Association of CYP2C19 Polymorphism With Proton Pump Inhibitors Effectiveness and With Fractures in Real-Life: Retrospective Cohort Study.

Symptom refractoriness of patients treated with proton pump inhibitors (PPIs) might be explained by polymorphism in CYP2C19. This is a retrospective cohort study in which we used the computerized database of Clalit Health Services to compose a cohort from cancer case-control studies' participants that had been genotyped, and that have been dispensed PPI (January 1, 2002 to November 10, 2020). We retrieved demographic and clinical variables on date of PPI initiation (cohort entry), and studies' questionnaires-reported consumption of foods/beverages known to increase peptic-related symptoms. Primary outcome was an abdominal pain diagnosis; secondary outcome was a composite of abdominal pain, visit to a gastroenterology clinic, change to another PPI, PPI dose increase, or metoclopramide prescription, reflecting symptoms persistence/recurrence; in a 2-year follow-up. We also evaluated the association between genetic groups and hip/wrist/spine fractures, in a long-term follow-up. Of 3,326 PPI initiators, there were 66 (2.0%), 739 (22.2%), 1394 (41.9%), 947 (28.5%), and 180 (5.4%) CYP2C19 poor, intermediate, normal, rapid, and ultra-rapid metabolizers, respectively. Being a poor metabolizer was associated with lower risk for the primary outcome, hazard ratio (HR) = 0.50 (95% confidence interval (CI) 0.27-0.91), HR = 0.52 (95% CI 0.28-0.94); and for the secondary outcome, HR = 0.57 (95% CI 0.38-0.86), HR = 0.58 (95% CI 0.39-0.87), in univariate and multivariable cox regression analyses, respectively. In long-term follow-up with 20,142 person-years of follow-up: 7.6% (5 cases) within the poor metabolizers group, and 11.6%, 12.9%, 12.8%, and 11.1% in the normal, intermediate, rapid, and ultra-rapid metabolizers groups, respectively, had a new fracture (nonsignificant). We conclude that CYP2C19 poor metabolizer status is associated with higher effectiveness of PPIs, and is not associated with higher risk for fractures.

Fractures due to Aromatase Inhibitor Therapy for Breast Cancer: A Real-World Analysis of FAERS Data in the Past 15 Years.

INTRODUCTION: The adverse effect of fractures by different aromatase inhibitor (AI) drugs has not been thoroughly assessed in real-world studies. OBJECTIVE: To assess the adverse events of fractures of real-world breast cancer patients caused by AI therapy through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The FAERS data from January 2004 to December 2018 were sorted out and analyzed for correlations between fractures and AI use. Disproportionate analysis and Bayesian analysis were adopted to quantify the signal, the association between the AIs and fractures. The onset time and outcome of fractures after different AI regimens were also compared. RESULTS: Out of 23,064 adverse reports, 657 fracture reports (2.85%) were analyzed. Anastrozole showed a positive association with 4 detection methods, while letrozole and exemestane did so with 2. More exemestane-related reports (44.62%) resulted in initial or prolonged hospitalization than anastrozole (30.12%, p = 0.013) and letrozole (29.43%, p = 0.006). The fracture onset time showed no significant difference among anastrozole, letrozole, and exemestane (median onset time: 46.95, 34.25, and 40.58 months, respectively; p = 0.236). CONCLUSIONS: Anastrozole should be prescribed with more medical care. Analysis of FAERS data identified fracture risk tendencies with AI regimens, which supported continuous monitoring, risk evaluations, and further comparative studies.

Coordinating Tissue Regeneration Through Transforming Growth Factor-ß Activated Kinase 1 Inactivation and Reactivation.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment ("drug on"), the impact of drug withdrawal ("drug off") implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment ("drug on") and subsequent withdrawal ("drug off") through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.

[Value of serum alkaline phosphatase for predicting 2-year fracture in patients with chronic kidney disease on dialysis].

OBJECTIVE: To explore the value of baseline serum alkaline phosphatase (ALP) for predicting 2-year fracture in patients with chronic kidney disease (CKD) on maintenance dialysis. METHODS: A total of 139 patients with CKD undergoing maintenance dialysis in our hospital were enrolled in this study. According to the median serum ALP level, the patients were divided into high ALP and low ALP groups. The demographic and clinical data of the patients including dialysis duration, serum calcium level, serum phosphorus level, and serum intact parathyroid hormone level were recorded, and their bone mineral density of the femur and the lumbar spine was measured using dual energy X-ray absorptiometry. The patients were followed up for 2 years and fracture events were recorded. The risk factors of fracture were analyzed using logistic regression analysis, and their predictive value for fracture was analyzed using receiver-operating characteristic (ROC) curve. RESULTS: The mean baseline serum ALP level was 132.55±167.68 U/L in these patients, significantly higher than that in the normal population (t=2.816, P=0.006). Baseline serum ALP level was negatively correlated with the bone mineral density of the lumbar spine (r=-0.203, P=0.006) and the femur (r=-0.196, P=0.021). Fractures occurred in 21 (15.1%) of the patients during the 2-year follow-up, and the fracture rate was significantly higher in patients with high ALP levels. Logistic regression analysis identified serum ALP level as an independent risk factor of fracture (OR: 1.010, P=0.001, 95%CI: 1.004-1.016). The areas under the ROC curve were 0.900 and 0.768 for serum ALP level and intact parathyroid hormone level in predicting 2-year fractures, respectively. CONCLUSIONS: Serum ALP may serve as a good indicator for predicting 2-year fractures in patients with CKD on maintenance dialysis.

Prevalence and risk factors for fragility fracture in systemic mastocytosis.

OBJECTIVES: Systemic mastocytosis (SM) is characterized by the accumulation of mast cells in tissues other than the skin. Bone involvement although frequent has not been thoroughly evaluated. Primary objective was to determine risk factors associated with fragility fractures (FF) in SM. Secondary objectives were to evaluate the ability of bone marrow tryptase (BMT) level to identify patients with FF, and to describe bone involvement in SM. METHODS: We analyzed retrospectively all consecutive patients seen in our expert center, with a diagnosis of SM according to the 2001 WHO criteria, and with complete bone assessment. We collected data about lifetime fractures, types of cutaneous manifestations, degranulation symptoms, blood and BMT levels, bone mineral density assessed by densitometry and KIT mutation. We performed a univariate analysis investigating the factors associated with FF and then a logistic multivariable regression analysis. We assessed the ability of bone marrow tryptase to identify patients with FF. RESULTS: Eighty-nine patients with SM were included. Thirty-six patients (40.4%) suffered from osteoporosis and twenty-five (28.1%) experienced lifetime FF. Univariate analysis identified age at diagnosis and disease onset, presence of telangiectasia macularis eruptiva perstans, digestive symptoms, mast cells activation symptoms, elevated BMT, low femoral and lumbar BMD, as associated with FF. Multivariate analysis identified elevated BMT, low femoral T score and older age at diagnosis as independently associated with FF. CONCLUSIONS: Low femoral T-score, BMT level, and older age at diagnosis are markers associated with FF in SM. BMT may represent an important biomarker to predict FF in SM patients.

Effects of pharmacological inhibition of cathepsin K on fracture repair in mice.

Cathepsin K inhibitors (CatK-I) have been developed and established to restore bone mass in both animal models of bone loss and postmenopausal osteoporotic patients. We investigated the effects of a CatK-I L-006235 on bone repair and compared to alendronate (ALN) for its known effects on fracture healing in preclinical models. Femoral fractures were performed on wild type mice that were given vehicle (CON), CatK-I or ALN from day 0 post-fracture until euthanasia. Radiologic and micro-CT analyses demonstrated that CatK-I enhanced mineralization within the calluses at day 21 post-fracture, but to a lesser degree than ALN. Histological analyses showed residual unmineralized and mineralized cartilage in the calluses of CatK-I and ALN treated groups at day 21 post-fracture compared to that in CON. CatK-I enhanced the number of tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts in the fracture calluses compared to ALN and CON treated groups. However, relative levels of serum C-terminal telopeptides of type I collagen (CTX) normalized to the number of TRAP+ osteoclasts within the calluses were significantly decreased in both CatK-I and ALN groups compared to CON. Additionally, the percentages of osteoblast surface over mineralized calluses and levels of the bone formation marker serum N-terminal propeptide of type I procollagen (P1NP) were comparable between CatK-I versus CON groups, while these bone formation parameters were decreased by ALN. Taken together, these results indicate that unlike ALN, CatK-I inhibits osteoclastic activity without changing bone formation, and the inhibition of CatK delayed but did not abrogate callus remodeling during bone repair.

Utility of serum tartrate-resistant acid phosphatase isoform 5b, bone alkaline phosphatase and osteocalcin in osteoporotic fractures in Chinese patients.

BACKGROUND: The goal was to find out the clinical significances of tartrate-resistant acid phosphatase isoform 5b (TRACP 5b), a biomarker of bone resorption, and bone alkaline phosphatase (BAP) and osteocalcin, two markers of bone formation, in evaluating the osteoporotic fracture risk in Chinese patients. METHODS: Thirty six Chinese osteoporotic fracture patients and 32 Chinese healthy subjects were included in the study. Bone mineral density (BMD) of lumbar spine and total body were determined by dual-energy X-ray absorptiometry in all subjects. Fasting blood samples were collected from all subjects and the serum concentrations of TRACP 5b, BAP, and osteocalcin were analyzed with enzyme-linked immunosorbent assay or immunoradiometric assay. RESULTS: With lower BMD, the osteoporotic fracture patients had elevated levels of TRACP 5b and BAP, compared with the healthy controls. No difference in serum osteocalcin level was observed between the fracture patients and the control. CONCLUSIONS: Elevated serum TRACP 5b and BAP, combined with or without increased osteocalcin, are valuable tools for the assessment of osteoporotic fracture risk in Chinese patients.

Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance.

Like bone mass, bone quality is specified in development, actively maintained postnatally, and disrupted by disease. The roles of osteoblasts, osteoclasts, and osteocytes in the regulation of bone mass are increasingly well defined. However, the cellular and molecular mechanisms by which bone quality is regulated remain unclear. Proteins that remodel bone extracellular matrix, such as the collagen-degrading matrix metalloproteinase (MMP)-13, are likely candidates to regulate bone quality. Using MMP-13-deficient mice, we examined the role of MMP-13 in the remodeling and maintenance of bone matrix and subsequent fracture resistance. Throughout the diaphysis of MMP-13-deficient tibiae, we observed elevated nonenzymatic cross-linking and concentric regions of hypermineralization, collagen disorganization, and canalicular malformation. These defects localize to the same mid-cortical bone regions where osteocyte lacunae and canaliculi exhibit MMP-13 and tartrate-resistant acid phosphatase (TRAP) expression, as well as the osteocyte marker sclerostin. Despite otherwise normal measures of osteoclast and osteoblast function, dynamic histomorphometry revealed that remodeling of osteocyte lacunae is impaired in MMP-13(-/-) bone. Analysis of MMP-13(-/-) mice and their wild-type littermates in normal and lactating conditions showed that MMP-13 is not only required for lactation-induced osteocyte perilacunar remodeling, but also for the maintenance of bone quality. The loss of MMP-13, and the resulting defects in perilacunar remodeling and matrix organization, compromise MMP-13(-/-) bone fracture toughness and postyield behavior. Taken together, these findings demonstrate that osteocyte perilacunar remodeling of mid-cortical bone matrix requires MMP-13 and is essential for the maintenance of bone quality.

Kinetic characteristics of myosin ATPase in dog skeletal muscles after shin bone fracture.

Kinetic characteristics of myosin from dog anterior tibial and gastrocnemius muscles after shin bone fracture were studied. Myosin affinity for ATP increased in muscles of the injured and contralateral limbs.

HSD11B1 polymorphisms predicted bone mineral density and fracture risk in postmenopausal women without a clinically apparent hypercortisolemia.

INTRODUCTION: Endogenous glucocorticoid (GC) may participate in bone physiology, even in subjects with no glucocorticoid excess. 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) is a primary regulator catalyzing the reduction of inactive cortisone to active cortisol. To elucidate genetic relevance of HSD11B1 variants to vertebral fracture and osteoporosis, we investigated the potential involvement of six HSD11B1 SNPs in postmenopausal women. METHODS: All exons, their boundaries and the promoter region (approximately 1.5 kb) were directly sequenced in 24 individuals. Six polymorphisms were selected and genotyped in all study participants (n=1329). BMD was measured using dual-energy X-ray absorptiometry. RESULTS: HSD11B1 +16374C>T and +27447G>C were associated with reduced vertebral fracture risk (p=0.016 and 0.032, respectively). Two of these (LD block2) in intron 5 (rs1000283 and rs932335) were significantly associated with bone mineral density (BMD) at the femoral neck (p=0.00005 and 0.0002, respectively). Specifically, HSD11B1 +16374C>T and +27447G>C polymorphisms were associated with higher BMD values of the femoral neck in multiple comparison (p=0.0002 and 0.0004, respectively) and Bonferroni corrected significance level (97% power). Consistent with these results, HSD11B1-ht21 and -ht22 comprising both SNPs also showed the evidence of association with BMD values of the femoral neck (p(domiant)=0.0002 and p(recessive)=0.00005, respectively). CONCLUSION: Our results provide preliminary evidence supporting an association of HSD11B1 with osteoporosis in postmenopausal women. Also, these findings demonstrate that +16374C>T polymorphism may be useful genetic markers for bone metabolism.

Misunderstood cardiac involvement with heart impairment in traumatic sternal fracture: an enzyme-guided evaluation.

BACKGROUND: Isolated sternal fractures occur more and more frequently in traffic road accidents in particular after the introduction of the seat-belt law. This study sets out to assess by laboratory parameters the incidence and consequences of pericardial and myocardial involvement in sternal injury. PATIENTS AND METHODS: Between June 1997 and March 2007, 50 consecutive patients were admitted to our Thoracic Surgical Unit with acute traumatic sternal fractures. X-ray, CT scan, standard 12-lead electrocardiogram (ECG) and echocardiographic evaluation were obtained in all patients. (28 males, 22 females), with displaced and undisplaced fractures. The patients were hospitalised for cardiorespiratory monitoring, pain control and physiotherapy. Oxygen implementation was performed to obtain an arterial saturation above 96%. Supplementary investigations or therapeutic interventions were assessed if clinically indicated. RESULTS: Our data, according to literature, show that sternal trauma must be careful evaluated by monitoring of vital parameters. In our collection we have no mortality with complex comorbidity. The interparametric relation between laboratory values and cardiac involvement was not significant anyway . The prolonged CK-MB peak level in a large number of patients is related with cardiac impairment. CONCLUSIONS: Our results suggest that in traumatic sternal fractures enzymatic activity of CK-MB, echocardiographic investigation and careful monitoring for the first 96 hours are necessary. The cardiac compliance is inadequate in polytrauma patients and can lead to cardiac impairment.

Associations between methotrexate treatment and methylenetetrahydrofolate reductase gene polymorphisms with incident fractures in Japanese female rheumatoid arthritis patients.

Several case reports have described associations between pathological nonvertebral fractures and low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. Furthermore, a significant association between the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene and incident fractures has been reported in postmenopausal women. We attempted to determine whether MTX use and MTHFR polymorphisms are associated with incident fracture risk in Japanese female RA patients. DNA samples, laboratory data, and clinical data were obtained from 731 female RA patients more than 50 years old as part of the Institute of Rheumatology Rheumatoid Arthritis (IORRA) observational cohort study. Genotyping of the MTHFR polymorphisms C677T and A1298C was performed using TaqMan SNP Genotyping Assays. MTX use, MTHFR polymorphisms, and other potential risk factors predictive of fracture were analyzed by Cox proportional hazards regression models, including time-dependent covariates. During 78 months from October 2000 to March 2007, 25 and 90 patients developed vertebral and nonvertebral fractures, respectively. Patients with nonvertebral fractures were more likely to take MTX (P = 0.011; odds ratio, 1.77; 95% confidence interval, 1.13-2.76) compared to patients without fractures. Although the C677T and A1298C polymorphisms were not significantly associated with incident fracture risk, MTX use, age, disease duration, and Japanese health assessment questionnaire score were significantly (P < 0.05) and independently associated with nonvertebral fracture incidence. Our results suggest that MTX use is associated with a nonvertebral fracture risk, whereas MTHFR polymorphism status does not appear to be a clinically useful marker for predicting fracture risk in Japanese female RA patients.

Acidic pH environments increase the expression of cathepsin B in osteoblasts: the significance of ER stress in bone physiology.

Hypoxia, inflammation, and acidity occur after bone fracture. To simplify the fracture model, we tested the effects of acidity in osteoblasts. We tested three osteoblast cell lines, MG63, MC3T3E1, and HOS cells, with MG63 cells showing much higher sensitivity to acidic pH. In physiologically acidic surroundings, pH 7.2, the endoplasmic reticulum stress response was measured through the expression of unfolded protein response proteins. Acidic surroundings time-dependently increased IL-6 secretion. Cathepsin B, a marker of the inflammation and angiogenic processes that occur after bone fracture, also increased. Thus, acidity can cause ER stress, increase IL-6, and increases cathepsin B expression in osteoblasts.

The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures.

A functional polymorphism in methylenetetrahydrofolate reductase (MTHFR) has been identified at codon 677 (C677T). The T-allele variant (valine type) has lower enzyme activity than the wild type (C-allele or alanine type), resulting in a slightly elevated homocysteine level, which has been recently recognized as a risk factor for fracture. However, whether subjects bearing the T allele have higher susceptibility to fractures is still controversial. We have investigated the effects of MTHFR polymorphism on fracture susceptibility in Japanese postmenopausal women. A total of 502 postmenopausal ambulatory Japanese women were followed up for 5.1 +/- 3.4 (mean +/- SD) years, and a total of 155 patients with incident fractures (121 patients with vertebral fractures and 34 cases with fractures at other sites) were recorded. When compared with the patients without any fractures, the patients with incident fractures were older, had more prevalent fractures, had higher urinary levels of bone turnover markers as well as plasma homocysteine level, but were shorter in body height and had lower bone mineral density. The prevalence of the TT genotype of MTHFR was significantly higher in the patients with incident fractures compared to the other genotypes. The subjects with the TT genotype had a higher incidence rate of fracture and higher plasma level of homocysteine than the subjects bearing the non-TT genotype. This relationship was observed in both osteoporotic and nonosteoporotic groups. The hazard ratio for TT genotype without osteoporosis, non-TT genotype with osteoporosis, and TT genotype with osteoporosis was 1.49 (0.91-2.45), 3.64 (2.50-5.29), and 7.21 (4.34-11.97), respectively, compared to the non-TT genotype without osteoporosis. A higher hazard ratio for the TT genotype with osteoporosis was still apparent after adjustment for age, body size, and number of prevalent vertebral fractures. These results indicate that the TT genotype of MTHFR may be a risk factor for future fracture in addition to the traditional risk factors.

Short-term administration of non-selective and selective COX-2 NSAIDs do not interfere with bone repair in rats.

Selective cyclooxygenase-2 non-steroidal anti-inflammatory drugs are known to inhibit bone repair, especially when long-term administration is required due to chronicle inflammatory diseases. In order to evaluate the action of this drug in bone repair during short-term administration, 48 rats underwent surgical bone defects in their tibias, being randomly distributed into three groups: (Group 1) negative control; (Group 2) animals treated with celecoxib, and (Group 3) animals treated with ketoprofen, both experimental groups at 1 mg/kg dose, beginning 1 h before the surgical procedure and after every 12 h for the following 3 days, or until the day of sacrifice. The animals were killed after 48 h, 7, 14, and 21 days. The tibias were removed for morphological, morphometric, and immunohistochemistry analysis for COX-2. No statistical significant differences were observed in the quality of bone repair and quantity of formed bone among the groups. COX-2 immunoreactivity of the celecoxib treated specimens was more intense in the first analyzed period, and no longer observed in the periods of 14 and 21 days. Such results suggest that the administration of the analyzed drugs in short periods does not interfere with the process of bone repair in the tibia of rats.

Aromatase expression in osteoarthritic and osteoporotic bone.

OBJECTIVE: Estrogen deprivation is a central mechanism in the development of osteoporosis with aging. Results from recent studies also suggest the involvement of estrogens in the pathophysiology of osteoarthritis (OA). Aromatization of androgenic precursors in peripheral tissue is the main source of estrogens in postmenopausal women and in men. However, the importance of aromatase expression in bone is a subject of controversy. This study was undertaken to determine aromatase expression in bone samples from patients with hip fracture and patients with OA. METHODS: We studied 104 patients with hip fracture (n = 60) or primary hip OA (n = 44). Aromatase expression was determined in trabecular bone samples from the femoral neck and in osteoblast cultures grown by the primary explant technique (n = 62), using real-time reverse transcriptase-polymerase chain reaction. RESULTS: Aromatase RNA was detected in bone samples at levels similar to those found in adipose tissue. Transcript levels were significantly lower in bone tissue samples obtained from patients with OA than in those obtained from patients with fracture (P = 0.00001). Likewise, primary cultures of osteoblast cells from OA patients revealed lower aromatase expression than those of cells from fracture patients (P = 0.012). Results were independent of age or sex differences. CONCLUSION: Our findings indicate that the aromatase gene is expressed in bone tissue in high amounts, similar to those found in adipose tissue, but transcript levels are lower in tissue samples and osteoblast cultures from patients with OA than in those from patients with hip fracture. Since estrogens may help to prevent local cartilage degradation, it can be speculated that such a reduced expression of aromatase could facilitate the development of OA.

Case report: multiple fractures in a patient with mutations of TWIST1 and TNSALP.

Hypophosphatasia is a rare inherited disorder characterized by defective skeletal mineralization and low alkaline phosphatase activities in the serum. The genetic cause of hypophosphatasia is believed related to inactivating mutations in the TNSALP gene, encoding tissue-nonspecific alkaline phosphatase. Another rare inheritable disease, Saethre-Chotzen syndrome, leads to premature fusion of the cranial sutures caused by heterozygous mutations of the human TWIST1 gene. Because the two disorders apparently are not genetically related (only reported individually) yet both involve defective skeletal formation, we believe it is important to report our findings on a patient harboring mutations of TNSALP and TWIST1.

A high activity index of stearoyl-CoA desaturase is associated with increased risk of fracture in men.

UNLABELLED: The activity index of stearoyl-CoA desaturase (SCD), a key enzyme in lipogenesis, was associated with increased risk of fracture in a longitudinal population-based cohort of men. This indicates that elevated levels of endogenous lipogenesis increase the risk of fracture and suggest a role for saturated fat in the pathogenesis of osteoporosis. INTRODUCTION: Osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, and experimental studies have indicated that increased adipogenesis can occur at the expense of osteoblasts, leading to bone loss. Stearoyl-CoA desaturase (SCD) converts saturated to monounsaturated fatty acids and is a key enzyme in lipogenesis. METHODS: Analysis was performed in a population-based, longitudinal cohort study of men (n = 2009). A product-to-precursor index (palmitoleic acid/palmitic acid) was used to estimate SCD activity in fasting serum analyzed in samples obtained at enrollment at age 50 years. Fractures were documented in 422 men during 35 years of follow-up. Cox regression analysis was used to determine the risk of fracture according to SCD activity index. RESULTS: The risk of fracture was highest among men with the highest levels of SCD activity index. Multivariable analysis of the risk of fracture in the highest quintile as compared to the lowest one showed that the rate ratio was 1.71 (95% CI 1.26-2.33) for any fracture, with an estimated population attributable risk of 15%. The risk was further increased within the highest quintile. CONCLUSIONS: Our results indicate that elevated levels of endogenous lipogenesis increase the risk of fracture and suggest a role for saturated fat in the pathogenesis of osteoporosis.

The COMT val158met polymorphism is associated with prevalent fractures in Swedish men.

INTRODUCTION: Sex steroids are important for growth and maintenance of the skeleton. Catechol-O-methyltransferase (COMT) is an estrogen degrading enzyme. The COMT val158met polymorphism results in a 60-75% difference in enzyme activity between the val (high activity=H) and met (low activity=L) variants. We have previously reported that this polymorphism is associated with bone mineral density (BMD) in young men. The aim of this study was to investigate associations between COMT val158met, BMD and fractures in elderly men. METHODS: Population-based study of Swedish men 75.4, SD 3.2, years of age. Fractures were reported using standardized questionnaires. Fracture and genotype data were available from 2,822 individuals. RESULTS: Total number of individuals with self-reported fracture was 989 (35.0%). Prevalence of >or=1 fracture was 37.2% in COMT(LL), 35.7% in COMT(HL) and 30.4% in COMT(HH) (p<0.05). Early fractures (50 years of age). The OR for fracture of the non-weight bearing skeleton in COMT(HH) compared with COMT(LL+HL) was 0.74 (95% CI 0.59-0.92). No associations between COMT val158met and BMD were found in this cohort of elderly men. CONCLUSIONS: The COMT val158met polymorphism is associated with life time fracture prevalence in elderly Swedish men. This association is mainly driven by early fractures (

Fractures and bone mineral density in adult women with 21-hydroxylase deficiency.

CONTEXT: Patients with classical congenital adrenal hyperplasia (CAH) receive lifelong, often supraphysiological, glucocorticoid therapy. Pharmacological doses of glucocorticoids are an established risk factor for osteoporosis. OBJECTIVE: Our objective was to evaluate bone mineral density (BMD), fracture prevalence, and markers of bone metabolism in adult females with CAH. DESIGN: This was a cross-sectional observational study. SETTING: Tertiary care referral centers were used in this study. PARTICIPANTS: We studied 61 women, aged 18-63 yr, with genetically verified CAH due to 21-hydroxylase deficiency. They were patients with salt wasting (n = 27), simple virilizing (n = 28), and nonclassical 21-hydroxylase deficiency (n = 6). A total of 61 age-matched women were controls. MAIN OUTCOME MEASURES: History of fractures was recorded. Total body, lumbar spine, and femoral neck BMD were measured by dual-energy x-ray absorptiometry. The World Health Organization criteria for osteopenia and osteoporosis were used. Serum marker of bone resorption, beta-C telopeptide was studied. RESULTS: The mean glucocorticoid dose in hydrocortisone equivalents was 16.9 +/- 0.9 mg/m2. Patients had lower BMD than controls at all measured sites (P < 0.001). In patients younger than 30 yr old, 48% were osteopenic vs. 12% in controls (P < 0.009). In patients 30 yr or older, 73% were osteopenic or osteoporotic vs. 21% in controls (P < 0.001). BMD was similar in the two classical forms and had no obvious relationship to genotypes. beta-C-telopeptide was decreased in older patients. More fractures were reported in patients than controls (P < 0.001). The number of vertebrae and wrist fractures almost reached significance (P = 0.058). CONCLUSIONS: Women with CAH have low BMD and increased fracture risk. BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.