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Chronic kidney disease and osteoporosis commonly co-exist in aged patients. Chronic kidney disease affects bone health because of its effect on mineral metabolism in the syndrome, Chronic Kidney Disease Mineral and Bone Disorder, resulting in an increased risk of fractures. Hip fracture risk may be as much as four-fold higher in the worst affected. Tools to estimate fracture risk such as FRAX® and measuring bone density can be used in patients with chronic kidney disease; however, bone density may underestimate fracture risk in this population as it does not give information on bone quality. While osteoporosis treatment in patients with chronic kidney disease stage 1-3 does not differ from the general population, in the absence of Chronic Kidney Disease Mineral and Bone Disorder, patients with disease stage 4-5 require special consideration. It is, however, of the utmost importance that these patients receive pharmacological treatment because of their high risk of fractures.

Summary Frailty reflects an accelerated health decline. Frailty is a consequence of fracture and contributes to fracture. Greater frailty was associated with higher fracture risk. Frail women were at immediate risk (within 24 months) of a hip or major fracture. Fracture prevention could be improved by considering frailty status. Introduction Frailty encompasses the functional decline in multiple systems, particularly the musculoskeletal system. Frailty can be a consequence of and contribute to fracture, leading to a cycle of further fractures and greater frailty. This study investigates this association, specifically time frames for risk, associated fracture types, and how grade of frailty affects risk. Methods The study is performed in the OPRA cohort of 1044, 75-year-old women. A frailty index was created at baseline and 5 and 10 years. Women were categorized as frail or nonfrail and in quartiles (Q1 least frail; Q4 most frail). Fracture risk was assessed over short (1 and 2 years) and long terms (5 and 10 years). Fracture risk was defined for any fracture, major osteoporotic fractures (MOFs), and hip and vertebral fracture, using models including bone mineral density (BMD) and death as a competing risk. Results For women aged 75, frailty was associated with higher risk of fracture within 2 years (Hip SHRadj. 3.16 (1.34–7.47)) and MOF (2 years SHRadj. 1.88 (1.12–3.16)). The increased risk continued for up to 5 years (Hip SHRadj. 2.02 (1.07–3.82)); (MOF SHRadj. 1.43 (0.99–2.05)). Grade of frailty was associated with increased 10-year probability of fracture (p = 0.03). Frailty predicted fracture independently of BMD. For women aged 80, frailty was similarly associated with fracture. Conclusion Frail elderly women are at immediate risk of fracture, regardless of bone density and continue to be at risk over subsequent years compared to identically aged nonfrail women. Incorporating regular frailty assessment into fracture management could improve identification of women at high fracture risk. Supplementary Information The online version contains supplementary material available at 10.1007/s00198-021-05886-7.

Purpose of Review This review outlines the scope of the problem in osteoporosis care and secondary fracture prevention and describes fracture prevention strategies, with a focus on the frail elderly. Recent Findings Despite heightened awareness among patients and clinicians alike and the availability of efficacious anti-osteoporosis medications, osteoporosis is still underdiagnosed and undertreated. However, the introduction of systematic risk assessment and secondary fracture prevention programmes has gained momentum, and evidence of success is accumulating. Summary We possess today the knowledge required to close the osteoporosis care gap. The basic components in a secondary prevention model are similar in all health care settings, number one being a dedicated fracture coordinator, with anti-osteoporosis medications and multifaceted falls prevention as cornerstones, particularly in the frailest, both in the near and long-term. Initiation of structured care pathways including the key elements – identification, investigation, intervention and follow-up of adherence – demonstrably reduces re-fracture rates and is cost-effective.

Purpose Distal radius fracture often compromises working ability, but clinical implications are less studied in men due to its lower incidence. This study therefore describes sick leave in men with distal radius fracture, specifically exploring the impact of patient- and fracture-related factors. Methods Professionally active men aged 20–65 with distal radius fracture were followed prospectively for 1-year (n = 88). Data included treatment method, radiographic parameters pre/post treatment, complications, health, lifestyle and occupational demand. Patient outcomes were self-reported sick leave; Disability of the Arm, Shoulder and Hand (DASH) score; pain (5 likert scale); SF-36: Physical Component Scale (PCS) and Mental Component Scale (MCS). Results Median sick leave was 4 weeks (IQR 0; 8); almost a third reported taking no sick leave. Categorizing sick leave into 3 groups (0–6, 7–12 and > 12 weeks), men with the longest sick leave had 22 points higher DASH score (p = 0.001) and 5 points lower PCS (p = 0.02) at 1 week and the difference remained over time; they were also older and more often treated surgically. The strongest predictors of length of sick leave were one-week post-fracture DASH score (rs = 0.4, p s = 0.56, p = 0.007, surgery rs = 0.42, p = 0.04). Conclusions Self-reported disability, pain and global health measurements as early as 1 week post-fracture are the strongest predictors of length of sick leave regardless of treatment; an important finding easily transferrable to clinical management of distal radius fractures.

Background Frailty captures the age-related declines in health leading to increased vulnerability, including falls which are commonplace in older women. The relationship between frailty and falls is complex, with one leading to the other in a vicious cycle. Aims This study addresses the gap in understanding how patterns of frailty and falls propensity interact, particularly in those who have not yet entered the falls-frailty cycle. Methods The Osteoporosis Risk Assessment cohort consists of 1044 community-dwelling women aged 75, with 10 years of follow-up. Investigations were performed and a frailty index constructed at baseline, 5 and 10 years. Falls were self-reported for each previous 12 months. Analysis was two-directional, firstly based on frailty status and second, based on falls status. Recurrent falls was the primary outcome. Results Baseline frailty was a significant predictor of recurrent falls after 5 and 10 years [(OR 2.55 (1.62–3.99); 3.04 (1.63–5.67)]. Among women who had no history of falls at age 75, frailty was a stronger predictor of falls at 5 years [OR 3.06 (1.59–5.89)] than among women who had previously fallen. Discussion Frailty is significantly associated with recurrent falls and most pronounced in those who are frail but have not yet fallen. Conclusions This suggests that frailty should be an integral part of falls-risk assessment to improve identification of those at risk of becoming fallers.

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Summary Reduced kidney function is associated with an increased fracture risk, although the relationship between an age-related decline and fractures needs further investigation. We followed kidney function and fracture risk for 10 years. A mild-moderate decline in kidney function was associated with fracture, but not in advanced age. Introduction With age, kidney function declines. Though well known that chronic kidney disease is associated with increased fracture risk, the extent to which the typical age-related decline contributes is unclear. In the OPRA cohort, a longitudinal study of older non-selected women, we investigated the association between kidney function and fracture. Methods Cystatin C–based kidney function estimates were available at age 75 (n = 981) and 80 (n = 685). Women were categorized by kidney function: normal (CKD stages 1 and 2), mild-moderate (3a), poor (3b-5), and imminent, short- and long-term fracture risk investigated. BMD measurements and kidney function for risk prediction were also evaluated; women were categorized by both reduced kidney function (stages 3–5) and osteoporosis status. Results In the short term, 2–3 years, mild-moderate kidney dysfunction was associated with the highest risk increase: osteoporotic fractures (2 years HRadj 2.21, 95% CI 1.27–3.87) and also up to 5 years (between 75 and 80 years) (HRadj 1.51, 1.04–2.18). Hip fracture risk was similarly increased. This association was not observed from age 80 nor for women with poorest kidney function. Reduced kidney function was associated with higher risk even without osteoporosis (osteoporotic fracture; HRadj 1.66, 1.08–2.54); risk increased by having both osteoporosis and reduced function (HRadj 2.53, 1.52–4.23). Conclusion Older women with mild-moderate reduction of kidney function are at increased risk of fractures, but not those with the worst function. Our findings furthermore confirm the value of osteoporosis assessment and it is possible that in this age group, age-related decline of kidney function has limited contribution compared with BMD. Electronic supplementary material The online version of this article (10.1007/s00198-019-05152-x) contains supplementary material, which is available to authorized users.

Context Vitamin D (25OHD) is involved in many physiological functions that decline with age, contributing to frailty and increased risk for negative health outcomes. Whether 25OHD is a long-term risk marker for frailty over a longer time and whether it is consistent with advancing age is unclear. Objective To investigate the association between 25OHD and frailty in older women followed for 10 years. Design and Setting Prospective, population-based, cohort study in Malmö, Sweden. Participants Community-dwelling women, age 75 years (N = 1044) with reassessments at ages 80 (n = 715) and 85 (n = 382) years. Methods Frailty was quantified using a 10-variable frailty index. Women were categorized as 25OHD insufficient ( Results At ages 75 and 80 years, women with insufficient 25OHD were frailer than women with sufficient 25OHD (0.23 vs 0.18, P < 0.001; and 0.32 vs 0.25, P = 0.001, respectively). At age 80 years, 25OHD insufficiency was associated with subsequent frailty 5 years later (0.41 vs 0.32; P = 0.011). Accelerated progression of frailty was not associated with lower 25OHD levels, and 25OHD level >75 nmol/L was not additionally beneficial with regard to frailty. No association between 25OHD and frailty was observed at age 85 years. Within the frailty index, variables associated with 25OHD were related to muscle strength and function. Conclusion In this study, 25OHD insufficiency was associated with increased frailty in all but the oldest old. This study supports the value of maintaining sufficient 25OHD levels for healthy aging.

Hip geometry (HG) is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: 1) Femoral neck length; 2) Neck-shaft angle; 3) Femoral neck width, and 4) Femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16-93 years. Association analyses were performed with ~ 2.5 million polymorphismsunder an additive model adjusted for age and body mass index; an additional analysis also adjusted for height. Replication analyses of meta-GWAS significant loci (at genome-wide significance, GWS, threshold p≤5x10-8) were performed in 7 additional cohorts in-silico. In meta-analysis not adjusting for height (combined Discovery and Replication stages), GWS associations were found on chr. 4 (in HHIP), chr. 8 (C8orf34), chr. 13 (FAM10A4 and DLEU2), and chr. 20 (inDDX27). The height-adjusted meta-analysis showed significant associations at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several HG signals overlapped with bone mineral density (BMD), including JAG1 on chr. 20, near TNFRSF11B (chr. 8), SOX6 and LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10-5). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p=0.0007), and rs6556301 (intergenic, chr.5) and PDLIM7 expression(p=0.005). In conclusion, we found associations between HG measures and several genes being part of biological pathways relevant to BMD and fractures. The results provide a defined set of genes facilitating further experimental exploration and validation to understand biological mechanisms underlying human bone geometry and etiology of bone fragility.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

This study investigates the sex steroid hormone profile in younger men with distal radius fracture (DRF) to elucidate if this could explain the low bone density and osteoporosis previously observed. In a case–control study, 73 men with DRF (mean age 38 ± 9 years; range, 20–51) was compared with 194 age‐matched, population controls. Performed assays: total testosterone (TT), calculated free testosterone (cFT), luteinizing hormone (LH), follicle‐stimulating hormone (FSH), sex hormone‐binding globulin (SHBG), and total estradiol (E2). BMD hip and spine were measured. Fracture cases had lower cFT (298 versus 329 pmol/L; p = 0.008), but not TT, compared with controls. FSH and SHBG were not statistically different. LH was almost 30% higher (5.7 versus 4.5 IU/L; p

Difficulty in obtaining bone tissue is an obstacle to studying epigenetics to understand gene–environment interactions, and their role in disease pathogenesis. Blood is an obvious alternative and in this proof of principle study, our aim was to systematically investigate whether blood is a viable surrogate for bone. We measured epigenome-wide DNA methylation at 850 K CpG sites in matched trabecular bone and peripheral blood collected from the same patients at the same time-point (n = 12 women; 66–85y), to investigate the between-tissue correspondence. What constituted a CpG site with corresponding methylation in both tissues was stringently defined. Only sites highly correlated (r2 > 0.74; FDR q-value

Maternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.

Summary In community dwelling, 75-year-old women followed 10 years, a frailty index was created at each of three visits. Frailty score increased by ~ 6–7% annually. A higher frailty score was equivalent to being 5–10 years chronologically older. Frailty was associated with low bone density and higher risk of dying. Introduction To understand the distribution of frailty among a population-based sample of older community-dwelling women, progression over 10 years, and association with mortality and osteoporosis. Methods The study is performed in a cohort designed to investigate osteoporosis. The OPRA cohort consists of 75-year-old women, n = 1044 at baseline, and follow-up at age 80 and 85. A frailty index (scored from 0.0–1.0) based on deficits in health across multiple domains was created at all time-points; outcomes were mortality up to 15 years and femoral neck bone density. Results At baseline, the proportion least frail, i.e., most robust (FI 0.0–0.1) constituted 48%, dropping to 25 and 14% at age 80 and 85. On average, over 10 years, the annual linear frailty score progression was approximately 6–7%. Among the least frail, 11% remained robust over 10 years. A higher frailty score was equivalent to being 5 to 10 years older. Mortality was substantially higher in the highest quartile compared to the lowest based on baseline frailty score; after 10 years, 48.7% had died vs 17.2% (p = 1.7 × 10−14). Mortality risk over the first 5 years was highest in the frailest (Q4 vs Q1; HRunadj 3.26 [1.86–5.73]; p

Background/Aims: Prospective data on age-related changes in kidney function are required, especially since the current Kidney Disease Improving Global Outcomes (KDIGO) definition has been suggested to classify a large number of elderly people with CKD. Objective: This study, a complement to our previous Cr-based study in the same cohort, is aimed at evaluating cystatin C (cysC)-based changes in kidney function during aging in older women and analyzing the association between CKD and mortality through 10 years of follow-up. Methods: cysC was available in 981 women from the Osteoporosis Prospective Risk Assessment (OPRA) cohort, all aged 75 years on entry. Reinvestigations were made after 5 (n = 685) and 10 years (n = 365). Kidney function was estimated (estimated glomerular filtration rate [eGFR]) using Chronic Kidney Disease Epidemiology Collaboration cysC and Caucasian, Asian, Pediatric, and Adult cysC equations and the change in function calculated. Women were staged equivalent to CKD stage 1, 2, 3a, or 3b–5 according to the KDIGO classification. Mortality risk was estimated for 5-year or 10-year follow-up time using Cox proportional hazard analyses (reference category, CKD stages 1 and 2). Results: Mortality risk for women with the worst kidney function (CKD stages 3b–5) increased during both 5-year follow-up times compared to that for women in stages 1 and 2 (age 75–80 years: adjusted Hazard Ratio [HRadj] 3.9, 95% confidence interval [CI] 2.3–6.5; age 80–85 years: HRadj 1.7, 95% CI 1.0–2.7). In contrast, women in stage 3a had increased risk only in the first 5-year follow-up (HRadj 1.7, 95% CI 1.0–3.0, age 75–80 years). Change in kidney function amounted to a loss of 1.9 (±1.4) mL/min/1.73 m2 per year during the 10-year follow-up, and at age 85 years, 4 of every 5 women had an eGFR equivalent to CKD. Conclusion: In the future, an age-adapted definition of CKD, lowering the threshold for CKD in the elderly, may be beneficial to avoid overdiagnosis of CKD.

Background and aim The Receptor Activity Modifying Proteins (RAMPs) are a group of accessory proteins, of which there are three in humans, that interact with a number of G-protein coupled receptors (GPCR) and play various roles in regulation of endocrine signaling. Studies in RAMP3 knockout (KO) mice reveal an age related phenotype with altered metabolic regulation and high bone mass. To translate these findings into a clinically relevant perspective, we investigated the association between RAMP3 gene variants, body composition and bone phenotypes in two population-based cohorts of Swedish women. Methods Five single nucleotide polymorphisms (SNP) in the vicinity of the RAMP3 gene were genotyped in the PEAK-25 cohort (n = 1061; 25 years) and OPRA (n = 1044; 75 years). Bone mineral density (BMD), fat mass and lean mass (total body; regional) were measured by DXA at baseline, 5 and 10 year follow-up. Results BMD did not differ with RAMP3 genotype in either cohort, although fracture risk was increased in the elderly women (OR 2.695 [95% CI 1.514–4.801]). Fat mass tended to be higher with RAMP3 SNPs; although only in elderly women. In the young women, changes in BMI and fat mass between ages 25–35 differed by genotype (p = 0.001; p

The implications of obesity and weight loss for human bone health are not well understood. Although the bone changes associated with weight loss are similar in humans and rodents, that is not the case for obesity. In humans, obesity is generally associated with increased bone mass, an outcome which is exacerbated by advanced age and menopause. In rodents, by contrast, bone mass decreases in proportion to severity and duration of obesity, and is influenced by sex, age and mechanical load. Despite these discrepancies, rodents are frequently used to model the situation in humans. In this review, we summarise the existing knowledge of the effects of obesity and weight loss on bone mass in humans and rodents, focusing on the translatability of findings from animal models. We then describe how animal models should be used to broaden the understanding of the relationship between obesity, weight loss, and skeletal health in humans. Specifically, we highlight the aspects of study design that should be considered to optimise translatability of the rodent models of obesity and weight loss. Notably, the sex, age, and nutritional status of the animals should ideally match those of interest in humans. With these caveats in mind, and depending on the research question asked, our review underscores that animal models can provide valuable information for obesity and weight-management research.

Awareness and knowledge about any disease is the first step to prevent and treat it, so this study evaluates osteoporosis awareness and knowledge in university students. Our results showed a high awareness and good knowledge of osteoporosis. Females were better informed than males. Knowledge increased with increasing education level. Osteoporosis is a worldwide health problem, including Saudi Arabia where vitamin D deficiency is common. Prevention of osteoporosis must begin by increasing awareness of the disease from a young age. This study aimed to assess awareness and knowledge of osteoporosis among young adults (18–30 years) attending Saudi universities, exploring the relationship between education and gender and the sources of information in this age group. A cross-sectional survey was conducted in 337 students (176 females; 161 males) randomly selected from four Saudi universities during January–December 2017. Education level ranged from preparatory year to undergraduate and postgraduate levels. A self-reported questionnaire was designed to assess awareness and knowledge of osteoporosis across several domains, including risk factors for the disease, prevalence, symptoms, prevention, and treatment. Overall, 92% of students had some awareness of osteoporosis through a variety of sources, predominantly via friends. Just over half of all students had a good or high knowledge level overall (53.4 ± 16.6%). Knowledge score correlated with education (r2 = 0.28) and gender (r2 = 0.27); p

The aim was to investigate embryo-foetal effects of continuous maternal insulin-induced hypoglycaemia extending throughout gestation or until gestation day (GD)17 (typical last day of dosing during pre-clinical evaluation) providing comparator data for safety assessment of longer-acting insulin analogues in non-diabetic rats. Pregnant rats received human insulin (HI)-infusion during gestation until either GD20 or GD17 (HI-GD20; HI-GD17). On GD20, foetal abnormalities and skeletal ossification/mineralisation were evaluated. HI-infusion induced continuous hypoglycaemia. Foetal skeletal and eye malformations (e.g. bent ribs, microphthalmia) were common in both groups. Foetal size and skeletal ossification/mineralisation decreased, particularly with infusion throughout gestation. Concluding, insulin-induced hypoglycaemia during gestation in non-diabetic rats is damaging to embryo-foetal growth and skeletal development, particularly after GD17. Three days without HI-infusion after GD17 allows for some developmental catch-up. Eye development is sensitive to HI-infusion before GD17. These results should serve as a benchmark during pre-clinical safety assessment of longer-acting insulin analogues tested in rats.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Background/Aims: Renal function deteriorates with age, but a few studies have addressed this longitudinally in elderly women. Our objective was, using 5 estimated glomerular filtration rates (eGFR)-equations, to evaluate changes in renal function and association with adverse outcomes for a decade in 75-year-old women. Methods: Plasma creatinine was measured at ages 75 (n = 1,011), 78 (n = 827), 80 (n = 689) and 85 (n = 363). Glomerular filtration rates were estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); Modification of Diet in Renal Disease (MDRD); revised Lund-Malmö (LM-rev); Berlin Initiative Study 1 (BIS1) and Cockcroft-Gault/body surface area (CG/BSA) equations. Mortality and comorbidity were investigated in women with chronic kidney disease (CKD) stage 3A and 3B-5. Results: Approximately, 95% of women had eGFR indicating CKD stage 2-3 and progression towards stage 3 was continuous. The women lost 22% of their eGFR during follow-up and loss accelerated between 80 and 85. Mean loss per decade was 16.6 ml/min/1.73 m2. Women in CKD stage 3B-5 had an adjusted hazard ratio for death of 3.5 (95% CI 2.1-5.8) compared to stage 1-2 during follow-up and increased risk of diabetes, heart failure and hypertension. The CG/BSA, BIS1 and LM-rev equations continuously predicted lower eGFR than the MDRD and CKD-EPI equations. Conclusion: eGFR in women aged 75-85 ranges from 30 to 89 ml/min/1.73 m2 (stage 2-3). Decline was 16.6 ml/min/1.73 m2 per decade; accelerated with age and appeared nonlinear. Women with CKD 3B-5 demonstrate an over 3-fold risk of death. eGFR 2 was associated with mortality, confirming the new KDIGO classification 3A and 3B, as clinically applicable in the elderly.

Frailty is a consequence of advanced aging, where the frailty phenotype tries to capture overall decline in health. Frailty involves multiple physiological systems that are intrinsically inter-related and with highly complex interactions. Frailty is closely linked to musculoskeletal health; musculoskeletal functioning is a key component in quantifying frailty, while at the same time, frailty is associated with the most common age-related musculoskeletal conditions: osteoporosis, fractures, falls, osteoarthritis, and spinal conditions. Beyond that, frailty includes additional physical domains such as nutrition and energy, psychological, and social factors. Despite its recognized role in aging health, there is still a lack of consensus on a core set of variables and how to best define clinically relevant thresholds. This would be of utmost importance for additional use to evaluate many aspects associated with musculoskeletal health, progression and personalized interventions, and rehabilitation.

Summary Kidney function decreases with age; however, the long-term influence on bone density (BMD) in older women already at risk of osteoporosis is unknown. We followed kidney function and bone loss for 10 years. Declining kidney function was adversely associated with bone loss and mineral homeostasis in old women, though it attenuated with advanced aging. Introduction Existing studies do not fully address the relationship between kidney function and bone metabolism with advanced aging in Caucasian women. This study describes the association between kidney function, BMD, bone loss and bone metabolism in older women and provides a review of the available literature for context. Methods We studied participants from the OPRA cohort with follow-up after 5 and 10 years. Using plasma cystatin C (cysC), estimated glomerular function rate (eGFR) was evaluated at age 75 (n = 981), 80 (n = 685) and 85 (n = 365). Women were stratified into “normal” function (CKD stages 1–2), “intermediate” (stage 3a) and “poor” (stages 3b–5), and outcome measures—BMD, bone loss and markers of mineral homeostasis—were compared. Results Femoral neck (FN) BMD positively associated with kidney function at 75 years old (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \widehat{\beta} $$\end{document}β^ = 0.001, p = 0.028) and 80 years old (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \widehat{\beta} $$\end{document}β^ = 0.001, p = 0.001), although with small effect size. Prevalence of osteoporosis (FN T-score ≤ − 2.5) did not differ with kidney function. Measured at age 75, women with poor kidney function had higher annual percentage bone loss over 5 years compared to those with normal function (2.3%, 95% CI 1.8–2.8 versus 1.3%, 95% CI 1.1–1.5, p = 0.007), although not when measured from age 80 or 85. Additionally, markers of mineral homeostasis (PTH, phosphate, vitamin D, calcium), CRP and osteocalcin differed by kidney function. Conclusions In old women, kidney function is associated with BMD, bone loss and altered mineral homeostasis; probably, a relationship attenuated in the very elderly. Electronic supplementary material The online version of this article (10.1007/s00198-017-4221-y) contains supplementary material, which is available to authorized users.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer’s Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129.

Summary This longitudinal study investigates the association between C-reactive protein (CRP), osteoporosis, fractures, and mortality in 1044 elderly women. CRP was not an indi- cator for low bone mineral density (BMD), bone loss, or fracture in elderly women; however, women with elevated CRP levels over a prolonged period lost more bone over the 10-year follow-up, although fracture risk was not increased. Introduction Inflammation may contribute to the pathophys- iology underlying impaired bone metabolism. This study in- vestigates the association between CRP, BMD, bone loss, fracture risk, and mortality in women aged 75 and above. Methods This longitudinal study is based on 1044 women, all age 75 at inclusion, reassessed at ages 80 and 85, with a mean follow-up time of 11.6 years (maximum 16.9 years). Results Women in the lowest CRP quartile (mean 0.63 mg/L) had lower BMD compared to those in the highest CRP quar- tile(mean5.74mg/L) attotalhip(TH)(0.809vs.0.871g/cm 2 , p

In community dwelling, 75-year-old women followed 10 years, a frailty index was created at each of three visits. Frailty score increased by ~ 6-7% annually. A higher frailty score was equivalent to being 5-10 years chronologically older. Frailty was associated with low bone density and higher risk of dying.To understand the distribution of frailty among a population-based sample of older community-dwelling women, progression over 10 years, and association with mortality and osteoporosis.The study is performed in a cohort designed to investigate osteoporosis. The OPRA cohort consists of 75-year-old women, n = 1044 at baseline, and follow-up at age 80 and 85. A frailty index (scored from 0.0-1.0) based on deficits in health across multiple domains was created at all time-points; outcomes were mortality up to 15 years and femoral neck bone density.At baseline, the proportion least frail, i.e., most robust (FI 0.0-0.1) constituted 48%, dropping to 25 and 14% at age 80 and 85. On average, over 10 years, the annual linear frailty score progression was approximately 6-7%. Among the least frail, 11% remained robust over 10 years. A higher frailty score was equivalent to being 5 to 10 years older. Mortality was substantially higher in the highest quartile compared to the lowest based on baseline frailty score; after 10 years, 48.7% had died vs 17.2% (p = 1.7 × 10The frailty index was highly predictive of mortality showing a threefold increased risk of death in the frailest both in a shorter and longer perspective. Only one in ten older women escaped progression after 10 years. Frailty and osteoporosis were associated.

Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n=4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p=1.7x109) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p=1.3x108) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5597 for femoral neck; n=4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3x1011; ESR1/C6orf97 joint p=1.4x1010). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p

To investigate the association between low vitamin D levels (50 nmol/L) and 10-year mortality in women aged 75 and older.Prospective with 15 years of follow-up.Malmö, Sweden.Population-based cohort of 75-year-old women (N = 1,044).Serum 25-hydroxyvitamin D (25(OH)D) levels at age 75 (n = 1,011), 80 (n = 642), and 85 (n = 348) were categorized as low (50 nmol/L), intermediate (50-75 nmol/L) and high (75 nmol/L) at all ages. Hazard ratios (HRs) for all-cause mortality between ages 75 and 90 were calculated according to 25(OH)D category.Between ages 80 and 90, all-cause mortality (HR = 1.8, 95% confidence interval (CI) = 1.3-2.4, P .001; adjusted for comorbidities (aHR) = 1.9, 95% CI = 1.4-2.6, P .001) was significantly higher in women with low 25(OH)D levels than in those with high levels. Osteoporosis had the greatest effect on mortality, but even after excluding women with osteoporotic fracture during the risk of dying associated with low 25(OH)D remained greater (HR = 1.8, 95% CI = 1.2-2.7, P = .002; aHR = 1.7, 95% CI = 1.2-2.5, P = .006).In this observational study of women aged 75 and older, 25(OH)D levels of less than 50 nmol/L were associated with greater all-cause mortality for up to 10 years. This difference was at least partially independent of comorbidities and fracture, indicating that low 25(OH)D not only is an indicator of impaired health, but also plays a role in disease outcome.

Peak bone mass is normally reached in the third decade of life. Previously, in the population-based PEAK-25 cohort (n = 1061, age 25.5 ± 0.2), we demonstrated that bone mineral density in the population-based PEAK-25 cohort is comparatively high; therefore, this study aimed to determine if the calcaneus microarchitecture mirrored this. In the process, we describe normative quantitative ultrasound (QUS) values for 25-yr-old women and the relationship between QUS values and extremes of body weight. QUS variables speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index were measured. Young adult values were based on the manufacturer-supplied QUS reference values. Analyses were performed in the cohort as a whole, and additionally, to understand the relationship between body weight and QUS values in young women, the variables were categorized into octiles for weight or body mass index (BMI) and the lowest and highest octiles were compared. In the cohort, SOS values, reflecting bone density, were higher (108 ± 18%), whereas BUA values, reflecting bone complexity, were lower (90 ± 14%) compared to the young adult reference population. SOS did not correlate with body weight or BMI. In the cohort, overall correlations between BUA weight, and BMI were small and positive (Pearson's r coefficients 0.261 and 0.197, respectively; p

Distal radius fracture is an early indicator of osteoporosis, yet little is known about men with this fracture and osteoporosis prevalence. The purpose of this cross-sectional, controlled study was to evaluate bone mineral density (BMD) in men, from working age to the elderly, with distal radius fracture. Recruitment was as follows: men who fractured during 1999-2000 were evaluated retrospectively in 2003 and men who fractured during 2003-2007 were followed prospectively for one year post-fracture. A total of 233 patients, response rate 40 %, were enrolled and compared with 643 controls. Fractures from all degrees of trauma were included. BMD was measured at femoral neck, total hip, and lumbar spine. Mean age at fracture was 52 years (21-88 years). Men aged 40-64 years had 5.4-6.7 % lower BMD at all sites compared to controls (p = 0.001) and in65 years BMD was lower by 10.7-13.8 % (p 0.001), while not significant at40 years (1.4-2.8 %; p = 0.228-0.487). Osteoporosis was more prevalent at all ages (20-39 years: 8.5 vs 1.5 %; 40-64 years: 16.8 vs 5.1 %;65 years: 23.3 vs 8.3 %) BMD did not differ with trauma level. Already from age 40, men with a distal radius fracture had lower BMD, the difference becoming more pronounced with increasing age. Also, the prevalence of osteoporosis was higher, surprisingly even in the youngest age group.

Degenerative changes of the lumbar spine may lead to misinterpretation of bone mineral density (BMD) measurements and cause underdiagnosis of osteoporosis. This longitudinal study of 1,044 women, 75 years at inclusion and followed for 10 years, shows that identification of apparent degenerative changes on the dual energy X-ray absorptiometry (DXA) scan can increase the proportion diagnosed. INTRODUCTION: In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated BMD values, consequently missing a large proportion of those with osteoporosis. Our aim was to determine the distribution and impact of degenerative changes on lumbar spine DXA over time and its clinical implications. METHODS: Participants were 1,044 women from the population-based Osteoporosis Risk Assessment cohort. All women were 75 years old at invitation and followed up after 5 years (n = 715) and 10 years (n = 382). Degenerative changes were evaluated visually on the DXA image for each vertebra L1 to L4 (intraobserver precision kappa values of 0.66-0.70). RESULTS: At baseline, apparent degenerative changes were more frequent in the inferior segments of the lumbar spine [5 % (L1), 15 % (L2), 26 % (L3), and 36 % (L4)] and increased over time. At 10 years, the prevalences were 20 % (L1), 39 % (L2), 59 % (L3), 72 % (L4), resulting in a significant increase in overall BMD. In women without apparent degenerative changes, BMD remained stable between 75 and 85 rather than an expected bone loss. At baseline, 37 % had osteoporosis (BMD < -2.5) at L1-L4; exclusion of women with apparent degenerative changes increased this proportion to 47 %. Using L1-L2, which was less prone to degenerative changes, 46 % of women were classified as osteoporotic regardless of degenerative changes. CONCLUSION: Degenerative changes were very common in elderly women, accelerated disproportionately over time, were increasingly frequent from vertebrae L1 to L4, and had significant impact on diagnosing osteoporosis. This suggests that routine reporting of spine BMD at L1-L2 would add valuable information for reassessment and monitoring.

Recreational physical activity in 25-year-old women in Sweden increases bone mineral density (BMD) in the trochanter by 5.5% when combining regularity and impact. Jogging and spinning were especially beneficial for hip BMD (6.4-8.5%). Women who enjoyed physical education in school maintained their higher activity level at age 25. INTRODUCTION: The aims of this study were to evaluate the effects of recreational exercise on BMD and describe how exercise patterns change with time in a normal population of young adult women. METHODS: In a population-based study of 1,061 women, age 25 (±0.2), BMD was measured at total body (TB-BMD), femoral neck (FN-BMD), trochanter (TR-BMD), and spine (LS-BMD). Self-reported physical activity status was assessed by questionnaire. Regularity of exercise was expressed as recreational activity level (RAL) and impact load as peak strain score (PSS). A permutation (COMB-RP) was used to evaluate combined endurance and impacts on bone mass. RESULTS: More than half of the women reported exercising on a regular basis and the most common activities were running, strength training, aerobics, and spinning. Seventy percent participated in at least one activity during the year. Women with high RAL or PSS had higher BMD in the hip (2.6-3.5%) and spine (1.5-2.1%), with the greatest differences resulting from PSS (p < 0.001-0.02). Combined regularity and impact (high-COMB-RP) conferred the greatest gains in BMD (FN 4.7%, TR 5.5%, LS 3.1%; p < 0.001) despite concomitant lower body weight. Jogging and spinning were particularly beneficial for hip BMD (+6.4-8.5%). Women with high-COMB-RP scores enjoyed physical education in school more and maintained higher activity levels throughout compared to those with low scores. CONCLUSION: Self-reported recreational levels of physical activity positively influence BMD in young adult women but to maximize BMD gains, regular, high-impact exercise is required. Enjoyment of exercise contributes to regularity of exercising which has short- and long-term implications for bone health.

Parathyroid hormone (PTH) is a principal regulator of calcium homeostasis. Previously, we studied single-nucleotide polymorphisms present in the major genes in the PTH pathway (PTH, PTHrP, PTHR1, PTHR2) in relation to bone mineral density (BMD) and fracture incidence. We found that haplotypes of the PTH gene were associated with fracture risk independent of BMD. In the present study, we evaluated the relationship between PTH haplotypes and femoral neck bone size. Hip structure analysis and BMD of the femoral neck was assessed by DXA in elderly women from the Malmö Osteoporosis Prospective Risk Assessment study. Data on hip fracture, sustained as a result of low trauma, after the age of 45 years were also analyzed. Haplotypes derived from six polymorphisms in the PTH locus were analyzed in 750 women. Carriers of haplotype 9 had lower values for hip geometry parameters cross-sectional moment of inertia (P = 0.029), femoral neck width (P = 0.049), and section modulous (P = 0.06), suggestive of increased fracture risk at the hip. However, this did not translate into an increased incidence of hip fracture in the studied population. Women who suffered a hip fracture compared to those who had not had longer hip axis length (HAL) (P < 0.001). HAL was not significantly different among haplotypes. Polymorphisms in the PTH gene are associated with differences in aspects of femoral neck geometry in elderly women; however, the major predictor of hip fracture in our population was HAL, to which PTH gene variation does not contribute significantly.

BACKGROUND: Polymorphisms in the apolipoprotein E (APOE) gene are associated with fracture risk, and a potential mechanism is through vitamin K transport.OBJECTIVE: We investigated the relation between dietary vitamin K(1) intake, APOE polymorphisms, and markers of bone health.DESIGN: We measured bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) in a cohort of Scottish women aged 49-54 y in 1990-1994 (baseline) and in 1997-2000 (visit 2). At visit 2, bone markers (urinary pyridinoline crosslinks and serum N-terminal propeptide of type 1 collagen) were measured, 3199 women completed a food-frequency questionnaire, and 2721 women were genotyped for APOE.RESULTS: Compared with quartile 3 (Q3) of energy-adjusted vitamin K(1) intake (mean: 116 microg/d), women in the lowest quartile (mean: 59 microg/d) had lower BMD (analysis of variance; FN, Q1: 0.831 +/- 0.122 g/cm(2); Q3: 0.850 +/- 0.126 g/cm(2); P < 0.001; LS, Q1: 1.000 +/- 0.170 g/cm(2); Q3: 1.020 +/- 0.172 g/cm(2); P = 0.009), remaining significant at the FN after adjustment for age, weight, height, menopausal status or use of hormone replacement therapy, socioeconomic status, and physical activity (P = 0.04). Vitamin K(1) intake was associated with reduced concentrations of pyridinoline crosslinks (Q1: 5.4 +/- 2.0 nmol/mmol; Q4: 5.1 +/- 1.9 nmol/mmol; P = 0.003). Carriers of the E2 allele had greater LS BMD at visit 2 and lost less BMD than did carriers of the E4 allele (E2: -0.50 +/- 1.22%/y; E4: -0.71 +/- 1.17%/y; P = 0.05). After adjustment for confounders, the P value for BMD loss (0.03 for LS and 0.04 for FN) did not reach the level of significance required for multiple testing (P = 0.012). No interaction was observed between dietary vitamin K and APOE on BMD.CONCLUSIONS: Vitamin K(1) intake was associated with markers of bone health, but no interaction was observed with APOE alleles on BMD or markers of bone turnover. (Less)

Bone morphogenetic protein-2 (BMP2) plays a key role in bone formation and maintenance. Studies of polymorphisms within the gene in relation to bone mineral density (BMD) and fracture have been inconsistent. Our aim was to investigate associations between polymorphisms in the BMP2 gene and bone mass, fracture, and quantitative ultrasound (QUS) measures at different stages of skeletal development. Study subjects were participants of two population-based cohorts of Swedish women: the PEAK-25 cohort of young adult women aged 25 years (n = 993) and the OPRA cohort of elderly women aged 75 years (n = 1,001). We analyzed four single-nucleotide polymorphisms (SNPs) across the BMP2 gene including the Ser37Ala SNP previously identified in relation to BMD, QUS of the calcaneus, and, in the elderly women, fracture. BMP2 gene variations were associated with QUS of bone, independent of BMD, but only in the young women. Even after adjusting for confounding factors, SNP rs235754 in the 3' region of the gene was significantly associated with the ultrasound parameters speed of sound (P = 0.003) and stiffness (P = 0.002). The 5' SNP rs235710 showed trends for QUS parameters (P = 0.02-0.07). No association with BMP2 SNPs was observed in either cohort for either BMD or fracture. While further, more extensive genotyping across the gene is recommended, as we may not have captured all information, our preliminary data suggest that variation in BMP2 may play a previously unidentified role in aspects of bone quality, which may be age- and site-dependent.

Men and women with hip fracture have higher short-term mortality. This study investigated mortality risk over two decades post-fracture; excess mortality remained high in women up to 10 years and in men up to 20 years. Cardiovascular disease (CVD) and pneumonia were leading causes of death with a long-term doubling of risk.Hip fractures are associated with increased mortality, particularly short term. In this study with a two-decade follow-up, we examined mortality and cause of death compared to the background population.We followed 1013 hip fracture patients and 2026 matched community controls for 22 years. Mortality, excess mortality, and cause of death were analyzed and stratified for age and sex. Hazard ratio (HR) was estimated by Cox regression. A competing risk model was fitted to estimate HR for common causes of death (CVD, cancer, pneumonia) in the short and long term (1 year).For both sexes and at all ages, mortality was higher in hip fracture patients across the observation period with men losing most life years (p 0.001). Mortality risk was higher for up to 15 years (women (risk ratio (RR) 1.9 [95 % confidence interval (CI) 1.7-2.1]); men (RR 2.8 [2.2-3.5])) and until end of follow-up ((RR 1.8 [1.6-2.0]); (RR 2.7 [2.1-3.3])). Excess mortality by time intervals, censored for the first year, was evident in women (80 years, up to 10 years;80 years, for 5 years) and in men80 years throughout. CVD and pneumonia were predominant causes of death in men and women with an associated higher risk in all age groups. Pneumonia caused excess mortality in men over the entire observation period.In a remaining lifetime perspective, all-cause and excess mortality after hip fracture was higher even over two decades of follow-up. CVD and pneumonia reduce life expectancy for the remaining lifetime and highlights the need to further improve post-fracture management.