Atypical femoral fracture in osteoporosis pseudoglioma syndrome associated with two novel compound heterozygous mutations in LRP5.

Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive condition of congenital blindness and severe childhood osteoporosis with skeletal fragility, caused by loss-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. We report the first case of atypical (subtrochanteric) femoral fracture (AFF) in OPPG, occurring in a 38-year-old man within the context of relatively low bone turnover and trabecular osteoporosis on bone histology. We identify two novel LRP5 mutations: R752W is associated with low bone mineral density (BMD), as demonstrated by the heterozygous carriage identified in his 57-year-old mother; however, the combination of this R752W mutation with another novel W79R mutation, causes a severe case of compound heterozygous OPPG. We undertake 3D homology modeling of the four extracellular YWTD ß-propeller/EGF-like domains (E1-E4) of LRP5, and show that both novel mutations destabilize the ß-propeller domains that are critical for protein and ligand binding to regulate Wnt signaling and osteoblast function. Although AFFs have been reported in other rare bone diseases, this is the first in a genetic condition of primary osteoblast dysfunction. The relatively low bone turnover observed, and knowledge of LRP5 function, implicates impaired bone remodeling in the pathogenesis of AFF.

The Influence of High-Impact Exercise on Cortical and Trabecular Bone Mineral Content and 3D Distribution Across the Proximal Femur in Older Men: A Randomized Controlled Unilateral Intervention.

Regular exercisers have lower fracture risk, despite modest effects of exercise on bone mineral content (BMC). Exercise may produce localized cortical and trabecular bone changes that affect bone strength independently of BMC. We previously demonstrated that brief, daily unilateral hopping exercises increased femoral neck BMC in the exercise leg versus the control leg of older men. This study evaluated the effects of these exercises on cortical and trabecular bone and its 3D distribution across the proximal femur, using clinical CT. Fifty healthy men had pelvic CT scans before and after the exercise intervention. We used hip QCT analysis to quantify BMC in traditional regions of interest and estimate biomechanical variables. Cortical bone mapping localized cortical mass surface density and endocortical trabecular density changes across each proximal femur, which involved registration to a canonical proximal femur model. Following statistical parametric mapping, we visualized and quantified statistically significant changes of variables over time in both legs, and significant differences between legs. Thirty-four men aged mean (SD) 70 (4) years exercised for 12-months, attending 92% of prescribed sessions. In traditional regions of interest, cortical and trabecular BMC increased over time in both legs. Cortical BMC at the trochanter increased more in the exercise than control leg, whereas femoral neck buckling ratio declined more in the exercise than control leg. Across the entire proximal femur, cortical mass surface density increased significantly with exercise (2.7%; p < 0.001), with larger changes (> 6%) at anterior and posterior aspects of the femoral neck and anterior shaft. Endocortical trabecular density also increased (6.4%; p < 0.001), with localized changes of > 12% at the anterior femoral neck, trochanter, and inferior femoral head. Odd impact exercise increased cortical mass surface density and endocortical trabecular density, at regions that may be important to structural integrity. These exercise-induced changes were localized rather than being evenly distributed across the proximal femur.

High impact exercise increased femoral neck bone mineral density in older men: a randomised unilateral intervention.

INTRODUCTION: There is little evidence as to whether exercise can increase BMD in older men with no investigation of high impact exercise. Lifestyle changes and individual variability may confound exercise trials but can be minimised using a within-subject unilateral design (exercise leg [EL] vs. control leg [CL]) that has high statistical power. PURPOSE: This study investigated the influence of a 12month high impact unilateral exercise intervention on femoral neck BMD in older men. METHODS: Fifty, healthy, community-dwelling older men commenced a 12month high impact unilateral exercise intervention which increased to 50 multidirectional hops, 7days a week on one randomly allocated leg. BMD of both femurs was measured using dual energy X-ray absorptiometry (DXA) before and after 12months of exercise, by an observer blind to the leg allocation. Repeated measures ANOVA with post hoc tests was used to detect significant effects of time, leg and interaction. RESULTS: Thirty-five men (mean±SD, age 69.9±4.0years) exercised for 12months and intervention adherence was 90.5±9.1% (304±31 sessions completed out of 336 prescribed sessions). Fourteen men did not complete the 12month exercise intervention due to: health problems or injuries unrelated to the intervention (n=9), time commitments (n=2), or discomfort during exercise (n=3), whilst BMD data were missing for one man. Femoral neck BMD, BMC and cross-sectional area all increased in the EL (+0.7, +0.9 and +1.2 % respectively) compared to the CL (-0.9, -0.4 and -1.2%); interaction effect P<0.05. Although the interaction term was not significant (P>0.05), there were significant main effects of time for section modulus (P=0.044) and minimum neck width (P=0.006). Section modulus increased significantly in the EL (P=0.016) but not in the CL (P=0.465); mean change +2.3% and +0.7% respectively, whereas minimum neck width increased significantly in the CL (P=0.004) but not in the EL (P=0.166); mean changes being +0.7% and +0.3% respectively. CONCLUSION: A 12month high impact unilateral exercise intervention was feasible and effective for improving femoral neck BMD, BMC and geometry in older men. Carefully targeted high impact exercises may be suitable for incorporation into exercise interventions aimed at preventing fractures in healthy community-dwelling older men.

Long-term effects of anti-tumour necrosis factor therapy on weight in patients with rheumatoid arthritis.

In patients with rheumatoid arthritis (RA), weight is an important prognostic factor. Preliminary evidence has indicated that treatment with anti-tumour necrosis factor (TNF) therapy can affect the weight of patients with RA, but the relationship between improved prognosis and weight changes remains to be clarified. Our aim was to investigate the effects of anti-TNF therapy on the weight of patients with RA following 24 months of treatment. Patients (n = 168) were selected for this retrospective analysis on the basis of having received anti-TNF therapy for the first time. Change in body weight after 12 and 24 months of treatment was calculated and analysed by multiple regression analysis using age, sex, baseline body mass index (BMI), baseline DAS28 score, disease-modifying antirheumatic drug use, steroid use and specific anti-TNF drug as explanatory variables. The mean weight change of the patient group after 12 months of treatment was +1.58 kg (95% CI 0.71 to 2.46 kg) and after 24 months was +1.80 kg (95% CI 0.69 to 2.67 kg). After 24 months, 64.3% of patients had gained weight. There was no statistically significant association between weight gain at 12 or 24 months and age, sex, steroid use at baseline, anti-TNF drug or baseline DAS28 score. Baseline BMI had a statistically significant negative association with weight gain at 12 and 24 months. RA patients with lower BMIs tend to gain weight with anti-TNF therapy. Further studies are required to determine if the weight gained is fat and/or muscle and the effects upon general health outcomes.

Risk factors for stress fracture in female endurance athletes: a cross-sectional study.

OBJECTIVE: To identify psychological and physiological correlates of stress fracture in female endurance athletes. DESIGN: A cross-sectional design was used with a history of stress fractures and potential risk factors assessed at one visit. METHODS: Female-endurance athletes (58 runners and 12 triathletes) aged 26.0±7.4 years completed questionnaires on stress fracture history, menstrual history, athletic training, eating psychopathology and exercise cognitions. Bone mineral density, body fat content and lower leg lean tissue mass (LLLTM) were assessed using dual-x-ray absorptiometry. Variables were compared between athletes with a history of stress fracture (SF) and those without (controls; C) using χ², analysis of variance and Mann-Whitney U tests. RESULTS: Nineteen (27%) athletes had previously been clinically diagnosed with SFs. The prevalence of current a/oligomenorrhoea and past amenorrhoea was higher in SF than C (p=0.008 and p=0.035, respectively). SF recorded higher global scores on the eating disorder examination questionnaire (p=0.049) and compulsive exercise test (p=0.006) and had higher LLLTM (p=0.029) compared to C. These findings persisted with weight and height as covariates. In multivariate logistic regression, compulsive exercise, amenorrhoea and LLLTM were significant independent predictors of SF history (p=0.006, 0.009 and 0.035, respectively). CONCLUSIONS: Eating psychopathology was associated with increased risk of SF in endurance athletes, but this may be mediated by menstrual dysfunction and compulsive exercise. Compulsive exercise, as well as amenorrhoea, is independently related to SF risk.

Rheumatoid cachexia and cardiovascular disease.

Both cachexia and cardiovascular disease are strongly associated with rheumatoid arthritis (RA) and linked to the chronic inflammatory process. Typically, rheumatoid cachexia occurs in individuals with normal or increased BMI (reduced muscle mass and increased fat mass). Classic cachexia (reduced muscle mass and reduced fat mass) is rare in RA but is associated with high inflammatory activity and aggressive joint destruction in patients with a poor cardiovascular prognosis. Conversely, obesity is linked to hypertension and dyslipidemia but, paradoxically, lower RA disease activity and less cardiovascular disease-related mortality. Rheumatoid cachexia might represent the 'worst of both worlds' with respect to cardiovascular outcome, but until diagnostic criteria for this condition are agreed upon, its effect on cardiovascular disease risk remains controversial.

Assessment of vitamin D status in male osteoporosis.

BACKGROUND: Clinical assessment of vitamin D status often relies on measuring total circulating 25-hydroxyvitamin D3 (25OHD3), but much of each vitamin D metabolite is bound to plasma vitamin D-binding protein (DBP), such that the percentage of free vitamin is very low. We hypothesized that measurement of free rather than total 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and 25OHD3 may provide better assessment of vitamin D status. We therefore aimed to assess vitamin D status in men with idiopathic osteoporosis, in whom possible secondary causes of osteoporosis had been excluded, and to determine the extent of change in biologically active "free" vitamin D caused by variation in plasma DBP concentrations. METHODS: We measured 1,25(OH)2D3 and 25OHD3 in plasma samples from 56 men with idiopathic osteoporosis [mean (SD) age, 59.6 (13.6) years; range, 21-86 years] and 114 male controls [62.4 (10.4) years; range, 44-82 years]. RESULTS: Mean total plasma 25OHD3 in the 56 men with osteoporosis and the 114 controls was 44.7 (21) and 43.3 (17) nmol/L, respectively; total plasma 1,25(OH)2D3 measured in randomly selected men with osteoporosis (n = 50) and controls (n = 50) was 90 (37) and 103 (39) pmol/L, respectively. Mean plasma DBP was significantly higher (P <0.001) in men with osteoporosis [224 (62) mg/L; n = 56] than in the controls [143 (34) mg/L; n = 114], but calculated free plasma 25OHD3 and 1,25(OH)2D3 were significantly lower in the osteoporotic men than in controls [6.1 (3.1) vs 9.1 (4.4) pmol/L (P <0.00001) and 77 (37) vs 142 (58) fmol/L (P <0.00001), respectively]. CONCLUSIONS: Measurement of total vitamin D metabolites alone, although providing a crude assessment of vitamin D status, may not give an accurate indication of the free (biologically active) form of the vitamin. The ratio of total 25OHD3 and 1,25(OH)2D3 to plasma DBP, rather than total circulating vitamin D metabolites, may provide a more useful index of biological activity. Further studies are required to substantiate this hypothesis.