Osteosarcopenia: where osteoporosis and sarcopenia collide.

The coexistence of osteoporosis and sarcopenia has been recently considered in some groups as a syndrome termed 'osteosarcopenia'. Osteoporosis describes low bone mass and deterioration of the micro-architecture of the bone, whereas sarcopenia is the loss of muscle mass, strength and function. With an ageing population the prevalence of both conditions is likely to increase substantially over the coming decades and is associated with significant personal and societal burden. The sequelae for an individual suffering from both conditions together include a greater risk of falls, fractures, institutionalization and mortality. The aetiology of 'osteosarcopenia' is multifactorial with several factors linking muscle and bone function, including genetics, age, inflammation and obesity. Several biochemical pathways have been identified that are facilitating the development of several promising therapeutic agents, which target both muscle and bone. In the current review we outline the epidemiology, pathogenesis and clinical consequences of 'osteosarcopenia' and explore current and potential future management strategies.

The epidemiology of osteoporosis.

INTRODUCTION: With a worldwide ageing population, the importance of the prevention and management of osteoporotic fragility fractures is increasing over time. In this review, we discuss in detail the epidemiology of fragility fractures, how this is shaped by pharmacological interventions and how novel screening programmes can reduce the clinical and economic burden of osteoporotic fractures. SOURCES OF DATA: PubMed and Google Scholar were searched using various combinations of the keywords 'osteoporosis', 'epidemiology', 'fracture', 'screening', `FRAX' and 'SCOOP'. AREAS OF AGREEMENT: The economic burden of osteoporosis-related fracture is significant, costing approximately $17.9 and £4 billion per annum in the USA and UK. AREAS OF CONTROVERSY: Risk calculators such as the web-based FRAX® algorithm have enabled assessment of an individual's fracture risk using clinical risk factors, with only partial consideration of bone mineral density (BMD). GROWING POINTS: As with all new interventions, we await the results of long-term use of osteoporosis screening algorithms and how these can be refined and incorporated into clinical practice. AREAS TIMELY FOR DEVELOPING RESEARCH: Despite advances in osteoporosis screening, a minority of men and women at high fracture risk worldwide receive treatment. The economic and societal burden caused by osteoporosis is a clear motivation for improving the screening and management of osteoporosis worldwide.

Intergenerational effect of early-life growth on offspring height: Evidence from the Hertfordshire Cohort Study.

BACKGROUND: Previous intergenerational (parent to child) and transgenerational (grandparent to grandchild) studies have shown there is a link between parental and offspring birthweight. OBJECTIVES: The aim was to explore the association between the early-life weight gain of an individual and the adult height of their children and grandchildren. METHODS: Study participants across three generations of the Hertfordshire Cohort Study (HCS) were included in this study. Health visitors recorded the birthweight (kg) and weight at 1 year (kg) of the original (F0 generation) HCS participants when they were born in Hertfordshire between 1931 and 1939. A conditional infant weight gain score for F0 participants was calculated using birthweight and weight at 1 year, and self-reported height (cm) of their children (F1 generation) and their grandchildren (F2 generation) was obtained from postal questionnaires. Due to the lack of clustering within family lines, linear regression analysis was used to compare intergenerational relationships. RESULTS: Data were available from 139 F0, 148 F1, and 198 F2 participants. A positive association was found between parental birthweight (F0) and offspring adult height; on average, a 1 kg increase in F0 birthweight was associated with a 2.04 cm increase in F1 adult height (beta 2.04, 95% confidence interval [CI] -0.03, 4.10). A positive association was found between F0 conditional weight gain during the first year of life and offspring (beta 1.53, 95% CI 0.45, 2.62) and grandchild height (beta 1.06, 95% CI 0.03, 2.10). Positive associations were also found between F0 weight at 1 year and offspring (beta 1.83, 95% CI 0.79, 2.87) and grandchild height (beta 0.91, 95% CI -0.10, 1.91). CONCLUSION: This study demonstrates an association between grandparental weight gain in early life and the heights of their children and grandchildren. The results of these analyses highlight the importance of early-life weight gain on the adult stature of subsequent offspring.

Does self-report of multimorbidity in later life predict impaired physical functioning, and might this be useful in clinical practice?

BACKGROUND: Multimorbidity has been shown in several studies to relate to impaired physical function in later life. AIMS: To examine if self-report of multimorbidity predicts impaired physical functioning, as assessed by formal physical function testing, in community-dwelling older adults. METHODS: Non-communicable diseases (NCDs) were self-reported by 443 older community-dwelling UK adults via questionnaire, asking the question: 'Have you been told by a doctor that you have any of the following conditions?' Assessments of walking speed, chair stands and balance allowed us to create a composite score (0-12) on which impaired physical functioning was defined as ≤ 9. RESULTS: The mean age of participants was 75.5 ± 2.5 years for men and 75.8 ± 2.6 for women. The proportion of individuals with impaired physical functioning was 71.2% in women and 56.9% in men. Having four or more NCDs was associated with an increased risk of poor physical function in men and women (p < 0.05). The number of medications and medicated systems was associated with gait speed (p < 0.03 and < 0.02, respectively) and timed up-and-go tests (p < 0.03 and < 0.02, respectively) in women but not men. DISCUSSION AND CONCLUSION: Self-report of 4 or more NCDs was associated with an increased risk of poor physical function, an outcome which has previously been associated with adverse clinical sequelae. This observation may inform development of a simple screening tool to look for poor physical function in older adults.

A diagnosis of knee osteoarthritis does not predict physical activity 2 years later in older adults: findings from the Hertfordshire Cohort Study.

Osteoarthritis (OA) can negatively impact levels of physical activity (PA), although current clinical advice promotes the benefits of staying active in preventing joint degeneration. In this study, we examine how knee OA, assessed by self-report, clinical assessment and radiographic assessment, impacts upon objectively measured PA 2 years later. The study population is comprised of 114 subjects from the Hertfordshire Cohort Study (HCS). The presence of OA at the knee was determined from self-report, and clinical and radiological examination, defined according to American College of Rheumatology (ACR) criteria and Kellgren and Lawrence grading system. Two years later, Gulf Coast Data Concepts (GCDC) tri-axial accelerometers were used to measure day-to-day levels of PA. Vertical acceleration peaks over 7 days, expressed in g units, were categorised into low (0.5 ≤ g < 1.0), medium (1.0 ≤ g < 1.5) and high (≥ 1.5 g) impacts. The study comprises 69 men and 45 women. The mean (SD) age was 78.5 (2.6) for men and 78.6 (2.7) for women. Low count numbers were recorded in the medium and high impact bands. We found no significant reduction in low, medium or high impacts in individuals who had been previously diagnosed with self-reported, radiographic or clinical knee OA in this sample after adjustment for age, sex and BMI. In our cohort, participants with knee OA were no less likely to partake in objectively measured weight-bearing activity 2 years after assessment than counterparts without a diagnosis of knee OA.

Impact of osteoarthritis on activities of daily living: does joint site matter?

BACKGROUND: We consider the relationships between a clinical and radiological diagnosis of knee or hip OA and activities of daily-living (ADL) in older adults. METHODS: Data were available for 222 men and 221 women from the Hertfordshire Cohort Study (HCS) who also participated in the UK component of the European Project on Osteoarthritis (EPOSA). Participants completed the EuroQoL survey where they reported if they had difficulties with mobility, self-care, usual activities and movement around their house. Hip and knee radiographs were graded for overall Kellgren and Lawrence score (positive definition defined as a 2 or above). Clinical OA was defined using American College of Rheumatology criteria. RESULTS: In men, a clinical diagnosis of hip or knee OA were both associated with reported difficulties in mobility, ability to self-care and performing usual-activities (hip OA: OR 17.6, 95% CI 2.07, 149, p = 0.009; OR 12.5, 95% CI 2.51, 62.3, p = 0.002; OR 4.92, 95% CI 1.06, 22.8, p = 0.042 respectively. Knee OA: OR 8.18, 95% CI 3.32, 20.2, p < 0.001; OR 4.29, 95% CI 1.34, 13.7, p = 0.014; OR 5.32, 95% CI 2.26, 12.5, p < 0.001 respectively). Similar relationships were seen in women, where in addition, a radiological diagnosis of knee OA was associated with difficulties performing usual activities (OR 3.25, 95% CI 1.61, 6.54, p = 0.001). In general, men with OA reported stronger associations between moving around the house, specifically around the kitchen (clinical hip OA: OR 13.7, 95% CI 2.20, 85.6, p = 0.005; clinical knee OA OR 8.45, 95% CI 1.97, 36.2, p = 0.004) than women. DISCUSSION AND CONCLUSION: Clinical OA is strongly related to the ability to undertake ADL in older adults and should be considered in clinic consultations when seeing patients with OA.

Determinants of circulating 25-hydroxyvitamin D concentration and its association with musculoskeletal health in midlife: Findings from the Hertfordshire Cohort Study.

INTRODUCTION: Several studies have reported the importance of vitamin D status to musculoskeletal health in populations of older adults. Here we report relationships between circulating serum 25(OH)D and musculoskeletal health in a community cohort of UK adults in midlife and investigate whether environmental (dietary intake, use of supplements) and/or genetic factors (4 SNPs previously related to vitamin D status) play more significant roles in determining vitamin D status in this population. METHODS: Participants were recruited from the Hertfordshire Cohort Study, an established longitudinal cohort study of community dwelling adults and were seen at baseline and follow up 9-12 years later. Lumbar spine and total femur BMD were measured at baseline using a Hologic QDR 4500 instrument. Osteoarthritis (OA) was defined by radiographs of the knees graded according to Kellgren & Lawrence at both time points. Serum 25(OH)D concentrations were measured using a DiaSorin Liaison chemiluminescent assay. Genotyping of 4 SNPs previously associated with 25(OH)D values were assessed: (rs12785878 (DHCR7), rs10741657 (CYP2R1) and rs6013897 (CYP24A1)) and a fourth SNP (rs4588), described as "a near-perfect proxy (i.e. substitute) for rs2282679 on the GC gene". RESULTS: 820 subjects (397 men, 423 women) participated at baseline, and 339 of these 820 subjects (164 men; 175 women) participated in a follow up study of OA progression. The median (IQR) age of participants at baseline was 64.0 (61.8-66.5) and 65.5 (63.3-67.6) for men and women respectively. Median circulating levels of 25(OH)D were 44.6 (35.0-63.0) nmol/L and 41.3 (29.8-53.5) nmol/L in men and women respectively. Circulating 25(OH)D was strongly associated with season of blood testing (p < 0.001). The greatest variance in a model of vitamin D status that included the four SNPs measured, season, and whether participants reported taking vitamin D supplements was explained by season of assay (17.9% men; 15.8% women). Higher femoral neck BMD was observed in men with higher baseline vitamin D status, after adjustment for age, season, BMI, smoker status, alcohol consumption, physical activity and social class (p = 0.01). Associations between 25(OH)D and BMD in women were not statistically significant in this population. There were no associations between circulating 25(OH)D and radiographic knee OA at either time point after adjustment for confounders and for duration of follow-up. CONCLUSION: Circulating 25(OH)D levels were generally lower than is recommended in community dwelling adults in midlife, with marked seasonal variation observed, but relationships with reported vitamin D supplementation were weaker. Circulating 25(OH)D was directly associated with hip BMD in men but relationships with BMD in women and radiographic OA were not seen in this sample.

Kinetic properties of Ca2+/calmodulin-dependent phosphodiesterase isoforms dictate intracellular cAMP dynamics in response to elevation of cytosolic Ca2+.

Multiply regulated adenylyl cyclases (AC) and phosphodiesterases (PDE) can yield complex intracellular cAMP signals. Ca2+-sensitive ACs have received far greater attention than the Ca2+/calmodulin-dependent PDE (PDE1) family in governing intracellular cAMP dynamics in response to changes in the cytosolic Ca2+ concentration ([Ca2+]i). Here, we have stably expressed two isoforms of PDE1, PDE1A2 and PDE1C4, in HEK-293 cells to determine whether they exert different impacts on cellular cAMP. Fractionation and imaging showed that both PDEs occurred mainly in the cytosol. However, PDE1A2 and PDE1C4 differed considerably in their ability to hydrolyze cAMP and in their susceptibility to inhibition by the non-selective PDE inhibitor, IBMX and the PDE1-selective inhibitor, MMX. PDE1A2 had an approximately 30-fold greater Km for cAMP than PDE1C4 and yet was more susceptible to inhibition by IBMX and MMX than was PDE1C4. These differences were mirrored in intact cells when thapsigargin-induced capacitative Ca2+ entry (CCE) activated the PDEs. Mirroring their kinetic properties, PDE1C4 was active at near basal cAMP levels, whereas PDE1A2 required agonist-triggered levels of cAMP, produced in response to stimulation of ACs. The effectiveness of IBMX and MMX to inhibit PDE1A2 and PDE1C4 in functional studies was inversely related to their respective affinities for cAMP. To assess the impact of the two isoforms on cAMP dynamics, real-time cAMP measurements were performed in single cells expressing the two PDE isoforms and a fluorescent Epac-1 cAMP biosensor, in response to CCE. These measurements showed that prostaglandin E1-mediated cAMP production was markedly attenuated in PDE1C4-expressing cells upon induction of CCE and cAMP hydrolysis occurred at a faster rate than in cells expressing PDE1A2 under similar conditions. These results prove that the kinetic properties of PDE isoforms play a major role in determining intracellular cAMP signals in response to physiological elevation of [Ca2+]i and thereby provide a rationale for the utility of diverse PDE1 species.

Impact of Rheumatoid Arthritis and Its Management on Falls, Fracture and Bone Mineral Density in UK Biobank.

Objectives: Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease which presents with polyarthritis in addition to extra-articular manifestations. Historically, studies have shown a link between RA and adverse musculoskeletal outcomes but these studies were reported before the widespread use of biologic therapies. The aim of this study was therefore to investigate associations between RA, RA medications and bone mineral density, falls and fractures, using UK Biobank data. Methods: Diagnosis of RA was made using Hospital Episode Statistics (HES) ICD-10 coding. We assessed RA relationships with estimated bone mineral density (eBMD) from heel quantitative ultrasound measurements, self-reported falls (in last year) and HES recorded fracture, adjusted for age, ethnicity, BMI, smoking status, and physical activity. Results: Of 502,543 participants, 3849 (1.4%) of women and 1643 (0.7%) of men had a diagnosis of RA. Median age of the participants was 57 years (IQR 50-63) in women and 58 (IQR 50-64) in men. RA was associated with lower eBMD (men: ß -0.244, 95% CI -0.378, -0.110 p < 0.001; women: ß -0.217, 95% CI -0.297, -0.138 p < 0.001) a reported fall in the last year (men: OR 1.54, 95% CI 1.26, 1.87 p < 0.001; women: OR 1.36, 95% CI 1.19, 1.56 p < 0.001) and fracture in women (OR 1.76, 95% CI 1.43, 2.16 p < 0.001). Corticosteroid therapy in men (ß -0.934, 95% CI -1.565, -0.304 p = 0.004) and disease modifying anti-rheumatic drug (DMARD) use in both sexes (men: ß -0.437, 95% CI -0.761, -0.112 p = 0.008; women: ß -0.243, 95% CI -0.421, -0.065 p = 0.007), but not biologic therapy, were associated with a lower eBMD with RA. Conclusions: RA was associated with lower eBMD, increased falls and fracture. Corticosteroid and DMARD therapy, but not biologic therapy, were associated with lower eBMD.

The incidence of sexually acquired reactive arthritis: a systematic literature review.

Reactive arthritis (ReA) is an inflammatory spondyloarthritis occurring after infection at a distant site. Chlamydia trachomatis is proposed to be the most common cause of ReA, yet the incidence of sexually acquired ReA (SARA) has not been well established. We therefore carried out a systematic literature review to collate and critically evaluate the published evidence regarding the incidence of SARA. MEDLINE and EMBASE databases were searched using free-text and MeSH terms relating to infection and ReA. The title and abstract of articles returned were screened independently by two reviewers and potentially relevant articles assessed in full. Data was extracted from relevant articles and a risk of bias assessment carried out using a validated tool. Heterogeneity of study methodology and results precluded meta-analysis. The search yielded a total of 11,680 articles, and a further 17 were identified from review articles. After screening, 55 papers were assessed in full, from which 3 met the relevant inclusion criteria for the review. The studies reported an incidence of SARA of 3.0-8.1 % and were found to be of low to moderate quality. More studies are required to address the lack of data regarding the incidence of SARA. Specific and sensitive classification criteria must be developed in order for consistent classification and valid conclusions to be drawn. In clinical practice, it is recommended clinicians discuss the possibility of ReA developing at the time of STI diagnosis and to encourage patients to return if they experience any relevant symptoms.

Insights into the residence in lipid rafts of adenylyl cyclase AC8 and its regulation by capacitative calcium entry.

Adenylyl cyclases (ACs) are a family of critically important signaling molecules that are regulated by multiple pathways. Adenylyl cyclase 8 (AC8) is a Ca(2+) stimulated isoform that displays a selective regulation by capacitative Ca(2+) entry (CCE), the process whereby the entry of Ca(2+) into cells is triggered by the emptying of intracellular stores. This selectivity was believed to be achieved through the localization of AC8 in lipid raft microdomains, along with components of the CCE apparatus. In the present study, we show that an intact leucine zipper motif is required for the efficient N-linked glycosylation of AC8, and that this N-linked glycosylation is important to target AC8 into lipid rafts. Disruption of the leucine zipper by site-directed mutagenesis results in the elimination of N-glycosylated forms and their exclusion from lipid rafts. Mutants of AC8 that cannot be N-glycosylated are not demonstrably associated with rafts, although they can still be regulated by CCE; however, raft integrity is required for the regulation of these mutants. These findings suggest that raft localized proteins in addition to AC8 are needed to mediate its regulation by CCE.