Determinants of trabecular bone score and prevalent vertebral fractures in women with fragility fractures: a cross-sectional sub-study of NoFRACT.

Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1-SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1-SQ3 fractures. SQ1-SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS. INTRODUCTION: Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1-SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1-SQ3 fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1-SQ3 fracture assessed. RESULTS: Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1-SQ3 fractures. In multiple variable analysis, higher age (ßper SD = - 0.26, 95% CI: - 0.36,- 0.15), parental hip fracture (ß = - 0.29, 95% CI: - 0.54,- 0.05), and daily alcohol intake (ß = - 0.43, 95% CI - 0.79, - 0.08) were associated with lower TBS. Higher BMD of femoral neck (ßper SD = 0.34, 95% CI 0.25-0.43) and lumbar spine (ßper SD = 0.40, 95% CI 0.31-0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (ORper SD = 1.94, 95% CI 1.51-2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09-2.71) were positively associated with SQ1-SQ3 fractures, while lumbar spine BMD (ORper SD = 0.75 95% CI 0.60-0.95) was negatively associated with SQ1-SQ3 fractures. No association between TBS and SQ1-SQ3 fractures was found. CONCLUSION: Since TBS and SQ1-SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment.

Serum parathyroid hormone is associated with increased cortical porosity of the inner transitional zone at the proximal femur in postmenopausal women: the Tromsø Study.

Serum parathyroid hormone (PTH) was associated with increased bone turnover markers and cortical porosity of the inner transitional zone at the proximal femur. These results suggest that PTH through increased intracortical bone turnover leads to trabecularisation of inner cortical bone in postmenopausal women. INTRODUCTION: Vitamin D deficiency leads to secondary hyperparathyroidism and increased risk for fractures, whereas its association with cortical porosity is less clear. We tested (i) whether serum 25-hydroxyvitamin D (25(OH)D) and PTH were associated with cortical porosity and (ii) whether the associations of 25(OH)D) and PTH with fracture risk are dependent on cortical porosity. METHODS: This case-control study included 211 postmenopausal women, 54-94 years old, with prevalent fractures and 232 controls from the Tromsø Study. Serum 25(OH)D, PTH, and bone turnover markers (procollagen type I N-terminal propeptide [PINP] and C-terminal cross-linking telopeptide of type I collagen [CTX]) were measured. Femoral subtrochanteric cortical and trabecular parameters were quantified using computed tomography, and femoral neck areal bone mineral density (FN aBMD) was quantified using dual-energy X-ray absorptiometry. RESULTS: Compared with controls, fracture cases exhibited reduced serum 25(OH)D and increased PTH, PINP, and CTX, increased femoral subtrochanteric cortical porosity, and reduced cortical thickness and FN aBMD (all, p < 0.05). Serum 25(OH)D was not associated with cortical parameters (all, p > 0.10). PTH was associated with increased PINP, CTX, and cortical porosity of the inner transitional zone and reduced trabecular bone volume/tissue volume and FN aBMD (p ranging from 0.003 to 0.054). Decreasing 25(OH)D and increasing PTH were associated with increased odds for fractures, independent of age, height, weight, calcium supplementation, serum calcium, cortical porosity, and thickness. CONCLUSIONS: These data suggest that serum PTH, not 25(OH)D, is associated with increased intracortical bone turnover resulting in trabecularisation of the inner cortical bone; nevertheless, decreasing 25(OH)D) and increasing PTH are associated with fracture risk, independent of cortical porosity and thickness.

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

Bone marrow lesions in hip osteoarthritis are characterized by increased bone turnover and enhanced angiogenesis.

OBJECTIVE: Bone marrow lesions (BML), previously denoted bone marrow edema, are detected as water signals by magnetic resonance imaging (MRI). Previous histologic studies were unable to demonstrate any edematous changes at the tissue level. Therefore, our aim was to investigate the underlying biological mechanisms of the water signal in MRI scans of bone affected by BML. METHODS: Tetracycline labeling in addition to water sensitive MRI scans of 30 patients planned for total hip replacement surgery was undertaken. Twenty-one femoral heads revealed BML on MRI, while nine were negative and used as controls (CON). Guided by the MRI images cylindrical biopsies were extracted from areas with BML in the femoral heads. Tissue sections from the biopsies were subjected to histomorphometric image analyses of the cancellous bone envelope. RESULTS: Patients with BML exhibited an average 40- and 18-fold increase of bone formation rate and mineralizing surface, respectively. Additionally, samples with BML demonstrated 2-fold reduction of marrow fat and 28-fold increase of woven bone. Immunohistochemical analysis showed a 4-fold increase of angiogenesis markers CD31 and von Willebrand Factor (vWF) in the BML-group compared to CON. CONCLUSION: This study indicates that BML are characterized by increased bone turnover, vascularity and angiogenesis in keeping with it being a reparatory process. Thus, the water signal, which is the hallmark of BML on MRI, is most probably reflecting increased tissue vascularity accompanying increased remodeling activity.

Comparative proteomic analysis of tear fluid in Graves' disease with and without orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is a severe organ-specific autoimmune inflammatory ocular complication most often associated with Graves' disease (GD). Besides the cosmetic problems these patients develop, GO may also cause severe, sight-threatening complications. Additionally, GO complicates the treatment of patients with GD, making the identification of Graves patients at risk for eye disease before they develop symptoms a critical step in the clinical management and quality of life of these patients. The high concentration of proteins in tear fluid makes it an important source for studying potential protein biomarkers for GO. PATIENTS AND METHODS: The aim of this study was to quantitatively compare tear fluid from GD patients with moderate/severe GO (GO) and patients with GD without GO (controls) using untargeted quantitative proteomics based on dimethyl labelling in combination with two-dimensional liquid chromatography-mass spectrometry. RESULTS: Among the 1212 proteins identified, 16 showed significant alterations in abundance between the two groups. Thus, in this study, we reveal a number of novel dysregulated proteins in GO which may contribute to a better understanding of the disease. In particular, upregulation of lacrimal gland proteins such as lysozyme C, lacritin, antileukoproteinase and zinc-alpha-2-glycoprotein 1 suggests involvement of the lacrimal gland in the pathogenesis of GO. CONCLUSIONS: It remains to be elucidated whether some of these proteins can be used as markers for patients at risk for developing GO as well as useful indicators for disease activity.

Measurement of cortical porosity of the proximal femur improves identification of women with nonvertebral fragility fractures.

UNLABELLED: We tested whether cortical porosity of the proximal femur measured using StrAx1.0 software provides additional information to areal bone mineral density (aBMD) or Fracture Risk Assessment Tool (FRAX) in differentiating women with and without fracture. Porosity was associated with fracture independent of aBMD and FRAX and identified additional women with fractures than by osteoporosis or FRAX thresholds. INTRODUCTION: Neither aBMD nor the FRAX captures cortical porosity, a major determinant of bone strength. We therefore tested whether combining porosity with aBMD or FRAX improves identification of women with fractures. METHODS: We quantified femoral neck (FN) aBMD using dual-energy X-ray absorptiometry, FRAX score, and femoral subtrochanteric cortical porosity using StrAx1.0 software in 211 postmenopausal women aged 54-94 years with nonvertebral fractures and 232 controls in Tromsø, Norway. Odds ratios (ORs) were calculated using logistic regression analysis. RESULTS: Women with fractures had lower FN aBMD, higher FRAX score, and higher cortical porosity than controls (all p < 0.001). Each standard deviation higher porosity was associated with fracture independent of FN aBMD (OR 1.39; 95% confidence interval 1.11-1.74) and FRAX score (OR 1.58; 1.27-1.97) in all women combined. Porosity was also associated with fracture independent of FRAX score in subgroups with normal FN aBMD (OR 1.88; 1.21-2.94), osteopenia (OR 1.40; 1.06-1.85), but not significantly in those with osteoporosis (OR 1.48; 0.68-3.23). Of the 211 fracture cases, only 18 women (9%) were identified using FN aBMD T-score < -2.5, 45 women (21%) using FRAX threshold >20%, whereas porosity >80th percentile identified 61 women (29%). Porosity identified 26% additional women with fractures than identified by the osteoporosis threshold and 21% additional women with fractures than by this FRAX threshold. CONCLUSIONS: Cortical porosity is a risk factor for fracture independent of aBMD and FRAX and improves identification of women with fracture.

Differences in bone mineral density, markers of bone turnover and extracellular matrix and daily life muscular activity among patients with recent motor-incomplete versus motor-complete spinal cord injury.

Spinal cord injury (SCI) leads to severe bone loss, but the associated mechanisms are poorly described in incomplete SCI individuals. The purpose of the study is to compare alterations in bone mineral density (BMD) and serum biomarkers of bone turnover in recent motor-incomplete to -complete SCI men, as well as to describe their physical activity and spasticity. We studied 31 men with acute SCI. Whole-body DXA scans, serum biomarkers and self-reported activity and spasticity were examined 1 and/or 3 and 12 months after the injury. We observed a decrease in proximal femur BMD (p < 0.02) in both the groups. Serum phosphate and carboxy-terminal-collagen crosslinks were significantly lower in motor-incomplete versus complete SCI men, whereas albumin-corrected Ca(2+) (p = 0.02) were lower only 3 months after injury. When data from all 31 SCI participants were pooled, we observed increased serum matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of MMP-2 (TIMP-2) (p < 0.02) whereas TIMP-1 decreased (p = 0.03). BMD correlated positively with self-reported activity (r = 0.59, p = 0.04) and negatively with spasticity (r = 0.74, p = 0.02) 12 months after injury. As a summary, men with motor-incomplete SCI developed significant proximal femur bone loss 12 months after injury and exhibited increased bone resorption throughout the first year after the injury. Compared with complete SCI men, incomplete SCI men show attenuated bone resorption. Our pooled data show increased turnover of extracellular matrix after injury and that increased exercise before and after injury correlated with reduced bone loss.

Effects of 3 years treatment with once-yearly zoledronic acid on the kinetics of bone matrix maturation in osteoporotic patients.

UNLABELLED: Once-yearly administration of intravenous zoledronic acid for 3 years in humans affects the kinetics of matrix filling in by mineral, independent of bone turnover. INTRODUCTION: Yearly 5-mg infusions of zoledronic acid (ZOL) for 3 years have shown pronounced antifracture efficacy. The purpose of the present study was to test whether ZOL affects the kinetics of forming bone material properties maturation. METHODS: Iliac crest biopsies from the HORIZON-PFT clinical trial were analyzed by Raman microspectroscopy in actively bone-forming surfaces as a function of tissue age in trabecular and osteonal bone, to determine ZOL's effect on bone material quality indices maturation kinetics. RESULTS: Mineral/matrix ratio increased in both groups as a function of tissue age, at both osteonal- and trabecular-forming surfaces; ZOL exhibiting the greatest increase in the trabecular surfaces only. The proteoglycan content showed a dependency on tissue age in both trabecular and osteonal surfaces, with ZOL exhibiting lower values in the tissue age 8-22 days in the trabecular surfaces. Mineral crystallinity (crystallite length and thickness) showed a dependence on tissue age, with ZOL exhibiting lower crystallite length compared with placebo only in the 8- to 22-day-old tissue at trabecular surfaces, while crystal thickness was lower in the 1- to 5-day-old tissue at both osteonal and trabecular surfaces. CONCLUSIONS: The results of the present study suggest that once-yearly administration of intravenous ZOL for 3 years in humans does not exert any adverse effects on the evolution of bone material properties at actively forming osteonal and trabecular surfaces, while it may have a beneficial effect on the progression of the mineral-to-matrix ratio and mineral maturity bone quality indices.

Treatment failure in osteoporosis.

UNLABELLED: Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided. INTRODUCTION: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture. METHODS: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making. RESULTS: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease. CONCLUSION: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.

Hormone replacement therapy or SERMS in the long term treatment of osteoporosis.

Replacement therapy with estrogen and progestogen (HT) or estrogen alone (ET) and selective estrogen receptor modulators (SERMS) still constitute valuable additions to the range of osteoporosis treatments available. Due to the diverse action on a wide variety of organs, HT/ET has the capacity to improve quality of life in most postmenopausal women,- more than other more specific osteoporosis treatments. The initial optimism associated with HRT 20-30 years ago was reduced considerably after the HT arm of WHI was stopped prematurely due to safety concerns. Later analyses of the WHI study have, however, tempered the negative messages emerging from the first publication in 2002. HT/ET still constitutes a first line choice for prevention of bone loss and fracture in the early postmenopausal period for a period of 5 years. However, in women with low risk of adverse events classically associated with HT/ET newer analyses show that treatment can be continued with an acceptable risk benefit ratio. These analyses have also highlighted the negative impact of progestogens on breast cancer risk an adverse effects on the cardiovascular system. Newer guidelines therefore suggest that a combination of a progestogen IUD and transdermal estrogen seems to be the best alternative for long term treatment. This combination minimizes cardiovascular safety concerns by avoiding the negative impact of first pass metabolism in the liver seen with oral compounds and minimizes exposure to progestogens. SERMS are valuable alternatives, particularly in osteopenic women (t-score -1,0 to -2,5) at increased risk of breast cancer, but their general lack of anti fracture efficacy towards non vertebral fractures limits their use in women at high risk of osteoporotic fracture.

Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON-Recurrent Fracture Trial.

UNLABELLED: This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS. INTRODUCTION: To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT). METHODS: In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg (n = 1,065) or placebo (n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables. RESULTS: At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 ± 0.56 vs. 5.42 ± 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 ± 4.91 vs. -1.69 ± 3.42), non-vertebral fractures (5.03 ± 2.48 vs. -1.07 ± 2.16), and clinical fractures (5.19 ± 2.25 vs. -0.72 ± 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775). CONCLUSION: ZOL significantly improves HRQoL in patients with low-trauma hip fracture.

Effect of hormone replacement therapy on bone formation quality and mineralization regulation mechanisms in early postmenopausal women.

Post-menopausal osteoporosis is characterized by a negative imbalance between bone formation and bone resorption resulting in a net bone loss, increasing the risk of fracture. One of the earliest interventions to protect against this was hormonal replacement therapy (HRT). Bone strength depends on both the amount and quality of bone, the latter including compositional / material and structural properties. Bone compositional / material properties are greatly dependent on both patient-, and tissue-age. Raman spectroscopy is an analytical tool ideally suited for the determination of bone compositional / material properties as a function of tissue age as it is capable of analyzing areas ~1 × 1 µm2 in tetracycline labeled bone forming areas. Using such analysis of humeri from an ovariectomized primate animal model, we reported that loss of estrogen results in alteration in the mineralization regulation mechanisms by osteoid organic matrix attributes at actively forming bone surfaces. In the present work, we used Raman microspectroscopic techniques to compare osteoid and youngest mineralized tissue composition, as well as relationships between osteoid organic matrix quality and quality attributes of the earliest mineralized tissue in paired iliac crest biopsies obtained from early postmenopausal women before and after two years of HRT therapy. Significant correlations between osteoid proteoglycans, sulfated proteoglycans, pyridinoline, and earliest mineralized tissue mineral content were observed, suggesting that in addition to changes in bone turnover rates, HRT affects the osteoid composition, mineralization regulation mechanisms, and potentially fibrillogenesis.

Does body height reduction influence interpretation of lung function in COPD patients?

Vertebral deformities are prevalent in chronic obstructive pulmonary disease (COPD) patients and may cause excessive loss of height. As height is used for calculating reference values for pulmonary function tests, larger than normal height reduction could cause overestimation of lung function. In this cross-sectional study of 465 COPD patients and 462 controls, we explored how often lung function is misinterpreted due to height reduction in COPD patients, and whether the number or severity of vertebral deformities correlate with height reduction. Measured height was compared to recalled tallest height (RTH) and height calculated from arm span (ASH) to assess height reduction. Vertebral deformities were assessed from radiographs and pulmonary function was assessed using standard formulae. Height reduction was frequent in both the study and control groups, and increased with the number and severity of vertebral deformities. When using current measured height, lung function was overestimated in a significant proportion of COPD patients at relatively modest height reductions. The effects were smallest for forced expiratory volume in 1 s and forced vital capacity, and most pronounced for total lung capacity and residual volume. Therefore, we propose that in COPD patients with excessive height reduction, one might use RTH or ASH in calculating predicted values. Furthermore, such patients should be evaluated for co-existing vertebral deformities and osteoporosis.

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial.

UNLABELLED: Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength. INTRODUCTION: To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength. METHODS: In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated. RESULTS: Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p < 0.01) and QCT (5.7%, p < 0.0001). Between-treatment differences were significant for trabecular spine (p = 0.0017) [non-parametric test], trabecular trochanter (10.7%, p < 0.0001), total hip (10.8%, p < 0.0001), and compressive strength indices at femoral neck (8.6%, p = 0.0001), and trochanter (14.1%, p < 0.0001). CONCLUSIONS: Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength.

Changes in bone quality after Roux-en-Y gastric bypass: A prospective cohort study in subjects with and without type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes (T2D) are associated with an increased risk of skeletal fractures despite a normal areal bone mineral density (aBMD) and low bone turnover, possibly due to reduced bone material strength. Roux-en-Y gastric bypass (RYGB) enables a substantial and persistent weight loss and resolution of obesity related comorbidities such as T2D. However, the procedure induces a decrease in aBMD and increased bone turnover and fracture rate. To our knowledge, changes in bone material strength after RYGB have not been explored. This study aimed to evaluate changes in factors influencing bone quality; bone material strength, aBMD and bone turnover markers, in a population with morbid obesity undergoing RYGB and whether these changes differed in participants with and without T2D. We also sought to assess factors associated with bone material strength and bone mineral density in obese subjects before and after RYGB. METHODS: We examined 34 participants before and one year after RYGB, of whom 13 had T2D. Bone material strength index (BMSi) was evaluated by impact microindentation, aBMD and body composition by Dual energy X-ray absorptiometry, levels of bone turnover markers and calciotropic hormones were estimated from fasting serum samples. Participants with and without T2D were comparable before surgery, with the exception of glycosylated hemoglobin (HbA1c). RESULTS: Preoperatively, BMSi was inversely associated with BMI, ßunadjusted -1.1 (-1.9 to -0.28), R2=0.19, p=0.010, and this association remained significant after adjusting for age and gender. After RYGB the participants had lost a mean±SD of 33.9±10.9kg, 48.7±14.2 % of total body fat, increased physical activity, unchanged vitamin D levels, and all but one of the 13 participants with T2D were in diabetes remission. BMSi increased from 78.1±8.5 preoperatively to 82.0±6.4 one year after RYGB, corresponding to an increase of 4.0±9.8 in absolute units or 6.3±14.0 %, p=0.037. The increase was comparable in participants with and without T2D. In subjects with T2D, a larger decrease in HbA1c was associated with a larger increase in BMSi ßunadjusted -9.2 (-16.5 to -1.9), R2=0.47, p=0.019. Bone turnover markers (CTX-1 and PINP) increased by 195.1±133.5 % and 109.5±70.6 %, respectively. aBMD decreased by 3.9±5.5 % in the lumbar spine, 8.2±4.6 % in the femoral neck, 11.6±4.9 % in total hip and 9.4±3.8 % in total body. CONCLUSION: Our findings indicate that bone material strength improves despite an increase in bone turnover and a decrease in aBMD one year after RYGB. Trends were statistically comparable in participants with and without T2D. However, improved glucose control was associated with improved bone material strength in participants with T2D.

Skeletal effects of plyometric exercise and metformin in ovariectomized rats.

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.

Evidence of estrogen receptors in normal human osteoblast-like cells.

In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17 beta-estradiol per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent, steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors. Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism.

Enhanced angiogenesis and increased bone turnover characterize bone marrow lesions in osteoarthritis at the base of the thumb.

OBJECTIVES: Little is known about tissue changes underlying bone marrow lesions (BMLs) in non-weight-bearing joints with osteoarthritis (OA). Our aim was to characterize BMLs in OA of the hand using dynamic histomorphometry. We therefore quantified bone turnover and angiogenesis in subchondral bone at the base of the thumb, and compared the findings with control bone from hip OA. METHODS: Patients with OA at the base of the thumb, or the hip, underwent preoperative MRI to assess BMLs, and tetracycline labelling to determine bone turnover. Three groups were compared: trapezium bones removed by trapeziectomy from patients with thumb base OA (n = 20); femoral heads with (n = 24); and those without (n = 9) BMLs obtained from patients with hip OA who underwent total hip arthroplasty. RESULTS: All trapezium bones demonstrated MRI-defined BMLs. Compared with femoral heads without BMLs, the trapezia demonstrated significantly higher bone turnover (mean sd 0.2 (0.1) versus 0.01 (0.01) µm3/µm2/day), mineralizing surface (18.5% (13.1) versus 1.4% (1.3)) and vascularity (5.2% (1.1) versus 1.2% (0.6)). Femoral heads with BMLs exhibited higher bone turnover (0.3 (0.2) versus 0.2 (0.1) µm3/µm2/day), a higher mineralization rate (26.6% (10.6) versus 18.6% (11.9)) and greater trabecular thickness (301.3 µm (108) versus 163.6 µm (24.8)) than the trapezia. CONCLUSION: Bone turnover and angiogenesis were enhanced in BMLs of both the thumb base and hip OA, of which the latter exhibited the highest bone turnover. Thus, the increase in bone turnover in weight-bearing joints like the hip may be more pronounced than less mechanically loaded osteoarthritic joints demonstrating BMLs. The histological changes observed may explain the water signal from BMLs on MRI.Cite this article: M. Shabestari, N. J. Kise, M. A. Landin, S. Sesseng, J. C. Hellund, J. E. Reseland, E. F. Eriksen, I. K. Haugen. Enhanced angiogenesis and increased bone turnover characterize bone marrow lesions in osteoarthritis at the base of the thumb. Bone Joint Res 2018;7:406-413. DOI: 10.1302/2046-3758.76.BJR-2017-0083.R3.

Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality.

Prospective, controlled clinical trials in postmenopausal osteoporosis typically compare effects of an active drug with placebo in addition to vitamin D and calcium supplementation in both treatment arms. While clinical benefits are documented, the effect of this supplementation in the placebo arm and in clinical practice on bone material composition properties is unknown. The purpose of the present study was to evaluate these bone quality indices (specifically mineral/matrix, nanoporosity, glycosaminoglycan content, mineral maturity/crystallinity, and pyridinoline content) in patients that either received long-term vitamin D (400-1200IU) and calcium (1.0-1.5g) supplementation, or did not. We have analyzed by Raman microspectroscopy the bone forming trabecular surfaces of iliac crest in pre-treatment samples of a teriparatide study and the endpoint biopsies of the control arm obtained from the HORIZON trial. In general, the mineral/matrix ratio and the glycosaminoglycan (GAG) content was higher while nanoporosity, (a surrogate for tissue water content), the mineral maturity/crystallinity (MMC) and the pyridinoline (Pyd) content was lower in patients without long-term supplementation. Moreover, all indices were significantly dependent on tissue age. In conclusion, vitamin D and calcium supplementation is associated with altered mineral and organic matrix properties.