansion and associated lipotoxicity are important drivers of age-related bone loss and hematopoietic bone marrow (HBM) atrophy. Fish oil and borage oil (rich in ω3 fatty acids) can partially prevent aged-related bone loss in SAMP8 mice. However, whether preservation of bone mass in this progeria model is associated with MAT volumes remains unknown.Results: MAT volume fraction (MAT%) showed a negative association with hematopoietic bone marrow (HBM%;r=-0.836, p<0.001) and bone (bone%;r=-0.344, p=0.013) volume fractions.Adjusting for multiple comparisons, bone% was higher and MAT% was lower in Fish oil (FO)-supplemented groups vs. controls (p<0.001). HBM% did not differ significantly between the four groups. However, in the group supplemented with FO, HBM comprised higher fractions and MAT constituted lower fractions of total marrow vs. controls (p<0.001).Conclusion: Feeding FO-enriched diet prevented age-related bone and HBM loss, by reducing MAT expansion. Our results further emphasize on the role(s) of MAT expansion in bone and HBM atrophy.Methods: SAMP8 mice (n>9 /group) were allocated into 4 categories and fed a control ration, FO-, sunflower oil (SFO)- and borage oil-enriched diets for lifetime. Femurs were scanned using microcomputed tomography (μCT) and bone, MAT, and HBM volumes were determined using an image analysis software.

Abstract 569: Functional Benefits of Muscle PGC-1alpha in Aged Animals

Metabolic homeostasis requires a complex network of transcriptional programs. PGC-1 (peroxisome-proliferator-activated receptor-γ coactivator-1) alpha is a potent transcriptional coactivator that coordinates the activation of a large number of nuclear-encoded genes, which, in turn, regulate numerous metabolic processes. Exercise strongly induces muscle PGC-1alpha in both humans and rodents. Over-expression of PGC-1alpha in skeletal muscle activates mitochondrial oxidative metabolism, fast-to-slow fiber-type switching, and neovascularization, leading to markedly increased endurance. In light of these findings, PGC-1alpha has been proposed to protect from age-associated sarcopenia, bone loss, and whole-body metabolic dysfunction, although these findings have been controversial. We therefore comprehensively evaluated muscle and whole-body function and metabolism in 24 month-old transgenic mice that over-express PGC-1alpha in skeletal muscle. We find that the powerful effects of PGC-1alpha on promoting muscle oxidative capacity and protection from muscle fatigability persist in aged animals, although at the expense of muscle strength. However, skeletal muscle PGC-1alpha does not prevent bone loss and in fact accentuates it, nor does it have long-term benefit on whole-body metabolic composition or insulin sensitivity. Interestingly, we see protection from sarcopenia in male animals with over-expression of PGC-1alpha in skeletal muscle but not in female animals. In summary, muscle-specific expression of PGC-1alpha into old age has beneficial effects on muscle fatigability and may protect from sarcopenia in males, but does not improve whole-body metabolism and appears to worsen age-related trabecular bone loss.

Long-term Patterns of Age-Related Facial Bone Loss in Black Individuals.

Facial skeletal changes that occur with aging have critical importance to the aesthetics of the aging face and the field of facial rejuvenation. Patterns of bony change may differ based on race, but existing research is limited primarily to white or unspecified racial populations. To longitudinally document patterns of facial skeletal change among black individuals. This retrospective case series study evaluated the medical records of patients treated at an urban tertiary medical center and with at least 2 facial computed tomographic (CT) images obtained at least 6 years apart between 1973 and 2017. All patients were self-identified black adults initially aged 40 to 55 years with no history of facial surgery who required repeated facial CT imaging that included the entire midface and cranium. All data analysis took place between August 1, 2018, and October 31, 2018. Facial CT scans were analyzed for 2-dimensional measurements to document changes in glabellar angle, bilateral maxillary angles, frontozygomatic junction width, orbital width, and piriform width. A total of 20 patients were included in our analysis (6 men, 14 women). The patients' mean (SD) initial age was 46.8 (5.8) years, with a mean (SD) follow-up of 10.7 (2.9) years. There was a significant increase in mean (SD) piriform aperture width from 3.24 (0.37) cm to 3.31 (0.32) cm (P = .002) and mean (SD) female orbital width from 3.77 (0.25) cm to 3.84 (0.19) cm (P = .04). There was a significant decrease in mean (SD) frontozygomatic junction width from 5.46 (1.38) mm to 5.24 (1.42) mm (P < .001). No significant differences were found in glabellar angles, maxillary angles, or male orbital width between initial and final imaging time points. This study is the first to our knowledge to document longitudinal bony changes of the face among a population of black individuals. Although significant facial skeletal changes can be observed over an average 10-year period, they are minor in comparison to previously published data among whites. This study suggests that there may be significant differences in facial bony aging between races which may have an impact on the aesthetics of aging and hold implications for facial rejuvenation. NA.

MiR-384-5p Targets Gli2 and Negatively Regulates Age-Related Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cells.

Aberrant microRNA expression correlates with age-related osteoporosis, which impairs bone formation by regulating osteoblastic activity, thus leading to age-related bone loss. In this study, we observed that miR-384-5p was significantly upregulated in bone marrow mesenchymal stem cells (BMSCs) from aged rats compared with BMSCs from young rats. In vitro functional assays revealed that overexpression of miR-384-5p in young BMSCs inhibited osteogenic differentiation and accelerated senescence, whereas knockdown of miR-384-5p in aged BMSCs had the opposite effects. Furthermore, we demonstrated that miR-384-5p inhibited the expression of Gli2 at both the mRNA and protein levels by directly binding to the 3' untranslated region of Gli2 mRNA. The osteogenic capacity of Gli2-knockdown BMSCs was rejuvenated by miR-384-5p inhibition. Finally, in vivo assays showed that the inhibition of miR-384-5p prevented bone loss and increased the osteogenic capacity in aged rats. Overall, our study suggests that miR-384-5p functions as a negative regulator of osteogenesis, indicating that the inhibition of miR-384-5p may be a therapeutic strategy against age-related bone loss.

Schisandra chinensis extract ameliorates age-related muscle wasting and bone loss in ovariectomized rats.

Exercise and healthy diet consumption support healthy aging. Schisandra chinensis (Turcz.) also known as "Baill." has anti-inflammatory and antioxidant properties. However, the role of S.chinensis as an antiaging compound has yet to be demonstrated. This study elucidated the antiaging effect of S.chinensis ethanol-hexane extract (C1) and the effect of C1 treatment on muscle and bone following physical exercise in ovariectomized (OVX) rats. RAW 264.7, human diploid fibroblasts (HDFs), C2C12 myoblasts, bone marrow macrophages, and MC3T3-E1 cells were used for in vitro, and muscle and bone of OVX rats were used for in vivo study to demonstrate the effect of C1. The C1 significantly inhibited the expression of inflammatory molecules, β-galactosidase activity, and improved antioxidant activity via down-regulation of reactive oxygen species in RAW 264.7 and aged HDF cells. The C1 with exercise improved muscle regeneration in skeletal muscle of OVX rats by promoting mitochondrial biogenesis and autophagy. C1 induced osteoblast differentiation, and C1+exercise modulated the bone formation and bone resorption in OVX rats. C1 exhibited anti-inflammatory, antioxidant, myogenic, and osteogenic effects. C1 with exercise improved age-related muscle wasting and bone loss. Therefore, S.chinensis may be a potential prevent agent for age-related diseases such as sarcopenia and osteoporosis.

Nutritional aspects of bone health: Not only a matter of vitamin D

In every stage of life an adequate intake of several micro- and macro-nutrients can favorably affect bone health. In pre-adult life an adequate consumption of such nutrients is essential to build peak bone mass. Later in life, a correct nutrition has a role in maintaining skeletal mass and blunt menopause- and age-related bone loss. The main involved nutrients are calcium, phosphate, vitamin D and proteins. Recent data also stress the relevance of flavonoids and other micro-nutrients. The skeletal availability of single nutritional factors also relies to their reciprocal proportion in diet composition. An adequate nutrition plays a relevant role in the maintenance of bone health throughout life, but should not be regarded as a treatment for osteoporosis.

Fragility Fractures in Older People in Japan Based on the National Health Insurance Claims Database

Fragility fractures associated with age-related bone loss are of urgent concern worldwide because they reduce QOL and pose financial burdens for health care services. Currently, national data in Japan are limited. This study provides quantitative data for older patients throughout Japan who, although otherwise relatively healthy, sustained fragility fractures and were hospitalized for them. The National Database of Health Insurance Claims and Specific Health Checkups of Japan was accessed to target patients aged 65 years or older who sustained fractures between May 2013 and September 2014 and were not hospitalized for at least 13 months prior to fracture. We investigated whether the first fracture sustained was fragility related at any of four locations (proximal humerus, distal radius, vertebra, or femoral neck) and whether it necessitated hospitalization. Fragility fractures were identified in 490138 of 1188754 patients (41.2%, 345980 patients/year; 1 : 4 male-to-female ratio). Regardless of gender, vertebral fractures were most common across the age cohorts studied (43286 males and 162767 females/year), and femoral neck fractures increased markedly with increased patient age. Approximately 80% of patients with femoral neck fractures were hospitalized (62.3% of males, 71.1% of females) compared with up to 10.4% of patients with other fragility fractures. Data provided in this study can be used as a baseline for evaluating the health economy and establishing health policy in Japan.