[Innovations in physical and rehabilitation medicine]. / Innovations en médecine physique et réadaptation.

Over the last decade, Physical and Rehabilitation Medicine (PRM) is a medical specialty that has evolved considerably in the various fields that concern it : from the management of low back pain and lumbosciatalgia or osteoporosis in a multidisciplinary manner, through the use of new technologies in neuro-locomotor rehabilitation and robotisation in amputee patients for example, the development of regenerative medicine and prevention in sports traumatology and, finally, the progress of electrophysiology techniques for the diagnosis of small-fibre neuropathies. These various advances will be discussed in this article.

Au cours de la dernière décennie, la Médecine Physique et Réadaptation (MPR) est une spécialité médicale qui a fortement évolué dans les différents domaines qui la concernent : de la prise en charge des lombalgies et lombosciatalgies ou encore de l'ostéoporose de manière pluridisciplinaire, en passant par l'utilisation des nouvelles technologies en rééducation neuro-locomotrice et de la robotisation en rééducation, chez les patients amputés par exemple, le développement de la médecine à vocation régénérative et la prévention en traumatologie du sport et, enfin, les progrès des techniques d'électrophysiologie pour le diagnostic des neuropathies à petites fibres. Ces différentes avancées seront abordées dans cet article.

[Fibromyalgia : state of the issue in 2017]. / Fibromyalgie : état de la question en 2017.

Fibromyalgia (FM), whose diagnostic criteria were originally established in 1990 and updated in 2010, consists of a syndrome characterized by the presence of deep and diffuse musculoskeletal pain associated with other subjective manifestations (sleep, mood, cognitive problems). The prevalence is assessed in the general population at 2.2 %. Various risk factors were identified: age, gender, level of education and socio-economic status. Various etiological hypotheses have been explored, whether in neuroimaging or from the point of view of possible neuroendocrine and cytokine perturbations. In addition, various potential pathogenic mechanisms have been identified: genetic predisposition, central amplification, diffuse inhibitory control failure, muscle as peripheral nociceptive afferents. Finally, with regard to treatment and clinical course, the first will be multidisciplinary and the second will not be marked by real remission. In addition, patients tend to reduce their activities (professional, physical or leisure), which degrades and perpetuates the situation, while they must remain as active as possible.

La fibromyalgie (FM), dont les critères diagnostiques ont été établis initialement en 1990 et mis à jour en 2010, consiste en un syndrome caractérisé par la présence de douleurs musculo-squelettiques profondes et diffuses, associées à d'autres manifestations subjectives (troubles du sommeil, de l'humeur et problèmes cognitifs). La prévalence est évaluée dans la population générale à 2,2 %. Divers facteurs de risque ont été mis en évidence : l'âge, le sexe, le niveau d'éducation et le statut socio-économique. Diverses hypothèses étiologiques ont été explorées, que ce soit en neuroimagerie ou du point de vue d'éventuelles perturbations neuroendocriniennes et des cytokines. En outre, divers mécanismes pathogènes potentiels ont été identifiés : la prédisposition génétique, l'amplification centrale, la défaillance du contrôle inhibiteur diffus, le muscle en tant qu'afférence nociceptive périphérique. Enfin, en ce qui concerne le traitement et l'évolution clinique, le premier sera pluridisciplinaire et la seconde ne sera pas marquée par une rémission réelle. En outre, les patients ont tendance à réduire leurs activités (professionnelles, physiques ou de loisirs), ce qui dégrade et pérennise la situation, alors qu'ils doivent rester aussi actifs que possible.

[OSTEOPOROSIS AND PERSONALIZED MEDICINE]. / OSTÉOPOROSE ET MÉDECINE PERSONNALISÉE.

Osteoporosis is at the very early stages of the implementation of personalized medicine. However, the development of FRAX®, an algorithm offering the opportunity to calculate, in an individual patient, his/her 10-year fracture risk improves the decision process on the appropriateness to initiate a pharmacological treatment. This algorithm helps the physician to select drugs which are active on non-vertebral fractures only in high risk patients. Taking into consideration patients' preferences, when selecting a therapeutic option, will improve long term adherence and subsequently efficacy and efficiency of the treatments. Attempts to define the natural course of osteoporosis or the response to therapy in individual patients by assessing their genetic profile remains, so far, inconclusive.

Efficacy and safety of currently marketed anti-osteoporosis medications.

During the past 2 decades, many interventions were proven effective in the management of postmenopausal osteoporosis. The objective of an anti-osteoporosis treatment is to reduce fracture rates, ideally at all skeletal sites (i.e. spine, hip, and other non-spine). The armamentarium against osteoporosis includes anti-resorptive agents (i.e. bisphosphonates, selective estrogen receptor modulators and denosumab), bone-forming agents (i.e. peptides from the parathyroid hormone family) and one agent with a dual mechanism of action (i.e. strontium ranelate). All these medications combine antifracture efficacy with a reasonable benefit/risk profile. However, the choice of a particular chemical entity, in one individual patient is based on the knowledge and expertise of the physician. Prioritization of drugs should be based on the individual profile of the patient, the severity of osteoporosis and the specific contraindications, warnings and precautions of use of the various available medications.

[Treatment of post-menopausic osteoporosis: what's new in 2014?]. / Traitement de l'ostéoporose post-ménopausique: quoi de neuf en 2014?

Management of osteoporosis involves both non pharmacological approaches, including changes in lifestyle and dietary habits combined, in patients at high risk of fracture or presenting with an established osteoporosis, to the use of drugs. Besides supplementation in calcium and vitamin D (at daily doses of 1 gr and 800 IU) in patients whose dietary intakes do not cover the recommended daily allowances, medications to be used for the management of osteoporosis may include inhibitors of bone resorption (bisphosphonates, denosumab and selective estrogen receptor modulators), stimulators of bone formation (teriparatide) or chemical entities decreasing bone resorption and stimulating bone formation (strontium ranelate). The selection of a particular medication, for a single individual patient, will depend on the severity of the disease as well as on the patient's believes and expectations. Local, skeletal and systemic tolerance of the various drugs should also be taken into account.

Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis.

Osteoporotic fractures are a major cause of morbidity in the elderly population. Since postmenopausal osteoporosis is related to an increase in osteoclastic activity at the time of menopause, inhibitors of bone resorption have genuinely been considered an adequate strategy for prevention and treatment of osteoporosis. Bisphosphonates and selective oestrogen receptor modulators are widely prescribed to treat osteoporosis. However, other antiresorptive drugs have been developed for the management of osteoporosis, with the objective of providing a substantial reduction in osteoporotic fractures at all skeletal sites, combined with an acceptable long-term skeletal and systemic safety profile. Denosumab, a human monoclonal antibody to receptor activator for nuclear factor kappa B ligand, has shown efficacy against vertebral, nonvertebral and hip fractures. Its administration every 6 months as a subcutaneous formulation might significantly influence compliance and persistence to therapy. Additional results regarding long-term skeletal safety (i.e. osteonecrosis of the jaw and atypical diaphyseal femoral fracture) are needed. Odanacatib, a selective cathepsin K inhibitor, is a promising new approach to the inhibition of osteoclastic resorption, with the potential to uncouple bone formation from bone resorption. Results regarding its anti-fracture efficacy are expected in the coming months.

Bone forming agents for the management of osteoporosis.

Osteoporotic fractures are a major cause of morbidity in the population. Antiresorptive agents have been, for more than 15 years, the mainstay of osteoporosis treatment worldwide. However, these medications provide only limited fracture reduction and may be linked to skeletal and non-skeletal long-term safety concerns. Therefore, some patients are considered candidates for bone-forming agents because they remain severely osteoporotic or because they failed antiresorptive therapy. Over the last decade, a particular interest was shown in the development of medications able to increase osteoblasts number, lifespan or activity, hence stimulating bone formation Peptides from the parathyroid hormone family and strontium ranelate were shown to significantly reduce fracture rates. The European Medicines Agency recently confirmed that strontium ranelate is the treatment of choice for patients with severe osteoporosis, men and women, without cardiovascular contra-indications for whom other anti-osteoporosis medications are inappropriate. New therapeutic options, including monoclonal antibodies against sclerostin seem to be promising but their role in the armamentarium of osteoporosis will depend on the results of the current phase 3 studies, assessing anti-fracture efficacy and long-term safety.

Osteonecrosis of the jaw in a male osteoporotic patient treated with denosumab.

Osteonecrosis of the jaw (ONJ) is a clinical condition associated with long-term exposure to inhibitors of bone resorption, mainly bisphosphonates. Denosumab (DMab) is a human monoclonal antibody of the receptor activator of nuclear factor kappa-B ligand. It prevents osteoclast-mediated bone resorption and is widely prescribed for the management of postmenopausal osteoporosis. Whereas ONJ has already been reported in women treated with DMab, we report for the first time the development of ONJ, following tooth extraction, in a male patient treated for idiopathic osteoporosis with DMab. Due to the constant increase in DMab prescription, for the management of osteoporosis, in both genders, physicians should be made aware of this potential risk.

Comparison of the proportion of patients potentially treated with an anti-osteoporotic drug using the current criteria of the Belgian national social security and the new suggested FRAX criteria.

To assess the number of anti-osteoporosis treatments that would be reimbursed by the Belgian social security if either FRAX or the current criteria were used to determine access to reimbursement. This is a retrospective study based on data from 1,000 women randomly selected from an outpatient hospital specialized in bone metabolism in Belgium. Proportions of potentially refunded treatments between FRAX and current criteria were compared. Out of the 1,000 women files, 890 have sufficient information to assess FRAX. In Belgium, current criteria include a bone mineral density (BMD) T score below -2.5 at the lumbar spine, the femoral neck or the total hip and/or at least a prevalent vertebral fracture. Using these criteria, 167 women (18.8 %) would have access to reimbursement. Using the criteria based on the validated Belgian FRAX tool, only 116 women (13.0 %) would have access to reimbursement, meaning that access to reimbursement based on FRAX criteria would reduce by 30 % the anti-osteoporosis drug expenses covered by the national social security. Interestingly, only 65 women out of the 116 (56.0 %) selected with the FRAX criteria were also selected with the current criteria of the national social security. A substantial proportion of individuals that would potentially receive a reimbursement for their treatment using the FRAX criteria do not have access to any refund for their treatment with the current criteria. Since patients identified with the FRAX tool are those with the highest risk profile for future fractures, reappraisals of treatment reimbursement guidelines are expected in Belgium.

Health-related quality of life after total knee or hip replacement for osteoarthritis: a 7-year prospective study.

OBJECTIVE: To assess health-related quality of life (HRQOL) in a prospective study with 7 years of follow-up in 49 consecutive patients who underwent a total joint replacement because of osteoarthritis. METHODS: Generic HRQOL was assessed with the short-form 36 (SF-36) and specific HRQOL with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Out of the 39 subjects who have completed the 7 years of follow-up of this study, 22 (56.4 %) underwent a hip replacement surgery and the other 17 (43.6 %) a knee replacement. Six months after surgery, a significant improvement, compared to preoperative scores, was observed in two of the eight dimensions of the SF-36 (i.e. physical function and pain). The same dimensions, pain and physical function, at the same time, 6 months after surgery, measured by the WOMAC, showed a significant improvement as well, but there was no significant change in the stiffness score. From 6 months to the end of follow-up, changes in SF-36 scores showed a significant improvement in physical function (p = 0.008), role-physical (p = 0.004) and role-emotional (p = 0.01) while all scores of the WOMAC improved (p < 0.001 for pain, p < 0.001 for stiffness and p < 0.01 for physical function). CONCLUSION: The improvements observed in HRQOL at short term after surgery, are at least maintained over a 7-year follow-up period.

A FRAX® model for the assessment of fracture probability in Belgium.

UNLABELLED: A country-specific FRAX® model was developed from the epidemiology of fracture and death in Belgium. Fracture probabilities were identified that corresponded to currently accepted reimbursement thresholds. INTRODUCTION: The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX®) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities. METHODS: Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck bone mineral density (BMD). Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium. RESULTS: Fracture probability increased with age, lower BMI, decreasing BMD T-score and all clinical risk factors used alone or combined. The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current reimbursement guidelines ranged from approximately 7.5% at the age of 50 years to 26% at the age of 80 years where a prior fragility fracture was used as an intervention threshold. For women at the threshold of osteoporosis (femoral neck T-score = -2.5 SD), the respective probabilities ranged from 7.4% to 15%. Several combinations of risk-factor profiles were identified that gave similar or higher fracture probabilities than those currently accepted for reimbursement in Belgium. CONCLUSIONS: The FRAX® tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX® model supports a shift from the current DXA-based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.

Glucosamine sulphate in the treatment of knee osteoarthritis: cost-effectiveness comparison with paracetamol.

INTRODUCTION: The aim of this study was to explore the cost-effectiveness of glucosamine sulphate (GS) compared with paracetamol and placebo (PBO) in the treatment of knee osteoarthritis. For this purpose, a 6-month time horizon and a health care perspective was used. MATERIAL AND METHODS: The cost and effectiveness data were derived from Western Ontario and McMaster Universities Osteoarthritis Index data of the Glucosamine Unum In Die (once-a-day) Efficacy trial study by Herrero-Beaumont et al. Clinical effectiveness was converted into utility scores to allow for the computation of cost per quality-adjusted life year (QALY) For the three treatment arms Incremental Cost-Effectiveness Ratio were calculated and statistical uncertainty was explored using a bootstrap simulation. RESULTS: In terms of mean utility score at baseline, 3 and 6 months, no statistically significant difference was observed between the three groups. When considering the mean utility score changes from baseline to 3 and 6 months, no difference was observed in the first case but there was a statistically significant difference from baseline to 6 months with a p-value of 0.047. When comparing GS with paracetamol, the mean baseline incremental cost-effectiveness ratio (ICER) was dominant and the mean ICER after bootstrapping was -1376 euro/QALY indicating dominance (with 79% probability). When comparing GS with PBO, the mean baseline and after bootstrapping ICER were 3617.47 and 4285 euro/QALY, respectively. CONCLUSION: The results of the present cost-effectiveness analysis suggested that GS is a highly cost-effective therapy alternative compared with paracetamol and PBO to treat patients diagnosed with primary knee OA.

[Anti-fracture efficacy of intravenous ibandronate: how to translate epidemiological studies into daily clinical practice]. / Efficacité anti-fracturaire de l'ibandronate administré par voie intraveineuse: de la complexité des études épidémiologiques interventionnelles à la pratique quotidienne.

Numerous epidemiological approaches are used to demonstrate the efficacy of a new chemical entity. In postmenopausal osteoporosis, anti-fracture efficacy can be assessed through prospective, randomized controlled trials, meta-analyses or real-life setting studies. Intravenous ibandronate was recently marketed, with the aim of optimizing drug absorption and adherence to treatment. Furthermore, this new formulation avoids gastrointestinal side effects and constrains linked to the oral intake of the medication. Spinal anti-fracture efficacy of IV ibandronate derives from a non-inferiority bridging study, using surrogate endpoints, i.e., bone mineral density and biochemical markers of bone turnover, compared to the oral daily formulation, previously registered for the treatment of osteoporosis in Europe. Coherent results from two separate meta-analyses have suggested that the non-vertebral anti-fracture efficacy of IV ibandronate is similar to that observed with oral, daily and weekly bisphosphonates. Similarly, a recent real-life setting study, based on claims from an US database, suggests that hip fractures are reduced, with IV ibandronate, to the same extend as they are with oral bisphosphonates. Notwithstanding, those results should probably be confirmed in an European setting, before being extrapolated, in daily practice, to the Belgian population.

Impact of chondroitin sulphate on health utility in patients with knee osteoarthritis: towards economic analysis.

OBJECTIVES: The first objective was to assess the effect of the chondroitin 4 and 6 sulphate (CS) on health-related quality of life using utility values in patients with knee osteoarthritis (OA) during a 24-month treatment course. The second objective was, using these data, to conduct economic analyses. METHODS: Data from the STOPP study was used. This study was a randomised, double-blind, placebo (PL) -controlled trial of 2-year duration. In the STOPP study, authors assessed quality of life using the Western Ontario and McMaster Osteoarthritis Index (WOMAC). WOMAC scores were translated into Health Utility Index (HUI) scores using a specific formula. Incremental cost effectiveness ratio (ICER) was calculated taking into account the cost of CS and its effect on HUI scores, compared to PL. RESULTS: At baseline, the mean (SD) HUI scores were 0.59 (0.17), and 0.59 (0.18) for the PL and CS groups, respectively (p=0.31 between the two groups). The mean (SD) HUI scores changes from baseline to 6 months were 0.02 (0.02), and 0.05 (0.01) for the PL and CS groups, respectively (p=0.03). After 24 months of follow-up, HUI score increases by 0.04 (0.02) in the PL group and by 0.05 (0.02) in the CS group (p=0.37). Using the price bracket of CS in Europe, ICER assessment always resulted in a cost below €30,000 per QALY gained, after 6, 12 and 24 months of treatment. CONCLUSION: CS treatment increases health utilities in patients with knee OA compared to PL over the first 6 months of treatment. Economic evaluation based on these data suggests that CS treatment could be considered as cost-effective in patients with knee OA up to a period of 24 months. A limitation in this study is the absence of direct utility assessment as well as the absence of effective treatment as comparator.

[A FRAX model for the assessment of fracture probability in Belgium]. / Rationalisation du remboursement des médicaments de l'ostéoporose: de la mesure isolée de la densité osseuse i l'intégration des facteurs cliniques de risque fracturaire. Validation de l'algorithme FRAX.

The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities. Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck BMD. Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium. Fracture probability increased with age, lower BMI, decreasing BMD T-Score, and all clinical risk factors used alone or combined. The FRAX tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX model supports a shift from the current DXA based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.

[Non-hormonal treatments of postmenopausal osteoporosis]. / Traitements non hormonaux de l'ostéoporose postménopausique.

In the last decade, several medications have been registered and marketed in osteoporosis. They have demonstrated their antifracture efficacy. Subsequently, the clinical management of osteoporosis becomes more sophisticated and complex. Bisphosphonates (alendronate, risedronate, ibandronate, ibandronate and zoledronate) have demonstrated their efficacy on the axial and appendicular skeleton. On scientific grounds, it seems difficult to distinguish between them, in terms of efficacy and/or safety. A special interest should be focused on the optimisation of patients' adherence, which remains poor with the daily and weekly formulations. Raloxifene, a selective estrogen receptor modulator, has shown antifracture efficacy at the level of the lumbar spine and, also, exerts collateral benefits on the breast. The peptides from the parathyroid hormone family are simulators of bone formation. They showed antifracture efficacy at the axial and appendicular skeleton. Due to their prohibitive costs, their use should be restricted to patients with severe osteoporosis. Strontium ranelate, with its unique mode of action combining inhibition of bone resorption and stimulation of bone formation, is characterized by a wide scatter of activity, both in terms of skeletal sites positively affected and of patients experiencing benefits of its administration. Currently, it is the only drug which has shown an extensive anti-fracture efficacy in elderly subjects over 80 years old.

Prevalence of vitamin D inadequacy in European postmenopausal women.

OBJECTIVE: Inadequate vitamin D level is associated with secondary hyperparathyroidism and increased bone turnover and bone loss, which in turn increases fracture risk. The objective of this study is to assess the prevalence of inadequate serum vitamin D levels in postmenopausal European women. There are no clear international agreements on what constitutes a level of vitamin D inadequacy, but recent publications suggest that the circulating level of vitamin D should be over 80 nmol/L or at least between 50 and 80 nmol/L. MATERIAL AND METHODS: Assessment of 25-hydroxyvitamin D [25(OH)D] was performed in 8532 European postmenopausal women with osteoporosis or osteopenia. European countries included France, Belgium, Denmark, Italy, Poland, Hungary, United Kingdom, Spain and Germany. Two cut-offs of 25(OH)D inadequacy were fixed : < 80 nmol/L and < 50 nmol/L. RESULTS: Mean (SD) age of the patients was 74.2 (7.1) years, body mass index was 25.7 (4.1) kg/m(2). Level of 25(OH)D was 61.0 (27.2) nmol/L. There was a highly significant difference of 25(OH)D level across European countries (p < 0.0001). The lowest level of 25(OH)D was found in France [51.5 (26.1) nmol/L] and the highest in Spain [85.2 (33.3) nmol/L]. In the whole study population, the prevalence of 25(OH)D inadequacy was 79.6% and 32.1% when considering cut-offs of 80 and 50 nmol/L, respectively and when considering patients aged less than 65 years, the prevalence reached 86% (cut-off of 80 nmol/L) and 45% (cut-off of 50 nmol/L). CONCLUSION: This study indicates a high prevalence of vitamin D [25(OH)D] inadequacy in European postmenopausal women. The prevalence could be even higher in some particular countries. A greater awareness of the importance of vitamin D inadequacy is needed to address this public health problem.

Current role of glucosamine in the treatment of osteoarthritis.

OBJECTIVES: To evaluate the interest of using the various preparations of glucosamine for symptomatic and structural management of osteoarthritis (OA). METHODS: A critical analysis of the literature based on an exhaustive search (Medline, PubMed and manual search within the bibliography of retrieved manuscripts) from 1980 to 2005. RESULTS: Despite multiple controlled clinical trials of the use of glucosamine in OA (mainly of the knee), controversy on efficacy related to symptomatic improvement continues. Differences in results originate from the differences in products, study design and study populations. Symptomatic efficacy described in multiple studies performed with glucosamine sulphate (GS) support continued consideration in the OA therapeutic armamentarium. The most compelling evidence of a potential for inhibiting the progression of OA is also obtain with GS. CONCLUSIONS: GS has shown positive effects on symptomatic and structural outcomes of knee OA. These results should not be extrapolated to other glucosamine salts [hydrochloride or preparations (over-the-counter or food supplements)] in which no warranty exists about content, pharmacokinetics and pharmacodynamics of the tablets.

Strontium ranelate in the prevention of osteoporotic fractures.

Osteoporosis results from a decrease in bone strength yielding increased susceptibility to fractures. Hip and spine fractures are a major cause of morbidity and mortality in the elderly population. With an increasingly ageing world population, early prevention of bone loss is essential for adequate control of this condition. Strontium ranelate (PROTELOS((R))), an oral drug for postmenopausal osteoporosis, has been reported to decrease bone resorption and to stimulate bone formation. The efficacy in reducing vertebral fractures, non-vertebral including hip fractures, and the safety of strontium ranelate has been initially demonstrated over 3 years in the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (TReatment Of Peripheral OSteoporosis) studies and confirmed recently over up to 5 years. A preplanned analysis of a sub-group of patients aged 80 years and over showed that, currently, strontium ranelate is the only antiosteoporotic agent to reduce vertebral and non-vertebral fractures in this age group.