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Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is a transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces. Furthermore, preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit, resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, mo 12 (M12) and mo 2 (M2) (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1 vs +1.5 μm; P = .012) and endocortical (+5.2 vs -1.7 μm; P = .02) surfaces; higher bone balance was due to lower final erosion depth (40.7 vs 43.7 μm; P = .05) on cancellous surfaces and higher completed wall thickness (50.8 vs 47.5 μm; P = .037) on endocortical surfaces. At M2, the final erosion depth was lower on the endocortical surfaces (42.7 vs 50.7 μm; P = .021) and was slightly lower on the cancellous surfaces (38.5 vs 44.6 μm; P = .11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9 vs 19.2 μm; P = .005) and mineralized wall thickness (18.3 vs 11.9 μm; P = .004) with romosozumab vs placebo. These evolving bone packets may reflect the early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Previous studies have demonstrated that the administration of zoledronic acid (ZOL) once yearly for 3 years or once over 3 years, yields similar antifracture efficacy. Bone turnover markers can predict the antifracture efficacy of antiresorptive agents, with procollagen type 1 N-terminal propeptide (P1NP) being the most useful marker. In this retrospective cohort study, we explored the effects of intravenous dosing of ZOL guided by serum (S)-P1NP assessment on bone mineral density (BMD) and fractures. Consenting patients ( N  = 202, mean age 68.2 years) with osteoporosis were treated with ZOL for an average of 4.4 (range 2-8) years. S-P1NP and BMD were measured at baseline and every 1-2 years. We assessed the number of subsequent vertebral and nonvertebral fractures in the 2-year time periods. The number of patients assessed was 202, 147, 69, and 29 at years 1-2, 3-4, 5-6, and 7-8, respectively. A new ZOL infusion was given if S-P1NP exhibited values above 35 μg/L. BMD increased by 6.2% (SD 4.0) over the first 2 years and stabilized in years 2-8 ( P  <.05). Median S-P1NP exhibited an initial reduction from 58.0 to 31.3 μg/L at year 2 and then increased to 39.0 μg/L at years 7-8. Compared with fractures observed in the last 2 years before baseline, fracture rates exhibited consistent reductions, for vertebral fractures odds ratio (OR) [95% confidence interval] = 0.61 [0.47, 0.80], P  <.001 and for nonvertebral fractures OR = 0.23 [0.18, 0.31], P  <.001. In conclusion, intermittent dosing of intravenous ZOL based on the assessment of S-P1NP with cut-off at 35 μg/L resulted in an initial increase followed by a stable BMD, suppression of S-P1NP, and stable reduction of fractures for 8 years. Only 39% of patients needed more than one infusion. This approach reduces healthcare costs and might also reduce the risk of rare side effects such as osteonecrosis of the jaw and atypical femoral fracture., Competing Interests: T.T.B. reports speaker fees from UCB, Amgen, Roche Diagnostics, and Pharma Prim. Advisory board for UCB. S.L.Ø. reports speaker fees from Novo Nordisk and Eli Lilly and is on the advisory board for Helseresepten. B.F.E.: none. E.F.E. reports consultant fees from UCB, Amgen, Gilead, and Pharma Medico, and honoraria from Amgen, Gedon Richter, and Novo Nordisk. Study support from Roche Diagnostics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

The validity of forearm fracture diagnoses recorded in five Norwegian hospitals was investigated using image reports and medical records as gold standard. A relatively high completeness and correctness of the diagnoses was found. Algorithms used to define forearm fractures in administrative data should depend on study purpose., Purpose: In Norway, forearm fractures are routinely recorded in the Norwegian Patient Registry (NPR). However, these data have not been validated. Data from patient administrative systems (PAS) at hospitals are sent unabridged to NPR. By using data from PAS, we aimed to examine (1) the validity of the forearm fracture diagnoses and (2) the usefulness of washout periods, follow-up codes, and procedure codes to define incident forearm fracture cases., Methods: This hospital-based validation study included women and men aged ≥ 19 years referred to five hospitals for treatment of a forearm fracture during selected periods in 2015. Administrative data for the ICD-10 forearm fracture code S52 (with all subgroups) in PAS and the medical records were reviewed. X-ray and computed tomography (CT) reports from examinations of forearms were reviewed independently and linked to the data from PAS. Sensitivity and positive predictive values (PPVs) were calculated using image reports and/or review of medical records as gold standard., Results: Among the 8482 reviewed image reports and medical records, 624 patients were identified with an incident forearm fracture during the study period. The sensitivity of PAS registrations was 90.4% (95% CI: 87.8-92.6). The PPV increased from 73.9% (95% CI: 70.6-77.0) in crude data to 90.5% (95% CI: 88.0-92.7) when using a washout period of 6 months. Using procedure codes and follow-up codes in addition to 6-months washout increased the PPV to 94.0%, but the sensitivity fell to 69.0%., Conclusion: A relatively high sensitivity of forearm fracture diagnoses was found in PAS. PPV varied depending on the algorithms used to define cases. Choice of algorithm should therefore depend on study purposes. The results give useful measures of forearm fracture diagnoses from administrative patient registers. Depending on local coding practices and treatment pathways, we infer that the findings are relevant to other fracture diagnoses and registers., (© 2023. The Author(s).)

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (± standard deviation) BMSi for men was 84.4 ± 6.9 and for women, 79.0 ± 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population., (© 2023. The Author(s).)

Background: Bone turnover markers (BTMs) have emerged as a useful tool for monitoring bone remodeling activity in the skeleton, and their serum levels correlate with bone loss rates in osteoporotic and normal individuals. Whether the same holds for other metabolic bone diseases is still subject to discussion., Methods: We analyzed the relation between levels of BTMs and TSH in 79 females on thyroid hormone substitution therapy for hypothyroidism. Based on the reference range for TSH (0.2-4.0 mU/L) in our lab, we assessed BTMs in five different groups of patients based on the following criteria: (1) hypothyroidism (TSH >4.0); (2) TSH in the high normal range (1.0-4.0); (3) TSH in the low normal range (0.2-1.0); (4) TSH below the normal range (0.01-0.2); (5) TSH undetectable (<0.01). We studied the relationship between TSH and four different bone markers: procollagen type 1 N-terminal propeptide (PINP), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin (OC), and bone specific alkaline phosphatase (BSAP). In a subgroup of patients, bone mineral density was assessed by a DXA scan., Results: PINP emerged as the most sensitive and dynamic BTM for assessment of bone turnover in this patient group, achieving significant rho values on nonparametric correlation analysis for both TSH (rho -0.47; p =0.0001) and FT4 (rho 0.27; p =0.018). CTX and OC also revealed significant correlations to TSH, albeit with lower rho values (-0.37 and -0.24, respectively). Categorical analysis showed that bone turnover increased significantly, albeit with pronounced interindividual variability for TSH values below the lower limit of normal (0.2 mU/l), with the most severe affected being women exhibiting suppression of TSH. Further analysis of loss rates by DXA in a limited subgroup of patients showed that this was accompanied by accelerated bone loss., Conclusion: PINP is the most sensitive marker of bone turnover in thyroid disorders. TSH values below the lower limit of normal are associated with increased bone turnover and accelerated bone loss, however, with pronounced interindividual variations. Assessment of PINP may be a valuable tool in cases where there is concern about possible adverse effects of thyroid hormone substitution therapy on bone., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Betty Ann Bjerkreim et al.)

Postmenopausal osteoporosis (PMOP) therapies are frequently evaluated by bone mineral density (BMD) gains against patients receiving placebo (calcium and vitamin D supplementation, a mild bone turnover-suppressing intervention), which is not equivalent to either healthy or treatment-naive PMOP. The aim of the present observational study was to assess the effects of TPTD treatment in PMOP (20 μg, once daily) at 6 (TPTD 6m; n = 28, age 65 ± 7.3 years), and 24 (TPTD 24m; n = 32, age 67.4 ± 6.15 years) months on bone quality indices at actively forming trabecular surfaces (with fluorescent double labels). Data from the TPTD-treated PMOP patients were compared with those in healthy adult premenopausal women (HC; n = 62, age 40.5 ± 10.6 years), and PMOP receiving placebo (PMOP-PLC; n = 94, age 70.6 ± 4.5 years). Iliac crest biopsies were analyzed by Raman microspectroscopy at three distinct tissue ages: mid-distance between the second label and the bone surface, mid-distance between the two labels, and 1 μm behind the first label. Mineral to matrix ratio (MM), mineral maturity/crystallinity (MMC), tissue water (TW), glycosaminoglycan (GAGs), and pyridinoline (Pyd) content were determined. Outcomes were compared by ANCOVA with subject age and tissue age as covariates, and health status as a fixed factor, followed by Sidak's post-hoc testing (significance assigned to p < 0.05). Both TPTD groups increased MM compared to PMOP-PLC. While TPTD 6m had values similar to HC, TPTD 24m had higher values compared to either HC or TPTD 6m. Both TPTD groups had lower MMC values compared to PMOP-PLC and similar to HC. TPTD 6m patients had higher TW content compared to HC, while TPTD 24m had values similar to HC and lower than either PMOP-PLC or TPTD 6m. Both TPTD groups had lower GAG content compared to HC group, while TPTD 6m had higher values compared to PMOP-PLC. Finally, TPTD 6m patients had higher Pyd content compared to HC and lower compared to PMOP-PLC, while TPTD 24m had lower values compared to PMOP-PLC and TPTD 6m, and similar to HC group. The results of the present study indicate that effects of TPTD on forming trabecular bone quality indices depend on treatment duration. At the recommended length of 24 m, TPTD restores bone mineral and organic matrix quality indices (MMC, TW, Pyd content) to premenopausal healthy (HC) levels., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The serum bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow-up of fracture patients. In this prospective cohort study, we explored the cut-off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP <30 μg/L and CTX <0.25 μg/L. AUC for discrimination of patients with >2% gain in BMD (lumbar spine and total hip) was largest at cut-off values for P1NP <30 μg/L and CTX <0.25 μg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR] logP1NP = 15.0; 95% confidence interval [CI] 2.7-83.3), p  = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 μg/L and CTX <0.25 μg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Background: Levels of thyroid-stimulating hormone (TSH) are believed to reflect degree of disease in patients with hypothyroidism, and normalization of levels is the treatment goal. However, despite adequate levels of TSH after starting levothyroxine (LT4) therapy, 5-10% of hypothyroid patients complain of persisting symptoms with a significant negative impact on quality of life. This indicates that TSH is not an optimal indicator of intracellular thyroid hormone effects in all patients. Our aim was to investigate different effects of LT3 and LT4 monotherapy on other biomarkers of the thyroid signaling pathway, in addition to adverse effects, in patients with residual hypothyroid symptoms., Methods: Fifty-nine female hypothyroid patients, with residual symptoms on LT4 monotherapy or LT4/liothyronine (LT3) combination therapy, were randomly assigned in a non-blinded crossover study and received LT4 or LT3 monotherapy for 12 weeks each. Measurements, including serum analysis of a number of biochemical and hormonal parameters, were obtained at the baseline visit and after both treatment periods., Results: Free thyroxine (FT4) was higher in the LT4 group, while free triiodothyronine (FT3) was higher in the LT3 group. The levels of reverse triiodothyronine (rT3) decreased after LT3 treatment compared with LT4 treatment. Both low-density lipoprotein (LDL) and total cholesterol levels were reduced, while sex hormone-binding globulin (SHBG) increased after LT3 treatment compared with LT4 treatment. The median TSH levels for both treatment groups were within the reference range, however, lower in the LT4 group than in the LT3 group. We did not find any differences in pro-B-type natriuretic peptide (NT pro-BNP), handgrip strength, bone turnover markers, or adverse events between the two treatment groups., Conclusion: We have demonstrated that FT4, FT3, rT3, cholesterol, and SHBG show significantly different values on LT4 treatment compared with LT3 treatment in women with hypothyroidism and residual symptoms despite normal TSH levels. No differences in general or bone-specific adverse effects were demonstrated. This trial is registered with NCT03627611 in May 2018., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this study., (Copyright © 2022 Betty Ann Bjerkreim et al.)

Objective: The effects of levothyroxine (LT4)/liothyronine (LT3) combination therapy on quality of life (QoL) in hypothyroid patients former on LT4 monotherapy have been disappointing. We therefore wanted to test the effects of LT3 monotherapy on QoL in hypothyroid patients with residual symptoms despite thyroid stimulating hormone (TSH) values within the reference range., Design: Female hypothyroid patients with residual symptoms on LT4 monotherapy or combination LT4/LT3 therapy received LT3 and LT4 monotherapy, respectively for 12 weeks in a non-blinded randomized crossover study., Methods: Fifty-nine patients aged 18-65 years were included. QoL was assessed using one disease-specific questionnaire (ThyPRO) and two generic questionnaires (Fatigue Questionnaire and SF-36) at baseline and at the end of the two treatment periods. Clinical indices of cardiovascular health (resting heart rate and blood pressure), as well as thyroid tests, were assessed at baseline and at the end of the two treatment periods., Results: After 12 weeks of LT3 treatment, 12 of the 13 domains of the ThyPRO questionnaire (physical, mental and social domains) showed significant improvements. The most pronounced improvements were less tiredness (mean -21 ± 26; P <0.0001) and cognitive complaints (mean -20 ± 20; P <0.0001). LT4 monotherapy exerted minor effects on two domains only (cognitive complaints and impaired daily life). All three dimensions' scores in the Fatigue Questionnaire (physical, mental and total fatigue) improved after LT3 treatment compared to baseline ( P <0.001), and in the SF-36 questionnaire 7 of 8 scales showed significantly better scores after LT3 treatment compared to baseline. There were no differences in blood pressure or resting heart rate between the two treatment groups. TSH in patients on LT3 was slightly higher (median 1.33 mU/L (interquartile range (IQR) 0.47-2.26)) than in patients on LT4 (median 0.61 mU/L (IQR 0.25-1.20; P <0.018). Five patients on LT3 dropped out of the study due to subjectively reported side effects, compared to only one on LT4., Conclusions: LT3 treatment improved QoL in women with residual hypothyroid symptoms on LT4 monotherapy or LT4/LT3 combination therapy. Short-term LT3 treatment did not induce biochemical or clinical hyperthyroidism, and no cardiovascular adverse effects were recorded. Further studies are needed to assess the long-term safety and efficacy of LT3 monotherapy., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611., Competing Interests: Authors SSH and EFE were employed by Pilestredet Park Specialist Center and LJO was employed by Balderklinikken. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Bjerkreim, Hammerstad, Gulseth, Berg, Omdal, Lee-Ødegård and Eriksen.)

The bone-forming agent romosozumab is a monoclonal antibody that inhibits sclerostin, leading to increased bone formation and decreased resorption. The highest levels of bone formation markers in human patients are observed in the first 2 months of treatment. Histomorphometric analysis of bone biopsies from the phase 3 FRAME trial (NCT01575834) showed an early significant increase in bone formation with concomitant decreased resorption. Preclinical studies demonstrated that most new bone formation after romosozumab treatment was modeling-based bone formation (MBBF). Here we analyzed bone biopsies from FRAME to assess the effect of 2 months of romosozumab versus placebo on the surface extent of MBBF and remodeling-based bone formation (RBBF). In FRAME, postmenopausal women aged ≥55 years with osteoporosis were randomized 1:1 to 210 mg romosozumab or placebo sc every month for 12 months, followed by 60 mg denosumab sc every 6 months for 12 months. Participants in the bone biopsy substudy received quadruple tetracycline labeling and underwent transiliac biopsies at month 2. A total of 29 biopsies were suitable for histomorphometry. Using fluorescence microscopy, bone formation at cancellous, endocortical, and periosteal envelopes was classified based on the appearance of underlying cement lines as modeling (smooth) or remodeling (scalloped). Data were compared using the Wilcoxon rank-sum test, without multiplicity adjustment. After 2 months, the median percentage of MBBF referent to the total bone surface was significantly increased with romosozumab versus placebo on cancellous (18.0% versus 3.8%; p = 0.005) and endocortical (36.7% versus 3.0%; p = 0.001), but not on periosteal (5.0% versus 2.0%; p = 0.37) surfaces, with no significant difference in the surface extent of RBBF on all three bone surfaces. These data show that stimulation of bone formation in the first 2 months of romosozumab treatment in postmenopausal women with osteoporosis is predominately due to increased MBBF on endocortical and cancellous surfaces. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Modern advances in molecular medicine have led to the reframing of osteoarthritis as a metabolically active, inflammatory disorder with local and systemic contributing factors. According to the 'inflammatory theory' of osteoarthritis, immune response to an initial damage is the key trigger that leads to progressive joint destruction. Several intertwined pathways are known to induce and govern articular inflammation, cartilage matrix degradation, and subchondral bone changes. Effective treatments capable of halting or delaying the progression of osteoarthritis remain elusive. As a result, supplements such as glucosamine and chondroitin sulphate are commonly used despite the lack of scientific consensus. A novel option for adjunctive therapy of osteoarthritis is LithoLexal ® Joint, a marine-derived, mineral-rich extract, that exhibited significant efficacy in clinical trials. LithoLexal ® has a lattice microstructure containing a combination of bioactive rare minerals. Mechanistic research suggests that this novel treatment possesses various potential disease-modifying properties, such as suppression of nuclear factor kappa-B, interleukin 1β, tumor necrosis factor α, and cyclooxygenase-2. Accordingly, LithoLexal ® Joint can be considered a disease-modifying adjunctive therapy (DMAT). LithoLexal ® Joint monotherapy in patients with knee osteoarthritis has significantly improved symptoms and walking ability with higher efficacy than glucosamine. Preliminary evidence also suggests that LithoLexal ® Joint may allow clinicians to reduce the dose of nonsteroidal anti-inflammatory drugs in osteoarthritic patients by up to 50%. In conclusion, the multi-mineral complex, LithoLexal ® Joint, appears to be a promising candidate for DMAT of osteoarthritis, which may narrow the existing gap in clinical practice.

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution., Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome., Results: Cold stimulated skin temperatures decreased less with LT3 vs . LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P <0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P <0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups., Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bjerkreim, Hammerstad, Gulseth, Berg, Lee-Ødegård, Rangberg, Jonassen, Budge, Morris, Law, Symonds and Eriksen.)

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.

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 μm 2 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., Competing Interests: None of the authors has any conflict of interest., (© 2021 Published by Elsevier Inc.)

Osteoarthritis (OA) is affecting large proportions of the population worldwide. So far, no effective disease modifying drug has been developed for this disease, limiting the therapeutic options to pain medications, physiotherapy and ultimately surgical approaches, mainly joint implant surgery. In vitro and animal studies have demonstrated that bisphosphonates have the potential to become effective modalities for the treatment of OA. This group of pharmacological agents modulates crucial aspects of OA pathogenesis (subchondral bone turnover and loss, bone marrow edema formation, cartilage degeneration and synovitis), and have shown clear efficacy in animal models of OA. Human studies have, however, so far been disappointing with only one of six clinical studies showing clear short-term efficacy. Possible reasons for these discrepancies will be discussed., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Secondary hyperparathyroidism (SHPT) after obesity surgery may affect bone health. Optimal vitamin D levels have not been established to prevent SHPT postoperatively. We investigated whether SHPT differed across threshold levels of serum 25-hydroxyvitamin D (S-25(OH)D) from 6 months up to 5 years after Roux-en-Y gastric bypass (RYGB)., Materials and Methods: We included 554 patients at follow-up 5 years postoperatively. Blood samples were analysed for S-25(OH)D, ionized calcium (iCa) and parathyroid hormone (PTH) during follow-up., Results: PTH and prevalence of SHPT increased from 6 months to 5 years postoperatively, while S-25(OH)D and iCa decreased (all P < 0.001). PTH and SHPT development are related with S-25(OH)D, and PTH differed between all subgroups of S-25(OH)D. SHPT occurred less frequently across all subgroups of S-25(OH)D ≥ 50 nmol/l during follow-up: odds ratio (OR) 0.44 (95% CI 0.36-0.54) in patients with S-25(OH)D ≥ 50 nmol/l, OR 0.38 (0.30-0.49) with S-25(OH)D ≥ 75 nmol/l and OR 0.19 (0.12-0.31) with S-25(OH) D ≥ 100 nmol/l, all compared with S-25(OH)D < 50 nmol/l. At 5 years, 208/554 patients (38%) had SHPT; SHPT was found in 94/188 patients (50%) with S-25(OH)D < 50 nmol/l, in 69/222 (31%) with S-25(OH)D 50-74 nmol/l, in 40/117 (34%) with S-25(OH)D 75-99 nmol/l and in 5/27 (19%) with S-25(OH)D ≥ 100 nmol/l. An interaction existed between S-25(OH)D and iCa. Bone alkaline phosphatase remained increased with SHPT., Conclusions: A significant relationship existed between S-25(OH)D and development of PTH and SHPT. The prevalence of SHPT was lower with threshold levels 25(OH)D ≥ 50 nmol/l and ≥ 75 nmol/l over the 5 years, and lowest with S-25(OH)D ≥ 100 nmol/l.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To assess tissue level changes of proteome and cytokine profiles of subchondral bone in hip osteoarthritis (OA) affected by bone marrow lesions (BMLs). We compared significant protein level differences in osteoarthritic bone with BMLs to control bone without bone marrow lesions., Methods: Subchondral bone biopsies were taken from femoral heads of end-stage osteoarthritis patients with (BML, n = 21) and without (CON, n = 9) BMLs. Proteins were extracted through a standardized Trizol protocol and used in the subsequent analyses. Angiogenesis and bone markers were assessed using multiplex immunoassays (Luminex). Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect significant differences in proteome and peptide profiles between BML and CON., Results: Multiplex immunoassays revealed increased tissue contents of vascular endothelial growth factors (VEGF-A/C/D), endothelin-1, angiopoietin-2 and interleukin-6 (IL-6) in bone with BMLs compared to control bone, whereas osteoprotegerin levels were reduced. Mass spectrometry demonstrated pronounced increase in the levels of hemoglobin (73-fold), serum albumin (30-fold), alpha-1-antitrypsin (9-fold), apolipoprotein A1 (4.7-fold), pre-laminin-A/C (3.7-fold) and collagen-alpha1-XII (3-fold) in BMLs, while aggrecan core protein (ACAN) and hyaluronan and proteoglycan link protein 1 (HAPL1) decreased 37- and 29-fold respectively., Conclusion: Reduced osteoprotegerin, ACAN and HAPL1 are consistent with osteoclastic activation and high remodeling activity in BMLs. The pronounced increase in angiogenesis markers, hemoglobin and serum albumin support the presence of increased vascularity in subchondral bone affected by BMLs in OA. VEGFs and IL-6 are known nociceptive modulators, and increased levels are in keeping with pain being a clinical feature frequently associated with BMLs., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: This observational safety study used national registers to compare the real world cardiovascular and skeletal safety of zoledronic acid (ZA) against oral bisphosphonates (oBP) and untreated population controls., Methods: Propensity score matched cohort study in Sweden and Denmark., Results: Matched cohort 1 included 8739 ZA users and 25,577 oBP users while matched cohort 2 included 8731 ZA users and 25,924 untreated subjects. In comparison to oBP users, heart failure risk was higher in ZA users, with an adjusted HR (adj) (95%CI) of 1.17 (1.04;1.32) and a higher all-cause mortality (adj HR 1.24 (1.15; 1.34)), however, there was no increased risk of cardiovascular mortality. In the comparison to untreated subjects, ZA users showed a higher risk of atrial fibrillation, adj HR 1.18 (1.05;1.32), arrhythmias adj HR 1.18 (1.06;1.31), and heart failure, adj HR 1.38 (1.24;1.54). Cardiovascular mortality was lower in ZA users (adj HR 0.87 (0.77; 0.98)) and risk of adverse skeletal outcomes was significantly higher, reflecting more severe osteoporosis in these patients. There was no association of cardiovascular risk with increasing exposure time. Sensitivity analyses produced similar findings with no substantial changes in event rates., Conclusions: We noted an increased risk of heart failure, fractures and death among ZA users compared with oral BP. The risk of cardiovascular and skeletal outcomes was higher in ZA users than in matched population controls, but there was no increase in cardiovascular mortality in ZA users compared to oral BP or untreated controls. Despite propensity score matching, it is not possible to determine with certainty whether the increased risk of cardiovascular outcomes is consistent with a true drug effect or higher baseline risk in patients who begin ZA treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest All authors state that they have no conflicts of interest, (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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 (β per SD = - 0.26, 95% CI: - 0.36,- 0.15), parental hip fracture (β = - 0.29, 95% CI: - 0.54,- 0.05), and daily alcohol intake (β = - 0.43, 95% CI - 0.79, - 0.08) were associated with lower TBS. Higher BMD of femoral neck (β per SD = 0.34, 95% CI 0.25-0.43) and lumbar spine (β per SD = 0.40, 95% CI 0.31-0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (OR per 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 (OR per 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.

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 (HbA 1c )., Results: Preoperatively, BMSi was inversely associated with BMI, β unadjusted -1.1 (-1.9 to -0.28), R 2 =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 HbA 1c was associated with a larger increase in BMSi β unadjusted -9.2 (-16.5 to -1.9), R 2 =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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1-SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm 2 ), total hip (800 versus 876 mg/cm 2 ), and lumbar spine (1024 versus 1062 mg/cm 2 ); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2-SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1-SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

Background: Roux-en-Y gastric bypass (RYGB) is a common surgical procedure for treatment of morbid obesity. RYGB induces considerable and sustained weight loss, and remission of obesity related-comorbidities. While studies have suggested negative effects of RYGB on bone health, long-term data are lacking. We aimed to evaluate the prevalence of aBMD below the expected range for age, osteopenia, osteoporosis and low-energy fractures in a defined patient cohort 10 years after RYGB. Secondly, we wanted to identify factors associated with increased risk of aBMD z-score or t-score of -1.1 or lower 10 years after RYGB., Methods: Patients undergoing RYGB surgery from June 2004 to December 2006 at the Department of Morbid Obesity and Bariatric Surgery, Oslo University Hospital, a tertiary referral centre for treatment of morbid obesity, were invited to a 10 year follow-up. Follow-up visits included morning fasting blood samples, clinical examination, anthropometric measures and dual energy X-ray absorptiometry (DXA)., Results: Out of 194 patients eligible for the study, 124 attended the 10 year follow-up and 122 (63%) were examined with DXA. Mean (SD) age was 50.3 (9.0) years, 118 (97%) were of Caucasian ethnicity, 94 were females (77%), of whom 41 (44%) were postmenopausal. Secondary hyperparathyroidism (SHPT) was noted in 37 participants (31%) and vitamin D deficiency (value below 50 nmol/L) and insufficiency (value below 75 nmol/L) in 40 (33%) and 91 (75%), respectively. Among the 63 participants who were premenopausal females or males 49 years or younger the prevalence of areal bone mineral density (aBMD) in the lower range of normal (z-score -1.1- to -1.9) was 30% (n = 19) and aBMD below the expected range for age (z-score ≤ -2.0) was noted in 8% (n = 5). Among the 59 participants who were postmenopausal females or males 50 years or older, the prevalence of osteopenia (t-score -1.1 to -2.4) was 51% (n = 30) and osteoporosis (t-score ≤ -2.5) was 27% (n = 16). The bone resorption markers CTX-1 and PINP were higher in participants with aBMD z-score or t-score of -1.1 or lower compared to participants with aBMD z-score or t-score of -1.0 or higher. Preoperative hypothyroidism, or higher age, postmenopausal status, BMI < 35 kg/m 2 , SHPT or higher PINP levels at 10 year follow-up were independently associated with aBMD z-score or t-score of -1.1 or lower 10 years after RYGB. Eighteen participants (15%) reported a clinical low-energy fracture after RYGB. In addition, vertebral fracture assessment by DXA revealed that 10 participants (8%) had experienced at least one moderate to severe morphometric vertebral fracture., Conclusion: Ten years after RYGB 27% of postmenopausal females and males 50 years or older were osteoporotic, and 8% of premenopausal females and males 49 years or younger exhibited aBMD below the expected range for age. The prevalence of fragility fractures was high. SHPT, higher age, postmenopausal status or higher PINP levels at 10 years and preoperative hypothyroidism were all independent risk factors for aBMD z-score or t-score of -1.1 or lower 10 years after RYGB., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bone marrow adipose tissue (BMAT) has been postulated to mediate skeletal fragility in type 2 diabetes (T2D) and obesity. Roux-en-Y gastric bypass (RYGB) induces a substantial weight loss and resolution of comorbidities. However, the procedure induces increased bone turnover and fracture rates. No previous study has evaluated biopsy-measured BMAT fraction preoperatively and after RYGB. In this study, we aimed to investigate BMAT fraction of the hip in participants with and without T2D preoperatively and 1 year after RYGB and explore factors associated with BMAT change. Patients with morbid obesity scheduled for RYGB were examined preoperatively and 1 year after RYGB. Forty-four participants were included and preoperative examinations were possible in 35. Of these, 33 (94%) met for follow-up, 2 were excluded, and BMAT estimation was not possible in 1. Eighteen (60%) of the participants were females and 11 (37%) had T2D. Preoperative BMAT fraction was positively associated with glycosylated hemoglobin and negatively associated with areal bone mineral density (aBMD). After RYGB, BMAT fraction decreased from 40.4 ± 1.7% to 35.6 ± 12.8%, p = 0.042, or with mean percent change of 10.7% of preoperative BMAT fraction. Change in BMAT fraction was positively associated with change in body mass index (BMI) and total body fat. In females, we observed a mean percent reduction of 22.4 ± 19.6%, whereas in males BMAT increased with a mean percent of 6.8 ± 37.5%, p = 0.009. For males, changes in estradiol were associated with BMAT change; this was not observed for females. In participants with and without T2D, the mean percent BMAT reduction was 5.8 ± 36.9% and 13.5 ± 28.0%, respectively, p = 0.52. We conclude that a high BMAT seems to be associated with lower aBMD and poorer glycemic control in obese subjects. After RYGB, we observed a significant decrease in BMAT. The reduction in BMAT did not differ between participants with and without T2D, but appeared sex specific. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc., (© 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.)

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR-pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR-pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R 2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more-separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver-operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Purpose: Norway has among the highest incidence rates of fractures in the world. Vertebral fracture assessment (VFA) and trabecular bone score (TBS) provide information about fracture risk, but their importance have not been studied in Norwegian patients with fragility fractures. The objectives of this study were to examine the clinical characteristics of a cohort of women and men with fragility fractures, their prevalence of vertebral fractures using VFA and prevalence of low TBS, and explore the differences between the sexes and patients with and without vertebral fractures., Methods: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative (NoFRACT) included 839 patients with fragility fractures. Of these, 804 patients had bone mineral density (BMD) of the total hip, femoral neck and/or spine assessed using dual energy x-ray absorptiometry, 679 underwent concomitant VFA, 771 had TBS calculated and 696 responded to a questionnaire., Results: Mean age was 65.8 (SD 8.8) years and 80.5% were women. VFA revealed vertebral fractures in 34.8% of the patients and 34.0% had low TBS (≤ 1.23), with no differences between the sexes. In all patients with valid measures of both VFA and TBS, 53.8% had either vertebral fractures, low TBS, or both. In the patients with osteopenia at the femoral neck, 53.6% had either vertebral fractures, low TBS, or both. Femoral neck BMD T-score ≤ -2.5 was found in 13.8% of all patients, whereas the corresponding figure was 27.4% using the skeletal site with lowest T-score. Women exhibited lower BMD at all sites and lower TBS than men (1.27 vs. 1.29), (all p < 0.05). Patients with prevalent vertebral fractures were older (69.4 vs. 64.0 years), exhibited lower BMD at all sites and lower TBS (1.25 vs.1.29) than those without vertebral fractures (all p < 0.05). Before assessment, 8.2% were taking anti-osteoporotic drugs (AOD), and after assessment, the prescription rate increased to 56.2%., Conclusions: More than half of the patients with fragility fractures had vertebral fractures, low TBS or both. The prescription of AOD increased seven fold from before assessment to after assessment, emphasizing the importance of risk assessment after a fragility fracture., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In randomized clinical trials (RCTs) with teriparatide, the number of patients with incident hip fractures was small and insufficiently powered to show statistically significant differences between groups. We, therefore, conducted a systematic review and meta-analysis of the efficacy of teriparatide in the reduction of hip and upper limb fractures in women and men with osteoporosis. A comprehensive search of databases until 22 November 2017 was conducted for RCTs of at least 6-month duration that reported non-spine fractures (hip, humerus, forearm, wrist), either as an efficacy or safety endpoint. Only RCTs that included patients with the approved treatment indications and dose for use of teriparatide were included; trials with off-label use of teriparatide were excluded. Two independent reviewers performed study selection and data extraction. Statistical procedures included Peto's method and Mantel-Haenszel with empirical correction, as most of the RCTs reported zero events in at least one of the treatment arms. Study results are expressed as odds ratios (OR) with 95% confidence intervals (CI). Publication bias and heterogeneity were evaluated with standard statistical tests. Twenty-three RCTs were included, 19 with an active-controlled arm (representing 64.9% of the patients included in the control group) and 11 double-blind, representing data on 8644 subjects, 3893 of them treated with teriparatide. Mean age (SD) was 67.0 (4.5) years, median treatment duration 18 months (range: 6 to 24 months). A total of 34 incident hip, 31 humerus, 31 forearm, and 62 wrist fractures were included. Meta-analysis results showed an OR (95% CI) for hip fractures of 0.44 (0.22-0.87; p = 0.019) in patients treated with teriparatide compared with controls. The effects on the risk of humerus [1.02 (0.50-2.08)], forearm [0.53 (0.26-1.08)] and wrist fractures [1.21 (0.72-2.04)] were not statistically significant (p > 0.05). This meta-analysis provides evidence of efficacy of teriparatide in reducing hip fractures by 56% in patients with osteoporosis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Teriparatide increases bone mass primarily through remodeling of older or damaged bone and abundant replacement with new mineralizing bone. This post hoc analysis investigated whether dual-energy X-ray absorptiometric (DXA) areal bone mineral density (aBMD) measurement adequately reflects changes of mineral and organic matrix content in cortical and trabecular bone. Paired biopsies and aBMD measurements were obtained before and at end of 2 years of teriparatide treatment from postmenopausal women with osteoporosis who were either alendronate pretreated (mean, 57.5 months) or osteoporosis-treatment naive. Biopsies were assessed by micro-computed tomography (μCT) to calculate mean cortical width (Ct.Wi), cortical area (Ct.Ar), and trabecular bone volume fraction (BV/TV). Fourier transformed infrared imaging (pixel size ∼6.3 × 6.3 μm 2 ) was utilized to calculate mineral and organic matrix density (mean absorption/pixel), as well as total mineral and organic contents of cortical and cancellous compartments (sum of all pixels in the compartment). Effect of pretreatment over time was analyzed using mixed model repeated measures. μCT derived Ct.Wi and BV/TV increased, accompanied by similar increases in the overall mineral contents of their respective bone compartments. Mineral density did not change. Marked increases in the total content of both mineral and organic matrix associated with volumetric growth in both compartments consistently exceeded those of aBMD. Increases in organic matrix exceeded increases in mineral content in both cortical and trabecular compartments. For percent changes, only change in Ct.Wi correlated to change in femoral neck aBMD (r = .38, p = 0.043), whereas no other significant correlations of Ct.Wi or BV/TV with lumbar spine, total hip, or femoral neck aBMD were demonstrable. These data indicate that 2 years of teriparatide treatment leads to an increased bone organic matrix and mineral content in the iliac crest. The magnitude of these increases in the iliac crest were not detected with conventional aBMD measurements at other skeletal sites. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

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) µm 3 /µm 2 /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) µm 3 /µm 2 /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., Competing Interests: Conflict of Interest Statement: None declared

Objective: The high prevalence of secondary hyperparathyroidism (SHPT) after obesity surgery is a concern for long-term bone health. Limited knowledge exists about optimal vitamin D and suppression of parathyroid hormone (PTH) after these procedures. The aim of this study was to investigate the prevalence of SHPT and its relation to vitamin D status., Design: A cross-sectional study at Oslo University Hospital, Norway., Patients: A total of 502 consecutive patients, age 22-64 years, attending 2-year follow-up after Roux-en-Y gastric bypass., Measurements: A serum intact PTH >7.0 pmol/L in the absence of elevated serum ionized calcium (iCa) was considered as SHPT. Vitamin D status was defined by serum concentrations of 25-hydroxyvitamin D (S-25(OH)D)., Results: Altogether, 171 patients (34%) had SHPT. The prevalence of SHPT varied across the range of S-25(OH)D (P < 0.001), being highest (71%) with S-25(OH)D < 25 nmol/L. Compared with S-25(OH)D < 50 nmol/L, the prevalence of SHPT was lower with S-25(OH)D ≥ 50 nmol/L (29.0%; RR = 0.64 (95%-CI:0.50-0.81)) and S-25(OH)D ≥ 75 nmol/L (27.7%; RR = 0.61 (95%-CI:0.44-0.84)). S-25(OH)D ≥ 100 nmol/L was associated with the lowest PTH and the lowest prevalence of SHPT (16.0%; RR = 0.35 (95%-CI:0.14-0.88) compared with S-25(OH)D < 50 nmol/L) and the most normal calcium distribution. These associations were most pronounced with iCa in the lower range. A synergistic association was found for S-25(OH)D and iCa on SHPT., Conclusions: Vitamin D deficient patients had the highest prevalence of SHPT 2 years after gastric bypass. PTH and the prevalence of SHPT were notably lower with S-25(OH)D ≥ 100 nmol/L, compared with lower target levels., (© 2017 John Wiley & Sons Ltd.)

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.

Introduction: The optimal duration of osteoporosis treatment is controversial. As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. Recent reports imply that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures., Methods: The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab and provide advice on management., Results: Data from phase 2 and 3 clinical trials underscore a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs) after discontinuation of denosumab. Clinical case series report multiple vertebral fractures after discontinuation of denosumab and a renewed analysis of FREEDOM and FREEDOM Extension Trial suggests, albeit does not prove, that the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption., Conclusion: There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking. Clinicians and patients should be aware of this potential risk. Based on available data, a re-evaluation should be performed after 5years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, since the optimal bisphosphonate regimen post-denosumab is currently unknown continuation of denosumab can also be considered until results from ongoing trials become available. Based on current data, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine-lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two-by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B 12 (0.4 mg) and vitamin B 6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B 12 (0.4 mg); (3) vitamin B 6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B 12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B 6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B 6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B 6 . In conclusion, treatment with folic acid plus vitamin B 12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B 6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

The aim of the study was to test, whether bone material strength differs between different subtypes of osteoporotic fracture and assess whether it relates to vertebral fracture severity. Cortical bone material strength index (BMSi) was measured by impact microindentation in 66 women with osteoporotic fracture and 66 age- and sex-matched controls without fracture. Bone mineral density (BMD) and bone turnover markers were also assessed. Vertebral fracture severity was graded by semiquantitative (SQ) grading. Receiver operator characteristic (ROC) curves were used to examine the ability of BMSi to discriminate fractures. Subjects with osteoporotic fractures exhibited lower BMSi than controls (71.5 ± 7.3 vs. 76.4 ± 6.2, p < 0.001). After adjusting for age and hip BMD, a significant negative correlation was seen between BMSi and vertebral fracture severity (r 2  = 0.19, p = 0.007). A decrease of one standard deviation (SD) in BMSi was associated with increased risk of fracture (OR 2.62; 95% CI 1.35, 5.10, p = 0.004). ROC curve areas under the curve (AUC) for BMSi in subjects with vertebral fracture (VF), hip fracture (HF), and non-vertebral non-hip fracture (NVNHFx), (mean; 95% CI) were 0.711 (0.608; 0.813), 0.712 (0.576; 0.843), 0.689 (0.576; 0.775), respectively. Combining BMSi and BMD provided further improvement in the discrimination of fractures with AUC values of 0.777 (0.695; 0.858), 0.789 (0.697; 0.882), and 0.821 (0.727; 0.914) for VFx, HFx, and NVNHFx, respectively. Low BMSi of the tibial cortex is associated with increased risk of all osteoporotic fractures and severity of vertebral fractures.

Objective: In observational studies, low vitamin D levels are associated with type 2 diabetes (T2D), impaired glucose metabolism, insulin sensitivity, and insulin secretion. We evaluated the efficacy of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with T2D and low vitamin D (25-hydroxyvitamin D [25(OH)D] <50 nmol/L)., Research Design and Methods: Sixty-two men and women with T2D and vitamin D deficiency participated in a 6-month randomized, double-blind, placebo-controlled trial. Participants received a single dose of 400,000 IU oral vitamin D 3 or placebo, and the vitamin D group received an additional 200,000 IU D 3 if serum 25(OH)D was <100 nmol/L after 4 weeks. Primary end points were total R d by euglycemic clamp with assessment of endogenous glucose production and first-phase insulin secretion by intravenous glucose tolerance test., Results: In the vitamin D group, the mean ± SD baseline serum 25(OH)D of 38.0 ± 12.6 nmol/L increased to 96.9 ± 18.3 nmol/L after 4 weeks, 73.2 ± 13.7 nmol/L after 3 months, and 53.7 ± 9.2 nmol/L after 6 months. The total exposure to 25(OH)D during 6 months (area under the curve) was 1,870 ± 192 and 1,090 ± 377 nmol/L per week in the vitamin D and placebo groups, respectively ( P < 0.001). Insulin sensitivity, endogenous glucose production, and glycemic control did not differ between or within groups after treatment ( P = 0.52). First-phase insulin secretion did not change significantly after treatment ( P = 0.10)., Conclusions: Replenishment with a large dose of vitamin D 3 to patients with T2D and vitamin D deficiency did not change insulin sensitivity or insulin secretion. These findings do not support such use of therapeutic vitamin D 3 supplementation to improve glucose homeostasis in patients with T2D., (© 2017 by the American Diabetes Association.)

Background: Graves' orbitopathy (GO) is an autoimmune inflammatory ocular complication and one of the most frequent manifestations of Graves' disease (GD). Clinical judgment of GO is subjective sometimes leading to clinical and therapeutic challenges. Better tools to diagnose this severe complication are warranted., Patients and Methods: The aim of the present study was to evaluate tear levels of LYZ, LACRT and AZGP1 in GD patients with or without GO, as possible biomarkers for GO. Tear samples were collected from GD patients with moderate-to-severe GO (n = 21) and no clinical signs of GO (n = 21). Additionally, 18 GD patients with mild GO and 9 patients without GO were included in a further part of the study., Results: Tear levels of LYZ (p < 0.001), LACRT (p = 0.004) and AZGP1 (p = 0.001) were significantly elevated in GD patients with moderate-to-severe GO compared to GD patients without GO. The discriminatory power of the three biomarkers, combined in a panel was confirmed by ROC plot analysis, with an AUC value of 0.93 (sensitivity of 95%; specificity of 80%). Since LYZ showed the best performance in discriminating between GD patients with (moderate-to-severe) and without GO (in combination with limited sample volume available), LYZ levels were also measured in tears from GD patients with mild GO and without GO. Significantly higher levels of LYZ were measured in GD patients with mild GO compared to those without GO (p = 0.003)., Conclusions: We have established a novel three-protein biomarker panel that is able to discriminate between GD patients with and without GO, which might aid in diagnostic evaluation of GO as well as an indicator for disease activity.

Background: People with multiple sclerosis have high risk of osteoporosis and fractures. A poor vitamin D status is a risk factor for MS, and vitamin D supplementation has been recommended both to prevent MS progression and to maintain bone health., Methods: We assessed the effect of 20,000 IU vitamin D 3 weekly compared to placebo on biochemical markers of bone metabolism in 68 persons with relapsing remitting multiple sclerosis., Results: Serum levels of 25-hydroxyvitamin D more than doubled in the vitamin D group, and parathyroid hormone decreased in the vitamin D group compared to the placebo group at week 48 and week 96. There was however no effect on bone formation as measured by procollagen type I N propeptide (PINP), or on bone resorption as measured by C-terminal cross-linking telopeptide of type I collagen (CTX1). Neither PINP nor CTX1 predicted bone loss from baseline to week 96., Conclusions: These findings corroborate the previously reported lack of effect of weekly high dose vitamin D supplementation on bone mass density in the same patients, and suggest that such vitamin D supplementation does not prevent bone loss in persons with MS who are not vitamin D deficient., Trial Registration: The trial was registered at ClinicalTrials.gov on April 4 2008, registration number NCT00785473 .

Increased cortical porosity has been suggested as a possible factor increasing fracture propensity in patients with type 2 diabetes mellitus (T2DM). This is a paradox because cortical porosity is generally associated with high bone turnover, while bone turnover is reduced in patients with T2DM. We therefore wanted to test the hypothesis that women with T2DM have lower bone turnover markers (BTM) and lower cortical porosity than those without diabetes, and that higher serum glucose and body mass index (BMI) are associated with lower BTM, and with lower cortical porosity. This cross-sectional study is based on a prior nested case-control study including 443 postmenopausal women aged 54-94years from the Tromsø Study, 211 with non-vertebral fracture and 232 fracture-free controls. Of those 443 participants, 22 women exhibited T2DM and 421 women did not have diabetes. All had fasting blood samples assayed for procollagen type I N-terminal propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX) and glucose, and femoral subtrochanteric architecture was quantified using low-resolution clinical CT and StrAx1.0 software. Women with T2DM had higher serum glucose (7.2 vs. 5.3mmol/L), BMI (29.0 vs. 26.4kg/m 2 ), and higher femoral subtrochanteric total volumetric bone mineral density (vBMD) (783 vs. 715mgHA/cm 3 ), but lower cortical porosity (40.9 vs. 42.8%) than nondiabetic women (all p<0.05). Each standard deviation (SD) increment in glucose was associated with 0.10-0.12 SD lower PINP and CTX, and 0.13 SD lower cortical porosity (all p<0.05). Each SD increment in BMI was associated with 0.10-0.18 SD lower serum PINP and CTX, and 0.19 SD thicker cortices (all p<0.05). Increasing glucose and BMI were associated with lower bone turnover suggesting that reduced intracortical and endocortical remodeling leads to reduced porosity and thicker cortices. Using low-resolution clinical CT, cortical porosity was lower in women with T2DM compared to women without diabetes. This indicates that other changes in bone qualities, not increased cortical porosity, are likely to explain the increased fracture propensity in patients with T2DM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Several guidelines have been reported for bone-directed treatment in women with early breast cancer (EBC) for averting fractures, particularly during aromatase inhibitor (AI) therapy. Recently, a number of studies on additional fracture related risk factors, new treatment options as well as real world studies demonstrating a much higher fracture rate than suggested by randomized clinical controlled trials (RCTs). Therefore, this updated algorithm was developed to better assess fracture risk and direct treatment as a position statement of several interdisciplinary cancer and bone societies involved in the management of AI-associated bone loss (AIBL)., Patients and Methods: A systematic literature review identified recent advances in the management of AIBL. Results with individual agents were assessed based on trial design, size, follow-up, and safety., Results: Several fracture related risk factors in patients with EBC were identified. Although, the FRAX algorithm includes fracture risk factors (RF) in addition to BMD, it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL., Conclusions: In all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score<-2.0 or with a T-score of <-1.5 SD with one additional RF, or with ≥2 risk factors (without BMD) for the duration of AI treatment. Patients with T-score>-1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12 - 24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.

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., Competing Interests: A Diez-Perez is speaker or advisor for Amgen, Lilly, Merck, UCB and Active Life Sci. Bo Abrahamsen reports current institutional research grants and contracts with Novartis and UCB, past institutional research contracts with Amgen and NPS Pharmaceuticals. D. Agnusdei has a consultancy contract with Eli Lilly. Erik F Eriksen is a speaker and advisor for Amgen, Lilly, Merck, IDS and Shire. Núria Guañabens is speaker or advisor for Amgen, Lilly and Alexion Pharmaceuticals. Robert Josse is medical advisory board member and speaker honoraria and research grant: Merck,Amgen,Lilly. Daniel Prieto-Alhambra’s research group has received unrestricted grants from AMGEN S.A. Jean-Yves Reginster has consulting fees or paid advisory boards in Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed-Takeda, NPS, IBSA-Genevrier, Theramex, UCB, Asahi Kasei, Endocyte, Radius Health also has lecture fees when speaking at the invitation of the commercial sponsors: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Merckle, Teijin, Teva, Analis, Theramex, Nycomed, NovoNordisk, Ebewee Pharma, Zodiac, Danone, Will Pharma, Amgen, PharmEvo. He has grant support from industry: Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Roche, Amgen, Lilly, Novartis, GlaxoSmithKline, Servier, Pfizer, Theramex, Danone, Organon, Therabel, Boehringer, Chiltern, Galapagos. M. Carola Zillikens has received fee for speaking and advice from Amgen, Eli Lilly and MSD. R. Eastell has consulting fees from Amgen, AstraZeneca, Chronos, GSK, Immunodiagnostic Systems, Fonterra Brands, Ono Pharma, Lilly, Bayer, Janssen Research, Alere, CL Biosystems, Teijin Pharm, D-Star, Roche Diagnostics, Inverness Medical; grant support from Amgen, Alexion, Immunodiagnostic Systems, Roche, AstraZeneca. Kim E Naylor, Maria Luisa Brandi, Cyrus Cooper, Elaine Dennison, Deborah Gold, Peyman Hadji, Mickael Hiligsmann, Robert Horne, John A Kanis, Barbara Obermayer-Pietsch, René Rizzoli, and Stuart Silverman have no conflict of interest.

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA)., Methods: We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years., Results: In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score ≤ -2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers., Conclusion: Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases.