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Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which involves not only the skeleton, but also the cardiopulmonary and gastrointestinal system, soft tissues, tendons, muscle, and joints, hearing, eyesight, dental health, and women's health in OI and potentially adds negative affect to health-related quality of life. We aim to guide clinicians as well as draw attention to obvious knowledge gaps and the need for further research in adult OI [ABSTRACT FROM AUTHOR]

Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings. Long-term treatment with the anti-resorptive drug denosumab results in a continuous gain in bone mineral density, whereas denosumab withdrawal results in a transient overshoot in bone turnover, with rapid bone loss. This Perspective explores the potential mechanisms underlying these effects. [ABSTRACT FROM AUTHOR]

Summary: In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. Introduction: In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. Methods: In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. Results: In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. Conclusions: Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab. [ABSTRACT FROM AUTHOR]

To facilitate the development of leadership competencies in a multidisciplinary group of 18 emerging bone experts from 6 European Countries and Brazil, to face future scenarios in the evolving field of fragility fractures, and to support secondary fracture prevention and improve patient outcomes. Changes brought by the COVID-19 pandemic have further highlighted this need. A 2.5-year community of practice (CoP) programme was established with two senior bone experts acting as mentors. The content was adapted during the COVID-19 pandemic. The education impact of the programme was assessed using an ethics-approved mixed-method design consisting of multiple sources of qualitative and quantitative data collected longitudinally. Quantitative data were analysed descriptively. Qualitative data underwent a thematic analysis. After participating in the programme, participants reported increased interprofessional collaboration and communication skills, better understanding of health economics and negotiation, application of adult learning principles to their work setting, development of competencies to critically appraise guidelines, enhanced abilities to facilitate behaviour change in others, and improved confidence leading their team through crisis situations. Although time was required for some physicians to get accustomed to the CoP concept and develop trust with other members, it was described as a beneficial real-world learning experience. An educational real-world CoP programme was effective in enhancing leadership competencies among future leaders in the bone field to improve care of fragility fracture patients. The results presented could guide the development of other CoPs in fragility fracture care as leadership competencies are increasingly required in that field. [ABSTRACT FROM AUTHOR]

This study evaluated the efficacy, safety, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of SB16 versus reference denosumab (DEN) up to 18 months in postmenopausal osteoporosis (PMO) patients, and assessed outcomes after switching from DEN to SB16 compared to those who continued with DEN or SB16. 457 PMO patients were initially randomized, with 407 re-randomized at Month 12 to either continue DEN (DEN+DEN), switch to SB16 (DEN+SB16), or continue SB16 (SB16 + SB16) through Month 18. Efficacy was assessed by the percent change from baseline in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck. Safety, PD, PK, and immunogenicity were evaluated throughout the study period. Mean percent changes from baseline in lumbar spine, total hip, and femoral neck BMD at Month 18 were comparable across treatment groups, indicating comparable efficacy between SB16 and DEN. The mean percent change in lumbar spine BMD was 6.8 % (SB16 + SB16), 6.2 % (DEN+SB16), and 6.8 % (DEN+DEN). Total hip BMD increased by 4.4 %, 3.5 %, and 4.0 %, and femoral neck BMD by 3.4 %, 3.1 %, and 2.7 % for SB16 + SB16, DEN+SB16, and DEN+DEN, respectively. Safety profiles were similar among groups, with no new safety concerns identified after switching. Only one patient in the DEN+SB16 group developed non-neutralizing anti-drug antibodies by Month 18, indicating a low immunogenicity risk for SB16. Switching from DEN to SB16 demonstrated comparable efficacy, safety, PD, PK, and immunogenicity in PMO patients relative to those who continued DEN. SB16 was well tolerated over 18 months, demonstrating comparable outcomes to DEN. • Switching from DEN to SB16 showed comparable efficacy, safety to continuing DEN. • SB16 maintained comparable BMD changes to DEN over 18 months in PMO patients. • SB16 was comparable to DEN in safety, PD, PK, and immunogenicity over 18 months. [ABSTRACT FROM AUTHOR]

Objective: Glucocorticoids constitute a considerable risk for developing osteoporosis in both younger and older adults. However, currently available bone imaging modalities and fracture‐risk assessment tools do not adequately capture the dramatic changes in bone microarchitecture, heterogeneity of glucocorticoid exposure, the impact of chronic disease and other osteoporosis risk factors on the assessment of osteoporosis in these individuals. Design: A narrative review is presented, following a systematic search of the literature from 2000 to 2021. Results: Our current appreciation of glucocorticoid‐induced osteoporosis (GIO) is focused on older populations, with limited evidence to guide the investigation, risk assessment and treatment in premenopausal women and men less than 50 years. The impact of the underlying chronic disease on secondary osteoporosis in these younger adults is also poorly understood. Conclusion: Through this narrative review, we provide a comprehensive overview of and recommendations for optimising the management of this common cause of secondary osteoporosis younger and older adults. [ABSTRACT FROM AUTHOR]

Efficient therapies are available for the treatment of osteoporosis. Anti-resorptive therapies, including bisphosphonates and denosumab, increase bone mineral density (BMD) and reduce the risk of fractures by 20-70%. Bone-forming or dual-action treatments stimulate bone formation and increase BMD more than the anti-resorptive therapies. Two studies have demonstrated that these treatments are superior to anti-resorptives in preventing fractures in patients with severe osteoporosis. Bone-forming or dual-action treatments should be followed by anti-resorptive treatment to maintain the fracture risk reduction. The BMD gains seen with bone-forming and dual-action treatments are greater in treatment-naïve patients compared to patients pretreated with anti-resorptive treatments. However, the antifracture efficacy seems to be preserved. Treatment failure will often lead to switch of treatment from orally to parentally administrated anti-resorptives treatment or from anti-resorptive to bone-forming or dual-action treatment. Osteoporosis is a chronic condition and therefore needs a long-term management plan with a personalized approach to treatment. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc. [ABSTRACT FROM AUTHOR]

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies. [ABSTRACT FROM AUTHOR]

We describe the pre-planned interim analysis of fracture outcomes, health-related quality of life (HRQoL) and back pain in patients with severe osteoporosis treated with teriparatide for up to 24 months in the Extended Forsteo (Forsteo(®) is a registered trade name of Eli Lilly and Company) Observational Study (ExFOS), a prospective, multinational, observational study. Data on incident clinical fractures, HRQoL (EQ-5D questionnaire) and back pain [100 mm visual analogue scale (VAS)] were collected. The number of patients with fractures was summarised in 6-month intervals and fracture rate over each 6-month period was assessed using logistic regression for repeated measures. Changes from baseline in EQ-5D and back pain VAS were analysed using mixed models for repeated measures. Of 1454 patients in the active treatment cohort, 90.6 % were female and 14.4 % were taking glucocorticoids. During teriparatide treatment (median duration 23.7 months), 103 patients (7.1 %) sustained a total of 122 incident clinical fractures (21 % vertebral, 79 % non-vertebral). A 49 % decrease in the odds of fractures and a 75 % decrease in the odds of clinical vertebral fractures were observed in the >18- to 24-month period versus the first 6-month period (both p < 0.05). EQ-5D scores and back pain VAS scores were significantly improved from baseline at each post-baseline observation during teriparatide treatment. In conclusion, patients with severe osteoporosis showed a significant reduction in the incident fracture rate during 24 months of teriparatide treatment in routine clinical practice, accompanied by a significant improvement in HRQoL and reduction in back pain. Results should be interpreted in the context of the non-controlled design of this observational study. [ABSTRACT FROM AUTHOR]

Osteoporosis is a common chronic disease and therefore a long-term management plan based on disease severity, comorbidities, other pharmacological treatments, gender, age and patient preferences is necessary. Consideration of treatment breaks may be included in the long-term management plan if the patient has been treated with a bisphosphonate, the disease is less severe, the response to treatment has been satisfactory and the risk of future fracture is estimated to be low. This perspective reviews the current evidence for long-term treatment with bisphosphonates and off treatment effects. Approaches to decision making and monitoring of treatment breaks are discussed. [ABSTRACT FROM AUTHOR]

Abstract Introduction Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies. Methods Patients received teriparatide 20 μg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age <75 or ≥75 years, diabetes, prior bisphosphonates use, rheumatoid arthritis (RA), glucocorticoid use, prior hip, and prior vertebral fracture. Results The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p <.005) for >6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p =.074, patients <75 years of age responded better), and diabetes for clinical fractures (p =.046, patients with diabetes responded better), although all of these subgroups experienced significant reductions over time. Glucocorticoids, prior bisphosphonate, and prior vertebral fracture were associated with increased CVF, NVF, and clinical fracture rates; RA, prior hip fracture and female gender were associated with higher NVF and clinical fracture rates; increased age was associated with higher CVF and clinical fracture rates. Conclusions Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies. Highlights • Limited information is available regarding the fracture efficacy of teriparatide in clinically important subgroups. • We merged the primary data from 8828 patients treated with teriparatide in four prospective observational studies. • Clinical vertebral, non-vertebral, clinical, and hip fracture rates decreased versus the first six months of treatment. • The fracture results with teriparatide were generally consistent across clinically relevant subgroups of patients. • The results should be interpreted in the context of the non-controlled design of the source studies. [ABSTRACT FROM AUTHOR]

This study aimed to describe clinical outcomes in patients prescribed teriparatide and followed up for 18 months after stopping the drug in real-life conditions. The Extended Forsteo® Observational Study analysed incident clinical fractures in 6-month intervals using logistic regression with repeated measures. Changes in back pain (visual analogue scale) and health-related quality of life (HRQoL; EQ-5D questionnaire) were analysed using mixed models for repeated measures. Patients were analysed if they had a post-baseline visit, regardless of whether and for how long they took teriparatide. Of 1531 patients analysed (90.7% female, mean age: 70.3 years), 76 (5.0%) never took teriparatide. Median treatment duration was 23.6 months. The adjusted odds of clinical fracture decreased by 47% in the > 12- to 18-month treatment period (p = 0.013) compared with the first 6-month period, with no statistically significant reduction in the > 18- to 24-month interval. The clinical fracture rate remained stable during the 18 months' post-teriparatide, when approximately 98% of patients took osteoporosis medication (51% bisphosphonates). Clinical vertebral fractures were reduced at every time period compared with the first 6 months. Adjusted mean back pain scores decreased and EQ-5D scores increased significantly at each post-baseline observation. In a real-life clinical setting, the risk of clinical fractures declined during 24 months of teriparatide treatment. This reduction was maintained 18 months after stopping teriparatide. In parallel, patients reported significant improvements in back pain and HRQoL. The results should be interpreted in the context of the non-controlled design of this observational study. [ABSTRACT FROM AUTHOR]

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 5 years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10 years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5 years, 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. [ABSTRACT FROM AUTHOR]

Background: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy.Methods: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 μg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301.Findings: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal.Interpretation: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture.Funding: Amgen, Astellas, and UCB Pharma. [ABSTRACT FROM AUTHOR]

Efficient therapies are available for the treatment of osteoporosis, however, there are still unmet needs. Anti-resorptive therapies only increase bone mineral density to a certain extent and reduce the risk of non-vertebral fractures by 20%, only one anabolic option is available — the effect of which levels off over time, and the evidence for combination therapy targeting both resorption and formation is limited. The current review will focus on emerging treatments of osteoporosis with the potential of enhanced anabolic effects (romosozumab and abaloparatide) or uncoupling of resorption and formation (odanacatib and romosozumab) as well as the effect of combination therapy. [ABSTRACT FROM AUTHOR]

Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional formulations of alendronate (ALN). The clinical effectiveness of ALN-EFF, however, has not been investigated. This study aims to investigate if ALN-EFF is non-inferior to ALN in suppressing bone turnover markers (BTM). We conducted a 16-week prospective, randomized, open-label study comprising 64 postmenopausal women with BMD T-score < −1 naïve to osteoporosis treatment. Participants were randomized 1:1 to ALN or ALN-EFF. We collected blood samples at 0, 4, 8, and 16 weeks. Non-inferiority margin was determined as 12% (80% of efficacy retained), and an SD of 15% on change in CTx. CTx decreased by 58.2% ± 24.1% in the ALN group and by 46.9% ± 23.3% (CI − 38.42:− 55.35) in the ALN-EFF group (p = 0.08). The non-inferiority limit was 46.6%. With ALN-EFF the CI crosses the non-inferiority limit thus the test for non-inferiority was indeterminate. PINP decreased by 45.7 ± 22.6% in the ALN group and by 35.1 ± 20.7% in the ALN-EFF group (p = 0.07). Changes over time in the BTMs were not significantly different between the groups, p > 0.10 for both CTx and PINP. There was no difference in frequency of AEs or compliance between the two groups, but rate of discontinuation was lower with ALN-EFF. In conclusion, suppression of BTMs was not significantly different between the groups but formal non-inferiority could not be established. [ABSTRACT FROM AUTHOR]

Background: Osteogenesis imperfecta (OI) is a heterogeneous rare connective tissue disorder commonly caused by mutations in the collagen type I genes. Pharmacological treatment has been most extensively studied in children, and there are only few studies comprising adult OI patients. Objectives: i) To review the literature on the current medical management of OI in children and adults, and thereby identify unmet medical needs and ii) to present an overview of possible future treatment options. Results: Individualization and optimization of OI treatment in adults remain a challenge, because available treatments do not target the underlying collagen defect, and available literature gives weak support for treatment decisions for adult patients. Conclusions: Bisphosphonates are still the most widely used pharmacological treatment for adult OI, but the current evidence supporting this is sparse and investigations on indications for choice and duration of treatment are needed. [ABSTRACT FROM AUTHOR]

Purpose: This study was undertaken to assess persistence with bisphosphonates and raloxifene and to identify determinants of adherence (patient age, level of information, educational status, etc.) among women with osteoporosis in three different clinical settings in Denmark. Methods: We compared persistence to therapy in three historical cohorts of women diagnosed with osteoporosis starting therapy between January 1999 and January 2004. The study comprised 878 patients treated and followed at Odense University Hospital, 285 patients diagnosed and followed at the Hellerup Osteoporosis Clinic (private practice), and 343 patients diagnosed at Aarhus University Hospital and followed by the referring general practitioner. Data on persistence and possible confounders were collected using a mailed questionnaire. Reminders were issued after 1-2 months to non-respondents. Results: Persistence at 2 years as estimated from Kaplan-Meyer analysis was 0.87, 0.84 and 0.88 in the three cohorts, respectively. There were no significant differences between the clinics. Level of persistence was not related to patient assessment of the adequacy of the clinical information provided by the prescribing doctor, presence of prior fractures or a family history of osteoporosis. However, patients who read the information leaflet on their osteoporosis medication tended to be more persistent with treatment (p<0.09). Conclusions: Women's persistence with bisphosphonates and raloxifene was surprisingly high and similar between treating centres. This may be due to a high level of public information available on osteoporosis in Denmark. [ABSTRACT FROM AUTHOR]

The European Forsteo Observational Study was designed to examine the effectiveness of teriparatide in postmenopausal women with osteoporosis treated for up to 18 months in normal clinical practice in eight European countries. The incidence of clinical vertebral and nonvertebral fragility fractures, back pain, and health-related quality of life (HRQoL, EQ-5D) were assessed. Spontaneous reports of adverse events were collected. All 1,648 enrolled women were teriparatide treatment-naive, 91.0% of them had previously received other anti-osteoporosis drugs, and 72.8% completed the 18-month study. A total of 168 incident clinical fractures were sustained by 138 (8.8%) women (821 fractures/10,000 patient-years). A 47% decrease in the odds of fracture in the last 6-month period compared to the first 6-month period was observed (P < 0.005). Mean back pain VAS was reduced by 25.8 mm at end point (P < 0.001). Mean change from baseline in EQ-VAS was 13 mm by 18 months. The largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort. There were 365 adverse events spontaneously reported, of which 48.0% were considered related to teriparatide; adverse events were the reason for discontinuation for 79 (5.8%) patients. In conclusion, postmenopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18-month treatment period. This was associated with a clinically significant improvement in HRQoL. Safety was consistent with current prescribing information. These results should be interpreted in the context of the open-label, noncontrolled design of the study. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results. Methods: We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G−1639-A (G−800-A, rs1800468), C−1348-T (C−509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures. Results: There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (−12 mg/cm2) in men with the T−1348 allele (p <0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09–2.64), p <0.05. Conclusions: This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C−1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies. [Copyright &y& Elsevier]

Transforming growth factor (TGF)-β1 is the most abundant growth factor in human bone. It is produced by osteoblasts and inhibits osteoclast proliferation and activity and stimulates proliferation and differentiation of preosteoblasts. Several polymorphisms have been described in the TGF-β1 gene. Previously, we and others have found associations between some of these polymorphisms and bone mass. We therefore wanted to examine if these polymorphisms are also predictors of osteoporotic fractures. The polymorphisms G−1639-A, C−1348-T, C−765insC, T29-C, G74-C, 713-8delC, C788-T, and T816-20-C were examined using RFLP and sequencing in 296 osteoporotic patients with vertebral fractures and 330 normal individuals. Bone mineral density (BMD) was examined at the lumbar spine and at the femoral neck by DXA. Genotype distributions were in H-W equilibrium. Linkage disequilibrium was found between the polymorphisms. The T816-20-C genotypes were distributed differently among osteoporotic patients and normal controls. The TT genotype was less common in individuals with osteoporotic fractures (χ2 = 6.02, P < 0.05). BMD was higher in individuals with the TT-genotype (T816-20-C) at the lumbar spine, 0.960 ± 0.173 g/cm2 compared with individuals with the TC or CC genotypes: 0.849 ± 0.181 g/cm2 and 0.876 ± 0.179 g/cm2, respectively (P < 0.001, ANOVA). Similar differences between genotypes were found at the different hip regions as well as at the total hip. Individuals with the TT-genotype (C−1348-T) had higher bone mass at the femoral neck: 0.743 ± 0.134 g/cm2 compared with 0.703 ± 0.119 g/cm2 in individuals with TC or CC genotypes (P < 0.05). Individuals with the CC-genotype (T29-C) had higher bone mass at the femoral neck, 0.735 ± 0.128 g/cm2 compared with 0.703 ± 0.120 g/cm2 in individuals with TC or TT genotypes (P < 0.05) and at the total hip: 0.852 ± 0.166 g/cm2 vs. 0.818 ± 0.149 g/cm2, respectively (P < 0.05). None of the other polymorphisms were distributed differently in patients and controls and did not affect BMD. In conclusion, The TT genotype of the T816-20-C polymorphism is less common in patients with osteoporotic fractures and is associated with higher bone mass both at the lumbar spine and at the hip. The C−1348-T and T29-C polymorphisms were distributed similarly in osteoporotic patients and normal controls, however, the rare genotypes were associated with higher bone mass at the hip. [Copyright &y& Elsevier]

Proteoglycans (PGs) are complex macromolecules consisting of a core protein and glycosaminoglycan (GAG) side chains. PGs are important for the constitution and functioning of the connective tissue. The normal composition of the GAG side chains defines the nature of the PGs and a wide range of biological events. Deficiencies of specific enzymes involved in the linkage of GAGs to the core protein to form functional PGs, lead to a heterogeneous disease group called Linkeropathies. This is a group of multisystem conditions characterized by different phenotypes that include skeletal dysplasia and various extra-skeletal features: developmental delay/intellectual disability, ophthalmological abnormalities including blue sclerae, facial characteristics, cardiac defects, abdominal wall defects (hernias), cutis laxa, hypermobility and hypotonia. The conditions show variable severity and often overlapping phenotypes. The enzyme β-1,3-glucuronyltransferase 3, encoded by B3GAT3 , is involved in the linkage process to form functional PGs. Biallelic pathogenic variants in B3GAT3 hence lead to Linkeropathy due to loss of function or decreased activity of this enzyme. We describe a 22-year-old female patient, born of consanguineous parents. The disease history includes congenital severe joint malalignment of elbows, hips, knees and feet, hypermobility, severe kyphoscoliosis, osteoporosis with multiple fractures in childhood, congenital diaphragmatic hernia, minor dental anomalies, digital malformations, and characteristic facial features. Whole exome sequencing was performed, and homozygosity for a novel in-frame deletion in B3GAT3 , (c.61_63delCTC (p.(Leu21del))) was detected. Both unaffected parents (double second cousins) were shown to be heterozygous carriers. This is the first report to describe homozygosity for this specific in-frame deletion in B3GAT3 (p.(Leu21del)). We present a young adult phenotype and a summary of previous reported patients with other biallelic B3GAT3 -variants for comparison. Previously described patients of B3GAT3 -deficiency were, however, all children with phenotypes ranging from prenatal manifestation and early lethality to less severe. We suggest that this novel homozygous in-frame deletion in B3GAT3 may be the cause of a recessive form of Linkeropathy. [ABSTRACT FROM AUTHOR]

Aim: We aimed to improve bone health management of children with cerebral palsy (CP) by reviewing studies investigating bisphosphonate therapy in children with CP and other types of secondary osteoporosis. Methods: We included trials on bisphosphonate treatment reporting any direct bone measurement or fracture outcome. All studies of patients with CP were included. We also included all controlled trials of children with secondary bone fragility as well as observational studies with ≥20 participants or at least 3 years of follow‐up. Studies were assessed according to PRISMA guidelines using the RoB2‐tool and the Newcastle‐Ottawa Scale. Results: We reviewed 1104 studies and found 37 eligible. Some studies were sufficiently homogeneous to include in a meta‐analysis, and we found a 1‐year effect on lumbar spine bone mineral density (BMD) Z‐score of +0.65 after oral and + 1.21 after intravenous bisphosphonates in children with secondary osteoporosis. Further, data on adverse events and post‐treatment follow‐up were reviewed. Limitations were heterogeneity and small size of the included studies. Conclusion: Meta‐analysis consistently showed significant BMD increases with bisphosphonates in children with secondary osteoporosis. Direct evidence of the effect of bisphosphonates on reducing fractures is lacking. We found no reports of long‐term adverse events yet longer studies are needed. [ABSTRACT FROM AUTHOR]

Pycnodysostosis is a rare autosomal recessive osteosclerotic skeletal dysplasia caused by variants in the cathepsin K gene (CTSK). Clinical features include short stature, bone fragility, characteristic facial features and acro-osteolysis of the distal phalanges. Usually, patients suffer from multiple bone fractures. The purpose of this study was to describe the Danish population of pycnodysostosis patients with respect to genotype, phenotype and the prevalence of complications. We collected medical history, performed clinical examination, collected blood- and urine samples, performed dual-energy x-ray absorptiometry scan (DXA) and high-resolution peripheral quantitative computed tomography scan (HRpQCT) and obtained clinical photos. Information about complications, bone mineral density and bone markers in the blood were collected and analysed. Ten patients with a median age of 32 years ranging from five to 51 years participated. The pycnodysostosis phenotype varied with respect to the number of bone fractures and degree of complications. DXA and HRpQCT showed high bone mineral density. A tendency of growth hormone treatment escalating growth and increasing final height was seen. A marker of bone resorption measured in blood was within normal range in nine patients and elevated in one patient. A novel pathogenic variant in CSTK causing pycnodysostosis was detected in two related patients. Moreover information about the patients' own health perception was reported. An example being they rated their mental health to be good despite multiple bone fractures. This study provides information about genotypes and phenotypes in a Danish pycnodysostosis population. It reports new data about the complications such as bone fractures and it elucidates the levels of bone turnover markers as well as the density of the bones in one of the biggest cohort of pycnodysostosis patients ever published. An individualised approach to treatment in this patient group is necessary as the phenotype including complications varies between patients. Additional studies are needed to further understand genotype-phenotype correlations. • A novel mutation c.547 A > C causing pycnodysostosis is presented. • DXA and HRpQCT showed high bone mineral density in the patients. • Quality of life is reported high from the pycnodysostosis patients. • Growth hormone may benefit final height of pycnodysotosis patients. • The phenotype and genotype of pycnodysostosis patients varies greatly. [ABSTRACT FROM AUTHOR]

Efficient therapies are available for the treatment of osteoporosis. Bisphosphonates and denosumab are the most commonly used antiresorptive therapies. Despite differences in the increase in bone mineral density seen with these drugs, the reductions in fracture risk are similar; 50–70%, 20%, and 40% for vertebral, non-vertebral and hip fractures, respectively. The bone-forming treatments; teriparatide and abaloparatide increase bone mineral density more than the antiresorptives and the reductions in fracture risk are 85% and 40–50% for vertebral and non-vertebral fractures, respectively, compared to placebo. The VERO study demonstrated a >50% reduction in vertebral and clinical fractures in women treated with teriparatide compared to risedronate. The dual-action treatment; romosozumab leads to more pronounced increases in BMD than other treatment modalities and reduces the risk of vertebral and clinical fractures by 73% and 36% compared to placebo after 12 months and the sequential treatment regime; romosozumab for 12 months followed by alendronate reduced the risk of vertebral, non-vertebral and hip fractures by 48%, 20% and 38%, respectively compared to alendronate after 2–3 years. The evidence for combination therapy targeting both resorption and formation is limited as only short-term studies with BMD as the endpoint have been performed. All bone-forming and dual-action treatments increase BMD and reduce the fracture risk, however, the effect wears off with time and treatment is therefore only temporary and should be followed by antiresorptive treatment with a bisphosphonate or denosumab. The sequence of treatment matters as the BMD response to teriparatide is reduced in patients previously treated with bisphosphonates; however, based on the findings of the VERO trial, the anti-fracture efficacy of bone-forming treatment in comparison with risedronate seems to be preserved after bisphosphonate therapy. The DATA study suggested that transitioning from denosumab to teriparatide is problematic due to the increase in bone resorption occurring after stopping denosumab. Studies have shown further improvements in BMD when transitioning from oral bisphosphonates to zoledronic acid or denosumab. Management of osteoporosis will in many patients include a long-term treatment plan. This will often include sequential therapy which in severe cases preferably should start with bone-forming followed by antiresorptive treatment. The severity of osteoporosis, reaching a treatment goal, and responding to treatment failure are important factors determining the treatment sequence in the individual patient. • The antiresorptive, bone-forming and dual-action treatments available • A long-term, individualized management plan • Treatment target and treatment failure • Combination therapy; bone-forming treatment in combination with antiresorptive treatment • Sequential treatment; antiresorptive or bone-forming treatment after other treatment modalities [ABSTRACT FROM AUTHOR]

Summary : To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. Introduction : Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). Methods: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). Results: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). Conclusion: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence. [ABSTRACT FROM AUTHOR]

Bone quality is probably important for the survival of knee arthroplasty (KA), but little is known about systemic bone mineral density and bone turnover in patients prior to KA surgery. The aim of this study was to explore the prevalence of osteoporosis and bone turnover in relation to knee osteoarthritis (OA) grade in patients scheduled for KA surgery. Prospective preoperative evaluation of 450 patients (259 females) prior to KA between 2014 and 2016 with standing knee radiography, Dual-energy X-ray absorptiometry (DXA), biomarkers for bone turnover (CTX, P1NP), and vitamin D. Grading of knee OA was done with the Altman Atlas and Kellgren Lawrence (KL). Adjustments for age and BMI were made. The mean age was 67.9 years (range 39-94), and mean BMI was 28.8 (SD 4.8). The prevalence of osteoporosis was 9.6% (CI 95% 7.2; 12.7), while the proportion of patients with osteopenia was 36.0%. T score was similar between KL OA grade 3 and 4 (p = 0.06); however, T score was lower (p = 0.02) with the worst knee OA grade (attrition). The median serum Vitamin D level was 78.5 nmol/L (range 10-196), and there was no association between serum vitamin D and the grade of OA (p > 0.88). P1NP was significantly higher in KL grade 4 compared to KL grade 3 (p = 0.03), but there was no association between KL grade and CTX (p = 0.21). 10% had osteoporosis, which is similar to the age-matched background population. Bone mineral density was lower with severe knee osteoarthritis (attrition), and P1NP was higher with worse osteoarthritis grading. [ABSTRACT FROM AUTHOR]

Objective: High‐resolution peripheral quantitative computed tomography (HR‐pQCT) requires longer immobilization time than conventional radiography, which challenges patient acceptance and image quality. Therefore, the aim was to investigate the acceptance of HR‐pQCT in patients with rheumatoid arthritis (RA), and secondly the effect of an inflatable hand immobilization device on motion artefacts of the metacarpophalangeal (MCP) joints. Methods: Fifty patients with established RA and a median (interquartile range) age of 64.3 (55.0‐71.2) years had their MCP joints scanned by HR‐pQCT with the hand positioned with and without an inflatable immobilization device followed by a full radiographic examination and a questionnaire on the imaging experience. The comparability of the erosion measures was investigated with and without the immobilization device using Bland‐Altman plot and intrareader repeatability by intraclass correlation coefficient. The motion artefacts were graded for each acquisition, and intrareader repeatability was investigated by Cohen's kappa coefficient. Results: Forty percent of the patients preferred HR‐pQCT imaging, only 6% preferred conventional X‐ray. Seventy‐four percent reported it was not difficult to keep their fingers steady during the scan. Sixty percent of the patients reported the immobilization device helped keep their fingers steady. However, as motion artefacts were sparse, no clinically relevant difference was observed concerning the effect of the immobilization device on readability. The intrareader repeatability and comparability for the erosion measures were excellent. Conclusion: The high patient acceptance adds to the feasibility of HR‐pQCT imaging of MCP joints in RA. The inflatable immobilization device did not reduce motion‐induced image degradation. [ABSTRACT FROM AUTHOR]

We examined patients with osteoporosis implementation of recommendations regarding a bone healthy lifestyle after the patients attended multifaceted osteoporosis group education (GE). Our findings suggest that GE can support and influence patients' transfer of preventive actions. Still patients are challenged by concerns related to social roles and physical ability. We investigated if and how patients implemented knowledge from attending multifaceted osteoporosis GE in their daily lives. An interpretive description design using ethnographic field work was applied. In all 14 women and three men diagnosed with osteoporosis who attended multifaceted GE at a Danish hospital participated. Data consisted of field work and individual interviews in the participants' everyday environment after completion of GE. After attending multifaceted GE, participants experienced increased attention to and reflected more on how to implement osteoporosis preventive actions or activities. Participants who felt confident on how to act and experienced a clear need and motivation, or who could make the preventive activity into a social event, demonstrated an increased implementation of the preventive activity. On the contrary, attending GE was in some cases not sufficient to overcome social and physical concerns, or to eliminate uncertainty about recommendations or to make participants identify with the osteoporosis diagnosis, which thus impeded implementation of a bone healthy lifestyle. Attending multifaceted GE can support and influence participants' transfer of preventive actions into daily life. Being aware of how concerns about valued social roles and physical ability interfere with the implementation of medical recommendations obviously needs attention during GE. [ABSTRACT FROM AUTHOR]

In patients with osteoporosis and severely reduced bone mass and/or recurring fractures, antiresorptive therapy may not be the optimal first-line treatment. Two recent clinical trials comparing bone-forming treatment with antiresorptive therapy have demonstrated that bone-forming treatment is superior in reducing the fracture risk in patients with severe osteoporosis. All of the currently available bone-forming agents—teriparatide, abaloparatide, and romosozumab—increase bone mineral density (BMD) and reduce the fracture risk; however, the effect wears off with time and treatment is therefore only transient. Thus, a bone-forming therapy should be followed by antiresorptive treatment with a bisphosphonate or denosumab. The BMD response to bone-forming treatment is reduced in patients previously treated with antiresorptive drugs; however, based on the findings of the VERO trial, the anti-fracture efficacy of bone-forming treatment in comparison with antiresorptives seems to be preserved. This review provides an overview of the existing bone-forming therapies for osteoporosis including considerations of sequential and combination therapy. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with an increased risk of fracture, which has been reported in several epidemiological studies. However, bone mineral density in T2D is increased and underestimates the fracture risk. Common risk factors for fracture do not fully explain the increased fracture risk observed in patients with T2D. We propose that the pathogenesis of increased fracture risk in T2D is due to low bone turnover caused by osteocyte dysfunction resulting in bone microcracks and fractures. Increased levels of sclerostin may mediate the low bone turnover and may be a novel marker of increased fracture risk, although further research is needed. An impaired incretin response in T2D may also affect bone turnover. Accumulation of advanced glycosylation endproducts may also impair bone strength. Concerning antidiabetic medication, the glitazones are detrimental to bone health and associated with increased fracture risk, and the sulphonylureas may increase fracture risk by causing hypoglycemia. So far, the results on the effect of other antidiabetics are ambiguous. No specific guideline for the management of bone disease in T2D is available and current evidence on the effects of antiosteoporotic medication in T2D is sparse. The aim of this review is to collate current evidence of the pathogenesis, detection and treatment of diabetic bone disease. [ABSTRACT FROM AUTHOR]

Introduction: Patients with chronic diseases like osteoporosis constantly have to make decisions related to their disease. Multifaceted osteoporosis group education (GE) may support patients' decision-making. This study investigated multifaceted osteoporosis GE focusing on the impact of GE on patients' decision-making related to treatment options and lifestyle.Material and Methods: An interpretive description design using ethnographic methods was utilized with 14 women and three men diagnosed with osteoporosis who attended multifaceted GE. Data consisted of participant observation during GE and individual interviews.Results: Attending GE had an impact on the patients' decision-making in all educational themes. Patients decided on new ways to manage osteoporosis and made decisions regarding bone health and how to implement a lifestyle ensuring bone health. During GE, teachers and patients shared evidence-based knowledge and personal experiences and preferences, respectively, leading to a two-way exchange of information and deliberation about recommendations. Though teachers and patients explored the implications of the decisions and shared their preferences, teachers stressed that the patients ultimately had to make the decision. Teachers therefore refrained from participating in the final step of the decision-making process.Conclusion: Attending GE has an impact on the patients' decision-making as it can initiate patient reflection and support decision-making. [ABSTRACT FROM AUTHOR]

Background Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. Methods In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1–L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. Results After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo −0.023 g/cm2 [95% confidence interval (CI) −0.039 to −0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015–0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. Conclusion Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis. [ABSTRACT FROM AUTHOR]

Objectives: To compare if the 4th and 5th metatarsophalangeal (MTP) joints evaluated by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) could classify more patients with erosive rheumatoid arthritis (RA) compared with conventional radiography (CR) of the hands, wrists, and feet. Furthermore, we characterize and quantify bone erosions in the two MTP joints by HR‐pQCT. Methods: This single‐center cross‐sectional study included patients with established RA (disease duration ≥5 years). Blinded to patient data, the number and volume of erosions in the 4th and 5th MTP joints were measured by HR‐pQCT, whereas the erosive scores by CR of 44 joints in the hands, wrists, and feet were assessed according to the Sharp/van der Heijde method. Results: Among 42 participants, 30 patients were classified with erosive RA and 12 with non‐erosive RA by CR. HR‐pQCT of two MTP joints could classify more patients with erosive RA compared with CR of 44 joints (p =.03). The optimal cut‐off value for the number and volume of erosions per patient in the 4th and 5th MTP joints by HR‐pQCT was 7.5 erosions and 11.7 mm3, respectively, for detecting erosive disease by CR. Erosions in the two MTP joints by HR‐pQCT were found most frequently and were largest at the lateral quadrant of the 5th metatarsal head. Conclusion: The superiority of HR‐pQCT of the 4th and 5th MTP joints compared with CR of 44 joints for classifying erosive RA provides a basis for larger studies evaluating if HR‐pQCT could be used for diagnosing erosive RA in the future. [ABSTRACT FROM AUTHOR]

Summary: In patients discontinuing long-term denosumab, RANKL levels are high 6 months after the last denosumab injection. Nine and 12 months after the last denosumab injection RANKL levels are lower, but TRAcP 5b levels are higher, suggesting that accumulated RANKL increases the number of active osteoclasts. Purpose: The rapid increase in bone turnover occurring when discontinuing long-term treatment with denosumab (DMAB), an antibody that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) is not fully understood. We aimed to investigate the mechanisms underlying the rebound activation of bone resorption by measuring tartrate-resistant acid phosphatase 5b (TRAcP 5b), RANKL, osteoprotegerin (OPG), C-terminal collagen crosslinks (CTX), and procollagen type I N-propeptide (P1NP) in patients discontinuing long-term DMAB. Methods: Sixty-one patients with BMD T-score > − 2.5 at the spine and hip discontinuing long-term DMAB were randomized to treatment with zoledronate (ZOL) 6 months (6 M group, n = 20), 9 months (9 M group, n = 20) or 12 months after the last DMAB injection or when bone turnover was high (12 M group, n = 21). Bone turnover markers were measured immediately before initiation of ZOL treatment. Results: We found higher CTX and PINP in the 9 M and 12 M groups compared to the 6 M group (p < 0.001). In the 6 M group, TRAcP 5b was lower and RANKL higher than in the other two groups (p < 0.001). TRAcP 5b correlated negatively with RANKL (R = − 0.54), and time since the last DMAB injection correlated positively with CTX (R = 0.56), PINP (R = 0.72), TRAcP 5b (R = 0.51) and negatively with RANKL (R = − 0.70) (p < 0.001 for all). We found no difference in OPG between groups. Conclusion: Following discontinuation of long-term DMAB, we find high levels of RANKL, which most likely result in an increase in the number of active osteoclasts (illustrated by TRAcP5b) causing an increased bone turnover. [ABSTRACT FROM AUTHOR]

Summary : In patients with non-metastatic prostate cancer, treated with radiation therapy and androgen deprivation therapy for 3 years and DMAB on average for 5 years, BMD was in the normal or osteopenic range. Discontinuation of DMAB led to a bone loss of 2–5%. In men with osteopenia, the bone loss was prevented by zoledronate. Purpose: Patients with prostate cancer receiving androgen deprivation therapy (ADT) are treated with denosumab (DMAB) to prevent fractures and preserve bone mass. We wanted to investigate the change in BMD in men with non-metastatic prostate cancer discontinuing DMAB. Methods: We conducted a retrospective cohort study based on medical records from patients referred to the Department of Endocrinology from the Department of Urology, Aarhus University Hospital between June 1, 2018, and June 1, 2021. We retrieved information on biochemistry and DXA performed 0–6 months after the last DMAB injection and a second DXA performed approximately 12 months after the first. In case of a BMD T-score ≤ − 1 at the lumbar spine or total hip at the first DXA, the patients were treated with zoledronate. The primary endpoint was change in lumbar spine BMD. Results: We included 50 patients with non-metastatic prostate cancer. The mean DMAB treatment duration was 5 ± 0.1 years. Among the patients treated with zoledronate (n = 9), BMD was maintained at the spine and femoral neck after a mean of 16 months. We found a significant decrease in BMD; − 4.9 ± 4.2%, − 1.9 ± 3.5%, and − 2.4 ± 3.6% at the spine, total hip, and femoral neck between the first and second DXA in the patients not treated with zoledronate (n = 24) (p ≤ 0.01 for all). One patient who did not receive ZOL sustained multiple fragility vertebral fractures after DMAB discontinuation. Conclusion: In men with non-metastatic prostate cancer, discontinuation of DMAB after stopping ADT led to an average bone loss of 2–5%. Zoledronate prevented bone loss in men with osteopenia. [ABSTRACT FROM AUTHOR]

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation. [ABSTRACT FROM AUTHOR]

Cathepsin K (CatK), a cysteine protease, is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix. Robust genetic and pharmacological preclinical studies consistently demonstrate that CatK inhibition increases bone mass, improves bone microarchitecture and strength. Recent advances in the understanding of the molecular and cellular mechanisms involved in bone modeling and remodeling suggest that inhibition of CatK decreases bone resorption, but increases the number of cells of osteoclast lineage. This in turn maintains the signals for bone formation, and perhaps may even increase bone formation on some cortical surfaces. Several CatK inhibitors, including relacatib, balicatib, odanacatib and ONO-5334 had entered clinical development for metabolic bone disorders with increased bone resorption, such as postmenopausal osteoporosis. However, odanacatib (ODN) is the only candidate continuing in development. ODN is a highly selective oral CatK inhibitor dosed once-weekly in humans. In a Phase 2 clinical trial, postmenopausal women treated with ODN had sustained reductions of bone resorption markers, while bone formation markers returned to normal after an initial decline within the first 2 years on treatment. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. ODN has also been demonstrated to improve bone mass in women with postmenopausal osteoporosis previously treated with alendronate and in men with osteoporosis. ODN is currently in a worldwide Phase 3 fracture outcome trial for the treatment of postmenopausal osteoporosis with interim results supporting its anti-fracture efficacy at the spine, hip and non-vertebral sites. [ABSTRACT FROM AUTHOR]

Summary: In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0–2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb.Purpose: In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0–2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb.Methods: In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0–2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb.Results: In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0–2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb.Conclusion: In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0–2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb. [ABSTRACT FROM AUTHOR]

• Conventional radiography (CR) is used to monitor erosive rheumatoid arthritis. • CR underestimates new erosions over one-year compared to computed tomography (CT). • CT has high sensitivity for detecting new erosions in finger joints over short-term. To compare the number of new erosions in two metacarpophalangeal (MCP) joints over one year assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) and conventional radiography (CR). Furthermore, to estimate the diagnostic accuracy of erosive progression by CR with HR-pQCT as the reference standard. Paired sets of image data were available from patients with RA (n = 310), who underwent HR-pQCT and CR, including the 2nd and 3rd MCP joints only of the dominant hand at baseline and at the one-year follow-up. Erosion number was determined using HR-pQCT and CR. Erosive volume was estimated from segmented HR-pQCT images, and erosion scores were obtained by the Sharp/van der Heijde method from CR. Erosive progression was defined as an increase in total erosion number or a study-specified increase in total erosive volume or total erosion score. At baseline, 250 erosions were identified by CR compared to 1864 erosions by HR-pQCT. After one year, 3 new erosions were detected by CR compared to 66 new erosions by HR-pQCT. Erosive progression was identified in 40 patients using HR-pQCT and in 3 patients using CR. With HR-pQCT as reference, CR had a sensitivity of 2.5% (95% CI: 0.1–13.2%) and a specificity of 99.3% (95% CI: 97.3–99.9%) for detecting erosive progression. HR-pQCT identified more than 20 times the number of new erosions, and more than 10 times as many patients with erosive progression than CR. HR-pQCT is a sensitive tool for monitoring new erosions and erosive progression over one year in RA. [ABSTRACT FROM AUTHOR]

Purpose: Cementless tibial components migrate initially until osseointegration and preserve periprosthetic bone. Cemented tibial components are fixed from surgery but loose periprosthetic bone. Little is known about bone formation and resorption biomarkers in relation to component fixation and bone mineral density (BMD) changes of cementless and cemented total knee arthroplasty. We hypothesize a similar migration of cemented and cementless tibial components between 1- and 2-year follow-up indicating a stable long-term fixation. Methods: In a prospective patient-blinded randomized study, we compared cementless (n = 27) and cemented (n = 26) tibial components with radiostereometry measured migration (MTPM = Maximum Total Point Motion: point of component that migrates the most) and changes in BMD and biochemical bone turnover markers (BTMs) until 24 months after surgery. Results: The mean MTPM between 12 and 24 months were similar between groups with − 0.06 mm (95% CI − 0.23; 0.11) in the cementless group compared to 0.02 mm (95% CI − 0.07; 0.11) in the cemented group. However, there was a higher proportion of cementless components (16/25) than cemented components (7/24) with continuous migration (MTPM > 0.2 mm) (p = 0.02). In the medial and anterior region below the tibial components, the BMD increased by mean 1.8% and 7.4% for cementless components and decreased by mean 8.6% and 4.2% for cemented components until 24-month follow-up. In both groups, BTMs initially showed increased bone resorption (CTx) and bone formation (P1NP) followed by normalization to pre-operative levels at 6 months post-surgery. Conclusion: More cementless components than cemented components showed continues migration which suggest a higher risk of early revision. Bone turnover increased post-surgery in both groups, but did not explain the difference in change in periprosthetic BMD. Level of evidence: I. [ABSTRACT FROM AUTHOR]

Spinal stenosis and degenerative spondylolisthesis share many symptoms and the same treatment, but their causes remain unclear. Bone mineral density has been suggested to play a role. The aim of this study was to investigate differences in spinal bone density between spinal stenosis and degenerative spondylolisthesis patients. 81 patients older than 60 years, who underwent DXA-scanning of their lumbar spine one year after a lumbar spinal fusion procedure, were included. Radiographs were assessed for disc height, vertebral wedging, and osteophytosis. Pain was assessed using the Low Back Pain Rating Scale pain index. T-score of the lumbar spine was significantly lower among degenerative spondylolisthesis patients compared with spinal stenosis patients (-1.52 versus -0.52, P = 0.04). Thirty-nine percent of degenerative spondylolisthesis patients were classified as osteoporotic and further 30% osteopenic compared to only 9% of spinal stenosis patients being osteoporotic and 30% osteopenic (P = 0.01). Pain levels tended to increase with poorer bone status (P = 0.06). Patients treated surgically for symptomatic degenerative spondylolisthesis have much lower bone mass than patients of similar age treated surgically for spinal stenosis. Low BMD might play a role in the development of the degenerative spondylolisthesis, further studies are needed to clarify this. [ABSTRACT FROM AUTHOR]

Older people are at increased risk of non-union after spinal fusion, but little is known about the factors determining the quality of the fusion mass in this patient group. The aim of this study was to investigate fusion mass bone quality after uninstrumented spinal fusion and to evaluate if it could be improved by additional direct current (DC) electrical stimulation. A multicenter RCT compared 40 and 100 μA DC stimulation with a control group of uninstrumented posterolateral fusion in patients older than 60 years. This report comprised 80 patients who underwent DEXA scanning at the 1 year follow-up. The study population consisted of 29 men with a mean age of 72 years (range 62-85) and 51 women with a mean age of 72 years (range 61-84). All patients underwent DEXA scanning of their fusion mass. Fusion rate was assessed at the 2 year follow-up using thin slice CT scanning. DC electrical stimulation did not improve fusion mass bone quality. Smokers had lower fusion mass BMD (0.447 g/cm) compared to non-smokers (0.517 g/cm) ( P = 0.086). Women had lower fusion mass BMD (0.460 g/cm) compared to men (0.552 g/cm) ( P = 0.057). Using linear regression, fusion mass bone quality, measured as BMD, was significantly influenced by gender, age of the patient, bone density of the remaining part of the lumbar spine, amount of bone graft applied and smoking. Fusion rates in this cohort was 34% in the control group and 33 and 43% in the 40 and 100 μA groups, respectively (not significant). Patients classified as fused after 2 years had significant higher fusion mass BMD at 1 year (0.592 vs. 0.466 g/cm, P = 0.0001). Fusion mass bone quality in older patients depends on several factors. Special attention should be given to women with manifest or borderline osteoporosis. Furthermore, bone graft materials with inductive potential might be considered for this patient population. [ABSTRACT FROM AUTHOR]

Abstract: In the Dosing IntraVenous Administration (DIVA) study, IV ibandronate injections (15–30 s duration) provided significantly greater gains in bone mineral density than daily oral ibandronate (P <0.001). Single transiliac bone biopsy was performed in a subgroup of women (n =109/1395) from DIVA to assess the impact of ibandronate on newly formed bone and bone remodeling. Patients received ibandronate IV injections 2 mg every 2 months, 3 mg every 3 months or oral ibandronate 2.5 mg daily, plus oral or IV placebo, as appropriate to maintain blinding. Of the 1395 participants from the DIVA study, 122 were enrolled in the substudy. Qualitative histological analysis was performed on all biopsy cores and 89 cores were considered to be evaluable for quantitative histomorphometry. Following 2 years of ibandronate treatment, trabecular bone maintained its normal lamellar structure with no evidence of woven bone, marrow fibrosis, cellular toxicity, or other qualitative abnormalities. Primary mineralization of new bone remained normal, as indicated by the slightly lower osteoid thickness and osteoid volume, with normal mineral apposition rate compared to healthy, postmenopausal women. Mineralizing surface, osteoid surface, activation frequency and bone formation rate were decreased in all ibandronate-treated groups compared with values from healthy, postmenopausal women. Specifically, the bone formation rate (BFR/BV and BFR/BS) was approximately 5 times lower in the ibandronate-treated (3 mg) group than in healthy, postmenopausal women. Histomorphometric analysis of transiliac bone biopsies demonstrated normal micro-structure of newly formed bone with normal mineralization and reduced remodeling after oral or IV ibandronate. [Copyright &y& Elsevier]

Context: Hyperthyroidism can lead to reduced bone mineral density (BMD) and increased fracture risk particularly in postmenopausal women, but the mechanism behind is still unclear. Objective: Prospective examination of the influence of thyroid hormones and/or thyroid autoantibodies on BMD in premenopause. Design: We have examined 32 premenopausal women with untreated active Graves' disease from time of diagnosis, during 18 months of antithyroid drug therapy (ATD) and additionally 18 months after discontinuing ATD. Variables of thyroid metabolism, calcium homeostasis and body composition were measured every 3 months. BMD of lumbar spine and femoral neck were measured at baseline, 18 ± 3 and 36 ± 3 months. Data were compared to base line, a sex- and age matched control group and a group of patients with Hashimoto's thyroiditis treated with non-suppressive doses of levothyroxine. Results: The study showed significantly (p < 0.002) lower BMD in the thyrotoxic state compared to the control group with subsequent significant improvement during 18 ± 3 months of ATD compared to baseline (p < 0.001). However, during the following 18 months after stopping ATD femoral neck BMD decreased again unrelated to age (more than 0.4% per year, p < 0,002). The wellestablished effect of thyrotoxicosis on calcium homeostasis was confirmed. The positive predictor for best BMD was TSH receptor antibodies (TRAb) while free T4 correlated negatively in the thyrotoxic female Graves' patients (p < 0.02 and p < 0.003). In healthy controls and patients with treated Graves' disease both TSH and T4 correlated negatively to the bone mass (BMC) (p < 0.003). Conclusion: The results indicated a clinically relevant impact of thyroid function on bone modulation also in premenopausal women with Graves' disease, and further indicated the possibility for a direct action of TRAb on bones. [ABSTRACT FROM AUTHOR]

Objective To investigate whether high-resolution peripheral quantitative CT (HR-pQCT) of two metacarpophalangeal (MCP) joints can more accurately classify patients as having erosive RA compared with conventional radiography (CR) of 44 joints in the hands, wrists and feet. Methods In this single-centre cross-sectional study, patients with established RA (disease duration ≥5 years) were investigated by HR-pQCT and CR. The second and third MCP joints of the dominant hand were assessed for erosions by HR-pQCT. CR of the hands, wrists and feet were scored according to the Sharp–van der Heijde (SHS) method. Results In total, 353 patients were included; 66 (18.7%) patients were classified as having non-erosive RA, and 287 (81.3%) had erosive RA by CR. The sensitivity and specificity (95% CI) of HR-pQCT for classifying patients as having erosive RA when standard CR of hands, wrists and feet was used as the reference was 89% (84, 92%) and 30% (20, 43%), respectively. Using HR-pQCT as the reference, the sensitivity and specificity of CR for classifying patients having erosive RA were 85% (80, 89%) and 38% (25, 52%), respectively. McNemar's χ2 test showed no significant difference between the sensitivities of patients classified as having erosive RA by HR-pQCT or by CR (2.14, P  = 0.177). Conclusion The diagnostic accuracy of HR-pQCT scanning of only two MCP joints and CR of 44 joints suggests the two modalities were comparable for classifying patients with established RA as having erosive disease. Clinical trial registration ClinicalTrials.gov (NCT03429426). [ABSTRACT FROM AUTHOR]

Aim: Bone erosions are the hallmark of rheumatoid arthritis (RA). High‐resolution peripheral quantitative computed tomography (HR‐pQCT) enables 3‐dimensional visualization of arthritic bone erosions at a high resolution. However, the degree of erosive disease could influence the reliability of HR‐pQCT evaluation. We aim to assess the intra‐ and inter‐reader variability of identification of erosions in the metacarpophalangeal (MCP) joints using HR‐pQCT in healthy controls and patients with RA, stratified according to van der Heijde‐modified Sharp Score (HSS) of radiographic erosions. Method: We analyzed HR‐pQCT images from 78 patients with RA and 25 healthy controls. Patients were allocated to one of three groups of mild, moderate or severe disease according to HSS of MCP joints 2 and 3. Total HR‐pQCT scans were analyzed twice in random order by three experienced readers, blinded to group distribution. The number of cortical interruptions and their classification as either erosions or cysts according to predefined criteria were recorded. Intraclass correlation coefficients (ICC) for cortical interruptions, erosions and cysts were calculated for each group using a 2‐way random‐effects model for inter‐reader ICC and a 2‐way mixed‐effects model for intra‐reader ICC. Results: The intra‐ and inter‐reader ICC were good to moderate for cortical interruptions and moderate for erosions throughout disease severity groups. The ICCs for the identification of cysts decreased with increasing degree of erosive disease. Conclusion: The detection of cortical interruptions is only minimally affected by the degree of erosive damage, whereas the distinction between erosions and cysts is more complex in patients with extensive erosive disease. [ABSTRACT FROM AUTHOR]