David G. Little

Bone remodeling during fracture repair : The cellular picture

Fracture healing is a complex event that involves the coordination of a variety of different processes. Repair is typically characterized by four overlapping stages: the initial inflammatory response, soft callus formation, hard callus formation, initial bony union and bone remodeling. However, repair can also be seen to represent a juxtaposition of two distinct forces: anabolism or tissue formation, and catabolism or remodeling. These anabolic/catabolic concepts are useful for understanding bone repair without giving the false impression of temporally distinct stages that operate independently. They are also relevant when considering intervention. In normal bone development, bone remodeling conventionally refers to the removal of calcified bone tissue by osteoclasts. However, in the context of bone repair there are two phases of tissue catabolism: the removal of the initial cartilaginous soft callus, followed by the eventual remodeling of the bony hard callus. In this review, we have attempted to examine catabolism/remodeling in fractures in a systematic fashion. The first section briefly summarizes the traditional four-stage view of fracture repair in a physiological manner. The second section highlights some of the limitations of using a temporal rather than process-driven model and summarizes the anabolic/catabolic paradigm of fracture repair. The third section examines the cellular participants in soft callus remodeling and in particular the role of the osteoclast in endochondral ossification. Finally, the fourth section examines the effects of delaying osteoclast-dependent hard callus remodeling and also poses questions regarding the crosstalk between anabolism and catabolism in the latter stages of fracture repair.

The incorporation of strontium and zinc into a calcium-silicon ceramic for bone tissue engineering.

In this study we developed novel scaffolds through the controlled substitution and incorporation of strontium and zinc into a calcium-silicon system to form Sr-Hardystonite (Sr-Ca(2)ZnSi(2)O(7), Sr-HT). The physical and biological properties of Sr-HT were compared to Hardystonite (Ca(2)ZnSi(2)O(7)) [HT]. We showed that Sr-HT scaffolds are porous with interconnected porous network (interconnectivity: 99%) and large pore size (300-500 microm) and an overall porosity of 78%, combined with a relatively high compressive strength (2.16+/-0.52 MPa). These properties are essential for enhancing bone ingrowth in load-bearing applications. Sr-HT ceramic scaffolds induced the attachment and differentiation of human bone derived cells (HOB), compared to that for the HT scaffolds. Sr-HT scaffolds enhanced expression of alkaline phosphatase, Runx-2, osteopontin, osteocalcin and bone sialoprotein. The in vivo osteoconductivity of the scaffolds was assessed at 3 and 6 weeks following implantation in tibial bone defects in rats. Histological staining revealed rapid new growth of bone into the pores of the 3D scaffolds with the Sr-HT and HT, relative to the beta-tricalcium phosphate (beta-TCP). In vivo, HT and Sr-HT produced distinct differences in the patterns of degradation of the materials, and their association with TRAP positive osteoclast-like cells with HT appearing more resistant compared to both Sr-HT and beta-TCP.

Optimal Timing of a Single Dose of Zoledronic Acid to Increase Strength in Rat Fracture Repair

We hypothesized that ZA treatment would bolster fracture repair. In a rat model for closed fracture healing, a single dose of ZA at 0, 1, or 2 wk after fracture significantly increased BMC and strength of the healed fracture. Delaying the dose (1 or 2 wk after fracture) displayed superior results compared with dosing at the time of fracture.

Novel Role of Y1 Receptors in the Coordinated Regulation of Bone and Energy Homeostasis

The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1-/- mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1-/- mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.

The Effect of Limb-Length Discrepancy on Gait*

We evaluated the gait of thirty-five neurologically normal children who had a limb-length discrepancy of the lower extremities that ranged from 0.8 to 15.8 per cent of the length of the long extremity (0.6 to 11.1 centimeters). The twenty-two boys and thirteen girls had an average age of thirteen years (range, eight to seventeen years). No patient had a substantial angular or rotational deformity of the lower extremities. We found no correlation between the actual discrepancy or the per cent discrepancy and any of the dependent kinematic or kinetic variables, including pelvic obliquity. Discrepancies of less than 3 per cent of the length of the long extremity were not associated with compensatory strategies. When a discrepancy was 5.5 per cent or more, more mechanical work was performed by the long extremity and there was a greater vertical displacement of the center of body mass. Clinically, this degree of discrepancy was manifested by the use of toe-walking as a compensatory strategy. Children who had less of a discrepancy were able to use a combination of compensatory strategies to normalize the mechanical work performed by the lower extremities.

Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats.

Osteonecrosis (ON) of the femoral head in childhood can lead to loss of femoral head architecture and subsequent deformity. When femoral head ON was surgically induced in 24 rats, zoledronic acid treatment and prophylaxis improved sphericity and maintenance of architecture at 6 weeks. This preliminary experiment supports the use of bisphosphonates in childhood ON.

Manipulation of the Anabolic and Catabolic Responses With OP‐1 and Zoledronic Acid in a Rat Critical Defect Model

Bone repair involves both anabolic and catabolic responses. We hypothesized that anabolic treatment with OP‐1 (BMP‐7) and anti‐catabolic treatment with zoledronic acid could be synergistic. In a rat critical defect, this combination therapy produced significant increases in new bone volume and strength.

Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling

INTRODUCTION It has been widely assumed that osteoclasts play a pivotal role during the entire process of fracture healing. Bisphosphonates (BPs) are anti-catabolic agents commonly used to treat metabolic bone diseases including osteoporosis, minimizing fracture incidence. Yet, fractures do occur in these patients and the potential for negative effects of BPs on healing has been suggested. We aimed to examine the effect of different dosing regimes of the potent BP zoledronic acid (ZA) on early endochondral fracture repair and later callus remodeling in a normal bone healing environment. METHODS Saline, a Bolus dose of 0.1 degrees mg/kg ZA or 5 weekly divided doses of 0.02 degrees mg/kg of ZA commenced 1 week post operatively in a rat closed fracture model. Samples at 1, 2, 4 and 6 weeks post fracture were used to analyze initial fracture union, and 12 and 26 weeks post fracture to investigate the progress of remodeling. RESULTS ZA did not alter the rate of endochondral fracture union. All fractures united by 6 weeks, with no difference in the progressive reduction of cartilaginous soft callus between control and treatment groups over time. ZA treatment increased hard callus bone mineral content (BMC), volume and increased callus strength at 6 and 26 weeks post fracture. Hard callus remodeling commenced at 4 weeks post fracture with Bolus ZA treatment but was delayed until after 6 weeks in the Weekly ZA group. By 12 and 26 weeks, Bolus ZA had equivalent callus content of remodeled neo-cortical bone to the Saline controls, whereas Weekly ZA remained reduced compared to Saline controls at these times (P<0.01). Callus material properties such as peak stress were significantly reduced in both ZA groups at 6 weeks. At 26 weeks, Bolus ZA-treated calluses generated peak stress equivalent to control values, whereas Weekly ZA callus peak stress remained significantly reduced, indicating remodeling delay. CONCLUSIONS Osteoclast inhibition with ZA does not delay endochondral fracture repair in healthy rats. Bolus ZA treatment increased net callus size and strength at 6 weeks while allowing hard callus remodeling to proceed in the long term, albeit more slowly than control. Prolonged bisphosphonate dosing during repair does not delay endochondral ossification but can significantly affect remodeling long after the drug is ceased.

Zoledronic Acid Prevents Osteopenia and Increases Bone Strength in a Rabbit Model of Distraction Osteogenesis

Prolonged healing times and stress‐shielding osteopenia remain problematic in distraction osteogenesis. In this study of 30 rabbits, zoledronic acid increased regenerate volume, mineralization, and tibial strength and prevented osteopenia over a 6‐week period. Translation to the clinical setting, if safe, could improve outcomes in distraction osteogenesis in children.

Hypothalamic Regulation of Cortical Bone Mass: Opposing Activity of Y2 Receptor and Leptin Pathways

NeuropeptideY–, Y2 receptor (Y2)‐, and leptin‐deficient mice show similar anabolic action in cancellous bone but have not been assessed in cortical bone. Cortical bone mass is elevated in Y2−/− mice through greater osteoblast activity. In contrast, leptin deficiency results in reduced bone mass. We show opposing central regulation of cortical bone.