Investigation of the genetic susceptibility to osteoporosis in the Irish population

Osteoporosis is a complex skeletal disorder characterized by compromised bone strength. Variation in bone mineral density (BMD) is a contributing factor. The aim of this research as to select informative single nucleotide polymorphisms (SNPs) in potential candidate genes from loci suggestively linked to BMD variation for fine mapping. The gene regulated by oestrogen in breast cancer 1 (GREB1), located at 2p25.1, was selected. GREB1 transcription is initiated early in the oestrogen receptor alpha regulated pathway. There was significant association between GREB1_03 and BMD variation at the lumbar spine and femoral neck (FN) in the discovery cohort. Significant association was observed between GREB1_04 and FN BMD in the replication cohort. The development and differentiation enhancing factor 2, the integrin cytoplasmic domain associated protein 1 and A-disintegrin and metalloprotease 17 were selected due to their respective roles in cell mobility and adhesion. There was no linkage or association observed between the Chr2 cluster SNPs and BMD. Two factors in bone remodelling are the attraction of bone cell precursors and endocrine regulation of the process, primarily through the action of parathyroid hormone (PTH). The C-C chemokine receptor type 3 (CCR3) encodes a CC chemokine receptor expressed in osteoclast precursors. The PTH receptor type 1 (PTHR1) encodes a G-protein coupled receptor for PTH. Association was observed between CCR3 haplotypes and BMD variation at the FN. There was no linkage or association observed between PTHR1 SNPs and BMD variation. Population genetic studies with complex phenotypes endeavour to elucidate the traits genetic architecture. This study presents evidence of association between GREB1 and BMD variation and as such, introduces GREB1 as a novel gene target for osteoporosis genetics studies. It affirms that common genomic variants in PTHR1 are not associated with BMD variation in Caucasians and supports the evidence that CCR3 may be contributing to BMD variation

Dietary patterns and bone mineral status in young adults: the Northern Ireland Young Hearts Project

Studies of individual nutrients or foods have revealed much about dietary influences on bone. Multiple food or nutrient approaches, such as dietary pattern analysis, could offer further insight but research is limited and largely confined to older adults. We examined the relationship between dietary patterns, obtained by a posteriori and a priori methods, and bone mineral status (BMS; collective term for bone mineral content (BMC) and bone mineral density (BMD)) in young adults (20-25 years; n 489). Diet was assessed by 7 d diet history and BMD and BMC were determined at the lumbar spine and femoral neck (FN). A posteriori dietary patterns were derived using principal component analysis (PCA) and three a priori dietary quality scores were applied (dietary diversity score (DDS), nutritional risk score and Mediterranean diet score). For the PCA-derived dietary patterns, women in the top compared to the bottom fifth of the 'Nuts and Meat' pattern had greater FN BMD by 0.074 g/cm(2) (P=0.049) and FN BMC by 0.40 g (P=0.034) after adjustment for confounders. Similarly, men in the top compared to the bottom fifth of the 'Refined' pattern had lower FN BMC by 0.41 g (P-0.049). For the a priori DDS, women in the top compared to the bottom third had lower FN BMD by 0.05 g/cm(2) after adjustments (P=0.052), but no other relationships with BMS were identified. In conclusion, adherence to a 'Nuts and Meat' dietary pattern may be associated with greater BMS in young women and a 'Refined' dietary pattern may be detrimental for bone health in young men.

Multicentre trial of weekly risedronate on bone density in adults with cystic fibrosis

Background: The aim of this study was to assess the efficacy, tolerability and safety of risedronate in adults with CF. Methods: Patients with a lumbar spine (LS), total hip (TH) or femoral neck (FN) bone mineral density (BMD) Z-score of -1 or less were randomised to receive risedronate 35mg weekly or placebo, and calcium (1g)+vitamin D (800IU). Results: At baseline, BMD Z-scores in the risedronate (n = 17) and placebo (n = 19) groups were similar. By 24. months, 7/17 risedronate patients vs 0/19 placebo patients stopped the study medication due to bone pain. After 24. months treatment, the mean difference (95% CI) in change in LS, TH and FN BMD between the risedronate vs placebo groups was 4.3% (0.4, 8.2) p = 0.03; 4.0% (-0.5, 8.6) p = 0.08; and 2.4% (-3.5, 8.2) p =0.41. Conclusions: After two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo. © 2011 European Cystic Fibrosis Society.

How useful is dual energy lateral vertebral assessment in a clinic setting?

Screening for osteoporotic vertebral fractures traditionally involves X-ray of the thoracic and lumbar spine. We evaluated use of dual energy X-ray technology in patients with osteoporosis. We found this technology useful in the clinic setting and it has advantages in that less radiation is delivered to the patient.

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.

Development of a sheep vertebroplasty model for bioceramic materials assessment

Development of a sheep vertebroplasty model for bioceramic materials assessment Sheep has been widely used as an animal orthopaedic model. Although several studies report anatomic and biomechanical similarities as well as distinctions of ovine lumbar vertebrae when compared to human’s, only a few studies describe its actual use as a vertebroplasty model. Due to distinct anatomic features, sheep lumbar vertebrae pose a challenge when developing a minimally invasive procedure for vertebroplasty material testing, under conditions meant to be the most similar to clinical procedure. The present work describes the development of an appropriate surgical percutaneous vertebroplasty model in the lumbar spine of sheep, applicable in vivo, that minimizes the risk of post-surgical complications. This model was mechanically evaluated ex-vivo regarding its safety, and used to evaluate the injectability and radiopacity of two new bioceramic materials when compared to a commercial bioceramic bone substitute (Cerament™ SpineSupport). Microtomography techniques helped in the development of the model and results assessment. Under fluoroscopic guidance, a defect was created through a bilateral modified parapedicular access in the cranial hemivertebrae of 30 sheep lumbar vertebrae (L4, L5 and L6). The manually drilled defect had an average volume of 1209 ±226 mm3 and allowed the novel materials injection through a standardized injection cannula placed in one of the entrance points. Adequate defect filling was observed with all tested materials. No mechanical failure was observed under loads higher than the physiological.

O impacto do excesso de gordura corporal sobre a remodelação óssea de adolescentes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influência de um programa de exercícios específicos em estudantes de violino

Introdução: A elevada prevalência de problemas musculosqueléticos relacionados com a performance musical (PMRPM) em estudantes universitários de música, sobretudo violinistas, justifica uma abordagem preventiva junto destes, nomeadamente, através do exercício. Este deve ser específico e baseado nos padrões de movimento durante a performance musical do violinista. Objetivos: verificar a influência de um programa de exercícios específicos (PEE) nos sintomas relacionados com a prática musical, na incapacidade funcional e na autoperceção da performance física e musical, em estudantes universitários de violino. Métodos: estudo quase-experimental baseado num estudo piloto com 24 estudantes para pesquisa da sintomatologia, e 4 para análise cinemática e cinética do gesto técnico. No estudo principal participaram 22 violinistas divididos equitativamente, e por disponibilidade, entre grupo experimental (GE) e grupo de controlo (GC). O GE realizou o PEE bissemanalmente, durante 8 semanas. No momento inicial e após 8 semanas, os participantes preencheram: Questionário de Performance (incluiu Escala Visual Analógica), Disabilities of the Arm, Shoulder and Hand, Oswestry Disability Index versão 2.0, Pain Catastrophizing Scale e Escala de Borg Modificada. Resultados: do estudo piloto constatou-se que os sintomas mais frequentes, dor e fadiga, localizavam-se na cintura escapular, ombros e coluna lombar; os ombros aparentavam maior risco de PMRPM; era necessário aumentar a endurance dos mobilizadores dos membros superiores (principalmente deltóide) e relaxar os estabilizadores da coluna cervical (sobretudo trapézio superior). No final do PEE, o GE apresentou significativamente melhores pontuações do que o GC na percentagem de violinistas com “dor na coluna lombar esquerda” (p=0,007), frequência da dor (U=8,5; W=29,5; p=0,016), número de locais com sintomas (U=18; W=84; p=0,003) e amplificação (U=26; W=92; p=0,021). Conclusão: Um PEE pode produzir efeitos positivos na diminuição dos sintomas relacionados com a prática musical e incapacidade funcional, e na melhoria de alguns parâmetros da performance física autoreportada, em estudantes universitários de violino.

Efeitos imediatos de um Sustained Natural Apophyseal Glide na atividade muscular dos eretores espinhais, na dor e na amplitude de flexão, em indivíduos com dor lombar crónica não específica

Introdução: O Sustained Natural Apophyseal Glide tem sido sugerido como uma técnica com potenciais benefícios na redução da dor e no aumento da amplitude de flexão lombar em indivíduos com dor lombar. Contudo, não existe evidência sobre esta técnica na atividade muscular dos eretores espinhais. Objetivo: Avaliar os efeitos imediatos de um Sustained Natural Apophyseal Glide na atividade muscular dos eretores espinhais, na intensidade da dor e na amplitude real de flexão lombar, em indivíduos com dor lombar crónica não específica. Métodos: Estudo experimental com uma amostra de 20 estudantes universitários, com dor lombar crónica não específica e com dor à flexão da coluna lombar, que foram aleatoriamente distribuídos em dois grupos: experimental - Sustained Natural Apophyseal Glide e placebo – intervenção placebo. Foram avaliadas a atividade muscular dos eretores espinhais recorrendo à eletromiografia de superfície (bioPLUX research®), a intensidade da dor através da Escala Visual Analógica e a amplitude real de flexão lombar pelo método de duplo inclinómetro (Universal Inclinometer®), antes e após a intervenção, pela análise do movimento de flexão-extensão do tronco. O nível de significância foi de 0,05. Resultados: Foram encontradas diferenças significativas, em ambos os grupos, para a fase de relaxamento (Grupo experimental: p=0,013 e Grupo placebo: p=0,047), assim como para a fase de extensão, no grupo experimental (p=0,037), verificando-se uma diminuição da atividade muscular da baseline para a avaliação final. A Análise da Covariância revelou que, relativamente à intensidade da dor, verificaram-se diferenças significativas entre os dois grupos (p=0,002), sendo que o grupo experimental diminuiu mais 2cm na Escala Visual Analógica do que o grupo placebo. Pela análise da amplitude real de flexão lombar, embora o aumento não fosse significativamente diferente entre os grupos (p=0,086), o grupo experimental teve mais 1,7º de aumento do que o grupo placebo. Conclusão: Os resultados sugerem que, a curto prazo, o Sustained Natural Apophyseal Glide parece produzir um efeito significativo na diminuição da atividade muscular dos eretores espinhais, durante o movimento dinâmico de extensão do tronco, assim como no alívio da dor. Embora não se tenham observado alterações significativas no aumento da amplitude articular, os resultados no grupo experimental foram superiores à diferença mínima detetável, sugerindo um efeito positivo da técnica aplicada.

In postmenopausal women with osteoporosis, denosumab significantly improved trabecular bone score (TBS), an index of trabecular microarchitecture

Background/Purpose: The trabecular bone score (TBS), a novel graylevel texture index determined from lumbar spine DXA scans, correlates with 3D parameters of trabecular bone microarchitecture known to predict fracture. TBS may enhance the identification of patients at increased risk for vertebral fracture independently of bone mineral density (BMD) (Boutroy JBMR 2010; Hans JBMR 2011). Denosumab treatment for 36 months decreased bone turnover, increased BMD, and reduced new vertebral fractures in postmenopausal women with osteoporosis (Cummings NEJM 2009). We explored the effect of denosumab on TBS over 36 months and evaluated the association between TBS and lumbar spine BMD in women who had DXA scans obtained from eligible scanners for TBS evaluation in FREEDOM. Methods: FREEDOM was a 3-year, randomized, double-blind trial that enrolled postmenopausal women with a lumbar spine or total hip DXA T-score __2.5, but not __4.0 at both sites. Women received placebo or 60 mg denosumab every 6 months. A subset of women in FREEDOM participated in a DXA substudy where lumbar spine DXA scans were obtained at baseline and months 1, 6, 12, 24, and 36. We retrospectively applied, in a blinded-to-treatment manner, a novel software program (TBS iNsightR v1.9, Med-Imaps, Pessac, France) to the standard lumbar spine DXA scans obtained in these women to determine their TBS indices at baseline and months 12, 24, and 36. From previous studies, a TBS _1.35 is considered as normal microarchitecture, a TBS between 1.35 and _1.20 as partially deteriorated, and 1.20 reflects degraded microarchitecture. Results: There were 285 women (128 placebo, 157 denosumab) with a TBS value at baseline and _1 post-baseline visit. Their mean age was 73, their mean lumbar spine BMD T-score was _2.79, and their mean lumbar spine TBS was 1.20. In addition to the robust gains in DXA lumbar spine BMD observed with denosumab (9.8% at month 36), there were consistent, progressive, and significant increases in TBS compared with placebo and baseline (Table & Figure). BMD explained a very small fraction of the variance in TBS at baseline (r2_0.07). In addition, the variance in the TBS change was largely unrelated to BMD change, whether expressed in absolute or percentage changes, regardless of treatment, throughout the study (all r2_0.06); indicating that TBS provides distinct information, independently of BMD. Conclusion: In postmenopausal women with osteoporosis, denosumab significantly improved TBS, an index of lumbar spine trabecular microarchitecture, independently of BMD.

A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX.

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.

Morphologie tridimensionnelle du bassin scoliotique

La scoliose idiopathique de l’adolescence (SIA) est une déformation tridimensionnelle de la colonne vertébrale et de la cage thoracique dont la cause est inconnue. Il semble que la ceinture pelvienne soit impliquée dans la pathogénie de la SIA, car des différences géométriques des os coxaux ont été observées. Notamment, une rotation du bassin ou une inclinaison latérale dans le sens de la courbe scoliotique ont été mises en évidence en plus des distorsions osseuses. Il est difficile de dissocier la rotation du bassin de son asymétrie, car la majorité des études porte sur des données radiologiques bidimensionnelles. Une analyse tridimensionnelle de la morphologie du bassin de patientes ayant une SIA, mais n’ayant pas reçu de traitement par corset ou chirurgie permettrait d’identifier le rôle du bassin dans la progression de la scoliose. Dix-sept jeunes filles atteintes de la SIA ont participé à cette étude pour lesquelles des radiographies bi-planaires en station debout étaient disponibles au moment du diagnostic par un chirurgien orthopédiste pédiatrique et à l’instant de la prescription d'un corset. Des radiographies postéro-antérieures et latérales avaient été prises au moyen du système EOS®. Douze repères anatomiques du bassin ont été identifiés sur les paires de radiographies, alors que quatre repères ont été identifiés sur la radiographie postéro-antérieure uniquement. Ces quatre derniers n’étaient pas identifiables sur la radiographie latérale à cause de la superposition des repères droits et gauches. La reconstruction tridimensionnelle du bassin a été réalisée à partir de deux clichés radiographiques des 12 premiers repères osseux. Au total, neuf paramètres tridimensionnels ont été calculés afin de quantifier l’asymétrie et la distorsion du bassin entre les deux temps donnés. Des paramètres bidimensionnels ont également été mesurés sur les quatre derniers repères osseux afin de documenter des déformations du bassin pertinentes à la pratique clinique, telle que la rotation axiale de celui-ci. Dans le but d'évaluer une possible asymétrie entre les os coxaux du bassin, les paramètres tridimensionnels du bassin gauche ont été comparés à ceux du côté droit à chaque temps, au moyen d'un test-t pour échantillon apparié. La morphologie pelvienne a été également évaluée par l'analyse multivariée (MANOVA) à mesures répétées à deux conditions (côté*temps). En conséquence, nous avons constaté une croissance osseuse statistiquement significative du bassin dans l’intervalle de temps entre le diagnostic de la scoliose et le port du corset (p=0,033). Une asymétrie significative entre les côtés gauche et droit du bassin (p=0,013) a également été constatée. En ce qui concerne les paramètres bidimensionnels, nous avons constaté une augmentation de la version pelvienne (p=0,024) au cours de la croissance des jeunes filles. Finalement, le bassin n'a pas présenté de distorsion, puisqu'une valeur de p de 0,763 a été observée. En conclusion, la croissance des jeunes filles atteintes de la scoliose idiopathique de l'adolescence est accompagnée d'une asymétrie morphologique entre les deux os coxaux du bassin. Cette asymétrie constatée au moment du diagnostic de la scoliose des filles a évolué jusqu'à l’instant où le port du corset a été prescrit. Quant aux paramètres bidimensionnels, nous pouvons conclure que la rotation du bassin vers l'arrière a augmenté au cours de la croissance des jeunes filles, produisant ainsi une rétroversion pelvienne dans le plan sagittal. La distorsion tridimensionnelle du bassin n'a toutefois pas été observée au cours de la croissance des jeunes filles.

L'évaluation systématique de la lombalgie selon les données probantes.

Les illustrations accompagnant le texte ont été dessinées par monsieur Mathieu Gagnon.

Suivi longitudinal de la densité osseuse et du statut en vitamine D chez des enfants prépubères avec une allergie au lait de vache non résolue.

Problématique : L'allergie au lait de vache (ALV) est reconnue comme une condition transitoire qui disparaît chez la majorité des enfants avant l’âge de 3-5 ans, mais des données récentes révèlent une persistance de l’ALV. Les enfants souffrant d’une ALV sont à risque d’apports insuffisants en calcium et en vitamine D, deux nutriments impliqués dans la santé osseuse. Une première étude transversale portant sur la santé osseuse d’enfants prépubères ALV a observé que la densité osseuse (DMO) lombaire était significativement inférieure à celle d’enfants sans allergie au lait de vache (SALV). Objectifs : Sur la base de ces résultats, nous désirons documenter l’évolution longitudinale de la santé osseuse, du statut en vitamine D, des apports en calcium et en vitamine D et de l’adhérence à la supplémentation des enfants ALV (n=36) et de comparer ces données aux enfants SALV (n=19). Résultats : Le gain annualisé de la DMO lombaire est similaire entre les enfants ALV et SALV. Bien qu’il n’y ait pas de différence significative entre les deux groupes, la DMO lombaire des enfants ALV demeure cependant inférieure à celle des témoins. Qui plus est, le score-Z de la DMO du corps entier tend à être inférieur chez les enfants-cas comparé aux témoins. Au suivi, la concentration de 25OHD et le taux d’insuffisance en vitamine D sont similaires entre les deux groupes tout comme les apports en calcium et en vitamine D. Davantage d’enfants ALV prennent un supplément de calcium au suivi comparativement au temps initial (42% vs. 49%, p<0,05), mais le taux d’adhérence à la supplémentation a diminué à 4 jours/semaine. Conclusion : Une évaluation plus précoce ainsi qu’une prise en charge de la santé osseuse des enfants ALV pourraient être indiquées afin de modifier l’évolution naturelle de leur santé osseuse. Les résultats justifient aussi le suivi étroit des apports en calcium et vitamine D par une nutritionniste et la nécessité d'intégrer la supplémentation dans le plan de traitement de ces enfants et d’assurer une surveillance de l’adhérence à la supplémentation.

2D-3D Rigid-Body Registration of X-Ray Fluoroscopy and CT Images

The registration of pre-operative volumetric datasets to intra- operative two-dimensional images provides an improved way of verifying patient position and medical instrument loca- tion. In applications from orthopedics to neurosurgery, it has a great value in maintaining up-to-date information about changes due to intervention. We propose a mutual information- based registration algorithm to establish the proper align- ment. For optimization purposes, we compare the perfor- mance of the non-gradient Powell method and two slightly di erent versions of a stochastic gradient ascent strategy: one using a sparsely sampled histogramming approach and the other Parzen windowing to carry out probability density approximation. Our main contribution lies in adopting the stochastic ap- proximation scheme successfully applied in 3D-3D registra- tion problems to the 2D-3D scenario, which obviates the need for the generation of full DRRs at each iteration of pose op- timization. This facilitates a considerable savings in compu- tation expense. We also introduce a new probability density estimator for image intensities via sparse histogramming, de- rive gradient estimates for the density measures required by the maximization procedure and introduce the framework for a multiresolution strategy to the problem. Registration results are presented on uoroscopy and CT datasets of a plastic pelvis and a real skull, and on a high-resolution CT- derived simulated dataset of a real skull, a plastic skull, a plastic pelvis and a plastic lumbar spine segment.