Geoff Nicholson

Novel UBA Domain Mutations of SQSTM1 in Paget's Disease of Bone: Genotype Phenotype Correlation, Functional Analysis, and Structural Consequences

Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin‐binding properties of the mutant UBA domain peptides.

Genomewide Search in Familial Paget Disease of Bone Shows Evidence of Genetic Heterogeneity with Candidate Loci on Chromosomes 2q36, 10p13, and 5q35

Paget disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and previous studies have shown that the PDB-like bone dysplasia familial expansile osteolysis is caused by activating mutations in the TNFRSF11A gene that encodes receptor activator of nuclear factor kappa B (RANK); however, linkage studies, coupled with mutation screening, have excluded involvement of RANK in the vast majority of patients with PDB. To identify other candidate loci for PDB, we conducted a genomewide search in 319 individuals, from 62 kindreds with familial PDB, who were predominantly of British descent. The pattern of inheritance in the study group as a whole was consistent with autosomal dominant transmission of the disease. Parametric multipoint linkage analysis, under a model of heterogeneity, identified three chromosomal regions with LOD scores above the threshold for suggestive linkage. These were on chromosomes 2q36 (LOD score 2.7 at 218.24 cM), 5q35 (LOD score 3.0 at 189.63 cM), and 10p13 (LOD score 2.6 at 41.43 cM). For each of these loci, formal heterogeneity testing with HOMOG supported a model of linkage with heterogeneity, as opposed to no linkage or linkage with homogeneity. Two-point linkage analysis with a series of markers from the 5q35 region in another large kindred with autosomal dominant familial PDB also supported linkage to the candidate region with a maximum LOD score of 3.47 at D5S2034 (187.8 cM). These data indicate the presence of several susceptibility loci for PDB and identify a strong candidate locus for the disease, on chromosome 5q35.

Prevention and treatment of glucocorticoid-induced osteoporosis: A comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium

High‐dose corticosteroids, used for many medical conditions, are associated with rapid bone loss from sites such as the vertebrae, and compression fractures can be observed within months. Recent trials suggest treatment with bisphosphonates or active vitamin D analogs can reduce bone loss and the risk of fracture associated with glucocorticoids, but few studies have directly compared such agents. We conducted a randomized, multicenter, open‐label trial to compare the efficacy of alendronate, calcitriol, and simple vitamin D in prevention and treatment of glucocorticoid‐induced bone loss. A total of 195 subjects (134 females and 61 males) commencing or already taking glucocorticoids were randomized to one of three groups: calcitriol, 0.5 to 0.75 μg/day; simple vitamin D (ergocalciferol, 30,000 IU weekly) plus calcium carbonate (600 mg daily); or alendronate, 10 mg/day plus calcium carbonate (600 mg daily). Over 2 years, mean lumbar bone mineral density change was +5.9% with alendronate, −0.5% with ergocalciferol, and −0.7% with calcitriol (p < 0.001). At the femoral neck, there was no significant difference in bone mineral density change between the treatments over 2 years: alendronate (+0.9%), ergocalciferol (−3.2%), and calcitriol (−2.2%). Lumbar bone loss varied according to whether patients were starting or receiving chronic glucocorticoids, and there was a significant treatment × prior glucocorticoid use interaction effect. Six of 66 calcitriol subjects, 1 of 61 ergocalciferol subjects, and 0 of 64 alendronate subjects sustained new vertebral fractures. These data do not suggest any difference between simple vitamin D and calcitriol but do show that alendronate was superior to either treatment for glucocorticoid induced bone loss.

Cohort Profile: Geelong Osteoporosis Study

The Geelong Osteoporosis Study (GOS) began as a population-based study designed to investigate the epidemiology of osteoporosis in Australia. Osteoporosis is a systemic skeletal disease characterized by low bone mineral density (BMD) and micro-architectural deterioration of bone tissue, with a consequent increase in susceptibility to fracture. Fragility fractures at the spine, hip, wrist and other sites are a major public health problem in both sexes because these fractures are responsible for considerable morbidity and mortality. Fractures cost the Australian community an estimated

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial

7 billion annually and this is expected to increase in absolute terms because of the ageing population. The cohort was recruited to address the need for definitive data on the prevalence of osteoporosis, to describe age-related changes in BMD and to characterize the risks for osteoporosis and fracture. Initially the GOS comprised only women; men were recruited later. In addition to the cohort study, the GOS has developed a comprehensive fracture register for the study region and has also conducted case–control studies to investigate risk factors for fracture. Only the cohort study will be described here.

Susceptibility to Paget's Disease of Bone Is Influenced by a Common Polymorphic Variant of Osteoprotegerin†

BACKGROUND Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking. AIMS To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health. METHOD A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D(3) (cholecalciferol) orally or placebo every autumn/winter for 3-5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression-Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants. RESULTS In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups. CONCLUSIONS The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3) is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study

To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Pagets disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB.

Independent and Combined Effects of Calcium-Vitamin D3 and Exercise on Bone Structure and Strength in Older Men: An 18-Month Factorial Design Randomized Controlled Trial

Objective: Reduced bone mineral density (BMD) in women with a history of depressive disorders has been shown in some, but not all studies. This study investigated the association between self-reported depression and BMD in an age-stratified community sample of perimenopausal women residing in the South-Eastern region of Australia. Design: Symptoms of depression in the year between July 2000 and July 2001 were ascertained by a self-report questionnaire based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Women in the perimenopausal group who had undergone a BMD total hip and spine assessment within the 12-month period after the depression assessment were included in the analysis, resulting in a sample of 78 women aged 45 to 60 years. Results: In this sample, 14 women were identified as depressed. There was no difference in age, hormone therapy (HT) use, or unadjusted BMD at the total hip or spine between the depressed and nondepressed women (P = 0.14, 0.89, 0.57, and 0.70, respectively), but the depressed women tended to be heavier [depressed (median weight, interquartile range = 80 kg, 66-94) vs nondepressed (72 kg, 61-80) P = 0.06]. Whereas there was no significant difference in age-, HT-, and weight-adjusted BMD at the spine [depressed (mean ± SE = 1.21 ± 0.05) vs nondepressed (1.28 ± 0.03 g/cm2) P = 0.18], adjusted BMD at the total hip for the depressed women was 7.8% lower than for the nondepressed [depressed (mean ± SE = 0.957 ± 0.038) vs nondepressed (1.038 ± 0.023 g/cm2) P = 0.04]. Conclusions: These results suggest that in perimenopausal women, self-reported depression is associated with lower BMD at the hip.

Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: Evidence for a founder effect in patients of British descent

CONTEXT Exercise and calcium-vitamin D are independently recognized as important strategies to prevent osteoporosis, but their combined effects on bone strength and its determinants remain uncertain. OBJECTIVE To assess whether calcium-vitamin D(3) fortified milk could enhance the effects of exercise on bone strength, structure, and mineral density in middle-aged and older men. DESIGN, SETTING, PARTICIPANTS An 18-month factorial design randomized controlled trial in which 180 men aged 50-79 years were randomized to the following: exercise + fortified milk; exercise; fortified milk; or controls. Exercise consisted of progressive resistance training with weight-bearing impact activities performed 3 d/week. Men assigned to fortified milk consumed 400 ml/d of 1% fat milk containing 1000 mg/d calcium and 800 IU/d vitamin D(3). MAIN OUTCOME MEASURES Changes in bone mineral density (BMD), bone structure, and strength at the lumbar spine (LS), proximal femur, mid-femur, and mid-tibia measured by dual energy x-ray absorptiometry and/or quantitative computed tomography. RESULTS There were no exercise-by-fortified milk interactions at any skeletal site. Main effect analysis showed that exercise led to a 2.1% (95% confidence interval, 0.5-3.6) net gain in femoral neck section modulus, which was associated with an approximately 1.9% gain in areal BMD and cross-sectional area. Exercise also improved LS trabecular BMD [net gain 2.2% (95% confidence interval, 0.2-4.1)], but had no effect on mid-femur or mid-tibia BMD, structure, or strength. There were no main effects of the fortified milk at any skeletal site. CONCLUSION A community-based multi-component exercise program successfully improved LS and femoral neck BMD and strength in healthy older men, but providing additional calcium-vitamin D(3) to these replete men did not enhance the osteogenic response.

Gene array identification of osteoclast genes: Differential inhibition of osteoclastogenesis by cyclosporin A and granulocyte macrophage colony stimulating factor

Mutations in the UBA domain of SQSTM1 are a common cause of Pagets disease of bone. Here we show that the most common disease‐causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin.