Biomedical subjects

David B Burr

Publications and source records attributed to David B Burr.

30 records · Page 2Linked to original sources

PubMed2003

Tissue mineralization is increased following 1-year treatment with high doses of bisphosphonates in dogs.

Suppression of bone turnover using anti-resorptive agents such as bisphosphonates prevents bone loss but also may increase tissue mineralization. This may make the bone more prone to initiate microcracks. The objective of this study was to determine whether suppression of remodeling caused by treatment of dogs for 1 year with five times the clinical dose of either alendronate or risedronate is associated with increased tissue mineralization and whether it changes the nature of the mineral crystal. Thirty-five dogs were divided into three weight-matched groups and treated daily for 1 year with a subcutaneous injection of saline (CON, n = 12), oral risedronate (RIS, 0.5 mg/kg/day, n = 11), or oral alendronate (ALN, 1.0 mg/kg/day, n = 12). Density fractionation, peripheral quantitative computerized tomography (pQCT), and quantitative backscattered electron microscopy (qBSE) were used to evaluate changes in mineral content of bone tissue from the vertebrae or ribs. Infrared microspectroscopy (IR) and X-ray diffraction were used to assess the quality of the mineral and some aspects of collagen structure in the thoracic vertebrae and iliac crest. Following 12 months of treatment, there was a significant shift toward higher density bone in both ALN (P = 0.04) and RIS (P = 0.002) by density fractionation methods. IR, pQCT, and qBSE did not detect any significant differences in mineralization, probably because of their lower sensitivity and/or because of the smaller region of interest they sample. No significant differences were found in the maturity of the mineral crystals or in their length or size. We conclude that treatment for 1 year with high doses of bisphosphonates which suppress bone remodeling up to 90% increases tissue mineralization, but does not change the nature of the mineral crystal.

Alendronate↗

PubMed2003

Effects of broad frequency vibration on cultured osteoblasts.

Bone is subjected in vivo to both high amplitude, low frequency strain, incurred by locomotion, and to low amplitude, broad frequency strain. The biological effects of low amplitude, broad frequency strain are poorly understood. To evaluate the effects of low amplitude strains ranging in frequency from 0 to 50 Hz on osteoblastic function, we seeded MC3T3-E1 cells into collagen gels and applied the following loading protocols for 3 min per day for either 3 or 7 days: (1) sinusoidal strain at 3 Hz, with 0-3000 microstrain peak-to-peak followed by 0.33 s resting time, (2) "broad frequency vibration" of low amplitude strain (standard deviation of 300 microstrain) including frequency components from 0 to 50 Hz, and (3) sinusoidal strain combined with broad frequency vibration (S + V). The cells were harvested on day 4 or 8. We found that the S + V stimulation significantly repressed cell proliferation by day 8. Osteocalcin mRNA was up-regulated 2.6-fold after 7 days of S + V stimulation, and MMP-9 mRNA was elevated 1.3-fold after 3 days of vibration alone. Sinusoidal stimulation alone did not affect the cell responses. No differences due to loading were observed in alkaline phosphatase activity and in mRNA levels of type I collagen, osteopontin, connexin 43, MMPs-1A, -3, -13. These results suggest that osteoblasts are more sensitive to low amplitude, broad frequency strain, and this kind of strain could sensitize osteoblasts to high amplitude, low frequency strain. This suggestion implies a potential contribution of stochastic resonance to the mechanical sensitivity of osteoblasts.

3T3 Cells↗

PubMed2003

Reconstructed bone end loads on the canine forelimb during gait.

The objective of this work was to determine bone loading conditions that, when applied to a finite element model, would best reproduce the in vivo strain field as measured by surface-mounted strain rosettes. The present study adopts the basic mathematical approach to load reconstruction introduced by Weinans and Blankevoort (J. Biomech. 28 (1995) 739) who determined the relationship between applied loads and bone strain distribution using ex vivo calibration testing. Our method eliminates the need for subsequent ex vivo calibration tests by instead substituting a computational calibration procedure. This first application of the method is with in vivo strains on the canine forelimb during gait (Coleman et al., J. Biomech. 35 (2002) 1677), but with further refinements the method could be used to reconstruct the in vivo loading conditions in living subjects.

Animals↗

PubMed2003

Microfractures and microcracks in subchondral bone: are they relevant to osteoarthrosis?

The existing data are consistent with the view that reactivation of the secondary center of ossification and not the stiffening of the metaphyseal trabecular bone is a mechanism of cartilage loss in idiopathic OA. The stiffening of the subchondral calcified structures would appear to be etiologically incidental and, as the arthrotic process progresses, sometimes locally transient. It is also now clear that although the apparent density of the subchondral cortical plate increases because of thickening of the plate as the OA process progresses, the elastic modulus of the bone might be reduced locally because of increases in vascularization and in the rate of bony remodeling subjacent to the cartilage. Microcracks in the subchondral mineralized tissues might contribute to degeneration of the hyaline cartilage by initiating vascular invasion of the calcified cartilage, leading to reactivation of the tidemark and enchondral ossification with subsequent thinning of the overlying articular cartilage. The thinning would tend to increase shear stresses at the base of the articular cartilage [38], overwhelming the ability of the cartilage to repair itself, resulting in cartilage degeneration. The pathogenesis of cartilage breakdown in OA is a biological and a mechanical process. OA can be understood only if the relationship between the mechanics and the biology is fully appreciated. Failure to properly absorb impact leads to microdamage in the subchondral plate and calcified cartilage. The authors believe that this action causes the secondary center of ossification at the tidemark to advance by enchondral ossification, leading to thickening of the mineralized tissues and thinning of the overlying hyaline articular cartilage. Microcracks will cause the initiation of targeted remodeling, accounting for the increased turnover and reduced material density of the subchondral plate. The resultant thinning of the articular cartilage might lead to initiation of further microdamage in bone and cartilage through a positive feedback mechanism, which can ultimately lead to complete loss of the articular cartilage. In this view, the mechanical overload that initiates microdamage of the subchondral bone provokes a biological response that potentiates the progression of articular cartilage damage in OA.

Aging↗

PubMed2003

Parathyroid hormone enhances mechanically induced bone formation, possibly involving L-type voltage-sensitive calcium channels.

PTH and mechanical loading might act synergistically on bone formation. We tested the in vivo effect of the L-type voltage-sensitive calcium channel (VSCC) blocker, verapamil, on bone formation induced by human PTH-(1-34) (PTH) injection with or without mechanical loading. Adult rats were divided into eight groups: vehicle, verapamil, PTH, or verapamil plus PTH with or without mechanical loading. Verapamil (100 mg/kg) was given orally 90 min before loading. PTH (80 micro g/kg) was injected sc 30 min before loading. Loading applied to tibia and ulna for 3 min significantly increased the bone formation rate on both the endocortical surface of tibia and the periosteal surface of ulna (P < 0.0001). Treatment with PTH enhanced load-induced bone formation by 53% and 76% (P < 0.001) on the endocortical and periosteal surfaces, respectively. Treatment with verapamil suppressed load-induced bone formation rate by 77% and 59% (P < 0.01). Furthermore, verapamil suppressed bone formation in rats subjected to PTH plus loading by 74% and 68% (P < 0.0001) at the tibia and ulna, respectively. In the groups without loading, neither verapamil nor PTH treatment significantly changed any bone formation parameter. This study indicates that L-type VSCCs mediate load-induced bone formation in vivo. Furthermore, PTH enhances load-induced bone adaptation through involvement of L-type VSCCs.

Animals↗

PubMed2003

Bone mineral and collagen quality in humeri of ovariectomized cynomolgus monkeys given rhPTH(1-34) for 18 months.

A recent study of ovariectomized monkeys, treated with recombinant human parathyroid hormone (rhPTH)(1-34) at 1 or 5 mg/kg/day for 18 months or for 12 months followed by 6 months withdrawal from treatment, showed significant differences in the geometry and histomorphometry of cortical bone of the midshaft humerus. To determine the extent to which the rapid bone turnover and cortical porosity induced by rhPTH(1-34) in ovariectomized monkeys modified mineral content, mineral crystal maturity and collagen maturity (cross-link distribution) in the cortical periosteal and endosteal regions, cross-sections of the cortical bone of the mid-humerus, were examined using Fourier transform infrared imaging (FTIRI). FTIRI analyses demonstrated that rhPTH(1-34) altered bone mineral and collagen properties in a dose-dependent manner. Mineral crystal maturity and collagen cross-link ratio (pyridinoline/dehydro-dihydroxylysinonorleucine) on both endosteal and periosteal surfaces decreased relative to ovariectomized animals, consistent with new bone formation. These changes were partially sustained after withdrawal of the higher dose of rhPTH(1-34), suggesting a prolonged after-effect on bone properties for at least two bone remodeling cycles. In conclusion, treatment of ovariectomized monkeys with rhPTH(1-34) had significant effects on cortical bone mineral-to-matrix ratio, mineral crystal maturity, and collagen cross-link ratio. These were fully reversible when the 1-microg rhPTH(1-34) treatment was withdrawn, but only partially reversed when the 5-microg rhPTH(1-34) dose was withdrawn.

Animals↗

PubMed2002

Characterization of dynamic three-dimensional strain fields in the canine radius.

This note describes a method to approximate the 3-D mechanical environment of a long bone during a normal daily activity. Our specific goal was to characterize the temporal and spatial strain distributions in the mid-shaft region of the canine radius during gait. Direct measurement of strains along the entire surface of in vivo bone is not feasible, so we employed a combination of experimental measurements and numerical interpolation techniques to approximate the time-varying longitudinal strain distribution. Using standard in vivo strain gauging techniques, we measured dynamic strains at nine locations (three locations on each of three cross sections, data pooled from two experimental animals) on the canine radius during trotting gait. These in vivo strain measurements were then used to approximate the time course of the strain field for the entire radius mid-shaft region using a 3-D numerical interpolation scheme using finite element basis functions. Despite limitations in the present implementation of the method, the results show that there are considerable time-dependent variations in the strain distribution occurring at different transverse sections along the length of the diaphysis with substantial anteroposterior bending and rotation of neutral axis locations during the gait cycle.

Activities of Daily Living↗

PubMed2002

Effects of biomechanical stress on bones in animals.

The signals that allow bone to adapt to its mechanical environment most likely involve strain-mediated fluid flow through the canalicular channels. Fluid can only be moved through bone by cyclic loading, and the shear stresses generated on bone cells are proportional to the rate of loading. The proportional relation between fluid shear stresses on cells and loading rate predicts that the magnitude of bone's adaptive response to loading should be proportional to strain rate. For lower loading frequencies within the physiologic range, experimental evidence shows this is true. It is also true that the mechanical sensitivity of bone cells saturates quickly, and that a period of recovery either between loading cycles or between periods of exercise can optimize adaptive response. Together, these concepts suggest that short periods of exercise, with a 4-8 h rest period between them, are a more effective osteogenic stimulus than a single sustained session of exercise. The data also suggest that activities involving higher loading rates are more effective for increasing bone formation, even if the duration of the activity is short.

Adaptation, Physiological↗

PubMed2002

Shorter, more frequent mechanical loading sessions enhance bone mass.

PURPOSE: The beneficial effects of exercise on bone mass and strength can be attributed to the sensitivity of bone cells to mechanical stimuli. However, bone cells lose mechanosensitivity soon after they are stimulated. We investigated whether the osteogenic response to a simulated high-impact exercise program lasting 4 months could be enhanced by dividing the daily protocol into brief sessions of loading, separated by recovery periods. METHODS: The right forelimbs of adult rats were subjected to 360 load cycles x d(-1), 3 d x wk(-1), for 16 wk. On each loading day, one group received all 360 cycles in a single, uninterrupted bout (360 x 1); the other group received 4 bouts of 90 cycles/bout (90 x 4), with each bout separated by 3 h. After sacrifice, bone mineral content (BMC), and areal bone mineral density (aBMD) were measured in the loaded (right) and nonloaded control (left) ulnae using DXA. Volumetric BMD (vBMD) and cross-sectional area (CSA) were measured at midshaft and the olecranon by using pQCT. Maximum and minimum second moments of area (I(MAX) and I(MIN)) were measured from the midshaft tomographs. RESULTS: After 16 wk of loading, BMC, aBMD, vBMD, midshaft CSA, I(MAX), and I(MIN) were significantly greater in right (loaded) ulnae compared with left (nonloaded) ulnae in the two loaded groups. When the daily loading regimen was broken into four sessions per day (90x4), BMC, aBMD, midshaft CSA, and I(MIN) improved significantly over the loading schedule that applied the daily stimulus in a single, uninterrupted session (360x1). CONCLUSION: Human exercise programs aimed at maintaining or improving bone mass might achieve greater success if the daily exercise regime is broken down into smaller sessions separated by recovery periods.

Animals↗

PubMed2002

L-type calcium channels mediate mechanically induced bone formation in vivo.

Cell and tissue culture studies suggest that the long-lasting (L-type) voltage-sensitive calcium channels (VSCC) play a role in the signaling cascade in bone cells after mechanical loading. We investigated whether the L-type VSCC mediates mechanically induced bone formation in vivo using two L-type VSCC antagonists verapamil and nifedipine. Female Sprague-Dawley rats were divided into five groups: control group (Veh), two verapamil-treated groups (20 mg/kg, Vera-L; 100 mg/kg, Vera-H), and two nifedipine-treated groups (20 mg/kg, Nife-L; 100 mg/kg, Nife-H). One bout of mechanical loading was applied to the right tibia 90 minutes after oral administration of verapamil or 30 minutes after oral administration of nifedipine. Mechanical loading increased mineralizing surface (MS/bone surface [BS]), mineral apposition rate (MAR), and bone formation rate (BFR/BS) on the endocortical surface in loaded tibias of control animals compared with nonloaded (left) tibias. Verapamil and nifedipine suppressed the load-induced increase in BFR/BS observed in vehicle-treated controls by 56-61% (p < 0.01) and 56-74% (p < 0.01), respectively. Yet, significant differences in MS/BS and BFR/BS between right and left limbs were found in verapamil- and nifedipine-treated animals, indicating that the treatments did not completely abolish load-induced bone formation. This study shows that blocking the L-type calcium channel in vivo substantially suppresses the mechanically induced increase in bone formation that normally would occur and suggests that the L-type calcium channel mediates mechanically induced bone adaptation in vivo.

Animals↗

PubMed2002

The effects of dynamic axial loading on the rat growth plate.

Longitudinal bone growth can be suppressed by compressive loading. In this study, we applied three different magnitudes (17, 8.5, and 4N) of compressive force to growing rat ulnas 10 minutes/day for 8 days and investigated the effects on the distal growth plate biology. Further, to investigate growth rate recovery after cessation of loading, we examined rats 7 days after the loading period. Longitudinal growth of the ulna was suppressed in a dose-dependent manner by applied compressive force. In the 17N group, the longitudinal mineralization rate (LMR) at the distal growth plate was suppressed completely by loading and did not recover. However, in the 8.5N and 4N groups, LMR suppression recovered in 1 week. In the 17N group, growth plate height and hypertrophic zone height were significantly greater than control; the number of hypertrophic chondrocytes was increased; and some traumatic changes such as cracks in the growth plate were found. In addition, 17N loading suppressed cartilage mineralization and capillary invasion beneath the growth plate, although the number of chondrocytes synthesizing vascular endothelial growth factor (VEGF) was increased. Our study shows longitudinal growth suppression caused by axial loading of the ulna, which is proportional to the magnitude of load. Only the largest load (17N) caused morphological changes in the distal growth plate cartilage. There was no association found between mineralization and type X collagen localization or capillary invasion and VEGF expression.

Animals↗

PubMed2002

Improved bone structure and strength after long-term mechanical loading is greatest if loading is separated into short bouts.

Mechanical loading presents a potent osteogenic stimulus to bone cells, but bone cells desensitize rapidly to mechanical stimulation. Resensitization must occur before the cells can transduce future mechanical signals effectively. Previous experiments show that mechanical loading protocols are more osteogenic if the load cycles are divided into several discrete bouts, separated by several hours, than if the cycles are applied in a single uninterrupted bout. We investigated the effect of discrete mechanical loading bouts on structure and biomechanical properties of the rat ulna after 16 weeks of loading. The right ulnas of 26 adult female rats were subjected to 360 load cycles/day, delivered in a haversine waveform at 17 N peak force, 3 days/week for 16 weeks. One-half of the animals (n = 13) were administered all 360 daily cycles in a single uninterrupted bout (360 x 1); the other half were administered 90 cycles four times per day (90 x 4), with 3 h between bouts. A nonloaded baseline control (BLC) group and an age-matched control (AMC) group (n = 9/group) were included in the experiment. The following measurements were collected after death: in situ mechanical strain at the ulna midshaft; ulnar length; maximum and minimum second moments of area (I(MAx) and I(MIN)) along the entire length of the ulnas (1-mm increments); and ultimate force, energy to failure, and stiffness of whole ulnas. Qualitative observations of bone morphology were made from whole bone images reconstructed from microcomputed tomography (microCT) slices. Loading according to the 360 x 1 and 90 x 4 schedules improved ultimate force by 64% and 87%, energy to failure by 94% and 165%, I(MAX) by 13% and 26% (in the middistal diaphysis), I(MIN) by 69% and 96% (in the middistal diaphysis), and reduced peak mechanical strain by 40% and 36%, respectively. The large increases in biomechanical properties occurred despite very low 5-12% gains in areal bone mineral density (aBMD) and bone mineral content (BMC). Mechanical loading is more effective in enhancing bone biomechanical and structural properties if the loads are applied in discrete bouts, separated by recovery periods (90 x 4 schedule), than if the loads are applied in a single session (360 x 1). Modest increases in aBMD and BMC can improve biomechanical properties substantially if the new bone formation is localized to the most biomechanically relevant sites, as occurs during load-induced bone formation.

Adaptation, Physiological↗