Combination of local and systemic parathyroid hormone enhances bone regeneration.

Parathyroid hormone is one of the most promising therapeutic agents for osteoporosis, but its use to facilitate bone regeneration in osseous defects is less clear. The purpose of the current study was to determine the effects of combining systematic parathyroid hormone and a local parathyroid hormone gene therapy in a critical-sized osteotomy model. Rats received bilateral femoral osteotomies followed by implantation of a gene-activated matrix encoding parathyroid hormone (1-34) on one side and a control gene-activated matrix on te opposite side. Systematic parathyroid hormone (1-34) or vehicle was injected daily and rats were sacrificed 6 weeks later. Systematic parathyroid hormone increased bone mineral density and bone mineral content measured by dual-energy xray absorptiometry analysis of tibias and vertebrae, and increased serum osteocalcin levels during healing of osteotomies. Furthermore, comparing osteotomy sites that received the same gene-activated matrices as vehicle-injected rats, parathyroid hormone-injected rats showed trends of greater bone areas via histomorphometric and microradiographic analyses and higher osteocalcin messenger ribonucleic acid expression via Northern blot analyses. The combination of systemic and local parathyroid hormone led to higher bone mineral density, bone mineral content, and bone area, a trend for greater radiographic-detected bone area and higher expression of osteocalcin in osteotomy sites when compared with the individual treatment or control groups. Local parathyroid hormone gene therapy enhanced the anabolic effect of systemic parathyroid hormone during osteotomy healing. This study supports the concept of a combined local and systemic approach for enhancing the repair of a fracture at risk for nonunion.

Mouse model for thoracic congenital scoliosis.

SUMMARY: This study sought to produce a dose-response curve for acute and chronic maternal carbon monoxide (CO) exposure versus vertebral anomalies in mouse offspring and to determine the critical day of exposure. In Part I, pregnant CD-1 mice were exposed to an acute dose of CO at 9 days of gestation. A positive dose-response relationship of acute maternal CO exposure and vertebral anomalies in the offspring was produced. In Part II, pregnant females were exposed to chronic CO for the first 11 days of gestation. Chronic exposure to CO did not produce significant vertebral anomalies. In Part III, pregnant females were exposed to an acute dose of 600 ppm of CO at gestation day 8, 9, or 10. Day 9 in this mouse breed is the critical day for maternal exposure to CO. The detected anomalies were predominately in the thoracic spine.

Biomechanical evaluation of calcium phosphate cement-augmented fixation of unstable intertrochanteric fractures.

OBJECTIVE: The purpose of this study was to evaluate the mechanical effects of using an injectable calcium phosphate cement, Norian Skeletal Replacement System (SRS), which is replaced by the native remodeling process, to augment sliding hip screw fixation of unstable intertrochanteric fractures in a cadaver model. DESIGN: Ten matched pairs of human cadaver femora were used. One randomly selected femur from each pair was designated as experimental, whereas the contralateral femur served as the control. SETTING: Testing was performed in the Orthopaedic Research Laboratories, The University of Michigan, Ann Arbor, Michigan, U.S.A. PATIENTS/PARTICIPANTS: Femora with no radiographic evidence of pathology and with below-normal bone mineral density in the neck region were accepted into the study. INTERVENTION: Three-part, intertrochanteric fractures were repaired by using a sliding hip screw and sideplate, without replacement of the posteromedial fragment. In the experimental side of each pair, SRS was used to grout the hip screw and to fill the posteromedial defect. MAIN OUTCOME MEASUREMENTS: Femora were subjected to simulated single-leg stance loading to approximately one body weight in a servohydraulic testing machine. Measurements of stiffness, medial bone surface strain, hip screw displacement, and sideplate strain were made in fractured femora. Stiffness and medial bone surface strain baseline data were obtained in the intact bone before fracture creation as well. RESULTS: Augmenting fixation with Norian SRS increased the fracture construct stiffness and minimized sliding hip screw displacement. It also maintained medial bone surface strain closer to the intact state and lowered sideplate strain relative to controls. However, there was no difference in the load to failure between SRS-augmented and control femora. CONCLUSIONS: SRS augmentation of unstable, intertrochanteric fractures significantly improved overall stability, facilitated load transfer across the fracture, and decreased both shortening of the proximal femur and stress on the sliding hip screw.

Effects of long-term administration of vitamin D3 analogs to mice.

This study explores the effects of chronic administration of vitamin D(3) compounds on several biological functions in mice. Knowledge of long-term tolerability of vitamin D(3) analogs may be of interest in view of their potential clinical utility in the management of various pathologies such as malignancies, immunological disorders and bone diseases. Four unique vitamin D(3) analogs (code names, compounds V, EO, LH and LA) and 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) were administered i.p. for 55 weeks to Balb/c mice. Each analog had previously been shown to have potent in vitro activities. After 55 weeks of administration, the mice had a profound decrease in their serum levels of interleukin-2 (IL-2). Likewise, several analogs depressed serum immunoglobulin G concentrations (compounds LH and LA), but levels of blood lymphocytes and splenic lymphocyte subsets (CD4, CD8 and CD19) were not remarkably depressed. The percent of committed myeloid hematopoietic stem cells was 4- to 5-fold elevated in the bone marrow of the mice that received analogs LH and V; nevertheless, their peripheral blood white and red cell counts and platelets were not significantly different in any of the groups. The mice that received 1,25(OH)(2)D(3) had a decrease in bone quantity and quality with a decrease in cross-sectional area and cortical thickness, and a 50% reduction in both stiffness and failure load compared with the control group. In contrast, the cohort that received a fluorinated analog (compound EO) developed bones with significantly larger cross-sectional area and cortical thickness as well as stronger mechanical properties compared with the control group. At the conclusion of the study, body weights were significantly decreased in all experimental mice. Their blood chemistries were normal. Extensive gross and microscopic autopsy analyses of the mice at the conclusion of the study were normal, including those of their kidneys. In conclusion, the vitamin D(3) analogs were fairly well tolerated. They did suppress immunity as measured by serum IL-2 and may provide a means to depress the immune response after organ transplantation and for autoimmune diseases. Use of these analogs prevented the detrimental effects of vitamin D(3) administration on mechanical and geometric properties of bone, while one analog (compound EO) actually enhanced bone properties. These results suggest that long-term clinical trials with the analogs are feasible.

Biomechanical and histological evaluation of a calcium phosphate cement.

It is often difficult to achieve stable fixation of a comminuted fracture associated with a metaphyseal defect. The injection of a resorbable cement into an osseous defect may help to stabilize the fracture and to maintain osseous integrity as the cement is resorbed and replaced by bone. The purpose of the present study was to evaluate the repair of a metaphyseal defect after treatment with an injectable calcium-phosphate cement. The injectable cement undergoes isothermic curing in vivo to form a carbonated apatite (dahllite) with a compressive strength of twenty-five megapascals. Either the cement or allograft bone was placed in proximal tibial metaphyseal and distal femoral metaphyseal defects in seventy-two dogs and was evaluated from twenty-four hours to seventy-eight weeks postoperatively. Histological examination showed that the cement was osteoconductive; nearly the entire surface area was covered with bone two weeks after the injection. The resulting bone-cement composite underwent gradual remodeling over time in a pattern that was qualitatively similar to the remodeling of normal cortical and cancellous bone. Osteoclasts were found to resorb the cement and were usually associated with adjacent new-bone formation. With increasing time in vivo, the cement was penetrated by small blood vessels that became surrounded by circumferential lamellae of bone and that closely resembled evolving haversian systems. This process occurred more rapidly in the cortex than in the medulla. Mechanical testing showed that, by eight weeks, the tibiae that had been treated with cement had reached nearly 100 per cent of the torsional strength of the contralateral, control (intact) tibiae; this finding paralleled the histological observations of bone apposition to the cement and rapid restoration of the cortex. At no time was fibrous tissue present between the cement and the bone, and there was no evidence of acute inflammation. Small particles of cement were present within occasional macrophages during the process of cement resorption, but the macrophages disappeared over time and were not associated with fibrosis or unexpected resorption of bone. Resorption of the cement was incomplete in the medullary area at seventy-eight weeks, but the pattern of cement resorption and bone-remodeling suggested gradual restoration of a physiological proportion of bone and marrow in both the cortical and the medullary region with maintenance of mechanical function.

Pubic symphysis repair strength in simulated bladder exstrophy using a sheep model.

OBJECTIVES: To investigate the mechanical strength of various pubic symphysis suture material in a simulated animal model of neonatal bladder exstrophy. METHODS: Neonatal lamb pelves, which are the approximate size of neonatal human pelves, were used. Twenty-four neonatal lamb pelves were divided into four equal groups. A midline symphysotomy was made through the cartilaginous pubic symphysis in three groups and repaired using two figure-of-eight sutures (size 0) placed through the cartilaginous pubis using polypropylene, braided polyester, or polyglactin. The fourth group served as the control. The pelves were then tested to ultimate load in pure tension at a strain rate of 0.25 mm/s until failure. RESULTS: There was a highly significant difference between the intact specimens and the repaired specimens (P = 0.0008). For the repaired specimens, there was a significant difference in the ultimate load normalized by pubic height between those repaired with polypropylene and polyglactin (P = 0.025), but not for those repaired with polypropylene and braided polyester (P = 0.11) or braided polyester and polyglactin (P = 0.11). CONCLUSIONS: Braided resorbable sutures are recommended for pubic symphysis repair, because they have a lower tendency to cut out of the cartilage.

Biomechanical study of sternal closure using rigid fixation techniques in human cadavers.

BACKGROUND: We believe rigid plate fixation may be superior to wire fixation in sternal closure, as rigid fixation used in the craniofacial skeleton has shown greater stability, lower postoperative pain, and accelerated bone healing. We hypothesize that sterna fixed with titanium plates are more stable mechanically than sterna fixed with wires. METHODS: The sterna from human cadavers were used in this two-phased study. Phase I compared wires to four-hole titanium straight plates. Phase II compared wires to four-hole titanium custom H plates. The sterna were tested biomechanically using all fixation methods. RESULTS: Phase I showed no statistically significant difference in the stiffness or lateral displacement between the wired and straight plated sterna. Phase II showed a statistically significant greater stiffness (p < 0.05) and less lateral displacement (p < 0.05) in the custom plated sterna over the wired sterna. CONCLUSIONS: Our results showed that custom titanium H plates were superior to wire fixation. Furthermore, our results established the importance of plate configuration in sternal fixation. Our study may have beneficial clinical implications, as decreased motion at the sternotomy site could mean less postoperative pain, a decreased incidence of infection, and accelerated bone healing.

Hip screw augmentation with an in situ-setting calcium phosphate cement: an in vitro biomechanical analysis.

OBJECTIVES/HYPOTHESIS: This study was performed to determine whether a new, in situ-setting calcium phosphate cement would have sufficient mechanical integrity to reinforce compression screw fixation of unstable intertrochanteric fractures. We compared the cut-out resistance of screws augmented with calcium phosphate cement to the cut-out resistance of screws augmented with polymethylmethacrylate (PMMA). We used PMMA as the standard for comparison because it is currently used clinically. Our hypothesis was that initial fixation strength with PMMA and calcium phosphate cement augmentation would not be significantly different from one another. STUDY DESIGN: Cut-out testing of compression hip screws in paired human cadaveric proximal femurs was performed before and after augmentation with PMMA or calcium phosphate cement. Bilateral testing was performed to allow pairwise comparisons of the materials used for augmentation, and repeated testing was done to provide an internal control for the effects of bone quality. The initial fixation of screws augmented with calcium phosphate cement was compared with that of screws augmented with PMMA. METHODS: Ten paired human femurs (mean age, 75 +/- 9.2 years) were implanted with Richards AMBI compression hip screws. Basicervical osteotomies were then performed, yielding isolated proximal fragments for mechanical testing. Preaugmentation cut-out tests were performed under displacement control, with cut-out continuing to five millimeters at two millimeters per second. The screws were then removed, and the screw tracks were filled with 2.0 cubic centimeters of PMMA (one side) or calcium phosphate cement (contralateral side). After augmentation, the screws were reinserted and the cements were allowed to harden for twenty-four hours. Postaugmentation testing followed the protocols for preaugmentation testing, and the initial fixation strength of screws augmented with calcium phosphate cement was compared with the initial fixation strength of screws augmented with PMMA using a two-way repeated measures analysis of variance. RESULTS: The cut-out behavior of screws augmented with calcium phosphate cement was not significantly different from the cut-out behavior of screws augmented with PMMA. With calcium phosphate cement, yield strength increased by 15.8 percent (from 1,354 +/- 632 newtons to 1,568 +/- 320 newtons); with PMMA, the yield strength increased by 26.8 percent (from 1,477 +/- 526 newtons to 1,834 +/- 225 newtons). However, only the increase with PMMA augmentation was significant at p < 0.05). The energy to yield increased significantly (41 percent, p < 0.05) with both types of augmentation (from 2,399 +/- 1,186 newton-millimeters to 3,378 +/- 857 newton-millimeters for calcium phosphate cement, and from 2,635 +/- 1,113 newton-millimeters to 3,741 +/- 426 newton-millimeters for PMMA), whereas the stiffness increased only slightly with PMMA augmentation (6.2 percent, from 481 +/- 180 newtons per millimeter to 511 +/- 92 newtons per millimeter) and fell slightly with calcium phosphate cement augmentation (10 percent, from 457 +/- 201 newtons per millimeter to 411 +/- 663 newtons per millimeter). CONCLUSIONS: The in situ-setting calcium phosphate cement investigated in this study compared favorably with PMMA in a single-cycle cut-out test of augmented compression hip screws in senile trabecular bone. Our results suggest that these materials may have promise as substitutes for PMMA in the salvage of compression hip screw fixation in elderly osteopenic patients with complex intertrochanteric fractures and that further study of their use in this application is warranted.