A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Pregnancy- and lactation-induced osteoporosis: a social-media-based survey.

BACKGROUND: Pregnancy- and lactation-induced osteoporosis (PLO) presenting as spinal fractures is rare, and the spectrum of clinical presentation, risk factors and pathophysiology are incompletely understood. The aim of this study was to delineate clinical parameters, risk factors and osteoporosis-related quality of life (QOL) of women with PLO. METHODS: Participants of a social-media (WhatsApp) PLO group and mothers of a parents' WhatsApp group (control group) were offered to fill a questionnaire, including an osteoporosis-related QOL section. The groups were compared using the independent Students t test for numerical variables, and the Chi-square test or Fisher's exact test for categorical variables. RESULTS: Twenty-seven women with PLO and 43 in the control group (aged 36.2 ± 4.7 and 38.8 ± 4.3 years, respectively, p = 0.04) participated. Among women with PLO, more than 5 vertebrae were involved in 13 (48%), 4 vertebrae in 6 (22%), and 3 or fewer vertebrae in 8 (30%). Among the 24 women with relevant data, 21 (88%) had nontraumatic fractures; 3 (13%) women had fractures during pregnancy, and the remaining during the early postpartum period. Diagnosis was delayed for over 16 weeks for 11 (41%) women; 16 (67%) received teriparatide. Significantly lower proportions of women in the PLO group engaged in physical activity over 2 hours/week, before and during pregnancy (37 vs. 67%, p < 0.015 and 11 vs. 44%, p < 0.003, respectively). A lower proportion of the PLO than the control group reported calcium supplementation during pregnancy (7% vs. 30%, p = 0.03) and a higher proportion reported treatment with low-molecular-weight-heparin during pregnancy (p = 0.03). Eighteen (67%) of the PLO group expressed fear of fractures and 15 (56%) fear of falls, compared to none and 2%, respectively, of the control group (p < 0.00001 for both). CONCLUSIONS: Most of the women with PLO who responded to our survey reported spinal fractures involving multiple vertebrae, delayed diagnosis, and treatment with teriparatide. Compared to a control group, they reported less physical activity and impaired QOL. For this uncommon yet severe condition, a multidisciplinary effort should be exerted for early identification and treatment, to alleviate back pain, prevent subsequent fractures and improve QOL.

The Effect of Teriparatide Treatment on the Risk of Fragility Fractures in Postmenopausal Women with Osteoporosis: Results from the Asian and Latin America Fracture Observational Study (ALAFOS).

The Asian and Latin America Fracture Observational Study (ALAFOS) is a prospective, observational, single-arm study conducted in 20 countries across Asia, Latin America and the Middle East. ALAFOS evaluated new clinical vertebral and non-vertebral fragility fractures in relation to time on teriparatide, in postmenopausal women with osteoporosis in real-life clinical practice. Clinical fragility fractures, back pain, and health-related quality of life (HRQoL) were recorded in 6-month intervals for ≤ 24 months during teriparatide treatment and up to 12-months post-treatment. Data were analysed with piecewise exponential regression with inverse probability weighting for time to event outcomes and mixed-model repeated measures for back pain and HRQoL. 3054 postmenopausal women started teriparatide and attended ≥ one follow-up visit (mean [SD] age 72.5 [10.4] years). The median (95% CI) time to treatment discontinuation was 22.0 months (21.2, 22.8). During the treatment period, 111 patients (3.6%) sustained 126 clinical fractures (2.98 fractures/100 patient-years). Rates of new clinical fragility fractures were significantly decreased during the > 6-12, > 12-18, and > 18-24-month periods, as compared with the first 6 months of treatment (hazard ratio [HR] 0.57; 95% CI 0.37, 0.88; p = 0.012; HR 0.35; 95% CI 0.19, 0.62; p < 0.001; HR 0.43; 95% CI 0.23, 0.83; p = 0.011; respectively). Patients also reported an improvement in back pain and HRQoL (p < 0.001). These results provide data on the real-world effectiveness of teriparatide in the ALAFOS regions and are consistent with other studies showing reduction of fractures after 6 months of teriparatide treatment. These results should be interpreted in the context of the noncontrolled design of this observational study.

The Risk of Bone Fractures in Post-Poliomyelitis Patients Transitioning to Middle Adulthood.

ObjectiveWhile osteoporotic fractures are reported in up to 40% of adults with post-poliomyelitis syndrome (PPS), clinical guidelines regarding bone mineral density (BMD) and indications for treatment are scarce. We investigated the characteristics of PPS patients, focusing on fractures and osteoporosis as the primary outcomes. METHODS: A cross-sectional retrospective data analysis from medical records of 204 PPS patients regarding their clinical characteristics and long-term outcome, with emphasis on bone metabolism status. RESULTS: Our cohort included 53% women; mean age was 65 years at study entry and 1.7 years at the diagnosis of acute poliomyelitis. The lower limb was involved in 97.5% of patients, and the BMD in the affected limb tended to be lower than the unaffected, with a mean T-score of -1.64 vs. -1.19, respectively (P = .06). Recurrent falls were documented in 39.2% of patients, and osteoporosis in 20.6%, being more frequent in women (P = .003) and patients with fractures (P = .002). At least one fracture occurred in 52.2% of patients, and more than one in 40.3%. The median age for the first fracture was 57.5 years (range, 30 to 83 years), and most fractures occurred in the affected limb (73.2%). CONCLUSIONS: Underdiagnosis and delayed treatment of osteoporosis in late-adulthood post-poliomyelitis patients underlie the need for comprehensive clinical guidelines to manage these patients, including recommendations on bone health assessment, medical treatment, and their inclusion as a high-risk group for bone fractures.

Study description and baseline characteristics of the population enrolled in a multinational, observational study of teriparatide in postmenopausal women with osteoporosis: the Asia and Latin America Fracture Observational Study (ALAFOS).

OBJECTIVE: To describe the study design and baseline patient characteristics of the Asia and Latin America Fracture Observational Study (ALAFOS) to better understand the profile of patients receiving teriparatide during the course of routine clinical practice in Asia, Latin America, the Middle East and Russia. METHODS: Prospective, observational, non-interventional study in postmenopausal women with osteoporosis who are prescribed teriparatide for up to 24 months, according to local medical standards, with a 12 month post-treatment follow-up. MEASURES: Demographics, risk factors for osteoporosis and fractures, history of fracture, prior osteoporosis medications, comorbidities, physical function, back pain and quality of life (QoL). RESULTS: In total 3031 postmenopausal women (mean age 72.5 years) recruited at 152 sites in 20 countries were analyzed; 62.9% had a history of fragility fracture after age 40 (33.0% of patients with spinal, 14.2% with hip fractures). The mean (SD) bone mineral density T-scores at baseline were -3.06 (1.40) and -2.60 (1.05) at the lumbar spine and femoral neck, respectively. At entry, 43.7% of patients were naïve to prior osteoporosis treatments; 40.5% of patients reported ≥1 fall in the past year. The median (Q1; Q3) EuroQoL Visual Analog Scale (EQ-VAS) for perceived overall health status was 60 (50; 80). The mean (SD) worst back pain Numeric Rating Scale in the last 24 hours was 4.6 (3.3). CONCLUSIONS: Our data indicates that patients who were prescribed teriparatide in the ALAFOS participant countries had severe osteoporosis, high prevalence of fractures, disabling back pain and poor QoL. The frequency of patients receiving prior osteoporosis medications was lower than in previous observational studies conducted in other locations.

Fracture Risk Assessment With FRAX Using Real-World Data in a Population-Based Cohort From Israel.

The predictive value of the World Health Organization's Fracture Risk Assessment Tool (FRAX) was evaluated using real-world community data. A population-based cohort of 141,320 women aged 50-90 years (median age, 58 years; interquartile range, 54-67) in 2004 was extracted from the central database of a large Israeli health-care services provider and insurer. Retrospective FRAX scores were calculated using computerized health records and compared with actual incidence of major osteoporotic fractures (MOFs) during the following 10 years. Fracture proportions of 6.9% for MOFs and 2.2% for hip fractures were expected, as opposed to 13.5% and 2.9% observed. The area under the receiver operating characteristic curve (AUC) of FRAX scores calculated without the inclusion of bone mineral density (BMD) data was 0.65 (95% confidence interval: 0.65, 0.66) for MOF and 0.82 (95% confidence interval: 0.81, 0.82) for hip fracture. A total of 16,578 subjects had BMD data at the index date, and their risk estimates based solely on BMD exhibited lower predictive performance for both MOFs (AUC = 0.62 vs. 0.65; P = 0.003) and hip fractures (AUC = 0.78 vs. 0.84; P < 0.001) as compared with FRAX. FRAX scores based on electronic health records provided reasonable discrimination despite some underestimation of the absolute risk of nonhip fractures. Integration of FRAX with routine clinical systems could increase implementation in daily practice and improve risk detection, especially for patients without BMD data.

[SHOULD PATIENTS WITH PRIMARY HYPERPARATHYROIDISM AND NEGATIVE IMAGING STUDIES BE REFERRED TO SURGERY?]

INTRODUCTION: Parathyroidectomy is the only curative treatment for primary hyperparathyroidism (PHPT). In cases where imaging fails to demonstrate an adenoma, a bilateral neck exploration (BNE) is performed. Negative imaging is thought to predict surgical failure, and patients with negative imaging are often not referred for surgery. These patients are at risk for disease progression. AIMS: Evaluate the effect of negative imaging on surgical findings and the cure rate in patients with PHPT. METHODS: A total of 133 patients underwent parathyroidectomy for PHPT. Data were retrospectively retrieved including preoperative imaging, surgical findings and results. A comparison was conducted between patients with negative and positive imaging. The main outcome measure was cure. RESULTS: A negative MIBI (methoxy-isobutyl-isonitrile) scan was seen in 30 (22%) patients and a negative US in 46 (34.5%). Patients with negative MIBI scan more commonly underwent BNE compared with patients with a positive scan (53% vs. 25%, respectively, p=0.0046). Patients with negative imaging had a significantly higher rate of multigland disease compared with patients with positive imaging (35% vs. 12%, p=0.004, for the MIBI scan; 27% vs. 12%, p=0.024, for the US, respectively). Overall cure rate was 96%. Highest cure rates were seen in patients with both positive MIBI and US (99% cure rate) and lowest cure rates of 67% in patients with triple negative imaging (MIBI scan, US and 4DCT (Dual computed tomography)) (p=0.003). CONCLUSIONS: Localization of an adenoma in preoperative imaging predicts very high cure rates in patients with PHPT. Negative imaging increases the risk for multigland disease and is associated with lower cure rates.

Impact of FRAX-based osteoporosis intervention using real world data.

OBJECTIVES: To estimate the implications and accuracy of the most common fracture prevention strategies: (1) fixed threshold by the National Osteoporosis Foundation (NOF), (2) age-dependent threshold by the National Osteoporosis Guideline Group (NOGG) and (3) osteoporotic bone mineral density (BMD). METHODS: A retrospective cohort of all 50-90years old female members in a nationally representative payer provider healthcare organization in Israel, with 10years of follow-up on incident events of major osteoporotic fractures. Since events are less frequent than non-events, balanced accuracy (the average between the accuracy obtained for patients with and without events) was used to measure performance. RESULTS: Overall among 141,320 women NOF and NOGG would recommend therapy for 17.3% and 2.8% respectively, with NOF exhibiting higher balanced accuracy: 74.1% vs. 54.2% for incident hip fractures detection and 60.0% vs. 51.6% for a composite outcome of major osteoporotic fractures. In patients with available BMD (n=16,578) the treatment intervention criteria of NOF, NOGG, osteoporotic femur neck or vertebral BMD were met by 30.5%, 9.3% and 24.6% of the population, with balanced accuracy of 70.1%, 56.5% and 62.3% respectively for hip fractures and 61.4%, 52.8%, 58.1% for major osteoporotic fractures. At the age of 75years or older the NOF hip fracture risk threshold (3%) was exceeded in most women regardless of risk factors other than age. CONCLUSIONS: In this large population-based study, detection of patients at high risk of sustaining a major osteoporotic fracture within 10 years was more accurate with the NOF fixed threshold criteria as compared with the age-varying NOGG or BMD-only. However, special consideration and further studies are warranted in patients aged 75years or older with preserved bone density, which may benefit from non-medicinal interventions.

Adherence With Bisphosphonates and Long-Term Risk of Hip Fractures: A Nested Case-Control Study Using Real-World Data.

BACKGROUND: Hip fracture is a major complication of osteoporosis. Bisphosphonate medication is the mainstay of treatment for osteoporosis. However, concerns have been raised regarding the effectiveness of bisphosphonates in reducing hip fracture risk after long-term use, particularly among patients with suboptimal adherence. OBJECTIVE: To examine the association between adherence with bisphosphonate therapy and long-term risk of hip fracture. METHODS: Included in the present nested case-control study were osteoporotic women (n = 14 357) who initiated bisphosphonate therapy in 2000-2010 and were retrospectively followed for incident hip fracture through November 2014. Within this cohort, each case of primary hip fractures was individually matched to 3 controls without a primary hip fracture. Proportion of follow-up days covered (PDC) with bisphosphonates was calculated from bisphosphonate purchases. Adherence was categorized into the following groups: purchase of 1 or 2 months' supply (reference group), at least 3 months' supply to PDC ≤20%, PDC >20% to ≤80%, PDC >80% to ≤100%. RESULTS: Included in the analysis were 426 case-control groups with a mean age (SD) of 73.7 years (7.9). Compared with the reference group, PDC of 80% to 100% with bisphosphonates was associated with a significant reduction in hip fracture risk for patients with 8 to 15 years of follow-up (OR = 0.39; 95% CI = 0.18-0.87). Among patients with a follow-up of up to 3 years, OR was 0.58 (95% CI = 0.31-1.06). CONCLUSIONS: Adherence with bisphosphonates among osteoporotic patients is associated with lower risk of hip fracture, with no indication of diminished effectiveness with long-term use.

Bioavailability, rheology and sensory evaluation of fat-free yogurt enriched with VD3 encapsulated in re-assembled casein micelles.

Vitamin D3 (VD3) deficiency is a global problem. Better ways are needed to enrich foods with this important nutraceutical. VD3 is fat-soluble, hence requiring a suitable vehicle for enriching nonfat foods. Our objectives were to assess the bioavailability of VD3, from fat-free yogurt, in re-assembled casein micelles (rCMs) compared to that in polysorbate-80 (PS80/Tween-80) a commonly used synthetic emulsifier, and to assess and compare their rheology and palatability. We enriched fat-free yogurt with VD3 loaded into either rCM (VD3-rCMs) or PS80 (VD3-PS80). In vivo VD3 bioavailability was evaluated by a large randomized, double blind, placebo-controlled clinical trial, measuring serum 25(OH)D increase in subjects who consumed fat-free yogurt with 50,000 IU of either VD3-rCM, VD3-PS80, or VD3-free placebo yogurt. Both VD3-rCM and VD3-PS80 increased the serum 25(OH)D levels by ∼8 ng ml(-1) and no significant differences in mean 25(OH)D levels were observed, evidencing the fact that VD3 bioavailability in rCM was as high as that in the synthetic emulsifier. VD3-rCM yogurt had a higher viscosity than VD3-PS80 yogurt. In sensory evaluations, panelists were able to discern between VD3-rCM and VD3-PS80 yogurt, and showed a dislike for PS80 yogurt, compared to rCM or the unenriched control. These results complement our past results showing higher protection against thermal treatment, UV irradiation, and deterioration during shelf life, conferred to hydrophobic nutraceuticals by rCM compared to that by the synthetic surfactant or to the unprotected bioactive, in showing the advantageous use of rCM over the synthetic emulsifier as a delivery system for the enrichment of food with VD3 and other hydrophobic nutraceuticals.

Atypical Femoral Fractures: Radiological Evaluation and Bisphosphonate Exposure.

BACKGROUND: Evidence suggests that prolonged bisphosphonate (BP) treatment predisposes to atypical fractures (AF), but the etiology has yet to be determined. Addressing causality begins with case identification, which requires radiological adjudication. However, many trials based their case findings on coded diagnoses. OBJECTIVES: To investigate the feasibility of case findings by the coding system and the reproducibility of radiological evaluations in two hospitals in Israel, and to compare BP exposure of AF patients to a control group with typical (intertrochanteric of femoral neck) fractures. METHODS: Diagnostic databases from 2007 to 2010 were reviewed and admission X-rays of patients were examined in two steps by two radiologists. Fractures were classified as atypical or not atypical according to published criteria. A 2:1 control group was created. Ambulatory drug acquisition was reviewed. RESULTS: Of the 198 patients who fulfilled the search criteria, 38 were classified by initial radiological opinion as AF. Subsequent radiological opinion judged 16 as not atypical. Of the AF patients, 80% were exposed to BP. Of those, 81% continued to receive BP treatment for 2.4 years after AF. Only one AF patient was discharged with suspected AF diagnosis. In the control group, 27% were exposed to BP prior to fracture (P < 0.001). CONCLUSIONS: Thorough radiological revision is mandatory for proper classification of AF, and even when performed there is significant inconsistency in interpretation. Conclusions drawn from trials based solely on coded diagnoses lead to significant bias. BP exposure was significantly higher in the AF group. Caregiver unawareness of AF leads to improper management.

Renal impairment among postmenopausal women with osteoporosis from a large health plan in Israel.

UNLABELLED: Bisphosphonates are a first-line treatment for osteoporosis but require adequate renal function. We estimated the prevalence of renal impairment among osteoporotic women in Israeli. Approximately 2.3 % of women had renal impairment at a level that makes them inappropriate for bisphosphonate use, demonstrating the need for alternative therapies for osteoporosis treatment. PURPOSE: The purpose of this study is to estimate the prevalence of renal impairment among postmenopausal osteoporotic women within a large Israeli health plan. METHODS: This was a retrospective analysis of Maccabi electronic medical records, including Israeli women aged ≥55 with either an osteoporosis diagnosis or osteoporosis-related fracture between January 1, 2007, and December 31, 2011. The estimated glomerular filtration rate (eGFR), which was calculated from the lowest serum creatinine levels reported during the study period, was used to classify stage 1-5 renal impairment: normal ≥90, mild 60-89, moderate 30-59, severe 15-29, and failure <15 mL/min/1.73 m(2), respectively. Outcomes were distributions of renal impairment across the study population and stratified by age and osteoporosis-defining event. RESULTS: A total of 15,608 patients met all eligibility criteria. Patients with stage 1-5 renal function accounted for 25.2, 54.9, 18.5, 1.2, and 0.3 %, respectively, of all patients. Of osteoporotic patients, 2.3 % had eGFR levels (<35 mL/min/1.73 m(2)) that make them inappropriate for bisphosphonate use. This rate was 1.6 % among patients with an osteoporosis diagnosis and 3.8 % among patients with osteoporosis-related fracture. Within the group of renally impaired patients, older patients were overrepresented. Of the fracture group, patients with hip fractures had a higher prevalence of renal dysfunction (9.3 %) than those having vertebral fractures (3.2 %) or other fractures (2.0 %). CONCLUSIONS: Among postmenopausal women with osteoporosis, 2.3 % had renal impairment which makes them inappropriate for bisphosphonate use in Israel.

Systemic glucocorticoids: important issues and practical guidelines for the dermatologist.

BACKGROUND: The potent anti-inflammatory and immunosuppressive effects of systemic glucocorticoids have led to their wide use in the treatment of dermatologic diseases. However, glucocorticoids have been designated the "archetypal double-edged sword of medicine" as a result of their various potential adverse side effects. Dermatologists face major challenges in their usage and require knowledge of both the risks related to their usage and strategies with which to manage them. OBJECTIVES: This brief review includes an evidence-based, strategic approach to the general risk management of systemic glucocorticoids with a focus on preventing glucocorticoid-induced osteoporosis (GIOP). METHODS: We assess which classes of corticosteroid are most likely to provoke allergic cross-reactions and outline the mechanism for glucocorticoid resistance. We examine how glucocorticoids both help and impair normal physiology. RESULTS: Five reactivity groups are defined, based on the structural and clinical characteristics of glucocorticoids. Tests for allergy reactions and mechanisms for glucocorticoid resistance are described. Guidelines for the prevention and treatment of GIOP are introduced. CONCLUSION: Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. It is hoped that the various recommendations for the protection of patients treated with systemic glucocorticoids will provide physicians with practical guidelines for prescribing.

Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties.

BACKGROUND: Flu-like symptoms (FLS) are common side effects of interferon beta (IFN-ß) treatment in patients with Multiple Sclerosis (PwMS) and are associated with post-injection cytokine surge. We hypothesized that vitamin D3 supplementation would ameliorate FLS by decreasing related serum cytokines' levels. METHODS: In a randomized, double blind study of 45 IFNß-treated PwMS, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 24 patients received 4,370 IU per day (high dose) for one year. FLS were assessed monthly by telephonic interviews. Serum levels of 25-hydroxy-D (25-OH-D), calcium, PTH, IL-17, IL-10 and IFN-γ were measured periodically. EDSS, relapses, adverse events and quality of life (QoL) were documented. RESULTS: 25-OH-D levels increased to a significantly higher levels and PTH levels decreased in the high dose group. There was no significant change in FLS. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL-10 and IFNγ were found. Hypercalcemia or other potential major adverse events were not observed. CONCLUSION: Vitamin D supplementation to IFN-ß treated PwMS, at the doses used, seems safe and associated with dose-dependent changes in IL-17 serum levels, while not affecting IFN-ß related FLS. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01005095.

The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) incidence is higher in geographic regions with less sunlight exposure. Both vitamin D and melatonin are essential mediators of the effect of sunlight in health, and as such are candidates to play a key role in MS. We hypothesized that vitamin D and melatonin may have related influences in patients with MS. METHODS: In a randomized, double blind study of 40 IFN-ß treated MS patients, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 19 patients received 4,370 IU vitamin D3 per day (high dose) for one year. Serum 25-hydroxy-vitamin-D (25-OH-D) and nighttime urine melatonin metabolite, 6-sulphatoxy-melatonin (6-SMT), were measured at baseline, 3 months and 1 year from enrolment. RESULTS: After 3 months supplementation, 25-OH-D levels increased and nighttime melatonin secretion decreased significantly in the high dose group, but not in the low dose group. After 1 year, a decrease in 25-OH-D levels, accompanied by an increase of urine nighttime 6-SMT were observed in the high dose group. Percent change in serum 25-OH-D was significantly and negatively correlated with percent change in urine 6-SMT after 3 months and between 3 months to 1 year. 25-OH-D levels by the end of the study were significantly and negatively correlated to BMI. CONCLUSIONS: Melatonin secretion is negatively correlated with alterations in serum 25-OH-D in IFN-ß treated patients with MS. The finding suggests that melatonin should be considered as a potential mediator of vitamin D neuro-immunomodulatory effects in patients with MS.

Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids.

OBJECTIVE: Long-term glucocorticoid use is accompanied by rapid bone loss; however, early treatment with bisphosphonates prevents bone loss and reduces fracture risk. The aim of this study was to examine the effects of two bisphosphonates, i.v. zoledronic acid (ZOL) versus oral risedronate (RIS), on bone turnover markers (BTMs) in subjects with glucocorticoid-induced osteoporosis (GIO). METHODS: Patients were randomly stratified according to the duration of pre-study glucocorticoid therapy [prevention subpopulation (ZOL, n = 144; RIS, n = 144) ≤3 months, treatment subpopulation (ZOL, n = 272; RIS, n = 273) >3 months]. Changes in ß-C-terminal telopeptides of type 1 collagen (ß-CTx), N-terminal telopeptide of type I collagen (NTx), procollagen type 1 N-terminal propeptide (P1NP) and bone-specific alkaline phosphatase (BSAP) from baseline were measured on day 10 and months 3, 6 and 12. RESULTS: At most time points, there were significantly greater reductions (P < 0.05) in the concentrations of serum ß-CTx, P1NP and BSAP and urine NTx in subjects on ZOL compared with RIS in both males and females of the treatment and prevention subpopulations. In pre- and post-menopausal women, there were significantly greater reductions in the concentrations of BTMs with ZOL compared with RIS. At 12 months, ZOL had significantly greater reductions compared with RIS (P < 0.05) for ß-CTx, P1NP, BSAP and NTx levels, independent of glucocorticoid dose. CONCLUSIONS: Once-yearly i.v. infusion of ZOL 5 mg was well tolerated in different subgroups of GIO patients. ZOL was non-inferior to RIS and even superior to RIS in the response of BTMs in GIO patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00100620.

Vitamin D status in young HIV infected women of various ethnic origins: incidence of vitamin D deficiency and possible impact on bone density.

BACKGROUND: Decreased bone mineral density (BMD) was reported in HIV infected patients. Mechanisms leading to this decrease are poorly understood. AIMS: To assess factors relating to BMD in young HIV infected Israeli women of Ethiopian and Caucasian origin. PATIENTS AND METHODS: 75 young HIV infected women aged 34.5 ± 8.5 followed up at the Institute of Allergy, Clinical Immunology & AIDS filled a questionnaire about sun exposure, daily calcium intake and dress habits. Data about HIV status and treatment regimens were collected from the patients' charts. Serum hydroxyvitamin D [25(OH)D] levels, bone turnover markers and bone densitometry were evaluated. RESULTS: 28 (65%) of Ethiopians and 2 (6.25%) of Caucasians had 25(OH)D serum levels <10 ng/ml (vitamin D deficiency), p = 0.001. 21 (67.7%) Ethiopians and 16 (39%) Caucasians avoided sun exposure, p = 0.019. Mean daily calcium intake was 491 ± 268.6 mg and 279 ± 252.6 mg, respectively, p = 0.001. Z scores < -1 found at Lumbar spine in 26 (89.7%), at Femoral neck in 20 (69%) at Total hip in 17 (58.6%) of vitamin D deficient patients compared to 20 (48.8%), 17 (41.5%), 9 (22%), in patients with 25(OH)D > 10 ng/ml, p < 0.01, <0.03, <0.001, respectively. Significantly more Ethiopian than Caucasian women covered their face (32.3% and 9.5%, p = 0.003) and hands (58.1% and 30.9%, p = 0.03). There was no difference in bone turnover markers levels. CONCLUSION: Poorer vitamin D status was observed in Ethiopian women might be one of the important factors related to lower BMD in this group.

Vitamin D deficiency in oncology patients--an ignored condition: impact on hypocalcemia and quality of life.

BACKGROUND: Vitamin D status is not evaluated routinely in cancer patients with bone metastasis who are treated with bisphosphonates. OBJECTIVES: To assess the effect of vitamin D status on risk of hypocalcemia and quality of life in these patients. METHODS: We performed laboratory tests for routine serum biochemistry, 25(OH)D, plasma parathyroid hormone (PTH) and bone turnover markers (CTX, P1NP) in 54 patients aged 57.5 +/- 13 years treated with intravenous bisphosphonates. RESULTS: Most of the patients (n = 44, 77.8%) did not receive calcium and vitamin D supplementation. Their mean serum 25(OH)D levels (12.83 +/- 6.86 ng/ml) correlated with vitamin D daily intake (P = 0.002). In 53 patients (98.1%) 25(OH) D levels were suboptimal (< 30 ng/ml). Albumin-corrected calcium levels correlated with plasma PTH (P = 0.001). No correlation was observed between daily calcium intake and serum calcium (P = 0.45). Hypocalcemia was observed in one patient. Mean plasma PTH was 88.5 - 65 ng/L. Plasma PTH correlated negatively with 25(OH)D serum levels (P = 0.003) and positively with P1NP (P = 0.004). Albumin-corrected calcium correlated negatively with P1NP (mean 126.9 +/- 191 ng/ml) but not with CTX levels (mean 0.265 +/- 0.1 ng/ml) (P < 0.001). There was no correlation among quality of life parameters, yearly sun exposure and 25(OH)D levels (P = 0.99). CONCLUSIONS: Vitamin D deficiency is frequent in oncology patients with bone metastasis treated with bisphosphonates and might increase bone damage. Our results indicate a minor risk for the development of severe hypocalcemia in vitamin D-deficient patients receiving bisphosphonate therapy. Although vitamin D deficiency might have some effect on the quality of life in these patients, it was not proven significant.

Dehydroepiandrosterone treatment effects on weight, bone density, bone metabolism and mood in women suffering from anorexia nervosa-a pilot study.

We investigated the effects of the administration of dehydroepiandrosterone (DHEA) on weight, bone metabolism, bone density and clinical mood symptoms in outpatient Anorexia Nervosa (AN) patients. AN patients (n=26) were double-blindly randomized to receive DHEA (100mg) or placebo for 6 months. Outcome measures were bone mineral density (BMD) and bone mineral content (BMC) measured by dual energy X-ray absorptiometry (DXA) and metabolism indexes, steroid hormones, and mood and eating disorder symptoms measured at baseline and at the 3 and 6 months follow-up visits. Mood and eating disorder symptoms were assessed monthly by the Beck Depression Inventory, Eating Disorder Inventory and Clinical Global Improvement Scales. No treatment or treatment by time interaction was observed for any bone density measures. Deoxypiridinolyne (DPD) was positively correlated with weight (P=0.02). An increase in body mass index (BMI) in the DHEA group was significantly higher at 4 months compared to the control group (P=0.05). Improvement of mood was significantly correlated with weight only in the DHEA group. Despite a significant decrease in DPD, no improvement in bone mineral density was detected. However, patients treated with DHEA benefited from a significant increase in BMI, which was positively correlated with improvement in mood.

Stability and bioavailability of vitamin D nanoencapsulated in casein micelles.

We have previously introduced the potential of casein micelles (CM) as natural nanovehicles for hydrophobic nutraceuticals, e.g. vitamin D (VD) (E. Semo, E. Kesselman, D. Danino and Y. D. Livney, Food Hydrocolloids, 2007, 21, 936-942). The aims of the current study were to improve performance by adding an ultra-high-pressure homogenization step, and to evaluate the protection conferred by re-assembled CM (rCM) against VD thermal and oxidative degradation, and the bioavailability of VD(3) in rCM, by a clinical trial. Dynamic-light-scattering showed that VD(3)-rCM had a diameter of 91 ± 8 nm (average ± standard error). When VD(3) was encapsulated in rCM and subjected to thermal treatment (80 °C, 1 min), no significant loss was observed (P > 0.05), compared to 13 and 14% loss of VD(3) emulsified with Tween-80 (a synthetic emulsifier typically used for VD solubilization) and of unencapsulated VD(3) respectively (P < 0.05). VD(3) in rCM was also more stable during 28 d cold storage (∼40% loss) compared to Tween-80 emulsified (∼50% loss) or to un-encapsulated (∼70% loss) VD(3). Ultra-high-pressure homogenization of VD(3)-rCM (∼155 MPa) significantly enhanced vitamin stability, resulting in only ∼10% loss after 28 d of storage. Bioavailability of a single-dose of 50,000 international-units (IU) VD(3) encapsulated in rCM, in 1% fat milk, investigated in a randomized double blinded placebo controlled clinical study with 87 human volunteers, was at least as high as that using an aqueous Tween-80-emulsified VD(3) supplement. We conclude that ultra-high-pressure homogenization treated rCM protect VD(3) against heat- and storage-induced degradation, and VD(3) encapsulated in rCM is highly bioavailable.