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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.)

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.)

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.)

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.

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.

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.)

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.)

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.)

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.)

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.

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 .

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.

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.

Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H(+)/K(+)ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by three-point bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Three-point bending test also showed higher Young's modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition., (© 2016 Society for Endocrinology.)

Human tear fluid is a complex mixture containing high concentrations of proteins and is increasingly becoming an important source for studying protein biomarkers of eye-related diseases such as Graves' ophthalmopathy. Today, the Schirmer tear test is the most widely used technique for tear collection. However, sample handling and protein extraction from these strips have been highly challenging. Cutting and removal of the Schirmer strips after extraction, which may lead to sample loss prior to downstream analysis, are some of the challenges to consider. To address some of these limitations, we have developed a single-unit filter-aided method for both sample handling and protein extraction. In addition, we systematically investigated the most suitable conditions for protein extraction from these strips. Among the different extraction conditions applied, extraction with 100 mM ammonium bicarbonate containing 50 mM NaCl resulted in the highest number of identified proteins using one-dimensional liquid chromatography tandem mass spectrometry (LC-MS/MS). Moreover, 1526 proteins were identified when the optimized extraction method was combined with two-dimensional LC-MS/MS analysis, demonstrating the applicability of this novel approach to the study of the tear proteome. This dataset of identified proteins represents a comprehensive catalogue of the tear proteome and may serve as a list for future biomarker research., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Low-grade inflammation is associated with fractures, while the relationship between inflammation and bone mineral density (BMD) is less clear. Moreover, any gender differences in the sensitivity to inflammation are still poorly elucidated. We therefore tested the hypothesis that high-sensitivity C-reactive protein (CRP) is an independent risk factor for low BMD and non-vertebral fractures, in both genders, and whether there are gender differences in these associations. CRP levels and BMD at the total hip and femoral neck were measured in 1902 women and 1648 men between 55 and 74 years of age, at baseline in the Tromsø Study, Norway, in 2001-2002. Non-vertebral fractures were registered from hospital X-ray archives during an average of 7.2 years follow-up. Linear regression analyses were used for CRP association with BMD and Cox proportional hazards model for fracture prediction by CRP. During 25 595 person-years follow-up, 366 (19%) women and 126 (8%) men suffered a non-vertebral fracture. There was no association between CRP and BMD in women, but an inverse association in men (p=0.001) after adjustment for age and body mass index. Each standard deviation (SD) increase in log-CRP was associated with an increased risk for non-vertebral fracture by 13% in women and 22% in men (hazard ratios (HRs) 1.13, 95% confidence interval (CI) 1.02-1.26, p=0.026 and 1.22, 95% CI=1.00-1.48, p=0.046, respectively). After adjustment for BMD and other risk factors, women with CRP in the upper tertile exhibited 39% higher risk for fracture than those in the lowest tertile of CRP (HR = 1.39, 95% CI = 1.06-1.83, p = 0.017), while men in the upper tertile exhibited 80% higher risk (HR=1.80, 95% CI=1.10-2.94, p=0.019). In summary, CRP was not associated with BMD in women but inversely associated in men, and predicted fractures in both genders. We infer that inflammation influence fracture risk in both women and men, although the biological mechanisms may differ between the genders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Insulin resistance and type 2 diabetes are more prevalent in people of South Asian ethnicity than in people of Western European origin. To investigate the source of these differences, we compared insulin sensitivity, insulin secretion, glucose and lipid metabolism in South Asian and Nordic subjects with type 2 diabetes., Methods: Forty-three Nordic and 19 South Asian subjects with type 2 diabetes were examined with intra-venous glucose tolerance test, euglycemic clamp including measurement of endogenous glucose production, indirect calorimetry measuring glucose and lipid oxidation, and dual x-ray absorptiometry measuring body composition., Results: Despite younger mean ± SD age (49.7 ± 9.4 vs 58.3 ± 8.3 years, p = 0.001), subjects of South Asian ethnicity had the same diabetes duration (9.3 ± 5.5 vs 9.6 ± 7.0 years, p = 0.86), significantly higher median [inter-quartile range] HbA1c (8.5 [1.6] vs 7.3 [1.6] %, p = 0.024) and lower BMI (28.7 ± 4.0 vs 33.2 ± 4.7 kg/m(2), p<0.001). The South Asian group exhibited significantly higher basal endogenous glucose production (19.1 [9.1] vs 14.4 [6.8] µmol/kgFFM · min, p = 0.003). There were no significant differences between the groups in total glucose disposal (39.1 ± 20.4 vs 39.2 ± 17.6 µmol/kgFFM · min, p = 0.99) or first phase insulin secretion (AUC0-8 min: 220 [302] vs 124 [275] pM, p = 0.35). In South Asian subjects there was a tendency towards positive correlations between endogenous glucose production and resting and clamp energy expenditure., Conclusions: Subjects of South Asian ethnicity with type 2 diabetes, despite being younger and leaner, had higher basal endogenous glucose production, indicating higher hepatic insulin resistance, and a trend towards higher use of carbohydrates as fasting energy substrate compared to Nordic subjects. These findings may contribute to the understanding of the observed differences in prevalence of type 2 diabetes between the ethnic groups.

The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Transient postoperative hypocalcemia is one of the most common complications after thyroidectomy. Permanent hypocalcemia, however, is rare, but usually requires life-long treatment and follow-up. The risk of permanent hypocalcemia has been shown to be significantly higher in patients with Graves' disease. In the present study we evaluated short-term and long-term changes in serum calcium, phosphate, magnesium, and parathyroid hormone (PTH) levels in order to characterize subjects at risk of postoperative hypoparathyroidism., Methods: Forty patients who underwent total thyroidectomy for Graves' disease were included in the study. Calcium, phosphate, magnesium, and PTH were measured before surgery and regularly during the year that followed., Results: Postoperative hypocalcemia was seen in 21/40 (53 %) patients. Undetectable PTH (<0.6 pmol/L) was registered in 11/40 (27 %) patients. All patients with measurable PTH 6-48 h after operation regained normal calcium. Of those with undetectable PTH after 6-48 h, four developed permanent hypocalcemia. We found a significantly lower serum calcium level before operation in patients who developed permanent hypocalcemia compared to those who did not (p < 0.001). We also found a significant correlation between the decrease in serum magnesium from time 0 to 48 h after operation and permanent hypocalcemia (p = 0.015)., Conclusions: Serum calcium prior to operation, serum PTH, and degree of decrease in magnesium levels in serum 48 h after operation may predict development of permanent hypocalcemia. Magnesium plays an important role in calcium homeostasis via stimulation of PTH secretion and modulation of PTH receptor sensitivity. Both mechanisms may have played a role for the findings reported in this article.

The majority of osteoporotic fractures happen in individuals with BMD t-scores in the osteopenic range (-2,5< t-score <-1). However, widespread use of anti-osteoporotic medication in this group based on t-score alone is not advisable because: 1) the number needed to treat is much higher (NNT>100) than in patients with fractured and t-score below -2,5 (NNT 10-20); 2)while specific osteoporosis treatments have demonstrated significant reductions of the fracture risk in patients with t-score <-2, 5, the efficacy in patients in the osteopenic range is less well established. Therefore, an osteopenic t-score does not in itself constitute a treatment imperative. Generally, osteopenia has to be associated with either low energy fracture(s) or very high risk for future fracture as assessed with risk calculators like FRAX to warrant specific osteoporosis therapy. Vertebral fractures are now conveniently assessed using lateral x-rays from DXA machines. In the vast majority of cases antiresorptive treatments (mainly hormone replacement therapy and SERMS in younger and bisphosphonates or Denosumab in older women) are the treatments of choice in this group of patients,-only rarely is anabolic therapy indicated.

The ever increasing use of magnetic resonance imaging in clinical practice has led to the recognition of a new entity, bone marrow lesions (BMLs). These lesions are characterized by excessive water signals in the marrow space and have emerged as a central component of many different diseases affecting the musculoskeletal system. BMLs have in particular been associated with a wide variety of inflammatory and non-inflammatory rheumatologic conditions and are not only considered significant sources of pain, but also linked to the worsening of patient prognosis in many disease states. In this review, we summarize the current knowledge on BMLs with an emphasis on the clinical and histological features of this entity in inflammatory and non-inflammatory disease and provide a unifying hypothesis based on the appearance with various imaging technologies. We also try to pair this hypothesis with the apparent beneficial effects of various treatment regimens, mainly within the group of bone antiresorptive drugs (calcitonin, bisphosphonates) on symptoms associated with BMLs.

Background: Low bone mass is prevalent in ambulatory multiple sclerosis (MS) patients even shortly after clinical onset. The mechanism is not known, but could involve shared etiological risk factors between MS and low bone mass such as hypovitaminosis D operating before disease onset, or increased bone loss after disease onset. The aim of this study was to explore the mechanism of the low bone mass in early-stage MS patients., Methodology/principal Findings: We performed a population-based case-control study comparing bone turnover (cross-linked N-terminal telopeptide of type 1 collagen; NTX, bone alkaline phosphatase; bALP), metabolism (25-hydroxy- and 1, 25-dihydroxyvitamin D, calcium, phosphate, and parathyroid hormone), and relevant lifestyle factors in 99 patients newly diagnosed with clinically isolated syndrome (CIS) or MS, and in 159 age, sex, and ethnicity matched controls. After adjustment for possible confounders, there were no significant differences in NTX (mean 3.3; 95% CI -6.9, 13.5; p = 0.519), bALP (mean 1.6; 95% CI -0.2, 3.5; p = 0.081), or in any of the parameters related to bone metabolism in patients compared to controls. The markers of bone turnover and metabolism were not significantly correlated with bone mass density, or associated with the presence of osteoporosis or osteopenia within or between the patient and control groups. Intake of vitamin D and calcium, reported UV exposure, and physical activity did not differ significantly., Conclusions/significance: Bone turnover and metabolism did not differ significantly in CIS and MS patients with prevalent low bone mass compared to controls. These findings indicate that the bone deficit in patients newly diagnosed with MS and CIS is not caused by recent acceleration of bone loss, and are compatible with shared etiological factors between MS and low bone mass.

Background: Treatment with bisphosphonates reduces the risk of new fractures and is the treatment of choice for osteoporosis. Denosumab inhibits bone resorption via a different mechanism than bisphosphonates, and is a new option in the treatment of osteoporosis. In this paper we give an overview of the mode of action and clinical effects., Material and Methods: The paper is based on a non-systematic literature search in Pubmed/Medline., Results: Denosumab is a human monoclonal antibody to receptor-activated nuclear factor kappa B (RANKL), a member of the TNF family that is formed in the osteoblast. Binding to RANKL results in reduced recruitment and activity of osteoclasts. Denosumab 60 mg given subcutaneously every six months is shown to inhibit bone resorption to a greater degree than bisphosphonates. In a three-year study of 7,868 women with postmenopausal osteoporosis, a reduction in the relative risk of vertebral, non-vertebral and hip fractures compared to placebo was found (68. 20 and 40 %, correspondingly). In the clinical trials with denosumab, the safety profile was similar to placebo, except for a slightly higher incidence of cellulitis and exanthema. Denosumab has also shown promising skeletal effects in the treatment of cancer and rheumatoid arthritis., Interpretation: Treatment with denosumab has an effect on postmenopausal osteoporosis and may be an alternative to treatment with bisphosphonates. There are few adverse effects and it is simple to administer.

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β-C-telopeptide of type I collagen [β-CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA-based BMD (e.g., quantitative computed tomography and finite-element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered., (Copyright © 2011 American Society for Bone and Mineral Research.)

Bone remodeling is a tightly regulated process securing repair of microdamage (targeted remodeling) and replacement of old bone with new bone through sequential osteoclastic resorption and osteoblastic bone formation. The rate of remodeling is regulated by a wide variety of calcitropic hormones (PTH, thyroid hormone, sex steroids etc.). In recent years we have come to appreciate that bone remodeling proceeds in a specialized vascular structure,--the Bone Remodeling Compartment (BRC). The outer lining of this compartment is made up of flattened cells, displaying all the characteristics of lining cells in bone including expression of OPG and RANKL. Reduced bone turnover leads to a decrease in the number of BRCs, while increased turnover causes an increase in the number of BRCs. The secretion of regulatory factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC also creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Circulating osteoclast- and osteoblast precursor cells have been demonstrated in peripheral blood. The dominant pathway regulating osteoclast recruitment is the RANKL/OPG system, while many different factors (RUNX, Osterix) are involved in osteoblast differentiation. Both pathways are modulated by calcitropic hormones.

Objectives: To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5 mg in reducing risk of clinical vertebral, nonvertebral, and any clinical fractures in elderly osteoporotic postmenopausal women., Design: A post hoc subgroup analysis of pooled data from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial., Setting: Multicenter, randomized, double-blind, placebo-controlled trials., Participants: Postmenopausal women (aged > or =75) with documented osteoporosis (T-score < or =-2.5 at femoral neck or >/=1 prevalent vertebral or hip fracture) or a recent hip fracture., Intervention: Patients were randomized to receive an intravenous infusion of ZOL 5 mg (n=1,961) or placebo (n=1,926) at baseline and 12 and 24 months., Measurements: Primary endpoints were incidence of clinical vertebral and nonvertebral and any clinical fracture after treatment., Results: At 3 years, incidence of any clinical, clinical vertebral, and nonvertebral fracture were significantly lower in the ZOL group than in the placebo group (10.8% vs 16.6%, 1.1% vs 3.7%, and 9.9% vs 13.7%, respectively) (hazard ratio (HR)=0.65, 95% confidence interval (CI)=0.54-0.78, P<.001; HR=0.34, 95% CI=0.21-0.55, P<.001; and HR=0.73, 95% CI=0.60-0.90, P=.002, respectively). The incidence of hip fracture was lower with ZOL but did not reach statistical significance. The incidence rate of postdose adverse events were higher with ZOL, although the rate of serious adverse events and deaths was comparable between the two groups., Conclusion: Once-yearly intravenous ZOL 5 mg was associated with a significant reduction in the risk of new clinical fractures (vertebral and nonvertebral) in elderly postmenopausal women with osteroporosis.

Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was approximately 6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality.

A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Paget's disease and metastatic bone disease, is osteonecrosis of the jaw (ONJ). The incidence of ONJ in the general population is unknown; this rare condition also may occur in patients not receiving bisphosphonates. Case reports have discussed ONJ development in patients with multiple myeloma or metastatic breast cancer receiving bisphosphonates as palliation for bone metastases. These patients are also receiving chemotherapeutic agents that might impair the immune system and affect angiogenesis. The incidence or prevalence of ONJ in patients taking bisphosphonates for osteoporosis seems to be very rare. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. A majority of ONJ occurs after tooth extraction. Furthermore, the underlying risk of developing ONJ may be increased in osteoporotic patients by comorbid diseases. Treatment for ONJ is generally conservative.

Background: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed., Methods: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture., Results: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups., Conclusions: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

Background: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period., Methods: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes., Results: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001)., Conclusions: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.), (Copyright 2007 Massachusetts Medical Society.)

In light of recent reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include an intravenous bisphosphonate, Novartis convened an international advisory board of experts in the fields of oral surgery and pathology, medical oncology, metabolic bone disease, and orthopedics to review existing data and provide updated recommendations on the clinical diagnosis, prevention, and management of ONJ in the oncology setting. Recommendations were developed to help guide healthcare professionals in early diagnosis and patient management. It is recommended that patients be encouraged to receive a dental examination prior to initiating bisphosphonate therapy and, if possible, complete any necessary dental procedures (e.g., tooth extraction) prior to initiating bisphosphonate therapy. Patients should receive regular dental visits during bisphosphonate therapy. Patients should be encouraged to practice good oral hygiene and minimize possible jaw trauma. If possible, patients should avoid dental surgery during treatment with bisphosphonates. If exposed bone is observed or reported in the oral cavity at any time (suspected ONJ), refer the patient to a dental professional immediately.

In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed.

Unlabelled: A single 5-mg infusion of zoledronic acid restores biochemical markers of bone turnover into the reference range in the majority of patients with Paget's disease and maintains biochemical remission for at least 2 years. This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy., Introduction: Zoledronic acid (ZOL) is a potent bisphosphonate that produces a rapid and complete control of the increased bone turnover of Paget's disease. Long-term control of disease activity is an important aim of treatment in the hope that this will reduce the risk of complications such as deformity, fracture, and degenerative joint disease., Materials and Methods: This study compares the ability of ZOL 5 mg given as a 15-minute intravenous infusion with risedronate (RIS) 30 mg daily by mouth for 60 days to maintain long-term control of bone turnover. No bisphosphonate was given during the extension study. All patients (n = 296) who achieved a therapeutic response, defined as normalization or a >75% reduction in the total alkaline phosphatase (total ALP) excess above the midpoint of the reference range, were eligible for inclusion., Results: ZOL maintained the mean level of total ALP at the middle of the reference range, whereas those treated with risedronate showed a linear increase in total ALP from the 6-month post-treatment time-point. Both treatments resulted in a linear relationship between the 6-month nadir and 24-month total ALP. The relationship for RIS was shifted upward, showing that for a given level of post-treatment biochemical activity, bone turnover increased with time. This was in contrast to the ZOL-treated patients where total ALP generally remained unchanged over this 18-month extension period. A similar pattern of response was seen with the other bone turnover markers., Conclusions: ZOL maintains bone turnover within the reference range over 24 months from the initiation of treatment. A reduction in the incidence and severity of long-term complications may require persistent normalization of bone turnover over many years, and this now seems a realistic possibility with ZOL.