J. del Pino-Montes

Calcitriol improves streptozotocin-induced diabetes and recovers bone mineral density in diabetic rats.

Vitamin D analogs exert a preventative effect on experimental diabetes, but whether or not they are able to halt progress of established diabetes is not yet known. Moreover, it is widely accepted that diabetes may induce osteoporosis, but the efficacy of vitamin D on diabetic osteoporosis is not clear. In order to help clarify these issues, we have tested the efficacy of calcitriol streptozotocin-induced diabetes. Streptozotocin (60 mg/Kg body weight) was injected in 3-month-old Wistar rats, randomly distributed into two groups: vehicle (olive oil) treated diabetic rats (D) and diabetic rats treated with 1.25-(OH)2D3 250 mg, three times a week (DT). Control animals (C) were treated with vehicle alone. The experiment lasted 8 weeks. The histology of the pancreata was evaluated. Blood gluclose and calcium and phosphate in serum and urine were measured. Finally, bone mineral density (BMD) of tibia and lumbar vertebrae were evaluated. After 8 weeks, diabetes persisted in 85% of the diabetic rats (D group), but in only 45% of vitamin D-treated group (DT). At the end of the experiment, DT animals were separated into two groups, those still remaining diabetic (DT-NR) and reversed animals (DT-R). Moreover, bone loss was observed in diabetic animals (D), whereas BMD of DT-R rats showed similar values to those of controls (C). Our results suggest that 1.25(OH)2D3 improves diabetes and, as such, may recover BMD in streptozotocin-induced diabetic rats.

Epidemiological study of Paget's disease of bone in a zone of the Province of Salamanca (Spain)

Bone Pagets disease is heterogeneously distributed and several foci of high prevalence have been reported in Spain. The aim of the present work was to determine the prevalence of the disease in a zone situated in the northwestern sector of the Province of Salamanca (Spain) using a cross sectional epidemiological study. Sample choice was based on a stratified sampling according to the residence, age and sex of the inhabitants of the zone. A sampling error of 5% and a confidence level of 95% were considered; these afforded a sample of 378 units. Final choice of the subjects was based on a random pathway method. Data collection was accomplished with a personal interview using a 31-item questionnaire and analytical screening (AP and GGT). The field work was carried out over a one-year period. The data were input onto a calculation sheet for analysis and epidemiological interpretation. Finally, clinico-radiological confirmation of the cases deemed positive in the screening was accomplished. The prevalence of PBD in the zone studied is 5.7% (95% CI: 4.5–6.9). The highest percentage of patients lies within the age group between 70–79 years; most of these patients were women. The mean residence time in the zone was 66 years. According to the findings, this geographic zone has a high prevalence of PBD.

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures.

SummaryTwo polymorphisms of the aromatase and estrogen receptor genes appeared to interact to influence the risk of hip fractures in women.IntroductionAllelic variants of the aromatase gene have been associated with bone mineral density and vertebral fractures. Our objective was to analyze the relationship between two polymorphisms of the aromatase and estrogen receptor genes and hip fractures.MethodsWe studied 498 women with hip fractures and 356 controls. A C/G polymorphism of the aromatase gene and a T/C polymorphism of the estrogen receptor α gene were analyzed using Taqman assays. Aromatase gene expression was determined in 43 femoral neck samples by real-time RT-PCR.ResultsThere were no significant differences in the overall distribution of genotypes between the fracture and control groups. However, among women with a TT genotype of the estrogen receptor, the CC aromatase genotype was more frequent in women with fractures than in controls (39 vs. 23%, p = 0.009). Thus, women homozygous for T alleles of estrogen receptor and C alleles of aromatase were at increased risk of fracture (odds ratio 2.0; 95% confidence interval 1.2–3.4). The aromatase polymorphism was associated with RNA levels in bone tissue, which were three times lower in samples with a CC genotype (p = 0.009).ConclusionsThese common polymorphisms of the aromatase and estrogen receptor genes appear to interact, influencing the risk of hip fractures in women.

Clinical and Genetic Advances in Paget’s Disease of Bone: a Review

Paget’s disease of bone (PDB) is the second most common metabolic bone disorder, after osteoporosis. It is characterised by focal areas of increased and disorganised bone turnover, coupled with increased bone formation. This disease usually appears in the late stages of life, being slightly more frequent in men than in women. It has been reported worldwide, but primarily affects individuals of British descent. Majority of PDB patients are asymptomatic, but clinical manifestations include pain, bone deformity and complications, like pathological fractures and deafness. The causes of the disease are poorly understood and it is considered as a complex trait, combining genetic predisposition with environmental factors. Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease. A number of mutations in this gene have been reported, pP392L being the most common variant among different populations. Most of these variants affect the ubiquitin-associated (UBA) domain of the protein, which is involved in autophagy processes. Genome-wide association studies enlarged the number of loci associated with PDB, and further fine-mapping studies, combined with functional analysis, identified OPTN and RIN3 as causal genes for Paget’s disease. A combination of risk alleles identified by genome-wide association studies led to the development of a score to predict disease severity, which could improve the management of the disease. Further studies need to be conducted to elucidate other important aspects of the trait, such as its focal nature and the epidemiological changes found in some populations. In this review, we summarize the clinical characteristics of the disease and the latest genetic advances to identify susceptibility genes. We also list current available treatments and prospective options.

Estudio de las deleciones de los genes GSTM1 y GSTT1 y del polimorfismo Ile105Val del gen GSTP1 en pacientes con enfermedad ósea de Paget

Summary Background: Paget’s disease of bone (PDB) is a disorder focussed on the bone with an increase in the number, size and activity of the osteoclasts. Some epidemiological data support the theory of its relationship with toxic or infectious environmental agents, whose interaction with some predisposing genetic alterations may lead to PDB. The glutathione S-transferases (GST) are involved in the metabolism of toxins, by catalysing the nucleophilic attack of the physiological substrate, reduced glutathione or GSH (g-GluCys-Gly) on the electrophilic centre of a great number of toxic structures. We studied whether the variability of the GSTM1, GSTP1 and GSTT1 genes is related to the risk of developing PDB. Patients and methods: We analysed 148 patients diagnosed with PDB, and 207 control individuals matched in sex and age with no history of bone alterations. Using genomic DNA obtained from peripheral blood the presence-absence of the GSTM1 and GSTT1 genes was studied by means of multiplex PCR. The study of the Ile105Val GSTP1 gene was carried out using PCR and subsequent digestion with the restriction enzyme BsmAI. The distribution of genotypes was analysed by means of the Pearson chi-square test. When statistically significant differences were found we carried out a multivariate logistical regression to determine the risk which the presence of a particular genotype could generate. We used the CSPSS 21.0 program. Differences were considered to be statistically significant when the value of p<0.05. Results: We found differences in the distribution of the presence-absence of the deletion in the GSTM1 gene; not being a carrier for the deletion or being a heterozygous carrier in the GSTM1 gene confers a lower risk of developing PDB (OR=0.56, 95% CI: 0.36-0.87; p=0.011). In the study of the GSTT1 and GSTP1 genes there were no significant differences. Conclusion: The detoxifying activity diminishes when two copies of the GSTM1 gene with deletions are inherited by reducing in enzyme activity, which has been associated with a greater susceptibility to some cancers, alcoholic hepatopathy and other inflammatory problems. We are not aware of any description of its association with PDB. PDB is observed more frequently in carriers of the homozygous deletion in the GSTM1 gene. This fact could explain the epidemiological findings which link PDB to exposure to certain environmental agents.