French law: what about a reasoned reimbursement of serum vitamin D assays?

The number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure <45 mL/min/1.73m2, any situation of malabsorption, clinical signs consistent with vitamin D deficiency or vitamin D overload, and calcium phosphorus evaluation. We suggest that the measurement of serum 25OHD concentration should remain reimbursed as part of these extended indications.

Bone mass and bone quality are altered by hypoactivity in the chicken.

Disuse induces a rapid bone loss in adults; sedentarity is now recognized as a risk factor for osteoporosis. Hypoactivity or confinement also decrease bone mass in adults but their effects are largely unknown and only few animal models have been described. We have used 10 chickens of the rapidly growing strain 857K bred in a large enclosure (FREE group); 10 others were confined in small cages with little space to move around (HYPO group). They were sacrificed at 53 days and femurs and tibias were evaluated by texture analysis, dual energy X-ray densitometry, microcomputed tomography (microCT) and histomorphometry. Hypoactivity had no effect on the length and diameter of the bones. Bone mineral density (BMD), microCT (trabecular bone volume and trabecular microarchitecture) and texture analysis were always found significantly reduced in the animals of the HYPO group. BMD was reduced at both femur and tibia diaphysises; BMD of the metaphysis was significantly reduced in the femur but not in the tibia. An increase in osteoid volume and surfaces was noted in the HYPO group. However, there was no alteration of the mineral phase as the osteoid thickness did not differ from control animals. Bone loss was much more pronounced at the lower femur metaphysis than at the upper metaphysis of the tibia. At the tibia, only microarchitectural changes of trabecular bone could be evidenced. The confined chicken represents a new method for the study of hypodynamia since these animals do not have surgical lesions.

Unwrapping microcomputed tomographic images for measuring cortical osteolytic lesions in the 5T2 murine model of myeloma treated by bisphosphonate.

Multiple myeloma is due to the proliferation of malignant plasma cells which increase the number of osteoclasts leading to trabecular and cortical bone osteolysis. The 5T2MM murine model reproduces the human disease and microcomputed tomography is a precise tool to investigate bone loss. Bisphosphonates (zoledronic acid or pamidronate) are used in preventing osteolysis. However, loss of cortical bone in not possible to quantify by histomorphometry on histological sections or microCT images. Osteolysis was studied in mice grafted with the 5THL subline to see if one drug was more active after 10 weeks. Mice were distributed into 4 groups: control, untreated, treated with pamidronate or with zoledronic acid. The left femurs were embedded undecalcified and sectioned at 7 µm. The right tibias and femurs were analyzed by microCT and trabecular morphometric parameters were obtained. Cortical bone osteolysis was analyzed by developing a new algorithm to unwrap microCT sections of the cortices, allowing measurement of the number of perforations, porosity and mean perforation area. The bisphosphonates had no significant effect on the tumor growth as evidence by the absence of effect on the M-protein level. Cortical perforations were evidenced on histological sections and their number seemed to be reduced by both bisphosphonates. MicroCT was used to quantify the trabecular bone: a bone loss was evidenced in the untreated myeloma group and both bisphosphonates appeared equal to preserve trabecular mass. However, the number and size of cortical perforations cannot be determined on 3D models. Unwrapping microCT images provided flat images allowing a precise determination of cortical perforations. Pamidronate did not reduce the number and size of cortical perforations but significantly reduced porosity. Zoledronic acid appeared significantly superior and considerably reduced all parameters. Unwrapping microCT image is a new method allowing the measurement of cortical perforations in bone malignancies, a parameter that cannot be measured correctly on 2D histological sections.

Usefulness of bone density measurement in fallers.

The objective of this systematic literature review is to discuss the latest French recommendation issued in 2012 that a fall within the past year should lead to bone mineral density (BMD) measurement using dual-energy X-ray absorptiometry (DXA). This recommendation rests on four facts. First, osteoporosis and fall risk are the two leading risk factors for nonvertebral fractures in postmenopausal women. Second, BMD measurement using DXA supplies significant information on the fracture risk independently from the fall risk. Thus, when a fall occurs, the fracture risk increases as BMD decreases. Third, osteoporosis drugs have been proven effective in preventing fractures only in populations with osteoporosis defined based on BMD criteria. Finally, the prevalence of osteoporosis is high in patients who fall and increases in the presence of markers for frailty (e.g., recurrent falls, sarcopenia [low muscle mass and strength], limited mobility, and weight loss), which are risk factors for both osteoporosis and falls. Nevertheless, life expectancy should be taken into account when assessing the appropriateness of DXA in fallers, as osteoporosis treatments require at least 12months to decrease the fracture risk. Another relevant factor is the availability of DXA, which may be limited due to geographic factors, patient dependency, or severe cognitive impairments, for instance. Studies are needed to better determine how the fall risk and frailty should be incorporated into the fracture risk evaluation based on BMD and the FRAX® tool.

Beneficial effects of a N-terminally modified GIP agonist on tissue-level bone material properties.

Bone remodeling is under complex regulation from nervous, hormonal and local signals, including gut hormones. Among the gut hormones, a role for the glucose-dependent insulinotropic polypeptide (GIP) has been suggested. However, the rapid degradation of GIP in the bloodstream by the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) precludes therapeutic use. To circumvent this problem, a series of N-terminally modified GIP agonists have been developed, with N-AcGIP being the most promising. The aims of the present study were to investigate the effects of N-AcGIP on bone at the micro-level using trabecular and cortical microstructural morphology, and at the tissue-level in rats. Copenhagen rats were randomly assigned into control or N-AcGIP-treated groups and received daily injection for 4 weeks. Bone microstructural morphology was assessed by microCT and dynamic histomorphometry and tissue-level properties by nanoindentation, qBEI and infra-red microscopy. Four week treatment with N-AcGIP did not alter trabecular or cortical microstructural morphology. In addition, no significant modifications of mechanical response and properties at the tissue-level were observed in trabecular bone. However, significant augmentations in maximum load (12%), hardness (14%), indentation modulus (13%) and dissipated energy (16%) were demonstrated in cortical bone. These beneficial modifications of mechanical properties at the tissue-level were associated with increased mineralization (22%) and collagen maturity (13%) of the bone matrix. Taken together, the results support a beneficial role of GIP, and particularly stable analogs such as N-AcGIP, on tissue material properties of bone.

Difficulties in the diagnosis of vertebral fracture in men: agreement between doctors.

UNLABELLED: The agreement for vertebral fracture (VF) diagnosis in men, between doctors is poor. OBJECTIVES: To assess the agreement for VF diagnosis, in men, on standard radiographs, between experts, before and after consensual workshop and establishing an algorithm. METHODS: The agreement between thirteen experimented rheumatologists has been calculated in thirty osteoporotic men. Then, the group discussed in a workshop and 28 other radiograph sets of osteoporotic men with follow-up radiographs and incident confirmed VF, have been reviewed. The experts identified and hierarchised 18 pathological features of vertebral deformation and established an algorithm of VF diagnosis. Eleven experts have realized a second reading of the first set of radiographs. We compared the agreement between the 2 readings without and with the algorithm. RESULTS: After consensus and the use of the algorithm the results are: number of fractured patients (with at least 1 VF) according to the experts varies from 13 to 26 patients out of 30 (13 to 28 during the first reading). The agreement between the experts at the patient level is 75% (70% at the first reading). Among the 390 vertebrae analyzed by the experts, the number of VF detected varies from 18 to 59 (18 to 98 at the first reading). The agreement between the experts at the vertebral level is 92% (89% at the first reading). The algorithm allows a good improvement of the agreement, especially for 8 of the 11 experts. Discrepancies for the VF diagnosis between experts exist. The algorithm improves the agreement.

Is androgen therapy indicated in men with osteoporosis?

Male osteoporosis is not rare, and its management is a public health issue. The clinical evaluation must include investigations for one or more etiological factors such as hypogonadism, which is found in 5% to 15% of men with osteoporosis. Gradual development of moderate hypogonadism is the most common situation, and the prevalence of hypogonadism increases with advancing age. The wealth of scientific data establishing a major role for sex hormones in growth, bone turnover, and the osteoporotic fracture risk is in striking contrast to the paucity of therapeutic trials. Androgen therapy did not consistently produce bone mass gains, and no data on potential anti-fracture effects are available. Androgen therapy was not associated with significant increases in mortality, prostate disorders, or cardiovascular events, but few data were obtained in patients older than 75 years. In practice, in a male patient with osteoporosis, a diagnosis of marked and persistent hypogonadism requires investigations for treatable causes. In patients younger than 75 years of age, androgen replacement therapy should be started, in collaboration with an endocrinologist. A history of fractures indicates a need for additional osteoporosis pharmacotherapy. The risk/benefit ratio of androgen therapy is unclear in men older than 75 years, in whom a reasonable option consists in combining fall-prevention measures, vitamin D supplementation, and a medication proven to decrease the risk of proximal femoral fractures.

Glucocorticoids reduce alveolar and trabecular bone in mice.

UNLABELLED: Glucocorticoid (GC) treatment is the main cause of secondary osteoporosis. There are some controversies about the relationships between alveolar bone loss and bone loss at the appendicular and axial skeleton. OBJECTIVE: To assess, in parallel, the effects of GCs on alveolar bone and on the tibia in a mice model. METHODS: Five-month-old male Swiss-Webster mice were randomized into two groups. Pellets releasing 5 mg/kg/day of prednisolone or control pellets were subcutaneously implanted for 28 days. After euthanasia, the right tibia and the right hemimandible of each mouse were analyzed by histomorphometry and microcomputed tomography. Alveolar bone consists of a thin slab between the incisor and the molar roots connected with the alveolar processes. A 2D-frontal section was done through the pulp chamber of the first molar and was used to measure the thickness of the alveolar bone slab. A 2D-sagittal section was done through the pulp chamber of the three molars and was used to measure bone volume in the alveolar processes. RESULTS: At day 28, thickness and bone volume of alveolar bone were significantly decreased in the GC group (P<0.05). At the tibia, GCs decreased bone formation with a reduced mineral apposition rate and bone formation rate and a significant decrease in BV/TV and Tb.Th (P<0.05). CONCLUSION: Although the amount of alveolar bone is very low in the mouse, this study shows that GCs can induce an alveolar bone loss in long-term treated animals.

IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation.

Interleukin-26 (IL-26), a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn's disease, suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin(+) fibroblast-like synoviocytes and CD68(+) macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20). Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t(+) Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R(-) or CCR6(-) CD161(-)) CD4(+) memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and chronic inflammatory disorders.

2012 update of French guidelines for the pharmacological treatment of postmenopausal osteoporosis.

OBJECTIVES: To update the evidence-based position statement published by the French National Authority for Health (HAS) in 2006 regarding the pharmacological treatment of postmenopausal osteoporosis, under the auspices of the French Society for Rheumatology and Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO), and with the participation of several learned societies (Collège National des Gynécologues et Obstétriciens Français, Groupe d'Étude de la Ménopause et du Vieillissement hormonal, Société Française de Chirurgie Orthopédique, Société Française d'Endocrinologie, and Société Française de Gériatrie et de Gérontologie). METHODS: A multidisciplinary panel representing the spectrum of clinical specialties involved in managing patients with postmenopausal osteoporosis developed updated recommendations based on a systematic literature review conducted according to the method advocated by the HAS. RESULTS: The updated recommendations underline the need for osteoporosis pharmacotherapy in women with a history of severe osteoporotic fracture. In these patients, any osteoporosis medication can be used; however, zoledronic acid is the preferred first-line medication after a hip fracture. In patients with non-severe fractures or no fractures, the appropriateness of osteoporosis pharmacotherapy depends on the bone mineral density and FRAX(®) values; any osteoporosis medication can be used, but raloxifene and ibandronate should be reserved for patients at low risk for peripheral fractures. Initially, osteoporosis pharmacotherapy should be prescribed for 5 years. The results of the evaluation done at the end of the 5-year period determine whether further treatment is in order. CONCLUSIONS: These updated recommendations are intended to provide clinicians with clarifications about the pharmacological treatment of osteoporosis.

[Osteoporosis in men]. / Ostéoporose chez l'homme.

Epidemiologic studies have shown that 25% of osteoporotic fractures occur in men. Their prognosis is poor with one third of deaths in the year following the proximal femur fracture. Screening is based on the analysis of risk factors (prolonged corticosteroid therapy, anti androgen, smoking or alcohol abuse, liver disease or chronic inflammatory diseases), taking into account fracture history and bone density measurement. The prescription of bisphosphonates or teriparatide must be preceded by an etiologic investigation, a withdrawal of bone loss-induced drugs (tobacco, alcohol, steroids), a recovery of walking and a specific action on fall risk, especially after 70 years.

Is transiliac bone biopsy a painful procedure?

Despite an increased availability of non-invasive procedures to assess bone mass, histological examination of undecalcified transiliac bone biopsies remains a very valuable tool in the diagnosis of metabolic or malignant bone disorders. Nonetheless, clinicians are sometimes reluctant to perform this "invasive" examination, arguing that it might be a painful procedure. The aim of our study was to evaluate pain and anxiety described by patients in the months following the biopsy and to characterize potential early or late side effects. A single interviewer conducted a phone survey (19 items questionnaire) in 117 patients in whom a bone biopsy had been performed by two experienced physicians, with the same material and similar anesthetic and technical procedure. The topics covered pain during or after the biopsy, anxiety, comparison of other potentially painful procedures, early or late side effects as well as global evaluation by the patients. Bone biopsy was judged as non-painful by almost 70% of patients; some discomfort was present in 25% in the following days. The procedure was described as similar as or less painful than bone marrow aspiration, venipuncture or tooth extraction. About 90% of the patients estimated that it was a quite bearable diagnostic procedure. Side effects were not serious. About 7% remembered a vasovagal episode, 47% of local bruising in the following days. There was no report of hematoma or infection. In experienced hands and adapted trephine, transiliac bone biopsy is a safe procedure that brings invaluable information in bone disorders.

Epidemiogenetic study of French families with Paget's disease of bone.

OBJECTIVE: To search for association with environmental factors and to determine SQSTM1/p62 mutations prevalence in French families with Paget's disease of bone (PDB). METHODS: Unrelated patients with a confirmed diagnosis of PDB were recruited in three Rheumatology departments and informed consent obtained. First- and second-degree relatives of each index case had a physical examination, blood taken for DNA extraction and biochemical measurements, and a whole-body bone scan. Exons 7 and 8 and exon-intron boundaries of SQSTM1/p62 (p62) gene were PCR-amplified before sequencing. Haplotype carriers of the p62(P392L) mutation were determined. Comparisons between PDB patients and healthy relatives were performed. RESULTS: We investigated 18 families consisting of 83 individuals: 20 patients with known PDB, three relatives with newly-diagnosed PDB and 60 healthy relatives. Index cases and/or relatives with Dupuytren's disease were found in eight (44.4%) out of the 18 families. Forty-three percent of PDB patients were former or current tobacco users versus 18% of healthy relatives (P=0.02; OR=3.37 (1.04-11.09)). Five index cases (27.8%) were carriers of SQSTM1/p62 mutations: three p62(P392L) mutations, one p62(P392L/A390X) double mutation and one p62(A390X) mutation. The p62(P392L) mutation was carried by haplotype 2 in all four index cases. CONCLUSION: Accurate phenotypic assessment of PDB patients' relatives allowed for diagnosing PDB in three asymptomatic relatives. There was evidence for an aggregation of Dupuytren's disease in PDB families (not associated with SQSTM1/p62 mutation), and for an association between PDB and tobacco use. Half of PDB familial forms carried a SQSTM1/p62 mutation, p62(P392L) mutation being the most frequent.

Evaluation of the bone status in high-level cyclists.

The purpose of this study was to evaluate the bone status in highly trained professional cyclists subjected to regular training and tough competitions. Bone mineral density (BMD) was measured at different regions of interest by dual-energy X-ray absorptiometry, and main biological parameters related to bone metabolism were obtained in 29 cyclists. Lumbar BMD was 0.94 ± 0.01g/cm(2) (Z-score=-1.28 ± 0.07), and 1 cyclist out of 4 had an abnormally low value (Z-score <-2). The mean Z-score at the total femoral site was -1.22 ± 0.21, and 45% of athletes had an Z-score of <-2. All femoral neck BMD values were within normal boundaries. The lowest BMD Z-score was measured at the midradius or 1/3 proximal site with a mean Z-score of -1.77 ± 0.78, but only 3 cyclists (15%) had Z-scores <-2. Biochemical parameters of bone formation (serum osteocalcin and alkaline phosphatase) were normal. Three cyclists had low 25-hydroxyvitamin D levels. Blood testosterone and thyroid stimulating hormone were in the normal range. Insulin-like growth factor 1 levels were in the normal range; however, a significant inverse correlation was found with lumbar BMD (r=0.495; p=0.003). We confirm that cycling has no positive effect on BMD, BMD being often lower than in normal controls at the lumbar site; femoral BMD is less concerned. The absence of beneficial changes at the spine can be explained by biomechanical conditions related to the cyclists' position, reducing loading strains. It is necessary to pay greater attention to the bone status of high-level athletes to prevent an increased risk of fractures.

Influence of vertebral fracture assessment by dual-energy X-ray absorptiometry on decision-making in osteoporosis: a structured vignette survey.

OBJECTIVE: Vertebral fracture assessment (VFA) is a radiographic method using DXA to diagnose vertebral fractures, validated for reproducibility, sensitivity and specificity as compared with spine radiographs. This study was designed to assess the impact of VFA results on decision-marking in osteoporosis, using a clinical vignette-based approach. METHODS: Twenty-nine rheumatologists provided data on post-menopausal women consulting for BMD measurement: clinical risk factors for osteoporosis, clinical characteristics of patients, BMD, T-score and VFA images. Standardized clinical vignettes were generated from these patients, and each rheumatologist assessed five vignettes assigned at random, in two distinct steps: first step without and second step with VFA data. At each step, they had to answer questions about the prescription of radiographs and treatments, using a yes/no format. RESULTS: A total of 117 vignettes were available [117 patients: mean age 65.1 (10.1) years, lumbar spine T-score: -1.64 (0.92)], 36.7% with a personal history of fracture. Rheumatologists intended to prescribe radiographs in 62.4 and 46.2% cases (P = 0.0206) before and after VFA results, respectively; a change occurred in 36.8% of patients, i.e. a de novo prescription of radiographs in 12 patients, and a deleted prescription in 31 patients. VFA data induced a therapeutic change for 30.8% of patients. CONCLUSION: This study shows that VFA results influence patient management, both for radiographs and treatment prescriptions.

[Prevalence of osteoporosis in male patients with risk factors]. / Identification par l'analyse des facteurs cliniques de risque et la densitométrie osseuse des hommes à risque d'ostéoporose.

UNLABELLED: Male osteoporosis is often secondary to other conditions. However the causes of osteoporosis in men are dramatically variable according to the authors. The aim of this observational multicenter study was to assess the main risk factors and causes for male patients with low bone mineral density (LBM). METHODS: The study was performed in a cohort of rheumatologists who usually prescribe bone mineral density assessment according to HAS criteria (one or more criteria) for bone mineral density (BMD) measurement as defined by: (a): vertebral fracture; (b): non traumatic non vertebral fracture; (c): corticosteroid therapy; (d): hypogonadism or GnRH agonist therapy; (e): endocrine disorders; (f): osteogenesis imperfecta (OI). BMD was measured by dual photon absorptiometry (DXA) at lumbar spine, femoral or total neck sites. Osteoporosis was defined as a T-score value less or equal to 2.5 at one of those region of interest (ROI); LBM as a T-score value between -1 and -2.5. RESULTS: A total of 431 rheumatologists included 1198 male patients (66.6 ± 12.2 years). According to DXA results, 888 patients (74.1 %) had osteoporosis and 231 (19.3 %) had osteopenia. BMD was considered as normal for 79 patients (6.6 %). A total of 1146 patients (95.7 %) satisfied to the criteria of reimbursement of DXA measurement. Six hundred and eighty-six patients (57.3 %) had suffered from vertebral fractures and 349 patients (29.2 %) from non vertebral fractures. Corticosteroids had been prescribed in 28.7 % of patients and 6.6 % were treated with GnRH agonists for prostate cancer. Hypogonadism was diagnosed in 27 %. Five patients suffered from OI. Other risk factors were detected: alcoholism and smoking in 28.1 % and 42.9 % respectively; rheumatoid arthritis or spondylarthropathy in 12.5 % of patients; chronic pulmonary disorders in 16.1 %. By contrast endocrinopathies were rare (2.5 %). Several risk factors were more frequently encountered for patients with osteoporosis as compared with osteopenia, i.e., smoking, alcohol abuse, low calcium intake, vitamin D insufficiency and maternal history of hip fracture. CONCLUSION: A diagnosis of osteoporosis (BMD ≤ 2.5) was established by rheumatologists in 74.1 % of patients with clinical risk factors: LBM was found in 93.4 %. In 95.7 % the criteria for reimbursement of DXA measurement were satisfied. DXA is useful in male patients with classical risk factors of osteoporosis to confirm the diagnosis of the disease and start a treatment.

What do we know about atypical femoral fractures? Insights and enigmas.

Although the existence of atypical femoral fractures is well established and bisphosphonate therapy is thought to be a major risk factor, the underlying mechanisms are poorly understood. Epidemiological data show that atypical femoral fractures account for only a small proportion of diaphyseal subtrochanteric femoral fractures, being about 100 times less common than proximal femoral fractures. Consequently, the existence of atypical femoral fractures does not call into question the extremely favorable risk/benefit ratio of bisphosphonate therapy in patients with osteoporosis. Clearly, the number of fractures prevented by bisphosphonate therapy far exceeds the number of atypical femoral fractures potentially related to bisphosphonates.

Extraskeletal effects of vitamin D: facts, uncertainties, and controversies.

Vitamin D was long viewed as a hormone acting chiefly to regulate calcium-phosphate metabolism and bone mineralization. Over the last decade, however, basic science and clinical researchers have produced a bewildering amount of information on the extraskeletal effects of vitamin D. This article is a review of the clinical and biological actions of vitamin D including effects on the immune system, auto-immune diseases, infections, cancer, metabolic syndrome, fall risk, cognitive function, and muscle function.