Targeting angiogenesis as a therapeutic means to reinforce osteocyte survival and prevent non-unions in the aftermath of radiotherapy

Authors

Alexis Donneys, Noah S. Nelson, Erin E. Page, Sagar S. Deshpande, Peter A. Felice, Catherine N. Tchanque-Fossuo, Joshua P. Spiegel and Steven R. Buchman

Abstract

Background: Radiotherapy exerts detrimental collateral effects on bone tissue through mechanisms of vascular damage and impediments to osteocytes, ultimately predisposing patients to the debilitating problems of late pathologic fractures and non-unions. We posit that angiogenic therapy will reverse these pathologic effects in a rat model of radiated fracture healing.

Methods: Three groups of rats underwent mandibular osteotomy. Radiated groups received a fractionated 35Gy dose prior to surgery. The deferoxamine group received local injections postoperatively. A 40-day healing period was allowed prior to histology. ANOVA (p<0.05) was used for group comparisons.

Results: Radiated fractures revealed a significantly decreased osteocyte count and corresponding increase in empty lacunae when compared to non-radiated fractures (p=0.001). With the addition of deferoxamine, these differences were not appreciated. Further, a 42% increase in bony unions was observed after deferoxamine therapy.

Conclusions: Targeting angiogenesis is a useful means for promoting osteocyte survival and preventing bone pathology after radiotherapy

Link To Article

http://dx.doi.org/10.1002/hed.23744

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength

Authors

B. P. Sinder, L. E. White, J. D. Salemi, M. S. Ominsky, M. S. Caird, J. C. Marini, K. M. Kozloff

Abstract

Summary Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect.

Introduction Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1.

Methods Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed.

Results Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength.

Conclusion Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.

Link To Article

http://dx.doi.org/10.1007/s00198-014-2737-y

High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep

Authors

M. J. K. Simon, F. T. Beil, W. Rüther, B. Busse, T. Koehne, M. Steiner, P. Pogoda, A. Ignatius, M. Amling, R. Oheim

Abstract

Summary Chronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass.

Introduction Understanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures.

Methods Dorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (μCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy.

Results The fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure.

Conclusions Our data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis.

Link To Article

http://dx.doi.org/10.1007/s00198-014-2707-4

Calcium and vitamin D intake maintained from preovariectomy independently affect calcium metabolism and bone properties in Sprague Dawley rats

Authors

C. Y. Park, W. H. Lee, J. C. Fleet, M. R. Allen, G. P. McCabe, D. M. Walsh, C. M. Weaver

Abstract

Summary The interaction of habitual Ca and vitamin D intake from preovariectomy to 4 months postovariectomy on bone and Ca metabolism was assessed. Higher Ca intake suppressed net bone turnover, and both nutrients independently benefitted trabecular structure. Habitual intake of adequate Ca and ~50 nmol/L vitamin D status is most beneficial.

Introduction Dietary strategies to benefit bone are typically tested prior to or after menopause but not through menopause transition. We investigated the interaction of Ca and vitamin D status on Ca absorption, bone remodeling, Ca kinetics, and bone strength as rats transitioned through estrogen deficiency.

Methods Sprague Dawley rats were randomized at 8 weeks to 0.2 or 1.0 % Ca and 50, 100, or 1,000 IU (1.25, 2.5, or 25 μg) vitamin D/kg diet (2 × 3 factorial design) and ovariectomized at 12 weeks. Urinary 45Ca excretion from deep-labeled bone was used to assess net bone turnover weekly. Ca kinetics was performed between 25 and 28 weeks. Rats were killed at 29 weeks. Femoral and tibiae structure (by μCT), dynamic histomorphometry, and bone Ca content were assessed.

Results Mean 25(OH)D for rats on the 50, 100, 1,000 IU vitamin D/kg diet were 32, 54, and 175 nmol/L, respectively. Higher Ca intake ameliorated net bone turnover, reduced fractional Ca absorption and bone resorption, and increased net Ca absorption. Tibial and femoral trabecular structures were enhanced independently by higher Ca and vitamin D intake. Tibial bone width and fracture resistance were enhanced by higher vitamin D intake. Dynamic histomorphometry in the tibia was not affected by either nutrient. A Ca × vitamin D interaction existed in femur length, tibial Ca content, and mass of the soft tissue/extracellular fluid compartment.

Conclusions Adequate Ca intake and serum 25(OH)D level of 50 nmol/L provided the most benefit for bone health, mostly through independent effects of Ca and vitamin D.

Link To Article

http://dx.doi.org/10.1007/s00198-014-2709-2

Osseointegration of dental implants in 3D-printed synthetic onlay grafts customized according to bone metabolic activity in recipient site

Authors

Faleh Tamimi, Jesus Torres, Khadijeh Al-Abedalla, Enrique Lopez-Cabarcos, Mohammad H. Alkhraisat, David C. Bassett, Uwe Gburece, Jake E. Barralet

Abstract

Onlay grafts made of monolithic microporous monetite bioresorbable bioceramics have the capacity to conduct bone augmentation. However, there is heterogeneity in the graft behaviour in vivo that seems to correlate with the host anatomy. In this study, we sought to investigate the metabolic activity of the regenerated bone in monolithic monetite onlays by using positron emission tomography–computed tomography (PET-CT) in rats. This information was used to optimize the design of monetite onlays with different macroporous architecture that were then fabricated using a 3D-printing technique. In vivo, bone augmentation was attempted with these customized onlays in rabbits. PET-CT findings demonstrated that bone metabolism in the calvarial bone showed higher activity in the inferior and lateral areas of the onlays. Histological observations revealed higher bone volume (up to 47%), less heterogeneity and more implant osseointegration (up to 38%) in the augmented bone with the customized monetite onlays. Our results demonstrated for the first time that it is possible to achieve osseointegration of dental implants in bone augmented with 3D-printed synthetic onlays. It was also observed that designing the macropore geometry according to the bone metabolic activity was a key parameter in increasing the volume of bone augmented within monetite onlays.

Link To Article

http://dx.doi.org/10.1016/j.biomaterials.2014.03.050

Anorganic bovine bone (ABB) vs. autologous bone (AB) plus ABB in maxillary sinus grafting. A prospective non-randomized clinical and histomorphometrical trial

Authors

Christian M. Schmitt, Tobias Moest, Rainer Lutz, Friedrich W. Neukam and Karl Andreas Schlegel

Abstract

Objectives This investigation focused on histological characteristics and 5-year implant survival after sinus floor augmentation with anorganic bovine bone (ABB, Bio-Oss®) and ABB plus autologous bone (AB) with a ratio of 1/1.

Material and methods Nineteen consecutive patients with bony atrophy of the posterior edentulous maxilla and a vertical bone height ≤4 mm were prospectively included in this study. In the first surgical stage, the maxillary sinus was non-randomized either augmented with ABB alone (n = 12) or a 1/1 mixture of ABB and AB (n = 7). After a mean healing period of 167 days, biopsies were harvested in the region of the grafted sinus with a trephine burr and implants were placed simultaneously, ABB n = 18 and ABB + AB n = 12. The samples were microradiographically and histomorphometrically analyzed judging the newly formed bone (bone volume, BV), residual bone substitute material volume (BSMV), and intertrabecular volume (soft tissue volume, ITV) in the region of the augmented maxillary sinus. Implant survival was retrospectively evaluated from patient's records.

Results No significant difference in residual bone substitute material (BSMV) in the ABB group (31.21 ± 7.74%) and the group with the mixture of ABB and AB (28.41 ± 8.43%) was histomorphologically determined. Concerning the de novo bone formation, also both groups showed statistically insignificant outcomes; ABB 26.02 ± 5.23% and ABB + AB 27.50 ± 6.31%. In all cases, implants were installed in the augmented sites with sufficient primary stability. After a mean time in function of 5 years and 2 months, implant survival was 93.75% in the ABB and 92.86% in the ABB + AB group with no statistically significant differences.

Conclusion The usage of ABB plus AB to a 1/1 ratio leads to an amount of newly formed bone comparable with the solitary use of ABB after grafting of the maxillary sinus. Considering that ABB is a non-resorbable bone substitute, it can be hypothesized that this leads to stable bone over time and long-term implant success. Importantly, in the sole use of ABB, bone grafting and therefore donor site morbidities can be avoided.

Link To Article

http://dx.doi.org/10.1111/clr.12396