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Osteonecrosis of the jaw (ONJ) is a rare but serious adverse event associated with antiresorptive treatment. There is little evidence regarding the incidence of ONJ among patients with osteoporosis who are treated with denosumab versus bisphosphonates (BPs). The aim of this study was to determine the risk of ONJ in a real-world population. Subjects who underwent at least one dual-energy X-ray absorptiometry (DXA) examination were included in the osteoporosis register of the Swiss Society of Rheumatology between January 1, 2015, and September 30, 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for ONJ, considering sequential therapies and drug holidays as covariates. Among 9956 registered patients, 3068 (89% female, median age 69���years [63 to 76]) were treated with BPs or denosumab for a cumulative duration of 11,101 and 4236 patient-years, respectively. Seventeen cases of ONJ were identified: 12 in patients receiving denosumab at the time of ONJ diagnosis and 5 in patients receiving oral or intravenous BP therapy. The diagnosis of ONJ was confirmed by independent and blinded maxillofacial surgeons, using the American Association of Oral and Maxillofacial Surgeons case definition of ONJ. The incidence of ONJ per 10,000 observed patient-years was 28.3 in patients receiving denosumab and 4.5 in patients with BP-associated ONJ, yielding a rate ratio of 6.3 (95% confidence interval [CI] 2.1 to 22.8), p���

Background There is an ongoing discussion about incorporating additional risk factors to established WHO fracture risk assessment tool (FRAX) to improve the prediction accuracy in clinical subgroups. We aimed to reach an expert consensus on possible additional predictive parameters for specific clinical subgroups. Methods Two-round modified Delphi survey: We generated a shortlist of experts from the authors’ lists of the pertinent literature and complemented the list with experts known to the authors. Participants were asked to name possible relevant risk factors besides the FRAX-parameters for the occurrence of osteoporotic fractures. Experts specified these possible predictors for specific subgroups of patients. In the second round the expert panel was asked to weight each parameter of every subgroup assigning a number between one (not important) to ten (very important). We defined the threshold for an expert consensus if the interquartile range (IQR) of a predictor was ≤2. The cut-off value of the median attributed weights for a relevant predictor was set at ≥7. Results Eleven experts of seven countries completed both rounds of the Delphi. The participants agreed on nine additional parameters for seven categories. For the category “secondary osteoporosis”, “older adults” and “nursing home patients”, there was a consensus that history of previous falls was relevant, while for men and postmenopausal women, there was a consensus that the spine fracture status was important. For the group “primary and secondary osteoporosis” the experts agreed on the parameters “high risk of falls”, “lumbar spine bone mineral density (BMD)” and “sarcopenia”. Conclusion This Delphi survey reached a consensus on various parameters that could be used to refine the currently existing FRAX for specific clinical situations or patient groups. The results may be useful for studies aiming at improving the predictive properties of instruments for fracture prediction.

Osteoporosis International, 16 (7), ISSN:0937-941X, ISSN:1433-2965, ISSN:0936-6555

This study intended to compare bone density and architecture in three groups of women: young women with anorexia nervosa (AN), an age-matched control group of young women, and healthy late postmenopausal women. Three-dimensional peripheral quantitative high resolution computed-tomography (HR-pQCT) at the ultradistal radius, a technology providing measures of cortical and trabecular bone density and microarchitecture, was performed in the three cohorts. Thirty-six women with AN aged 18–30 years (mean duration of AN: 5.8 years), 83 healthy late postmenopausal women aged 70–81 as well as 30 age-matched healthy young women were assessed. The overall cortical and trabecular bone density (D100), the absolute thickness of the cortical bone (CTh), and the absolute number of trabecules per area (TbN) were significantly lower in AN patients compared with healthy young women. The absolute number of trabecules per area (TbN) in AN and postmenopausal women was similar, but significantly lower than in healthy young women. The comparison between AN patients and post-menopausal women is of interest because the latter reach bone peak mass around the middle of the fertile age span whereas the former usually lose bone before reaching optimal bone density and structure. This study shows that bone mineral density and bone compacta thickness in AN are lower than those in controls but still higher than those in postmenopause. Bone compacta density in AN is similar as in controls. However, bone inner structure in AN is degraded to a similar extent as in postmenopause. This last finding is particularly troubling.

Objectives: To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach. Methods: The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality. Results: 497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research. Conclusion: The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

Trabecular bone architecture is one of the main factors influencing the mechanical behavior of cancellous bone. To assess the three-dimensional trabecular microstructure of intact bones, we introduced the concept of noninvasive bone biopsy, a method to assess and analyze cancellous bone based upon three-dimensional peripheral quantitative computed tomography in vivo (3D-pQCT). The aim of this work was to demonstrate the potential of noninvasive bone biopsies as a basis for structural and mechanical analysis of trabecular bone in the process of rapid bone loss. A group of six healthy young male volunteers was measured to provide data on the reproducibility of structural parameters. Baseline and 1-month follow-up measurements were performed to provide data on short-term precision of the procedure, and three of the controls were reanalyzed within 3-6 months to estimate long-term precision. Prior to structural evaluation, the baseline and follow-up measurements were repositioned three-dimensionally to ensure matching volumes of interest (VOI). Trabecular bone density (TBD) as well as structural indices were analyzed for all measurements. The VOIs were analyzed morphometrically by evaluating bone volume (BV/TV) and trabecular number (Tb.N) based on a direct three-dimensional approach. Trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp) were derived from these two indices. The data of the measurements at 1 month to determine the short-term precision was in excellent agreement with the baseline measurements. The results showed that structural parameters can be reproduced in vivo with a coefficient of variation of less than 0.5%. With a typical spread of 4% for the structural indices within the group of healthy volunteers, an intraclass correlation of better than 0.98 was reached. We conclude that high-resolution 3D-pQCT has the potential to detect structural changes in trabecular bone during therapeutic and diagnostic trials.

Objectives:To develop evidence-based recommendations for the diagnosis of hand osteoarthritis (OA).Methods:The multidisciplinary guideline development group, representing 15 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation, research evidence was searched for systematically. Whenever possible, the sensitivity, specificity and likelihood ratio (LR) were calculated; relative risk and odds ratios were estimated for risk factors for hand OA. Quality of evidence was categorised using the European League Against Rheumatism (EULAR) hierarchy, and strength of recommendation was assessed by the EULAR visual analogue scale.Results:Diagnostic topics included clinical manifestations, radiographic features, subgroups, differential diagnosis, laboratory tests, risk factors and comorbidities. The sensitivity, specificity and LR varied between tests depending upon the cut-off level, gold standard and controls. Overall, no single test could be used to define hand OA on its own (LR Conclusion:Ten key recommendations for diagnosis of hand OA were developed using research evidence and expert consensus. Diagnosis of hand OA should be based on assessment of a composite of features.

OBJECTIVE: To compare the efficacy and safety of intraarticular hylan and 2 hyaluronic acids (HAs) in osteoarthritis (OA) of the knee. METHODS: This was a multicenter, patient-blind, randomized controlled trial in 660 patients with symptomatic knee OA. Patients were randomly assigned to receive 1 cycle of 3 intraarticular injections per knee of 1 of 3 preparations: a high molecular weight cross-linked hylan, a non-cross-linked medium molecular weight HA of avian origin, or a non-cross-linked low molecular weight HA of bacterial origin. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 6 months. Secondary outcome measures included local adverse events (effusions or flares) in injected knees. During months 7-12, patients were offered a second cycle of viscosupplementation. RESULTS: Pain relief was similar in all 3 groups. The difference in changes between baseline and 6 months between hylan and the combined HAs was 0.1 on the WOMAC pain score (95% confidence interval [95% CI] -0.2, 0.3). No relevant differences were observed in any of the secondary efficacy outcomes, and stratified analyses provided no evidence for differences in effects across different patient groups. There was a trend toward more local adverse events in the hylan group than in the HA groups during the first cycle (difference 2.2% [95% CI -2.4, 6.7]), and this trend became more pronounced during the second cycle (difference 6.4% [95% CI 0.6, 12.2]). CONCLUSION: We found no evidence for a difference in efficacy between hylan and HAs. In view of its higher costs and potential for more local adverse events, we see no rationale for the continued use of hylan in patients with knee OA.

Background: Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR standing committee for clinical trials met in 1998 to determine the methodological and logistical approach required for the development of evidence-based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available therapies for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. Methods: The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and key words. All European language publications in the form of systematic reviews, meta-analyses, randomized-controlled trials, controlled trials and observational studies were included. During stage three all of the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and where practical the numbers needed to treat (NNT) and the effect size (ES) for each therapy was calculated. The fourth stage involved determination of key clinical propositions by expert consensus employing a Delphi approach. The final stage involved ranking of these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. Results: Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. Conclusions: These are the first clinical guidelines on knee OA to combine an evidence-based approach and a consensus approach across a wide range of treatment modalities. It is apparent that only certain clinical propositions are supported by substantial research-based evidence, while others are not. There is thus an urgent need for future well designed trials to address key clinical questions. (Less)

Method We report a case of a 24-year-old woman with anorexia nervosa (AN), obsessive-compulsive disorder (OCD), and osteoporosis. During 8 years of illness, her body mass index (BMI) fluctuated between 10 and 13,5 kg/m2. She developed hyperactivity and the habit to stand for all daily activities. She did not allow herself to sit at any time, she had “standing obsession.” A few weeks after her admission to an inpatient unit for eating disorders, she reported pain in both ankles. Results and Discussion The rheumatological diagnosis was bilateral osteonecrosis of the talus and generalized osteoporosis. The latter and excessive biomechanical stress could be interpreted as the cause for this serious and irreversible bone destruction. The following case shows how the psychiatric comorbidity of a patient suffering from an eating disorder with a chronic course can lead to severe somatic complications. © 2001 by John Wiley & Sons, Inc. Int J Eat Disord 29: 363–369, 2001.

Gemass WHO wird Osteoporose uber die Knochendichte definiert. Eine tiefe Knochendichte allein hat jedoch fur die Betroffenen keinen spurbaren Krankheitswert. Es stellt sich deshalb die Frage, wo die Grenze zwischen gesund und krank zu ziehen ist. Verschiedene klinische Risikofaktoren beeinflussen das Risiko fur Fragilitatsfrakturen auch unabhangig von der Knochendichte.

Alle bis heute verwendeten Kriterien zur Messung der Gewebedestruktion bei rheumatoider Arthritis (RA) und Arthrose (OA) zeigen erst ein relativ spates Stadium des Krankheitsprozesses an. Die Verfugbarkeit von biochemischen Markern, mit denen die Krankheitsaktivitat oder die Gelenkzerstorung im Sinne einer Risikoabschatzung vorausgesagt und deren Verlaufswerte zur Erfolgskontrolle bei Therapie eingesetzt werden konnten, ware ein wichtiger Fortschritt. Patienten und Methoden: In dieser Querschnittsstudie wurden 37 RA- und 20 OA-Patienten mit einer Krankheitsdauer von 119±130 rsp.41±73 Monaten untersucht. Als Parameter der Krankheitsaktivitat bzw. der Gewebezerstorung wurden BSR, CRP, Disease Activity Score (DAS), der funktionelle Status der RA gemas American College of Rheumatology sowie zwei radiologische Scoring Systeme (Larsen Score bei RA- und die Kellgren-Lawrence Kriterien bei OA-Patienten) bestimmt. Mittels enzyme-linked immunosorbent assay (ELISA) wurde cartilage oligomeric matrix protein (COMP) im Serum und in der Synovialflussigkeit dieser Patienten gemessen. Zusatzlich wurden mittels Gel-Elektrophorese und Immunoblot die COMP-Fragmente in der Synovialflussigkeit ermittelt. Resultate und Diskussion: Der mittlere COMP-Wert in der Synovialflussigkeit betrug bei RA-Patienten 38ug/ml, bei OA-Patienten 46ug/ml, im Serum 6,5ug/ml rsp. 3,4ug/ml. Bei RA-Patienten korrelierte eine zunehmende Krankheitsaktivitat (DAS) mit einem erhohten COMP-Wert, sowohl in der Synovialflussigkeit als auch im Serum. Eine erhohte Freisetzung von kleinen COMP-Fragmenten in der Synovialflussigkeit, wies auf eine vermehrte proteolytische Aktivitat hin. Diese Ergebnisse beruhen wahrscheinlich auf einem erhohten Umsatz von Knorpelmatrix im entzundeten Gelenk bei RA. Die RA-Patienten in dieser Querschnittsstudie wiesen auserdem eine Korrelation von abnehmendem COMP-Spiegel mit Abnahme der korperlichen Funktion bzw. zunehmender Gelenkzerstorung, auf. Dies deutet auf einen Verlust an Gelenkknorpel mit verminderter Gesamtmenge und Umsatz von COMP hin. Bei OA-Patienten mit kurzer Krankheitsdauer wurde eine signifikante Korrelation zwischen zunehmend (aber insgesamt wenig) reduzierter Gelenkspaltweite und einem erhohtem COMP-Wert in der Synovialflussigkeit gefunden. Dieser Zusammenhang legt nahe, das im kurz- bis mittelfristigen Verlauf des Krankheitsprozesses ein erhohter Umsatz an Knorpelmolekulen beobachtet werden kann.

In vivo examinations of bone microarchitecture have become available recently through high resolution computed tomography (3D-QCT) and magnetic resonance imaging. The spatial resolution of the resulting images, however, is not sufficient to depict individual trabeculae in their true shape. Nevertheless, structural indices such as relative bone volume, trabecular number, mean thickness and mean separation can be extracted with the help of a ridge detection algorithm. Precision of the procedure is of the order of 1%, accuracy is ascertained using a micro-CT based calibration. In this work we report first results of time serial examinations. Eighteen healthy postmenopausal women (no HRT) were measured at months 0, 6, and 12, and the temporal changes were analyzed. Examination site was the distal radius. The above mentioned structural indices, the average densities and the thickness of the cortical shell were determined. Of the 18 women 6 showed no significant bone loss of any kind, 5 lost primarily cancellous bone, 4 lost primarily cortical bone, and 3 had a substantial loss of cortical as well as cancellous bone. We conclude that even in a homogenous group such as postmenopausal women, there are considerable differences in the reason why bone is weakend and that high resolution 3D-QCT allows to differentiate between various types of bone loss.

Osteoarthritis is the most common joint disease. In addition to known risk factors e.g. genetics, age and hormonal status it has been suggested that chronic-repetitive micro- and substantial (macro-) injury may play an important pathogenetic role. In a longitudinal case-study we examined Judo-players for clinical and radiological changes of the finger joints over the course of 16 years. All examined 8 players demonstrated soft tissue changes including Heberden nodes and radiological changes typical for osteoarthritis of the finger joints. Changes were symmetrical and were not restricted to joints with tendon ruptures or fractures in the anamnesis. Degenerative changes were progressive and more pronounced in active players. Subjectively, symptoms were usually mild. Extensive Judo seems to be a risk factor for the development of osteoarthritis of the finger joints due to chronic-repetitive micro- and substantial (macro-) injury.

Schweiz Med Forum 2009;9(36):633 633 En 1993, un groupe d’experts mandates par l’Organisation Mondiale de la Sante a defini l’osteoporose comme une maladie caracterisee par une masse osseuse abaissee, avec des defauts structuraux, conduisant a une fragilite osseuse augmentee et a un risque accru de fracture [1]. Ce groupe a propose egalement une definition operationnelle, un seuil diagnostique, qui est une diminution de 2,5 ecarts-type de la densite minerale osseuse de surface mesuree a la colonne lombaire ou au femur proximal, par rapport a une population de jeunes adultes en bonne sante, donc une population avec un risque fracturaire extremement faible. Il existe une relation inverse entre le risque fracturaire et la densite minerale osseuse. Cette derniere explique une large proportion de la variancede la resistancemecanique.Cetteapprochedupatient par une mesure quantitative d’un determinant de la resistance mecanique osseuse permet un diagnostic avant que ne survienne la complication de la maladie, la premiere fracture. Cette definition a servi a l’identification des patients a recruter dans les essais cliniques pour l’evaluation de l’efficacite et la securite des nouveaux agents therapeutiques et sert de base au remboursement des traitements: un remboursement est consenti si le patient est osteoporotique, donc si sa densite minerale osseuse est en-dessous du seuil de –2,5 ecarts-type, ce fameux T-Score qui est maintenant bien ancre dans la vie quotidienne. Une ordonnance de 2003 precise les indications pour le remboursement de l’examen osteodensitometrique (tab. 1 p). L’osteodensitometrie axiale (colonne et femur proximal) permet de poser le diagnostic de la maladie, mais n’est pas un outil de depistage systematique, en raison d’une sensibilite par trop insuffisante et d’une specificite imparfaite quant a la prediction des fractures. En effet, un nombre important de sujets subissent une fracture a basse energie, donc sur une chute de leur propre hauteur, sans que le seuil diagnostique d’osteoporose soit depasse. La fracture est un evenement stochastique, Prof. Rene Rizzoli Service des Maladies Osseuses Hopital Cantonal, 1211 Geneve 14 Rene.Rizzoli@unige.ch

This study assessed the ability of quantitative ultrasound (QUS) and digital X-ray radiogrammetry (DXR) to identify osteopenia and osteoporosis in patients with knee osteoarthritis (OA). One hundred and sixty-one patients with painful knee OA (81 men, 80 women; age 62.6+/-9.2 years, range 40-82 years) were included in this cross-sectional study and underwent dual-energy X-ray absorptiometry (DXA) of both hips and the lumbar spine, QUS of the phalanges and calcanei of both hands and heels, and DXR using radiographs of both hands. Unpaired t-test, Mann-Whitney U test, ROC analysis and Spearman's rank correlation were used for comparisons and correlation of methods. Using DXA as the reference standard, we defined a low bone mineral density (BMD) as a T-score < or =-1.0 at the lumbar spine or proximal femur. In contrast to phalangeal or calcaneal QUS, DXR was able to discriminate patients with a low BMD at the lumbar spine (p

OBJECTIVES: To develop evidence based recommendations for the management of hand osteoarthritis (OA). METHODS: The multidisciplinary guideline development group comprised 16 rheumatologists, one physiatrist, one orthopaedic surgeon, two allied health professionals, and one evidence based medicine expert, representing 15 different European countries. Each participant contributed up to 10 propositions describing key clinical points for management of hand OA. Final recommendations were agreed using a Delphi consensus approach. A systematic search of Medline, Embase, CINAHL, Science Citation Index, AMED, Cochrane Library, HTA, and NICE reports was used to identify the best available research evidence to support each proposition. Where possible, the effect size and number needed to treat were calculated for efficacy. Relative risk or odds ratio was estimated for safety, and incremental cost effectiveness ratio was used for cost effectiveness. The strength of recommendation was provided according to research evidence, clinical expertise, and perceived patient preference. RESULTS: Eleven key propositions involving 17 treatment modalities were generated through three Delphi rounds. Treatment topics included general considerations (for example, clinical features, risk factors, comorbidities), non-pharmacological (for example, education plus exercise, local heat, and splint), pharmacological (for example, paracetamol, NSAIDs, NSAIDs plus gastroprotective agents, COX-2 inhibitors, systemic slow acting disease modifying drugs, intra-articular corticosteroids), and surgery. Of 17 treatment modalities, only six were supported by research evidence (education plus exercise, NSAIDs, COX-2 inhibitors, topical NSAIDs, topical capsaicin, and chondroitin sulphate). Others were supported either by evidence extrapolated from studies of OA affecting other joint sites or by expert opinion. Strength of recommendation varied according to level of evidence, benefits and harms/costs of the treatment, and clinical expertise. CONCLUSION: Eleven key recommendations for treatment of hand OA were developed using a combination of research based evidence and expert consensus. The evidence was evaluated and the strength of recommendation was provided.

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women ≥70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not. Introduction: As the number of hip fracture is expected to increase during these next decades, it is important to develop strategies to detect subjects at risk. Quantitative bone ultrasound (QUS), an ionizing radiation-free method, which is transportable, could be interesting for this purpose. Materials and Methods: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a multicenter cohort study, which compared three QUSs for the assessment of hip fracture risk in a sample of 7609 elderly ambulatory women ≥70 years of age. Two QUSs measured the heel (Achilles+; GE-Lunar and Sahara; Hologic), and one measured the heel (DBM Sonic 1200; IGEA). The Cox proportional hazards regression was used to estimate the hazard of the first hip fracture, adjusted for age, BMI, and center, and the area under the ROC curves were calculated to compare the devices and their parameters. Results: From the 7609 women who were included in the study, 7062 women 75.2 ± 3.1 (SD) years of age were prospectively followed for 2.9 ± 0.8 years. Eighty women reported a hip fracture. A decrease by 1 SD of the QUS variables corresponded to an increase of the hip fracture risk from 2.3 (95% CI, 1.7, 3.1) to 2.6 (95% CI, 1.9, 3.4) for the three variables of Achilles+ and from 2.2 (95% CI, 1.7, 3.0) to 2.4 (95% CI, 1.8, 3.2) for the three variables of Sahara. Risk gradients did not differ significantly among the variables of the two heel QUS devices. On the other hand, the phalanges QUS (DBM Sonic 1200) was not predictive of hip fracture risk, with an adjusted hazard risk of 1.2 (95% CI, 0.9, 1.5), even after reanalysis of the digitalized data and using different cut-off levels (1700 or 1570 m/s). Conclusions: In this elderly women population, heel QUS devices were both predictive of hip fracture risk, whereas the phalanges QUS device was not.

Objective: To evaluate the level of acceptability of the EULAR recommendations for the management of knee osteoarthritis (KOA) in practice. Methods: A questionnaire was sent to general practitioners, rheumatologists, rehabilitators, and orthopaedic surgeons in five European countries (France, Spain, Belgium, Switzerland, Italy). Practitioners were asked to give their opinion on the 10 EULAR recommendations and on 23 treatment modes for KOA. Practitioners' opinions were compared with those of the expert task force involved in the development of these recommendations. Results: The overall response rate was 10.4% (4204 replies). Results were similar across countries and specialties. Of the 23 treatment modes proposed, only joint lavage and intra-articular (IA) corticosteroid injections were more strongly recommended by the expert task force than by the responders as a whole, while the opposite was true for spa therapy. Principal component analysis showed: (1) some practitioners preferred "hard line" treatments (surgery, IA injections, or non-steroidal anti-inflammatory drugs (NSAIDs)); (2) there was a difference between those prescribing pharmacological (paracetamol) or non-pharmacological measures with low iatrogenicity (exercises, sticks, education), and those prescribing less well validated treatments closer to "alternative" medicine; (3) each specialist tended to advocate modes that they were most familiar with: rheumatologists were more likely to recommend IA injections and NSAIDs; orthopaedic surgeons, surgical procedures; rehabilitators, education and all non-pharmacological modes; general practitioners, spa therapy and opioids. Conclusions: A multidisciplinary approach is optimal in the management of this chronic disease with its variable course.

Bone ultrasound measures (QUSs) can assess fracture risk in the elderly. We compared three QUSs and their association with nonvertebral fracture history in 7562 Swiss women 70–80 years of age. The association between nonvertebral fracture was higher for heel than phalangeal QUS. Introduction: Because of the high morbidity and mortality associated with osteoporotic fractures, it is essential to detect subjects at risk for such fractures with screening methods. Because quantitative bone ultrasound (QUS) discriminated subjects with osteoporotic fractures from controls in several cross-sectional studies and predicted fractures in prospective studies, QUS could be more practical than DXA for screening. Material and Methods: This cross-sectional and retrospective multicenter (10 centers) study was performed to compare three QUSs (two heel ultrasounds: Achilles+ [GE-Lunar] and Sahara [Hologic]; the phalanges: ultrasound DBM sonic 1200 [IGEA]) for determining by logistic regression nonvertebral fracture odds ratio (OR) in a sample of 7562 Swiss women, 75.3 ± 3.1 years of age. The two heel QUSs measured the broadband ultrasound attenuation (BUA) and the speed of sound (SOS). In addition, Achilles+ calculated the stiffness index (SI) and the Sahara calculated the quantitative ultrasound index (QUI) from BUA and SOS. The DBM sonic 1200 measured the amplitude-dependent SOS (AD-SOS). Results: Eighty-six women had a history of atraumatic hip fracture after the age of 50, 1594 had a history of forearm fracture, and 2016 had other nonvertebral fractures. No fracture history was reported by 3866 women. Discrimination for hip fracture was higher than for the other nonvertebral fractures. The two heel QUSs had a significantly higher discrimination power than the QUSs of the phalanges, with standardized ORs, adjusted for age and body mass index, ranging from 2.1 to 2.7 (95% CI = 1.6, 3.5) compared with 1.4 (95% CI = 1.1, 1.7) for the AD-SOS of DBM sonic 1200. Conclusion: This study showed a high association between heel QUS and hip fracture history in elderly Swiss women. This could justify integration of QUS among screening strategies for identifying elderly women at risk for osteoporotic fractures.

Because of the important morbidity and mortality associated with osteoporosis, it is essential to detect subjects at risk by screening methods, such as bone quantitative ultrasounds (QUSs). Several studies showed that QUS could predict fractures. None, however, compared prospectively different QUS devices, and few data of quality controls (QCs) have been published. The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk is a prospective multicenter study that compared three QUSs for the assessment of hip fracture risk in a population of 7609 women age ≥70 yr. Because the inclusion phase lasted 20 mo, and because 10 centers participated in this study, QC became a major issue. We therefore developed a QC procedure to assess the stability and precision of the devices, and for their cross-calibration. Our study focuses on the two heel QUSs. The water bath system (Achilles+) had a higher precision than the dry system (Sahara). The QC results were highly dependent on temperature. QUS stability was acceptable, but Sahara must be calibrated regularly. A sufficient homogeneity among all the Sahara devices could be demonstrated, whereas significant differences were found among the Achilles+ devices. For speed of sound, 52% of the differences among the Achilles+ was explained by the water's temperature. However, for broadband ultrasound attenuation, a maximal difference of 23% persisted after adjustment for temperature. Because such differences could influence measurements in vivo, it is crucial to develop standardized phantoms to be used in prospective multicenter studies.

Background Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR standing committee for clinical trials met in 1998 to determine the methodological and logistical approach required for the development of evidence-based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available therapies for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. Methods The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and key words. All European language publications in the form of systematic reviews, meta-analyses, randomized-controlled trials, controlled trials and observational studies were included. During stage three all of the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and where practical the numbers needed to treat (NNT) and the effect size (ES) for each therapy was calculated. The fourth stage involved determination of key clinical propositions by expert consensus employing a Delphi approach. The final stage involved ranking of these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. Results Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. Conclusions These are the first clinical guidelines on knee OA to combine an evidence-based approach and a consensus approach across a wide range of treatment modalities. It is apparent that only certain clinical propositions are supported by substantial research-based evidence, while others are not. There is thus an urgent need for future well designed trials to address key clinical questions

We investigated the expression of cartilage oligomeric matrix protein (COMP) in normal and rheumatoid arthritis (RA) synovial fibroblasts. In situ hybridization (ISH) was conducted on synovial specimens from five RA patients applying specific probes for COMP or fibroblast collagen type I. ISH was combined with immunohistochemistry, applying antibodies to the macrophage marker CD68. Ribonuclease protection assay (RPA) and rapid amplification of 3'-cDNA ends (3'-RACE) were performed on total RNA from normal and RA synovial fibroblast cultures. Protein extracts from fibroblasts and culture supernatants were compared with synovial fluids and protein extracts from isolated chondrocytes by Western blot utilizing polyclonal and monoclonal antibodies (18-G3 mAb) to COMP. COMP mRNA was detected in fibroblasts of RA synovium by ISH, and in normal and RA synovial fibroblast cultures by RPA. 3'-RACE demonstrated sequence homology of chondrocyte and synovial fibroblast COMP along the coding sequence. COMP protein was detected in synovial fibroblasts and culture supernatants by immunoblot. Using polyclonal antibodies, the major portion of COMP from fibroblasts and culture supernatants was present as low-molecular-weight (LMW) bands, corresponding to those found in synovial fluids. These LMW COMP bands, however, were not detected in any of the cells or tissues tested using 18-G3 mAb. In protein extracts from chondrocytes and in COMP purified from cartilage, these LMW bands could not be detected. In conclusion, the data suggest that certain forms of COMP detected in synovial fluid are secreted from synovial fibroblasts and could be distinguished by specific mAbs from COMP secreted by chondrocytes.

An advanced analysis of the mechanical properties of bone should include information about the microarchitecture of cancellous bone in addition to its density. It has recently been shown that high-resolution quantitative computed tomography and magnetic resonance imaging have the potential to assess such information in a noninvasive way in patients. Both techniques, however, lack sufficient spatial resolution to image the individual trabeculae with true precision. In this work, a new parameter, Ridge number density (RND), is introduced. RND is a measure for the trabecular number, which can be extracted directly from high-resolution three-dimensional (3D) images of patients. We applied the RND technique to a test group of nine healthy, postmenopausal women measured repetitively with a high-resolution 3D peripheral quantitative computed tomography (3D-pQCT) system with 165 x 165 x 165 microm3 voxel size. Simultaneously with the RND determination, the trabecular bone density (TBD) was also assessed in the same volume of interest. The examination site was the distal radius. The intersubject variability of the measured test group was 10.5% for RND and 26.3% for TBD. The root mean square error between first and second examinations (midterm reproducibility) was 1.6% and 1.1%, respectively. RND is determined independently from TBD and pertains to the structure of the cancellous bone. As such, it might add crucial information in cases where bone mass or bone density measurements alone give ambiguous results.

Objective. Based on the results of two recently published, randomized, double-blind and placebo-controlled studies, a possible improvement in rheumatoid arthritis disease activity after oral tolerization with triple helical collagen type II has been suggested. The goal of this study was to go one step further and ask the question whether collagen type II can sustain the therapeutic effect induced by methotrexate, the most widely accepted disease-modifying anti-rheumatic drug in patients with long-standing rheumatoid arthritis. Methods. Ninety-two patients with rheumatoid arthritis on stable therapy with methotrexate were enrolled in a 3 month double-blind, randomized and comparative study to examine the efficacy of oral triple helical collagen type II as compared to continuing methotrexate. The dose of methotrexate (or the respective placebo drug) and of concomitant corticosteroids was not changed and intra-articular corticosteroids were not allowed during the 3 months. The primary study endpoint was disease activity as measured by physician and patients. Results. While patients under ongoing therapy with methotrexate had, as expected, no change in disease activity, almost all parameters of disease activity and outcome in patients under a daily oral dose of 0.5 mg triple helical collagen type II worsened significantly (highly significant difference in swollen joints, between the two groups, P < 0.0001). No significant differences in side-effects between the two groups during the study period could be demonstrated. Conclusions. Substitution of methotrexate with daily 0.5 mg of triple helical collagen type II in patients with rheumatoid arthritis leads to a significant increase in disease activity, suggesting that oral collagen type II at the given dose is not capable of sustaining the methotrexate-induced anti-inflammatory effect in patients with long-standing rheumatoid arthritis.

Serum levels of several molecules originating from joints and cartilages have been shown to rise during the preradiological stages of osteoarthritis (OA). Using a dog model of posttraumatic OA, we have shown that serum levels of markers of aggrecan degradation (antigenic keratan sulfate) and synovial proliferation/metabolism (hyaluronan) rise within 1-2 weeks after the injury and remain elevated for at least 13 weeks. These changes, which precede the development of OA lesions, are consistent with the view that traumatic injury to a single synovial joint gives rise to a state of hypermetabolism that is local at first but becomes systemic with time.

BACKGROUND: With the broad availability of effective medications, identifying individuals bearing a higher risk for osteoporotic fractures has become an issue of major concern in modern medicine. In recent years various prognostic instruments have become available showing conflicting results regarding estimated risks for individual patients. OBJECTIVE: To provide an overview of current evidence and of opportunities for further research. METHODOLOGY/PRINCIPAL FINDINGS: Systematic review: We identified studies describing the development of instruments and all subsequent validations in electronic databases and reference lists of included studies. We screened for inclusion, read full papers and extracted data on salient clinical features, performance characteristics and quality in duplicate. Searches retrieved 5,275 records of which full texts of 167 papers were obtained after screening titles and abstract. We included 35 studies enrolling a total of 609,969 patients (median 2546) reporting on 31 derivations and 12 validations after assessing full texts. Median follow-up time was 4.1 years (IQR 3 to 7.7). Only four studies validated an instrument that was developed by another group. None of the existing instruments was validated more than once. The five most frequent included variables in the final model were age, body mass index, bone mass index, past history of falls, and maternal history of fractures. The methodological quality of the studies was moderate. CONCLUSION: There is a plethora of evidence available studying the association of risk profiles and the development of osteoporotic fractures. The small number of out-of-sample validations, the large variety of study characteristics, outcomes and follow-up periods impedes from deriving robust summaries and from conclusions regarding the clinical performance of many tools. First and foremost, future activity in this field should aim at reaching a consensus among clinical experts in respect to the existing instruments. Then we call for careful validations and expedient adaptations for local circumstances of the most promising candidates.

Cartilage matrix protein (CMP) is a noncollagenous glycoprotein with a molecular mass of 148 kDa consisting of three identical subunits linked together at their C-terminal assembly domains via a coiled-coil α-helix (Hauser and Paulsson 1994). Electron microscopy of the native protein showed trimers with compact ellipsoid subunits, each consisting of two von Willebrand factor A-domains linked via one EGF-like repeat. CMP is a highly insoluble protein which appears to become covalently crosslinked within the cartilage matrix with maturation.