Celia L Gregson

MUSCLE SIZE, STRENGTH AND PHYSICAL PERFORMANCE AND THEIR ASSOCIATIONS WITH BONE STRUCTURE IN THE HERTFORDSHIRE COHORT STUDY

Sarcopenia is associated with a greater fracture risk. This relationship was originally thought to be explained by an increased risk of falls in sarcopenic individuals. However, in addition, there is growing evidence of a functional muscle‐bone unit in which bone health may be directly influenced by muscle function. Because a definition of sarcopenia encompasses muscle size, strength, and physical performance, we investigated relationships for each of these with bone size, bone density, and bone strength to interrogate these hypotheses further in participants from the Hertfordshire Cohort Study. A total of 313 men and 318 women underwent baseline assessment of health and detailed anthropometric measurements. Muscle strength was measured by grip strength, and physical performance was determined by gait speed. Peripheral quantitative computed tomography (pQCT) examination of the calf and forearm was performed to assess muscle cross‐sectional area (mCSA) at the 66% level and bone structure (radius 4% and 66% levels; tibia 4% and 38% levels). Muscle size was positively associated with bone size (distal radius total bone area β = 17.5 mm2/SD [12.0, 22.9]) and strength (strength strain index (β = 23.3 mm3/SD [18.2, 28.4]) amongst women (p < 0.001). These associations were also seen in men and were maintained after adjustment for age, height, weight‐adjusted‐for‐height, limb‐length‐adjusted‐for‐height, social class, smoking status, alcohol consumption, calcium intake, physical activity, diabetes mellitus, and in women, years since menopause and estrogen replacement therapy. Although grip strength showed similar associations with bone size and strength in both sexes, these were substantially attenuated after similar adjustment. Consistent relationships between gait speed and bone structure were not seen. We conclude that although muscle size and grip strength are associated with bone size and strength, relationships between gait speed and bone structure and strength were not apparent in this cohort, supporting a role for the muscle‐bone unit.

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

SummaryHigh bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder.IntroductionHigh bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia.MethodsTwo hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex.ResultsIndividuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m2, p < 0.001).ConclusionIndividuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.

LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion

Summary Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis

We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.

Prevalence of radiographic hip osteoarthritis is increased in high bone mass.

Summary Objective Epidemiological studies have shown an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. In this study, we used a novel approach to investigate this question, determining whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls. Design HBM cases came from the UK-based HBM study: HBM was defined by BMD Z-score. Unaffected relatives of index cases were recruited as family controls. Age-stratified random sampling was used to select further population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs were pooled and assessed by a single observer blinded to case-control status. Analyses used logistic regression, adjusted for age, gender and body mass index (BMI). Results 530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female) were analysed. The prevalence of radiographic OA, defined as Croft score ≥3, was higher in cases compared with controls (20.0% vs 13.6%), with adjusted odds ratio (OR) [95% CI] 1.52 [1.09, 2.11], P = 0.013. Osteophytes (OR 2.12 [1.61, 2.79], P < 0.001) and subchondral sclerosis (OR 2.78 [1.49, 5.18], P = 0.001) were more prevalent in cases. However, no difference in the prevalence of joint space narrowing (JSN) was seen (OR 0.97 [0.72, 1.33], P = 0.869). Conclusions An increased prevalence of radiographic hip OA and osteophytosis was observed in HBM cases compared with controls, in keeping with a positive association between HBM and OA and suggesting that OA in HBM has a hypertrophic phenotype.

Assessment and management of fracture risk in patients with Parkinson's disease

Parkinsons disease (PD) is associated with substantially increased fracture risk, particularly hip fracture, which can occur relatively early in the course of PD. Despite this, current national clinical guidelines for PD fail to adequately address fracture risk assessment or the management of bone health. We appraise the evidence supporting bone health management in PD and propose a PD-specific algorithm for the fracture risk assessment and the management of bone health in patients with PD and related movement disorders. The algorithm considers (i) calcium and vitamin D replacement and maintenance, (ii) quantification of prior falls and fractures, (iii) calculation of 10-year major osteoporotic and hip fracture risks using Qfracture, (iv) application of fracture risk thresholds, which if fracture risk is high (v) prompts anti-resorptive treatment, with or without dual X-ray absorptiometry, and if low (vi) prompts re-assessment with FRAX and application of National Osteoporosis Guidelines Group (NOGG) guidance. A range of anti-resorptive agents are now available to treat osteoporosis; we review their use from the specific perspective of a clinician managing a patient population with PD. In conclusion, our current evidence base supports updating of guidelines globally concerning the management of PD, which presently fail to adequately address bone health.

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 β‐propeller/EGF‐like domains (E1–E4) of LRP5, and show that both novel mutations destabilize the β‐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.

Jump Power and Force Have Distinct Associations With Cortical Bone Parameters: Findings From a Population Enriched by Individuals With High Bone Mass

Context: Little is known of the relationships between muscle function and bone, based on the recently developed technique of jumping mechanography. Objective: Our objective was to determine associations between peak ground reaction force and peak power during a 1-legged hopping test and a single 2-legged jump, respectively, and cortical bone parameters. Design and Setting: This was a cross-sectional observational study in participants from the high bone mass cohort. Participants: Participants included 70 males (mean age 58 years) and 119 females (mean age 56 years); high bone mass cases and controls were pooled. Main Outcome Measures: Total hip bone mineral density (BMD) (measured by dual-energy x-ray absorptiometry scanning) and mid-tibial peripheral quantitative computed tomography (Stratec XCT2000L). Results: Jump power was positively related to hip BMD (standardized β [95% confidence interval] = 0.29 [0.07, 0.51], P = .01), but hopping force was not (0.03 [−0.16, 0.22], P = .74) (linear regression analysis adjusted for age, gender, height, and weight). In 113 participants with force and peripheral quantitative computed tomography data, both jump power and hopping force were positively associated with tibial strength strain index (0.26 [0.09, 0.44], P < .01; and 0.24 [0.07, 0.42], P = .01 respectively). Although hopping force was positively associated with bone size (total bone area 0.22 [0.03, 0.42], P = .02), jump power was not (0.10 [−0.10, 0.30], P = .33). In contrast, jump power was inversely associated with endocortical circumference adjusted for periosteal circumference (−0.24 [−0.40, −0.08], P < .01) whereas no association was seen for hopping force (−0.10 [−0.26, 0.07], P = .24). Conclusions: Although power and force are both positively associated with cortical bone strength, distinct mechanisms appear to be involved because power was primarily associated with reduced endocortical expansion (reflected by endocortical circumference adjusted for periosteal circumference, and hip BMD), whereas force was associated with increased periosteal expansion (reflected by total bone area).

The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: findings from a pQCT case-control study

High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans. pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls. HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm3), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β − 0.01 [− 0.02, 0.01], p = 0.41), but declined in family controls (− 0.05 [− 0.03, − 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD. HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.