A review of epigenetics and its association with ageing of muscle and bone.

Ageing is defined as the 'increasing frailty of an organism with time that reduces the ability of that organism to deal with stress'. It has been suggested that epigenetics may underlie the observation that some individuals appear to age faster than others. Epigenetics is the study of changes which occur in an organism due to changes in expression of the genetic code rather than changes to the genetic code itself; that is, epigenetic mechanisms impact upon the function of DNA without changing the DNA sequence. It is important to recognise that epigenetic changes, in contrast to genetic changes, can vary according to different cell types and therefore can demonstrate significant tissue-specificity. There are different types of epigenetic mechanisms: histone modification, non-coding RNAs and DNA methylation. Epigenetic clocks have been developed using statistical techniques to identify the optimal combination of CpG sites (from methylation arrays) to correlate with chronological age. This review considers how epigenetic factors may affect rates of ageing of muscle and bone and provides an overview of current understanding in this area. We discuss studies using first-generation epigenetic clocks, as well as the second-generation iterations, which appear to show stronger associations with the ageing muscle phenotype. We also review epigenome-wide association studies that have been performed in various tissues examining relationships with osteoporosis and fracture. It is hoped that an understanding of this area will lead to interventions that might prevent or reduce rates of musculoskeletal ageing in later life.

Assessment of Activity Profiles in Older Adults and Lower Limb Bone Parameters: Observations from the Hertfordshire Cohort Study.

As muscle strength and function decline with age the optimal high-impact physical activity (PA) required for bone remodelling is rarely achievable in older adults. This study aimed to explore the activity profiles of community-dwelling older men and women and to assess the relationship between individual PA profiles and lower limb bone parameters. Participants from the Hertfordshire Cohort Study wore triaxial accelerometers for 7 days and counts of low (0.5-1.0 g), medium (1.0-1.5 g), and high (> 1.5 g) vertical-impact activity were calculated. Two years later, participants underwent a pQCT scan of the tibia (4% and 38% sites) to obtain measures of bone mineral density and bone geometry. Linear regression was used to quantify associations between bone and PA loading profiles adjusting for age, sex, loading category, and BMI. Results are presented as ß [95% confidence interval]. Bone and PA data were available for 82 participants. The mean (SD) age at follow-up was 81.4(2.7) years, 41.5% (n = 34) were women. The median low-impact PA count was 5281 (Inter-quartile range (IQR) 2516-12,977), compared with a median of only 189 (IQR 54-593) in medium, and 39 (IQR 9-105) in high-impact counts. Positive associations between high-impact PA and cortical area (mm2), polar SSI (mm3), and total area (mm2) at the 38% slice (6.21 [0.88, 11.54]; 61.94 [25.73, 98.14]; 10.09 [3.18, 16.99], respectively). No significant associations were found at distal tibia. These data suggest that maintaining high (> 1.5 g)-impact activity is difficult for older adults to achieve; however, even small amounts of high-impact PA are positively associated with selected cortical bone parameters 2 years later.

Differential relationships between parent-child DXA and pQCT bone measures: Results from the Southampton Women's Survey.

AIM: To investigate the associations between indices of bone health in childhood and corresponding parental measures. METHODS: The Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (ß-coefficients (95%CI) unit/unit for each bone measure). RESULTS: Data were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (ß = 0.26 g·cm-2/g·cm-2 (0.21,0.32)) and father-child aBMD (ß = 0.16 g·cm-2/g·cm-2 (0.11,0.21)), P-difference in ß = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (ß = 0.33 mm2/mm2 (0.17,0.48)), but little evidence of a father-offspring association (ß = -0.06 mm2/mm2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (ß = 0.48 mg·cm-3/mg·cm-3 (0.15,0.82)) than mothers (ß = 0.27 mg·cm-3/mg·cm-3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height. CONCLUSIONS: Whilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects. SUMMARY: In an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships.

Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people.

Osteoporosis, a common chronic metabolic bone disease is associated with considerable morbidity and mortality. As the prevalence of osteoporosis increases with age, a paralleled elevation in the rate of incident fragility fractures will be observed. This narrative review explores the origins of bone and considers physiological mechanisms involved in bone homeostasis relevant to management and treatment. Secondary causes of osteoporosis, as well as osteosarcopenia are discussed followed by an overview of the commonly used pharmacological treatments for osteoporosis in older people.

Adiposity and bone microarchitecture in the GLOW study.

Low body mass index (BMI) is an established risk factor for fractures in postmenopausal women but the interaction of obesity with bone microarchitecture is not fully understood. In this study, obesity was associated with more favourable bone microarchitecture parameters but not after parameters were normalised for body weight. INTRODUCTION: To examine bone microarchitecture in relation to fat mass and examine both areal bone mineral density (aBMD) and microarchitecture in relation to BMI categories in the UK arm of the Global Longitudinal Study of Osteoporosis in Women. METHODS: Four hundred and ninety-one women completed questionnaires detailing medical history; underwent anthropometric assessment; high-resolution peripheral quantitative computed tomography (HRpQCT) scans of the radius and tibia and DXA scans of whole body, proximal femur and lumbar spine. Fat mass index (FMI) residuals (independent of lean mass index) were derived. Linear regression was used to examine HRpQCT and DXA aBMD parameters according to BMI category (unadjusted) and HRpQCT parameters in relation to FMI residuals (with and without adjustment for anthropometric, demographic and lifestyle covariates). RESULTS: Mean (SD) age was 70.9 (5.4) years; 35.0% were overweight, 14.5% class 1 obese and 7.7% class 2/3 obese. There were significant increasing trends according to BMI category in aBMD of whole body, hip, femoral neck and lumbar spine (p ≤ 0.001); cortical area (p < 0.001), thickness (p < 0.001) and volumetric density (p < 0.03), and trabecular number (p < 0.001), volumetric density (p < 0.04) and separation (p < 0.001 for decreasing trend) at the radius and tibia. When normalised for body weight, all HRpQCT and DXA aBMD parameters decreased as BMI increased (p < 0.001). FMI residuals were associated with bone size and trabecular architecture at the radius and tibia, and tibial cortical microarchitecture. CONCLUSION: Significant trends in HRpQCT parameters suggested favourable bone microarchitecture at the radius and tibia with increasing BMI but these were not proportionate to increased weight.

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

COVID-19 and associations with frailty and multimorbidity: a prospective analysis of UK Biobank participants.

BACKGROUND: Frailty and multimorbidity have been suggested as risk factors for severe COVID-19 disease. AIMS: We investigated, in the UK Biobank, whether frailty and multimorbidity were associated with risk of hospitalisation with COVID-19. METHODS: 502,640 participants aged 40-69 years at baseline (54-79 years at COVID-19 testing) were recruited across UK during 2006-10. A modified assessment of frailty using Fried's classification was generated from baseline data. COVID-19 test results (England) were available for 16/03/2020-01/06/2020, mostly taken in hospital settings. Logistic regression was used to discern associations between frailty, multimorbidity and COVID-19 diagnoses, after adjusting for sex, age, BMI, ethnicity, education, smoking and number of comorbidity groupings, comparing COVID-19 positive, COVID-19 negative and non-tested groups. RESULTS: 4510 participants were tested for COVID-19 (positive = 1326, negative = 3184). 497,996 participants were not tested. Compared to the non-tested group, after adjustment, COVID-19 positive participants were more likely to be frail (OR = 1.4 [95%CI = 1.1, 1.8]), report slow walking speed (OR = 1.3 [1.1, 1.6]), report two or more falls in the past year (OR = 1.3 [1.0, 1.5]) and be multimorbid (≥ 4 comorbidity groupings vs 0-1: OR = 1.9 [1.5, 2.3]). However, similar strength of associations were apparent when comparing COVID-19 negative and non-tested groups. However, frailty and multimorbidity were not associated with COVID-19 diagnoses, when comparing COVID-19 positive and COVID-19 negative participants. DISCUSSION AND CONCLUSIONS: Frailty and multimorbidity do not appear to aid risk stratification, in terms of positive versus negative results of COVID-19 testing. Investigation of the prognostic value of these markers for adverse clinical sequelae following COVID-19 disease is urgently needed.

Approaches to the diagnosis and prevention of frailty.

An individual who is living with frailty has impairments in homeostasis across several body systems and is more vulnerable to stressors that may ultimately predispose them to negative health-related outcomes, disability and increased healthcare use. Approximately a quarter of individuals aged > 85 years are living with frailty and as such the identification of those who are frail is a public health priority. Given that the syndrome of frailty is defined by progressive and gradual loss of physiological reserves there is much scope to attempt to modify the trajectory of the frailty syndrome via physical activity and nutritional interventions. In this review we give an up to date account on the identification of frailty in clinical practice and offer insights into physical activity and nutritional strategies that may be beneficial to modify or reverse the frailty syndrome.

Bone densitometry worldwide: a global survey by the ISCD and IOF.

In a global survey of fracture liaison services, most reported that DXA access met needs. However, adherence to basic DXA quality and reporting procedures was confirmed by only around 50% of institutions and many required education for operators/interpreters. Overall, there is significant variability in the access to, and quality of, DXA services worldwide. INTRODUCTION: While the use of dual-energy X-ray absorptiometry (DXA) has been widely adopted worldwide for the assessment of bone mineral density, the quality of DXA facilities is unknown. To address this, a global survey of fracture liaison services (FLS) was conducted by the International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) to assess the quality of their DXA facilities. METHODS: A questionnaire for the accessibility and quality of DXA services was co-created by representatives of the ISCD and the IOF and made available to institutions who participated in the Capture the Fracture Best Practice Framework. From a list of 331 contacted invitees, 124 FLS centres responded; analyses were based on 121 centres with suitable data. RESULTS: Over 70% of institutions reported that, for over 90% of the time, DXA access met service needs, and the scanning/reporting quality was perceived as excellent. However, 25% of DXA facilities reported not being accredited by a professional/governmental organization, and adherence to some basic DXA quality assurance and reporting procedures was confirmed by < 50% of services. Importantly, in excess of 50% of institutions stated that they desired ongoing education in osteoporosis and DXA for operators and interpreters. CONCLUSION: There is significant variability in the access to and quality of DXA services for established FLS worldwide. Despite two decades of training initiatives in osteoporosis densitometry, many centres are falling short of the standards of the IOF-ISCD Osteoporosis Essentials criteria.

Self-perceived Fracture Risk in the Global Longitudinal Study of Osteoporosis in Women: Its Correlates and Relationship with Bone Microarchitecture.

The purpose of this study is to examine correlates of self-perceived fracture risk (SPR) and relationships between SPR and subsequent bone density and microarchitecture in the UK arm of the Global Longitudinal Study of Osteoporosis in Women. 3912 women completed baseline questionnaires detailing medical history and SPR; 492 underwent HRpQCT scans of the radius and tibia and DXA scans of total body, hip, femoral neck and lumbar spine a median of 7.5 years later. Correlates of SPR were examined and a cluster analysis of potential predictors of SPR performed. SPR in relation to HRpQCT and aBMD parameters was examined using linear regression with and without adjustment for anthropometric, demographic and lifestyle covariates. Mean (SD) baseline age was 69.0 (9.0) years; 56.6% reported a similar SPR; 28.6% lower SPR; 14.9% higher SPR compared to women of similar age. In mutually-adjusted analysis, higher SPR was associated (p < 0.05) with: lower physical activity and educational attainment; use of anti-osteoporosis medications (AOM) and calcium supplements; greater number of falls in the previous year; history of fracture since aged 45; family history of hip fracture; and increased comorbidity. Higher SPR, history of fracture, and use of AOM, calcium and vitamin D clustered together. Even after adjustments that included AOM use, higher SPR was associated with: lower radial trabecular volumetric density and number, and higher trabecular separation; lower tibial cortical area and trabecular volumetric density; and lower aBMD at the femoral neck. Despite greater AOM use, women with higher baseline SPR had poorer subsequent bone health.

Infant milk feeding and bone health in later life: findings from the Hertfordshire cohort study.

Using data from the Hertfordshire cohort study, this study examined the effect of breastfeeding and bottle feeding on adult lumbar spine and femoral neck bone mineral content (BMC) and bone mineral density (BMD). The type of infant milk feeding was significantly associated with lumbar spine BMD in males. INTRODUCTION: Using data from the Hertfordshire cohort study (HCS), this study aims to examine the effect of infant milk feeding on bone health in later life by comparing the effect of breastfeeding and bottle feeding on lumbar spine and femoral neck BMC and BMD. METHODS: Information about infant milk feeding, birth weight (kg) and weight at 1 (kg) was collected by health visitors between 1931 and 1939 in Hertfordshire. BMC and BMD measurements were taken by DXA scan between 1998 and 2004. Linear regression models adjusted for conditional weight at 1, age at DXA scan, sex, adult BMI, smoking behaviour, alcohol consumption, physical activity, dietary calcium, and prudent diet score. RESULTS: Infant milk feeding was significantly associated with lumbar spine BMD (b = - 0.028; 95% CI, - 0.055; - 0.000; p value, 0.047) in males. On average, males who consumed breastmilk alternatives in infancy had lower lumbar spine BMD measurements than those who were fed only breastmilk. These associations remained significant in fully adjusted models. There were no significant associations between infant milk feeding and bone health for females. CONCLUSIONS: Significant associations between infant milk feeding and lumbar spine BMD in males indicate that breastmilk may be protective for the bone health of male babies. The evidence presented here underscores the potential lifelong benefits of breastfeeding and may highlight the differences between osteoporotic risk factors for males and females.

Jumping Joints: The Complex Relationship Between Osteoarthritis and Jumping Mechanography.

We investigated the relationship between lower limb osteoarthritis (OA) and muscle strength and power (assessed by jumping mechanography) in UK community-dwelling older adults. We recruited 249 older adults (144 males, 105 females). OA was assessed clinically at the knee according to ACR criteria and radiographically, at the knee and hip, using Kellgren and Lawrence grading. Two-footed jumping tests were performed using a Leonardo Mechanography Ground Reaction Force Platform to assess maximum muscle force, power and Esslinger Fitness Index. Linear regression was used to assess the relationship between OA and jumping outcomes. Results are presented as ß (95% confidence interval). The mean age of participants was 75.2 years (SD 2.6). Males had a significantly higher maximum relative power during lift off (mean 25.7 W/kg vs. 19.9 W/kg) and maximum total force during lift off (mean 21.0 N/kg vs. 19.1 N/kg) than females. In adjusted models, we found significant associations in males between clinical knee OA and maximum relative power [- 6.00 (CI - 9.10, - 2.94)] and Esslinger Fitness Index [- 19.3 (- 29.0, - 9.7)]. In females, radiographic knee OA was associated with total maximum power [- 2.0 (- 3.9, - 0.1)] and Esslinger Fitness Index [- 8.2 (- 15.9, - 0.4)]. No significant associations were observed for maximum total force. We observed significant negative associations between maximum relative power and Esslinger Fitness Index and clinical knee OA in males and radiographic knee OA in females. We have used novel methodology to demonstrate relationships between muscle function and OA in older adults.

Fracture risk following intermission of osteoporosis therapy.

Given the widespread practice of recommending drug holidays, we reviewed the impact of medication discontinuation of two common anti-osteoporosis therapies (bisphosphonates and denosumab). Trial evidence suggests the risk of new clinical fractures, and vertebral fracture increases when osteoporosis treatment with bisphosphonates or denosumab is stopped. INTRODUCTION: The aim of this paper was to review the available literature to assess what evidence exists to inform clinical decision-making with regard to drug holidays following treatment with bisphosphonates (BiP) or denosumab. METHODS: Systematic review. RESULTS: Differing pharmacokinetics lead to varying outcomes on stopping therapy. Prospective and retrospective analyses report that the risk of new clinical fractures was 20-40% higher in subjects who stopped BiP treatment, and vertebral fracture risk was approximately doubled. Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%. Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g. prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture. CONCLUSIONS: The view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence. Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.

Longitudinal Change in Peripheral Quantitative Computed Tomography Assessment in Older Adults: The Hertfordshire Cohort Study.

There are few longitudinal data on change in bone structure and muscle mass, strength and function in later life. We report these, and consider bone-muscle interrelationships in older men and women. We studied 188 men and 166 women from the Hertfordshire Cohort Study, who underwent peripheral quantitative computed tomography (pQCT) of the radius and tibia in 2004-2005 and then again in 2011-2012. Grip strength and gait speed were also assessed at both timepoints. Percentage change per year was calculated for grip strength, gait speed, muscle cross-sectional area (mCSA), fat cross-sectional area (fCSA) and diaphyseal bone parameters [total area (Tt.Ar), cortical area (Ct.Ar), cortical density (cBMD) and trabecular density (tBMD)]. The mean (SD) age of men and women at baseline was 68.9 (2.5) and 69.2 (2.6) years, respectively. Rates of muscle area and strength loss did not differ by sex. Tt.Ar increased with age and faster in men [mean (SD) 1.78 (1.64) %/year] than women [mean (SD) 1.03 (1.69) %/year] in the radius (p < 0.001). In both the radius (p = 0.006) and tibia (p < 0.001), Ct.Ar reduced more rapidly in women than men. Change in Ct.Ar was associated with change in muscle area in the corresponding limb (radius; men: regression coefficient 0.36, 95% CI 0.20-0.52, p < 0.001; tibia; men: regression coefficient 0.14, 95% CI 0.00-0.27, p = 0.043, women: regression coefficient 0.16, 95% CI 0.01-0.30, p = 0.032). We have demonstrated that muscle strength and function decrease faster than muscle mass and have provided further evidence that changes in bone structure with age differ by sex.

Diet Quality and Bone Measurements Using HRpQCT and pQCT in Older Community-Dwelling Adults from the Hertfordshire Cohort Study.

There are few data describing associations between dietary patterns and bone microarchitecture. This study investigated the relationship between diet quality and HRpQCT and pQCT measures in older adults. Data were available for 184 men and 166 women. Dietary data were collected at baseline (1998-2003) using an administered food frequency questionnaire. A 'prudent' diet score (PDS) was identified using principal component analysis and used as an indicator of dietary quality. HRpQCT and pQCT images were acquired at follow-up in 2012, from the non-dominant distal radius and tibia using Scanco XtremeCT and Stratec XCT2000 instrument scanners, respectively. The mean (SD) PDS was - 0.24 (1.23) for men and 0.62 (1.14) for women. In women, a significant positive relationship was found between baseline dietary pattern and total and trabecular area at both the radius and the tibia, measured by HRpQCT. Similar trends were observed with pQCT parameters. Positive associations were observed for tibia total area (38% slice). At the radius, significant positive associations were found for total area (4% slice) and polar strength strain index (33% slice). All relationships remained robust to adjustment. For men, although patterns were similar, there were no significant associations for HRpQCT outcomes. Significant associations were observed for baseline PDS and polar strength strain and total area (66% slice) at the radius, measured by pQCT. Our data suggest that diets high in fruit, vegetables, oily fish and whole grain cereals in early old age are associated with greater bone size but not volumetric bone density or microarchitecture in later life in women.

Relationships between markers of inflammation and bone density: findings from the Hertfordshire Cohort Study.

Among 365 Hertfordshire Cohort Study participants (aged 59-71 years at baseline), higher adiponectin and adiponectin to leptin ratios were associated with lower baseline lumbar spine and femoral neck bone mineral density (BMD). Lower IL-10 was associated with accelerated decline in lumbar spine BMD. This suggests that bone health can be influenced by changes in immune phenotype and alterations in adipokine homeostasis. INTRODUCTION: The aim of this study was to examine the association between indices of inflammation and BMD in a population-based cohort of older adults in the UK. METHODS: Analyses were based on a sample of 194 men and 171 women of the Hertfordshire Cohort Study (community-living, older adults). Dual energy X-ray absorptiometry (DXA) was performed at the lumbar spine and proximal femur at baseline and repeated at a median of 4.5 years (inter-quartile range 3.6 to 5.2). Inflammatory markers (CRP, TNF, IL-1ß, IL-6, IL-8, IL-10, adiponectin and leptin) were ascertained at baseline using enzyme-linked immunosorbent assay (ELISA) techniques and Bio-Plex Pro Assays. Gender-adjusted linear regression was used to examine the associations between markers of inflammation and outcomes with and without adjustment for anthropometric and lifestyle factors. RESULTS: The mean (SD) ages at baseline were 64.4 (2.5) and 66.5 (2.7) years for men and women respectively. Higher levels of adiponectin and adiponectin to leptin ratios were each associated with lower baseline lumbar spine and femoral neck BMD in gender-adjusted (p < 0.01) and fully adjusted (p < 0.05) analyses. Lower levels of IL-10 and TNF were each associated with accelerated decline in lumbar spine BMD in both gender-adjusted (p ≤ 0.05) and fully adjusted (p < 0.05) analyses. CONCLUSIONS: In a cohort of older adults, high levels of adiponectin and adiponectin to leptin ratios were both associated with lower BMD at the lumbar spine and femoral neck at baseline, and lower IL-10 was associated with accelerated decline in BMD at the lumbar spine. This adds weight to the theory that bone health can be influenced by changes in immune phenotype and alterations in adipokine homeostasis.

Muscle Mass, Muscle Morphology and Bone Health Among Community-Dwelling Older Men: Findings from the Hertfordshire Sarcopenia Study (HSS).

Sarcopenia and osteoporosis are associated with poor health outcomes in older people. Relationships between muscle and bone have typically been reported at a functional or macroscopic level. The aims of this study were to describe the relationships between muscle morphology and bone health among participants of the Hertfordshire Sarcopenia Study (HSS). 105 older men, mean age 72.5 (SD 2.5) years, were recruited into the HSS. Whole body lean mass as well as appendicular lean mass, lumbar spine and femoral neck bone mineral content (BMC) and bone mineral density (BMD) were obtained through dual-energy X-ray absorptiometry scanning. Percutaneous biopsy of the vastus lateralis was performed successfully in 99 participants. Image analysis was used to determine the muscle morphology variables of slow-twitch (type I) and fast-twitch (type II) myofibre area, myofibre density, capillary and satellite cell (SC) density. There were strong relationships between whole and appendicular lean body mass in relation to femoral neck BMC and BMD (r ≥ 0.43, p < 0.001). Type II fibre area was associated with both femoral neck BMC (r = 0.27, p = 0.01) and BMD (r = 0.26, p = 0.01) with relationships robust to adjustment for age and height. In unadjusted analysis, SC density was associated with whole body area (r = 0.30, p = 0.011) and both BMC (r = 0.26, p = 0.031) and area (r = 0.29, p = 0.017) of the femoral neck. We have demonstrated associations between BMC and changes in muscle at a cellular level predominantly involving type II myofibres. Interventions targeted at improving muscle mass, function and quality may improve overall musculoskeletal health. Larger studies that include women are needed to explore these relationships further.

Bone Phenotype Assessed by HRpQCT and Associations with Fracture Risk in the GLOW Study.

The epidemiology and pathogenesis of fractures in postmenopausal women has previously been investigated in the Global Longitudinal study of Osteoporosis in Women (GLOW). To date, however, relationships between bone imaging outcomes and fracture have not been studied in this cohort. We examined relationships between high-resolution peripheral quantitative computed tomography (HRpQCT) parameters and fracture in the UK arm of GLOW, performing a cluster analysis to assess if our findings were similar to observations reported from older participants of the Hertfordshire Cohort Study (HCS), and extended the analysis to include tibial measurements. We recorded fracture events and performed HRpQCT of the distal radius and tibia and dual-energy X-ray absorptiometry (DXA) of the hip in 321 women, mean age 70.6 (SD 5.4) years, identifying four clusters at each site. We saw differing relationships at the radius and tibia. Two radial clusters (3 and 4) had a significantly lower hip areal bone mineral density (p < 0.001) compared to Cluster 1; only individuals in Cluster 4 had a significantly higher risk of fracture (p = 0.005). At the tibia, clusters 1, 3 and 4 had lower hip areal bone mineral density (p < 0.001) compared to Cluster 2; individuals in Cluster 3 had a significantly higher risk of fracture (p = 0.009). In GLOW our findings at the radius were very similar to those previously reported in the HCS, suggesting that combining variables derived from HRpQCT may give useful information regarding fracture risk in populations where this modality is available. Further data relating to tibial HRpQCT-phenotype and fractures are provided in this paper, and would benefit from validation in other studies. Differences observed may reflect age differences in the two cohorts.

Correlates of Level and Loss of Grip Strength in Later Life: Findings from the English Longitudinal Study of Ageing and the Hertfordshire Cohort Study.

Characterisation of grip strength (GS) using isometric dynamometry is central to the definition of sarcopenia. Determinants of low GS include: older age, shorter stature, low physical activity, poor nutrition, socioeconomic disadvantage and multimorbidity. Less is known about risk factors for accelerated loss of GS. We investigated determinants of level and 8-year loss of GS in 3703 men and women (aged 52-82 years) in the English Longitudinal Study of Ageing (ELSA). Four hundred and forty-one men and women (aged 59-71 years) who participated in a 10-year follow-up of the Hertfordshire Cohort Study (HCS) were used for replication. Variables were harmonised between cohorts. Change in GS was characterised using mixed-effects models in ELSA and a residual change approach in HCS and analysed for men and women combined. Men in ELSA and HCS had higher average levels of GS at baseline, and accelerated rates of loss, compared with women. In ELSA, older age, shorter stature and multimorbidity were correlated with lower level, and accelerated rate of loss, of GS in both sexes (accelerated loss of 0.04 (95% CI 0.00-0.08) standard deviation scores per additional morbidity after multivariable adjustment). Socioeconomic disadvantage, low level of physical activity and poorer self-reported health were also correlated with low GS level, but not loss rate, after multivariable adjustment. Analysis in HCS yielded similar results. Our results identify multimorbidity as a modifiable determinant of loss of muscle strength in later life, and raise the possibility that developmental influences may impact on rate of involutional decline in muscle strength.

Relationships Between Markers of Inflammation and Muscle Mass, Strength and Function: Findings from the Hertfordshire Cohort Study.

We investigated the longitudinal relationships between inflammation markers and the following outcomes in a UK cohort study: appendicular lean mass (ALM); walking speed; level and change in grip strength; and sarcopenia defined by the European Working Group on Sarcopenia in Older People. Analyses were based on 336 community-dwelling older men and women (aged 59-70 years) who participated in the Hertfordshire Cohort Study (HCS). Inflammation markers were ascertained at baseline using enzyme-linked immunosorbent assay techniques and Bio-Plex Pro Assays. Grip strength was measured at baseline and follow-up [median follow-up time: 10.8 years (inter-quartile range 10.2-11.6)] and change in grip strength was ascertained using a residual change approach. At follow-up, ALM was ascertained using dual-energy X-ray absorptiometry, customary walking speed was measured and sarcopenia status was ascertained. Gender-adjusted linear and Poisson regression was used to examine the associations between inflammation markers and outcomes with and without adjustment for anthropometric and lifestyle factors. Higher C-reactive protein was associated (p < 0.04) with lower grip strength and accelerated decline in grip strength from baseline to follow-up. Higher cortisol was associated with lower ALM (p < 0.05). Higher interleukin-8 (IL-8) was associated with lower ALM (p < 0.05) and increased risk of sarcopenia [fully-adjusted relative risk per SD increase in IL-8: 1.37 (95% CI 1.10, 1.71), p = 0.005]. All associations were robust in fully-adjusted analyses. Inflammation markers were associated with measures of muscle mass, strength and function in HCS. Further work is required to replicate these associations and to delineate the underlying mechanisms.