Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment.

BACKGROUND: Cyclooxygenase-2-specific anti-inflammatory drugs (coxibs) and nonspecific nonsteroidal anti-inflammatory drugs have been shown to inhibit experimental fracture-healing. The present study tested the hypothesis that these effects are reversible after short-term treatment. METHODS: With use of a standard model of fracture-healing, identical ED50 dosages of either a nonsteroidal anti-inflammatory drug (ketorolac), a coxib (valdecoxib), or vehicle (control) were orally administered to rats for either seven or twenty-one days and fracture-healing was assessed with biomechanical, histological, and biochemical analyses. RESULTS: When healing was assessed at twenty-one days, the seven-day treatment produced only a trend for a higher rate of nonunion in valdecoxib and ketorolac-treated animals as compared with controls. No differences were observed at thirty-five days. The twenty-one-day treatment produced significantly more nonunions in valdecoxib-treated animals as compared with either ketorolac-treated or control animals (p < 0.05), but these differences disappeared by thirty-five days. The dose-specific inhibition of these drugs on prostaglandin E2 levels and the reversibility of the effects after drug withdrawal were assessed in fracture calluses and showed that ketorolac treatment led to twofold to threefold lower levels of prostaglandin E2 than did valdecoxib. Withdrawal of either drug after six days led to a twofold rebound in these levels by fourteen days. Histological analysis showed delayed remodeling of calcified cartilage and reduced bone formation in association with valdecoxib treatment. CONCLUSIONS: Cyclooxygenase-2-specific drugs inhibit fracture-healing more than nonspecific nonsteroidal anti-inflammatory drugs, and the magnitude of the effect is related to the duration of treatment. However, after the discontinuation of treatment, prostaglandin E2 levels are gradually restored and the regain of strength returns to levels similar to control.

Mechanics of avian fibrous periosteum: tensile and adhesion properties during growth.

We report the results of direct mechanical tests of the fibrous periosteum from the tibiotarsi of white leghorn chicks at 4, 6, 8, 9, 10, 11, 12, and 14 weeks of age using a newly developed sample isolation technique. Additionally, this technique allows the determination of the apparent in vivo load on the fibrous periosteum. The periosteum has a highly nonlinear stress-strain relationship at all ages. For loading below the in vivo level, the periosteum is pliant and mean tensile modulus is 3.35 MPa (+/- 1.84 SD, n = 75). For loading above the in vivo level, tensile stiffness is nearly two orders of magnitude greater. In the region of high stiffness, mean modulus is 229.5 MPa (+/- 89.6, n = 72). In vivo, the periosteum is loaded at the transition between these two stiffness regions. We interpret this as indicating that, in vivo, the collagen fibers of the periosteum are aligned, but subject to minimal loading. Stress levels in the periosteum corresponding to in vivo conditions indicate modest loading, and mean apparent in vivo stress levels are 0.92 MPa (+/- 0.37 SD, n = 67). A second technique demonstrated that the adhesion of the periosteum in the diaphyseal region (1-6 weeks of age) is minimal, but is substantial in the metaphyseal region. The metaphyseal adhesion will affect the transmission of load between the physes. These studies suggest that growth of the fibrous periosteum follows the longitudinal growth of the bone, rather than the periosteum having a direct mechanical influence on growth plate activity. Comparison of tensile properties over the course of growth indicates a substantial increase in periosteal stiffness in the early portion of the growth period, which reaches a maximum at approximately 9 weeks posthatching. There is also a marked decline in periosteal stiffness as growth rate declines in the latest stages of growth (14 weeks). This suggests that the basic properties of periosteal collagen may undergo a transition during the course of this tissue's brief functional lifetime; that is, during long bone growth.

The role of osteocytes in bone regulation: mineral homeostasis versus mechanoreception.

Early work on the role of osteocytes in bone regulation suggested that the primary function of these cells was osteolysis. This lytic function was not precisely defined but included mineral homeostasis and at least the initiation of matrix remodeling, if not a primary role in remodeling. This paper is an attempt to promote the concept of osteocytic osteolysis as a method of systemic mineral homeostasis and to separate it from bone remodeling. Although recent investigations have pointed to mechanotransduction as a primary function of osteocytes, resulting in a general abandonment of the osteocytic osteolysis concept, the corpus of evidence suggests that osteocytes likely have a multipurpose role in the biology of bone. The osteocyte network represents an enormous surface area over which the cells interface with the surrounding matrix, useful for both strain detection and matrix mineral access. Osteocytes have been found to possess receptors for PTH, a known regulator of mineral ion homeostasis. Cultured osteocytes placed on dentin slices demonstrated no capacity to pit the dentin, but they were not treated with a regulating factor such as PTH, nor does mineral homeostasis require substantial bone volume removal. Scaling relationships suggest that osteocyte density is inversely proportional to body mass, R(2) = 0.86, and thus directly proportional to metabolic rate. Thus, species with higher metabolic rates (and therefore a greater demand for immediate access to minerals) have more osteocytes per bone volume. Finally, osteocytes express molecules typically associated with nerve cells and which are involved with glutamate neurotransmission. By this system, almost instantaneous messages may be transmitted throughout the network, an important feature in cells whose homeostatic function would be utilized on a scale of seconds, rather than hours or days. Experimental procedures for determining the role of the osteocyte in mineral homeostasis would require calcium mobilization from the bone matrix on a relatively immediate time scale. The experimental procedure would then be coupled with a high resolution histomorphometric analysis of lacunar radiographic area and mineral density. Added to this would be an in vitro study of mineral activation capacity via cultured osteocytes treated with PTH. Osteocytic osteolysis would be confirmed by an increase in the demineralized volume of osteocytic lacunae and the identification of a chemical mechanism by which osteocytes can readily access the mineral portion of their immediate bone matrix. It should also be true that a reverse capacity exists by which osteocytes can remineralize their immediate matrix utilizing alkaline phosphatase for example, a chemical which they, like osteoblasts, are known to generate. It is thus proposed that osteocytes are both mechanoreceptors and systemic mineral homeostasis regulators.

Computer-assisted screw insertion into the first sacral vertebra using a three-dimensional image intensifier: results of a controlled experimental investigation.

Currently there are few data available regarding the application and efficacy of computer-assisted procedures in the sacral spine. In order to optimize and standardize this procedure, a controlled experimental investigation has been performed. The aim of the study is to systematically assess the efficacy of a novel three-dimensional image intensifier used for navigated transiliac screw insertion into the first sacral vertebra. Screws were inserted iliosacrally into the first sacral vertebra of preserved human cadaver specimens. The instrument navigated procedure was performed with the "Siremobil Iso-C(3D) " (Siemens Medical Solutions) and the "Navigation System" by Stryker. The accuracy and quality of the imaging procedure as well as the fluoroscopic exposure times were measured. These results were compared to three control groups (CT-based navigation, C-arm navigation, and fluoroscopic guidance). In each group a total amount of 20 screws was implanted. Screw position was postoperatively assessed by Iso-C(3D) or CT-scan. The navigated procedure using the Iso-C(3D) provided good feasibility characteristics without requiring a specific matching process. It revealed the shortest procedure time of all navigated procedures and significantly decreased fluoroscopic time compared to C-arm navigation and fluoroscopic guidance. Furthermore, Iso-C(3D) navigation showed no screw malposition and was in this regard superior to C-arm navigated and fluoroscopic guided procedures. The quality of imaging was sufficient for accurate placement, but did not share the high-resolution level of CT-based navigation. These findings indicate that application of the Iso-C(3D) for navigated transiliac screw insertion into S1 can be recommended as a feasible and safe technique, enabling the surgeon to reduce procedure and fluoroscopic time. Further progress in improving the quality of the Iso-C(3D) image should be attempted.

The mechanical behaviour of a novel mammalian intervertebral joint.

The mechanics of mammalian intervertebral joints are complicated by the viscoelastic nature of the connective tissues joining vertebrae, and by multiple vertebral articulations and complex morphologies. Further, interspecific variation in these structures can greatly compound their functional variation between species, making comparative mechanical analyses even more difficult. Despite these sources of variation however, mammalian intervertebral joints universally exhibit a creep relaxation behaviour based on the viscoelastic nature of the soft tissue joint. We have evaluated, in 6 degrees of freedom, the mechanical signature of a novel mammalian lumbar intervertebral joint found in the Scutisorex spine, and compared it with a more typical mammalian joint in the Rattus (rat) lumbar spine. Scutisorex, the hero shrew, is an East African species of shrew with what is likely the most highly modified vertebral morphology in the entire history of mammals. Thus we decided to evaluate the mechanical behaviour of the intervertebral joint of this species, comparing it with a more representative mammal species in Rattus. We built a custom, 6 degrees of freedom, intervertebral joint transducer and a combined axial moment and load application system in order to quantify and compare the complex mechanical behaviour of these joints. Our results suggest that the Scutisorex joint is 5 times more resilient to simple axial torsion per body mass unit than Rattus, and that the complex load (combined axial compression and torsion) mechanical signature of Scutisorex is probably novel among all mammalian intervertebral joints. Under significant but physiological axial compression the Scutisorex intervertebral joint demonstrates no creep relaxation behaviour, simulating the mechanical behaviour of a rigid construct rather than a viscoelastic joint. The purpose of this rigid intervertebral joint in the ecology of Scutisorex remains unknown.

The dynamics of flight-initiating jumps in the common vampire bat Desmodus rotundus.

Desmodus rotundus, the common vampire bat (Phyllostomidae: Desmodontinae), exhibits complex and variable terrestrial movements that include flight-initiating vertical jumps. This ability is unique among bats and is related to their unusual feeding behavior. As a consequence of this behavior, the wing is expected to have design features that allow both powered flight and the generation of violent jumps. In this study, high-speed cine images were synchronized with ground reaction force recordings to evaluate the dynamics of jumping behavior in D. rotundus and to explore the functional characteristics of a wing operating under competing mechanical constraints. The pectoral limbs are responsible for generating upward thrust during the jump. The hindlimbs stabilize and orient the body over the pectoral limbs. The thumbs (pollices) stabilize the pectoral limb and contribute to extending the time over which vertical force is exerted. Peak vertical force can reach 9.5 times body weight in approximately 30 ms. Mean impulse is 0.0580+/-0.007 N s (mean +/- s.d., N=12), which accelerates the animal to a mean take-off velocity of 2.38+/-0.24 m s-1. A model of the muscular activity during jumping is described that accounts for the characteristic force output shown by these animals during flight-initiating jumps.