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Biomedical subjects

David B Burr

Publications and source records attributed to David B Burr.

At least 19 recordsLinked to original sources
PubMed2006

Raloxifene enhances vertebral mechanical properties independent of bone density.

Anti-remodeling agents produce similar reductions in vertebral fracture risk despite large differences in BMD changes suggesting the mechanism of fracture risk reduction may differ among these agents. Forty-eight intact (non-ovariectomized) skeletally mature female beagle dogs were treated orally for 12 months with clinically relevant doses of risedronate (RIS, 0.10 mg/kg/day), alendronate (ALN, 0.2 mg/kg/day), raloxifene (RAL, 0.50 mg/kg/day), or saline (VEH, 1 ml/kg/day). After sacrifice, the following measurements were made on vertebral bone: areal (aBMD) and volumetric (vBMD) bone mineral densities, tissue mineralization by ash content, static and dynamic histomorphometric parameters, microdamage, and extrinsic and intrinsic measures of biomechanical strength, stiffness and energy to fracture. At these doses, RAL suppressed bone turnover (-20%) significantly less than the bisphosphonates (-66 and -71%) and did not produce significant differences in aBMD, vBMD, BV/TV or percent ash compared to VEH-treated animals. Microdamage accumulation in RAL-treated animals was not significantly different than VEH; both RIS and ALN had significantly higher crack surface density compared to VEH. Stiffness was significantly higher than VEH in all treatment groups. Ultimate load divided by aBMD, a measure of strength independent of BMD, was significantly higher only in RAL-treated animals compared to VEH (+16%, P = 0.015). Based on these data, we conclude that raloxifene produces improvements in bone mechanical properties in ways that do not involve increases in BMD.

Absorptiometry, Photon↗
PubMed2006

Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia.

Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 microg/kg/day or alendronate at 0.1, 1.0 or 10 microg/kg/day subcutaneously for 17 days to 6-month-old female Sprague-Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22-29% for risedronate, 26-36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41-50% for risedronate, 43-52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.

Alendronate↗
PubMed2006

Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate.

One year of treatment with bisphosphonates at 5x the dose used for post-menopausal osteoporosis significantly increases failure load and microdamage, and decreases toughness at multiple skeletal sites in intact female beagles. The goal of this study was to determine if similar changes occur with doses equivalent to those used for post-menopausal osteoporosis treatment. Skeletally-mature female beagles were treated daily for 1 year with vehicle (VEH) or one of three doses of risedronate (RIS; 0.05, 0.10, 0.50 mg/kg/day) or alendronate (ALN; 0.10, 0.20, 1.00 mg/kg/day). Doses of ALN corresponded to treatment dose for PMO, 1/2 that dose, and 5x that dose on a mg/kg basis; RIS was given at a dose-equivalent to ALN. Vertebral density, geometry, percent ash, static/dynamic histology, microdamage, and biomechanical parameters were quantified. Trabecular bone activation frequency (Ac.f) was dose-dependently lower in RIS-treated groups (-40%, -66%, -84%, P < 0.05 vs. VEH) while the three ALN groups were all similarly lower compared to VEH (-65%, -71%, -76%; P <0.05). Crack surface density (Cr.S.Dn) was significantly higher than VEH for all doses of RIS and ALN (+2.9 to 5.4-fold vs. VEH). Stiffness was significantly increased with both agents while there were no significant changes in any other structural or estimated material properties. Cr.S.Dn and Ac.f exhibited a significant non-linear correlation (r(2) = 0.21; P < 0.001) while there was no relationship between Cr.S.Dn and any mechanical properties. These results document that 1 year of bisphosphonate treatment at clinical doses allows significant accumulation of microdamage in the vertebra but this is offset by increases in bone volume and mineralization such that there is no significant impairment of mechanical properties.

Alendronate↗
PubMed2006

Chemical makeup of microdamaged bone differs from undamaged bone.

Microdamage naturally occurs in bone tissue as a result of cyclic loading placed on the body from normal daily activities. While it is usually repaired through the bone turnover process, accumulation of microdamage may result in reduced bone quality and increased fracture risk. It is unclear whether certain areas of bone are more susceptible to microdamage than others due to compositional differences. This study examines whether areas of microdamaged bone are chemically different than undamaged areas of bone. Bone samples (L3 vertebrae) were harvested from 15 dogs. Samples were stained with basic fuchsin, embedded in poly-methylmethacrylate, and cut into 5-microm-thick sections. Fuchsin staining was used to identify regions of microdamage, and synchrotron infrared microspectroscopic imaging was used to determine the local bone composition. Results showed that microdamaged areas of bone were chemically different than the surrounding undamaged areas. Specifically, the mineral stoichiometry was altered in microdamaged bone, where the carbonate/protein ratio and carbonate/phosphate ratio were significantly lower in areas of microdamage, and the acid phosphate content was higher. No differences were observed in tissue mineralization (phosphate/protein ratio) or crystallinity between the microdamaged and undamaged bone, indicating that the microdamaged regions of bone were not over-mineralized. The collagen cross-linking structure was also significantly different in microdamaged areas of bone, consistent with ruptured cross-links and reduced fracture resistance. All differences in composition had well-defined boundaries in the microcrack region, strongly suggesting that they occurred after microcrack formation. Even so, because microdamage results in an altered bone composition, an accumulation of microdamage might result in a long-term reduction in bone quality.

Alendronate↗
PubMed2006

Stress fractures: pathophysiology, epidemiology, and risk factors.

A stress fracture represents the inability of the skeleton to withstand repetitive bouts of mechanical loading, which results in structural fatigue and resultant signs and symptoms of localized pain and tenderness. To prevent stress fractures, an appreciation of their risk factors is required. These are typically grouped into extrinsic and intrinsic risk factors. Extrinsic risk factors for stress fractures are those in the environment or external to the individual, including the type of activity and factors involving training, equipment, and the environment. Intrinsic risk factors for stress fractures refer to characteristics within the individual, including skeletal, muscle, joint, and biomechanical factors, as well as physical fitness and gender. This article discusses these extrinsic and intrinsic risk factors, as well as the pathophysiology and epidemiology of stress fractures.

Female↗
PubMed2005

Age-related change in the damage morphology of human cortical bone and its role in bone fragility.

Application of cyclic loading results in the formation of distinct strain-dependent microdamage morphologies. It is still unknown; however, how the morphology of microdamage affects age-related increase in bone fragility. In this study, four-point bending fatigue tests were conducted on aging human bone (age 26 to 89) in conjunction with histological evaluation of the resultant tensile (diffuse damage) and compressive (linear microcracks) damage to identify the damage morphologies associated with an increase in age-related bone fragility. The results demonstrate that young donors (38 +/- 9 years) had a longer fatigue life (P < 0.05) and formed more diffuse damage than the older donors (82 +/- 5 years) (P < 0.05). In contrast, old donors had a shorter fatigue life and formed more linear microcracks than the younger donors (P < 0.05). Linear microcracks were longer in older than in younger donors (P < 0.05) and were associated with weak lamellar interfaces. Areas of diffuse damage were, however, larger in younger than in older donors (P < 0.05), and these showed no relationship with the lamellar arrangement of bone. These findings show, for the first time, that the propensity of bone to form a particular damage morphology is subject to change with age and that the propensity of young donors to form diffuse damage over interlamellae linear microcracks plays a critical role in the ability of bone to dissipate energy and resist a catastrophic fracture. Age-related changes in damage morphology may therefore be an important contributor to the increased bone fragility in the elderly.

Adult↗
PubMed2005

Imaging bone microdamage in vivo with positron emission tomography.

Microdamage accumulation in bone is now considered a contributing cause for bone fragility in older women. However, there is still no method to detect and quantify microdamage in vivo. We have found that positron emission tomography (PET) may be useful to detect and quantify bone microdamage in vivo using a high-resolution PET scanner with [18F]NaF as the tracer. We have done several experiments using the rat ulnar loading model that demonstrate that (1) high-resolution [18F]NaF PET can detect newly created microdamage in vivo; (2) the microdamage detected in this way is co-localized with damage detected by histological and autoradiographic procedures; and (3) high-resolution [18F]NaF PET can distinguish between the effects of mechanical loading that does not produce damage and fatigue loading that creates microdamage. The high-resolution [18F]NaF PET shows promise as a non-invasive means to image bone microdamage.

Animals↗
PubMed2005

Osteoblast responses one hour after load-induced fluid flow in a three-dimensional porous matrix.

When bone is loaded, substrate strain is generated by the external force and this strain induces fluid flow that creates fluid shear stress on bone cells. Our current understanding of load-driven gene regulation of osteoblasts is based primarily on in vitro studies on planer two-dimensional tissue culture substrates. However, differences between a flat layer of cells and cells in 3-dimensional (3D) ECM are being recognized for signal transduction. Proliferation and differentiation of osteoblasts are affected by substrate geometry. Here we developed a novel 3D culture system that would mimic physiologically relevant substrate strain as well as strain-induced fluid flow in a 3D porous collagen matrix. The system allowed us to evaluate the responses of osteoblasts in a 3D stress-strain environment similar to a mechanical field to which bone is exposed. Using MC3T3-E1 osteoblasts grown in the 3D collagen matrix with and without hydroxyapatite deposition, we tested the role of strain and the strain-induced fluid flow in the expression of the load-responsive genes such as c-fos, egr1, cox2, osteopontin, and mmp1B involved in transcriptional regulation, osteogenesis, and rearrangement of ECM. Strain-induced fluid flow was visualized with a microspheres approximately 3 microm in diameter in real time, and three viscoelastic parameters were determined. The results obtained by semi-quantitative PCR, immunoblot assay, enzymatic activity assays for collagenase and gelatinase, and mechanical characterization of collagen matrices supported the dominant role of strain-induced fluid flow in expression of the selected genes one hour after the mechanical treatment.

3T3 Cells↗
PubMed2005

The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib.

We evaluated the effects of suppressed bone remodeling caused by bisphosphonate on microdamage accumulation and degree of mineralization of bone (DMB) for the dog rib in two independent studies. Study 1: 36 female beagles, 1-2 years old, were treated daily for 1 year with saline vehicle, risedronate at 0.5 mg/kg/day, or alendronate at 1.0 mg/kg/day. Study 2: 29 beagles, 1 year old, were given lactose, or incadronate at 0.3 mg/kg/day or 0.6 mg/kg/day for 3 years. In both studies, the ninth rib was harvested. Intracortical remodeling was significantly suppressed following either 1 year or 3 years of bisphosphonate treatment without impairment of primary mineralization, although the remodeling rate was obviously lower in study 2 than in study 1 because of the aging of animals. Microdamage accumulation was significantly increased following any bisphosphonate treatment in response to the extent of remodeling suppression. One-year treatment with risedronate or alendronate did not significantly affect the mean DMB or osteonal distribution based on DMB. In contrast, mean DMB was significantly increased following 3 years of incadronate treatments, and osteonal distributions based on DMB showed a dose-dependent shift toward the higher values in incadronate-treated animals when compared with controls. Our results demonstrated that DMB was increased following only 3 years but not 1 year of bisphosphonate treatment. This finding suggests that suppressed remodeling induced by long-term bisphosphonate treatment increased DMB by increasing the population of old, highly mineralized osteons; however, the expression of this phenomenon depends on duration of the treatment because the secondary mineralization is a very slow process.

Animals↗
PubMed2005

Microdamage accumulation in the monkey vertebra does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene.

Long-term suppression of bone turnover with alendronate has previously been shown to increase the degree of mineralization and accumulation of microdamage in animal bones. In an effort to ascertain if other suppressors of bone resorption can also affect mineralization and microdamage accumulation, we evaluated bones from cynomolgus macaques treated with raloxifene or conjugated equine estrogens (CEE). Cynomolgus monkeys (Macaca fascicularis) were randomized, ovariectomized (except for Sham controls), and orally treated each day for 2 years with vehicle (Sham and Ovx controls), 1 mg/kg raloxifene (R1), 5 mg/kg raloxifene (R5), or 0.04 mg/kg CEE. The functional quality of the mineralized matrix was analyzed postnecropsy by biomechanical testing, histomorphometry, biochemistry, and nanoindentation. Failure testing of the whole vertebra showed no significant differences in vertebral strength among groups. Similarly, failure testing of a beam of pure bone that was machined from the femoral diaphysis also showed no differences in material strength (ultimate stress) between groups. Histomorphometry of the L2 centrum showed that Ovx tended to increase activation frequency relative to Sham controls. Estrogen (CEE) treatment for 2 years at about four times the clinical exposure tended to reduce activation frequency (Ac.f) by 41% compared to Ovx. Treatment with raloxifene at either approximately the clinical dose or five times higher nonsignificantly lowered Ac.f by 34% and 23%, respectively, relative to Ovx. Raloxifene had similar effects on serum osteocalcin, a biochemical measure of systemic bone turnover. Analysis of microcrack surface density in the cancellous bone of L3 showed a 40% reduction for Ovx relative to Sham. CEE microcrack surface density was not different than Sham whereas the R5 crack density was significantly less than Sham and CEE. R1 microcrack surface density was not significantly different from Sham or Ovx. No significant differences in crack length were observed among the groups. Hardness, which is a measure of the state of mineralization, and elastic modulus were measured for both trabecular bone on a micron scale by nanoindentation. No significant differences between groups were observed. In summary, differences in functional bone quality of the lumbar spine were not observed between Sham, Ovx, or treated monkeys. CEE increased microcracks from Ovx to Sham levels, whereas raloxifene had no effect on microdamage accumulation. We conclude that suppressing bone turnover by 40% or less offers protection against microdamage accumulation that could result in an increased risk of vertebral fracture.

Animals↗
PubMed2005

Does early PTH treatment compromise bone strength? The balance between remodeling, porosity, bone mineral, and bone size.

The treatment of osteoporotic women with recombinant human parathyroid hormone (rhPTH) increases bone mineral density and reduces fracture risk. However, there has been concern that the initiation of therapy in women with low bone mass may cause an early and transient increased fracture risk because PTH stimulates bone remodeling, which in its first phase is associated with bone resorption. Animal and human studies suggest, however, that the stimulation of remodeling caused by rhPTH(1-34) does not lead to a deterioration of bone's mechanical properties or to an increased fracture risk even early in the treatment. There are several reasons for this. Bone biomarkers associated with formation rise earlier than those associated with resorption, suggesting that there is an initial period prior to the stimulation of remodeling during which bone formation occurs on surfaces without prior resorption. This initial period of formation may protect the patient from the later small and transient losses that occur through remodeling. Moreover, the increased remodeling occurs on cancellous surfaces or close to the endosteal surface of bone, where its mechanical effect is minimal. Additionally, these transient losses may be compensated by periosteal apposition that maintains the overall strength of the bone. Thus, the early stimulation of bone formation without prior resorption, and the redistribution of bone from cancellous and endocortical surfaces to the periosteal surface combine to prevent the mechanical deterioration that could otherwise occur with a transient acceleration of bone remodeling in a patient with low bone mass.

Animals↗
PubMed2005

Human femoral neck has less cellular periosteum, and more mineralized periosteum, than femoral diaphyseal bone.

Periosteal expansion enhances bone strength and is controlled by osteogenic cells of the periosteum. The extent of cellular periosteum at the human femoral neck, a clinically relevant site, is unclear. This study was designed to histologically evaluate the human femoral neck periosteal surface. Femoral neck samples from 11 male and female cadavers (ages 34-88) were histologically assessed and four periosteal surface classifications (cellular periosteum, mineralizing periosteum, cartilage, and mineralizing cartilage) were quantified. Femoral mid-diaphysis samples from the same cadavers were used as within-specimen controls. The femoral neck surface had significantly less (P<0.05) cellular periosteum (18.4+/-9.7%) compared to the femoral diaphysis (59.2+/-13.8%). A significant amount of the femoral neck surface was covered by mineralizing periosteal tissue (20-70%). These data may provide an alternate explanation for the apparent femoral neck periosteal expansion with age and suggest the efficiency of interventions that stimulate periosteal expansion may be reduced, albeit still possible, at the femoral neck of humans.

Adult↗
PubMed2004

Bone adaptation to a mechanical loading program significantly increases skeletal fatigue resistance.

UNLABELLED: Using a mechanical loading program to induce bone adaptation, we found that small (<2-fold) changes in the structural properties of the rat ulna increased its fatigue resistance >100-fold. This indicates that a moderate exercise program may be an effective preventative strategy for stress fractures. INTRODUCTION: There are currently limited preventative strategies for stress fractures. Because stress fracture risk is directly influenced by skeletal properties, it has been hypothesized that modification of these properties using a mechanical loading program may positively influence risk. The aim of this study was to investigate whether the bone changes associated with a mechanical loading program can enhance skeletal fatigue resistance. MATERIALS AND METHODS: Site-specific mechanical loading was performed on one forearm of adult female Sprague-Dawley rats using the axial compression loading model. Loading was performed 3 days/week for 5 consecutive weeks to induce adaptation. The loaded and nonloaded ulnas in each animal were removed after the loading program, and their material and structural properties were determined. The ulna pairs were subsequently loaded until fatigue failure at the same constant peak axial load. RESULTS: Mechanical loading induced consistent and predictable changes in the structural properties of loaded ulnas, with the largest change being a nearly 2-fold increase in midshaft minimum second moment of area (I(MIN)). The mechanical-loading induced bone changes resulted in a >100-fold increase in fatigue resistance in loaded ulnas, with resistance being exponentially related to the structural properties of the ulna. CONCLUSIONS: This study found that by enhancing the structural properties of a bone through a mechanical loading program, its fatigue resistance could be significantly improved. This indicates that an exercise program aimed at modifying bone structure may be used as a possible prevention strategy for stress fractures.

Animals↗
PubMed2004

Periosteum: biology, regulation, and response to osteoporosis therapies.

Periosteum contains osteogenic cells that regulate the outer shape of bone and work in coordination with inner cortical endosteum to regulate cortical thickness and the size and position of a bone in space. Induction of periosteal expansion, especially at sites such as the lumbar spine and femoral neck, reduces fracture risk by modifying bone dimensions to increase bone strength. The cell and molecular mechanisms that selectively and specifically activate periosteal expansion, as well as the mechanisms by which osteoporosis drugs regulate periosteum, remain poorly understood. We speculate that an alternate strategy to protect human bones from fracture may be through targeting of the periosteum, either using current or novel agents. In this review, we highlight current concepts of periosteal cell biology, including their apparent differences from endosteal osteogenic cells, discuss the limited data regarding how the periosteal surface is regulated by currently approved osteoporosis drugs, and suggest one potential means through which targeting periosteum may be achieved. Improving our understanding of mechanisms controlling periosteal expansion will likely provide insights necessary to enhance current and develop novel interventions to further reduce the risk of osteoporotic fractures.

Animals↗
PubMed2004

Anatomy and physiology of the mineralized tissues: role in the pathogenesis of osteoarthrosis.

Synovial joints are composed of several different kinds of tissue that interact to protect normal joint function. Three subchondral mineralized tissues can be identified-calcified cartilage, subchondral cortical bone, and subchondral trabecular bone-which are distinguished morphologically, physiologically, and mechanically. Each responds to mechanical and pharmaceutical stimuli in different ways through processes of growth, modeling, and remodeling, and changes in each may have a distinct effect on the health of the joint. It is important to distinguish between the structural properties of these tissues and their material properties as these change differently in osteoarthrosis (OA). It is likely that changes in the mineral content and thickness of the calcified cartilage play a greater role in the pathogenesis of OA than has been realized, whereas changes in trabecular bone are probably not causative. Changes in the subchondral cortical bone may accelerate progression of pre-existing disease, but the combined effects of increased subchondral bone turnover and greater subchondral bone volume are not at all clear. Ultimately, the efficacy of bone anti-resorptive therapies for OA will depend upon whether the increased structural stiffness of the subchondral mineralized tissues predisposes the cartilage to deteriorate, whether the increased bone turnover that occurs in OA is itself a causative factor, or whether the lower tissue elastic modulus offsets the increased structural stiffness of the subchondral plate in an attempt to protect the cartilage from damage.

Animals↗
PubMed2003

A model for mechanotransduction in bone cells: the load-bearing mechanosomes.

The skeleton's response to mechanical force, or load, has significance to space travel, the treatment of osteoporosis, and orthodontic appliances. How bone senses and processes load remains largely unknown. The cellular basis of mechanotransduction, however, likely involves the integration of diffusion-controlled signaling pathways with a solid-state scaffold linking the cell membrane to the genes. Here, we integrate various concepts from models of connective membrane skeleton proteins, cellular tensegrity, and nuclear matrix architectural transcription factors, to describe how a load-induced deformation of bone activates a change in the skeletal genetic program. We propose that mechanical information is relayed from the bone to the gene in part by a succession of deformations, changes in conformations, and translocations. The load-induced deformation of bone is converted into the deformation of the sensor cell membrane. This, in turn, drives conformational changes in membrane proteins of which some are linked to a solid-state signaling scaffold that releases protein complexes capable of carrying mechanical information, "mechanosomes", into the nucleus. These mechanosomes translate this information into changes in the geometry of the 5' regulatory region of target gene DNA altering gene activity; bending bone ultimately bends genes. We identify specific candidate proteins fitting the profile of load-signaling mechanosomes.

Animals↗