Vera Lúcia Szejnfeld

Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43

Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the α1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43–/fl mice, with Cx43–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

Sarcopenia associada ao envelhecimento: aspectos etiológicos e opções terapêuticas

A prevalencia de incapacidade e dependencia funcional e maior em idosos e esta intimamente associada a reducao da massa muscular, que ocorre, ate mesmo, em individuos saudaveis. A sarcopenia parece decorrer da interacao complexa de disturbios da inervacao, diminuicao de hormonios, aumento de mediadores inflamatorios e alteracoes da ingestao proteico-calorica que ocorrem durante o envelhecimento. A perda de massa e forca muscular e responsavel pela reducao de mobilidade e aumento da incapacidade funcional e dependencia. Quando associada a fragilidade, esta perda gera custos economicos e sociais. Neste artigo, pretende-se avaliar aspectos relacionados a genese da sarcopenia, bem como analisar possiveis opcoes terapeuticas e de prevencao.The high prevalence of inability and functional dependence is an important problem in elderly people. It is closely related with aging decrease of lean muscle mass that occurs even in healthy subjects. Skeletal muscle mass deficiency, or sarcopenia, results from complex interactions between innervations disturbances, hormones deficiency, inflammatory cytokines and restriction in caloric-proteic ingestion. Loss of skeletal muscle mass and strength results in disability and functional dependency that are associated to frailty in many elderly people. These conditions represent enormous economic and social budget. In this article, we evaluate pathogenesis of sarcopenia and discuss potential therapies.

Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis

We studied the function of osteoblast cadherins in vivo by transgenic expression of a truncated N-cadherin with dominant-negative action, driven by an osteoblast-specific promoter (OG2-NcadΔC). During the first 3 months of life, bone mineral density was reduced, whereas percent body fat was increased in transgenic animals compared with wild-type littermates, with associated decreased bone formation rate and osteoblast number, but normal osteoclast number. Osteoblast differentiation was delayed in calvaria cells isolated from transgenic mice. Likewise, the number of osteoblast precursors in bone marrow stromal cells from OG2-NcadΔC mice was decreased compared with wild-type cultures, whereas the number of adipogenic precursors was increased. In vitro, a transcriptionally active β-catenin mutant reversed the delay in osteoblast differentiation and the exuberant adipogenesis. Thus, in vivo disruption of cadherin function hinders osteoblast differentiation and favors, indirectly, bone marrow progenitor cell commitment to the alternative adipogenic lineage via interference with β-catenin signaling. This results in decreased bone formation, delayed acquisition of peak bone mass and increased body fat.

Bone mineral density and body composition in postmenopausal women with psoriasis and psoriatic arthritis

IntroductionThe aim of the present study was to compare bone mineral density (BMD) and body composition (BC) measurements as well as identify risk factors for low BMD and osteoporotic fractures in postmenopausal women with psoriasis (Ps) and psoriatic arthritis (PsA).MethodsA cross-sectional study was carried out in 45 PsA women, 52 Ps women and 98 healthy female controls (HC). Clinical risk factors for low bone density and osteoporotic fracture were evaluated by a specific questionnaire. An X-ray absorptiometry (DXA) at the lumbar spine, total femur and total body was performed on all patients. Skin and joint outcomes were measured by specific tools (PASI, HAQ and DAS28). Morphometric vertebral fractures were evaluated by lumbar and thoracic spine X-ray, according to Genants method.ResultsThere were no significant differences in age, body mass index (BMI), total lean mass and bone mineral density among the groups. However, the PsA group had a significantly higher body fat percentage (BF%) than the Ps and HC groups. Osteoporotic fractures were more frequently observed in PsA and Ps groups than in the HC group (P = 0.01). Recurrent falls and a longer duration of disease increased the risk of fracture (odds ratio (OR) = 18.3 and 1.08, respectively) in the PsA group (P = 0.02). Disability was the main factor related to osteoporotic fracture in the Ps group (odds ratio (OR) = 11.1) (P = 0.02).ConclusionsPs and PsA patients did not present lower BMD. However, they had a higher prevalence of osteoporotic fractures and higher risk of metabolic syndrome. Patients with a longer duration of disease, disability and recurrent falls need preventive measures.

Risk factors for osteoporotic fractures and low bone density in pre and postmenopausal women

OBJECTIVE To estimate the prevalence and analyze risk factors associated to osteoporosis and low-trauma fracture in women. METHODS Cross-sectional study including a total of 4,332 women older than 40 attending primary care services in the Greater São Paulo, Southeastern Brazil, between 2004 and 2007. Anthropometrical and gynecological data and information about lifestyle habits, previous fracture, medical history, food intake and physical activity were obtained through individual quantitative interviews. Low-trauma fracture was defined as that resulting from a fall from standing height or less in individuals 50 years or older. Multiple logistic regression models were designed having osteoporotic fracture and bone mineral density (BMD) as the dependent variables and all other parameters as the independent ones. The significance level was set at p<0.05. RESULTS The prevalence of osteoporosis and osteoporotic fractures was 33% and 11.5%, respectively. The main risk factors associated with low bone mass were age (OR=1.07; 95% CI: 1.06;1.08), time since menopause (OR=2.16; 95% CI: 1.49;3.14), previous fracture (OR=2.62; 95% CI: 2.08;3.29) and current smoking (OR=1.45; 95% CI: 1.13;1.85). BMI (OR=0.88; 95% CI: 0.86;0.89), regular physical activity (OR=0.78; 95% CI: 0.65;0.94) and hormone replacement therapy (OR=0.43; 95% CI: 0.33;0.56) had a protective effect on bone mass. Risk factors significantly associated with osteoporotic fractures were age (OR=1.05; 95% CI: 1.04;1.06), time since menopause (OR=4.12; 95% CI: 1.79;9.48), familial history of hip fracture (OR=3.59; 95% CI: 2.88;4.47) and low BMD (OR=2.28; 95% CI: 1.85;2.82). CONCLUSIONS Advanced age, menopause, low-trauma fracture and current smoking are major risk factors associated with low BMD and osteoporotic fracture. The clinical use of these parameters to identify women at higher risk for fractures might be a reasonable strategy to improve the management of osteoporosis.OBJETIVO: Estimar a prevalencia e analisar os fatores de risco associados com osteoporose e fratura por baixo impacto entre mulheres. METODOS: Estudo transversal realizado com 4.332 mulheres acima de 40 anos de idade provenientes de atendimento primario de saude na area metropolitana da Grande Sao Paulo, SP, entre 2004 e 2007. Dados antropometricos e ginecologicos e relativos a habitos de vida, fratura previa, antecedentes pessoais, ingestao alimentar e atividade fisica foram avaliados por meio de entrevista individual e quantitativa. Fratura por baixo impacto foi definida como decorrente de queda da propria altura ou menos em individuos com mais de 50 anos de idade. Modelos de regressao multivariada e logistica analisaram, respectivamente, a densidade ossea e a fratura por osteoporose como variaveis dependentes e todas as outras como independentes. O nivel de significância estatistica estabelecido foi p < 0,05. RESULTADOS: A prevalencia de osteoporose e de fraturas por fragilidade ossea foi de 33% e 11,5%, respectivamente. Os principais fatores de risco associados com baixa densidade ossea foram idade (OR = 1,07; IC 95%: 1,06;1,08), menopausa (OR = 2,16; IC 95%: 1,49;3,14), fratura previa (OR = 2,62; IC 95%: 2,08;3,29) e tabagismo atual (OR = 1,45; IC 95%: 1,13;1,85). Por outro lado, elevado IMC (OR = 0,88; IC 95%: 0,86;0,89), atividade fisica regular (OR = 0,78; IC 95%: 0,65;0,94) e terapia hormonal atual (OR = 0,43; IC 95%: 0,33;0,56) desempenharam papel protetor. Os fatores de risco significativamente relacionados com fratura por osteoporose foram idade (OR = 1,05; IC 95%: 1,04;1,06), menopausa (OR = 4,12; IC 95%: 1,79;9,48), historia familiar de fratura de quadril (OR = 3,59; IC 95%: 2,88;4,47) e baixa densidade ossea (OR = 2,28; IC 95%: 1,85;2,82). CONCLUSOES: Idade avancada, menopausa, fratura previa por baixo impacto e tabagismo atual sao os principais fatores de risco associados com baixa densidade ossea, a qual se associa com as fraturas por fragilidade ossea. O uso clinico desses parâmetros para identificar mulheres de maior risco para fraturas pode ser uma estrategia interessante para melhorar a abordagem da osteoporose.

Diretrizes para prevenção e tratamento da osteoporose induzida por glicocorticoide

UNLABELLED Glucocorticoids (GC) are used in almost all medical specialties, and approximately 0.5% of the general population of the United Kingdom receives those medications. With the increased survival of patients with rheumatological diseases, morbidity secondary to the use of those medications represents an important aspect of the management of our patients. The incidences of vertebral and non-vertebral fractures are elevated, ranging from 30% to 50% of the individuals on GC for over three months. Thus, osteoporosis and frailty fractures should be prevented and treated in all patients initiating or already on GC. There are several recommendations on this topic elaborated by several international societies, but consensus still lacks. Recently, the American College of Rheumatology has published new recommendations, but they are based on the WHO Fracture Risk Assessment Tool (FRAX®) to evaluate the risk for each individual, and, thus, cannot be completely used for the Brazilian population. Thus, the Committee for Osteoporosis and Bone Metabolic Disorders of the Brazilian Society of Rheumatology, along with the Brazilian Medical Association and the Brazilian Association of Physical Medicine and Rehabilitation, has elaborated the Brazilian Guidelines for Glucocorticoid-Induced Osteoporosis (GIO), based on the better available scientific evidence and/or expert experience. METHOD OF EVIDENCE COLLECTION The bibliographic review of scientific articles of this guideline was performed in the MEDLINE database. The search for evidence was based on real clinical scenarios, and used the following keywords (MeSH terms): Osteoporosis, Osteoporosis/ chemically induced*= (Glucocorticoids= Adrenal Cortex Hormones, Steroids), Glucocorticoids, Glucocorticoids/administration and dosage, Glucocorticoids/therapeutic use, Glucocorticoids/adverse effects, Prednisone/adverse effects, Dose-Response Relationship, Drug, Bone Density/drug effects, Bone Density Conservation Agents/pharmacological action, Osteoporosis/prevention & control, Calcium, Vitamin D, Vitamin D deficiency, Calcitriol, Receptors, Calcitriol; 1-hydroxycholecalciferol, Hydroxycholecalciferols, 25-Hydroxyvitamin D3 1-alpha-hydroxylase OR Steroid Hydroxylases, Prevention and Control, Spinal fractures/prevention & control, Fractures, Spontaneous, Lumbar Vertebrae/injuries, Lifestyle, Alcohol Drinking, Smoking OR tobacco use disorder, Movement, Resistance Training, Exercise Therapy, Bone density OR Bone and Bones, Dual-Energy X-Ray Absorptiometry OR Absorptiometry Photon OR DXA, Densitometry, Radiography, (Diphosphonates Alendronate OR Risedronate Pamidronate OR propanolamines OR Ibandronate OR Zoledronic acid, Teriparatide OR PTH 1-34, Men AND premenopause, pregnancy, pregnancy outcome maternal, fetus, lactation, breast-feeding, teratogens, Children (6-12 years), adolescence (13-18 years). GRADE OF RECOMMENDATION AND LEVEL OF EVIDENCE A) Data derived from more consistent experimental and observational studies; B) Data derived from less consistent experimental and observational studies; C) Case reports (uncontrolled studies); D) Expert opinion without explicit critical appraisal, or based on consensus, physiological studies or animal models. OBJECTIVE To establish guidelines for the prevention and treatment of GIO.

Body composition and nutritional profile of male adolescent tennis players

Abstract In this cross-sectional study, we evaluated the body composition and dietary intake of 44 adolescent tennis players. After being divided into two groups (age 10–13 years and age 14–18), the players had their weight, height, and sexual maturation assessed. Dual-energy X-ray absorptiometry was used to assess body composition. Food intake was obtained from a non-consecutive 4-day food record. The data were analysed using the Virtual Nutri v.1.0 software and compared with the present recommendations for adolescent athletes or dietary reference intakes. Body mass index and body fat for tennis practice were adequate for 89% and 71% of the tennis players respectively, regardless of age group. A calorie deficit greater than 10% of energy expenditure was observed in 32% of the sample. Fifty percent of the athletes consumed carbohydrates in accordance with recommended values. Protein and lipid intakes were above recommended values, while fibre, calcium, potassium, magnesium, and folic acid intakes were below recommendation for 98%, 80%, 100%, 100%, and 98% of the tennis players respectively. The observed nutritional deficiencies represent an additional barrier for adolescents engaged in competitive sports to achieve an optimum nutrition to maintain growth, health, and performance.

Cálcio dietético: estratégias para otimizar o consumo

RESUMO O calcio e um nutriente essencial necessario em diversas funcoes biologicas. Estudos tem demonstrado a associacao entre o baixo consumo de calcio e doencas cronicas, entre elas osteoporose, câncer de colon, hipertensao arterial e obesidade. Entretanto, grande parte da populacao brasileira apresenta consumo de calcio abaixo do recomendado. Este artigo objetiva revisar os fatores endogenos (idade e estado hormonal) e exogenos (fitatos, oxalatos, sodio, compostos bioativos e vitamina D) que influenciam a absorcao do calcio, bem como as principais metodologias utilizadas para avaliar a absorcao e biodisponibilidade desse nutriente. discorre-se sobre os possiveis fatores para o baixo consumo de calcio: 1) Habito alimentar – substituicao de leite por bebidas com baixo teor de calcio como o refrigerante, refeicoes realizadas fora de casa e a nao realizacao de refeicoes como o cafe da manha; 2) Alto custo dos alimentos fontes de calcio. Alem disso, este artigo discute as estrategias para otimizar o consumo do calcio, que incluem: 1) Aumentar o conhecimento sobre a importância do consumo de calcio para a saude e as principais fontes alimentares desse nutriente; 2) Aumentar a disponibilidade de alimentos fortificados com calcio; 3) Uso de suplementos em grupos especificos – quando e como administrar os sais de calcio. Palavras-chave: calcio, absorcao, biodisponibilidade, consumo, sais de calcio.

Development of Mice with Osteoblast-Specific Connexin43 Gene Deletion

Genetic deficiency of Cx43 in vivo causes skeletal developmental defects, osteoblast dysfunction and perinatal lethality. To determine the role of Cx43 in the adult skeleton, we developed two models of osteoblast-specific Cx43 gene deletion using Cre mediated replacement of a “floxed” Cx43 allele with a LacZ reporter gene. Cre recombinase expression in osteoblasts was driven by either the osteocalcin OG2 promoter or the 2.3 kb fragment of the Colα1(I) promoter. Homozygous Cx43fl/flmice, in which the Cx43 coding region is flanked by two loxP sites, were crossed with Cre expressing mice in a heterozygous Cx43-null background [Cx43±; Colα1(I)-Cre or Cx43±; OG2-Cre]. Cx43 gene ablation was demonstrated in tissues by selective X-gal staining of cells lining the endosteal surface, and in cultured osteoblastic cells from calvaria using different approaches. Although no LacZ expression was observed in proliferating calvaria cells, before osteoblast differentiation begins, post-proliferative cells isolated from conditional knockout mice [Cx43fl/−; Colα1(I)-Cre or Cx43fl/−; OG2-Cre] developed strong LacZ expression as they differentiated, in parallel to a progressive disappearance of Cx43 mRNA and protein abundance relative to controls. Selective Cre mediated Cx43 gene inactivation in bone forming cells will be useful to determine the role of Cx43 in adult skeletal homeostasis and overcome the perinatal lethality of the conventional null model.

Bone density in white Brazilian women: Rapid loss at the time around the menopause

Dual energy x-ray absorptiometry (DXA) was used to measure bone mineral density (BMD) of the lumbar spine and proximal femur (neck, Wards triangle, and trochanter) in 417 normal women (aged 20–79) living in São Paulo, Brazil. Bone density decreased with age at all sites. At the spine, the greatest decrease occurred during the sixth decade, with an average 11.4% bone loss compared with the previous decade. Stratifying the subjects according to menopausal status revealed that the fastest bone occurred at the time around the menopause (ages 45–60) when the rate of bone loss (-0.66%/year) was almost twice as rapid as in postmenopausal women (-0.39%/year). Although significant linear rates of bone loss were detected in all proximal femur sites before the menopause, a menopause-dependent pattern was less evident that at the spine. Lifetime rates of bone loss at the appendicular skeleton were-0.43,-0.62, and-0.35%/year at the femoral neck, Wards triangle, and trochanteric area, respectively. After the menopause, BMD declined with menopausal age at all sites, although the rate of bone loss was faster at the femoral neck (-0.62%/year) and Wards triangle (-0.84%/year) than at the spine-0.49%/year). The results are consistent with the notion that in women, the fastest bone loss occurs at the time round the menopause, most likely consequent to ovarian failure; and that faster rates of bone loss are detected at the proximal femur than at the lumbar spine in late postmenopausal women.