Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the RANKL Locus and Potential Pleiotropic Effects on Bone

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMDC associations that had p<1×10−5 in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2×10−14, n = 5739). Each minor allele was associated with a decrease in BMDC of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males −6.77mg/cm3 per C allele, p = 2×10−6; females −2.79 mg/cm3 per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development

Reduction in Fracture Rate and Back Pain and Increased Quality of Life in Postmenopausal Women Treated with Teriparatide: 18-Month Data from the European Forsteo Observational Study (EFOS)

The European Forsteo Observational Study was designed to examine the effectiveness of teriparatide in postmenopausal women with osteoporosis treated for up to 18 months in normal clinical practice in eight European countries. The incidence of clinical vertebral and nonvertebral fragility fractures, back pain, and health-related quality of life (HRQoL, EQ-5D) were assessed. Spontaneous reports of adverse events were collected. All 1,648 enrolled women were teriparatide treatment-naive, 91.0% of them had previously received other anti-osteoporosis drugs, and 72.8% completed the 18-month study. A total of 168 incident clinical fractures were sustained by 138 (8.8%) women (821 fractures/10,000 patient-years). A 47% decrease in the odds of fracture in the last 6-month period compared to the first 6-month period was observed (P < 0.005). Mean back pain VAS was reduced by 25.8 mm at end point (P < 0.001). Mean change from baseline in EQ-VAS was 13 mm by 18 months. The largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort. There were 365 adverse events spontaneously reported, of which 48.0% were considered related to teriparatide; adverse events were the reason for discontinuation for 79 (5.8%) patients. In conclusion, postmenopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18-month treatment period. This was associated with a clinically significant improvement in HRQoL. Safety was consistent with current prescribing information. These results should be interpreted in the context of the open-label, noncontrolled design of the study

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Real-world effectiveness of osteoporosis treatment in the oldest old

Summary We studied effectiveness of osteoporosis treatment in women older than 80 years, who often are not included in clinical trials. Treatments were as effective on bone density and fractures as in younger women. Introduction To study real-world effectiveness of osteoporosis treatment on BMD and fractures in the oldest old women (≥ 80 years) compared with women (60–79 years) in the clinical setting using Swedish health register data. Methods National registers and data from DXA machines were used to study effectiveness of all available osteoporosis treatments in women 60–79 and ≥ 80 years using three approaches: (1) Total Hip BMD change up to 8 years after treatment start; (2) fracture incidence where patients served as their own controls, comparing the first 3 months after treatment start with the subsequent 12 months; and (3) comparison of fracture incidence post-fracture in women ≥ 80 years treated with osteoporosis treatment or calcium/vitamin D. Results Analysis 1: Total Hip BMD increased by up to 6.7% and 7.7% in women 60–79 and ≥ 80 years old, respectively. The mean increase in BMD was 1.1%-units per year in both age groups. Analysis 2: Relative to the 3-month baseline, fracture incidence decreased during the subsequent 12 months of treatment. Incidence rate ratios were estimated at 0.65, 0.74, 0.29, and 0.81 for any, hip, vertebral, and non-hip-non-vertebral fracture, respectively. Analysis 3: A 24-month incidence of any fracture in women ≥ 80 years given post-fracture osteoporosis treatment was lower (HR = 0.78) than in women given calcium/vitamin D, but treatment allocation was not random, with lower mortality (HR = 0.51) in patients receiving OP treatment. Conclusions Osteoporosis medication in women &gt; 80 years in clinical practice likely works, and the magnitude of effect is similar to what was estimated in younger women. The choice between osteoporosis treatment and calcium/vitamin D after fracture in women ≥ 80 years is not random but appears associated with the patient’s health status and presence of vertebral fractures, rather than the known risk profile of sustaining a fracture at a high age

Risk of imminent fracture following a previous fracture in a Swedish database study

The SummaryThis study examined the imminent risk of a future fracture within 1 and 2years following a first fracture in women aged 50years and older and assessed independent factors associated with risk of subsequent fractures. The study highlights the need to intervene rapidly after a fracture to prevent further fractures.IntroductionThis study aims to determine the imminent risk of subsequent fractures within 1 and 2years following a first fracture and to assess independent factors associated with subsequent fractures.MethodsRetrospective, observational cohort study of women aged 50years with a fragility fracture was identified from Swedish national registers. Clinical/demographic characteristics at the time of index fracture and cumulative fracture incidences up to 12 and 24months following index fracture were calculated. Risk factors for subsequent fracture were identified using multivariate regression analysis.ResultsTwo hundred forty-two thousand one hundred eight women (mean [SD] age 74 [12.5] years) were included. The cumulative subsequent fracture incidence at 12months was 7.1% (95% confidence interval [CI], 6.9-7.2) and at 24months was 12.0% (95% CI, 11.8-12.1). The rate of subsequent fractures was highest in the first month (similar to 15 fractures per 1000 patient-years) and remained steady between 4 and 24months (similar to 5 fractures/1000 patient-years). Higher age was an independent risk factor for imminent subsequent fractures (at 24months, sub-distribution hazard ratio [HR], 3.07; p&lt;0.001 for women 80-89years [reference 50-59years]). Index vertebral fracture was a strong independent risk factor for subsequent fracture (sub-distribution HR, 2.72 versus hip fracture; p&lt;0.001 over 12months; HR, 2.23; p&lt;0.001 over 24months).ConclusionsOur findings highlight the need to intervene rapidly after any fragility fracture in postmenopausal women. The occurrence of a fragility fracture provides healthcare systems with a unique opportunity to intervene to reduce the increased risk of subsequent fractures