Determinants of trabecular bone score and prevalent vertebral fractures in women with fragility fractures: a cross-sectional sub-study of NoFRACT.

Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1-SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1-SQ3 fractures. SQ1-SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS. INTRODUCTION: Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1-SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1-SQ3 fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1-SQ3 fracture assessed. RESULTS: Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1-SQ3 fractures. In multiple variable analysis, higher age (ßper SD = - 0.26, 95% CI: - 0.36,- 0.15), parental hip fracture (ß = - 0.29, 95% CI: - 0.54,- 0.05), and daily alcohol intake (ß = - 0.43, 95% CI - 0.79, - 0.08) were associated with lower TBS. Higher BMD of femoral neck (ßper SD = 0.34, 95% CI 0.25-0.43) and lumbar spine (ßper SD = 0.40, 95% CI 0.31-0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (ORper SD = 1.94, 95% CI 1.51-2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09-2.71) were positively associated with SQ1-SQ3 fractures, while lumbar spine BMD (ORper SD = 0.75 95% CI 0.60-0.95) was negatively associated with SQ1-SQ3 fractures. No association between TBS and SQ1-SQ3 fractures was found. CONCLUSION: Since TBS and SQ1-SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment.

A combination of low serum concentrations of vitamins K1 and D is associated with increased risk of hip fractures in elderly Norwegians: a NOREPOS study.

UNLABELLED: The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures. INTRODUCTION: This case-cohort study aims to investigate the associations between serum vitamin K1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association. METHODS: The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994-2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases (n = 1090) and in a randomly selected subcohort (n = 1318). Cox proportional hazards regression with quartiles of serum vitamin K1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K1 ≥ 0.76 and 25(OH)D ≥ 50 nmol/l, II: vitamin K1 ≥ 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K1 < 0.76 and 25(OH)D ≥ 50 nmol/l, and IV: vitamin K1 < 0.76 and 25(OH)D < 50 nmol/l. RESULTS: Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18-1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum α-tocopherol. No increased risk was observed in the groups low in one vitamin only. CONCLUSION: Combination of low concentrations of vitamin K1 and 25(OH)D is associated with increased risk of hip fractures.

Plasma dimethylglycine, nicotine exposure and risk of low bone mineral density and hip fracture: the Hordaland Health Study.

UNLABELLED: In the large community-based Hordaland Health Study, low plasma dimethylglycine was associated with low bone mineral density in both middle-aged and elderly subjects and to an increased risk of subsequent hip fracture among the elderly. These associations seemed to be particularly strong among subjects exposed to nicotine. INTRODUCTION: Dimethylglycine (DMG) is a product of the choline oxidation pathway and formed from betaine during the folate-independent remethylation of homocysteine (Hcy) to methionine. Elevated plasma DMG levels are associated with atherosclerotic cardiovascular disease and inflammation, which in turn are related to osteoporosis. High plasma total Hcy and low plasma choline are associated with low bone mineral density (BMD) and hip fractures, but the role of plasma DMG in bone health is unknown. METHODS: We studied the associations of plasma DMG with BMD among 5315 participants (46-49 and 71-74 years old) and with hip fracture among 3310 participants (71-74 years old) enrolled in the Hordaland Health Study. RESULTS: In age and sex-adjusted logistic regression models, subjects in the lowest versus highest DMG tertile were more likely to have low BMD (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.43-1.99). The association was stronger in participants exposed compared to those unexposed to nicotine (OR 2.31, 95% CI 1.73-3.07 and OR 1.43, 95% CI 1.16-1.75, respectively, p interaction = 0.008). In the older cohort, Cox regression analyses adjusted for sex showed that low plasma DMG was associated with an increased risk of hip fracture (hazard ratio [HR] 1.70, 95% CI 1.28-2.26). A trend toward an even higher risk was found among women exposed to nicotine (HR 3.41, 95% CI 1.40-8.28). CONCLUSION: Low plasma DMG was associated with low BMD and increased risk of hip fractures. A potential effect modification by nicotine exposure merits particular attention.

Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture. A NOREPOS study.

UNLABELLED: We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51% higher risk in the lowest compared to the highest quartile. INTRODUCTION: Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up. METHODS: We performed a case-cohort analysis among 21,774 men and women aged 65-79 years who participated in four community-based health studies in Norway 1994-2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n = 1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed. RESULTS: Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) µmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95% confidence interval (CI) 1.04-1.20) per 10-µmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95% CI 1.17-1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95% CI 1.05-1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio. CONCLUSIONS: Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.

Interferon gamma (IFN-γ)-mediated inflammation and the kynurenine pathway in relation to risk of hip fractures: the Hordaland Health Study.

UNLABELLED: The cytokine interferon gamma (IFN-γ) stimulates neopterin release and tryptophan degradation into kynurenines through the kynurenine pathway. High levels of neopterin were associated with increased hip fracture risk, as were some of the kynurenines, suggesting a role of IFN-γ-mediated inflammation in the processes leading to hip fracture. INTRODUCTION: Low-grade systemic inflammation has been associated with bone loss and risk of fractures. Interferon gamma (IFN-γ) initiates macrophage release of neopterin and also stimulates degradation of tryptophan along the kynurenine pathway as part of cell-mediated immune activation. Plasma neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Risk of hip fracture was investigated in relation to markers of inflammation and metabolites in the kynurenine pathway (kynurenines). METHODS: Participants (71 to 74 years, N = 3,311) in the community-based Hordaland Health Study (HUSK) were followed for hip fractures from enrolment (1998-2000) until 31 December 2009. Plasma C-reactive protein (CRP), neopterin, KTR, and six kynurenines were investigated as predictors of hip fracture, using Cox proportional hazards regression analyses. RESULTS: A hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.3-2.7) for hip fracture was found in the highest compared to the lowest quartile of neopterin (p trend across quartiles <0.001). CRP and KTR were not related to hip fracture risk. Among the kynurenines, a higher risk of fracture was found in the highest compared to the lowest quartiles of anthranilic acid and 3-hydroxykynurenine. For subjects in the highest quartiles of neopterin, CRP, and KTR compared to those in no top quartiles, HR was 2.5 (95% CI 1.6-4.0). CONCLUSIONS: This may indicate a role for low-grade immune activation in the pathogenic processes leading to hip fracture.

Procollagen type 1 amino-terminal propeptide (P1NP) and risk of hip fractures in elderly Norwegian men and women. A NOREPOS study.

The current study aimed to assess a possible association between the bone turnover marker procollagen type 1 amino-terminal propeptide (P1NP) and future hip fractures in elderly Norwegian men and women and to elucidate the relation between P1NP, bone mineral density and 25-hydroxyvitamin D (25(OH)D). Men and women aged 71 to 77 from two population based health studies in Norway (1999-2001) were followed for a median period of 7.3 years with respect to hip fractures. The study was designed as a case-cohort study. P1NP and 25(OH)D were analysed in frozen serum samples obtained at baseline in hip fracture patients (n=340) and in randomly selected sex stratified sub-cohorts. Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) in a subset of participants. Cox proportional hazards regression with inverse probability weighting and robust variance was performed. No significant correlation between 25(OH)D and P1NP was found. A negative correlation between P1NP and BMD was observed in women (Rho=-0.36, p=0.001). A similar trend was observed in men. No association between quartiles of P1NP and rate of subsequent hip fractures was found. Spline analyses suggested a higher rate of hip fracture at P1NP levels above 60 µg/L in both men and women. A higher hip fracture rate, which was independent of BMD, was also indicated in women with very low levels of P1NP.

Interferon (IFN)-γ-mediated inflammation and the kynurenine pathway in relation to bone mineral density: the Hordaland Health Study.

The risk of osteoporosis increases in inflammatory disorders. In cell-mediated immune activation, interferon (IFN)-γ stimulates macrophage release of neopterin and increases the activity of indoleamine 2,3-dioxygenase (IDO), thereby stimulating tryptophan degradation along the kynurenine pathway. Plasma levels of neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Several kynurenine pathway metabolites (kynurenines) possess immunomodulatory properties. The aim of this study was to investigate associations between markers of IFN-γ-mediated inflammation and kynurenines with bone mineral density (BMD). The community-based Hordaland Health Study (HUSK), with middle-aged (46-49 years) and older (71-74 years) participants, was conducted from 1998 to 2000 (n = 5312). Hip BMD in relation to neopterin, KTR and kynurenines were investigated, using linear and logistic regression analyses. In the oldest group, neopterin (P ≤ 0·019) and KTR (P ≤ 0·001) were associated inversely with BMD after multiple adjustment. Comparing the highest to the lowest quartiles, the odds ratios of low BMD (being in the lowest quintile of BMD) in the oldest cohort were for neopterin 2·01 among men and 2·34 among women (P ≤ 0·007) and for KTR 1·80 for men and 2·04 for women (P ≤ 0·022). Xanthurenic acid was associated positively with BMD in all sex and age groups while 3-hydroxyanthranilic acid was associated positively with BMD among women only (P ≤ 0·010). In conclusion, we found an inverse association between BMD and markers of IFN-γ-mediated inflammation in the oldest participants. BMD was also associated with two kynurenines in both age groups. These results may support a role of cell-mediated inflammation in bone metabolism.

Low-energy distal radius fractures in middle-aged and elderly men and women--the burden of osteoporosis and fracture risk : A study of 1794 consecutive patients.

UNLABELLED: One third of 218 men and half of 1,576 women with low-energy distal radius fractures met the bone mineral density (BMD) criteria for osteoporosis treatment. A large proportion of patients with increased fracture risk did not have osteoporosis. Thus, all distal radius fracture patients >or=50 years should be referred to bone densitometry. INTRODUCTION: Main objectives were to determine the prevalence of patients with a low-energy distal radius fracture in need of osteoporosis treatment according to existing guidelines using T-score or=50 years were included. BMD was assessed by dual energy X-ray absorptiometry (DXA) at femoral neck, total hip, and lumbar spine (L2-L4). The WHO fracture risk assessment tool (FRAX(R)) was applied to calculate the 10-year fracture risk. RESULTS: T-scores or=50 years should be referred to bone densitometry, and if indicated, offered medical treatment.