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.

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.

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.

[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.

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.

Quantification of dendritic cells and osteoclasts in the bone marrow of patients with monoclonal gammopathy.

The purpose of this study was to find histological clues for reliable differentiation between monoclonal gammopathy of undetermined significance (MGUS) and myeloma when clinical parameters are controversial. Differential appearance of dendritic cells and osteoclasts, two cell types developing from the monocytic lineage upon distinct cytokine activation profile, might be a useful approach. Bone and bone-marrow biopsies performed in 105 patients were studied using histomorphometry after identification of osteoclasts (by histochemical identification of tartrate resistant acid phosphatase) and dendritic cells (by immunohistochemical detection of the S-100 protein). Patients were classified by the World Health Organization criteria but histopathological criteria were more adapted to identify MGUS (53 cases), myeloma (46), B-cell lymphoma (six) since six myeloma were not correctly classified. Histomorphometry was compared to 15 control cases. The number of marrow dendritic cell was significantly increased with B-cell lymphoma >MGUS >myeloma > controls. Dendritic cell were often mixed with lymphoma cells. Myeloma had increased bone resorption with a high osteoclast number and moderate increase in dendritic cells. B-cell lymphomas had a considerable increase in dendritic cell but presented mononucleated osteoclasts. These findings can help in the classification of MGUS in the early stages of the disease and could help to propose preventive treatments.

Thyroxine therapy in euthyroid patients does not affect body composition or muscular function.

OBJECTIVE: The main objective of the study was to evaluate the effects of small increments in thyroxine (T4) levels following levothyroxine (L-T4) administration on the body composition of women patients. The secondary objective was to assess the effect of the therapy on energy expenditure and muscular function. METHODS: The prospective, randomized study consisted of a 12-month follow-up of 37 women with thyroid nodules. The patients were divided into two groups for comparison, one treated with L-T4 (20 women) and the other untreated (17 women). L-T4 dose was individually adjusted to obtain a serum thyroid-stimulating hormone in the lower portion of the normal range. Multiple tests, including bioelectrical impedance analysis, dual-energy X-ray absorptiometry, air displacement plethysmography, measurement of waist circumference, and skinfold anthropometry, were used to investigate the muscular, fat, and water compartments; energy expenditure and muscular function were assessed by cycle ergometry. RESULTS: There were no significant differences in body composition, heart rate, energy metabolism, or muscular function between the group of women treated with L-T4 and the untreated group. CONCLUSION: The controlled increase of circulating T4 does not appear to modify the body composition or muscular function in women patients.

Effects of risedronate in a rat model of osteopenia due to orchidectomy and disuse: densitometric, histomorphometric and microtomographic studies.

Dual energy X-ray absorptiometry (DXA), histomorphometry and X-ray microtomography (microCT) were used to assess effects of risedronate and testosterone in a combined rat model of orchidectomy (ORX) and local paralysis induced by botulinum neurotoxin (BTX). Four groups of mature rats were studied for 1 month: SHAM operated; ORX and right hindlimb immobilization (BTX); ORX+BTX+risedronate or testosterone. Changes in bone and body composition were measured by DXA (BMC, lean and fat mass), histomorphometry (BV/TV2D, Tb.Th and microarchitectural parameters) and microCT (BV/TV3D, SMI and cortical parameters). ORX and BTX had additive effects on bone loss since differences were maximized on the immobilized bone. The decrease in BMC on the tibial metaphysis reached -33.6% vs. -11.3% in the non-immobilized limb. BV/TV and Tb.N decreased and Tb.Sp increased in both hindlimbs whereas Tb.Th was significantly lower only in the immobilized limb. Decrease of tibial cortical area and thickness was greater in the immobilized limb. Risedronate prevented BMC, BV/TV and architecture loss but not reduction in Tb.Th. Cortical bone was preserved only in the non-immobilized limb. Testosterone was unable to prevent trabecular and cortical bone loss, but it prevents loss of whole body lean mass. In conclusion, ORX and BTX resulted in additive effects on bone loss. Risedronate had protective effects on trabecular bone loss but was less effective on cortical bone.

[Disc herniation-induced sciatica: medical or surgical treatment?]. / Conduite à tenir devant une lomboradiculalgie.

Radiculopathy is a common condition, characterized by a spontaneous regression: in 95 percent of patients, it resolves without surgery, within 1 to 12 months. To shorten the course of this disease, enable patients to resume social and professional activities and avoid chronicity, several therapeutic solutions have been assessed. Based on scientific evidence supporting effectiveness, physicians may prescribe analgesics, NSAID and epidural infiltrations, which probably relieve the pain and improve the quality of life without really modifying the mid-term prognosis. Following a specialized physical, social and professional assessment, surgery may be offered to patients who keep experiencing radicular (and not lumbar) pain. The complication rate is approximately 1 to 3 percent. The effectiveness of surgery is well established, especially with an improved recovery time (50 percent as compared to medical treatment). However, the superiority of a particular surgical technique has not been demonstrated. To date, we are still lacking evidence to demonstrate the effectiveness of percutaneous techniques in good methodological conditions. Finally, confinement to bed, cortisone administered per os or IV, localized spinal manipulations, corsets, vertebral tractions and physiotherapy have no demonstrated impact on the course of sciatica.

Paget's disease of bone in the French population: novel SQSTM1 mutations, functional analysis, and genotype-phenotype correlations.

UNLABELLED: Mutation screening of the SQSTM1 gene in 94 French patients with PDB revealed two novel point-mutations (A381V and L413F) and two new compound heterozygous genotypes (P392L/A381V and P392L/A390X). Functional analysis showed an increased level of SQSTM1/p62 protein in PDB patients and truncated forms of the protein encoded by the A390X allele. Clinical data indicate that PDB patients with SQSTM1 mutation are younger at PDB diagnosis and have more extensive bone lesions. INTRODUCTION: Paget's disease of bone (PDB) is a common chronic disease of the skeleton, with a strong genetic component. A recurrent mutation (P392L) was first identified on chromosome 5, in the Sequestosome 1 (SQSTM1) gene. Several other mutations of the SQSTM1 gene have been described in PDB patients, affecting the ubiquitin-associated domain (UBA) of the SQSTM1/p62 protein. The objectives of this study were to evaluate the frequency of the SQSTM1 mutations in French PBD patients, to study the expression of the SQSTM1/p62 protein, and to search for genotype-phenotype correlations. MATERIALS AND METHODS: Blood was obtained from 94 unrelated French PDB patients and 100 controls for mutation screening of exons 7 and 8, encoding for the UBA domain of SQSTM1. Epstein-Barr virus (EBV)-immortalized B-cell lymphocytes were established from 13 patients, giving access to functional analysis of the gene and the SQSTM1/p62 expressions using real-time PCR and Western blot. RESULTS: Mutations of the SQSTM1 gene were identified in 12 of the 94 PDB patients (13%). Eight patients carried P392L. Two novel missense mutations were identified: L413F and A381V. This A381V mutation and A390X were found in distinct patients already carriers of P392L. The SQSTM1/p62 protein expression in PDB patients increased when zero, one, or two mutations were present, and SQSTM1 truncated forms were associated with the A390X mutation. The mean age of PDB diagnosis was younger in patients with the SQSTM1 mutation. PDB was more extensive in patients who carried a SQSTM1 mutation. CONCLUSIONS: Mutations of SQSTM1 are present in the French population. PDB patients with and without the SQSTM1 mutation have an increased level of SQSTM1/p62, caused by overproduction of the protein, probably involved in the pathophysiology of PDB. The presence of the SQSTM1 mutation may be a worsening factor for PDB.

Trabecular bone microarchitecture is related to the number of risk factors and etiology in osteoporotic men.

Microarchitecture of trabecular bone is a very important component of bone quality in osteoporosis and a determinant of vertebral fracture in men with low bone mineral density (BMD). In contrast to women, male osteoporosis is, in most cases, secondary. The relationships between microarchitecture and different risk factors have never been evaluated in men. About 152 men with low BMD at the lumbar spine or hip (BMD, T-score < -2.5) were included in this study. Risk factors were: age, BMI, alcohol intake, corticosteroid therapy, hypogonadism, and chronic diseases. Transiliac bone biopsies were obtained and histomorphometry was done on an image analyzer; the following parameters were measured: cortical thickness (Ct.Th), trabecular bone volume (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp) and number (Tb.N), interconnectivity Index (ICI), star volume of the bone marrow, and strut analysis with node and free-end count. The 50 men with two risk factors had a lower BMD, lower Ct.Th and a significant higher star volume than those with one factor or idiopathic osteoporosis. The 26 men with at least three risk factors, had a lower BMD, a reduction of BV/TV and Ct.Th and a marked disorganization of the trabecular network (increased Tb.Sp, ICI, star volume, and free-end to free-end struts). The prevalence of vertebral fractures was higher in these patients. When the main risk factor was considered, a marked decrease in trabecular bone connectivity was observed in hypogonadic men. In osteoporotic men, higher the number of risk factors, lower the connectivity of trabecular network and higher the vertebral fracture risk.

Medullar fat influences texture analysis of trabecular microarchitecture on X-ray radiographs.

Alteration of trabecular architecture is a predictor of fracture risk in osteoporosis. Until now, microarchitecture analysis is difficult to evaluate in routine clinical practice for osteoporosis. Texture analysis on X-ray images has been advocated to be a suitable method to assess microarchitecture in bone diseases. The X-ray acquisition conditions have been often taken into consideration; however, the influence of anatomical conditions on texture parameters has received little interest. Because fat is a well-known problem with computed tomography and densitometry, we have designed a cadaver study to compare the influence of marrow lipids on numerous texture parameters. Twenty-one human distal radii were obtained, radiographed, and analyzed using a software that measures: heterogeneity, skeletonized parameters, run-lengths and fractal dimensions. Texture parameters were measured before, and after an extensive delipidation period lasting 3 weeks. Quality of the radiographs was improved after defatting. Delipidation had a very significant effect on measurements: afterwards defatting, the images were less blurred, and a better delineation of trabeculae and marrow cavities was obtained. This provoked an increase of parameters based on the grey level distribution but had no influence on parameters describing the reticulated honeycomb microarchitecture of the trabeculae (i.e., fractal dimension). Some parameters appeared anisotropy-sensitive, due to the different constitution and size of the trabeculae. The fat content of bone marrow induces noise that can modify some texture parameters. One should take into account the fat content of the marrow when using texture analysis to compare patients with osteoporosis due to various etiologies.

Drug combination strategies for osteoporosis.

Several medications are effective in reducing the incidence of osteoporotic fractures. Vertebral and nonvertebral fractures can be reduced by 30-65% by administering anticatabolic agents (e.g. raloxifene, alendronate, and risedronate) or anabolic agents (e.g. the active parathyroid hormone fragment teriparatide and strontium ranelate). These medications were investigated in placebo-controlled randomized trials in vast populations. Study extensions provided information on long-term efficacy and safety. However, the best strategy for using these medications in high-risk individuals remains unclear. For instance, the relative merits of starting with an anabolic agent or on an anticatabolic agent have not been compared. The patient's age, severity of the osteoporosis (bone mineral density and risk factor profile), specific characteristics of each medication, and patient preferences regarding drug-dosing modalities should be considered. Compliance must be evaluated regularly. Whereas minimal treatment durations have been determined, optimal durations remain incompletely evaluated and should be determined on a case-by-case basis according to the severity of the bone disease and to the treatment response in terms of clinical features and bone mineral density. Synchronous and t treatment combinations have been evaluated. Disappointing results were obtained with synchronous parathyroid hormone and bisphosphonate therapy. In contrast, the parathyroid hormone-bisphosphonate sequence holds promise for the treatment of severe postmenopausal osteoporosis with at least two vertebral fractures. However, little is known about potential synergies among medications in terms of fracture risk reduction. Synchronous and sequential regimens have not been compared in randomized clinical trials, and such trials would be extraordinarily difficult to design. Nevertheless, available data allow a number of suggestions regarding treatment strategies. The most important step is deciding to start effective treatment (raloxifene, bisphosphonate, teriparatide, or strontium ranelate) in patients at risk for fractures. Patients should be given detailed information on potential benefits and long-term treatment modalities.

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.

Comparison insight bone measurements by histomorphometry and microCT.

UNLABELLED: Morphometric analysis of 70 bone biopsies was done in parallel by microCT and histomorphometry. microCT provided higher results for trabecular thickness and separation because of the 3D shape of these anatomical objects. INTRODUCTION: Bone histomorphometry is used to explore the various metabolic bone diseases. The technique is done on microscopic 2D sections, and several methods have been proposed to extrapolate 2D measurements to the 3D dimension. X-ray microCT is a recently developed imaging tool to appreciate 3D architecture. Recently the use of 2D histomorphometric measurements have been shown to provide discordant results compared with 3D values obtained directly. MATERIAL AND METHODS: Seventy human bone biopsies were removed from patients presenting with metabolic bone diseases. Complete bone biopsies were examined by microCT. Bone volume (BV/TV), Tb.Th, and Tb.Sp were measured on the 3D models. Tb.Th and Tb.Sp were measured by a method based on the sphere algorithm. In addition, six images were resliced and transferred to an image analyzer: bone volume and trabecular characteristics were measured after thresholding of the images. Bone cores were embedded undecalcified; histological sections were prepared and measured by routine histomorphometric methods providing another set of values for bone volume and trabecular characteristics. Comparison between the different methods was done by using regression analysis, Bland-Altman, Passing-Bablock, and Mountain plots. RESULTS: Correlations between all parameters were highly significant, but microCT overestimated bone volume. The osteoid volume had no influence in this series. Overestimation may have been caused by a double threshold used in microCT, giving trabecular boundaries less well defined than on histological sections. Correlations between Tb.Th and Tb.Sp values obtained by 3D or 2D measurements were lower, and 3D analysis always overestimated thickness by approximately 50%. These increases could be attributed to the 3D shape of the object because the number of nodes and the size of the marrow cavities were correlated with 3D values. CONCLUSION: In clinical practice, microCT seems to be an interesting method providing reliable morphometric results in less time than conventional histomorphometry. The correlation coefficient is not sufficient to study the agreement between techniques in histomorphometry. The architectural descriptors are influenced by the algorithms used in 3D.

Recommendations for monitoring antiresorptive therapies in postmenopausal osteoporosis.

Antiresorptive agents are effective in preventing and treating postmenopausal osteoporosis, provided they are taken as directed. Regular physical examinations including height measurements may fail to ensure optimal compliance. Bone mineral density (BMD) measurement is indispensable for determining whether treatment is warranted. The measurement can be repeated after 2 years at least, provided quality-control procedures are adequate. BMD changes over time should be compared to the least significant change calculated from the in vivo BMD reproducibility at the measurement center. However, BMD changes are not correlated with the fracture risk reduction induced by antiresorptive treatment. Biochemical markers for bone turnover can be monitored after only 3-6 months provided steps are taken to control for intraindividual variability. They are useful when patient compliance is poor or the treatment response inadequate.

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.

Divergent effect of endogenous and exogenous sex steroids on the insulin-like growth factor I response to growth hormone in short normal adolescents.

The lower responsiveness to GH in women than in men is probably due to a divergent effect of gonadal steroids. It is unknown, however, how the progressive increase in sex steroid production that occurs during puberty affects this responsiveness. To compare the effects of puberty and sex steroid administration on responsiveness to GH, we used the IGF-I generation test, in which the peak IGF-I level 24 h after a single injection of GH (2 mg/m2) was studied in 117 healthy short subjects (56 females and 61 males). The subjects, aged 8-16 yr, were divided into four groups: prepuberty, early puberty, midpuberty, or pubertal delay. In the latter group, the IGF-I response was determined before and after priming with oral 17beta-estradiol in girls and im testosterone in boys. We also tested for an association between body composition (by dual energy x-ray absorptiometry) and the IGF-I response to GH. The IGF-I increment in response to GH (change in IGF-I from baseline) was correlated with the growth velocity sd score (P < 0.05). Progression throughout puberty was associated with an increase in both baseline IGF-I (P < 0.05) and the IGF-I increment in response to GH (P < 0.05), with no gender difference. Pubertal category (pre-, early, and midpuberty; P < 0.05) and fat percentage (P < 0.05) were the main positive predictors of the IGF-I increment in response to GH, expressed as micrograms per liter as well as sd score, independently of baseline IGF-I. After sex steroid priming, both the GH peak in response to insulin-induced hypoglycemia and baseline IGF-I were increased (P < 0.05, after vs. before sex steroid). However, the IGF-I increment in response to GH decreased after oral 17beta-estradiol (P < 0.05), whereas it was unchanged after testosterone administration. Endogenous gonadal steroid secretion appears to result in increased responsiveness to GH in peripubertal girls and boys. By contrast, exogenous estrogen and testosterone, respectively, produce a relative decrease and no change in responsiveness to GH in similar populations, possibly through the achievement of sex steroid concentrations exceeding physiological ranges for age. Fat percentage was a positive determinant of the responsiveness to GH, suggesting a link between the energy stores and the anabolic action of GH.

Comparison of pencil-, fan-, and cone-beam dual X-ray absorptiometers for evaluation of bone mineral content in excised rat bone.

The aim of the present study was to assess the reproducibility and accuracy of measurements done on excised rat bone with three different generations of densitometers: Hologic QDR2000 pencil beam, Hologic QDR4500 fan beam, and Lunar PIXImus cone beam. The coefficients of variation for repeated measurements of bone mineral content (BMC) were 0.62 and 0.85% for pencil beam, 1.73 and 3.59% for fan beam, and 0.70 and 1.52% for cone beam for femur and tibia, respectively. BMC and ash weight were linearly correlated: 0.998 for pencil, 0.984 for fan, and 0.995 for cone beam. However, the three densitometers overestimated BMC by 10.9, 12.6, and 3.1%, respectively, and the overestimation was found to be dependent on the net BMC. The highest coefficient of correlation was found between BMC measurements from pencil and cone beam (r = 0.995). Data from cone-beam DXA were, respectively, 8.8 and 9.2% lower than those from penciland fan-beam DXA. We conclude that the three DXA instruments precisely and accurately measure BMC in excised rat bone; however, DXA overestimates BMC with a dependence on the bone ash weight. This dependence was less pronounced with the cone-beam technology.