High Frequencies of Genetic Variants in Patients with Atypical Femoral Fractures.

This study explores the genetic factors associated with atypical femoral fractures (AFF), rare fractures associated with prolonged anti-resorptive therapy. AFF are fragility fractures that typically appear in the subtrochanteric or diaphyseal regions of the femur. While some cases resemble fractures in rare genetic bone disorders, the exact cause remains unclear. This study investigates 457 genes related to skeletal homeostasis in 13 AFF patients by exome sequencing, comparing the results with osteoporotic patients (n = 27) and Iberian samples from the 1000 Genomes Project (n = 107). Only one AFF case carried a pathogenic variant in the gene set, specifically in the ALPL gene. The study then examined variant accumulation in the gene set, revealing significantly more variants in AFF patients than in osteoporotic patients without AFF (p = 3.7 × 10-5), particularly in ACAN, AKAP13, ARHGEF3, P4HB, PITX2, and SUCO genes, all of them related to osteogenesis. This suggests that variant accumulation in bone-related genes may contribute to AFF risk. The polygenic nature of AFF implies that a complex interplay of genetic factors determines the susceptibility to AFF, with ACAN, SUCO, AKAP13, ARHGEF3, PITX2, and P4HB as potential genetic risk factors. Larger studies are needed to confirm the utility of gene set analysis in identifying patients at high risk of AFF during anti-resorptive therapy.

Speech therapy and hyperbaric oxygen for aphasia after carbon monoxide intoxication.

Acute carbon monoxide (CO) intoxication may result in delayed neurological sequelae, which can include amnesia, ataxia, aphasia, emotional lability, disorientation, dysphagia, and other manifestations. A 27-year-old man reported symptoms of aphasia with agraphia and alexia in a review after CO intoxication. The patient received outpatient speech therapy, as well as repeated sessions of hyperbaric oxygen for 15 days, interspersing speech therapy with hyperbaric oxygen therapy for two months. After this period of combined treatment the aphasic symptomatology remitted, and oral and written language was normal. The complete disappearance of aphasia with agraphia and alexia confirms the efficacy of the combined intervention. More data from large clinical studies are needed to assess the outcomes of hyperbaric oxygen treatment in patients with delayed neurological sequelae after CO intoxication, but this case suggests it may be a good therapeutic option in combination with specific speech therapy.

Estrogen receptor genes polymorphisms determine serum lipid profile in healthy postmenopausal women treated with calcium, vitamin D, and genistein.

Cardiovascular risk increases in women after menopause. Unfavorable lipid-lipoprotein changes due to a lack of estrogens may have an important role in this context. Estrogen actions are mainly mediated by their binding to two estrogen receptors (ERs) whose signaling may be conditioned by different factors. Calcium, vitamin D, and genistein, among others, cause a beneficial effect on serum lipid profile by its modulation. Some genetic factors can also determine this signal. We determined the possible additive effect of genistein on calcium and vitamin D supplementation regarding serum lipid profile changes and whether ER polymorphisms may mediate in this effect. We performed a prospective, double blind study in which women were randomized in two groups: one group received calcium and vitamin D and the other group received calcium, vitamin D and genistein. Subsequently, we studied rs9340799, rs928554, and rs4986938 ER polymorphisms in both groups. Our results showed that being a carrier of the variant allele G of rs928554 polymorphism was associated with a greater decrease in triglyceride levels and that the homozygous AA genotype of rs9340799 polymorphism was associated with a greater decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels after calcium, vitamin D, and genistein supplementation. This is the first report showing an association between polymorphisms in ER genes and an improvement of the serum lipid profile after taking calcium, vitamin D, and genistein supplementation in postmenopausal women. It reinforces the hypothesis that genetic factors are crucial in ER signalling.

Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study.

Atraumatic subtrochanteric and diaphyseal (atypical) femoral fractures are a rare, but important adverse event in patients treated with potent anti-resortive agents. The mechanisms involved are unknown and particularly the association with genetic variants has not been explored. The aim of the study was to identify rare genetic variants that could be associated with the occurrence of these fractures. We performed a genome-wide analysis of up to 300,000 variants, mainly distributed in gene coding regions, in 13 patients with atypical femoral fractures and 268 control women, either healthy or with osteoporosis. Twenty one loci were more frequent in the fracture group, with a nominal p value between 1 × 10(-6) and 2.5 × 10(-3). Most patients accumulated two or more allelic variants, and consequently the number of risk variants was markedly different between patients and controls (p = 2.6 × 10(-22)). The results of this pilot study suggest that these fractures are polygenic and are associated with the accumulation of changes in the coding regions of several genes.

Polymorphisms of the farnesyl diphosphate synthase gene modulate bone changes in response to atorvastatin.

Although their primary therapeutic indications are different, aminobisphosphonates and statins target enzymes in the mevalonate pathway, which is critical for bone homeostasis. Previous studies have shown that some polymorphisms of the gene encoding farnesyl diphosphate synthase (FDPS), the main target of aminobisphosphonates, modulate the response to these drugs. In this study, we explored whether those single nucleotide polymorphisms (SNPs) also influence the changes in bone mineral density (BMD) following therapy with statins. Sixty-six patients with coronary heart disease were studied at baseline and after 1-year therapy with atorvastatin. BMD was measured by DXA. Three SNPs of the FDPS gene (rs2297480, rs11264359 and rs17367421) were analyzed by using Taqman assays. The results showed that there was no association between the SNPs and basal BMD. However, rs2297480 and rs11264359 alleles, which are in linkage disequilibrium, were associated with changes in hip BMD following atorvastatin therapy. Thus, patients with AA genotype at the rs2297480 locus had a 0.8 ± 0.8 % increase in BMD at the femoral neck, whereas in patients with AC/CC genotypes, BMD showed a 2.3 ± 0.8 % decrease (p = 0.02). Similar results were obtained regarding changes of BMD at the femoral trochanter and when alleles at the rs11264359 locus were analyzed. However, there was no association between BMD and rs17367421 alleles. In conclusion, these results suggest that polymorphisms of the FDPS gene may influence the bone response to various drugs targeting the mevalonate pathway, including not only aminobisphosphonates but also statins.

Wnt-related genes and large-joint osteoarthritis: association study and replication.

Osteoarthritis (OA) has a strong genetic component, and experimental evidence suggests the involvement of the Wnt pathway in its pathogenesis. Hence, we explored the association of common single nucleotide polymorphisms (SNPs) related to the Wnt pathway with hip and knee OA. Seventy-eight SNPs were analyzed in 606 patients undergoing joint replacement and in 680 control subjects. SNPs were located in WNT1, WNT10A, WNT16, DVL2, FZD5, BCL9, SFRP1, TCF7L1 and SFRP4 genes. SNPs significantly associated with OA were genotyped in an independent group of 369 patients and 407 controls. One SNP in WNT10A, rs3806557, was associated with hip OA in men (OR 0.65, 95% CI 0.46-0.93; p = 0.017), but the association was not confirmed in the replication phase. The TCF7L1 polymorphism rs11547160 was also associated with hip OA in the discovery set, but not in the replication set. Similarly, the SFRP4 SNP rs1052981 was associated with knee OA in women with OR of 2.73 (95% CI 1.29-5.8; p = 0.006), but the association was not replicated. The BCL9 polymorphism rs2353525 was associated with knee OA in women, both in the unadjusted and in the age- and BMI-adjusted analysis (OR 2.01; 95% CI 1.34-2.98; p = 0.0006). A similar, but not statistically significant, trend was observed in the replication phase. In the combined analysis, OR was 3.13 (1.34-7.28; p = 0.009). These data suggest that some SNPs of genes related to the Wnt pathway and, specifically BCL9, influence the genetic predisposition to osteoarthritis of the large joints in a sex- and joint-specific way.

Metabolomic patterns, redox-related genes and metals, and bone fragility endpoints in the Hortega Study.

BACKGROUND: The potential joint influence of metabolites on bone fragility has been rarely evaluated. We assessed the association of plasma metabolic patterns with bone fragility endpoints (primarily, incident osteoporosis-related bone fractures, and, secondarily, bone mineral density BMD) in the Hortega Study participants. Redox balance plays a key role in bone metabolism. We also assessed differential associations in participant subgroups by redox-related metal exposure levels and candidate genetic variants. MATERIAL AND METHODS: In 467 participants older than 50 years from the Hortega Study, a representative sample from a region in Spain, we estimated metabolic principal components (mPC) for 54 plasma metabolites from NMR-spectrometry. Metals biomarkers were measured in plasma by AAS and in urine by HPLC-ICPMS. Redox-related SNPs (N = 341) were measured by oligo-ligation assay. RESULTS: The prospective association with incident bone fractures was inverse for mPC1 (non-essential and essential amino acids, including branched-chain, and bacterial co-metabolites, including isobutyrate, trimethylamines and phenylpropionate, versus fatty acids and VLDL) and mPC4 (HDL), but positive for mPC2 (essential amino acids, including aromatic, and bacterial co-metabolites, including isopropanol and methanol). Findings from BMD models were consistent. Participants with decreased selenium and increased antimony, arsenic and, suggestively, cadmium exposures showed higher mPC2-associated bone fractures risk. Genetic variants annotated to 19 genes, with the strongest evidence for NCF4, NOX4 and XDH, showed differential metabolic-related bone fractures risk. CONCLUSIONS: Metabolic patterns reflecting amino acids, microbiota co-metabolism and lipid metabolism were associated with bone fragility endpoints. Carriers of redox-related variants may benefit from metabolic interventions to prevent the consequences of bone fragility depending on their antimony, arsenic, selenium, and, possibly, cadmium, exposure levels.

Genetic polymorphisms of the Wnt receptor LRP5 are differentially associated with trochanteric and cervical hip fractures.

Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We tested the hypothesis that genetic factors have different influences on both types of fractures. Ten polymorphisms of genes known to play an important role in skeletal homeostasis [estrogen receptor alpha (ESR1), aromatase (CYP19A1), type I collagen (COL1A1), and lipoprotein receptor-related protein 5 (LRP5)] were analyzed in 471 Spanish patients with fragility hip fractures. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (P = 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR = 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with one or two rare alleles and 7.5 in those with three or four rare alleles (P for trend = 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1, and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or an extended group of 818 patients. These results suggest that LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies.

Influence of Obesity on Bone Turnover Markers and Fracture Risk in Postmenopausal Women.

Background and aims: The relationship between obesity and bone metabolism is controversial. In recent decades, the protective role of obesity in the development of osteoporosis is questioned. The aims of this study are the following: to evaluate the differences in bone turnover markers between postmenopausal women with and without obesity and to compare the risk of fracture at five years between these groups. Methods: An observational longitudinal prospective cohort study of postmenopausal women with obesity (O) (body mass index (BMI) > 30 kg/m2) and non-obesity (NoO) (BMI < 30 kg/m2) is designed. 250 postmenopausal women are included in the study (NoO: 124 (49.6%) and O: 126 (50.4%)). It measures epidemiological variables, dietary variables (calcium intake, vitamin D intake, smoking, alcohol consumption, and physical activity), biochemicals (ß-crosslap, type I procollagen amino-terminal peptide (P1NP), 25OH-vitamin D, and parathyroid hormone (PTH)), anthropometric variables, and fracture data five years after the start of the study. The mean age is 56.17 (3.91) years. Women with obesity showed lower levels of vitamin D (O: 17.27 (7.85) ng/mL, NoO: 24.51 (9.60) ng/mL; p < 0.01), and higher levels of PTH (O: 53.24 (38.44−65.96) pg/mL, NoO: 35.24 (25.36−42.40) pg/mL; p < 0.01). Regarding the bone formation marker (P1NP), it was found to be high in women without obesity, O: 45.46 (34.39−55.16) ng/mL, NoO: 56.74 (45.34−70.74) ng/mL; p < 0.01; the bone resorption marker (ß-crosslap) was found to be high in women with obesity, being significant in those older than 59 years (O: 0.39 (0.14) ng/mL, NoO 0.24 (0.09) ng/mL; p < 0.05). No differences are observed in the risk of fracture at 5 years based on BMI (OR = 0.90 (95%CI 0.30−2.72); p = 0.85). Conclusions: Postmenopausal women with obesity showed lower levels of bone formation markers; older women with obesity showed higher markers of bone resorption.

Long-term visual pathway alterations after elemental mercury poisoning: report of a series of 29 cases.

BACKGROUND: There are few clinical data on retinal involvement after acute exposure to high concentrations mercury and the available reports are based on a small number of patients suffering chronic exposure. The purpose of this paper is to report findings in workers acutely exposed to very high concentrations of mercury vapor with the aim of providing data on a possible direct retinal involvement. METHODS: Twenty-nine patients and 16 controls were evaluated in a comparative case series. Mercury levels in blood and urine samples, visual acuity (VA), contrast sensitivity (CS), visual field (VF), color discrimination and optical coherence tomography (OCT) were recorded. The pattern reversal visual-evoked potentials (PRVEP), full-field and multifocal electroretinography (ffERG/mfERG), pattern electroretinography (PERG), systemic symptoms, presence of erethism, and electromyography (EMG) were also gathered. A descriptive analysis was performed. The correlations between variables also were studied. In addition, electrophysiological data from those patients with deeper VF defects (group 1) were compared with a normal control group. RESULTS: Twenty-six workers exhibited symptoms of erethism. The EMG showed sensorimotor polyneuropathy and multiple mononeuropathy. The VA was slightly affected in 48.27% (n = 14) of subjects. Loss of CS in at least one of four spatial frequencies and color vision alterations occurred in 96.5% (n = 28) and 44.8% (n = 13), respectively. VF alterations were identified in 72.4% (n = 21) patients. No morphologic changes were seen in the OCT scans. Latencies over 100 milliseconds and reduced amplitudes of P100 were found in the PRVEP (p < 0.05). The reduced amplitude of the b wave at the ffERG, of the P50 at the PERG and of the P1 wave at the mfERG results (p < 0.05) suggested that the outer retina was involved. Significant negative correlations among blood mercury levels, VA, and ffERG were observed. CONCLUSIONS: In this case series, showed that acute exposure to mercury vapor had a hazardous effect on the visual system. Although neurologic and visual pathway involvement was clearly demonstrated, the differences found compared to control support the existence of a direct functional retinal damage and participation in impaired vision in mercury poisoning.

Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians.

BACKGROUND: Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (ESR1) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians. METHODS: We analyzed those two SNPs and another neighbour SNP located on the exon 4 of ESR1 in 787 patients with hip fractures and 953 controls from Spain. RESULTS: The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples. CONCLUSIONS: This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of ESR1 and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.

Polymorphisms of the WNT10B gene, bone mineral density, and fractures in postmenopausal women.

Wnt ligands are important regulators of skeletal homeostasis. Wnt10B tends to stimulate the differentiation of common mesenchymal precursors toward the osteoblastic lineage, while inhibiting adipocytic differentiation. Hence, we decided to explore the association of WNT10B allelic variants with bone mineral density and osteoporotic fractures. A set of tag SNPs capturing most common variations of the WNT10B gene was genotyped in 1438 Caucasian postmenopausal women, including 146 with vertebral fractures and 432 with hip fractures. We found no association between single SNPs and spine or hip bone mineral density (BMD). In the multilocus analysis, some haplotypes showed a slight association with spine BMD (P = 0.03), but it was not significant after multiple-test correction. There was no association between genotype and vertebral or hip fractures. Transcripts of WNT10B and other Wnt ligands were detected in human bone samples by real-time PCR. However, there was no relationship between genotype and RNA abundance. Thus, WNT10B is expressed in the bone microenvironment and may be an important regulator of osteoblastogenesis, but we have not found evidence for a robust association of common WNT10B gene allelic variants with either BMD or fractures in postmenopausal women.

Effects of Atorvastatin on vitamin D levels in patients with acute ischemic heart disease.

Vitamin D deficiency is a risk factor for osteoporosis and other chronic diseases, including type 1 diabetes, hypertension, metabolic syndrome, and ischemic heart disease. Cholesterol and vitamin D share the 7-dehydrocholesterol metabolic pathway. This study evaluated the possible effect of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Eighty-three patients (52 men and 31 women) with an acute coronary syndrome (75 with acute myocardial infarction and 8 with unstable angina) were included. After diagnosis, patients received atorvastatin as secondary prevention. Serum vitamin D was measured by high-performance liquid chromatography at baseline and at 12 months. Atorvastatin treatment produced a statistically significant decrease in cholesterol and triglyceride levels and an increase in vitamin D levels (41+/-19 vs 47+/-19 nmol/L, p=0.003). Vitamin D deficiency was decreased by 75% to 57% at 12 months. In conclusion, atorvastatin increases vitamin D levels. This increase could explain some of the beneficial effects of atorvastatin at the cardiovascular level that are unrelated to cholesterol levels.

OST risk index and calcaneus bone densitometry in osteoporosis diagnosis.

The gold-standard method for osteoporosis diagnosis is by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and/or hip. DXA is expensive and alternative approaches are being analyzed. The objective of this study was to evaluate whether the Osteoporosis Self-Assessment Tool (OST) combined with calcaneal DXA improves the sensitivity and specificity of the DXA. One hundred and sixty-one (67 males and 94 females) outpatients referred due to suspected osteoporosis or lumbar pain were included. Hip, spinal, or calcaneal DXA was performed in all patients and the OST index was administered. The cutoff point for patients of high- or low-risk osteoporosis was 2 for women and 3 for men. The mean OST index value was 3.62+/-4.3. Twenty-seven percent of the patients were osteoporotic. Sixty-two percent presented a low risk and 38% a high risk. In men, the OST had a sensitivity of 39% and a specificity of 86%, whereas in women the sensitivity was 94% with a specificity of 59%. The combination of the calcaneal DXA with the OST index did not modify the validity of DXA in men. In women, the sensitivity of the different cutoff points was improved at the expense of a decrease in the specificity without modifying the area under the curve. The combination of the calcaneal DXA with the OST index did not improve the value of each of the separate techniques. The OST index is useful in women to facilitate the densitometry indication for hip and/or spine.

Ghrelin and bone mass in postmenopausal hypertensive women.

BACKGROUND: Ghrelin, a recently discovered peptide mainly secreted by the stomach, has an orexigenic effect which stimulates secretion of the growth hormone. It also has vasodilator effects which reduce blood pressure and stimulate in vitro, bone formation. OBJECTIVES: To evaluate the effect of ghrelin on bone mass and bone remodeling markers in postmenopausal hypertensive women. MATERIAL AND METHODS: 25 postmenopausal hypertensive women, light to moderate based on the JNC-VII criteria, were studied. They had a mean age of 58 +/- 8 years, a body mass index of 28 +/- 6 and a hypertension development time of 65 +/- 84 months. Osteocalcin, PTHi, 25-vitamin D, ghrelin in serum and deoxypiridinoline in urine were determined in all patients. A lumbar spine densitometer was made (DXP Lunar, Madison, Wisc., USA). RESULTS: Diminished levels of ghrelin were observed in the osteoporotic group (40 +/- 19 vs. 78 +/- 40, p = 0.027). When the patients were separated according to ghrelin tertiles, a greater bone mass was observed in the upper tertiles, which was associated with a decrease in the urinary deoxypiridinoline. When the total population was analyzed, no relation between the ghrelin and bone mass was found, nor with any of the parameters of calcium metabolism. Only a statistically significant relation between ghrelin and deoxypiridinoline was observed (r = -0.428, p = 0.026). CONCLUSIONS: In postmenopausal hypertensive women, ghrelin may produce a protecting effect over bone mass through an anticatabolic mechanism manifested by a decrease of bone resorption.

Impact of obesity on bone metabolism. / Influencia de la obesidad sobre el metabolismo óseo.

High weight is a protective factor against osteoporosis and risk of fracture. In obesity, however, where overweight is associated to excess fat, this relationship does not appear to be so clear, excess weight has sometimes been associated to decreased bone mass. Obesity interferes with bone metabolism through mechanical, hormonal, and inflammatory factors. These factors are closely related to weight, body composition, and dietary patterns of these patients. The net beneficial or harmful effect on bone mass or risk of fracture of the different components of this condition is not well known. We need to recognize patients at a greater risk of bone disease related to obesity to start an adequate intervention.

Miel alucinógena del Himalaya: ¿la próxima intoxicación? / Hallucinogenic Himalayan honey: the next poison?

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Circulating sclerostin and estradiol levels are associated with inadequate response to bisphosphonates in postmenopausal women with osteoporosis.

INTRODUCTION: The biological mechanisms associated with an inadequate response to treatment with bisphosphonates are not well known. This study investigates the association between circulating levels of sclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women with postmenopausal osteoporosis. METHODS: This case-control study is based on 120 Spanish women with postmenopausal osteoporosis being treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n=66, mean age 68.2±8 years) without incident fractures during 5 years of treatment, or inadequate responders (IRs, n=54, mean age 67±9 years), with incident fractures between 1 and 5 years of treatment. Bone mineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of the distal radius were assessed. Sclerostin concentrations were measured by ELISA and 17ß-estradiol levels by radioimmunoassay based on ultrasensitive methods. RESULTS: In the ARs group, sclerostin serum levels were significantly lower (p=0.02) and estradiol concentrations significantly higher (p=0.023) than in the IRs group. A logistic regression analysis was performed, including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D, previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture (OR 14.04, 95% CI 2.38-82.79, p=0.004) and sclerostin levels (OR 1.11, 95% CI 1.02-1.20, p=0.011), both adjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associated with the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameter on bone microstructure. CONCLUSIONS: Sclerostin and estradiol levels are associated with the response to bisphosphonate therapy in women with postmenopausal osteoporosis.