Understanding the relationship between muscle and bone in older adults: an investigation of two cohorts

Bone and muscle are interconnected tissues forming the ‘muscle-bone unit’. Sarcopenia and osteoporosis are common conditions in older adults; the characterisation of the relationship between muscle and bone is fundamental to the development of potential novel preventive and therapeutic strategies that benefit both tissues. This thesis presents data from two cohorts, the Hertfordshire cohort study (HCS) and Southampton Longitudinal Study of Ageing (SaLSA) that consider relationships between muscle and bone in later life. Using existing data available from the Hertfordshire Cohort Study (HCS), the association between sarcopenia or/and osteoporosis with frailty was assessed. Co-existence of sarcopenia and osteoporosis were associated with a much higher risk of frailty than either condition alone, while sarcopenia and osteoporosis were both closely linked with multimorbidity. The overall prevalence of frailty was 8.1% with the risk increasing with age, while corresponding figures for pre-frailty were 57.5%, with the risk increasing with age only in females. Furthermore, possible determinants, such as demographic and anthropometric, of muscle density were considered and the relationships of muscle density measures to the clinical outcomes of falls and fractures were reported. Demographic and anthropometric (female sex, older age, and lower adiposity), rather than lifestyle factors such as physical activity and diet, were associated with lower muscle density, approximately 11 years later. Forearm muscle density was associated with previous fracture, rather than falls history. In addition, the relationships between other sarcopenia components including muscle size, strength and function were considered with the clinically important outcomes of falls and fractures in HCS. Observed relationships between muscle mass and strength but not function with falls and fractures were reported; sexual dimorphism was also described in the above-mentioned relationships. Finally, we present results from a new community-based cohort of older adults in Southampton, SaLSA. Initially we have investigated the impact of the COVID19 pandemic on lifestyle factors associated with musculoskeletal health in older adults living in their own homes. Greater nutritional risk and sarcopenia risk were associated with being in a worse category for change in diet quality in SaLSA during the 1st year of the pandemic. Investigating the factors leading to these changes, understanding whether they are reversible, and recognising the consequences to musculoskeletal health is required. Future work is described using this new cohort of older adults that will allow the investigation of muscle bone interrelationships in greater detail than has been previously possible. Given the interrelation between bone and muscle, future studies, such as SaLSA, might allow us to better understand muscle-bone crosstalk, with the aim of developing preventative strategies to retard or prevent deterioration of both tissues with age

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

The interplay of muscle and bone in later life

Muscle-bone interactions have long been of interest for basic, clinical and translational scientists. Skeletal muscle and bone are recognised as interacting tissues, the so-called ‘muscle-bone unit,’ in which these two tissues communicate to coordinate their development and their response to loading or injury. A wealth of epidemiological data supports the concept of muscle-bone interactions. In this chapter, we will describe how commonly the clinical conditions of both sarcopenia and osteoporosis occur together in individuals, review shared risk factors for the two conditions and discuss possible management strategies

A pas de deux of osteoporosis and sarcopenia: osteosarcopenia

The musculoskeletal conditions osteoporosis and sarcopenia are highly prevalent in older adults. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, whereas sarcopenia is identified by the loss of muscle strength, function and mass. Osteoporosis represents a major health problem contributing to millions of fractures worldwide on an annual basis, whereas sarcopenia is associated with a range of adverse physical and metabolic outcomes. They both affect physical and social function, confidence and quality of life as well as contributing to high health-care costs worldwide. Osteosarcopenia is the term given when both conditions occur concomitantly and it has been suggested that interactions between these two conditions may accelerate individual disease progression as co-existence of osteoporosis and sarcopenia is associated with higher morbidity from falls, fracture, disability as well as mortality. In this review, we will outline the epidemiology, pathogenesis and clinical consequences of osteosarcopenia and discuss available management strategies

Establishing a resource to assess musculoskeletal health in older adults in the post-COVID-19 era: Time to SaLSA?

Sarcopenia and osteoporosis are associated with morbidity and mortality. The development and progression of these two interrelated conditions are related to genetic and lifestyle factors, including nutrition and physical activity. Restrictions placed on individuals due to the COVID-19 pandemic and infection have led to widespread lifestyle modifications, with data suggesting a negative impact on physical activity levels. There is an urgent need to understand the effect of the pandemic on musculoskeletal health in older adults, at a time when COVID-19 infection and restrictions remain a barrier to research studies. We tested the feasibility of recruiting local community-dwelling older people to establish a new cohort investigating musculoskeletal health—the Southampton Longitudinal Study of Ageing (SaLSA). We invited 1993 community-dwelling older adults registered at the Living Well GP partnership in Southampton, UK, to participate in a study. Questionnaires were completed by participants on health, lifestyle, medication use, comorbidities, physical activity, nutrition, sarcopenia, osteoporosis, and quality of life. Permission was sought for future contact. Descriptive statistics were used on the initial pilot of 175 returned questionnaire data. The median age of participants was 80.4 years in both sexes, 81.3 years (77.9–84) in females, and 81.1 years in males (77.3–83.6). The majority (N = 168/171, 98%) of participants were of white Caucasian background; 36/53 (68%) female participants and 38/119 (32%) male participants lived alone. Over 80% (295/353) consented to be contacted for future studies. Recruitment of participants from a primary care practice into a research study was feasible. The next steps are to perform detailed musculoskeletal phenotyping through physical performance measures, grip strength dynamometry, DXA scanning, high-resolution peripheral quantitative computed tomography (HRpQCT), thigh ultrasound, and muscle biopsy, in a subset of participants. Our vision for SaLSA is to build a platform for discovery science and mechanistic studies, with the goal of improving the health care of older people

Tocilizumab (Actemra)

Tocilizumab (TCZ), is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody which has a main use in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA). This article provides an overview of TCZ including looking into the past at the discovery of interleukin-6 (IL-6) as a pro-inflammatory cytokine. It also looks at how tocilizumab was developed, manufactured and tested to ensure both safety and efficacy in a human population. The article then explores the advantages and disadvantages of using TCZ when compared to other biologics approved in RA, sJIA and pJIA and finally looks ahead to the future and the emerging role of IL-6 and its blockade by TCZ as a treatment for giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and large vessel vasculitis (LVV)

Associations of osteoporosis and sarcopenia with frailty and multimorbidity among participants of the Hertfordshire Cohort Study

Background: Ageing is commonly associated with sarcopenia (SP) and osteoporosis (OP), both of which are associated with disability, impaired quality of life and mortality. The aims of this study were to explore the relationships between SP, OP, frailty and multimorbidity in community dwelling older adults participating in the Hertfordshire Cohort Study (HCS), and to determine whether co-existence of osteoporosis and sarcopenia was associated with a significantly heavier health burden. Methods: At baseline, 405 participants self-reported their comorbidities. Cut-offs for low grip strength and appendicular lean mass index were used according to the EWSGOP2 criteria to define SP. OP was diagnosed when T-scores of < -2.5 were present at the femoral neck or the participant reported use of the anti-osteoporosis medications including hormone replacement therapy (HRT), raloxifene or bisphosphonates. Frailty was defined using the standard Fried definition. Results: 199 men and 206 women were included in the study. Baseline median (IQR) age of participants was 75.5 (73.4 - 77.9) years. 26 (8%) and 66 (21.4%) of the participants had SP and OP respectively. 83 (20.5%) reported 3 or more comorbidities. The prevalence of pre-frailty and frailty in the study sample was 57.5% and 8.1% respectively. Having SP only was strongly associated with frailty (OR 8.28, 95% CI 1.27, 54.03; p=0.027) while the association between having OP alone and frailty was weaker (OR 2.57, 95% CI 0.61,10.78; p=0.196). The likelihood of being frail was substantially higher in the presence of co-existing SP and OP (OR 26.15, 95% CI 3.13,218.76; p=0.003). SP alone and OP alone were both associated with having 3 or more comorbidities (OR 4.71, 95% CI 1.50, 14.76, p=0.008 and OR 2.86, 95% CI 1.32, 6.22; p=0.008 respectively) though the co-existence of SP and OP was not significantly associated with multimorbidity (OR. 3.45, 95% CI 0.59, 20.26; p=0.171). Conclusions: Individuals living with frailty were often osteosarcopenic. Multimorbidity was common in individuals with either sarcopenia or osteoporosis. Early identification of SP and OP not only allows implementation of treatment strategies but also presents an opportunity to mitigate frailty risk

Relationships between muscle parameters and history of falls and fractures in the Hertfordshire Cohort Study: do all muscle components relate equally to clinical outcomes?

In previous work, relationships between muscle and bone size and strength have been demonstrated and were stronger in females, suggesting possible sexual dimorphism. Here we examine sex-specific associations between individual muscle sarcopenia components with clinical outcomes (falls and fractures). 641 participants were recruited. Muscle mass was assessed as cross-sectional area (CSA) by peripheral quantitative computed tomography of the calf, grip strength (GpS) by Jamar dynamometry and function by gait speed (GtS). Falls and fractures were self-reported. Ordinal and logistic regression were used to examine the associations between muscle measurements and outcomes with and without adjustment for confounders. Mean (SD) age was 69.3 (2.6) years. CSA, GpS, and GtS were greater among males (p < 0.002). A higher proportion of females had fallen since age 45 (61.3% vs 40.2%, p < 0.001); in the last year (19.9% vs 14.1%, p = 0.053); and reported a previous fracture since age 45 (21.8% vs 18.5%, p = 0.302), than males. Among females, greater CSA was related to reduced risk of falling and fewer falls in the previous year in fully adjusted analysis only (p < 0.05); higher GpS was related to lower risk of falls since age 45 in unadjusted analysis (p = 0.045) and lower risk of fracture since age 45 in both unadjusted and fully adjusted analysis (p < 0.045). No statistically significant associations were observed for GtS among either sex for any relationships between muscle measurements and clinical outcomes studied. We observed relationships between muscle mass and strength but not function with falls and fractures in females only; further longitudinal studies are required to reproduce these results

Mortality, bone density and grip strength: lessons from the past and hope for the future?

Objectives: therapeutic advances in management of osteoporosis and sarcopenia have occurred at different rates over the last two decades; here we examined associations between grip strength and bone mineral density (BMD) with subsequent all-cause and cause-specific mortality in a UK community-dwelling cohort.Methods: data from 495 men and 414 women from the Hertfordshire Cohort Study were analysed. Grip strength was assessed by grip dynamometry; femoral neck BMD was ascertained using DXA; deaths were recorded from baseline (1998–2004) until 31st December 2018. Grip strength and BMD in relation to mortality outcomes (all-cause, cardiovascular-related, cancer-related, and mortality due to other causes) were examined using Cox regression with adjustment for age and sex.Results: mean (SD) baseline age of participants was 64.3 (2.5) and 65.9 (2.6) years in men and women respectively. Lower grip strength was associated with increased risk of all-cause mortality (hazard ratio (95% CI): 1.30 (1.06,1.58), p = 0.010) and cardiovascular-related mortality (1.75 (1.20,2.55), p = 0.004). In contrast, BMD was not associated with any of the mortality outcomes (p > 0.1) for all associations.Conclusion: we report strong relationships between grip strength and mortality in comparison with BMD. We hypothesize that this may reflect better recognition and treatment of low BMD in this cohort