Effect of vitamin D supplementation on free and total vitamin D: A comparison of Asians and Caucasians

ObjectivesIt is well established that UK Asians typically have lower vitamin D levels than Caucasians. It is also known that vitamin D binding protein (DBP) is lower in some races than Caucasians. To investigate how ethnicity, skin colour and genetic variation affect the response to vitamin D (15000 IU) administered to young Asian and Caucasian men.DesignProspective, single?centre clinical trial.ParticipantsSixty young men (18?25 year) of Asian (n = 30) and Caucasian (n = 30) origin.MeasurementsWe measured serum calcium, phosphate, magnesium, alkaline phosphatase, albumin, parathyroid hormone; total 25 hydroxyvitamin D (25OHD); calculated and directly measured free 25OHD; DBP at baseline and 4 weeks; DBP genotype, skin colour (Fitzpatrick scale), dietary vitamin D and calcium intake at baseline; and urine calcium:creatinine ratio at baseline, 1 and 4 weeks.ResultsAt baseline, Asians had lower serum total 25OHD (26.4 [13.7] vs 34.1 [12.3] nmol/L P = 0.0272) and DBP (6.7 [3.4] vs 9.6 [4.4] nmol/L; P = 0.0065) but similar free 25OHD (16.7 [10.4] vs 17.8 [7.5] pmol/L P = 0.6530). After dosing, total 25OHD rose similarly in each group (?56 nmol/L), but measured free 25OHD rose more in Asians (18.1 [9.4] vs 12.2 [13.3] pmol/L P = 0.0464). Lower DBP at baseline, possibly reflecting genotype differences, was associated with a greater change in measured free 25OHD in Caucasians, but not in Asians.ConclusionsAsian compared with Caucasian males had a larger increment in measured free 25OHD following 150 000 units vitamin D3, possibly reflecting differences in DBP affinity for 25OHD. Ethnicity should be considered when devising guidelines for the treatment of vitamin D deficiency

Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease

BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non - vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger se - quencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFR P4 , the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4 , like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treat - ment of Sfrp4- deficient mice with a soluble Bmp2 receptor (RAP-661) or with anti - bodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical- bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss Na - tional Foundation and the National Institutes of Health.

11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn’t met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects

Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial

Background: Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Methods: Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. Results: When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell’s c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Conclusions: Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study

The effect of teriparatide treatment on circulating periostin and its relationship to regulators of bone formation and BMD in postmenopausal women with osteoporosis

Context: Treatment of postmenopausal osteoporosis with teriparatide (PTH 1-34) increases bone formation and improves bone microarchitecture. A possible modulator of this mechanism of action is periostin. In vitro experiments have shown that periostin may regulate osteoblast differentiation and bone formation through Wnt signaling. Periostin secretion is increased by PTH in preclinical models, but the effect of teriparatide treatment of postmenopausal osteoporosis on periostin is not currently known. Objectives, to: i) determine the effect of teriparatide treatment on circulating levels of periostin and other regulators of bone formation and ii) investigate how changes in periostin relate to changes in bone turnover markers, regulators of bone formation and bone mineral density. Participants and design: 20 women with postmenopausal osteoporosis, a two-year open-label single-arm study. Intervention: Teriparatide 20 mcg was administered by subcutaneous injection daily over 104 weeks. Periostin, sclerostin and DKK-1, PINP and CTX were measured in fasting serum collected at baseline (two visits) then at weeks 1,2,4,12,26,52,78 and 104. BMD was measured at the lumbar spine, total hip and femoral neck by DXA. Results: Periostin levels increased by 6.6% (95% CI -0.4, 13.5) after 26 weeks teriparatide treatment and significantly by 12.5% (95% CI 3.3,21.0, P<0.01) after 52 weeks. Change in periostin was positively correlated with change in lumbar spine BMD at week 52 (r=0.567(95% CI 0.137,0.817), P<0.05) and femoral neck BMD at week 104(r=0.682(95% CI 0.261,0.885), P<0.01). Conclusion: Teriparatide therapy increases periostin secretion; it is unclear whether this increase mediates the effect of the drug on bone

The Clinical Utility of Bone Turnover Markers in Postmenopausal Women with Osteoporosis

Postmenopausal osteoporosis is characterised by increased bone turnover, a negative balance (where bone resorption exceeds bone formation), reduced BMD and increased fracture risk. Diagnosis is based on assessment of BMD measured by DXA. The development of specific and sensitive bone turnover markers such as PINP and CTX are widely used in clinical studies. The overall aim of this thesis was to investigate the clinical utility of BTMs in a population based study and in clinical trials of licenced antiresorptive treatments. Postmenopausal and premenopausal women were recruited and whole blood, serum and urine samples were collected. Several diseases and treatments were identified that influenced bone turnover markers in older women and these needed to be excluded for establishing healthy reference intervals. In postmenopausal osteoporosis the negative balance between bone resorption and formation may be associated with the low BMD, bone loss and increased vertebral and non-vertebral fracture risk. Antiresorptive treatments inhibit bone resorption in the short-term by having direct action on mature osteoclasts. There was also a later effect mediated by a reduction in the population of circulating osteoclast precursors. With bisphosphonate treatments bone balance is positive relative to healthy premenopausal women. The clinical utility of sclerostin remains unclear but it does appear to be related to bone resorption and bone formation and levels of which are reduced with raloxifene treatment. Bone turnover markers provide additional information to BMD assessments about bone remodelling. The combined assessment of bone turnover and bone balance may help identify patients at risk of bone loss and fracture. These findings can be used to investigate the mechanisms of actions of current and future treatments that are being developed in order to identify the most suitable for patients with postmenopausal osteoporosis

Effect of age and gender on serum growth differentiation factor 15 and its relationship to bone density and bone turnover

Senescent cells and senescence-associated secretory phenotype (SASP) proteins are involved in age-related bone loss. Growth differentiation factor 15 (GDF 15), a stress-responsive cytokine member of the transforming growth factor-β (TGF-β) superfamily, is one of the key SASP proteins. It is strongly associated with age and higher levels correlate with frailty and are detected in several conditions and diseases. It also modulates appetite and body weight through the binding to its receptor glial cell- derived neurotrophic factor family receptor alpha- like (GFRAL) in the brainstem. The GDF 15 involvement in bone metabolism has been studied in several murine models, however, it is still unclear in humans. Therefore, this study aims to determine whether GDF 15 is associated with bone mineral density (BMD) and bone turnover, and to establish the effect of age and gender on its levels. Serum GDF 15 was measured with an ELISA from R&D Systems in 180 healthy women and men from the “XtremeCT study”, divided into three age groups which represent different stages of skeletal development (16–18, 30–32, over 70 years). We also measured bone resorption marker C-terminal telopeptide of type I collagen (CTX) and bone formation markers N-terminal propeptide of type I collagen (PINP), osteocalcin (OC) and bone alkaline phosphatase (BAP) using iSYS-IDS analyser. Parathyroid hormone (PTH), 25hydroxyvitamin D (25OH-vitamin D), Insulin-like Growth Factor I (IGF-1), estradiol and testosterone were measured using the Cobas automated analyser (Roche Diagnostics). We assessed BMD at spine and total hip by dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT) of the radius and tibia. Univariate analysis of variance with the post-hoc Sheffe test and multiple linear regression has been used to assess the effect of age and gender. Spearman's rank correlation was used to evaluate the associations between GDF 15 and the other variables. We found GDF 15 levels significantly associated with age (p < 0.001) and gender (p = 0.008), with a significant gender ∗ age interaction (p < 0.001). Significantly higher levels of GDF 15 were found in subjects aged over 70 compared with the younger people (p < 0.001) and significantly higher levels were detected in men. We did not find any significant correlation between GDF 15 and bone turnover markers (BTMs), BMD, HRpQCT measures and hormones in any of the age groups. In conclusion, age and gender are determinants of GDF15 and much higher levels are found in older people and in men. Since no association was found between GDF 15 and bone health measures, we hypothesize that the effect of GDF 15 on bone might be exert by other tissue, such as muscle

Oxytocin, a new determinant of bone mineral density in post-menopausal women: analysis of the OPUS cohort.

International audience: Introduction: Oxytocin (OT), a neurohypophysial hormone regulated by estrogen and leptin, may play a role in bone metabolism in humans as suggested by animal studies. This study assess the relationship between OT and bone status in a large population of post menopausal women. Subjects and methods: Subjects were included in the Osteoporosis and Ultrasound study (OPUS), a 6-yr prospective study in a population-based cohort. Final visit data were used for this cross-sectional study. OT, leptin and estradiol serum levels were measured in 1097 post-menopausal women and compared with bone mineral density (BMD), fractures and the bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (PINP), bone alkaline phosphatase (bone ALP) and C-telopeptide of type 1 collagen (CTX). Results: Median age was 70.8 years, 16% were osteoporotic, 48% osteopenic, and 29% had at least one fracture. OT serum level was related to spine (r=+0.12, p=0.0002) and total hip BMD (r=+0.21, p<0.0001) and with BTM (PINP: r=-0.13, p<0.0001, bone ALP: r=-0.07, p=0.02, CTX: r=-0.18, p<0.0001). The relationship of OT with BMD was independent of BTM. After adjustment for confounding factors, the correlation between OT serum level and BMD remains significant at the hip in women with unmeasureable oestradiol or leptin above the median value. There was no significant relationship between OT serum levels and fractures. Conclusion: High OT levels are associated with high BMD especially at the hip in women with low estradiol or high leptin serum levels. The mechanism may be explained by the effect of OT on bone turnover