Joanna Makovey

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

Effect of antiepileptic medication on bone mineral measures

Objective: Long-term antiepileptic drug (AED) use has been associated with bone disease, but many previous studies have been limited by inadequate control subjects. We used a cotwin affected sib-pair model to investigate this issue. Methods: The authors studied 31 female twin (15 monozygous and 16 dizygous) and four sibling pairs (<3 years age difference) aged 21 to 75 years, in which one member had >12 months of AED treatment. Areal bone mineral density (ABMD, g/cm2) was measured at the lumbar spine (LS), total hip (TH), femoral neck (FN), and total forearm (FA). Three primary a priori defined subgroups were analyzed: a) use for >2 years, b) use of enzyme-inducing AEDs, or c) age older than 40 years. Results: For all pairs (n = 35), there were no significant within-pair differences in any ABMD measure. However, in Subgroup a (n = 27), there was a within-pair difference at the FA (0.513 vs 0.534, −3.9%, p = 0.016). In Subgroup b (n = 29), there was also a within-pair difference at the FA for AED user vs nonuser (0.508 vs 0.529, −3.8%, p = 0.010). In Subgroup c (n = 15), there were within-pair differences at the FA (0.492 vs 0.524, −6.1%, p = 0.017) and the LS (0.884 vs 0.980, −9.8%, p = 0.036). Conclusions: Patients using AEDs for >2 years, in particular those taking enzyme-inducing AEDs and those older than 40 years, have significantly lower bone mineral density at clinically relevant fracture risk sites.

Gender differences in plasma ghrelin and its relations to body composition and bone – an opposite‐sex twin study

Background  Ghrelin, a peptide hormone that plays a role in the regulation of appetite and body adiposity, may also play a role in bone metabolism.

Association between serum cholesterol and bone mineral density

BACKGROUND Hypercholesterolaemia has been associated with low bone mineral density (BMD) in some but not all studies. OBJECTIVES To examine the influence of age, menopausal status and hormone replacement therapy (HRT) on the relationship between serum cholesterol and BMD in women. PATIENTS AND MEASUREMENTS 497 female participants (age range 20-81) comprising 224 premenopausal and 273 postmenopausal women (156 on HRT and 117 no HRT) underwent measurements of bone mineral density (BMD) and serum lipid profile. RESULTS Total serum cholesterol (TC) and low density lipoprotein (LDL) levels were higher and lumbar spine BMD was lower in postmenopausal women not taking HRT compared to those taking HRT. TC and LDL were negatively associated with BMD at all measured sites among postmenopausal women not taking HRT in univariate regression analysis (all p<0.05). High density lipoprotein (HDL) had inverse relationships with BMD at all sites in pre-menopausal women and those who were exposed to HRT (p<0.05). In fully adjusted regression models the relationships between TC and BMD remained significant at the lumbar spine and whole body (p<0.05) and between LDL and lumbar spine BMD only (p<0.05). For subjects in the other groups, no significant associations between TC or LDL and BMD were found. Significant interactions between total cholesterol and LDL levels with HRT were detected among post-menopausal women in the regression analyses (all p<0.05). No such interactions were found between HDL levels and HRT. CONCLUSION There is a modest inverse relationship between lumbar spine and whole body BMD and serum TC and LDL levels and in post-menopausal women and HDL in pre-menopausal women. HRT use appears to modify these relationships. The mechanisms of this relationship require further study.

Genetic effects on bone loss in peri- and postmenopausal women: a longitudinal twin study.

This longitudinal twin study was designed to assess the heritability of bone loss in peri‐ and postmenopausal women. A sample of 724 female twins was studied. Baseline and repeat BMD measurements were performed. Results of genetic model‐fitting analysis indicated genetic effects on bone loss account for ∼40% of the between‐individual variation in bone loss at the lumbar spine, forearm, and whole body.

Serum uric acid plays a protective role for bone loss in peri- and postmenopausal women: A longitudinal study☆

OBJECTIVE Oxidative stress has been linked to osteoporosis. Serum uric acid (UA), a strong endogenous antioxidant, has been associated with higher bone mineral density (BMD), lower bone turnover and lower prevalence of fractures in a large cross-sectional study of men. Whether this relationship is present in women and how UA relates to changes in BMD longitudinally has not been examined. METHODS A sample of 356 peri- and postmenopausal women, mean age 60.5 years was studied. Each individual had baseline BMD and body composition measurements by dual energy x-ray absorptiometry (DXA) and at least one repeat measure, on average 9.7 years later. Annual rate of change in BMD (A%ΔBMD) was calculated. UA was measured at each DXA visit. Calciotropic hormones and bone turnover markers were measured at the final visit only. RESULTS Cross-sectional data analyses revealed that women with higher UA levels had significantly higher absolute BMD measures at all skeletal sites. These women also had higher measures of body weight and its components such as lean mass (LM) and fat mass (FM). Results of multiple regression analyses showed a positive association between UA and BMD that remained significant even after accounting for possible confounders including LM and FM. Regression analyses of the longitudinal BMD data demonstrated significant associations between serum UA levels and annual rates of change in BMD at all skeletal sites. After adjustment associations remained significant for lumbar spine, forearm and whole body BMD but not for hip BMD. CONCLUSION Higher serum UA levels appear to be protective for bone loss in peri- and postmenopausal women and this relationship is not affected by changes in body composition measures.

Is There a Dose-Response Relationship Between Weight Loss and Symptom Improvement in Persons With Knee Osteoarthritis?

We examined the dose‐response relationship between weight reduction and pain/functional improvement in persons with symptomatic knee osteoarthritis (KOA) participating in a community‐based weight loss program.

The effect of anterior cruciate ligament injury on bone curvature: Exploratory Analysis in the KANON Trial.

OBJECTIVE Investigate the 5-year longitudinal changes in bone curvature after acute anterior cruciate ligament (ACL) injury, and identify predictors of such changes. METHODS In the KANON-trial (ISRCTN 84752559), 111/121 young active adults with an acute ACL tear to a previously un-injured knee had serial 1.5 T MR images from baseline (within 5 weeks from injury) to 5 years after injury. Of these, 86 had ACL reconstruction (ACLR) performed early or delayed, 25 were treated with rehabilitation alone. Measures of articulating bone curvature were obtained from computer-assisted segmentation of MR images. Curvature (mm(-1)) was determined for femur, tibia, medial/lateral femur, trochlea, medial/lateral tibia. Age, sex, treatment, BMI, meniscal injury, osteochondral fracture on baseline MR images were tested for association. RESULTS Over 5 years, curvature decreased in each region (P < 0.001) suggesting flattening of convex shapes and increased concavity of concave shapes. A higher BMI was associated with flattening of the femur (P = 0.03), trochlea (P = 0.007) and increasing concavity of the lateral tibia (LT) (P = 0.011). ACLR, compared to rehabilitation alone, was associated with flatter curvature in the femur (P < 0.001), medial femoral condyle (P = 0.006) and trochlea (P = 0.003). Any meniscal injury at baseline was associated with a more flattened curvature in the femur (P = 0.038), trochlea (P = 0.039), lateral femoral condyle (P = 0.034) and increasing concavity of the LT (P = 0.048). CONCLUSION ACL injury is associated with significant changes in articulating bone curvature over a 5 year period. Higher BMI, baseline meniscal injury and undergoing ACL reconstruction (as distinct from undergoing rehabilitation alone) are all associated with flattening of the articulating bone.

Comparative effectiveness of anti-tumor necrosis factor drugs on health-related quality of life among patients with inflammatory arthritis.

To compare the relative effectiveness of anti–tumor necrosis factor (anti‐TNF) therapies on health‐related quality of life (HRQOL) by inflammatory arthritis types.

Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study.

Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA‐discordant same‐sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed.