Chronic skeletal unloading of the rat femur: Mechanisms and functional consequences of vascular remodeling

Authors

John N. Stabley, Rhonda D. Prisby, Bradley J. Behnke, Michael D. Delp

Abstract

Chronic skeletal unloading diminishes hindlimb bone blood flow. The purpose of the present investigation was to determine 1) whether 7 and 14days of skeletal unloading alter femoral bone and marrow blood flow and vascular resistance during reloading, and 2) whether putative changes in bone perfusion are associated with a gross structural remodeling of the principal nutrient artery (PNA) of the femur. Six-month old male Sprague–Dawley rats were assigned to 7-d or 14-d hindlimb unloading (HU) or weight-bearing control groups. Bone perfusion was measured following 10min of standing (reloading) following the unloading treatment. Histomorphometry was used to determine PNA media wall thickness and maximal diameter. Bone blood flow, arterial pressure and PNA structural characteristics were used to calculate arterial shear stress and circumferential wall stress. During reloading, femoral perfusion was lower in the distal metaphyseal region of 7-d HU rats, and in the proximal and distal metaphyses, diaphysis and diaphyseal marrow of 14-d HU animals relative to that in control rats. Vascular resistance was also higher in all regions of the femur in 14-d HU rats during reloading relative to control animals. Intraluminal diameter of PNAs from 14-d HU rats (138±5μm) was smaller than that of control PNAs (162±6μm), and medial wall thickness was thinner in PNAs from 14-d HU (14.3±0.6μm) versus that of control (18.0±0.8μm) rats. Decreases in both shear stress and circumferential stress occurred in the PNA with HU that later returned to control levels with the reductions in PNA maximal diameter and wall thickness, respectively. The results demonstrate that chronic skeletal unloading attenuates the ability to increase blood flow and nutrient delivery to bone and marrow with immediate acute reloading due, in part, to a remodeling of the bone resistance vasculature.

Link to Article

http://dx.doi.org/10.1016/j.bone.2013.09.003

A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD

Authors

Sharon M. Moe, Neal X. Chen, Christopher L. Newman, Vincent H. Gattone II, Jason M. Organ, Xianming Chen, Matthew R. Allen

Abstract

Patients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about over-suppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for ten weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by microCT and both equally suppressed mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification.

Link to Article

http://dx.doi.org/10.1002/jbmr.2089

Assessment of epidural versus intradiscal biocompatibility of PEEK implant debris: an in vivo rabbit model

Authors

Nadim J. Hallab, Qi-Bin Bao, Tim Brown

Abstract

Purpose: To understand the relative histopathological effects of PEEK particulate debris when applied within the epidural versus the intervertebral disc space. We hypothesized that due to the avascular nature of the intervertebral disc acting as a barrier to immune cells, the intradiscal response would be less than the epidural response. Methods: The inflammatory effects of clinically relevant doses (3 mg/5-kg rabbit) and sizes (1.15 µm diameter) of PEEK implant debris were assed when placed dry on epidural and intradiscal tissues in an in vivo rabbit model. The size of the particulate was based on wear particulate analysis of wear debris generated from simulator wear testing of PEEK spinal disc arthroplasty devices. Local and systemic gross histology was evaluated at the 3- and 6-month time points. Quantitative immunohistochemistry of local tissues was used to quantify the common inflammatory mediators TNF-α, IL-1β, and IL-6. Results: Both treatments did not alter the normal appearance of the dura mater and vascular structures; however, limited epidural fibrosis was observed. Epidural challenge of PEEK particles resulted in a significant (30 %) increase (p < 0.007) in TNF-α and IL-1β at both 3 and 6 months compared to that of controls, and IL-6 at 6 months (p < 0.0001). Intradiscal challenge of PEEK particles resulted in a significant increase in IL-1β, IL-6 and TNF-α at 6-months post-challenge (p ≤ 0.03). However, overall there were only moderate increases in the relative amount of these cytokines when compared with surgical controls (10–20 %). In contrast, epidural challenge resulted in a 50–100 % increase. Conclusions: The results of this study are similar to past investigations of PEEK, whose results have not been shown to elicit an aggressive immune response. The degree to which these results will translate to the clinical environment remains to be established, but the pattern of subtle elevations in inflammatory cytokines indicated both a mild persistence of responses to PEEK debris, and that intradiscal implant debris will likely result in less inflammation than epidural implant debris.

Link to Article

http://dx.doi.org/10.1007/s00586-013-2904-4

Intracortical Bone Remodeling Variation Shows Strong Genetic Effects

Authors

L. M. Havill, M. R. Allen, J. A. K. Harris, S. M. Levine, H. B. Coan, M. C. Mahaney, D. P. Nicolella

Abstract

Intracortical microstructure influences crack propagation and arrest within bone cortex. Genetic variation in intracortical remodeling may contribute to mechanical integrity and, therefore, fracture risk. Our aim was to determine the degree to which normal population-level variation in intracortical microstructure is due to genetic variation. We examined right femurs from 101 baboons (74 females, 27 males; aged 7–33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po). Through evaluation of the covariance in intracortical properties between pairs of relatives, we quantified the contribution of additive genetic effects (heritability [h 2]) to variation in these traits using a variance decomposition approach. Significant age and sex effects account for 9 % (Ct.Po) to 21 % (W.Th) of intracortical microstructural variation. After accounting for age and sex, significant genetic effects are evident for On.Ar (h 2 = 0.79, p = 0.002), %On.B (h 2 = 0.82, p = 0.003), and W.Th (h 2 = 0.61, p = 0.013), indicating that 61–82 % of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48–75 % of the total phenotypic variance. Our results demonstrate that normal, population-level variation in cortical microstructure is significantly influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.

Link to Article

http://dx.doi.org/10.1007/s00223-013-9775-x

Production and repair of implant-induced microdamage in the cortical bone of goats after long-term estrogen deficiency

Authors

Z. Yu, G. Wang, T. Tang, L. Fu, X. Yu, L. Cao, Z. Zhu, K. Dai, S. Qiu

Abstract

Summary: By using an ovariectomized goat model, we found that estrogen depletion decreases bone quality and makes it susceptible to screw-induced mechanical microdamage. Both diffuse microdamage and linear cracks accumulated up to 3 weeks after screw implantation, and the microdamage was repaired gradually after 4–8 months. Introduction: The aim of this study was to observe the effect of long-term estrogen deficiency on the creation and repair of microdamage in cortical bone adjacent to bone screw. Methods: Cortical bone screws were placed in the tibial diaphyses 28 months after ovariectomy (OVX) or sham operation (Sham-Op) in female goats. The goats were euthanized at 0 day, 21 days, 4 months, and 8 months after screw implantation. Microdamage morphology and repair were examined in peri-screw bone using histomorphometric method, and the nanomechanical properties of peri-screw bone were examined with nanoindentation testing. Results: Tibiae from ovariectomized goats in which screws had been placed had significantly higher levels of diffuse microdamage and significantly more linear cracks than those from sham goats, and the diffuse microdamage was more obvious than linear cracks in the region adjacent to the implant. Both diffuse microdamage and linear cracks accumulated up to day 21 and then gradually repaired at 4 and 8 months after surgery. The trend for bone remodeling in each group was consistent with changes in the level of microdamage. Nanoindentation testing showed that both elastic modulus and hardness in peri-screw bone were significantly decreased in OVX group compared to Sham-Op group. The hardness and elastic modulus also showed a downward trend up to 4 months after screw implantation and then exhibited some recovery after 8 months. Conclusions: Estrogen depletion decreases bone quality and makes it vulnerable to screw-induced mechanical damage, which may compromise the initial stability of an orthopedic implant.

Link to Article

http://dx.doi.org/10.1007/s00198-013-2496-1

Effect of maxillomandibular fixation on condylar growth in juvenile Macaca mulatta: a cephalometric and histologic study

Authors

Goran Isacsson, David S. Carlson, James A. McNamara, Jr. and Annika M. Isberg

Abstract

The effect of maxillomandibular fixation on the growth of the mandibular condyle was studied in eight control and eight experimental male juvenile monkeys. All animals had metallic implants placed throughout the craniofacial complex in order to facilitate cephalometric analysis of growth-related changes in the maxillomandibular complex during jaw immobilization. Every 3, 6, 12, and 24 wk after insertion of the appliance two experimental animals were killed for histologic analysis. Cephalometric analysis indicated no major deviation from normal maxillary or mandibular growth in the experimental animals. The condylar growth in the experimental animals was comparable with that of the controls. Histologic analysis indicated that the articular connective tissue in experimental joints remained the same thickness as in the controls. On the postero-superior aspect of the condyle, the thickness of the prechondroblastic-chondroblastic cell layer was reduced by 70-80% in the experimental animals. On the posterior aspect this cell layer was not visible after 12 wk of fixation, but was replaced by a periosteum-like, cell-rich tissue which appeared to be active in appositional formation of cancellous bone. These results indicate that long-term maxillomandibular fixation does not cause major alterations in the growth of condyle or the entire mandible despite a profound decrease of the prechondroblastic-chondroblastic cell layer in the postero-superior and posterior regions of the condyle. The growth is probably due to a compensatory appositional bone formation along the surface of the condyle. It is also concluded that jaw mobility is not a prerequisite for normal maxillary or mandibular growth.

Link to Article

http://prod.umdentistry.com/sites/default/files/departments/opd/090.pdf