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Skeletal muscles are essential for locomotion and body metabolism regulation. As muscles age, they lose strength, elasticity, and metabolic capability, leading to ineffective motion and metabolic derangement. Both cellular and extracellular alterations significantly influence muscle aging. Satellite cells (SCs), the primary muscle stem cells responsible for muscle regeneration, become exhausted, resulting in diminished population and functionality during aging. This decline in SC function impairs intercellular interactions as well as extracellular matrix production, further hindering muscle regeneration. Other muscle-resident cells, such as fibro-adipogenic progenitors (FAPs), pericytes, and immune cells, also deteriorate with age, reducing local growth factor activities and responsiveness to stress or injury. Systemic signaling, including hormonal changes, contributes to muscle cellular catabolism and disrupts muscle homeostasis. Collectively, these cellular and environmental components interact, disrupting muscle homeostasis and regeneration in advancing age. Understanding these complex interactions offers insights into potential regenerative strategies to mitigate age-related muscle degeneration., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/objective: By having a better understanding of transitions in osteosarcopenia, interventions to reduce morbidity and mortality can be better targeted. The aim of this study was to show the rationale and method of using minimal clinically important differences (MCID's) to classify transitions, and the effects of demographic variables on transitions in a 9-year follow-up data from the New Mexico Aging Process Study (NMAPS)., Methods: Transitions were identified in four aspects of osteosarcopenia: bone mineral density (BMD), appendicular skeletal muscle mass/body mass index ratio (ASM/BMI), grip strength and gait speed. Transitions were identified using a MCID score. As there is currently no available MCID for BMD and ASM/BMI, those were determined using a distribution-based and an anchor-based method. Total transitions were calculated for all four measures of osteosarcopenia in all transition categories (maintaining a health status, beneficial transition, harmful transitions). Poisson regression was used to test for effects of demographic variables, including age, sex, physical activity, medication, and health status, on transitions., Results: Over the 9-year follow-up, a total of 2163 MCID-derived BMD transitions were reported, 1689 ASM/BMI transitions, 2339 grip strength transitions, and 2151 gait speed transitions. Additionally, some MCID-derived transition categories were associated with sex, age, and health status., Conclusion: Use of MCID-derived transitions reflected the fluctuation and the dynamic nature of health in older adults. Future research should focus on transitions of modifiable markers in osteosarcopenia to design intervention trials., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Bone and muscle are closely linked mechanically and biochemically. Bone hormones secreted during bone remodeling might be linked to muscle mass and strength maintenance. Exercise elicits high mechanical strain and is essential for bone health. However, the relationship between commonly used bone turnover markers (BTMs) and muscle function in community dwelling older adults remains unclear. It is also unknown how acute exercise with differing mechanical strain may affect BTMs, and whether baseline muscle function alters BTM responses differently. We tested the hypothesis that BTMs are associated with muscle function, and that acute exercise could change the circulating levels of BTMs. Thirty-five older adults (25 females/10 males, 72.8 ± 6.0 years) participated. Baseline assessments included body composition (DXA), handgrip strength and a physical performance test (PPT) (gait speed, timed-up-and-go [TUG], stair ascent/descent). Leg muscle quality (LMQ) and stair climb power (SCP) were calculated. Participants performed (randomized) 30 min aerobic (AE) (cycling 70%HR Peak ) and resistance (RE) (leg press 70%RM, jumping) exercise. Serum β-isomerized C-terminal telopeptides (β-CTX), procollagen of type I propeptide (P1NP), total osteocalcin (t)OC and ucOC were assessed at baseline and post-exercise. Data were analyzed using linear mixed models and simple regressions, adjusted for sex. At baseline, higher muscle strength (LMQ, handgrip) was related to higher P1NP, higher SCP was related to higher P1NP and β-CTX, and better physical performance (lower PPT) related to higher P1NP and β-CTX (p < 0.05). Exercise, regardless of mode, decreased β-CTX and tOC (all p < 0.05), while P1NP and ucOC remained unaltered. Higher baseline handgrip strength, SCP and LMQ was associated with lower post-exercise β-CTX responses, and poorer baseline mobility (increased TUG time) was associated with higher post-exercise β-CTX. Independently of exercise mode, acute exercise decreased β-CTX and tOC. Our data suggest that in older adults at baseline, increased BTM levels were linked to better muscle function. Altogether, our data strengthens the evidence for bone-muscle interaction, however, mechanisms behind this specific component of bone-muscle crostalk remain unclear., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Two mechanisms implicated in telomere shortening are oxidative stress and inflammation, both of which are linked to bone and muscle loss suggesting a pathological link between telomere attrition and osteosarcopenia. Using older adults aged 60 years and over in the UK Biobank, we examined the association between leukocyte telomere length and osteosarcopenia., Methods: Baseline leukocyte telomere length was measured using a multiplex qPCR technique and expressed as the amount of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Osteosarcopenia data was from the first imaging visit and defined by WHO criteria (femoral neck bone density T score ≤ -1) for osteopenia/osteoporosis plus either the EWGSOP2 (low appendicular lean mass/height 2 and low grip strength) or SDOC (low grip strength and slow walking pace) criteria for sarcopenia. Binary or multinomial logistic regression models were used to associate telomere length and osteosarcopenia or its components, adjusting for the covariates: age, sex, race, education, Townsend deprivation index, alcohol, smoking, BMI/weight, physical activity levels., Results: Among 20,400 older adults (mean age: 67.79 ± 4.9 years, 53% men), the prevalence of osteosarcopenia by EWGSOP2 (n = 96, 0.47%) or SDOC (n = 205, 1%) criteria was low at the first imaging visit (mean 8.82 years after baseline). Baseline telomere length was not associated with osteosarcopenia by EWGSOP2 (Relative Risk (RR): 1.00, 95% CI: 0.82-1.23 comparing osteosarcopenia to normal (non-osteopenic, non-osteoporotic, and non-sarcopenic) per Standard Deviation (SD) increase in telomere length) or SDOC (RR: 0.95, 95% CI: 0.83-1.09) criteria. Longer telomere length was associated with a lower risk of slow walking pace (Odds Ratio: 0.92, 95% CI: 0.87-0.99 per SD increase in telomere length, p = 0.021). Telomere length, however, was not associated with low grip strength, low bone density or low appendicular lean mass/height 2 (p > 0.05)., Conclusions: In this population-based study, telomere length was not associated with osteosarcopenia; however, slow walking pace was. Further studies are needed to reexamine this relationship, including a greater number of the oldest-old (≥75 years) where osteosarcopenia is more prevalent., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: It is not known how measures of body composition, strength and physical performance are interrelated or how empirical groupings of these measures relate to disability and mobility disability., Methods: Muscle mass was assessed by D 3 -creatine dilution (D 3 Cr muscle mass) in 1345 men (84.1 ± 4.1 years) enrolled in the Osteoporotic Fractures in Men (MrOS) study. Participants completed anthropomorphic measures, walk speed, grip strength, chair stands, and dual x-ray absorptiometry (DXA) estimated appendicular lean mass (ALM) and body fat percentage. Men reported limitations in mobility, activities of daily living (ADLs) and instrumental ADLs at initial and over 2.2 ± 0.3 years. Factor analysis reduced variables into related groups and negative binomial models calculated relative risk (RR) of factors with mobility and disability outcomes., Results: Factor analysis reduced 10 variables into four factors: Factor 1, body composition, including ALM, body fat percentage, weight and muscle mass; Factor 2, body size and lean mass, including height, weight and ALM; Factor 3, muscle mass, strength and performance, including walk speed, chair stands, grip strength, and muscle mass; and Factor 4, lean mass and weight, including ALM and weight. Only Factor 3 was significantly associated (p-value < .001) with prevalent disability (RR per standard deviation increment in factor score (reflecting higher muscle mass, strength and physical performance) 0.44, 0.35-0.56) and mobility disability (RR 0.22, 0.17 0.28), and incident mobility disability (RR 0.37, 0.27-0.50)., Conclusion: D 3 Cr muscle mass was the only body composition variable that co-segregated with strength and physical performance measures, and contributed to a factor that was associated with disability outcomes in older men., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Old age is associated with declines in bone density and muscle mass and function, which predisposes to mobility disability, falls, and fractures. Poor nutritional status, a risk factor for several age-related pathologies, becomes prevalent in old age and contributes to the structural and functional changes of the musculoskeletal system that increases the risk of osteoporosis, sarcopenia, osteosarcopenia, and physical frailty. The biological mechanisms underpinning these pathologies often overlap and include loss of proteostasis, impaired redox functioning, and chronic low-grade inflammation. Thus, provision of nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties may be an effective strategy to offset these age-related pathologies. We searched PUBMED for pre-clinical and clinical work examining the effects of nutrients with a combined effect on muscle and bone. This review summarizes recent evidence on the mechanisms of action and potential clinical use of nutrients that concomitantly improve muscle and bone health in older persons., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Circulating osteoprogenitor (COP) cells are a relatively newly discovered mesenchymal precursors population in the peripheral blood. While some aspects of their physiology have been documented in vitro, little is known about their behavior in vivo. To facilitate understanding regarding their potential role in the management of musculoskeletal disease, more research into how these cells respond to growth factors and hormones in vivo is still required. To this end, we performed a randomized controlled pilot study investigating the effect of vitamin D supplementation on COP cells in healthy older adults. Twenty-two individuals were recruited and stratified through their baseline vitamin D levels into deficient (<35 nmol/L), insufficient (35-49 nmol/L) and sufficient (>50 nmol/L) groups, and then randomized to receive either a 50,000 IU bolus dose of vitamin D, along with a 1000 IU daily supplement for six weeks, or the 1000 IU supplement alone. Participants were assessed at baseline, week three, and week six, with the primary outcome being a change in the number of COP cells. Secondary outcomes were vitamin D, markers of bone formation and resorption, parathyroid hormone, and calcium. The study showed that, independently of the dosing, increasing vitamin D levels led to a concomitant 52% increase in COP cell number (p < 0.001). There were no differences between strata, or any of the secondary outcomes in the trial. This suggests that COP cells are regulated in some way by vitamin D, similar to the bone marrow mesenchymal stem cell. Future studies are needed to evaluate the long-term effects of vitamin D supplementation, and how COP cells may be involved in chronic musculoskeletal disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: We aimed to identify combinations of health service use specific to each major osteoporotic fracture (MOF) site - hip, distal forearm, vertebrae and humerus - associated with recovery of health-related quality of life (HRQoL) 12-months post-MOF., Methods: Patients were 4126 adults aged ≥50 years with a MOF (1657 hip, 1354 distal forearm, 681 vertebral, 434 humerus) from the International Costs and Utilities Related to Osteoporotic fractures Study (Australia, Austria, Estonia, France, Italy, Lithuania, Mexico, Russia, Spain and the UK). HRQoL (pre-fracture and 12-months post-fracture) was measured using the EQ-5D-3L. Health service use data were collected via interviews and medical record reviews and included in-hospital care, outpatient care, supported living, community health services, and medication use. Latent class analyses were undertaken to identify different combinations of health service use ("classes"); and logistic regression to assess associations between classes and HRQoL recovery. Fracture site-specific analyses were performed using pooled data from all 10 countries., Results: The proportion of patients who recovered to their pre-fracture HRQoL at 12-month follow-up varied across fracture sites: 37.3%, 65.8%, 48.9% and 49.5% for hip, distal forearm, vertebrae, and humerus, respectively. We observed several site-specific classes associated with improved odds of HRQoL recovery. Generally, the combination of hospital presentations without admission; primary care center visits; use of osteoporosis-related medications; vitamin D/calcium supplementation; and non-opioid analgesic use was associated with greater likelihood of HRQoL recovery., Conclusion: The identified fracture site-specific health service use pathways associated with recovery of HRQoL could potentially improve the management and health outcomes of patients treated for a MOF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Bone turnover is the cellular machinery responsible for bone integrity and strength and, in the clinical setting, it is assessed using bone turnover markers (BTMs). Acute exercise can induce mechanical stress on bone which is needed for bone remodelling, but to date, there are conflicting results in regards to the effects of varying mechanical stimuli on BTMs., Objectives: This systematic review examines the effects of acute aerobic, resistance and impact exercises on BTMs in middle and older-aged adults and examines whether the responses are determined by the exercise mode, intensity, age and sex., Methods: We searched PubMed, SCOPUS, Web of Science and EMBASE up to 22nd April 2020. Eligibility criteria included randomised controlled trials (RCTs) and single-arm studies that included middle-aged (50 to 65 years) and older adults (>65 years) and, a single-bout, acute-exercise (aerobic, resistance, impact) intervention with measurement of BTMs. PROSPERO registration number CRD42020145359., Results: Thirteen studies were included; 8 in middle-aged (n = 275, 212 women/63 men, mean age = 57.9 ± 1.5 years) and 5 in older adults (n = 93, 50 women/43 men, mean age = 68.2 ± 2.2 years). Eleven studies included aerobic exercise (AE, 7 middle-aged/4 older adults), and two included resistance exercise (RE, both middle-aged). AE significantly increased C-terminal telopeptide (CTX), alkaline phosphatase (ALP) and bone-ALP in middle-aged and older adults. AE also significantly increased total osteocalcin (tOC) in middle-aged men and Procollagen I Carboxyterminal Propeptide and Cross-Linked Carboxyterminal Telopeptide of Type I Collagen in older women. RE alone decreased ALP in older adults. In middle-aged adults, RE with impact had no effect on tOC or BALP, but significantly decreased CTX. Impact (jumping) exercise alone increased Procollagen Type 1 N Propeptide and tOC in middle-aged women., Conclusion: Acute exercise is an effective tool to modify BTMs, however, the response appears to be exercise modality-, intensity-, age- and sex-specific. There is further need for higher quality and larger RCTs in this area., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Contributing to bone loss with aging is a progressive reduction in osteoblast number and function leading to decreased bone formation. In aging bone, mesenchymal stem cells decrease in number and their differentiation potential into osteoblasts is reduced. Instead, there is a shift towards adipogenic differentiation and increased lipid accumulation in the marrow of osteoporotic bones. Bone marrow adipocytes produce palmitic acid (PA), a saturated fatty acid, which is toxic to osteoblasts in vitro. Vitamin D (1,25(OH) 2 D 3 ) stimulates osteoblastogenesis and has known anti-apoptotic effects on osteoblasts, as such it may protect human primary osteoblasts from PA-induced lipotoxicity. Here, the effects of PA (250 μM) or 1,25(OH) 2 D 3 (10 -8  M), alone or in combination, on osteoblast differentiation and mineralization, viability and autophagy were investigated. In PA-treated osteoblasts, 1,25(OH) 2 D 3 ameliorated the decrease in the mRNA transcript abundance of representative palmitoylation (ZDHHC1, ZDHHC2 and ZDHHC12) and osteogenic (alkaline phosphatase and osteocalcin) genes. Collectively these gene regulate signaling pathways pertinent to osteoblastogenesis. In osteoblasts treated with PA and 1,25(OH) 2 D 3 , the capacity to undergo differentiation and mineralization was recovered and cell viability was increased when compared to osteoblasts treated with PA alone. 1,25(OH) 2 D 3 , irrespective of PA treatment, increased the expression of key osteogenic signaling proteins; specifically, SMAD1-3,5, Runx2 and β-catenin. 1,25(OH) 2 D 3 also attenuated the high level of impaired autophagy induced by PA and potentiated a shift towards activated, functional autophagy and increased flux through autolysosomes. Altogether, these findings provide in vitro evidence regarding the potential of 1,25(OH) 2 D 3 to protect osteoblasts from lipotoxicity by modulating autophagy and facilitating cell differentiation, which may enhance bone formation in an osteoporotic microenvironment with a high level of marrow adipose tissue., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Osteocalcin (OC), an osteoblast-specific secreted protein expressed by mature osteoblasts, is used in clinical practice and in research as a marker of bone turnover. The carboxylated (cOC) and undercarboxylated (ucOC) forms may have a different biological function but age-specific reference ranges for these components are not established. Given the different physiological roles, development of reference ranges may help to identify people at risk for bone disease., Methods: Blood was collected in the morning after an overnight fast from 236 adult men (18 to 92 years old) free of diabetes, antiresorptive, warfarin or glucocorticoid use. Serum was analyzed for total osteocalcin (tOC) and the ucOC fraction using the hydroxyapatite binding method. cOC, ucOC/tOC and cOC/tOC ratios were calculated. Reference intervals were established by polynomial quantile regression analysis., Results: The normal ranges for young men (≤30 years) were: tOC 17.9-56.8 ng/mL, ucOC 7.1-22.0 ng/mL, cOC 8.51-40.3 ng/mL (2.5th to 97.5th quantiles). Aging was associated with a "U" shaped pattern for tOC, cOC and ucOC levels. ucOC/tOC ratio was higher, while cOC/tOC ratio was lower in men of advanced age. Age explained ∼31%, while body mass index explained ∼4%, of the variance in the ratios., Conclusions: We have defined normal reference ranges for the OC forms in Australian men and demonstrated that the OC ratios may be better measures, than the absolute values, to identify the age-related changes on OC in men. These ratios may be incorporated into future research and clinical trials, and their associations with prediction of events, such as fracture or diabetes risk, should be determined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Osteoporosis is highly prevalent in older persons. While many advances have been made in the field of osteoporosis, current treatments have been affected by unexpected side effects and limited efficacy; therefore, new approaches to identify disease mechanisms and pathways are required. This review focuses on the influence of tryptophan metabolites, particularly kynurenines and serotonin on bone. The kynurenine (KYN) pathway is associated with osteoblastogenesis and can be linked to the pathophysiology of osteoporosis. The activity of osteoblasts is reduced by 3-hydroxykynurenine (3-HKYN), a product of KYN. In addition, decreasing concentrations of 3-hydroxyanthranilic acid with aging can be one of the causes of bone loss. In contrast, picolinic acid, an end-product of the KYN pathway, acts as a bone anabolic. On the other hand, gut-derived serotonin (GDS) inhibits bone formation, whereas brain-derived serotonin enhances bone formation and decreases bone resorption. Overall, understanding the exact mechanisms of action of tryptophan metabolites on bone could have great potential to develop effective treatments for osteoporosis and other bone diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Lipotoxicity is defined as cellular toxicity observed in the presence of an abnormal accumulation of fat and adipocyte-derived factors in non-fat tissues. Palmitic acid (PA), an abundant fatty acid in the bone marrow and particularly in osteoporotic bones, affects osteoblastogenesis and osteoblast function, decreasing their survival through induction of apoptosis and dysfunctional autophagy. In this study, we hypothesized that PA also has a lipotoxic effect on osteocytes in vitro., Methods: Initially, we tested the effect of PA on osteocyte-derived factors DKK1, sclerostin and RANKL. Then, we tested whether PA affects survival and causes apoptosis in osteocytes. Subsequently, we investigated the effect of PA on autophagy by detecting the membrane component LC3-II (Western blot) and staining it and lysosomes with Lysotracker Red dye., Results: PA decreases RANKL, DKK1 and sclerostin expression in osteocytes. In addition, we found that PA induces apoptosis and reduces osteocyte survival. PA also caused autophagy failure identified by a significant increase in LC3-II and a reduced number of autophagosomes/lysosomes in the cytoplasm., Conclusion: In addition to the effects of PA on RANKL, DKK1 and sclerostin expression, which could have significant deleterious impact on bone cell coupling and bone turnover, PA also induced apoptosis and reduced autophagy in osteocytes. Considering that apoptosis and cell dysfunction are two common changes occurring in the osteocytes of osteoporotic bone, our findings suggest that PA could play a role in the pathogenesis of the disease. Suppression of these effects could bring new potential targets for therapeutic interventions in the future., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bone and fat cells have an antagonistic relationship. Adipocytes exert a toxic effect on bone cells in vitro through the secretion of fatty acids, which are synthesized by fatty acid synthase (FAS). Inhibition of FAS in vitro rescues osteoblasts from fat-induced toxicity and cell death. In this study, we hypothesized that FAS inhibition would mitigate the loss of bone mass in ovariectomized (OVX) mice. We treated OVX C57BL/6 mice with cerulenin (a known inhibitor of FAS) for 6 weeks and compared their bone phenotype with vehicle-treated controls. Cerulenin-treated mice exhibited a significant decrease in body weight, triglycerides, leptin, and marrow and subcutaneous fat without changes in serum glucose or calciotropic hormones. These effects were associated with attenuation of bone loss and normalization of the bone phenotype in the cerulenin-treated OVX group compared to the vehicle-treated OVX group. Our results demonstrate that inhibition of FAS enhances bone formation, induces uncoupling between osteoblasts and osteoclasts, and favors mineralization, thus providing evidence that inhibition of FAS could constitute a new anabolic therapy for osteoporosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Non-hereditary heterotopic ossification (NHHO) may occur after musculoskeletal trauma, central nervous system (CNS) injury, or surgery. We previously described circulating osteogenic precursor (COP) cells as a bone marrow-derived type 1 collagen + CD45 + subpopulation of mononuclear adherent cells that are able of producing extraskeletal ossification in a murine in vivo implantation assay. In the current study, we performed a tissue analysis of COP cells in NHHO secondary to defined conditions, including traumatic brain injury, spinal cord injury, cerebrovascular accident, trauma without neurologic injury, and joint arthroplasty. All bone specimens revealed the presence of COP cells at 2-14 cells per high power field. COP cells were localized to early fibroproliferative and neovascular lesions of NHHO with evidence for their circulatory status supported by their presence near blood vessels in examined lesions. This study provides the first systematic evaluation of COP cells as a contributory histopathological finding associated with multiple forms of NHHO. These data support that circulating, hematopoietic-derived cells with osteogenic potential can seed inflammatory sites, such as those subject to soft tissue injury, and due to their migratory nature, may likely be involved in seeding sites distant to CNS injury., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Lamin A is a protein of the nuclear lamina. Low levels of lamin A expression are associated with osteosarcopenia in mice. In this study, we hypothesized that low lamin A expression is also associated with frailty in humans. We aimed to develop a non-invasive method to quantify lamin A expression in epithelial and circulating osteoprogenitor (COP) cells, and to determine the relationship between lamin A expression and frailty in older individuals. COP cells and buccal swabs were obtained from 66 subjects (median age 74; 60% female; 26 non-frail, 23 pre-frail, and 17 frail) participating at the Nepean Osteoporosis and Frailty (NOF) Study. We quantified physical performance and disability, and stratified frailty in this population. Lamin A expression in epithelial and COP cells was quantified by flow cytometry. Linear regression models estimated the relationship between lamin A expression in buccal and COP cells, and prevalent disability and frailty. Lamin A expression in buccal cells showed no association with either disability or frailty. Low lamin A expression values in COP cells were associated with frailty. Frail individuals showed 60% lower levels of lamin A compared to non-frail (95% CI -36 to -74%, p<0.001) and 62% lower levels compared to pre-frail (95%CI -40 to -76%, p<0.001). In summary, we have identified lamin A expression in COP cells as a strong indicator of frailty. Further work is needed to understand lamin A expression as a risk stratifier, biomarker, or therapeutic target in frail older persons., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Circulating osteoprogenitor (COP) cells are blood-borne cells which express a variety of osteoblastic markers and are able to form bone nodules in vivo. Whereas a high percentage of COP cells (%COP) is associated with vascular calcification, low %COP has been associated with disability and frailty. However, the reference range of %COP in age- and gender-matching populations, and the age-related changes in %COP remain unknown. A cross-sectional study was undertaken in 144 healthy volunteers in Western Sydney (20-90year-old, 10 male and 10 female subjects per decade). %COP was quantified by flow cytometry. A high inter-and intra-rater reliability was found. In average, in this healthy population average of %COP was 0.42. There was no significant difference in %COP among the age groups. Similarly, no significant difference was found in %COP with gender, weight, height or BMI. In addition, we identified a normal reference range of %COP of 0.1-3.8%. In conclusion, in addition to the identification of steady levels of COP cells with age, we also identified a normal reference range of %COP, which could be used in future studies looking at musculoskeletal diseases in older populations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70years. The study also aims to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation. An immunoassay was used to quantify total OC (tOC), with hydroxyapatite pre-treatment for ucOC. We determined associations of absolute and relative (ucOC/tOC; ucOC%) measures of ucOC with lower-limb muscle strength, heel ultrasound measures of speed of sound (SOS) and broadband ultrasound attenuation (BUA), bone turnover markers (BTMs; P1NP and CTx) and the acute phase protein alpha-1-antichymotrypsin (α-ACT). ucOC%, but not absolute ucOC concentration, was positively associated with hip flexor, hip abductor and quadriceps muscle strength (all p<0.05). ucOC% was negatively associated with α-ACT (β-coefficient=-0.24, p=0.02). tOC was positively associated with both P1NP and CTx (p<0.001). For each per unit increase in tOC (μg/L) there was a corresponding lower BUA, SOS and SI (β-coefficient = -0.28; -0.23 and -0.23, respectively; all p<0.04). In conclusion, ucOC% is positively associated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in musculoskeletal interactions in humans. Whilst tOC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function., (Copyright © 2014 Elsevier Inc. All rights reserved.)

While sarcopenia and sarcopenic obesity have been recognized in the last decade, a combined concept to include decreased muscle mass and strength, as well as decreased bone mass with coexistence of adiposity is discussed here. We introduce a new term, osteopenic obesity, and operationalize its meaning within the context of osteopenia and obesity. Next, we consolidate osteopenic obesity with the already existing and more familiar term, sarcopenic obesity, and delineate the resulting combined condition assigning it the term osteosarcopenic obesity. Identification and possible diagnosis of each condition are discussed, as well as the interactions of muscle, fat and bone tissues on cellular level, considering their endocrine features. Special emphasis is placed on the mesenchymal stem cell commitment into osteoblastogenic, adipogenic and myogenic lineages and causes of its deregulation. Based on the presented evidence and as expounded within the text, it is reasonable to say that under certain conditions, osteoporosis and sarcopenia could be the obesity of bone and muscle, respectively, with the term osteosarcopenic obesity as an encompassment for all., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The relationships between conjugated linoleic acid (CLA) status, bone, body composition, and the effect of CLA on calciotropic hormones are unclear. A cross-sectional study was designed to examine the association between c9, t11 CLA status in erythrocyte membranes (RBC) and body composition. This preceded a dose-response trial investigating if c9, t11 CLA affected parathyroid hormone (PTH). It was hypothesized that (1) higher c9, t11 CLA status in RBC will be associated with a lower fat and higher bone mass and that (2) PTH will be reduced by 30% after supplementation of c9, t11 CLA. Fifty-four men (age, 19-53 years) were included in the cross-sectional analysis, of which 31 were studied in the dose-response trial and randomized to 1 of 3 groups: placebo (n = 10), 1.5 g/d (n = 11), or 3.0 g/d (n = 10) of c9, t11 CLA for 16 weeks. Men with RBC c9, t11 CLA status above the median had higher whole body bone mineral density (BMD) (1.359 ± 0.024 vs 1.287 ± 0.023 g/cm(2); P = .04) and whole body lean mass (WBL) percentage (78.8% ± 0.9% vs 75.3% ± 1.0%; P = .01), whereas body mass index (24.8 ± 0.5 kg/m(2) vs 27.3 ± 0.9 kg/m(2); P = .01) and whole body fat mass percentage (17.3% ± 0.9% vs 21.3% ± 1.1%; P = .007) were lower. In regression analysis, RBC c9, t11 CLA status accounted for a significant proportion (r(2) = 0.10) of the variation in whole body BMD (P = .03). There were no time or treatment differences among any bone or biomarkers of bone metabolism including PTH. These findings indicate that RBC c9, t11 CLA status, a reflection of long-term (~4 months) dietary CLA intake, positively relates to BMD. However, c9, t11 CLA supplementation does not appear to affect PTH in healthy men., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The ability of exercise to decrease fat mass and increase bone mass occurs through mechanical biasing of mesenchymal stem cells away from adipogenesis and toward osteoblastogenesis. The mechanism explaining this effect remains poorly understood. Lamin A/C knockdown inhibits osteoblastogenesis while favors adipogenesis in vitro. In this study, we hypothesized that the presence of lamin A/C is required for the anabolic response of bone during exercise. Three-month-old female lamin A/C haploinsufficient (Lmna(+/-)) mice were exposed to strenuous maximal exercise protocol (2 sessions/week, 40 min/session) for 6 weeks. Wild type (WT) (exercise and sedentary) and sedentary Lmna(+/-) mice were used as controls. To determine changes in bone microarchitecture and cell numbers, distal femur was analyzed by microCT and histomorphometry respectively. Finally, levels of expression of nuclear β-catenin and sclerostin, two proteins involved in the anabolic response to exercise, were determined by immunofluorescence. Histomorphometry analysis showed a significant increase in bone volume fraction (BV/TV) in exercised vs. sedentary WT mice. In contrast, exercised Lmna(+/-) mice showed a significant reduction in microarchitecture as compared with sedentary Lmna(+/-) controls including trabecular and cortical thinning. In addition, we found a significant increase in bone cells number in exercised vs. sedentary WT mice whereas exercised Lmna(+/-) mice showed a significant reduction in osteoblasts and osteocytes number as compared with sedentary Lmna(+/-) controls. Finally, levels of activated β-catenin in osteoblasts and osteocytes were significantly decreased while sclerostin expression was increased in exercised Lmna(+/-) mice as compared with exercised WT controls. In summary, our data indicate that the presence of lamin A/C is required for the anabolic effect of exercise on bone thus suggesting a new important role of lamin A/C in bone biology., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Marrow fat infiltration is one of the hallmarks of age-related bone loss. This fat infiltration has been quantified by invasive and noninvasive methods. However, the validity of the noninvasive methods has not been correlated with a gold standard. In this study we aim to validate the usefulness of marrow fat quantification by correlating microCT (μCT) images with histology analysis. Fat volume (FV) and bone volume (BV) of distal femora of young (4 months) and old (27 months) Louvain/c (LOU) rats (n=22) were quantified by histology and compared with μCT images analyzed by an image analysis software (SliceOMatic). We found that for SliceOMatic/μCT the intra-rater reliability for duplicate measurements was 0.94 (p<0.001) and the inter-rater reliability for FV/BV ratio in young and old rats was 98% and 99% respectively. Both methods showed a significant increase (~2 fold) in the FV/BV ratio in the old rats as compared with their young counterparts (p<0.001). A significantly higher correlation (r2=0.85) in the old rats was found between our noninvasive method and histology. Furthermore, our noninvasive method showed good agreement with histology. In conclusion, noninvasive quantification of FV/BV ratio using an image analysis software is as reliable as histology for identifying age related marrow fat changes with high inter and intra-rater reliability. These findings provide a new noninvasive method for quantifying marrow fat, which is useful and can be tested not only in animals but also in human studies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Therapy with bisphosphonates, including alendronate (ALN), is considered a safe and effective treatment for osteoporosis. However, recent studies have reported an unexpected increase in serious atrial fibrillation (AF) in patients treated with bisphosphonates. The mechanism that explains this side effect remains unknown. Since AF is associated with an altered sarcoendoplasmic reticulum calcium load, we studied how ALN affects cardiomyocyte calcium homeostasis and protein isoprenylation in vitro. Acute and long-term (48h) treatment of atrial and ventricular cardiomyocytes with ALN (10(-8)-10(-6)M) was performed. Changes in calcium dynamics were determined by both fluorescence measurement of cytosolic free Ca(2+) concentration and western blot analysis of calcium-regulating proteins. Finally, effect of ALN on protein farnesylation was also identified. In both atrial and ventricular cardiomyocytes, ALN treatment delayed and diminished calcium responses to caffeine. Only in atrial cells, long-term exposure to ALN-induced transitory calcium oscillations and led to the development of oscillatory component in calcium responses to caffeine. Changes in calcium dynamics were accompanied by changes in expression of proteins controlling sarcoendoplasmic reticulum calcium. In contrast, ALN minimally affected protein isoprenylation in these cells. In summary, treatment of atrial cardiomyocytes with ALN-induced abnormalities in calcium dynamics consistent with induction of a self-stimulatory, pacemaker-like behavior, which may contribute to the development of cardiac side effects associated with these drugs.

Increasing marrow adipogenesis plays a causative role in the pathogenesis of age-related bone loss that could be associated with high cytokine production. In this study, we characterized the age-related changes in cytokine expression by bone marrow (BM) adipocytes as compared with subcutaneous (SC) fat. BM and SC adipocytes were isolated from young (4 months) and old (24 months) male C57BL/6J. Total proteins were extracted and proteomic analysis of 96 cytokines was performed using a cytokine antibody array. Proteins showing a significant change were grouped according with their known function in bone. We found a significant age-induced difference in the expression of 53 cytokines. As compared with SC adipocytes, aging BM adipocytes showed a more pro-adipogenic, anti-osteoblastogenic and pro-apoptotic phenotype. These data suggest that, with aging, BM adipocytes become significantly more toxic than SC adipocytes. These cytokines, if secreted, could play a role in the pathogenesis of age-related bone loss by affecting other cells within the marrow milieu.

Inbred albino Louvain (LOU) rats are considered a model of healthy aging due to their increased longevity in the absence of obesity and with a low incidence of common age-related diseases. In this study, we characterized the bone phenotype of male and female LOU rats at 4, 20 and 27 months of age using quantitative micro computed tomographic (mCT) imaging, histology and biochemical analysis of circulating bone biomarkers. Bone quality and morphometry of the distal femora, assessed by mCT, was similar in male and female rats at 4 months of age and deteriorated over time. Histochemical staining of undecalcified bone showed a significant reduction in cortical and trabecular bone by 20 months of age. The reduction in mineralized tissue was accompanied by reduced numbers of osteoblasts and osteoclasts and a significant increase in marrow adiposity. Biochemical markers of bone turnover, C-telopeptide and osteocalcin, correlated with the age-related bone loss whereas the calciotropic hormones PTH and vitamin D remained unchanged over time. In summary, aged LOU rats exhibit low-turnover bone loss and marrow fat infiltration, which are the hallmarks of senile osteoporosis, and thus represent a novel model in which to study the molecular mechanisms leading to this disorder.

Until recently, vitamin D was only considered as one of the calciotrophic hormones without major significance in other metabolic processes in the body. Several recent findings have demonstrated that vitamin D plays also a role as a factor for cell differentiation, function and survival. Two organs, muscle and bone, are significantly affected by the presence, or absence, of vitamin D. In bone, vitamin D stimulates bone turnover while protecting osteoblasts of dying by apoptosis whereas in muscle vitamin D maintains the function of type II fibers preserving muscle strength and preventing falls. Furthermore, two major changes associated to aging: osteoporosis and sarcopenia, have been also linked to the development of frailty in elderly patients. In both cases vitamin D plays an important role since the low levels of this vitamin seen in senior people may be associated to a deficit in bone formation and muscle function. In this review, the interaction between vitamin D and the musculoskeletal components of frailty are considered from the basic mechanisms to the potential therapeutic approach. We expect that these new considerations about the importance of vitamin D in the elderly will stimulate an innovative approach to the problem of falls and fractures which constitutes a significant burden to public health budgets worldwide.

Osteoporosis, a key predictor of hip fractures can be treated using a variety of safe and effective interventions. Nevertheless, optimally effective strategies for the prevention of hip fractures must also incorporate efforts to address a broad range of other potentially reversible factors. Hyperthyroidism, anticonvulsants, caffeine and smoking may decrease bone mass and increase fracture risk at any age. In older individuals it is important to also consider additional risk factors, including long-acting benzodiazepines, poor vision and sarcopenia. The presence of sarcopenia, an age-related decline in muscle bulk and quality enhances the risk of frailty and possibly also hip fracture, particularly if associated with diminished functional mobility, lower quadriceps strength and poor balance or body sway. In this review we examine evidence which indicates the presence of endocrine-immune dysregulation in both osteoporosis and sarcopenia. Post-menopausal declines in serum estrogen and androgen levels contribute to increases in local bone levels of cytoclastic cytokines, followed by increased osteoclastogenesis and bone loss. Similarly, the presence of decreased gonadal hormones and IGF-1, combined with unusually high peripheral levels of cytokines, inflammatory mediators and coagulation markers all enhance the risk of sarcopenia and frailty. We propose that a translational research approach which emphasizes common pathophysiologic mechanisms in osteoporosis and sarcopenia could accelerate the speed of discovery of effective strategies for both frailty and hip fracture prevention.

Apoptosis plays an important role in the regulation of bone turnover. Previously, we showed that 1,25(OH)2D3, the active form of vitamin D, may increase osteoblast survival by inhibiting apoptosis induced by serum deprivation. Human osteoblasts express the Fas receptor on their surface and its interaction with Fas ligand has been closely associated with human osteoblast apoptosis. To investigate the mechanism of 1,25(OH)2D3 inhibition of apoptosis in osteoblasts isolated from human calvaria, cells were exposed to Fas antibody. Visualization of apoptotic cells using annexin V revealed a significant decrease in apoptosis at 48 h in the presence of 1,25(OH)2D3 (14 +/- 4%, P < 0.04) compared with non-treated cells (52 +/- 4%). Furthermore, flow cytometric analysis of TUNEL-labeled osteoblasts showed a significant decrease in apoptotic cells in 1,25(OH)2D3-treated cultures (12 +/- 2%) at 48 h compared with non-treated cultures (44 +/- 3%, P < 0.04). Additionally, cells treated with 1,25(OH)2D3 survived longer as found by MTS analysis. To further explore the mechanism of 1,25(OH)2D3-mediated inhibition of apoptosis, we examined the changes in activation of death domain proteins, cleavage of caspases and mitochondrial regulators of apoptosis by Western blot analysis. A significant inhibition of caspase-8 cleavage and activity in 1,25(OH)2D3-treated cells was observed in conjunction with a decrease in the expression of the proapoptotic protein Bax with a significant increase in the expression of antiapoptotic protein Bcl-2. Furthermore, the levels of p21Cip1/WAF1, which inhibits the cleavage of caspase-8, was found to be highly induced in 1,25(OH)2D3-treated cells. In summary, these results demonstrate that the anti-apoptotic effect of 1,25(OH)2D3 in human osteoblasts after the activation of Fas-ligand is mediated by the regulation of components of both the mitochondrial and Fas-related pathways.

Senile osteoporosis is the endpoint of a continuum that starts after the third decade of life when peak bone mass is attained and then is followed by a progressive and irreversible decline in bone mass. One of the mechanisms that could explain this is the increasing levels of adipogenesis in bone marrow seen with increasing age, probably due to alterations in the differentiation of mesenchymal stem cells (MSC). Senescence accelerated mice (SAM-P/6) constitute an accepted model for senile osteoporosis since their loss of bone mineral density is clearly due to high levels of adipogenesis and a deficit in osteoblastogenesis. It is known that MSC expressing a ligand-activated transcription factor known as peroxisome proliferators-activated receptor gamma 2 (PPARgamma2) are committed to differentiate into adipocytes. The regulation of PPARgamma2 activation may play a role in the control of adipogenic differentiation of MSC and thus contribute to their differentiation into osteoblasts in order to form new bone. Our previous studies have shown that the active form of vitamin D (1,25(OH)(2)D(3)) plays a role as a bone forming agent because it induces osteoblastogenesis and inhibits adipogenesis in bone marrow of SAM-P/6 mice. To elucidate the role of 1,25(OH)(2)D(3) on the expression of PPARgamma2 we treated 4-month old SAM-P/6 mice with 1,25(OH)(2)D(3) (18pmol/24 h) or vehicle during 6 weeks. Initially we found that with aging the levels of PPARgamma2 expression increase in bone marrow of SAM-P/6 (P<0.001) We then measured the changes in the expression of PPARgamma2 by semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence. We found a significant reduction of PPARgamma2-expressing cells in 1,25(OH)(2)D(3)-treated (32% +/-6) as compared to vehicle (76% +/-5) treated mice (p<0.01) In summary, this study shows that the administration of 1,25(OH)(2)D(3) in an in vivo model of senile osteoporosis is associated with reduction in PPARgamma2 a key transcription factor for the adipose differentiation of MSC.