Association of renal function with bone mineral density and fracture risk in the Longitudinal Aging Study Amsterdam.

Early renal dysfunction is associated with a 38% increased fracture risk in individuals aged 65 years and older. In men but not women, early renal dysfunction is associated with decreased femoral neck bone mineral density (BMD) which can be partially explained by increased parathyroid hormone (PTH) concentrations. INTRODUCTION: It is uncertain whether early renal dysfunction is associated with osteoporosis and increased fracture risk. The aim of this study was to determine the relationship of decreased renal function with BMD and fracture risk and the role of PTH therein. METHODS: We analyzed data of participants aged 65 years and older from the Longitudinal Aging Study Amsterdam. A 6-year fracture follow-up was obtained in 1477 participants. BMD was measured by dual-energy x-ray absorptiometry (n = 535) and vertebral fractures by lateral spinal radiograph (n = 527) in a subsample at baseline. Glomerular filtration rate (eGFR) was estimated according to the modification of diet in renal disease equation and assessed by the five stages of chronic kidney disease (CKD). RESULTS: In men and women, eGFR < 57 ml/min/1.73 m2 (lowest quartile) compared to eGFR > 74 ml/min/1.73 m2 (highest quartile) was associated with a 38% increase in fracture risk after adjustment for relevant confounders [hazard ratio (95%CI): 1.38 (1.17 to 1.61)]. Also, CKD stages 3a and 3b were associated to a 28 and 46% increase in fracture risk, respectively, as compared to CKD stages 1 and 2 together (eGFR > 60 ml/min/1.73 m2) after adjustment for confounders. Renal function was not associated with prevalent vertebral fractures. In men, but not women, lowest quartile of eGFR was related to lower femoral neck BMD as compared to the highest quartile eGFR [unstandardized B (95%CI) - 0.052 g/cm2 (- 0.098 to - 0.006)], after adjustment for relevant confounders. Further adjustment for PTH attenuated this relationship by 27%. CONCLUSIONS: In men and women, early decreased renal function (eGFR < 60 ml/min/1.73 m2) was related to increased incident any fracture risk but not with increased prevalence of vertebral fractures. In men, but not women, early renal dysfunction was related to lower femoral neck BMD which could statistically be partially explained by increased PTH concentrations.

Prediction of insufficient serum vitamin D status in older women: a validated model.

We developed an externally validated simple prediction model to predict serum 25(OH)D levels < 30, < 40, < 50 and 60 nmol/L in older women with risk factors for fractures. The benefit of the model reduces when a higher 25(OH)D threshold is chosen. INTRODUCTION: Vitamin D deficiency is associated with increased fracture risk in older persons. General supplementation of all older women with vitamin D could cause medicalization and costs. We developed a clinical model to identify insufficient serum 25-hydroxyvitamin D (25(OH)D) status in older women at risk for fractures. METHODS: In a sample of 2689 women ≥ 65 years selected from general practices, with at least one risk factor for fractures, a questionnaire was administered and serum 25(OH)D was measured. Multivariable logistic regression models with backward selection were developed to select predictors for insufficient serum 25(OH)D status, using separate thresholds 30, 40, 50 and 60 nmol/L. Internal and external model validations were performed. RESULTS: Predictors in the models were as follows: age, BMI, vitamin D supplementation, multivitamin supplementation, calcium supplementation, daily use of margarine, fatty fish ≥ 2×/week, ≥ 1 hours/day outdoors in summer, season of blood sampling, the use of a walking aid and smoking. The AUC was 0.77 for the model using a 30 nmol/L threshold and decreased in the models with higher thresholds to 0.72 for 60 nmol/L. We demonstrate that the model can help to distinguish patients with or without insufficient serum 25(OH)D levels at thresholds of 30 and 40 nmol/L, but not when a threshold of 50 nmol/L is demanded. CONCLUSIONS: This externally validated model can predict the presence of vitamin D insufficiency in women at risk for fractures. The potential clinical benefit of this tool is highly dependent of the chosen 25(OH)D threshold and decreases when a higher threshold is used.

Design of the SALT Osteoporosis Study: a randomised pragmatic trial, to study a primary care screening and treatment program for the prevention of fractures in women aged 65 years or older.

BACKGROUND: Several drugs have become available for the treatment of osteoporosis. However, screening and treatment of patients with a high fracture risk is currently not recommended in the Netherlands, because the effectiveness of bone sparing drugs has not been demonstrated in the general primary care population. Here we describe the design of the SALT Osteoporosis study, which aims to examine whether the screening and treatment of older, female patients in primary care can reduce fractures, in comparison to usual care. METHODS: A randomised pragmatic trial has been designed using a stepwise approach in general care practices in the Netherlands. Women aged ≥65 years, who are not prescribed bone sparing drugs or corticosteroids are eligible for the study. First, women with at least one clinical risk factor for fractures, as determined by questionnaires, are randomly assigned to the intervention or control group. Second, women in the intervention group having a high fracture risk according to our screening program, including an adapted fracture risk assessment (FRAX) tool, combined with dual-energy x-ray absorptiometry (DXA), and instant vertebral assessment (IVA), are offered a structured treatment program. The women in the control group receive care as usual and will undergo the same screening as the intervention group at the end of the trial. The follow-up duration will be three years and the primary outcome is time to first incident fracture and the total number of fractures. DISCUSSION: The results of the current study will be very important for underpinnings of the prevention strategy of the osteoporosis guidelines. TRIAL REGISTRATION: ID NTR2430 . Registered 26 July 2010.

Effects of 1,25(OH)2 D3 and 25(OH)D3 on C2C12 Myoblast Proliferation, Differentiation, and Myotube Hypertrophy.

An adequate vitamin D status is essential to optimize muscle strength. However, whether vitamin D directly reduces muscle fiber atrophy or stimulates muscle fiber hypertrophy remains subject of debate. A mechanism that may affect the role of vitamin D in the regulation of muscle fiber size is the local conversion of 25(OH)D to 1,25(OH)2 D by 1α-hydroxylase. Therefore, we investigated in a murine C2C12 myoblast culture whether both 1,25(OH)2 D3 and 25(OH)D3 affect myoblast proliferation, differentiation, and myotube size and whether these cells are able to metabolize 25(OH)D3 and 1,25(OH)2 D3 . We show that myoblasts not only responded to 1,25(OH)2 D3 , but also to the precursor 25(OH)D3 by increasing their VDR mRNA expression and reducing their proliferation. In differentiating myoblasts and myotubes 1,25(OH)2 D3 as well as 25(OH)D3 stimulated VDR mRNA expression and in myotubes 1,25(OH)2 D3 also stimulated MHC mRNA expression. However, this occurred without notable effects on myotube size. Moreover, no effects on the Akt/mTOR signaling pathway as well as MyoD and myogenin mRNA levels were observed. Interestingly, both myoblasts and myotubes expressed CYP27B1 and CYP24 mRNA which are required for vitamin D3 metabolism. Although 1α-hydroxylase activity could not be shown in myotubes, after treatment with 1,25(OH)2 D3 or 25(OH)D3 myotubes showed strongly elevated CYP24 mRNA levels compared to untreated cells. Moreover, myotubes were able to convert 25(OH)D3 to 24R,25(OH)2 D3 which may play a role in myoblast proliferation and differentiation. These data suggest that skeletal muscle is not only a direct target for vitamin D3 metabolites, but is also able to metabolize 25(OH)D3 and 1,25(OH)2 D3 . J. Cell. Physiol. 231: 2517-2528, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Regulation of CYP27B1 mRNA Expression in Primary Human Osteoblasts.

The enzyme 1α-hydroxylase (gene CYP27B1) catalyzes the synthesis of 1,25(OH)2D in both renal and bone cells. While renal 1α-hydroxylase is tightly regulated by hormones and 1,25(OH)2D itself, the regulation of 1α-hydroxylase in bone cells is poorly understood. The aim of this study was to investigate in a primary human osteoblast culture whether parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), calcitonin, calcium, phosphate, or MEPE affect mRNA levels of CYP27B1. Our results show that primary human osteoblasts in the presence of high calcium concentrations increase their CYP27B1 mRNA levels by 1.3-fold. CYP27B1 mRNA levels were not affected by PTH1-34, rhFGF23, calcitonin, phosphate, and rhMEPE. Our results suggest that the regulation of bone 1α-hydroxylase is different from renal 1α-hydroxylase. High calcium concentrations in bone may result in an increased local synthesis of 1,25(OH)2D leading to an enhanced matrix mineralization. In this way, the local synthesis of 1,25(OH)2D may contribute to the stimulatory effect of calcium on matrix mineralization.

Vitamin D status and health-related quality of life in patients with Type 2 diabetes.

AIMS: To test whether vitamin D status was associated with health-related quality of life in people with Type 2 diabetes mellitus. METHODS: Demographic and clinical characteristics, including health-related quality of life scores, were obtained from 241 adult patients with Type 2 diabetes managed with oral hypoglycaemic agents. Health-related quality of life was assessed using the Short-Form 36 Health Survey. Multiple logistic regression analysis was used to investigate the association between vitamin D status and health-related quality of life, with adjustment for confounders. RESULTS: The mean age of the patients included in the study was 67 ± 8 years. Their mean HbA1c concentration was 52 ± 8 mmol/mol (6.9 ± 0.7%) and their mean serum 25-hydroxyvitamin D concentration was 59 ± 23 nmol/l. Vitamin D deficiency (serum 25-hydroxyvitamin D < 50 nmol/l) was present in 38% of patients. No significant associations were found between vitamin D status and health-related quality of life. CONCLUSIONS: Vitamin D status was not associated with health-related quality of life in patients with Type 2 diabetes. This could be explained by the relatively high serum 25-hydroxyvitamin D concentration, good glycaemic control and relatively good health-related quality of life of all patients. A prospective study among patients with vitamin D deficiency and poor glycaemic control would be interesting for future research.

Arterial stiffness is not associated with bone parameters in an elderly hyperhomocysteinemic population.

Several studies have observed positive associations between bone disease and cardiovascular disease. A potential common pathway is hyperhomocysteinemia; however, to date, there is a lack of data regarding hyperhomocysteinemic populations. Therefore, we examined both cross-sectionally and longitudinally, whether there is an association between bone parameters and arterial stiffness in a hyperhomocysteinemic population, and investigated the potential common role of homocysteine (hcy) level on these associations. Cross-sectional and longitudinal data of the B-PROOF study were used (n = 519). At both baseline and 2-year follow-up we determined bone measures-incident fractures and history of fractures, bone-mineral density (BMD) and quantitative ultrasound (QUS) measurement. We also measured arterial stiffness parameters at baseline-pulse wave velocity, augmentation index and aortic pulse pressure levels with applanation tonometry. Linear regression analysis was used to examine these associations and we tested for potential interaction of hcy level. The mean age of the study population was 72.3 years and 44.3 % were female. Both cross-sectionally and longitudinally there was no association between arterial stiffness measures and BMD or QUS measurements or with incident fractures (n = 16) within the 2-3 years of follow-up. Hcy level did not modify the associations and adjustment for hcy did not change the results. Arterial stiffness was not associated with bone parameters and fractures, and hcy neither acted as a pleiotropic factor nor as a mediator. The potential association between bone and arterial stiffness is therefore not likely to be driven by hyperhomocysteinemia.

Low vitamin D status is associated with more depressive symptoms in Dutch older adults.

PURPOSE: The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged ≥65 years. METHODS: 25-Hydroxyvitamin D (25(OH)D) was measured, and five 'vitamin D-related genes' were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. RESULTS: A clear cross-sectional and prospective association between serum 25(OH)D and depressive symptom score was observed. Fully adjusted models indicated a 22 % (RR 0.78, 95 % CI 0.68-0.89), 21 % (RR 0.79, 95 % CI 0.68-0.90), and 18 % (RR 0.82, 95 % CI 0.71-0.95) lower score of depressive symptoms in people in the second, third, and fourth 25(OH)D quartiles, when compared to people in the first quartile (P for trend <0.0001). After 2 years of daily 15 µg vitamin D supplementation, similar associations were observed. 25(OH)D concentrations did not significantly interact with the selected genes. CONCLUSION: Low serum 25(OH)D was associated with higher depressive symptom scores. No interactions between 25(OH)D concentrations and vitamin D genetic make-up were observed. In view of the probability of reverse causation, we propose that the association should be further examined in prospective studies as well as in randomized controlled trials.

Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning.

BACKGROUND: Vitamin D deficiency is common in older persons. The objectives of this study were: To examine the cross-sectional and longitudinal association between serum 25-hydroxyvitamin D (25(OH)D) and cognitive functioning in older persons; and to explore the optimal cut-off for serum 25(OH)D. METHODS: Data of the Longitudinal Aging Study Amsterdam (LASA) were used. Serum 25(OH)D was determined using a competitive protein binding assay in 1995/6 (n = 1,320). Cognitive functioning was assessed in 1995/6 and 1998/9 using the Mini-Mental State Examination (MMSE, general cognitive functioning), Raven's Colored Progressive Matrices (RCPM, ability of nonverbal and abstract reasoning), the Coding Task (CT, information processing speed), and the 15 Words Test (15WT, immediate memory and delayed recall). The data were analyzed using linear regression analyses and restricted cubic spline functions. The MMSE was normalized using ln(31-MMSE). RESULTS: Mean serum 25(OH)D was 53.7 nmol/L. After adjustment for confounding, patients with serum 25(OH)D levels below 30 nmol/L had significantly lower general cognitive functioning (beta of ln(31-MMSE) = 0.122; p = 0.046) and slower information processing speed (beta = -2.177, p = 0.001) as compared with patients having serum 25(OH)D levels ≥ 75 nmol/L in the cross-sectional analyses. For both outcomes, the optimal cut-off was about 60 nmol/L. No other significant associations were observed. CONCLUSIONS: A lower serum 25(OH)D was significantly associated with lower general cognitive functioning and slower information processing speed, but not with a faster rate of cognitive decline.

Osteocalcin and the pituitary-gonadal axis in older men: a population-based study.

OBJECTIVE: Osteocalcin is a well-known marker of bone formation. Recently, mice lacking osteocalcin or its receptor were reported to be subfertile with low testosterone and high luteinizing hormone concentrations. In parallel, in humans, a loss-of-function mutation of the osteocalcin receptor was associated with hypergonadotropic hypogonadism. This suggests that osteocalcin is necessary for normal pituitary-gonadal axis function. Our objective was to determine the association between physiological variations in osteocalcin and the pituitary-gonadal axis in older men. DESIGN AND PATIENTS: Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a representative sample of the older Dutch population (65-88 years). MEASUREMENTS: Serum levels of total (T), free (FT) and bioavailable (bioT) testosterone, luteinizing hormone (LH) and osteocalcin were determined. Data were analysed using linear regression analyses and adjusted for age, BMI, 25-hydroxyvitamin D, parathyroid hormone and vitamin K antagonist use. RESULTS: A total of 614 men participated in the study. The median age was 75·4 (69·8-81·2) years, and the median osteocalcin level was 1·8 (1·3-2·4) nmol/l. Serum osteocalcin was inversely associated with FT (adjusted B = -0·22 ± 0·09 ng/dl, P = 0·012) and bioT (adjusted B = -0·26 ± 0·08 nmol/l, P < 0·01), but not with total T. Furthermore, osteocalcin was positively associated with LH (adjusted B = 0·09 ± 0·03 U/l, P < 0·01). CONCLUSIONS: Serum osteocalcin was negatively associated with free and bioavailable testosterone and positively with luteinizing hormone levels.

Vitamin D status is associated with skin autofluorescence in patients with type 2 diabetes mellitus: a preliminary report.

BACKGROUND: Skin autofluorescence is a non-invasive measurement of advanced glycation end products (AGE), which are suggested to be one of the major agents in the pathogenesis and progression of diabetes related cardiovascular complications. Recently, low vitamin D status has been linked to the progression of type 2 diabetes mellitus (T2DM) and cardiovascular disease. The aim of this study is to investigate the association between vitamin D status and skin autofluorescence in patients with T2DM. METHODS: In this preliminary report skin autofluorescence was measured non-invasively with an AGE-reader in 245 patients with T2DM treated with lifestyle advice, metformin and/or sulphonylurea-derivatives. All patients were randomly assigned to receive either vitamin D 50,000 IU/month or placebo for 6 months. RESULTS: Skin autofluorescence was significantly higher in patients with a serum 25(OH)D < 50 nmol/l compared to patients with a serum 25(OH)D > 75 nmol/l (2.81 versus 2.41; p < 0.001). Mean serum 25(OH)D was 60.3 ± 23.4 nmol/l and was independently associated with skin autofluorescence (ß -0.006; p < 0.001). Mean vitamin D increased from 60.8 to 103.6 nmol/l in the intervention group, however no effect was seen on accumulation of skin AGEs after 6 months compared to placebo. CONCLUSIONS: Vitamin D status is independently associated with skin auto fluorescence in patients with well-controlled T2DM. No effect was seen on the amount of skin AGEs after a short period of 6 months vitamin D supplementation. Further research with longer follow-up and measurement of circulating advanced glycation end products is needed to elucidate the causality of the association.

The association between vitamin D status and parameters for bone density and quality is modified by body mass index.

The association of vitamin D status with bone mineral density (BMD) and Quantitative Ultrasound measurements (QUS) has been inconsistent in previous studies, probably caused by moderating effects. This study explored (1) the association of vitamin D status with QUS and BMD, and (2) whether these associations were modified by body mass index (BMI), age, gender, or physical activity. Two-independent cohorts of the Longitudinal Aging Study Amsterdam (LASA-I, 1995/1996, aged ≥65; LASA-II, 2008/2009, aged 61-71) and baseline measurement of the B-vitamins for the prevention of osteoporotic fractures (B-PROOF) study (2008-2011, aged 65+) were used. QUS measurements [broadband ultrasound attenuation (BUA) and speed of sound (SOS)] were performed at the calcaneus in all three cohorts (N = 1,235, N = 365, N = 1319); BMD was measured by Dual X-ray absorptiometry (DXA) in B-PROOF (N = 1,162 and 1,192 for specific sites) and LASA-I (N = 492 and 503). The associations of vitamin D status with BUA and BMD were modified by BMI. Only in persons with low-to-normal BMI (<25 kg/m(2)) and serum 25(OH)D <25 nmol/L was associated with lower BUA as compared to the reference group (≥50 nmol/L) in LASA-I and B-PROOF. Furthermore, in LASA-I, these individuals had lower BMD at the hip and lumbar spine. In LASA-II, no associations with BUA were observed. Vitamin D status was not associated with SOS, and these associations were not modified by the effect modifiers tested. The association between vitamin D status and BUA and BMD was modified by BMI in the older-aged cohorts: there was only an association in individuals with BMI <25 kg/m(2).

The association between low vitamin D and depressive disorders.

It has been hypothesized that hypovitaminosis D is associated with depression but epidemiological evidence is limited. We investigated the association between depressive disorders and related clinical characteristics with blood concentrations of 25-hydroxyvitamin D [25(OH)D] in a large cohort. The sample consisted of participants (aged 18-65 years) from the Netherlands Study of Depression and Anxiety (NESDA) with a current (N=1102) or remitted (N=790) depressive disorder (major depressive disorder, dysthymia) defined according to DSM-IV criteria, and healthy controls (N=494). Serum levels of 25(OH)D measured and analyzed in multivariate analyses adjusting for sociodemographics, sunlight, urbanization, lifestyle and health. Of the sample, 33.6% had deficient or insufficient serum 25(OH)D (<50 nmol l(-1)). As compared with controls, lower 25(OH)D levels were found in participants with current depression (P=0.001, Cohen's d=0.21), particularly in those with the most severe symptoms (P=0.001, Cohen's d=0.44). In currently depressed persons, 25(OH)D was inversely associated with symptom severity (ß=-0.19, s.e.=0.07, P=0.003) suggesting a dose-response gradient, and with risk (relative risk=0.90, 95% confidence interval=0.82-0.99, P=0.03) of having a depressive disorders at 2-year follow-up. This large cohort study indicates that low levels of 25(OH)D were associated to the presence and severity of depressive disorder suggesting that hypovitaminosis D may represent an underlying biological vulnerability for depression. Future studies should elucidate whether-the highly prevalent-hypovitaminosis D could be cost-effectively treated as part of preventive or treatment interventions for depression.

Bone density in apheresis donors and whole blood donors.

Apheresis donation using citrate causes acute decrease in serum calcium and increase in serum parathyroid hormone. Long-term consequences, such as decrease in bone mineral density (BMD), are not known. In this study, we compared the BMD of 20 postmenopausal apheresis donors (mean donation number 115 times in up to 15 years) with that of 20 whole blood donors (for 15 years or more) aged 55-70. BMD in the lumbar spine was not lower in apheresis donors than in blood donors (mean ± SD 1.00 ± 0.18 vs. 0.92 ± 0.12, P = 0.09). In the hip, BMD was not different between the groups.

Five new cases of breast cancer in transsexual persons.

Cross-sex hormone treatment of transsexual people may be associated with the induction and growth stimulation of hormone-related malignancies. We report here five cases of breast cancer, three in female-to-male (FtoM) transsexual subjects and two in male-to-female (MtoF) transsexual subjects. In the general population the incidence of breast cancer increases with age and with duration of exposure to sex hormones. This pattern was not recognised in these five transsexual subjects. Tumours occurred at a relatively young age (respectively, 48, 41, 41, 52 and 46 years old) and mostly after a relatively short span of time of cross-sex hormone treatment (9, 9-10 but in one after 30 years). Occurrence of breast cancer was rare. As has been reported earlier, breast tumours may occur in residual mammary tissue after breast ablation in FtoM transsexual people. For adequate treatment and decisions on further cross-sex hormone treatment it is important to have information on the staging and histology of the breast tumour (type, grade and receptor status), with an upcoming role for the androgen receptor status, especially in FtoM transsexual subjects with breast cancer who receive testosterone administration. This information should be taken into account when considering further cross-sex hormone treatment.

Heterogeneous pattern of bone disease in adult type 1 Gaucher disease: clinical and pathological correlates.

Gaucher disease (GD) is a lysosomal storage disorder characterized by accumulation of glucosylceramide in macrophages, so-called Gaucher cells, as a result of a deficiency of the lysosomal enzyme glucocerebrosidase. Bone complications are an important cause of morbidity of GD and are thought to result from imbalance in bone remodeling. Bone manifestations among GD patients demonstrate a large variation including increased osteoclastic bone resorption, low bone formation and osteonecrosis. The purpose of the current case series is to describe the histological features observed in undecalcified bone samples, obtained from three GD patients, and evaluate the relationship with clinical features in these patients. Bone fragments were obtained from three adult type 1 GD patients with variable degrees of bone disease during orthopedic surgery. Specimens were embedded without prior decalcification in methylmethacrylate and prepared for histology according to standardized laboratory procedures. Histology revealed a heterogeneous pattern of bone involvement. High cellularity of bone marrow, abundant presence of Gaucher cells (GCs) and high turnover were observed in a patient with a history of multiple bone complications, while minimal bone turnover and few GCs were detected in the mildest affected patient in this series. An intermediate picture with relatively low bone turnover and a substantial amount of Gaucher cells was demonstrated in the third, moderately affected patient. No gross abnormalities in three biochemical markers of bone turnover (osteocalcin, N-terminal propeptide of type 1 procollagen and type 1 collagen C-terminal telopeptide) were noted. Plastic embedding and subsequent Goldner and TRAP staining offered a unique possibility to study bone histological findings in GD. Our data show that bone manifestations in GD may vary both clinically as well as histologically and bone disease in GD will likely require a personalized approach.

Longitudinal changes and seasonal variations in serum 25-hydroxyvitamin D levels in different age groups: results of the Longitudinal Aging Study Amsterdam.

UNLABELLED: Vitamin D levels remained fairly stable during ageing with increasing levels in persons aged 55-65 years old and decreasing levels in persons aged 65-88 years old. The seasonal variation was larger than the longitudinal change. Our findings implicate that vitamin D supplementation becomes more important in older age groups and during wintertime. INTRODUCTION: Longitudinal changes in serum 25-hydroxyvitamin D (25-OHD) levels during aging have not been studied extensively. Two studies showed increasing serum 25-OHD levels. One of these studies suggested that there might be decreasing levels in persons aged 65 years and older. The objectives of the current study are the following: (1) to examine longitudinal changes in serum 25-OHD levels in different age groups and (2) to describe the seasonal variation in different age groups. METHODS: Data of the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study, were used. Two different cohorts were included: (1) younger cohort: aged 55-65 years old at baseline, n = 738, follow-up of 6 years and (2) older cohort: aged 65-88 years old at baseline, n = 1,320, follow-up of 13 years. RESULTS: At baseline, average levels were 56.5 nmol/L in the younger cohort and 51.1 nmol/L in the older cohort. In the younger cohort, a longitudinal increase in the mean serum 25-OHD levels of 4 nmol/L in 6 years was observed; in the older cohort, a longitudinal decrease in the mean serum 25-OHD levels of 4 nmol/L in 13 years was observed. The seasonal variation was ±12 nmol/L in the younger cohort and ±7 nmol/L in the older cohort. CONCLUSIONS: Long-term serum 25-OHD levels remained fairly stable during aging with slightly increasing levels in persons aged 55-65 years old and slightly decreasing levels in persons aged 65-88 years old. On average, the seasonal variation was larger than the longitudinal change. Our findings implicate that vitamin D supplementation becomes more important in older age groups and during wintertime.

Optimizing fracture prevention: the fracture liaison service, an observational study.

UNLABELLED: The response rate to the invitation to the fracture liaison service and reasons for non-response were evaluated in 2,207 fragility fracture patients. Fifty-one percent responded; non-responders were most often not interested (38 %) or were hip fracture patients. After 1 year of treatment, 88 % was still persistent and 2 % had a new fracture. INTRODUCTION: To increase the percentage of elderly fracture patients undergoing a dual energy x-ray absorptiometry (DXA) measurement, and to investigate why some patients did not respond to invitation to our fracture liaison service (FLS). METHODS: In four Dutch hospitals, fracture patients ≥ 50 years were invited through a written or personal invitation at the surgical outpatient department, for a DXA measurement and visit to our FLS. Patients who did not respond were contacted by telephone. In patients diagnosed with osteoporosis, treatment was started. Patients were contacted every 3 months during 1 year to assess drug persistence and the occurrence of subsequent fractures. RESULTS: Of the 2,207 patients who were invited, 50.6 % responded. Most frequent reasons for not responding included: not interested (38 %), already screened/under treatment for osteoporosis (15.7 %), physically unable to attend the clinic (11.5 %), and death (5.2 %). Hip fracture patients responded less frequently (29 %) while patients with a wrist (60 %) or ankle fracture (65.2 %) were more likely to visit the clinic. In 337 responding patients, osteoporosis was diagnosed and treatment was initiated. After 12 months of follow-up, 88 % of the patients were still persistent with anti-osteoporosis therapy and only 2 % suffered a subsequent clinical fracture. CONCLUSION: In elderly fracture patients, the use of a FLS leads to an increased response rate, a high persistence to drug treatment, and a low rate of subsequent clinical fractures. Additional programs for hip fracture patients are required, as these patients have a low response rate.

B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness.

BACKGROUND AND AIMS: Hyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated. METHODS AND RESULTS: Baseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine-gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels. CONCLUSION: Homocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness.

Does frailty predict increased risk of falls and fractures? A prospective population-based study.

UNLABELLED: A frailty concept that includes psychological and cognitive markers was prospectively shown to be associated with increased risk of multiple falls and fractures among 1,509 community dwelling older adults, especially in those aged 75 and over. The predictive ability of frailty is not superior to falls history. INTRODUCTION: The concept of frailty has been defined with or without psychological and cognitive markers. Falls are associated with multiple risk factors, including cognitive and mood disorders. The purpose of this study was to investigate the association of a comprehensive concept of frailty and its components with falls and fractures in community-dwelling older adults and to compare its predictive ability with having a history of falls. METHODS: One thousand five hundred nine participants in the Longitudinal Aging Study Amsterdam aged ≥65 were assessed to determine fall history and the prevalence of nine frailty markers, including cognitive and psychological factors. The number of falls and time to second fall were prospectively registered for 1 year. Fractures were registered for 6 years. RESULTS: Frailty was significantly associated with time to second fall: hazard ratio of 1.53 [95% confidence interval (CI), 1.07-2.18] and area under the receiver operating characteristic curve (AUC) of 0.58 (CI, 0.53-0.62). In participants aged ≥75, frailty was associated with ≥2 falls: odds ratio (OR) of 1.74 (CI, 1.19-2.55) and AUC of 0.62 (CI, 0.55-0.68). Frailty, adjusted for age and sex, was significantly associated with ≥2 fractures: OR of 3.67 (CI, 1.47-9.15). The AUCs for falls history (aged ≥75) ranged from 0.62 (CI, 0.58-0.67) for ≥1 falls to 0.67 (CI, 0.59-0.74) for ≥3 falls. CONCLUSIONS: A concept of frailty including psychological and cognitive markers is associated with both multiple falls and fractures. However, frailty is not superior to falls history for the selection of old persons at increased risk of recurrent falls.