A pedicled bone graft from the acromion: an anatomical investigation regarding surgical feasibility.

OBJECTIVE: To investigate the technical feasibility of harvesting a vascularized bone graft from the acromion pedicled on the acromial branch. BACKGROUND: Complex fractures of the proximal humerus may result in partial or total avascular necrosis of the head fragment. Treatment of avascular necrosis of the humeral head is dependent upon the stage of disease as well as the dimension and location of necrosis. In general, the outcome is poor and complete restoration of the shoulder function is rarely attained. Contrary to osteonecrosis of carpal bones (where vascularized bone grafts have been routinely carried out for decades), reports of analogous procedures at the humeral head are anecdotal. METHODS: Based on selective post-mortem computer-tomographic angiography of 5 and the dissection of 30 embalmed human cadaver shoulders, we describe the anatomy of the acromial branch of the thoracoacromial trunk. The main focus was the constancy of its anatomical course, its dimensions and potential use as a nutrient vessel for a pedicled bone graft from the acromion. RESULTS: The course of the acromial branch revealed a constant topographic relationship to anatomical landmarks. Its terminal branches reliably supplied the anterior part of the acromion. The vascularized bone graft could be sufficiently mobilized to allow tension-free transfer to the humeral head as well as to the lateral two-thirds of the clavicle. CONCLUSION: We demonstrated the feasibility of vascularized bone graft harvesting from the acromion. This technique could be a joint-preserving procedure for osteonecrosis of the humeral head or may assist in the revision of a clavicular pseudoarthrosis.

Synthetic RGD-containing alpha-helical coiled coil peptides promote integrin-dependent cell adhesion.

Integrin receptors are the main mediators of cell adhesion to the extracellular matrix. They bind to their ligands by interacting with short amino acid sequences, such as the RGD sequence. Soluble, small RGD-based peptides have been used to block integrin-binding to ligands, thereby interfering with cell adhesion, migration and survival, while substrate-immobilized RGD sequences have been used to enhance cell binding to artificial surfaces. This approach has several important medical applications, e.g. in suppression of tumor angiogenesis or stimulation of bone formation around implants. However, the relatively weak affinity of short RGD-containing peptides often results in incomplete integrin inhibition or ineffective ligation. In this work, we designed and synthesized several new multivalent RGD-containing molecules and tested their ability to inhibit or to promote integrin-dependent cell adhesion when used in solution or immobilized on substrates, respectively. These molecules consist of an oligomeric structure formed by alpha-helical coiled coil peptides fused at their amino-terminal ends with an RGD-containing fragment. When immobilized on a substrate, these peptides specifically promoted integrin alphaVbeta3-dependent cell adhesion, but when used in solution, they blocked alphaVbeta3-dependent cell adhesion to the natural substrates fibronectin and vitronectin. One of the peptides was nearly 10-fold more efficient than fibronectin or vitronectin in promoting cell adhesion, and almost 100-fold more efficient than a linear RGD tripeptide in blocking adhesion. These results indicate that alpha-helical coiled coil peptides carrying an amino-terminal RGD motif can be used as soluble antagonists or surface-immobilized agonists to efficiently inhibit or promote integrin alphaVbeta3-mediated cell adhesion, respectively.

European French-speaking study from the GEMO group on bone metastases management: a special focus on external beam radiotherapy practice survey.

This study seeks to perform a survey of patterns of practice among the different physicians involved in the bone metastases management, with special focus on external beam radiotherapy (EBRT).A questionnaire about bone metastases based on clinical cases and supplemented with general questions, including medical therapies, EBRT and metabolic radiotherapy strategies, surgery, and supportive care approaches, was sent to 4,706 French-speaking physicians in Belgium, France, Luxemburg, and Switzerland.Overall, 644 questionnaires were analyzed. Twenty-eight percent concerned the radiotherapy approach and were judged adequate to respond to the part dedicated to EBRT. Sixty-nine percent of physicians used a total dose irradiation of 30 Gy delivered in ten fractions. A large majority (75%) used two opposed fields prescribed at mid-depth (30%), or with non-equally weighted fields (45%). Seventy percent irradiated also above and below the concerned vertebra. A dosimetry planning treatment was done in 85% and high-energy megavoltage photons were used in 42%. Moreover, 54% physicians used short course radiotherapy in routine.Radiotherapy remains the mainstay of treatment of bone metastases, but there is substantial heterogeneity in clinical practice. Guidelines and treatment protocols are required to improve the treatment quality.

Dexamethasone-loaded poly(epsilon-caprolactone) intravitreal implants: a pilot study.

PURPOSE: Poly(epsilon-caprolactone) (PCL) is a biodegradable and biocompatible polymer that presents a very low degradation rate, making it suitable for the development of long-term drug delivery systems. The objective of this pilot study is to evaluate the feasibility and characteristics of PCL devices in the prolonged and controlled intravitreous release of dexamethasone. METHODS: The in vitro release of dexamethasone was investigated and the implant degradation was monitored by the percent of mass loss and by changes in the surface morphology. Differential scanning calorimetry was used to evaluate stability and interaction of the implant and the drug. The short-term tolerance of the implants was studied after intravitreous implantation in rabbit eye. Results: PCL implant allows for a controlled and prolonged delivery of dexamethasone since it releases 25% of the drug in 21 weeks. Its low degradation rate was confirmed by the mass loss and scanning electron microscopy studies. Preliminary observations show that PCL intravitreous implants are very well tolerated in the rabbit eye. CONCLUSION: This study demonstrates the PCL drug delivery systems allowed to a prolonged release of dexamethasone in vitro. The implants demonstrated a strikingly good intraocular short-term tolerance in rabbits eyes. The in vitro and preliminary in vivo studies tend to show that PCL implants could be of interest when long-term sustained intraocular delivery of corticosteroids is required.

Trabecular bone score: a noninvasive analytical method based upon the DXA image.

The trabecular bone score (TBS) is a gray-level textural metric that can be extracted from the two-dimensional lumbar spine dual-energy X-ray absorptiometry (DXA) image. TBS is related to bone microarchitecture and provides skeletal information that is not captured from the standard bone mineral density (BMD) measurement. Based on experimental variograms of the projected DXA image, TBS has the potential to discern differences between DXA scans that show similar BMD measurements. An elevated TBS value correlates with better skeletal microstructure; a low TBS value correlates with weaker skeletal microstructure. Lumbar spine TBS has been evaluated in cross-sectional and longitudinal studies. The following conclusions are based upon publications reviewed in this article: 1) TBS gives lower values in postmenopausal women and in men with previous fragility fractures than their nonfractured counterparts; 2) TBS is complementary to data available by lumbar spine DXA measurements; 3) TBS results are lower in women who have sustained a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; 4) TBS predicts fracture risk as well as lumbar spine BMD measurements in postmenopausal women; 5) efficacious therapies for osteoporosis differ in the extent to which they influence the TBS; 6) TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality. Based on these data, lumbar spine TBS holds promise as an emerging technology that could well become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment.

Combining bone resorption markers and heel quantitative ultrasound to discriminate between fracture cases and control

Rapport de synthèse : L'ostéoporose est reconnue comme un problème majeur de santé publique. Comme il existe actuellement des traitements préventifs efficaces pour minimiser le risque de fracture, il est essentiel de développer des nouvelles stratégies de détection des femmes à risque de fracture. Les marqueurs spécifiques du remodelage osseux dosés dans les urines ainsi que les ultrasons quantitatifs du talon ont été étudiés comme outils cliniques pour prédire le risque fracturaire chez les femmes âgées. Il n'existe cependant que très peu de donnée sur la combinaison de ces deux outils pour améliorer la prédiction du risque de fracture. Cette étude cas-contrôle, réalisée chez 368 femmes âgées de 76 ans en moyenne d'une cohorte suisse de femmes ambulatoires, évalue la capacité discriminative entre 195 femmes avec fracture non-vertébrale à bas traumatisme et 173 femmes sans fractures - de deux marqueurs urinaires de la résorption osseuse, les pyridinolines et les deoxypyridinolines, ainsi que deux ultrasons quantitatifs du talon, le Achilles+ (GE-Lunar, Madison, USA) et le Sahara (Hologic, Waltham, USA). Les 195 patientes avec une fracture ont été choisies identiques aux 173 contrôles concernant Page, l'indice de masse corporel, le centre médical et la durée de suivi jusqu'à la fracture. Cette étude montre que les marqueurs urinaires de la résorption osseuse ont une capacité environ identique aux ultrasons quantitatifs du talon pour discriminer entre les patientes avec fracture non-vertébrale à bas traumatisme et les contrôles. La combinaison des deux tests n'est cependant pas plus performante qu'un seul test. Les résultats de cette étude peuvent aider à concevoir les futures stratégies de détection du risque fracturaire chez les femmes âgées, qui intègrent notamment des facteurs de risque cliniques, radiologiques et biochimiques. Abstract : Summary : This nested case-control analysis of a Swiss ambulatory cohort of elderly women assessed the discriminatory power of urinary markers of bone resorption and heel quantitative ultrasound for non-vertebral fractures. The tests all discriminated between cases and controls, but combining the two strategies yielded no additional relevant information. Introduction : Data are limited regarding the combination of bone resorption markers and heel quantitative bone ultrasound (QUS) in the detection of women at risk for fracture. Methods In a nested case-control analysis, we studied 368 women (mean age 76.213.2 years), 195 with low-trauma non-vertebral fractures and 173 without, matched for age, BMI, medical center, and follow-up duration, from a prospective study designed to predict fractures. Urinary total pyridinolines (PYD) and deoxypyridinolines (DPD) were measured by high performance liquid chromatography. All women underwent bone evaluations using Achilles+ and Sahara heel QUS. Results : Areas under the receiver operating-characteristic curve (AUC) for discriminative models of the fracture group, with 95% confidence intervals, were 0.62 (0.560.68) and 0.59 (0.53-0.65) for PYD and DPD, and 0.64 (0.58-0.69) and 0.65 (0.59-0.71) for Achilles+ and Sahara QUS, respectively. The combination of resorption markers and QUS added no significant discriminatory information to either measurement alone with an AUC of 0.66 (0.600.71) for Achilles+ with PYD and 0.68 (0.62-0.73) for Sahara with PYD. Conclusions : Urinary bone resorption markers and QUS are equally discriminatory between non-vertebral fracture patients and controls. However, the combination of bone resorption markers and QUS is not better than either test used alone.

TBS (trabecular bone score) and diabetes-related fracture risk.

CONTEXT: Type 2 diabetes is associated with increased fracture risk but paradoxically greater bone mineral density (BMD). Trabecular bone score (TBS) is derived from the texture of the spine dual x-ray absorptiometry (DXA) image and is related to bone microarchitecture and fracture risk, providing information independent of BMD. OBJECTIVE: This study evaluated the ability of lumbar spine TBS to account for increased fracture risk in diabetes. DESIGN AND SETTING: We performed a retrospective cohort study using BMD results from a large clinical registry for the province of Manitoba, Canada. Patients: We included 29,407 women 50 years old and older with baseline DXA examinations, among whom 2356 had diagnosed diabetes. MAIN OUTCOME MEASURES: Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident nontraumatic major osteoporotic fractures (mean follow-up 4.7 years). RESULTS: Diabetes was associated with higher BMD at all sites but lower lumbar spine TBS in unadjusted and adjusted models (all P < .001). The adjusted odds ratio (aOR) for a measurement in the lowest vs the highest tertile was less than 1 for BMD (all P < .001) but was increased for lumbar spine TBS [aOR 2.61, 95% confidence interval (CI) 2.30-2.97]. Major osteoporotic fractures were identified in 175 women (7.4%) with and 1493 (5.5%) without diabetes (P < .001). Lumbar spine TBS was a BMD-independent predictor of fracture and predicted fractures in those with diabetes (adjusted hazard ratio 1.27, 95% CI 1.10-1.46) and without diabetes (hazard ratio 1.31, 95% CI 1.24-1.38). The effect of diabetes on fracture was reduced when lumbar spine TBS was added to a prediction model but was paradoxically increased from adding BMD measurements. CONCLUSIONS: Lumbar spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD.

Staphylococcal biofilm formation on the surface of three different calcium phosphate bone grafts: a qualitative and quantitative in vivo analysis.

Differences in physico-chemical characteristics of bone grafts to fill bone defects have been demonstrated to influence in vitro bacterial biofilm formation. Aim of the study was to investigate in vivo staphylococcal biofilm formation on different calcium phosphate bone substitutes. A foreign-body guinea-pig infection model was used. Teflon cages prefilled with β-tricalcium phosphate, calcium-deficient hydroxyapatite, or dicalcium phosphate (DCP) scaffold were implanted subcutaneously. Scaffolds were infected with 2 × 10(3) colony-forming unit of Staphylococcus aureus (two strains) or S. epidermidis and explanted after 3, 24 or 72 h of biofilm formation. Quantitative and qualitative biofilm analysis was performed by sonication followed by viable counts, and microcalorimetry, respectively. Independently of the material, S. aureus formed increasing amounts of biofilm on the surface of all scaffolds over time as determined by both methods. For S. epidermidis, the biofilm amount decreased over time, and no biofilm was detected by microcalorimetry on the DCP scaffolds after 72 h of infection. However, when using a higher S. epidermidis inoculum, increasing amounts of biofilm were formed on all scaffolds as determined by microcalorimetry. No significant variation in staphylococcal in vivo biofilm formation was observed between the different materials tested. This study highlights the importance of in vivo studies, in addition to in vitro studies, when investigating biofilm formation of bone grafts.

Nouvelles thérapies pour les maladies osseuses de l'enfant [New therapies for children affected by bone diseases].

Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.

Alterations of bone microarchitecture in young patients with inflammatory bowel diseases are associated with fracture risk during growth

Aims: Inflammatory bowel diseases (IBD) appearing during childhood and adolescence compromise peak bone mass acquisition and increase fracture risk. The structural determinants of bone fragility in IBD however remain unknown. Methods: We investigated volumetric bone mineral density (vBMD), trabecular and cortical bone microstructure at distal radius and tibia by high-resolution pQCT (XtremeCT, Scanco, Switzerland), aBMD at distal radius, hip and spine and vertebral fracture assessment (VFA) by DXA in 107 young patients (mean age 22.8 yrs, range 12.2-33.7 yrs; 62 females and 45 males) with Crohn's disease (n=75), ulcerative colitis (n=25), undetermined colitis (n=2), and no definitive diagnosis (n=5), and in 389 healthy young individuals. Results: Mean disease duration was 6.1 yrs, 89/107 IBD patients received corticosteroids, 83 other immunomodulators, and 59 vitamin D. Clinical fractures were reported by 38 patients (mean age at 1st fracture, 12.6 yrs), the vast majority of the forearm, arm or hand; 5 had vertebral crush fractures (Grade 1 or 2) and 11 had multiple fractures. As compared to healthy controls (matched 2:1 for age, sex, height and fracture history), the 102 patients with established IBD had similar weight but significantly lower aBMD at all sites, lower trabecular (Tb) BV/TV and number, and greater Tb separation and inhomogeneous Tb distribution (1/SD TbN) at both distal radius and tibia, lower tibia cortical thickness (CTh), but no differences in cortical vBMD nor bone perimeter. Among IBD's, aBMD was not associated with fractures (by logistic regression adjusted for age, age square, sex, height, weight and protein intake). However, radius and tibia Tb BV/TV, thickness and SD 1/TbN, as well as radius Tb separation and perimeter, were significantly associated with fracture risk (fully adjusted as above), whereas cortical vBMD and CTh were not. After adjustment for aBMD at radius, respectively at femur neck, radius SD 1/TbN and tibia BV/TV, TbTh and perimeter remained independently associated with fracture risk. Conclusions: Young subjects with IBD have low bone mass and poor bone microarchitecture compared to healthy controls. Alterations of bone microarchitecture, particularly in the trabecular bone compartment, are specifically associated with increased fracture risk during growth.

Trabecular bone score is associated with volumetric bone density and microarchitecture as assessed by central QCT and HRpQCT in Chinese American and white women.

Although high-resolution peripheral quantitative computed tomography (HRpQCT) and central quantitative computed tomography (QCT) studies have shown bone structural differences between Chinese American (CH) and white (WH) women, these techniques are not readily available in the clinical setting. The trabecular bone score (TBS) estimates trabecular microarchitecture from dual-energy X-ray absorptiometry spine images. We assessed TBS in CH and WH women and investigated whether TBS is associated with QCT and HRpQCT indices. Areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry, lumbar spine (LS) TBS, QCT of the LS and hip, and HRpQCT of the radius and tibia were performed in 71 pre- (37 WH and 34 CH) and 44 postmenopausal (21 WH and 23 CH) women. TBS did not differ by race in either pre- or postmenopausal women. In the entire cohort, TBS positively correlated with LS trabecular volumetric bone mineral density (vBMD) (r = 0.664), femoral neck integral (r = 0.651), trabecular (r = 0.641) and cortical vBMD (r = 0.346), and cortical thickness (C/I; r = 0.540) by QCT (p < 0.001 for all). TBS also correlated with integral (r = 0.643), trabecular (r = 0.574) and cortical vBMD (r = 0.491), and C/I (r = 0.541) at the total hip (p < 0.001 for all). The combination of TBS and LS aBMD predicted more of the variance in QCT measures than aBMD alone. TBS was associated with all HRpQCT indices (r = 0.20-0.52) except radial cortical thickness and tibial trabecular thickness. Significant associations between TBS and measures of HRpQCT and QCT in WH and CH pre- and postmenopausal women demonstrated here suggest that TBS may be a useful adjunct to aBMD for assessing bone quality.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

Purpose/Objective(s): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL.Materials/Methods: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242).Results: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities.Conclusions: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and completeCXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.Author Disclosure: L. Cai, None; M.C. Stauder, None; Y.J. Zhang, None; P. Poortmans, None; Y.X. Li, None; N. Constantinou, None; J. Thariat, None; S. Kadish, None; M. Ozsahin, None; R.O. Mirimanoff, None.

PPARβ/δ governs Wnt signaling and bone turnover.

Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARβ/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARβ/δ amplified Wnt-dependent and β-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARβ/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARβ/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARβ/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.