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Highlights • Cryoglobulinemia is frequent in SLE, but mostly asymptomatic. • Sixty-six percent of SLE patients tested positive for cryoglobulins, and 15% of the SLE patients with cryoglobulinemia developed a cryoglobulinemic vasculitis. • Features of the cryoglobulinemic vasculitis mainly involved skin, joints, and general signs. Severe manifestations of vasculitis were rare.

Abstract Background To assess current practice regarding the management of rheumatoid arthritis patients among general practitioners of a French region, and their perception about the deployment of a multidisciplinary collaboration. Methods A cross-sectional online survey was sent to the general practitioners of a French region. The questionnaire comprised of 3 sections to collect data regarding 1/demographics, 2/practice and knowledge in rheumatoid arthritis, and 3/perception about the deployment of a multidisciplinary collaboration. Results 1/A total of 247 general practitioners (M/F ratio: 1.4; mean age: 46.7 years) completed the survey. 2/More than half of general practitioners believed that their role was very or extremely important in disease diagnosis (72.5%), and management of comorbidities (67.2%). Among respondents, 6.1% considered that they did not face any difficulty concerning the patient management and 61.5% had already identified causes of non-adherence. 3/A total of 151 (61.1%) general practitioners were willing to participate in a multidisciplinary programme to improve medication adherence in rheumatoid arthritis. Conclusions General practitioners are motivated to contribute to an overall management of rheumatoid arthritis patients. Nevertheless, they need professional education about rheumatoid arthritis treatment and training in motivational interviews before getting involved in a multidisciplinary collaboration.

Osteoporosis is a common non-communicable disease with enormous societal costs. Antiosteoporosis medications have been proven efficacious in reducing the refracture rate and mortality; moreover, we have now convincing evidence about the cost-effectiveness of antiosteoporotic medications. However, albeit preventable and treatable, osteoporosis has been somehow neglected by health authorities. Drugs approval has been unnecessarily lengthy, especially when compared with other non-communicable diseases. Herein, we discuss the issue of procrastinating drug approval in osteoporosis and future implications.

The objective of this study was to develop a serum biochemical marker of the degradation of type III and IV collagens, as an index of synovium turnover, and evaluate its performance in patients with rheumatoid arthritis (RA). An enzyme-linked immunosorbent assay for serum synovial collagen fragments (Col3-4) was developed using an antibody recognizing a specific sequence from human type III collagen, which shares 70% homology with type IV collagen. Immunohistochemistry was performed to localize Col3-4 and the matrix metalloprotease MMP-9 which is upregulated in RA synovial fibroblasts in the synovial tissue from a RA patient. Serum Col3-4 was measured in patients with RA (n = 66, 73% women, mean age 62 years, median disease activity score 28 with erythrocyte sedimentation rate (DAS28-ESR) 2.6) and in sex and age matched healthy controls (n = 70, 76% women, mean age 59 years). Col3-4 immunoassay demonstrated adequate analytical performances and recognized a circulating neoepitope resulting from the cleavage of type III and IV collagens. In RA synovium tissue, Col3-4 fragments were localized in the lining layer where destructive fibroblasts are present and around blood vessels rich in type IV collagen. MMP-9 colocalized with Col3-4 staining and efficiently released Col3-4 fragments from type III and type IV collagen digestion. Serum Col3-4 was markedly increased in patients with RA (+240% vs controls, p < 0.0001) and correlated with DAS28-ESR (r = 0.53, p < 0.0001). Patients with RA and active disease (DAS28-ESR > 3.2, n = 20) had 896% (p < 0.0001) higher levels than subjects with low activity (n = 46). Serum Col3-4 is a specific and sensitive biochemical marker reflecting MMP- mediated type III and IV collagen degradation from synovial tissue. Serum Col3-4 levels are markedly increased in patients with RA, particularly in those with active disease, suggesting that it may be useful for the clinical investigation of RA.

The differences in bone nanomechanical properties between cortical (Ct) and trabecular (Tb) bone remain uncertain, whereas knowing the respective contribution of each compartment is critical to understand the origin of bone strength. Our purpose was to compare bone mechanical and intrinsic properties of Ct and Tb compartments, at the bone structural unit (BSU) level, in iliac bone taken from a homogeneous untreated human population.Among 60 PMMA-embedded transiliac bone biopsies from untreated postmenopausal osteoporotic women (64 ± 7 year-old), >2000 BSUs were analysed by nanoindentation in physiological wet conditions [indentation modulus (elasticity), hardness, dissipated energy], by Fourier transform infrared (FTIRM) and Raman microspectroscopy (mineral and organic characteristics), and by X-ray microradiography (degree of mineralization of bone, DMB). BSUs were categorized based on tissue age, osteonal (Ost) and interstitial (Int) tissues location and bone compartments (Ct and Tb).Indentation modulus was higher in Ct than in Tb BSUs, both in Ost and Int. dissipated energy was higher in Ct than Tb, in Int BSUs. Hardness was not different between Ct and Tb BSUs. In Ost or Int BSUs, mineral maturity (conversion of non-apatitic into apatitic phosphates) was higher in Ct than in Tb, as well as for collagen maturity (Ost). Mineral content assessed as mineral/matrix (FTIRM and Raman) or as DMB, was lower in Ct than in Tb. Crystallinity (FTIRM) was similar in BSUs from Ct and Tb, and slightly lower in Ct than in Tb when measured by Raman, indicating that the crystal size/perfection was quite similar between Ct and Tb BSUs. The differences found between Ost and Int tissues were much higher than the difference found between Ct and Tb for all those bone material properties. Multiple regression analysis showed that Indentation modulus and dissipated energy were mainly explained by mineral maturity in Ct and by collagen maturity in Tb, and hardness by mineral content in both Ct and Tb.In conclusion, in untreated human iliac bone, Ct and Tb BSUs exhibit different characteristics. Ct BSUs have higher indentation modulus, dissipated energy (Int), mineral and organic maturities than Tb BSUs, without difference in hardness. Although those differences are relatively small compared to those found between Ost and Int BSUs, they may influence bone strength at macroscale.

Elevated circulating lipoprotein (a) [Lp(a)] is associated with an increased risk of first and recurrent cardiovascular events; however, the effect of baseline Lp(a) levels on long-term outcomes in an elderly population is not well understood. The current single-center prospective study evaluated the association of Lp(a) levels with incident acute coronary syndrome to identify populations at risk of future events. Lp(a) concentration was assessed in 755 individuals (mean age of 71.9 years) within the community and followed for up to 8 years (median time to event, 4.5 years; interquartile range, 2.5–6.5 years). Participants with clinically relevant high levels of Lp(a) (>50 mg/dl) had an increased absolute incidence rate of ASC of 2.00 (95% CI, 1.0041) over 8 years (P = 0.04). Moreover, Kaplan-Meier cumulative event analyses demonstrated the risk of ASC increased when compared with patients with low (

Despite the development of non-invasive methods, bone histomorphometry remains the only method to analyze bone at the tissue and cell levels. Quantitative analysis of transiliac bone sections requires strict methodologic conditions but since its foundation more 60 years ago, this methodology has progressed. Our purpose was to review the evolution of bone histomorphometry over the years and its contribution to the knowledge of bone tissue metabolism under normal and pathological conditions and the understanding of the action mechanisms of therapeutic drugs in humans. The two main applications of bone histomorphometry are the diagnosis of bone diseases and research. It is warranted for the diagnosis of mineralization defects as in osteomalacia, of other causes of osteoporosis as bone mastocytosis, or the classification of renal osteodystrophy. Bone biopsies are required in clinical trials to evaluate the safety and mechanism of action of new therapeutic agents and were applied to anti-osteoporotic agents such as bisphosphonates and denosumab, an anti-RANKL, which induces a marked reduction of the bone turnover with a consequent elongation of the mineralization period. In contrast, an increased bone turnover with an extension of the formation site is observed with teriparatide. Romosozumab, an anti-sclerostin, has a dual effect with an early increased formation and reduced resorption. Bone histomorphometric studies allow us to understand the mechanism of coupling between formation and resorption and to evaluate the respective role of bone modeling and remodeling. The adaptation of new image analysis techniques will help bone biopsy analysis in the future.

Introduction Patients with erosive hand osteoarthritis (EHOA) experience pain and inflammation, two features that can be targeted by vagus nerve stimulation using electrical auricular transcutaneous vagus nerve stimulation (tVNS). A pilot study demonstrated the feasibility of the procedure, so we designed a randomised sham-controlled trial to determine the safety and efficacy of tVNS in EHOA.Methods and analysis ESTIVAL Study (Essai randomisé comparant la STImulation auriculaire transcutanée du nerf Vague versus sham stimulation dans l’Arthrose DigitaLe Érosive symptomatique et inflammatoire) is a superiority, randomised, double-blind sham-controlled trial comparing two parallel arms: active and sham tVNSs in a 1:1 ratio. Patients with symptomatic EHOA (score ≥40/100 mm on a visual analogue scale (VAS) for pain of 0–100 mm) and inflammatory EHOA (≥1 clinical and ultrasonography-determined interphalangeal synovitis) are included in 18 hospital centres (17 rheumatology and 1 rehabilitation departments) in France. Active and sham tVNSs use an auricular electrode connected to the Vagustim device, with no electric current delivered in the sham group. Patients undergo stimulation for 20 min/day for 12 weeks. The follow-up visits take place at weeks 4, 8 and 12. The enrolment duration is 2 years and started in April 2021; 156 patients are scheduled to be included. The primary outcome is the difference in self-reported hand pain in the previous 48 hours measured on a VAS of 0–100 mm between baseline and week 12. Secondary outcomes include other pain outcomes, function, quality of life, serum biomarker levels, compliance and tolerance. For a subset of patients, MRI of the hand is performed at baseline and week 12 to compare the change in Outcome Measures in Rheumatology/Hand Osteoarthritis MRI Scoring System subscores. The primary analysis will be performed at the end of the study according to the intent-to-treat principle.Ethics and dissemination Ethics approval was obtained from the institutional review board (Comité de Protection des Personnes, 2020-A02213-36). All participants will be required to provide written informed consent. The findings will be published in peer-reviewed journals.Trial registration number NCT04520516; Pre-results.Protocol version and number V.2 of 11 March 2021.

Introduction: The use of teriparatide has been reported in children with hypoparathyroidism as an investigational physiologic replacement therapy.Methods: We aimed to retrospectively report our pediatric experience of bi-daily sub-cutaneous teriparatide. Results are presented as median (25th−75th quartile). As part of the routine follow-up of these patients with hypoparathyroidism, total calcium at H0 (i.e., just before injection) and H4 (i.e., 4 h after teriparatide injection) and other biomarker parameters were regularly assessed.Results: At a median age of 10.7 (8.1–12.6) years, an estimated glomerular filtration rate (eGFR) of 110 (95–118) mL/min/1.73 m2, calcium levels of 1.87 (1.81–1.96) mmol/L and an age-standardized phosphate of 3.8 (2.5–4.9) SDS, teriparatide therapy was introduced in 10 patients at the dose of 1.1 (0.7–1.5) μg/kg/day (20 μg twice daily), with further adjustment depending on calcium levels. Six patients already displayed nephrocalcinosis. Severe side effects were reported in one child: two episodes of symptomatic hypocalcemia and one of iatrogenic hypercalcemia; one teenager displayed dysgueusia. Calcium levels at H0 did not significantly increase whilst calcium at H4 and phosphate levels significantly increased and decreased, respectively. After 12 months, eGFR, calcium and age-standardized phosphate levels were 108 (90–122) mL/min/1.73 m2, 2.36 (2.23–2.48) mmol/L, 0.5 (−0.1 to 1.5), and 68 (63–74) nmol/L, respectively, with a significant decrease in phosphate levels (p = 0.01). Urinary calcium and calcium/creatinine ratio remained stable; no nephrolithiasis was observed but two moderate nephrocalcinosis appeared.Conclusion: Intermittent teriparatide therapy significantly improves calcium and phosphate control, without increasing calciuria. It appears to be safe and well-tolerated in children.

In recent years, markers research has focused on the structural components of cartilage matrix. Specifically, a second generation of degradation markers has been developed against type II collagen neoepitopes generated by specific enzymes. A particular effort has been made to measure the degradation of minor collagens III and X of the cartilage matrix. However, because clinical data, including longitudinal controlled studies, are very scarce, it remains unclear whether they will be useful as an alternative to or in combination with current more established collagen biological markers to assess patients with osteoarthritis (OA). In addition, new approaches using high-throughput technologies allowed to detect new types of markers and improve the knowledge about the metabolic changes linked to OA. The relative advances coming from phenotype research are a first attempt to classify the heterogeneity of OA, and several markers could improve the phenotype characterization. These phenotypes could improve the selection of patients in clinical trials limiting the size of the studies by selecting patients with OA characteristics corresponding to the metabolic pathway targeted by the molecules evaluated. In addition, the inclusion of rapid progressors only in clinical trials would facilitate the demonstration of efficacy of the investigative drug to reduce joint degradation. The combination of selective biochemical markers appears as a promising and cost-effective approach to fulfill this unmet clinical need. Among the various potential roles of biomarkers in OA, their ability to monitor drug efficacy is probably one of the most important, in association with clinical and imaging parameters. Biochemical markers have the unique property to detect changes in joint tissue metabolism within a few weeks.

Abstract Objectives In the context of the scarcity of biomarkers for knee osteoarthritis (OA), we examined the associations of prevalent and incident OA with the expression levels of serum miRNAs in subjects with and without OA. Methods With a next-generation sequencing approach, we compared the miRome expression of 10 women with knee OA and 10 age-matched healthy subjects. By real-time qPCR, we analyzed the expression levels of 19 miRNAs at baseline selecting 43 women with prevalent knee OA (Kellgren Lawrence score of 2/3), 23 women with incident knee OA over a 4-year follow-up and 67 healthy subjects without prevalent or incident OA matched for age and body mass index. Results Serum miR-146a-5p was significantly increased in the group of prevalent knee OA compared with controls (relative quantification (RQ); median [Interquartile range] 1.12 [0.73; 1.46] vs 0.85 [0.62; 1.03], p = 0.015). The likelihood of prevalent knee OA was significantly increased (odds ratio [95% confidence interval (CI)] 1.83 [1.21–2.77], p = 0.004) for each quartile increase in serum miR-146a-5p. The women with miR-146a-5p levels above the median (0.851) had a higher risk of prevalent knee OA compared to those below the median [95% CI] 4.62 [1.85–11.5], p = 0.001. Moreover, we found a significant association between the baseline level of serum miR-186-5p and the risk of incident knee OA (Q4 vs Q1–3; odds ratio [95% CI] 6.13 [1.14–32.9], p = 0.034). Conclusion We showed for the first time that miR-146a-5p and miR-186-5p are significantly associated with prevalent and incident knee OA, respectively.

Abstract Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of the GNAS gene. The mutation leads to overactivity in the target tissues and to a wide phenotype of clinical features that vary in severity and age of onset. The rarity of the disease and its variable presentation to multiple specialities often leads to misdiagnosis and inappropriate variability in investigations and treatments. To address this, our international consortium of clinicians, researchers, and patients’ advocates has developed pragmatic clinical guidelines for best clinical practice for the definition, diagnosis, staging, treatment and monitoring for FD/MAS to empower patients and support clinical teams in both general and specialised healthcare settings. With the lack of strong evidence to inform care, the guidelines were developed based on review of published literature, long-standing extensive experience of authors, input from other healthcare professionals involved in the care of FD/MAS patients and feedback from patients and patient groups across the globe. This has led to the formulation of a set of statements to inform healthcare professionals, patients, their families, carers and patient groups of the best practice of care. It is anticipated the implementation of these recommendations will lead to improvement in the care of patients with FD/MAS internationally.

(1) Background: The Vaccine Coverage Rate of influenza remains low and omnichannel efforts are required to improve it. The objective was to evaluate the feasibility and outcomes of a QR Code nudging system in outpatient departments. (2) Methods: The study was performed in 6 departments ensuring ambulatory activities in a French university Hospital between November and December 2021. By scanning QR codes, users accessed anonymously to the ELEFIGHT® web app, which provides medical information on influenza and invites them to initiate a discussion about influenza prevention with their physicians during the consultation. (3) Results: 351 people made 529 scans with an average reading time of 1 min and 4 s and a conversion rate of 32%, i.e., people willing to engage in a discussion. (4) Conclusions: The study suggests that direct access to medical information through QR codes in hospitals might help nudge people to raise their awareness and trigger their action on influenza prevention.

Purpose: Beside areal bone mineral density (aBMD), evaluation of fragility fracture risk mostly relies on global microarchitecture. However, microarchitecture is not a uniform network. Therefore, this study aimed to compare local structural weakness to global microarchitecture on whole vertebral bodies and to evaluate how local and global microarchitecture was associated with bone biomechanics. Methods: From 21 human L3 vertebrae, aBMD was measured using absorptiometry. Parameters of global microarchitecture were measured using HR-pQCT: trabecular bone volume fraction (Tb.BV/TVglobal), trabecular number, structure model index and connectivity density (Conn.D). Local minimal values of aBMD and Tb.BV/TV were identified in the total (Tt) or trabecular (Tb) area of each vertebral body. “Two dimensional (2D) local structural weakness” was defined as Tt.BMDmin, Tt.BV/TVmin and Tb.BV/TVmin. Mechanical testing was performed in 3 phases: 1/ initial compression until mild vertebral fracture, 2/ unloaded relaxation, and 3/ second compression until failure. Results: Initial and post-fracture mechanics were significantly correlated with bone mass, global and local microarchitecture. Tt.BMDmin, Tt.BV/TVmin, Tb.BV/TVmin, and initial and post-fracture mechanics remained significantly correlated after adjustment for aBMD or Tb.BV/TVglobal (p

Introduction Subclinical intestinal inflammation and gut dysbiosis have been reported in patients with spondyloarthritis (SpA). In common practice, rheumatologists are increasingly confronted with patients with inflammatory rheumatism who are on gluten-free diets (GFDs), despite the lack of reliable data from controlled studies. This study aims to determine the impact of a GFD on the quality of life of patients with axial SpA.Methods and analysis The GlutenSpA study is a 24-week, randomised, double-blinded, placebo-controlled, multicentre trial. Patients with axial SpA (n=200) will follow a 16-week GFD and be randomly assigned (1:1) to an experimental or control arm. In the experimental arm with receive at least 6 gluten-free breads per day + 200 g of gluten-free penne pasta per week + 6 rice flavour capsules per day. The control arm will receive at least 6 gluten-containing breads per day + 200 g of gluten-containing penne pasta per week + 6 vital gluten-containing capsules per day. The primary end-point is the variation in Assessment of SpondyloArthritis International Society—Health Index (ASAS-HI) questionnaire between week 16 and baseline. A second open-label period of 8 weeks will follow the intervention period, during which the patient will be free to decide whether they will follow the GFD. The secondary outcomes comprise several patient-reported outcomes (SpA activity (Bath Ankylosing Spondylitis Disease Activity Index)), fatigue (Functional Assessment of Chronic Illness Therapy), depression (Hospital Anxiety and Depression Scale), functional disability index (Bath Ankylosing Spondylitis Functional Index)), variations in body mass index and Homeostasis Model Assessment Index and variations in the abundance and type of bacterial species found in the gut microbiota for a subgroup of patients (n=40). The data will be analysed using the intention-to-treat principle.The regional ethics committee (CPP Nord-ouest IV) has approved the study (IDRCB 2018-A00309-46). The results of the trial will be submitted for publication in peer-reviewed journals. The authors have no relationship that may have influenced the submitted work.Trial registration number NCT04274374.

ABSTRACT The 3‐year placebo‐controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7‐year open‐label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long‐term control group, thus limiting the ability to fully evaluate long‐term efficacy. This analysis provides a quantitative estimate of the long‐term antifracture efficacy of denosumab based on two approaches: comparison with FRAX®‐ (Fracture Risk Assessment Tool‐) and virtual twin‐estimated 10‐year fracture rates. Subjects who were randomized to denosumab in the FREEDOM trial, continued into the Extension study, completed the 10‐year visit, and missed ≤1 dose in the FREEDOM trial and ≤1 dose in the Extension (n = 1278) were included in the analysis. The 10‐year observed cumulative incidence of major osteoporotic fracture (MOF) and hip fractures was compared with the 10‐year fracture probability predicted at baseline by FRAX, a computer‐based fracture risk algorithm, and with that estimated for a hypothetical cohort of 10‐year placebo controls (virtual twins). The observed 10‐year fracture incidence was lower than the 10‐year probability predicted by FRAX for both MOF (10.75% [95% CI, 9.05 to 12.46] versus 15.63% [95% CI, 15.08 to 16.18], respectively), and hip fractures (1.17% [95% CI, 0.58 to 1.76] versus 5.62% [95% CI, 5.28 to 5.97], respectively). The observed fracture incidence was also lower than the fracture rate estimated in a hypothetical cohort of 10‐year placebo controls for MOF (23.13% [95% CI, 17.76 to 28.87]; relative risk 0.49 [95% CI, 0.36 to 0.64]). These data support the long‐term efficacy of denosumab in reducing MOF and hip fractures in postmenopausal women with osteoporosis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

PurposeTo investigate the efficacy and tolerance of systemic treatments for the prevention of HLA-B27-associated acute uveitis (AU) recurrence.MethodsRetrospective review of patients with HLA-B27-associated uveitis followed in our tertiary center over a 15-year period. Systemic treatments were prescribed to patients with frequent (more than 2 flares per year) or severe uveitis, according to a step-up strategy.Results101 patients (51.5% of men, 88.1% of white Europeans) with a median age of 37 years. AU was mostly recurrent (68.3%) and associated with spondyloarthritis (60.4%). After a median follow-up duration of 22 months (3-73), 37.6% of the patients have received systemic treatment. 88.5% of the patients have been treated with sulfasalazine (SSZ) for ophthalmologic purposes (23/26). Methotrexate (MTX) and anti-TNFα agents have been initiated for a rheumatologic indication in 81.8% (9/11) and 100% of the patients (13/13), respectively. The annual uveitis relapse rate significantly decreased on SSZ (0.37 recurrences/year versus baseline 2.46 recurrences/year; pConclusionWe report an open-label strategy to prevent the recurrences of HLA-B27-associated AU. First-line sulfasalazine reduced uveitis relapses. The use of anti-TNFα agents for ophthalmologic purposes was unnecessary with rare exceptions.

ContextMicroRNA (miRNA) regulate post-transcriptionally the expression of osteogenesis and angiogenesis associated genes and emerge as potential non-invasive biomarkers in vascular and bone diseases. Severe abdominal aortic calcification (AAC) is associated with higher risk of cardiovascular event and of fragility fracture.ObjectiveTo identify miRNA linked to the aggravation of AAC and to incident osteoporotic fracture.DesignPostmenopausal women (>50 years) with available serum at inclusion and data for each outcome (Kauppila score and incident fracture) were selected from the OFELY prospective cohort. We conducted a case-control study in 434 age-matched women, 50% with incident osteoporotic fracture over 20 years of follow-up and a second study in 183 women to explore AAC over 17 years.MethodsSerum expression of three miRNA involved in vascular calcification and bone turnover regulation (miRs-26a-5p,-34a-5p, and -223-5p) was quantified at baseline by TaqMan Advanced miRNA technology and expressed by relative quantification. Outcomes were the association of miRNA levels with (1) incident osteoporotic fractures during 20 years, (2) AAC aggravation during 17 years.ResultsMiRNA level was not associated with incident fractures (miR-26a-5p: 1.06 vs 0.99, p = 0.07; miR-34a-5p: 1.15 vs 1.26, p = 0.35; miR-223a-5p: 1.01 vs 1.05, p = 0.32). 93 women had an increase in Kauppila score over 17 years while 90 did not. None of the miRNAs was associated with an aggravation in AAC (miR-26a-5p: 1.09 vs 1.10, p = 0.95; miR-34a-5p: 0.78 vs 0.73, p = 0.90; miR-223-5p: 0.97 vs 0.78, p = 0.11).ConclusionsCirculating miR-26a-5p, -34a-5p and -223-5p are not significantly associated with incident fracture and AAC aggravation.

We previously developed an image analysis approach for the determination of local sites of bone remodelling using time-lapse in vivo HR-pQCT. The involved image filtering for removing noise was chosen rather aggressively, and also removed some effects of the bone remodelling. In this paper, we quantify these filtering settings using ex vivo reproducibility HR-pQCT images, and determine the least-detectable bone remodelling using in vivo reproducibility HR-pQCT images, as well as testing whether the approach is capable of capturing age-related bone remodelling by use of in vivo long-term HR-pQCT images. We found that a threshold value of 225 mg HA/cm3 for the filtering led to acceptable results with falsely determined bone remodelling of less than 0.5%, and that the least-detectable bone formation and bone resorption are 2.0 ± 1.0% and 2.2 ± 0.7% respectively. We also found that age-related local bone remodelling can be captured satisfactorily in postmenopausal women. The latter revealed new insights into the effect of ageing on bone remodelling, and showed that bone remodelling seems to take place through a few small formation packets and many large resorption volumes leading to a net bone loss. We conclude that local in vivo bone remodelling can be successfully assessed with time-lapse in vivo HR-pQCT capable of assessing age-related changes in bone remodelling.

The original version of this article [1] unfortunately included an error to an author’s name. Paul Arundel was inadvertently presented as Paul Arunde.

For accurate analysis of bone formation and resorption during fracture healing, correct registration of follow-up onto baseline image is required. A per-fragment approach could improve alignment compared to standard registration based on the whole fractured region. In this exploratory study, we tested the effect of fragment size and displacement on a per-fragment registration, and compared the results of this per-fragment registration to the results of the standard registration in two stable fractures and one unstable fracture. To test the effect of fragment size and displacement, high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of three unfractured radii were divided into subvolumes. Different displacements in x-, y, or z-direction or rotations around each axis were applied, and each subvolume was registered onto the initial volume to realign it. Next, registration of follow-up onto baseline scan was performed in two stable and one unstable fracture. After coarsely aligning the follow-up onto the baseline scan, a more accurate registration was performed of the whole fracture, i.e. the standard registration, and of each fracture fragment separately, i.e. per-fragment registration. Alignment was checked using overlay images showing baseline, follow-up and overlap between these scans, and by comparing correlation coefficients between the standard and per-fragment registration. Generally, subvolumes as small as 300 mm3 that were displaced up to 0.82 mm in x- or y-, or up to 1.64 mm in z-direction could be realigned correctly. For the fragments of all fractures, correlation coefficients were higher after per-fragment registration compared to standard registration. Most improvement was found in the unstable fracture and one fragment of the unstable fracture did not align correctly. This exploratory study showed that image registration of individual subvolumes, such as fracture fragments, is feasible in both stable and unstable fractures, and leads to better alignment of these fragments compared to an approach that is based on registration using the whole fractured region. This result is promising for additional analysis of bone formation and resorption in HR-pQCT studies on fracture healing.

Treatment initiation rates following fragility fractures have often been reported to be low and in recent years numerous programs have been implemented worldwide to increase them. This study aimed at describing osteoporosis (OP) treatment initiation in a representative sample of women who were hospitalized for a distal forearm fracture (DFF) or proximal humerus fracture (PHF) in 2009-2011 in France. The data source was a nationwide sample of 600,000 individuals, extracted from the French National Insurance Healthcare System database. All women aged 50 years and older who were hospitalized for a DFF or PHF between 2009 and 2011 and who had not received any OP treatment in the preceding 12 months were included in a retrospective cohort study. OP treatments initiated during the year following the fracture were analyzed. From 2009 to 2011, 729 women were hospitalized for a DFF or a PHF and 284 were on OP treatment at the time of the fracture occurrence. Among the 445 women who had no prevalent OP treatment, 131 (29.4%) received supplementation treatment only (vitamin D and/or calcium) and 42 (9.4%) received a pharmacologic OP treatment in the year following their fracture. Pharmacological OP treatments included bisphosphonates (n = 21), strontium ranelate (n = 14), hormone replacement therapy (n = 4), or raloxifene (n = 3). General practitioners prescribed 75% of initial OP treatments. Despite the guidelines published in 2006 and the numerous initiatives to promote post-fracture OP treatment, OP treatment initiation rate in women who were hospitalized for a fragility fracture remained low in 2009-2011 in France.

Previous studies have shown that microdamage accumulates in bone as a result of physiological loading and occurs naturally in human trabecular bone. The purpose of this study was to determine the factors associated with pre-existing microdamage in human vertebral trabecular bone, namely age, architecture, hardness, mineral and organic matrix. Trabecular bone cores were collected from human L2 vertebrae (n = 53) from donors 54-95 years of age (22 men and 30 women, 1 unknown) and previous cited parameters were evaluated. Collagen cross-link content (PYD, DPD, PEN and % of collagen) was measured on surrounding trabecular bone. We found that determinants of microdamage were mostly the age of donors, architecture, mineral characteristics and mature enzymatic cross-links. Moreover, linear microcracks were mostly associated with the bone matrix characteristics whereas diffuse damage was associated with architecture. We conclude that linear and diffuse types of microdamage seemed to have different determinants, with age being critical for both types.

In postmenopausal osteoporosis, an impairment in enzymatic cross-links (ECL) occurs, leading in part to a decline in bone biomechanical properties. Biochemical methods by high performance liquid chromatography (HPLC) are currently used to measure ECL. Another method has been proposed, by Fourier Transform InfraRed Imaging (FTIRI), to measure a mature PYD/immature DHLNL cross-links ratio, using the 1660/1690 cm(-1) area ratio in the amide I band. However, in bone, the amide I band composition is complex (collagens, non-collagenous proteins, water vibrations) and the 1660/1690 cm(-1) by FTIRI has never been directly correlated with the PYD/DHLNL by HPLC. A study design using lathyritic rats, characterized by a decrease in the formation of ECL due to the inhibition of lysyl oxidase, was used in order to determine the evolution of 1660/1690 cm(-1) by FTIR Microspectroscopy in bone tissue and compare to the ECL quantified by HPLC. The actual amount of ECL was quantified by HPLC on cortical bone from control and lathyritic rats. The lathyritic group exhibited a decrease of 78% of pyridinoline content compared to the control group. The 1660/1690 cm(-1) area ratio was increased within center bone compared to inner bone, and this was also correlated with an increase in both mineral maturity and mineralization index. However, no difference in the 1660/1690 cm(-1) ratio was found between control and lathyritic rats. Those results were confirmed by principal component analysis performed on multispectral infrared images. In bovine bone, in which PYD was physically destructed by UV-photolysis, the PYD/DHLNL (measured by HPLC) was strongly decreased, whereas the 1660/1690 cm(-1) was unmodified. In conclusion, the 1660/1690 cm(-1) is not related to the PYD/DHLNL ratio, but increased with age of bone mineral, suggesting that a modification of this ratio could be mainly due to a modification of the collagen secondary structure related to the mineralization process.