Urban-Rural Differences in Hip Fracture Mortality: A Nationwide NOREPOS Study.

Higher hip fracture incidence in urban than in rural areas has been demonstrated, but urban-rural differences in posthip fracture mortality have been less investigated, and the results are disparate. Hence, the aims of the present register-based cohort study were to examine possible urban-rural differences in short- and long-term mortality in Norwegian hip fracture patients and their potential associations with sociodemographic variables, and to investigate possible urban-rural differences in excess mortality in hip fracture patients compared with the general population. Data were provided from the NOREPOS hip fracture database, the 2001 Population and Housing Census, and the National Registry. The urbanization degree in each municipality was determined by the proportion of inhabitants living in densely populated areas (rural: <1/3, semirural: 1/3 to 2/3, and urban: >2/3). Age-adjusted mortality rates and standardized mortality ratios were calculated for hip fracture patients living in rural, semirural, and urban municipalities. A flexible parametric model was used to estimate age-adjusted average and time-varying HRs by category of urbanization with the rural category as reference. Among 96,693 hip fracture patients, urban residents had higher mortality than their rural-dwelling counterparts. The HR of mortality in urban compared with rural areas peaked during the first 1 to 2 years postfracture with a maximum HR of 1.20 (95% CI, 1.10 to 1.30) in men and 1.15 (95% CI, 1.08 to 1.21) in women. The differences were significant during approximately 5 years after fracture. Adjusting for sociodemographic variables did not substantially change the results. However, absolute 30-day mortality was not significantly different between urban and rural residents, suggesting that health-care quality immediately postfracture does not vary by urbanization. The novel findings of a higher long-term mortality in urban hip fracture patients might reflect disparities in health status or lifestyle, differences in posthip fracture health care or rehabilitation, or a combination of several factors. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Vitamin B-6 Status Correlates with Disease Activity in Rheumatoid Arthritis Patients During Treatment with TNFα Inhibitors.

BACKGROUND: A frequent observation in inflammatory conditions, including rheumatoid arthritis (RA), is low circulating amounts of pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B-6. Recently, a functional marker of vitamin B-6 status, the ratio of 3-hydroxykynurenine (HK): xanthurenic acid (XA) in plasma (HK: XA), was proposed. OBJECTIVE: We investigated vitamin B-6 status in patients with RA before and after established treatment with TNFα inhibitors. METHODS: We performed a longitudinal study of RA patients (n = 106, 36% men, median age 54 y) starting first treatment with a TNFα inhibitor (infliximab, etanercept, adalimumab, golimumab, or certolizumab). Clinical assessment (Disease Activity Score for 28 standard joints, DAS28), joint ultrasonography, and blood draw were performed at baseline and after 3 mo treatment. Plasma concentrations of PLP, HK, and XA were measured by liquid chromatography-tandem mass spectrometry. Associations of changes in vitamin B-6 markers with change in DAS28 were assessed by generalized additive models regression and with European League Against Rheumatism (EULAR) response categories by linear regression. RESULTS: At baseline PLP was inversely correlated with CRP (ρ = -0.27, P = 0.007), whereas HK: XA correlated with DAS28 (ρ = 0.46, P < 0.001), CRP (ρ = 0.36, P < 0.001), and ultrasonography scores (ρ = 0.29-0.35, P ≤ 0.003). After 3 mo treatment, the change (a 33% overall reduction) in DAS28 was related to changes in both PLP (ß = -0.28, P = 0.01) and HK: XA (ß = 0.33, P < 0.001). Good responders (45%) according to EULAR criteria experienced a 31% increase in PLP (P = 0.003) and an 11% decrease in HK: XA (P = 0.1), whereas nonresponders (24%) experienced a 25% increase in HK: XA (P = 0.02). CONCLUSION: Two independent measures of vitamin B-6 status confirm an association with disease activity in RA patients. The association of HK: XA with disease activity may also imply perturbations in kynurenine metabolism in RA. This trial was registered at helseforskning.etikkom.no as 2011/490.

Feasibility of cardiovascular disease risk assessments in rheumatology outpatient clinics: experiences from the nationwide NOCAR project.

OBJECTIVE: The European League Against Rheumatism recommends implementing cardiovascular disease (CVD) risk assessments for patients with inflammatory joint diseases (IJDs) into clinical practice. Our goal was to design a structured programme for CVD risk assessments to be implemented into routine rheumatology outpatient clinic visits. METHODS: The NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR) started in April 2014 as a quality assurance project including 11 Norwegian rheumatology clinics. CVD risk factors were recorded by adding lipids to routine laboratory tests, self-reporting of CVD risk factors and blood pressure measurements along with the clinical joint examination. The patients' CVD risks, calculated by the European CVD risk equation SCORE, were evaluated by the rheumatologist. Patients with high or very high CVD risk were referred to their primary care physician for initiation of CVD preventive measures. RESULTS: Data collection (autumn 2015) showed that five of the NOCAR centres had implemented CVD risk assessments. There were 8789 patients eligible for CVD risk evaluation (rheumatoid arthritis (RA), 4483; ankylosing spondylitis (AS), 1663; psoriatic arthritis (PsA), 1928; unspecified and other forms of spondyloarthropathies (SpA), 715) of whom 41.4 % received a CVD risk assessment (RA, 44.7%; AS, 43.4%; PsA, 36.3%; SpA, 30.6%). Considerable differences existed in the proportions of patients receiving CVD risk evaluations across the NOCAR centres. CONCLUSION: Patients with IJD represent a patient group with a high CVD burden that seldom undergoes CVD risk assessments. The NOCAR project lifted the offer of CVD risk evaluation to over 40% in this high-risk patient population.

B Vitamins and Hip Fracture: Secondary Analyses and Extended Follow-Up of Two Large Randomized Controlled Trials.

Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine-lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two-by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B12 (0.4 mg); (3) vitamin B6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B6 . In conclusion, treatment with folic acid plus vitamin B12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). © 2017 American Society for Bone and Mineral Research.

Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation.

BACKGROUND: Few studies have assessed bone health in lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Therefore, we aimed to assess bone mineral density (BMD) at six different skeletal sites and to investigate associations between clinical factors and BMD in these survivors. MATERIAL AND METHODS: Eligible lymphoma survivors were aged ≥18 years at diagnosis and at HDT-ASCT given between 1987 and 2008. Participants responded to questionnaires, blood samples were drawn, and a dual energy X-ray absorptiometry (DXA) was performed. Mean Z-score was applied for assessment of BMD in relation to age. Prevalence of Z-scores ≥-1, between -1 and -2, and ≤-2 is reported for each measurement site and for the lumbar spine, femoral neck, and hip in combination. Likewise, T-scores were applied to assess the prevalence of normal BMD (≥-1), osteopenia (between -1 and -2.5), and osteoporosis (≤-2.5). RESULTS: We included 228 lymphoma survivors, of whom 62% were males. The median age at survey was 56 years, and median observation time from HDT-ASCT was eight years. Among males, Z-scores were lower at the left femoral neck and higher at the ultra-distal (UD) radius and whole body compared to the Lunar reference database. In females, Z-scores were lower at UD radius and one-third (33%) radius and higher at the whole body. Using a classification based on Z-scores at the lumbar spine, femoral neck, and hip in combination, 25% of males and 16% of females had Z-scores <-1 and >-2, while 8% and 6% had Z-scores ≤-2. According to T-scores, 35% of males and 41% of females had osteopenia, while 8% and 13% had osteoporosis, respectively. CONCLUSION: BMD was close to normal for age in this population of long-term lymphoma survivors treated with HDT-ASCT.

No increase in risk of hip fracture at high serum retinol concentrations in community-dwelling older Norwegians: the Norwegian Epidemiologic Osteoporosis Studies.

BACKGROUND: Norway has the highest hip fracture rates worldwide and a relatively high vitamin A intake. Increased fracture risk at high intakes and serum concentrations of retinol (s-retinol) have been observed in epidemiologic studies. OBJECTIVE: We aimed to study the association between s-retinol and hip fracture and whether high s-retinol may counteract a preventive effect of vitamin D. DESIGN: We conducted the largest prospective analysis of serum retinol and hip fracture to date in 21,774 men and women aged 65-79 y (mean age: 72 y) who attended 4 community-based health studies during 1994-2001. Incident hip fractures occurring up to 10.7 y after baseline were retrieved from electronic hospital discharge registers. Retinol determined by high-pressure liquid chromatography with ultraviolet detection in stored serum was available in 1154 incident hip fracture cases with valid body mass index (BMI) data and in a subcohort defined as a sex-stratified random sample (n = 1418). Cox proportional hazards regression weighted according to the stratified case-cohort design was performed. RESULTS: There was a modest increased risk of hip fracture in the lowest compared with the middle quintile of s-retinol (HR: 1.41; 95% CI: 1.09, 1.82) adjusted for sex and study center. The association was attenuated after adjustment for BMI and serum concentrations of α-tocopherol (HR: 1.16; 95% CI: 0.88, 1.51). We found no increased risk in the upper compared with the middle quintile. No significant interaction between serum concentrations of 25-hydroxyvitamin D and s-retinol on hip fracture was observed (P = 0.68). CONCLUSIONS: We found no evidence of an adverse effect of high serum retinol on hip fracture or any interaction between retinol and 25-hydroxyvitamin D. If anything, there tended to be an increased risk at low retinol concentrations, which was attenuated after control for confounders. We propose that cod liver oil, a commonly used food supplement in Norway, should not be discouraged as a natural source of vitamin D for fracture prevention.

Educational Inequalities in Post-Hip Fracture Mortality: A NOREPOS Study.

Hip fractures are associated with high excess mortality. Education is an important determinant of health, but little is known about educational inequalities in post-hip fracture mortality. Our objective was to investigate educational inequalities in post-hip fracture mortality and to examine whether comorbidity or family composition could explain any association. We conducted a register-based population study of Norwegians aged 50 years and older from 2002 to 2010. We measured total mortality according to educational attainment in 56,269 hip fracture patients (NORHip) and in the general Norwegian population. Both absolute and relative educational inequalities in mortality in people with and without hip fracture were compared. There was an educational gradient in post-hip fracture mortality in both sexes. Compared with those with primary education only, the age-adjusted relative risk (RR) of mortality in hip fracture patients with tertiary education was 0.82 (95% confidence interval [CI] 0.77-0.87) in men and 0.79 (95% CI 0.75-0.84) in women. Additional adjustments for Charlson comorbidity index, marital status, and number of children did not materially change the estimates. Regardless of educational attainment, the 1-year age-adjusted mortality was three- to fivefold higher in hip fracture patients compared with peers in the general population without fracture. The absolute differences in 1-year mortality according to educational attainment were considerably larger in hip fracture patients than in the population without hip fracture. Absolute educational inequalities in mortality were higher after hip fracture compared with the general population without hip fracture and were not mediated by comorbidity or family composition. Investigation of other possible mediating factors might help to identify new targets for interventions, based on lower educational attainment, to reduce post-hip fracture mortality.

Mortality following the first hip fracture in Norwegian women and men (1999-2008). A NOREPOS study.

Hip fractures are associated with increased mortality and their incidence in Norway is one of the highest worldwide. The aim of this nationwide study was to examine short- and long-term mortality after hip fractures, burden of disease (attributable fraction and potential years of life lost), and time trends in mortality compared to the total Norwegian population. Information on incident hip fractures between 1999 and 2008 in all persons aged 50 years and older was collected from Norwegian hospitals. Death and emigration dates of the hip fracture patients were obtained through 31 December 2010. Standardized mortality ratios (SMRs) were calculated and Poisson regression analyses were used for the estimation of time trends in SMRs. Among the 81,867 patients with a first hip fracture, the 1-year excess mortality was 4.6-fold higher in men, and 2.8-fold higher in women compared to the general population. Although the highest excess mortality was observed during the first two weeks post fracture, the excess risk persisted for twelve years. Mortality rates post hip fracture were higher in men compared to women in all age groups studied. In both genders aged 50 years and older, approximately 5% of the total mortality in the population was related to hip fractures. The largest proportion of the potential life-years lost was in the relatively young-old, i.e. less than 80 years. In men, the 1-year absolute mortality rates post hip fracture declined significantly between 1999 and 2008, by contrast, the mortality in women increased significantly relatively to the population mortality.

Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study.

BACKGROUND: Despite considerable interest, the relationship between circulating 25-hydroxyvitamin D and the risk of hip fracture is not fully established. OBJECTIVE: The objective of the study was to study the association between serum 25-hydroxyvitamin D concentrations [s-25(OH)D] and the risk of hip fracture in Norway, a high-latitude country that has some of the highest hip fracture rates worldwide. METHODS: A total of 21 774 men and women aged 65-79 years attended 4 community-based health studies during 1994-2001. Information on subsequent hip fractures was retrieved from electronic hospital discharge registers, with a maximum follow-up of 10.7 years. Using a stratified case-cohort design, s-25(OH)D was determined by HPLC-atmospheric pressure chemical ionization-mass spectrometry in stored serum samples in hip fracture cases (n = 1175; 307 men, 868 women) and in gender-stratified random samples (n = 1438). Cox proportional hazards regression adapted for the case-cohort design was performed. RESULTS: We observed an inverse association between s-25(OH)D and hip fracture; those with s-25(OH)D in the lowest quartile (<42.2 nmol/L) had a 38% [95% confidence interval (CI) 9-74%] increased risk of hip fracture compared with the highest quartile (≥67.9 nmol/L) in a model accounting for age, gender, study center, and body mass index. The association was stronger in men than in women: hazard ratio 1.65 (95% CI 1.04-2.61) vs hazard ratio 1.25 (95% CI 0.95-1.65). CONCLUSION: In this prospective case-cohort study of hip fractures, the largest ever reported, we found an increased risk of hip fracture in subjects in the lowest compared with the highest quartile of serum 25-hydroxyvitamin D. In accordance with the findings of previous community-based studies, low vitamin D status was a modest risk factor for hip fracture.

Evaluation of the body adiposity index in a Caucasian population: the Hordaland health study.

In this study, we compared the relationships of body mass index (BMI) and body adiposity index (BAI) with body fat percentage (BF%) in a Caucasian, European population. BF% was measured by dual-energy x-ray absorptiometry in a population-based cross-sectional study of 5,193 middle-aged (47-49 years) and elderly (71-74 years) men and women from the Hordaland Health Study in western Norway from 1997 to 1999. In the total population, the correlation between BAI and BF% was stronger (r = 0.78) than the correlation between BMI and BF% (r = 0.56) with similar results in the middle-aged and elderly groups. However, in men and women separately, BMI was a better correlate of BF% (for men, r = 0.76; for women, r = 0.81) than was BAI (for men, r = 0.57; for women, r = 0.72). BMI was also a better correlate of BF% than was BAI assessed by partial correlations adjusted for sex (for BMI-BF%, r = 0.79; for BAI-BF%, r = 0.67). Bland-Altman plots and BF%-stratified analyses showed that BAI tended to overestimate BF% in lean subjects and to underestimate it in those with higher proportions of body fat, but that it predicted BF% well for those whose BMI was in a normal range. At the individual level and in population studies adjusted for sex, BMI outperforms BAI as a predictor of BF%.

Plasma stearoyl-CoA desaturase indices: association with lifestyle, diet, and body composition.

OBJECTIVE: Stearoyl-coenzyme A desaturase-1 (SCD1) is a key enzyme in fatty acid and energy metabolism. Increased hepatic SCD1 activity is associated with obesity and obesity-related diseases. We examined the relations of two plasma SCD activity indices (16:1n-7/16:0, 18:1n-9/18:0) with body composition, and the association of lifestyle and dietary variables with the plasma SCD indices. DESIGN AND METHODS: This population-based, cross-sectional study of 2021 elderly (71-74 y) men and women from the Hordaland Health Study in Western Norway was conducted using a validated food frequency questionnaire, body composition measurements by dual-energy X-ray absorptiometry and determination of the plasma fatty acid profile. RESULTS: In multivariate regression analyses, plasma SCD indices were positively associated with BMI and body fat (P < 0.001 for both). From the 2.5th to 97.5th percentiles of plasma SCD-16 and SCD-18 indices, fat mass differed by about 8 kg and 5 kg, respectively. Intake of polyunsaturated fatty acids were negatively associated with SCD-16 (partial r = -0.30) and SCD-18 (partial r = -0.24) (P < 0.001 for both). Alcohol intake was positively associated with SCD-16 (partial r = 0.26) and SCD-18 (partial r = 0.16) (P < 0.001 for both), whereas coffee consumption and physical activity were inversely associated with SCD-16 (P = 0.026 and P = 0.006, respectively) and SCD-18 (P = 0.001 and P = 0.022, respectively). CONCLUSIONS: In this elderly population, plasma markers of SCD1 activity are associated with increased adiposity. Furthermore, modifiable dietary habits and lifestyle are associated with plasma SCD indices. These results suggest that SCD1 activity may be a promising target for weight control.

Ten-year risk of second hip fracture. A NOREPOS study.

BACKGROUND: Second hip fracture risk is elevated after the first, however whether risk differs with age, by sex or over time is not well known. OBJECTIVE: To examine the risk of second hip fracture by sex, age and time after first hip fracture. DESIGN: Data on all hip fractures in subjects 50 years and older and treated in Norwegian hospitals during 1999-2008 were retrieved. Surgical procedure codes and additional diagnosis codes were used to define incident fractures. Survival analyses with and without adjustment for competing risk of death were used to estimate the risk of second hip fracture. RESULTS: Among the 81,867 persons who sustained a first hip fracture, 6161 women and 1782 men suffered a second hip fracture during follow-up. The overall age-adjusted hazard ratio (HR) of a second hip fracture did not differ between the sexes (women versus men, HR=1.03; 95% confidence interval (CI): 0.98-1.09). Taking competing risk of death into account, the corresponding age-adjusted HR of a second hip fracture was 1.40 (95% CI: 1.33-1.47) in women compared to men. The greater risk in women was due to a higher mortality in men. Based on competing risk analyses, we estimate that 15% of women and 11% of men will have suffered a second hip fracture within 10 years after the first hip fracture. The ten-year cumulative incidence was above 10% in all age-groups, except in men 90 years and older. CONCLUSION: Fracture preventive strategies have a large potential in both women and men who suffer their first hip fracture due to the high risk of another hip fracture.

Serum level of under-carboxylated osteocalcin and bone mineral density in early menopausal Norwegian women.

PURPOSE: Serum level of under-carboxylated osteocalcin (ucOC) is considered a sensitive measure of vitamin K status, and ucOC levels are associated with bone mineral density (BMD) and fracture risk in elderly persons. The aim of this study was to assess the relationship between ucOC and BMD in early menopausal women. METHODS: The data reported here come from the enrollment in a double-blinded placebo-controlled randomized trial comprising 334 healthy Norwegian women between 50 and 60 years, 1-5 years after menopause, not using warfarin or medication known to affect bone metabolism. Total hip, femoral neck, lumbar spine, and total body BMD and serum level of ucOC and total osteocalcin were measured, and information of lifestyle was collected through questionnaires. The association between ucOC and BMD at all measurement sites was assessed by multiple regression analyses adjusting for possible confounding variables. RESULTS: The absolute serum level of ucOC was significantly and negatively associated with BMD at all measurements sites, both in univariate analyses (p < 0.01) and in multivariate analyses adjusting for years since menopause, smoking status and weight (p < 0.01). However, serum ucOC, expressed as percentage of the total osteocalcin level, was not associated with BMD at any site. CONCLUSIONS: Achievement of adequate vitamin K nutritional intake is important, but ucOC expressed as percentage of total osteocalcin levels as reflection of vitamin K status does not seem to play a central role in determining BMD levels in early menopausal women.

Hip fractures in Norway 1999-2008: time trends in total incidence and second hip fracture rates: a NOREPOS study.

Declining incidences of hip fractures are reported from western countries. Norway has among the highest rates in the world. The aim of this study was to investigate trends in total hip fracture rates in Norway between 1999 and 2008 and risk of second hip fractures. All hospitalizations given a hip fracture diagnosis code (International Classification of Diseases (ICD) 9 or ICD 10) (cervical, trochanteric or subtrochanteric) in Norwegian hospitals were retrieved with accompanying surgical procedure codes and additional diagnoses. A total of 93,123 hip fractures were identified between 1999 and 2008 in persons ≥50 years. Annual incidences of hip fractures were calculated and tested for trends. Rates of first and second hip fractures (2006-2008) were compared. The age-standardized total incidence of hip fracture decreased by 13.4 % (95 % confidence interval (CI): 11.0-15.6) in women and 4.8 % (95 % CI: 0.7, 8.7) in men. Age-adjusted rates of second hip fractures did not change in the observation period. In those with a prior hip fracture, the age-standardized risk of a subsequent hip fracture was 2.5-fold (95 % CI: 2.5, 2.6) in women, and 4.6-fold (95 % CI: 4.5, 4.7) in men. Total hip fracture rates declined in both genders during 1999-2008, whereas rates of second hip fractures did not change.

Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland Health Study.

BACKGROUND: Evidence of the effect of vitamin K on bone health is conflicting. The aim was to investigate the association between intake of vitamins K1 and K2 and subsequent risk of hip fracture in a general population sample, as well as potential effect modification by apolipoprotein E gene (APOE) status by presence of the E4 allele. METHODS: 1238 men and 1569 women 71-75 years of age were included in the community-based Hordaland Health Study 1997-1999 in Western Norway. Information on hip fracture was obtained from hospitalizations in the region from enrolment until 31 December 2009. Information on intake of vitamins K1 and K2 collected at baseline was used as potential predictors of hip fracture in Cox proportional hazards regression analyses. RESULTS: Participants in the lowest compared to the highest quartile of vitamin K1 intake had increased risk of suffering a hip fracture (hazard ratio (HR)=1.57 [95% CI 1.09, 2.26]). Vitamin K2 intake was not associated with hip fracture. Presence of APOE4-allele did not increase the risk of hip fracture, nor was there any effect modification with vitamin K1 in relation to risk of hip fracture. CONCLUSIONS: A low intake of vitamin K1, but not K2, was associated with an increased risk of hip fractures.

Dietary intake of protein is positively associated with percent body fat in middle-aged and older adults.

Data on associations between dietary intake of macronutrients and body composition in the general population are sparse. This population-based, cross-sectional study of 4478 middle-aged (47-49 y) and elderly (71-74 y) men and women from the Hordaland Health Study in western Norway was conducted using a validated FFQ and measurements by dual-energy X-ray absorptiometry. The relation between macronutrient intake [percentage of total energy intake (E%)] and percent body fat was investigated in the total population and in a subgroup with intermediate BMI and stable weight (BMI within the 25th-75th percentile and weight change <5% during the last 6 y; n = 975). In the total population, protein intake (E%) was associated with higher percent body fat (partial r = 0.11; P < 0.001) in multivariate linear regression analysis. In the subgroup with intermediate BMI and stable weight, there was no association between protein intake (E%) and percent body fat. Fat intake (E%) was positively associated (partial r = 0.07) whereas carbohydrate intake (E%) was inversely associated (partial r = -0.07) with percent body fat (P = 0.042 for both) in the subgroup with intermediate BMI and stable weight. Both in the total population and in the stable weight group, physical activity was inversely related to adiposity (partial r = -0.15 and -0.12, respectively; P < 0.001). Our results may explain some of the conflicting data on the effects of macronutrients in different populations and suggest the potential importance of protein intake as a factor in obesity.

More forearm fractures among urban than rural women: the NOREPOS study based on the Tromsø study and the HUNT study.

Higher rates of hip fracture and all fractures combined have been observed in urban compared with rural areas, but whether there are urban-rural differences in distal forearm fracture rates is less studied. The aim of this longitudinal study was to compare the incidence of forearm fracture in postmenopausal women in urban and rural areas in Norway and to investigate risk factors that could explain potential fracture differences. The study included data from 11,209 women aged 65 years or more who participated in two large health studies, the Tromsø Health Study in 1994-1995 and the Nord-Trøndelag Health Study in 1995-1997. Forearm bone mineral density (BMD) was measured by single-energy X-ray absorptiometry in a subsample of women (n = 7333) at baseline. All women were followed with respect to hospital-verified forearm fractures (median follow-up 6.3 years). A total of 9249 and 1960 women lived in areas classified as rural and urban, respectively. Urban women had an increased forearm fracture risk [relative risk (RR) = 1.29, 95% confidence interval (CI) 1.09-1.52] compared with women in rural areas. Rural women had higher body mass index (BMI) than urban women, and the RR was moderately reduced to 1.21 (95% CI 1.02-1.43) after BMI adjustments. Rural women had the highest BMD. In the subgroup with measured BMD, adjustments for BMD changed the urban versus rural RR from 1.21 (95% CI 0.96-1.52) to 1.05 (95% CI 0.83-1.32), suggesting that BMD is an important explanatory factor. In conclusion, higher rates of forearm fractures was found in urban compared with rural women.

Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene.

PURPOSE: To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS). METHODS: Eight family members in three generations underwent ophthalmic, dental, and general medical examinations, including radiologic examination of the spine. Bone mineral density (BMD) and serum levels of vitamin D, parathyroid hormone, and biochemical markers for bone turnover were measured. Skin biopsies were examined by light and transmission electron microscopy. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and MC1R genotyping. RESULTS: At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced BMD, dental anomalies, hearing loss, and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c.10016G>A, that was predicted to affect the fourth of the five zinc finger domains of ZNF469 by changing the first cysteine to a tyrosine (p.Cys3339Tyr). Both affected individuals were homozygous for the common red hair variant R151C at the MC1R locus. CONCLUSIONS: BCS is a disorder that affects a variety of connective tissues. Reduced BMD and atypical dental crown morphology have not been reported previously. The results confirm that BCS is associated with mutations in ZNF469. The association with red hair in some individuals with BCS is likely to occur by chance.

Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone.

UNLABELLED: Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone. OBJECTIVE: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105). MAIN OUTCOME MEASURES: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity. RESULTS: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine. CONCLUSIONS: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.

Neurological features and enzyme therapy in patients with endocrine and exocrine pancreas dysfunction due to CEL mutations.

OBJECTIVE: To further define clinical features associated with the syndrome of diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase (CEL) gene and to assess the effects of pancreatic enzyme substitution therapy. RESEARCH DESIGN AND METHODS: Nine patients with CEL gene mutation, exocrine deficiency, and diabetes were treated and followed for 30 months. RESULTS: Treatment improved symptoms in seven of nine patients. Exocrine and endocrine function assessed by fecal elastase and A1C were not affected, although fecal lipid excretion was reduced. Vitamin E was low in all patients but increased with treatment (P < 0.001 at 30 months) and improved in five subjects. A predominantly demyelinating neuropathy was seen in a majority of patients, and carpal tunnel syndrome was common. CONCLUSIONS: Pancreatic enzyme substitution alleviated symptoms and malabsorption and normalized vitamin E levels. Glycemic control was not significantly affected. The CEL syndrome seems associated with a demyelinating neuropathology.