[Which adjuvant measures should be associated with long-term oral corticosteroid therapy in inflammatory diseases? A summary of existing French recommendations]. / Quelles mesures adjuvantes associer à une corticothérapie orale prolongée dans le cadre des maladies inflammatoires ? Synthèse des recommandations françaises disponibles.

It is common to initiate a long-term corticosteroid therapy for inflammatory diseases. Various specialists are involved in this prescription, and associated measures to prevent side effects are not consensual, with the exception of osteoporosis. The specialty of the prescriber has indeed a significant impact on the attention paid to the adjuvant associated measures. The aim of this review was to draw a summary of the side effects of long-term corticosteroid therapy and of the existing recommendations related to associated measures to prevent them. Unfortunately, it is difficult to give clear recommendations because of the lack of evidence in some fields, especially as they should be adapted to patient's age and comorbidities. We propose a summary table of associated measures to long-term steroid therapy prescription and suggest a monitoring frequency.

Bone lesions in systemic mastocytosis: Bone histomorphometry and histopathological mechanisms.

Osteoporosis is considered the most frequent skeletal manifestation of systemic mastocytosis (SM). We performed a retrospective analysis of sixty patients (37 males and 23 females) who underwent a bone biopsy in the assessment of SM or in the assessment of unexplained bone fragility. Thirty-three had simultaneously a bone marrow biopsy with a Jamshidi's needle; this sample was used for immunohistochemical analysis (tryptase, c-KIT. CD20, VCAM-1). Bone biopsy was realized in 42 cases in the assessment of SM to provide histologic proof of the disease and in 18 cases in the assessment of unexplained bone fragility and surprisingly revealed a SM. An increased bone turnover was observed in patients with SM with elevated eroded surfaces, osteoclast number and bone formation rate. In addition to nodules of mast cells (MC), a high number of MC was directly apposed on the trabeculae, affixed on the osteoblasts or the lining cells. The VCAM-1 adhesion protein recognizing α4ß7 and α4ß1 integrins may be a candidate to explain this particular adherence. One third of the bone marrow biopsies did not exhibit MC nodules or MC infiltration and led to a false negative diagnosis for SM. SM can be discovered in the assessment of fracture or osteoporosis. Transiliac bone biopsy allows for the diagnosis of the disease more accurately than bone marrow biopsy; it also provides a histomorphometric analysis of bone remodeling.

GLP-2 administration in ovariectomized mice enhances collagen maturity but did not improve bone strength.

Osteoporosis and bone fragility are progressing worldwide. Previous published literature reported a possible beneficial role of gut hormones, and especially glucagon-like peptide-2 (GLP-2), in modulating bone remodeling. As now (Gly2)GLP-2 is approved in the treatment of short bowel syndrome, we thought to investigate whether such molecule could be beneficial in bone fragility. MC3T3 and Raw 264.7 were cultured in presence of ascending concentrations of (Gly2)GLP-2. Collagen crosslinks, maturity, lysyl oxidase activity and osteoclastogenesis were then analyzed. Furthermore, (Gly2)GLP-2, at the clinical approved dose of 50 µg/kg/day, was also administered to ovariectomized Balb/c mice for 8 weeks. Hundred µg/kg zoledronic acid (once iv) was also used as a positive comparator. Bone strength, microarchitectures and bone tissue composition were analyzed by 3-point bending, compression test, microCT and Fourier transform infrared imaging, respectively. In vitro, (Gly2)GLP-2 was potent in enhancing bone matrix gene expression but also to dose-dependently enhanced collagen maturation and post-processing. (Gly2)GLP-2 was also capable of reducing dose-dependently the number of newly generated osteoclasts. However, in vivo, (Gly2)GLP-2 was not capable of improving neither bone strength, at the femur diaphysis or lumbar vertebrae, nor bone microarchitecture. On the other hand, at the tissue material level, (Gly2)GLP-2 significantly enhances collagen maturity and reduce phosphate/amide ratio. Overall, this study highlights that despite modification of bone tissue composition, (Gly2)GLP-2, at the clinical approved dose of 50 µg/kg/day, did not provide real beneficial effects in improving bone strength in a mouse model of bone fragility. Further studies are recommended to validate the best dose and regimen of administration to significantly enhance bone strength.

Osteoporosis treatment and 10 years' oestrogen receptor+ breast cancer outcome in postmenopausal women treated with aromatase inhibitors.

BACKGROUND: Risk factors for breast cancer relapse are well-known, such as large tumour size or lymph node involvement. The aim of our study was to analyse the influence of bone mineral density, fractures and bisphosphonate or vitamin D prescription on 10 years' breast cancer outcome. PATIENTS AND METHODS: This is a longitudinal and prospective cohort of 450 postmenopausal women with local oestrogen receptor (ER)+ breast cancer. For every patient, we analysed tumour characteristics, bone status at the beginning of aromatase inhibitor treatment and 10 years' cancer outcome with Cox model. RESULTS: Mean follow-up was 10.3 ± 3.0 years. Seventy nine women died, and 75 had a relapse; 30.7% had a history of fracture, 16.9% had a T-score ≤ -2.5 and 11.3% had vitamin D deficiency. Bisphosphonates were prescribed to 35.3% women for osteoporosis for a mean duration of 5 ± 1.7 years. Tumour size (hazard ratio [HR] = 1.32, P ≤ 0.01) and the number of lymph nodes involved (HR = 1.07, P = 0.03) were significantly associated with relapse. Bisphosphonate treatment was significantly associated with a decreased risk of relapse (HR = 0.51, P = 0.03). Age at cancer diagnosis (HR = 1.07, P ≤ 0.01) and vitamin D deficiency (HR = 1.85, P = 0.04) were significantly associated with an increased risk of death, whereas bisphosphonate treatment was associated with a decreased risk of death (HR = 0.46, P = 0.01). CONCLUSION: Osteoporosis treatment, including vitamin D and bisphosphonates, is associated with a 50% reduction of relapse and death in women treated with aromatase inhibitors for ER+ breast cancer.

Osteoporosis in Stickler syndrome. A new family case with bone histology study.

The Stickler syndrome (SS) has been described as a "hereditary progressive arthro-ophtalmopathy" by Stickler in 1965, due to mutations on the collagen genes. Currently about 40 different genes have been identified which encode for at least 27 different collagens. The majority of mutations occur in the COL2A1 gene on chromosome 12q13 (SS type I). Mutations in COL11A1 are less frequent (SS type II). More recently, mutations in COL11A2 and in the COL9A1 gene have been reported with particular phenotypes. The main features of this autosomal inherited disease are ocular, auditory with orofacial abnormalities and early-onset osteoarthritis. We report the clinical presentation of an adult and his son, with a particular focus on the bone status of the father, radiography, bone densitometry and transiliac bone biopsy showing that he was suffering from osteoporosis. The lumbar bone mineral density was low with a Z-score at -2.9. Transiliac bone biopsy showed a dramatic decrease of trabecular bone volume (8.6%; Nl: 19.5±4.9%), thin trabeculae and a disorganized trabecular network. A slight increase of osteoid parameters was observed. Bone resorption was markedly increased with an excessive number of active (TRAcP+) osteoclasts. The cortical width was normal, but a slight increase of cortical porosity was found. Osteoporosis has been rarely described in the SS. It might be useful to systematically perform a bone densitometry in all patients with SS and to discuss the indication of a transiliac bone biopsy in severe cases.

Cerebral toxoplasmosis and anti-TNFα: a case report.

We report a case that documents the second known patient treated by anti-TNFα who has been diagnosed a cerebral toxoplasmosis.

Fibrodysplasia ossificans progressiva. A case report and focus on the BMP signaling pathway.

Fibrodysplasia ossificans progressiva is a very rare heritable disease characterized by a progressive heterotopic endochondal ossification, occurring in the first decade of life, and leading thereafter to a severe ankylosis of the spine, limbs and jaw, with a progressive and severe functional disability. To date the cause of the disease remains unknown and no medical treatment has been proved efficient. It has recently been shown that a recurrent mutation in activation domain of the activin-receptor IA (ACVR1), a BMP receptor, could lead to an abnormal signalling pathway of BMP-4 and contribute to the occurrence of the devastating lesions characteristic of the disease.

Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance.

Monoclonal gammopathies of undetermined significance (MGUS) have been shown to be associated with an increased risk of fractures. This study describes prospectively the bone status of MGUS patients and determines the factors associated with vertebral fracture. We included prospectively 201 patients with MGUS, incidentally discovered, and with no known history of osteoporosis: mean age 66.6±12.5 years, 48.3% women, 51.7% immunoglobulin G (IgG), 33.3% IgM and 10.4% IgA. Light chain was kappa in 64.2% patients. All patients had spinal radiographs and bone mineral density measurement in addition to gammopathy assessment. At least one prevalent non-traumatic vertebral fracture was discovered in 18.4% patients and equally distributed between men and women. Fractured patients were older, had a lower bone density and had also more frequently a lambda light chain isotype. Compared with patients with κ light chain, the odds ratio of being fractured for patients with λ light chain was 4.32 (95% confidence interval 1.80-11.16; P=0.002). These results suggest a high prevalence of non-traumatic vertebral fractures in MGUS associated with lambda light chain isotype and not only explained by low bone density.

Elevated hepatocyte growth factor levels in osteoarthritis osteoblasts contribute to their altered response to bone morphogenetic protein-2 and reduced mineralization capacity.

PURPOSE: Clinical and in vitro studies suggest that subchondral bone sclerosis due to abnormal osteoblasts is involved in the progression of osteoarthritis (OA). Human osteoblasts isolated from sclerotic subchondral OA bone tissue show an altered phenotype, a decreased canonical Wnt/ß-catenin pathway, and a reduced mineralization in vitro as well as in vivo. These alterations were linked with an abnormal response to BMP-2. OA osteoblasts release factors such as the hepatocyte growth factor (HGF) that contribute to cartilage loss whereas chondrocytes do not express HGF. HGF can stimulate BMP-2 expression in human osteoblasts, however, the role of HGF and its effect in OA osteoblasts remains unknown. Here we investigated whether elevated endogenous HGF levels in OA osteoblasts are responsible for their altered response to BMP-2. METHODS: We prepared primary human subchondral osteoblasts using the sclerotic medial portion of the tibial plateaus of OA patients undergoing total knee arthroplasty, or from tibial plateaus of normal individuals obtained at autopsy. The expression of HGF was evaluated by qRT-PCR and the protein production by western blot analysis. HGF expression was reduced with siRNA technique whereas its activity was inhibited using the selective inhibitor PHA665752. Alkaline phosphatase activity (ALPase) and osteocalcin release were measured by substrate hydrolysis and EIA respectively. Canonical Wnt/ß-catenin signaling (cWnt) was evaluated both by target gene expression using the TOPflash TCF/lef luciferase reporter assay and western blot analysis of ß-catenin levels in response to Wnt3a stimulation. Mineralization in response to BMP-2 was evaluated by alizarin red staining. RESULTS: The expression of HGF was increased in OA osteoblasts compared to normal osteoblasts and was maintained during their in vitro differentiation. OA osteoblasts released more HGF than normal osteoblasts as assessed by western blot analysis. HGF stimulated the expression of TGF-ß1. BMP-2 dose-dependently (1 to 100 ng/ml) stimulated both ALPase and osteocalcin in normal osteoblasts whereas, it inhibited them in OA osteoblasts. HGF-siRNA treatments reversed this response in OA osteoblasts and restored the BMP-2 response. cWnt is reduced in OA osteoblasts compared to normal, and HGF-siRNA treatments increased cWnt in OA osteoblasts almost to normal. Smad1/5/8 phosphorylation in response to BMP-2, which is reduced in OA osteoblasts, was corrected when these cells were treated with PHA665752. The BMP-2-dependent mineralization of OA osteoblasts, which is also reduced compared to normal, was only partially restored by PHA665752 treatment whereas 28 days treatment with HGF reduced the mineralization of normal osteoblasts. CONCLUSION: OA osteoblasts expressed more HGF than normal osteoblasts. Increased endogenous HGF production in OA osteoblasts stimulated the expression of TGF-ß1 and reduced their response to BMP-2. Inhibiting HGF expression or HGF signaling restored the response to BMP-2 and Smad1/5/8 signaling. In addition, decreased HGF signaling partly corrects the abnormal mineralization of OA osteoblasts while increased HGF prevents the normal mineralization of normal osteoblasts. In summary, we hypothesize that sustained elevated HGF levels in OA osteoblasts drive their abnormal phenotype and is implicated in OA pathophysiology.

Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.

UNLABELLED: A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Fracture incidence after 3 years of aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: A prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates. RESULTS: Among 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment. CONCLUSION: This real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women.

Trabecular microarchitecture in established osteoporosis: relationship between vertebrae, distal radius and calcaneus by X-ray imaging texture analysis.

INTRODUCTION: Osteoporosis is an alteration of bone mass and microarchitecture leading to an increased risk of fractures. A radiograph is a 2D projection of the 3D bone network exposing a texture, that can be assessed by texture analysis. We compared the trabecular microarchitecture of the spine, radius and calcaneus in a series of osteoporotic cadavers. MATERIALS AND METHODS: Thirty-four cadavers (11 men, 23 women), mean age 85.2±2.1years, were radiographed from T4 to L5 to identify those with vertebral fractures (FV). Non-fractured vertebrae (NFV), radius and calcaneus were taken and analyzed by densitometry, radiography and texture analysis under run-length, skeletonization of the trabeculae, and fractal geometry. RESULTS: Six subjects (five women, one man) were selected, mean age 82.5±5.5years. Twelve calcanei and 10 radii were taken. Two radii were excluded. The texture of NFV was significantly correlated (P<0.01) with that of the radius for horizontal run-lengths. No relationship between the texture of NFV and calcaneus was found. DISCUSSION: In the horizontal direction (perpendicular to the stress lines), the microarchitecture of NFV and radius showed a disappearance of the transverse rods anchoring the plates. Due to its particular microarchitecture, the calcaneus is not representative of the vertebral status. CONCLUSION: Bone densitometry provides no information about microarchitecture. Texture analysis of X-ray images of the radius would be a minimally invasive tool, providing an early detection of microarchitectural alterations. LEVEL OF EVIDENCE: IV retrospective study.

Micro and macroarchitectural changes at the tibia after botulinum toxin injection in the growing rat.

The aim of this study was to analyze bone microarchitecture and macroarchitecture of tibia in a disuse model in growing rats. Eight-weeks-old Copenhagen rats were injected intramuscularly with 1.5 units BTX in the quadriceps muscle of the right hind limb. Saline injection was done at the left hind limb to serve as control. Five rats were killed at day 1 and represented the baseline group (D1), 5 rats were killed at day 14 (D14), 5 at day 21 (D21), 5 at day 28 (D28) and 5 at day 35 (35). For each group, muscle surface, parameters of bone microarchitecture and macroarchitecture (including length, width and curvature of the tibia) were measured using microtomography. Paralysis occurred as soon as day 2. At the left hind limb, muscle surface area, cortical thickness, cross sectional total area and growth in length significantly increased during the time study. At the right hind limb, muscle surface area, bone trabecular volume, and cortical thickness decreased as soon as day 14 associated with an increased cortical porosity. Growth in length did not differ from left side; cross sectional total area did not increase and the diaphyseal cross section acquired a more rounded shape. There was no modification of the curvature between right and left hind limbs during the time study. In this murine model of unilateral muscle paralysis in growing animals, we showed a rapid muscle loss leading to a decreased growth in width; however growth in length and curvature were unaltered.

High prevalence of vertebral fractures in women with breast cancer starting aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe bone status in a large cohort of postmenopausal women with nonmetastatic breast cancer, at the initiation of aromatase inhibitor therapy. PATIENTS AND METHODS: A prospective, transversal and clinical study was conducted. Each woman had an extensive medical history, a biological evaluation, a bone mineral density (BMD) measurement and spinal X-rays. RESULTS: Four hundred and ninety-seven women aged 63.8 ± 9.6 years were included in this study. Eighty-five percent of these women had a 25-OH vitamin D concentration <75 nmol/l. One hundred and fifty-six women (31.4%) had a T-score < -2 at one of the three site measurements. Ninety-five women (19.1%) had a history of nonvertebral fracture with a total of 120 fractures. Spine X-rays evaluation revealed that 20% of the women had at least one vertebral fracture. The presence of vertebral fracture was associated with nonvertebral fracture history [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.4] and with spine BMD (OR 1.4, 95% CI 1.1-1.7). The prevalence of vertebral fracture reached 62.9% in women with age above 70 years and femoral T-score < -2.5. CONCLUSION: Before starting aromatase inhibitor therapy for breast cancer, a large proportion of women had a vitamin D insufficiency and vertebral fractures.

Bone metastasis: histological changes and pathophysiological mechanisms in osteolytic or osteosclerotic localizations. A review.

The development of a bone metastasis involves interactions between the tumor cells, the bone marrow microenvironment and the bone cells themselves. A better understanding of the pathophysiological changes occurring in bone metastasis can be obtained from histopathological examination of invaded specimens. This review focuses on the main molecular mechanisms implied in the localization and growth of malignant cells in the bone marrow. The corresponding histologic developmental stages are illustrated both in osteolytic (or mixed metastasis) or in the osteosclerotic forms by histological analysis, immunohistochemistry and microcomputed tomographic analysis of bone samples. In both cases, the malignant cells find a "fertile soil" in the bone marrow microenvironment. They use the growth factors released by bone cells for the coupling between osteoclasts/osteoblasts to promote their own development. In turn, they elaborate a variety of cytokines that can promote osteoclastogenesis (PTHrP, IL-1, IL-6…) or on the contrary, other growth factors that can boost the osteoblastic activity (ET1, IGFs). A "vicious circle" occurs between the malignant cells and the bone cells leading to the radiological expression of the metastasis.

[Two consecutive episodes of intracerebral hemorrhage as the presenting feature of polyarteritis nodosa]. / Deux hémorragies cérébrales révélatrices d'une périartérite noueuse.

We report a case of polyarteritis nodosa revealed by intracranial haemorrhage. A 40-year-old woman presented two episodes of cerebral haemorrhage twelve days apart, the second due to an aneurysm rupture. The diagnosis of polyarteritis nodosa (PAN) was based on the following criteria: histological aneurysm examination, angiography suggesting PAN with cerebral, renal and splenic localizations, loss of weight and cutaneous nodules. Cerebral haemorrhage in PAN is rare and exceptionally the presenting feature of the disease.