Cancellous Bone Osseointegration Is Enhanced by In Vivo Loading

Authors

Xu Yang, Natalie H. Kelly, Jane Han, Turya Nair, Timothy M. Wright, Marjolein C.H. van der Meulen, and Mathias P.G. Bostrom

Abstract

Biophysical stimuli may be an effective therapy to counteract age-related changes in bone structure that affect the primary stability of implants used in joint replacement or fracture fixation. The influence of controlled mechanical loading on osseointegration was investigated using an in vivo device implanted in the distal lateral femur of 12 male rabbits. Compressive loads (1 MPa, 1 Hz, 50 cycles/day, 4 weeks) were applied to a porous titanium foam implant and the underlying cancellous bone. The contralateral limbs served as nonloaded controls. Backscattered electron imaging indicated that the amount of bone ingrowth was significantly greater in the loaded limb than in the nonloaded control limb, whereas the amount of underlying cancellous periprosthetic bone was similar. No significant difference in the mineral apposition rate of the bone ingrowth or periprosthetic bone was measured in the loaded compared to the control limb. Histological analysis demonstrated newly formed woven bone in direct apposition to the implant coating, with a lack of fibrous tissue at the implant–periprosthetic bone interface in both loaded and nonloaded implants. The lack of fibrous tissue demonstrates that mechanical stimulation using this model significantly enhanced cancellous bone ingrowth without the detrimental effects of micromotion. These results suggest that biophysical therapy should be further investigated to augment current treatments to enhance long-term fixation of orthopedic devices. Additionally, this novel in vivo loading model can be used to further investigate the influence of biophysical stimulation on other tissue engineering approaches requiring bone ingrowth into both metallic and nonmetallic cell-seeded scaffolds.

Link to Article

http://dx.doi.org/10.1089/ten.tec.2009.0776

Bone Growth, Maintenance and Loss in the Neolithic Community of Çatalhöyük, Turkey: Preliminary Results

Authors

Sabrina C. Agarwal, Bonnie Glencross, and Patrick Beauchesne

Abstract

Bioarchaeologists have long been interested in the health and the quality of life of early complex societies, particularly with increased sedentism in the context of the adoption of agriculture (Cohen and Armelagos 1984, Cohen and Crane-Kramer 2007, Larsen 1995, Roberts and Cox 2003, Steckel et al. 2002). While studies of health and disease patterns based on skeletal remains for the ancient Near East are numerous (e.g., Smith et al. 1984, Molleson 1994, Horwitz and Smith 2000, Smith and Horwitz 2005, Eshed et al. 2004, 2006, Schultz et al. 2007, Roberts and Buikstra 2007), few sites have yielded large collections of human skeletons in conjunction with detailed archaeological evidence of settlement, lifestyle, diet, and living conditions. The site of Çatalhöyük in the Konya Basin of south-central Turkey is a rare exception, with remarkable archaeological and paleoenvironmental context, revealing changes in community size and structure, shifts in mobility, and the use of plant and animal resources across time. Bioarchaeological evidence from Çatalhöyük provides a unique perspective on early population aggregation, resource use, and consequences of early farming and urbanization on health and lifestyle.

Link to Article

http://escholarship.org/uc/item/9m13784c

Corticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism

Authors

Holger Henneicke, Markus Herrmann, Robert Kalak, Tara C. Brennan-Speranza, Uta Heinevetter, Nicky Bertollo, Robert E. Day, Dörte Huscher, Frank Buttgereit, Colin R. Dunstan, Markus J. Seibel, and Hong Zhou

Abstract

The pathogenesis of glucocorticoid-induced osteoporosis remains ill defined. In this study, we examined the role of the osteoblast in mediating the effects of exogenous glucocorticoids on cortical and trabecular bone, employing the Col2.3-11βHSD2 transgenic mouse model of osteoblast-targeted disruption of glucocorticoid signalling. Eight week-old male transgenic (tg) and wild-type (WT) mice (n = 20–23/group) were treated with either 1.5 mg corticosterone (CS) or placebo for 4 weeks. Serum tartrate-resistant acid phosphatase 5b (TRAP5b) and osteocalcin (OCN) were measured throughout the study. Tibiae and lumbar vertebrae were analysed by micro-CT and histomorphometry at endpoint. CS suppressed serum OCN levels in WT and tg mice, although they remained higher in tg animals at all time points (p < 0.05). Serum TRAP5b levels increased in WT mice only. The effect of CS on cortical bone differed by site: At the endosteal surface, exposure to CS significantly increased bone resorption and reduced bone formation, resulting in a larger bone marrow cavity cross-sectional area (p < 0.01). In contrast, at the pericortical surface bone resorption was significantly decreased accompanied with a significant increase in pericortical cross-sectional area (p < 0.05) while bone formation remained unaffected. Vertebral cortical thickness and area were reduced in CS treatment mice. Tg mice were partially protected from the effects of exogenous CS, both on a cellular and structural level. At the CS doses used in this study, trabecular bone remained largely unaffected. Endocortical osteoblasts appear to be particularly sensitive to the detrimental actions of exogenous glucocorticoids. The increase in tibial pericortical cross-sectional area and the according changes in pericortical circumference suggest an anabolic bone response to GC treatment at this site. The protection of tg mice from these effects indicates that both catabolic and anabolic action of glucocorticoids are, at least in part, mediated by osteoblasts.

Link to Article

http://dx.doi.org/10.1016/j.bone.2011.06.013

Guided bone regeneration in pig calvarial bone defects using autologous mesenchymal stem/progenitor cells – A comparison of different tissue sources

Authors

Philipp Stockmann, Jung Park, Cornelius von Wilmowsky, Emeka Nkenke, Endre Felszeghy, Jan-Friedrich Dehner, Christian Schmitt, Christian Tudor, and Karl Andreas Schlegel

Abstract

Due to donor side morbidity and the absence of osteogenic properties in bone substitutes, there is a growing need for an alternative to traditional bone grafting within the scope of tissue engineering. This animal study was conducted to compare the in vivo osteogenic potential of adipose-derived (AD), periosteum-derived (PD) and bone marrow-derived (BM) mesenchymal stem/progenitor cells (MSC). Autologous mesenchymal stem/progenitor cells of named tissue origin were induced into osteogenic differentiation following in vitro cell expansion. Ex vivo cultivated cells were seeded on a collagen scaffold and subsequently added to freshly created monocortical calvarial bone defects in 21 domestic pigs. Pure collagen scaffold served as a control defect. The animals were sacrificed at specific time points and de novo bone formation was quantitatively analyzed by histomorphometry. Bone volume/total defect volume (BV/TV) and the mineralization rate of newly formed bone were compared among the groups. In the early stages of wound healing, up to 30 days, the test defects did not show better bone regeneration than those in the control defect, but the bone healing process in the test defects was accelerated in the later stage compared to those in the control defect. All the test defects showed complete osseous healing after 90 days compared to those in the control defect. During the observation period, no significant differences in BV/TV and mineralization of newly formed bone among the test defects were observed. Irrespective of the tissue sources of MSC, the speed and pattern of osseous healing after cell transplantations into monocortical bone defects were comparable. Our results indicate that the efficiency of autologous AD-MSC, PD-MSC and BM-MSC transplantation following ex vivo cell expansion is not significantly different for the guided regeneration of bone defects.

Link to Article

http://dx.doi.org/10.1016/j.jcms.2011.05.004

Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody

Authors

Paul J. Kostenuik, Susan Y. Smith, Jacquelin Jolette, Joseph Schroeder, Ian Pyrah, Michael S. Ominsky

Abstract

This study examined the effects of denosumab, an anti-RANKL antibody that inhibits bone resorption, on bone histomorphometry in adult ovariectomized cynomolgus monkeys (OVX cynos). A month after surgery, OVX cynos were treated with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg/month) for 16months (n=14–20/group). Sham controls were treated with vehicle (Sham-Veh; n=17). Areal and volumetric BMD, urine NTx, and serum osteocalcin were measured at baseline and months 3, 6, 12, and 16. Double fluorochrome labels were injected prior to iliac and rib biopsies at month 6 and month 12, and prior to sacrifice at month 16. Histomorphometry was performed on these biopsies, the tibial diaphysis, the L2 vertebra, and the proximal femur. Strength of humeral cortical beams, femur diaphysis, femur neck, and trabecular cores of L5–L6 vertebrae was determined by destructive biomechanical testing. There was no evidence of woven bone, osteomalacia, or other bone histopathologic changes with OVX or with denosumab. OVX-Veh animals exhibited significantly greater bone remodeling at all skeletal sites relative to Sham-Veh controls. Both doses of denosumab markedly inhibited bone remodeling at all sites, including significant reductions in trabecular eroded surfaces (48–86% lower than OVX-Veh controls), cortical porosity (28–72% lower), and dynamic parameters of bone formation (81–100% lower). Decreased fluorochrome labeling with denosumab was related to reductions in cortical porosity and trabecular eroded surfaces, and regression analyses suggested that these reductions contributed to denosumab-related increments in BMD and bone strength. Denosumab-treated animals with the lowest levels of fluorescent labeling exhibited the greatest structural bone strength values at each site. Intracortical remodeling had no relationship with material properties including ultimate strength, elastic modulus or toughness (r2=0.00–0.01). These data suggest that remodeling inhibition with denosumab improved structural strength without altering material properties under these experimental conditions. Greater structural strength in the denosumab-treated animals can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and cortical porosity.

Link to Article

http://dx.doi.org/10.1016/j.bone.2011.03.769

Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts

Authors

Steeve Kwan Tata, Jean-Pierre Pelletiera, François Mineaua, Judith Carona, and Johanne Martel-Pelletier

Abstract

In osteoarthritis (OA) the progression of cartilage degeneration has been associated with remodeling of the subchondral bone. Human OA subchondral bone osteoblasts were shown to have an abnormal phenotype and altered metabolism leading to an abnormal resorptive process. Bone resorption is suggested to occur, at least in part, through the increased levels of two proteolytic enzymes, MMP-2 and MMP-9, and RANKL, which are mainly produced by osteoblasts. In this study, we investigated in human OA subchondral bone osteoblasts the modulatory effect of strontium ranelate on the above key factors. Human subchondral bone osteoblasts were cultured in a medium containing 0.1, 1 and 2 mM of strontium ranelate for 18 h for mRNA and 72 h for protein determination. The effect of strontium ranelate was evaluated on the expression (qPCR) of MMP-2, MMP-9, OPG, RANKL (total), RANKL-1, and RANKL-3, on the production of OPG (ELISA), membranous RANKL (flow cytometry), and MT1-MMP, ADAM17, and ADAM19 (Western blot). After incubation of osteoblasts with pre-osteoclasts (i.e., differentiated human peripheral blood mononuclear cells), the resorbed surface was measured using a sub-micron synthetic calcium phosphate thin film. Firstly, the expression levels of MMP-2, MMP-9, OPG, and RANKL were determined in normal and OA subchondral bone osteoblasts. As expected, the gene expression of MMP-9 and RANKL were not detectable in normal cells, whereas MMP-2 was very low but detectable and OPG demonstrated high gene expression. Further experiments looking at the effect of strontium ranelate on expression levels, except for OPG, were performed only on the OA subchondral bone osteoblasts. In OA cells, the expression levels of MMP-2 and MMP-9 were significantly decreased by strontium ranelate at 1 mM (p ≤ 0.005, p ≤ 0.02, respectively) and 2 mM (p ≤ 0.003, p ≤ 0.007), and for MMP-9 only at 0.1 mM (p ≤ 0.05). In normal cells, the expression of OPG was increased with strontium ranelate at 2 mM, and in OA both the expression (p ≤ 0.02) and synthesis (p ≤ 0.002) of OPG were significantly increased with strontium ranelate at 1 and 2 mM. RANKL (total) as well as the isoforms RANKL-1 and RANKL-3 were significantly increased by strontium ranelate at 1 and 2 mM. Of note, it is known that the different RANKL isoforms differentially regulate RANKL membranous localization: RANKL-3, in contrast to RANKL-1, prevents such membranous localization. This is reflected by the significant (p ≤ 0.02) reduction in the level of membranous RANKL by strontium ranelate at 2 mM. This latter finding was not likely to be related to a proteolytic cleavage of membranous RANKL, as the enzymes known to cleave it, MT1-MMP, ADAM17 and ADAM19, were unaffected by strontium ranelate. In addition, OA osteoblasts treated with strontium ranelate induced a significant (p ≤ 0.002) decrease in resorbed surface at the three tested concentrations. This study provides new insights into the mode of action of strontium ranelate on the metabolism of human OA subchondral bone osteoblasts. These data suggest that strontium ranelate may exert a positive effect on OA pathophysiology by inhibiting, in these cells, the synthesis of key factors leading to bone resorption, a feature associated with the OA process.

Link to Article

http://dx.doi.org/10.1016/j.bone.2011.06.005