Philip N. Sambrook

Loss of muscle strength, mass (sarcopenia), and quality (specific force) and its relationship with functional limitation and physical disability: the Concord Health and Ageing in Men Project.

OBJECTIVES: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men.

Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis.

OBJECTIVESnTo investigate the regulation of sclerostin (SOST) in osteoarthritis (OA) and its potential effects on articular cartilage degradation.nnnMETHODSnSOST and other Wnt-β-catenin components were immuno-localised in osteochondral sections of surgically-induced OA in knees of sheep and mice, and human OA samples obtained at arthroplasty. Regulation of SOST mRNA and protein expression by ovine chondrocytes in response to interleukin-1α (IL-1α) or tumour necrosis factor-α (TNFα) was examined in explant cultures. The effect of 25 or 250 ng/ml recombinant SOST alone or in combination with IL-1α, on ovine articular cartilage explant aggrecan degradation, and chondrocyte gene expression of Wnt-β-catenin pathway proteins, metalloproteinases and their inhibitors, and cartilage matrix proteins was quantified.nnnRESULTSnContrary to being an osteocyte-specific protein, SOST was expressed by articular chondrocytes, and mRNA levels were upregulated in vitro by IL-1α but not TNFα. Chondrocyte SOST staining was significantly increased only in the focal area of cartilage damage in surgically-induced OA in sheep and mice, as well as end-stage human OA. In contrast, osteocyte SOST was focally decreased in the subchondral bone in sheep OA in association with bone sclerosis. SOST was biologically active in chondrocytes, inhibiting Wnt-β-catenin signalling and catabolic metalloproteinase [matrix metalloproteinases (MMP) and distintegrin and metalloproteinase with thrombospndin repeats (ADAMTS)] expression, but also decreasing mRNA levels of aggrecan, collagen II and tissue inhibitors of metalloproteinaes (TIMPs). Despite this mixed effect, SOST dose-dependently inhibited IL-1α-stimulated cartilage aggrecanolysis in vitro.nnnCONCLUSIONSnThese results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.

Impact of Prevalent Fractures on Quality of Life: Baseline Results From the Global Longitudinal Study of Osteoporosis in Women

OBJECTIVEnTo examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease).nnnPATIENTS AND METHODSnFractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36).nnnRESULTSnReductions in EQ-5D health-utility scores and SF-36-measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for >/=3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease).nnnCONCLUSIONnPrevious fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life.

Frailty and use of health and community services by community-dwelling older men: the Concord Health and Ageing in Men Project

BACKGROUNDnfrailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated.nnnMETHODSnthe cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria.nnnRESULTSnoverall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status.nnnCONCLUSIONnfrailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive interventions.

The Association of Alanine Transaminase With Aging, Frailty, and Mortality

The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53-2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45-5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging.

Serum uric acid is associated with bone health in older men: A cross‐sectional population‐based study

Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross‐sectional analysis consisted of 1705 community‐dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population‐based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (βu2009=u20090.12 to 0.14, pu2009<u2009.001), serum calcium (βu2009=u20090.11, pu2009=u2009.001), parathyroid hormone (βu2009=u20090.09, pu2009=u2009.002), 25‐hydroxyvitamin D (βu2009=u20090.09, pu2009=u2009.005), and was negatively associated with urinary excretion amino‐terminal cross‐linked telopeptide of type 1 collagen (βu2009=u2009–0.09, pu2009=u2009.006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R2u2009=u20090.10 to 0.22). In multiple logistic regression analyses, above‐median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR)u2009=u20090.42, 95% confidence interval (CI) 0.22–0.81, pu2009=u2009.010) and lumbar spine (ORu2009=u20090.44, 95% CI 0.23–0.86, pu2009=u2009.016) and a lower prevalence of vertebral (ORu2009=u20090.62, 95% CI 0.43–0.91, pu2009=u2009.015) and nonvertebral (ORu2009=u20090.51, 95% CI 0.29–0.89, pu2009=u2009.018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men.

Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study

SummaryIn a study of 2005 institutionalized older people, use of oral bisphosphonates was associated with a 27% reduction in risk of death compared to non-users after adjusting for potential confounders.IntroductionThis study investigated whether reductions in mortality reported in a trial of intravenous zoledronate after hip fracture could be seen in older people taking oral bisphosphonates.MethodsTwo thousand and five institutionalized older people (mean age 85.7xa0years) were assessed at baseline and followed up for hip fracture and death for at least 5xa0years. Cox proportional hazards regression was used to estimate effects of bisphosphonates on risk of death.ResultsAt baseline, 78 subjects were taking oral bisphosphonates. Over 5xa0years of follow-up, 1,596 participants (80%) died. Use of bisphosphonates was associated with a 27% reduction in risk of death compared to non-users after adjusting for age, gender, type of institution, immobility, number of medications, weight, cognitive function, co-morbidities, and hip fracture incidence during the follow-up period (hazard ratio 0.73; 95% CI, 0.56 to 0.94; Pu2009=u20090.02).ConclusionOral bisphosphonates are associated with a reduction in the risk of death in the elderly. The mechanism of effect requires further investigation.

Hip fracture causes excess mortality owing to cardiovascular and infectious disease in institutionalized older people: A prospective 5-year study

An increasing risk of death after hip fracture has been well documented, but the duration and causes remain unclear, especially in very frail older people. This is a nested case‐control study of 229 hip fracture cases and 229 controls matched by age, gender, institution type, and follow‐up period from a cohort of 2005 institutionalized older people. The residents were assessed at baseline and followed up for hip fracture and death for at least 5 years. Time to death was measured from the same time for each case (time of the hip fracture) and the matched control. The study sample consisted of 90 males and 368 females with a mean age of 86 years (range 67 to 102 years). The hazard ratio (HR) of death for the cases compared with the controls was 3.09 [95% confidence interval (CI) 1.83–5.22, pu2009<u2009.001] for the first 3 months, 1.99 (95% CI 1.13–3.51, pu2009=u2009.02) for the period of 3 to 9 months, and 0.88 (95% CI 0.64–1.22, pu2009=u2009.46) for the period beyond 9 months following a fracture, after adjusting for age, gender, institution type, weight, immobility, cognitive function, comorbidities, and number of medications. The main causes of the excess mortality in the first 9 months were infections (HRu2009=u20096.66, 95% CI 1.95–22.77, pu2009=u2009.002) for females and cardiac disease (HRu2009=u20092.68, 95% CI 1.39–5.15, pu2009=u2009.003) for both males and females. Bisphosphonate use was associated with a reduction in mortality after hip fracture (pu2009=u2009.002). Intensive medical supervision to reduce cardiovascular and infective complications should be provided for frail older people with recent hip fracture to reduce mortality.

Evidence that bone mineral density plays a role in degenerative disc disease: the UK Twin Spine Study

Objective Osteoarthritis (OA) and osteoporosis are often considered to lie at opposite ends of a spectrum of bone phenotypes. Lumbar degenerative disc disease (LDD) may be associated with low back pain (LBP) and is similar in many ways to OA. LDD is reported in small studies to be associated with increased spine bone mineral density (BMD). The present work aimed to confirm this association in a large population sample using MRI and explore the relationship further, in particular to determine whether it is mediated genetically. Methods A population based sample (N=908, age range 32–74 years) of UK female twins having MRI of the lumbar spine was used in this study. LDD traits and summary measures and their relationship with BMD at the lumbar spine and hip were examined using multivariate multiple regression and maximum likelihood based variance decomposition. Results There was a significant positive correlation between LDD and BMD at the lumbar spine and hip, which remained significant after adjustment for confounders. Both traits were highly heritable and the associations between them were mediated genetically. Conclusions A clear, significant and independent association of BMD at hip and lumbar spine with LDD was found which is, in part, genetically mediated. The association with the non-axial site, the hip, is of particular interest and suggests a systemic bone effect. This should encourage the search for pleiotropic genes to help in the understanding of the bone–cartilage relationship. Moreover, genetic variants identified could provide novel therapeutic targets in the management of LBP.

Protease Activated Receptor-2 Mediates Activated Protein C–Induced Cutaneous Wound Healing via Inhibition of p38

Activated protein C (APC) is a natural anticoagulant that exerts anti-inflammatory and cytoprotective properties mediated through the protease activated receptor (PAR)-1. APC can also proteolytically cleave PAR-2, although subsequent function is unknown. On the basis of recent evidence that APC promotes wound healing, the aim of this study was to determine whether APC acts through PARs to heal murine excisional wounds or to regulate human cultured keratinocyte function and to determine the signaling mechanisms. Topical administration of APC accelerated wound healing in wild-type mice and, unexpectedly, in PAR-1 knockout mice. PAR-2 knockout mice healed significantly slower than wild-type mice, and healing was not altered by adding APC, indicating that APC acts through PAR-2 to heal wounds. In cultured human primary keratinocytes, APC enhanced PAR-2, stimulated proliferation, activated phosphatidylinositol 3-kinase/Src/Akt, and inhibited phosphorylated (P)-p38. Inhibiting PAR-1 or PAR-2, by small-interfering RNA or blocking antibody, reversed APC-induced keratinocyte proliferation and Akt activation. Blocking PAR-2, but not PAR-1, reversed the inhibition of P-p38 by APC. Furthermore, inhibition of P-p38 accelerated wound healing in wild-type mice. In summary, although APC acts through both PAR-1 and PAR-2 to activate Akt and to increase keratinocyte proliferation, APC-induced murine wound healing depends on PAR-2 activity and inhibition of P-p38.