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Summary Objectives Positive effects of irisin on osteogenic differentiation of periodontal ligament (PDL) cells have been identified previously, this study aims to examine its effect on orthodontic tooth movement (OTM) in vivo. Materials and methods The maxillary right first molars of male Wistar rats (n = 21) were moved mesially for 14 days, with submucosal injection of two dosages of irisin (0.1 or 1 μg) or phosphate-buffered saline (control) every third day. OTM was recorded by feeler gauge and micro-computed tomography (μCT). Alveolar bone and root volume were analysed using μCT, and plasma irisin levels by ELISA. Histological characteristics of PDL tissues were examined, and the expression of collagen type I, periostin, osteocalcin (OCN), von Willebrand factor (vWF) and fibronectin type III domain-containing protein 5 (FNDC5) in PDL was evaluated by immunofluorescence staining. Results Repeated 1 μg irisin injections suppressed OTM on days 6, 9, and 12. No significant differences were observed in OTM in the 0.1 μg irisin group, or in bone morphometric parameters, root volume or plasma irisin, compared to control. Resorption lacunae and hyalinization were found at the PDL-bone interface on the compression side in the control, whereas they were scarce after irisin administration. The expression of collagen type I, periostin, OCN, vWF, and FNDC5 in PDL was enhanced by irisin administration. Limitations The feeler gauge method may overestimate OTM. Conclusions Submucosal irisin injection reduced OTM by enhancing osteogenic potential of PDL, and this effect was more significant on the compression side.

Objective Type 1 diabetes (T1D) is associated with substantial fracture risk. Bone mineral density (BMD) is, however, only modestly reduced, suggesting impaired bone microarchitecture and/or bone material properties. Yet, the skeletal abnormalities have not been uncovered. Men with T1D seem to experience a more pronounced bone loss than their female counterparts. Hence, we aimed to examine different aspects of bone quality in men with T1D. Design and Methods In this cross-sectional study, men with T1D and healthy male controls were enrolled. BMD (femoral neck, total hip, lumbar spine, whole body) and spine trabecular bone score (TBS) were measured by dual x-ray absorptiometry, and bone material strength index (BMSi) was measured by in vivo impact microindentation. HbA1c and bone turnover markers were analyzed. Results Altogether, 33 men with T1D (43 ± 12 years) and 28 healthy male controls (42 ± 12 years) were included. Subjects with T1D exhibited lower whole-body BMD than controls (P = 0.04). TBS and BMSi were attenuated in men with T1D vs controls (P = 0.016 and P = 0.004, respectively), and T1D subjects also had a lower bone turnover. The bone parameters did not differ between subjects with or without diabetic complications. Duration of disease correlated negatively with femoral neck BMD but not with TBS or BMSi. Conclusions This study revealed compromised bone material strength and microarchitecture in men with T1D. Moreover, our data confirm previous studies which found a modest decrease in BMD and low bone turnover in subjects with T1D. Accordingly, bone should be recognized as a target of diabetic complications.

Summary Bisphosphonates reduce fractures in randomized controlled trials (RCT); however, there is less information from real life. In our population including 14,990 women and 13,239 men, use of bisphosphonates reduced risk of fractures in hip and forearm in women. The magnitude of the effect was comparable to results from RCT. Introduction The objective was to examine if treatment with bisphosphonates (BPs) was associated with reduced risk of fractures in the hip and forearm in women and men in the general population. Methods In a cohort study based on data from the third wave of the population-based HUNT Study (HUNT3), the fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database, 14,990 women and 13,239 men 50–85 years were followed from the date of participating in HUNT3 (2006–2008) until the date of first fracture in the hip or forearm, death, or end of study (31 December 2012). Hazard ratios with 95% confidence intervals for hip and forearm fracture according to use of BPs were estimated using Cox proportional hazards models with time-dependent exposure. Adjustment for individual FRAX® fracture risk assessment scores was included. Results BPs, predominantly alendronate, were used by 9.4% of the women and 1.5% of the men. During a median of 5.2 years of follow-up, 265 women and 133 men had a hip fracture, and 662 women and 127 men had a forearm fracture. Compared with nonusers of BPs, the hazard ratios with 95% confidence interval for a fracture among users of BPs adjusted for age and FRAX® were 0.67 (0.52–0.86) for women and 1.13 (0.50–2.57) for men. Among users of glucocorticoids, the corresponding figures were 0.35 (0.19–0.66) and 1.16 (0.33–4.09), respectively. Conclusions Use of BPs was associated with reduced risk of fractures in hip and forearm in women, and the magnitude of effect is comparable to results from RCTs. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc/4.0/.

Objective Bisphosphonates like alendronate mainly exert their effects on osteoclasts. However, osteoblasts are also affected, but exposed to a much lower concentration in vivo than the osteoclasts. Given that the effects are dose-dependent, the intention of the study was to identify a therapeutically relevant concentration of alendronate for in vitro studies on osteoblasts. Materials and methods Primary human osteoblasts were incubated with alendronate (5, 20 and 100 µM) for 1, 3, 7 and 14 days. Proliferation and viability were assessed, and the effects on cellular growth and function were evaluated by multianalyte profiling of selected proteins in cell culture media using the Luminex 200TM. Results The viability was not affected by any of the dosages. Exposure to 5 µM alendronate had a neutral effect on osteoblast proliferation, and on secretion of osteogenic and inflammatory markers, while enhancing synthesis of a marker of angiogenesis. 20 µM alendronate induced a decline in proliferation and affected angiogenic and osteogenic biomarkers adversely. 100 µM alendronate reduced proliferation dramatically, and this dosage was excluded from further experiments. Conclusion A concentration of 5 µM alendronate exerted effects on human osteoblasts that may translate to those observed in vivo and could therefore be relevant for in vitro studies.

Given the scarcity of data on diabetes prevalence and associated risk factors among women in rural Nepal, we aimed to examine this, using glycated hemoglobin (HbA1c) as a diagnostic tool. A cross-sectional survey addressing reproductive health and non-communicable diseases was conducted in 2012–2013 among non-pregnant, married women in Bolde, a rural district of Nepal. HbA1c ≥ 6.5% (48 mmol/mol) was used as diagnostic criterion for diabetes, a cut-off of 7.0% (53 mmol/mol) was used to increase the specificity. HbA1c was measured in 757 women (17–86 years). The prevalence of diabetes and prediabetes was 13.5% and 38.5%, respectively. When using 7.0% as a cut-off, the prevalence of diabetes was 5.8%. Aging, intake of instant noodles and milk and vegetarian food (ns) were associated with increased risk for diabetes. Waist circumference was higher among women with diabetes, although not significant. The women were uneducated (87.6%), and only 12% had heard about diabetes. In conclusion, we observed a higher prevalence of diabetes and prediabetes than anticipated among rural, Nepalese women. The increased risk was mainly attributed to dietary factors. In contrast to most previous studies in Nepal, we used HbA1c as diagnostic criterion.

Objective Due to gastrointestinal side effects of oral bisphosphonates (BPs), proton pump inhibitors (PPIs) are often prescribed. PPIs may enhance the risk of osteonecrosis of the jaw, a rare side effect of BPs. Therefore, the objective of this study was to evaluate the effects of the oral BP alendronate (ALN) and the PPI omeprazole (OME) alone and in combination on primary human osteoblasts and gingival fibroblasts in vitro. Methods Human gingival fibroblasts and normal human osteoblasts were incubated with either 5 μM of ALN or 1 μM of OME, or ALN + OME for 1, 3, 7 or 14 days. Effect on viability was evaluated by the lactate dehydrogenase activity in the medium and on proliferation by quantifying 3H-thymidin incorporation. Multianalyte profiling of proteins in cell culture media was performed using the Luminex 200TM system to assess the effect on selected bone markers and cytokines. Results The proliferation of osteoblasts and fibroblasts was reduced upon exposure to ALN + OME. ALN induced an early, temporary rise in markers of inflammation, and OME and ALN + OME promoted a transient decline. An initial increase in IL-13 occurred after exposure to all three options, whereas ALN + OME promoted IL-8 release after 7 days. OME and ALN + OME promoted a transient reduction in vascular endothelial growth factor (VEGF) from osteoblasts, whereas ALN and ALN + OME induced a late rise in VEGF from fibroblasts. Osteoprotegerin release was enhanced by ALN and suppressed by OME and ALN + OME. Conclusions ALN + OME seemed to exaggerate the negative effects of each drug alone on human osteoblasts and gingival fibroblasts. The anti-proliferative effects, modulation of inflammation and impairment of angiogenesis, may induce unfavorable conditions in periodontal tissue facilitating development of osteonecrosis., Highlights • Alendronate and omeprazole reduce proliferation in osteoblasts and fibroblasts. • Unchanged viability after exposure to either drug or the combination • Omeprazole, alone and combined with alendronate, cause impairment of angiogenesis. • Alendronate promotes an initial, transient increase in pro-inflammatory cytokines.

Hypovitaminosis D is prevalent worldwide, and especially in South-Asia. According to the Institute of Medicine (IOM), 25(OH)D levels below 30 nmol/L are defined as vitamin D deficiency (VDD) and levels between 30–50 nmol/L as insufficiency (VDI). Besides its role in calcium homeostasis, it has been postulated that vitamin D is involved in metabolic syndrome. Given the scarcity of data on vitamin D status in Nepal, we aimed to examine the prevalence of VDD and VDI, as well as the determinants and association with metabolic parameters (lipids, HbA1c), in a cohort of women in rural Nepal. Altogether, 733 women 48.5 ± 11.7 years of age were included. VDD and VDI were observed in 6.3 and 42.4% of the participants, respectively, and the prevalence increased by age. Women reporting intake of milk and eggs > 2 times weekly had higher 25(OH)D levels than those reporting intake < 2 times weekly. Women with vitamin D levels < 50 nmol/L displayed higher levels of cholesterol, LDL-cholesterol, triglycerides, and HbA1c. Additionally, a regression analysis showed a significant association between hypovitaminosis D, dyslipidemia, and HbA1c elevation. In conclusion, VDI was prevalent and increased with age. Milk and egg intake > 2 times weekly seemed to decrease the risk of VDI. Moreover, hypovitaminosis D was associated with an adverse metabolic profile.

Objective The objective was to examine the effects of repetitive local administration of adiponectin on experimental tooth movement in rats. Materials and methods The maxillary right first molar of male Wistar rats (n = 24) was moved mesially for 14 days, with local adiponectin injections (0.2 or 2 μg) every third day. Micro-computed tomography was performed at days 0, 6 and 14 and molar movement, bone density and bone volume fraction were calculated from the scans. Changes in extracellular matrix collagen and cell numbers in the periodontal ligament were analyzed histologically, and levels of circulating cytokines were measured by Luminex and ELISA. Results Adiponectin injections induced a reduction in tooth movement after 12 and 14 days compared to controls. No tooth movement was observed between days 3 and 14 in the group receiving the highest dosage (2 μg) of adiponectin. Differences in bone density and bone volume fractions between treatment and control groups were not identified. Relative size and morphology of collagen fibrils, and cell number in the periodontal region after adiponectin injections were unchanged compared to controls. Levels of circulating adiponectin or other selected factors in plasma were not influenced by the adiponectin injections. Conclusions Submucosal injections of adiponectin prevented experimental tooth movement in rats. The effect was dosage-dependent and local. Adiponectin injections caused no detectable changes in bone density, periodontal cell number or collagen content.

Rotational culture promotes primary human osteoblasts (hOBs) to form three-dimensional (3D) multicellular spheroids with bone tissue-like structure without any scaffolding material. Cell-based bone models enable us to investigate the effect of different agents on the mechanical strength of bone. Given that low dietary intake of both vitamin D and K is negatively associated with fracture risk, we aimed to assess the effect of these vitamins in this system. Osteospheres of hOBs were generated with menaquinone-4 (MK-4; 10μM) and 25-hydroxyvitamin D3 [25(OH)D3; 0.01μM], alone and in combination, or without vitamins. The mechanical properties were tested by nanoindentation using a flat-punch compression method, and the mineralized extracellular bone matrix was characterized by microscopy. The in vitro response of hOBs to MK-4 and 25(OH)D3 was further evaluated in two-dimensional (2D) cultures and in the 3D bone constructs applying gene expression analysis and multiplex immunoassays. Mechanical testing revealed that 25(OH)D3 induced a stiffer and MK-4 a softer or more flexible osteosphere compared with control. Combined vitamin conditions induced the same flexibility as MK-4 alone. Enhanced levels of periostin (p < 0.001) and altered distribution of collagen type I (COL-1) were found in osteospheres supplemented with MK-4. In contrast, 25(OH)D3 reduced COL-1, both at the mRNA and protein levels, increased alkaline phosphatase, and stimulated mineral deposition in the osteospheres. With the two vitamins in combination, enhanced gene expression of periostin and COL-1 was seen, as well as extended osteoid formation into the central region and increased mineral deposition all over the area. Moreover, we observed enhanced levels of osteocalcin in 2D and osteopontin in 3D cultures exposed to 25(OH)D3 alone and combined with MK-4. In conclusion, the two vitamins seem to affect bone mechanical properties differently: vitamin D enhancing stiffness and K2 conveying flexibility to bone. These effects may translate to increased fracture resistance in vivo. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Received in original form October 27, 2019; revised form July 6, 2020; accepted July 8, 2020. Accepted manuscript online July 14, 2020. Address correspondence to: Janne E Reseland, Department of Biomaterials, Faculty of Dentistry, PO Box 1109 Blindern, N-0317 Oslo, Norway. E-mail: j.e. reseland@odont.uio.no JBMR® Plus (WOA), Vol. 00, No. 00, Month 2020, e10394. DOI: 10.1002/jbm4.10394 © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Objective To assess the association between levels of vitamin D and urinary incontinence (UI) in pregnancy. Design A cross‐sectional study. Secondary analysis of a randomised controlled trial. Setting Two university hospitals in Norway. Population A total of 851 healthy, pregnant women >18 years in gestational weeks 18–22 with a singleton live fetus. Methods Data on UI were collected from a questionnaire at inclusion and serum analysis of 25‐hydroxy vitamin D (25(OH)D) was performed. Univariable and multivariable logistic regression analyses were applied to study associations between exposure and outcomes. Main outcome measures Prevalence of self‐reported UI, stress (SUI) and urge (UUI) or mixed UI. Results In total, 230/851 (27%) of the participants were vitamin D insufficient (25(OH)D

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Summary: Proton pump inhibitors (PPIs) have been linked to increased risk of fracture; the data have, however, been diverging. We did not find any increased risk of fractures among users of PPIs in a Norwegian population of 15,017 women and 13,241 men aged 50–85 years with detailed information about lifestyle and comorbidity. Introduction: Proton pump inhibitors (PPIs) are widely prescribed and have been linked to increased risk of fracture. Methods: We used data from the Nord-Trøndelag Health Study (HUNT3), The Fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database, including 15,017 women and 13,241 men aged 50–85 years. The study population was followed from the date of participating in HUNT3 (2006–2008) until the date of first fracture (forearm or hip), death, or end of study (31 December 2012). The Cox proportional hazards model with time-dependent exposure to PPIs was applied, and each individual was considered as unexposed until the first prescriptions was filled. To be included, the prescription of PPIs should minimum be equivalent to 90 defined daily doses (DDD) in the period. Individuals were defined as exposed until 6 months after end of drug supply. Results: The proportion of women and men using PPIs was 17.9% and 15.5%, respectively. During a median of 5.2 years follow-up, 266 women and 134 men had a first hip fracture and 662 women and 127 men, a first forearm fracture. The combined rate/1000 patient-years for forearm and hip fractures in women was 49.2 for users of PPIs compared with 64.1 among non-users; for men 18.6 and 19.8, respectively. The hazard ratios with 95% confidence interval for the first forearm or hip fracture among users of PPIs in the age-adjusted analysis were 0.82 (0.67–1.01) for women and 1.05 (0.72–1.52) for men. Adjusting for age, use of anti-osteoporotic drugs, and FRAX, the HR declined to 0.80 (0.65–0.98) in women and 1.00 (0.69–1.45) in men. Conclusions: Use of PPIs was not associated with an increased risk of fractures.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H+/K+ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by three-point bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Three-point bending test also showed higher Young’s modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition.

Epidemiological studies suggest increased fracture risk in patients using proton pump inhibitors (PPIs). We have previously shown that the H(+) /K(+) ATPase beta subunit knockout (KO) mouse, which is a model of PPI-use, have lower bone mineral density (BMD) and impaired bone quality compared to wild type (WT) mice. Like PPI users, these KO mice display elevated gastric pH and hypergastrinemia, which in turn stimulates gastric histamine release. Previous studies have suggested a negative effect of histamine on bone, thus, we wanted to study whether a histamine 1 receptor (H1R) antagonist could improve bone quality in KO mice. Female KO and WT mice aged 8 weeks received either an H1R antagonist (cetirizine) or polyethylene glycol (PEG) for 6 months. At the end of the study, KO mice displayed elevated plasma histamine levels compared to WT. As demonstrated previously, the KO mice also exhibited lower whole body BMD, reduced mechanical bone strength, and impaired bone quality assessed by μCT. No significant differences, however, were found between the KO groups receiving cetirizine or PEG for any of the measured bone parameters. In vitro gene expression analyses of histamine receptors revealed the presence of H1R and H2R both in osteoblasts and osteoclasts, and H3R in late stage osteoblasts. In conclusion, administration of the H1R antagonist cetirizine in a concentration of 3 mg/kg did not rescue the osteoporotic phenotype in H(+) /K(+) ATPase beta subunit KO mice. It can, however, not be ruled out that histamine may influence bone via other receptors. J. Cell. Biochem. 117: 2089-2096, 2016. © 2016 Wiley Periodicals, Inc.

In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0 nmol/L completed a four months intervention with vitamin D3 20,000 IU per week versus placebo. Mean serum 25(OH)D increased to 89.0 nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2 pg/mL and 1.5 ng/mL, respectively, P 6.5 pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects. © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Estrogen deficiency causes bone loss and skeletal muscle dysfunction, and attenuates the musculoskeletal effects of exercise. The anti-diabetic drug metformin has been suggested to promote beneficial skeletal effects. To explore whether metformin can improve musculoskeletal training response during estrogen deficiency, we investigated the skeletal effects of plyometric exercise and metformin, in an ovarectomized (OVX) rat model of osteoporosis. Female Sprague Dawley rats, 12 weeks of age, rats were allocated to a sham-operated group (Sham), and four OVX groups; metformin (OVX-Met), exercise (OVX-Ex), combined metformin and exercise (OVX-MetEx) and a control group (OVX-Ctr), n = 12/group. Dual X-ray absorptiometry, micro computed tomography, fracture toughness testing, histomorphometry and plasma analyses were performed to explore skeletal effects. All intervention groups exhibited a higher gain in femoral bone mineral density (BMD) than OVX-Ctr (p < .01). The combined intervention also resulted in a higher gain in femoral and spine BMD compared to OVX-Met (p < .01). Both exercise groups displayed improved microarchitecture, including both cortical and trabecular parameters (p < .05). This was most evident in the OVX-MetEx group where several indices were at sham level or superior to OVX-Ctr (p < .05). The OVX-MetEx group also exhibited an enhanced toughening effect compared to the other OVX groups (p < .05). The beneficial skeletal effects seemed to be mediated by inhibition of bone resorption and stimulation of bone formation. The training response (i.e. jumping height) was also greater in the metformin treated rats compared to OVX-Ex (p < .01), indicating a performance-enhancing effect of metformin. Both exercise groups displayed higher lean mass than OVX-Ctr (p < .05). In conclusion, the combination of plyometric exercise and metformin improved trabecular microarchitecture and bone material properties relative to OVX controls. However, no additive effect of the combined intervention was observed compared to exercise alone. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background Vitamin A and D deficiency is prevalent in pregnant women worldwide. Both vitamins are involved in fetal skeletal development. A positive association between maternal vitamin D levels and offspring bone mineral density (BMD) at adulthood has been observed. The impact of maternal vitamin A status in pregnancy on offspring peak bone mass remains unclear. Method and findings Forty-one mother-child pairs were recruited from a population-based prospective cohort study in Trondheim, Norway, where pregnant women were followed from gestational week 17. Their term-born infants were followed from birth (1986–88). Regression analyses were performed for vitamin A (retinol), 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in maternal serum (gestational weeks 17, 33, 37) and cord blood. Offspring BMD and spine trabecular bone score (TBS), a measure of bone quality, were analyzed by dual x-ray absorptiometry at 26 years. Average levels during pregnancy of retinol, 25(OH)D and 1,25(OH)2D were 1.66 (0.32) μmol/L, 59.0 (20.6) nmol/L, and 251.3 (62.4) pmol/L, respectively. 1,25(OH)2D levels were similar in those with 25(OH)D levels 75 nmol/L. After adjustment for maternal age, BMI, smoking, and education, and offspring birth weight, maternal serum retinol was positively associated with offspring spine BMD [mean change 30.8 (CI 7.6, 54.0) mg/cm2 per 0.2 μmol/L retinol], and with offspring TBS, although non-significant (p = 0.08). No associations were found between maternal 25(OH)D and 1,25(OH)2D levels and offspring bone parameters. Vitamin levels in cord blood were not associated with offspring BMD or TBS. Conclusions This is the first study to show an association between maternal vitamin A status and offspring peak bone mass. Our findings may imply increase future risk for osteoporotic fracture in offspring of mothers with suboptimal vitamin A level. No associations were observed between 25(OH)D and 1,25(OH)2D and offspring BMD. Copyright: © 2019 Balasuriya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman’s rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells. © 2019 Jorde et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

This trial protocol of the Norwegian Capture the Fracture Initiative (NoFRACT) intends to use registry data from Norway and a stepped wedge cluster design to investigate the effect of a standardized intervention program on the rate of subsequent fracture among patients with a fragility fracture., Key Points Question What is the effect of a fracture liaison service on the rate of subsequent fractures? Findings This trial protocol intends to use merged outcome data from national registers to include 82 000 women and men 50 years and older with a fragility fracture treated in 7 hospitals in Norway in a stepped wedge cluster randomized clinical trial introducing a standardized intervention program. The use of outcome data from national registers, which include all patients in the analysis regardless of whether they are exposed to the intervention (intention to treat), should ensure that outcomes are assessed in a standardized way. Meaning The design of this trial is intended to overcome the ethical challenges associated with traditional randomized clinical trials and to generate new knowledge on how to improve the current standard of care., Importance Fragility fracture is a major health issue because of the accompanying morbidity, mortality, and financial cost. Despite the high cost to society and personal cost to affected individuals, secondary fracture prevention is suboptimal in Norway, mainly because most patients with osteoporotic fractures do not receive treatment with antiosteoporotic drugs after fracture repair. Objectives To improve secondary fracture prevention by introducing a standardized intervention program and to investigate the effect of the program on the rate of subsequent fractures. Design, Setting, and Participants Trial protocol of the Norwegian Capture the Fracture Initiative (NoFRACT), an ongoing, stepped wedge cluster randomized clinical trial in 7 hospitals in Norway. The participating hospitals were cluster randomized to an intervention starting date: May 1, 2015; September 1, 2015; and January 1, 2016. Follow-up is through December 31, 2019. The outcome data were merged from national registries of women and men 50 years and older with a recent fragility fracture treated at 1 of the 7 hospitals. Discussion The NoFRACT trial is intended to enroll 82 000 patients (intervention period, 26 000 patients; control period, 56 000 patients), of whom 23 578 are currently enrolled by January 2018. Interventions include a standardized program for identification, assessment, and treatment of osteoporosis in patients with a fragility fracture that is led by a trained coordinating nurse. The primary outcome is rate of subsequent fracture (per 10 000 person-years) based on national registry data. Outcomes before (2008-2015; control period) and after (2015-2019; intervention period) the intervention will be compared, and each hospital will act as its own control. Use of outcomes from national registry data means that all patients are included in the analysis regardless of whether they are exposed to the intervention (intention to treat). A sensitivity analysis with a transition window will be performed to mitigate possible within-cluster contamination. Results Results are planned to be disseminated through publications in peer-reviewed journals and presented at local, national, and international conferences. Conclusions By introducing a standardized intervention program for assessment and treatment of osteoporosis in patients with fragility fractures, we expect to document reduced rates of subsequent fractures and fracture-related mortality. Trial Registration ClinicalTrials.gov Identifier: NCT02536898

Summary Use of anti-osteoporotic drugs (AODs) was examined in a Norwegian population 50–85 years. Among them with Fracture Risk Assessment Tool (FRAX) score for major osteoporotic fracture ≥ 20, 25% of the women and 17% of the men received AODs. The strongest predictors for AODs were high age in women and use of glucocorticoids among men. Introduction To examine the use of anti-osteoporotic drugs (AODs) and to identify predictors for prescriptions. Methods Data were obtained from the Nord-Trøndelag Health Study (HUNT3) performed in 2006–2008 and the Norwegian Prescription Database, including 15,075 women and 13,386 men aged 50–85 years. Bone mineral density (BMD) in the femoral neck was measured in a subgroup of 4538 women and 2322 men. High fracture risk was defined as a FRAX score for major osteoporotic fracture (MOF) ≥ 20%; in the subgroup with BMD, high risk was in addition defined as FRAXMOF ≥ 20% or T-score ≤ − 2.5. Hazard ratios (HRs) for predictors of incident use of AODs within 2 years after HUNT3 were estimated by Cox’ proportional hazards model. Results Among individuals with FRAX MOF ≥ 20%, 25% of the women and 17% of the men were treated with AODs. Among those with FRAX MOF

Low birthweight (LBW) has emerged as a risk factor of metabolic syndrome (MetS). Whether adults with very low birthweight (VLBW) born preterm are at higher risk than individuals who were term-born small for gestational age (tb-SGA) is not established. We assessed metabolic outcomes, including relation with skeletal parameters, in these two LBW categories.This follow-up cohort study included 189 individuals (females 51%), aged 25 to 28 years; 55 were preterm VLBW (≤1500 g), 59 were tb-SGA (10th percentile), and 75 were controls (≥10th percentile). Outcomes were indices of MetS: blood pressure (BP), waist circumference, fasting glucose, lipid profile, and association between calculated MetS score and bone mineral density (BMD) and trabecular bone score (TBS), a measure of bone quality.Compared with controls, individuals with VLBW displayed higher systolic [mean (SD), 126 (13.3) vs 119 (12.3) mm Hg; 95% CI, 1.27 to 11.48 mm Hg] and diastolic [71.9 (7.6) vs 68.6 (7.1) mm Hg; 95% CI, 0.3 to 6.2 mm Hg] BP, higher glycated hemoglobin, higher C-peptide, increased insulin resistance (Homeostatic Model Assessment 2), and lower high-density lipoprotein cholesterol [1.34 (0.3) vs 1.50 (0.4); 95% CI, 0.32 to 0.01]. Substantial differences were mainly seen between control females and females with VLBW. The adults who were tb-SGA had higher waist circumference and higher total and low-density lipoprotein cholesterol compared with controls. In males, MetS score correlated positively with BMD and inversely with TBS.The LBW groups and preferentially females in the VLBW group displayed a less favorable metabolic profile than did controls. The inverse association between MetS score and bone quality suggests enhanced future fracture risk.

Fourth generation composite femurs (4GCFs, models #3406 and #3403) simulate femurs of males80 years with good bone quality. Since most hip fractures occur in old women with fragile bones, concern is raised regarding the use of standard 4GCFs in biomechanical experiments. In this study the stability of hip fracture fixations in 4GCFs was compared to human cadaver femurs (HCFs) selected to represent patients with hip fractures. Ten 4GCFs (Sawbones, Pacific Research Laboratories, Inc., Vashon, WA, USA) were compared to 24 HCFs from seven females and five males60 years. Proximal femur anthropometric measurements were noted. Strain gauge rosettes were attached and femurs were mounted in a hip simulator applying a combined subject-specific axial load and torque. Baseline measurements of resistance to deformation were recorded. Standardized femoral neck fractures were surgically stabilized before the constructs were subjected to 20,000 load-cycles. An optical motion tracking system measured relative movements. Median (95% CI) head fragment migration was 0.8mm (0.4 to 1.1) in the 4GCF group versus 2.2mm (1.5 to 4.6) in the cadaver group (p=0.001). This difference in fracture stability could not be explained by observed differences in femoral anthropometry or potential overloading of 4GCFs. 4GCFs failed with fracture-patterns different from those observed in cadavers. To conclude, standard 4GCFs provide unrealistically stable bone-implant constructs and fail with fractures not observed in cadavers. Until a validated osteopenic or osteoporotic composite femur model is provided, standard 4GCFs should only be used when representing the biomechanical properties of young healthy femurs.

This study assessed distal femur and lumbar spine bone mineral density (BMD) Z-scores in children with cerebral palsy. BMD z-score was lower in non-ambulatory than in ambulatory children. Somewhat surprisingly, among ambulatory children, those with better walking abilities had higher BMD z-score than those with more impaired walking ability. Children with cerebral palsy (CP) have increased risk for low bone mineral density (BMD). The aim was to explore the difference in BMD at the distal femur and lumbar spine between ambulatory and non-ambulatory children with CP and the relationship between vitamin D status and BMD. Fifty-one children (age range 8–18 years; 20 girls) with CP participated. Their BMD Z-scores were measured in the lumbar spine and the distal femur using dual X-ray absorptiometry, and 25-hydroxy-vitamin D (25-OHD) concentrations were measured in serum. Children with GMFCS level I–III were defined as ‘walkers’ while children with level IV–V were defined as ‘non-walkers. Non-walkers had lower mean BMD Z-scores (range −1.7 to −5.4) than walkers at all sites (range −0.8 to −1.5). Among walkers, BMD Z-scores at the distal femur were lower in those with GMFCS level II than with level I (p values

Estrogen deficiency promotes bone loss and skeletal muscle dysfunction. Peroxisome proliferator-activated receptors (PPARs) have 3 subtypes (α, δ, and γ). PPARγ agonists induce bone loss, whereas PPARα agonists increase bone mass. Although PPARδ agonists are known to influence skeletal muscle metabolism, the skeletal effects are unsettled. This study investigated the musculoskeletal effects of the PPARδ agonist GW501516 in ovariectomized (OVX) rats. Female Sprague Dawley rats, 12 weeks of age, were allocated to a sham-operated group and 3 OVX groups; high-dose GW501516 (OVX-GW5), low-dose GW501516 (OVX-GW1), and a control group (OVX-CTR), respectively (n = 12 per group). Animals received GW501516 or vehicle (methylcellulose) daily for 4 months by gavage. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry at the femur, spine, and whole body. Bone microarchitecture at the proximal tibia was assessed by microcomputed tomography, and dynamic histomorphometry was performed. Quadriceps muscle morphology and the relative expression of mitochondrial proteins were analyzed. Bone metabolism markers and metabolic markers were measured in plasma. After 4 months, the OVX-GW5 group displayed lower femoral BMD than OVX-CTR. Trabecular separation was higher in the GW-treated groups, compared with OVX-CTR. The OVX-GW5 group also exhibited lower cortical area fraction and a higher structure model index than OVX-CTR. These effects coincided with impaired bone formation in both GW groups. The OVX-GW5 group displayed elevated triglyceride levels and reduced adiponectin levels, whereas no effects on muscle morphology or mitochondrial gene expression appeared. In summary, the PPARδ agonist GW501516 negatively affected bone properties in OVX rats, whereas no effects were detected in skeletal muscle.

Summary Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD) for hip fracture prediction was validated in a Norwegian population 50–90 years. Fracture risk increased with higher FRAX score, and the observed number of hip fractures agreed well with the predicted number, except for the youngest and oldest men. Self-reported fall was an independent risk factor for fracture in women. Introduction The primary aim was to validate FRAX without BMD for hip fracture prediction in a Norwegian population of men and women 50–90 years. Secondary, to study whether information of falls could improve prediction of fractures in the subgroup aged 70–90 years. Methods Data were obtained from the third survey of the Nord-Trøndelag Health Study (HUNT3), the fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database (NorPD), including 15,432 women and 13,585 men. FRAX hip without BMD was calculated, and hip fractures were registered for a median follow-up of 5.2 years. The number of estimated and observed fractures was assessed, ROC curves with area under the curve (AUC), and Cox regression analyses. For the group aged 70–90 years, self-reported falls the last year before HUNT3 were included in the Cox regression model. Results The risk of fracture increased with higher FRAX score. When FRAX groups were categorized in a 10-year percentage risk for hip fracture as follows

Context and objectives Peak bone mass (PBM) is regarded as the most important determinant of osteoporosis. Growing evidence suggests a role of intrauterine programming in skeletal development. We examined PBM and trabecular bone score (TBS) in adults born preterm with very low birth weight (VLBW) or small for gestational age (SGA) at term compared with term-born controls. Design, setting, participants, and outcomes This follow-up cohort study included 186 men and women (25 to 28 years); 52 preterm VLBW (≤1500 g), 59 term-born SGA ( 10th percentile). Main outcome was bone mineral density (BMD) by dual x-ray absorptiometry. Secondary outcomes were bone mineral content (BMC), TBS, and serum bone markers. Results VLBW adults had lower BMC and BMD vs controls, also when adjusted for height, weight, and potential confounders, with the following BMD Z-score differences: femoral neck, 0.6 standard deviation (SD) (P = 0.003); total hip, 0.4 SD (P = 0.01); whole body, 0.5 SD (P = 0.007); and lumbar spine, 0.3 SD (P = 0.213). The SGA group displayed lower spine BMC and whole-body BMD Z-scores, but not after adjustment. Adjusted odds ratios for osteopenia/osteoporosis were 2.4 and 2.0 in VLBW and SGA adults, respectively. TBS did not differ between groups, but it was lower in men than in women. Serum Dickkopf-1 was higher in VLBW subjects vs controls; however, it was not significant after adjustment for multiple comparisons. Conclusions Both low-birth-weight groups displayed lower PBM and higher frequency of osteopenia/osteoporosis, implying increased future fracture risk. The most pronounced bone deficit was seen in VLBW adults.

Resistance training is beneficial for maintaining bone mass. We aimed to investigate the skeletal effects of high doses of antioxidants [vitamin C + E (α-tocopherol)] supplementation during 12-week supervised strength training in healthy, elderly men METHODS: Design: double-blinded randomized placebo-controlled study. Participants followed a supervised, undulating periodic exercise program with weekly adjusted load: 3 sessions/week and 3-15 repetitions maximum (RM) sets/exercise. The control group (CG, n = 17, 67 ± 5 years) received placebo and the antioxidant group (AO, n = 16, 70 ± 7 years) 1000 mg vitamin C + 235 mg vitamin E, daily. Areal bone mineral density (aBMD) at whole body, lumbar spine (L1-L4), total hip, and femoral neck were measured by dual energy X-ray absorptiometry and muscle strength by 1RM. Serum analyses of bone-related factors and adipokines were performed.In the CG, total hip aBMD increased by 1.0% (CI: 0.3-1.7) versus pretest and lumbar spine aBMD increased by 0.9% (CI: -0.2 to 2.0) compared to the AO. In the CG, there was an increase in serum concentrations of insulin-like growth factor 1 [+27.3% (CI: -0.3 to 54.9)] and leptin [+31.2% (CI: 9.8-52.6)) versus pretest, and a decrease in sclerostin [-9.9% (CI: 4.4-15.3)] versus pretest and versus AO. Serum bone formation markers P1NP and osteocalcin increased in both groups, while the bone resorption marker CTX-1 remained unchanged.High doses of antioxidant supplementations may constrain the favorable skeletal benefits of 12 weeks of resistance exercise in healthy elderly men.

The musculoskeletal effects of exercise are attenuated by estrogen deficiency. The peroxisome proliferator-activated receptor-α agonist fenofibrate exerts beneficial effects in bone and muscle. We therefore examined whether fenofibrate could enhance the musculoskeletal training response during estrogen deficiency. We investigated the combined effects of 8 weeks of fenofibrate and jumping exercise in ovariectomized (OVX) Sprague Dawley rats. Female rats were allocated to a sham-operated group and four OVX groups; fenofibrate (OVX-Fen), exercise (OVX-Ex), combined fenofibrate and exercise (OVX-FenEx), and a control group (OVX-Ctr) (n = 12/group). Fenofibrate (90 mg/kg/d) or methylcellulose was given by gavage. The combination of exercise and fenofibrate resulted in enhanced femoral bone mineral density (BMD) and improved bone microarchitecture compared with fenofibrate alone as well as increased trabecular BMD compared with OVX-Ctr. These effects were not seen in the OVX-Ex group. Femoral BMD was normalized in both exercise groups relative to sham and increased more in all intervention groups compared with OVX-Ctr. A higher plasma level of the bone formation marker type 1 collagen amino propeptide was observed in the OVX-Fen and OVX-FenEx groups compared with controls. Lean mass and soleus muscle weight were higher in the OVX-FenEx group than in the OVX-Ctr group, which coincided with lower mRNA levels of Atrogin1. These results suggest that peroxisome proliferator-activated receptor-α activation improves the musculoskeletal effects of exercise during estrogen deficiency.