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Biomedical subjects

C H Turner

Publications and source records attributed to C H Turner.

At least 109 records · Page 6Linked to original sources
PubMed1995

A physiologically based pharmacokinetic model for fluoride uptake by bone.

A sex-specific, physiologically based pharmacokinetic (pbpk) model has been developed to describe the absorption, distribution, and elimination of fluorides in rats and humans. Growth curves generated by plotting mean body weights (kg) against age (weeks or years) are included in the simulation model to allow the integration of chronic fluoride exposure from birth to old age. The model incorporates age and body weight dependence of the physiological processes that control the uptake of fluoride by bone and the elimination of fluoride by the kidneys. Six compartments make up the model. These are lung, liver, kidney, bone, and slowly and rapidly perfused compartments. The model also includes two bone subcompartments: a small, flow-limited, rapidly exchangeable surface bone compartment and a bulk virtually nonexchangeable inner bone compartment. The inner bone compartment contains nearly all of the whole body content of fluoride, which, in the longer time frame, may be mobilized through the process of bone modeling and remodeling. The model has been validated by comparing the model predictions with experimental data gathered in rats and humans after drinking water and dietary ingestion of fluoride. This physiological model description of absorption, distribution, and elimination of fluoride from the body permits the analysis of the combined effect of ingesting and inhaling fluorides on the target organ, bone. Estimates of fluoride concentrations in bone are calculated and related to chronic fluoride toxicity. The model is thus useful for predicting some of the long-term metabolic features and tissue concentrations of fluoride that may be of value in understanding positive or negative effects of fluoride on human health. In addition, the pbpk model provides a basis for across-species extrapolation of the effective fluoride dose at the target tissue, bone, in the assessment of risk from different exposure conditions.

Adult↗
PubMed1995

Mechanotransduction and the functional response of bone to mechanical strain.

Mechanotransduction plays a crucial role in the physiology of many tissues including bone. Mechanical loading can inhibit bone resorption and increase bone formation in vivo. In bone, the process of mechanotransduction can be divided into four distinct steps: (1) mechanocoupling, (2) biochemical coupling, (3) transmission of signal, and (4) effector cell response. In mechanocoupling, mechanical loads in vivo cause deformations in bone that stretch bone cells within and lining the bone matrix and create fluid movement within the canaliculae of bone. Dynamic loading, which is associated with extracellular fluid flow and the creation of streaming potentials within bone, is most effective for stimulating new bone formation in vivo. Bone cells in vitro are stimulated to produce second messengers when exposed to fluid flow or mechanical stretch. In biochemical coupling, the possible mechanisms for the coupling of cell-level mechanical signals into intracellular biochemical signals include force transduction through the integrin-cytoskeleton-nuclear matrix structure, stretch-activated cation channels within the cell membrane, G protein-dependent pathways, and linkage between the cytoskeleton and the phospholipase C or phospholipase A pathways. The tight interaction of each of these pathways would suggest that the entire cell is a mechanosensor and there are many different pathways available for the transduction of a mechanical signal. In the transmission of signal, osteoblasts, osteocytes, and bone lining cells may act as sensors of mechanical signals and may communicate the signal through cell processes connected by gap junctions. These cells also produce paracrine factors that may signal osteoprogenitors to differentiate into osteoblasts and attach to the bone surface. Insulin-like growth factors and prostaglandins are possible candidates for intermediaries in signal transduction. In the effector cell response, the effects of mechanical loading are dependent upon the magnitude, duration, and rate of the applied load. Longer duration, lower amplitude loading has the same effect on bone formation as loads with short duration and high amplitude. Loading must be cyclic to stimulate new bone formation. Aging greatly reduces the osteogenic effects of mechanical loading in vivo. Also, some hormones may interact with local mechanical signals to change the sensitivity of the sensor or effector cells to mechanical load.

Bone Density↗
PubMed1995

Calcaneal ultrasonic measurements discriminate hip fracture independently of bone mass.

We studied 336 elderly white women, of whom 22 had previously suffered a hip fracture and 22 had previously suffered a vertebral fracture. All subjects were 60 years old or older with a mean age of 73:7 years. Measurements of ultrasonic transmission velocity (UTV), broad-band ultrasonic attenuation (BUA) and stiffness (STF) were made at the os calcis using a Lunar Achilles ultrasound device. Measurements of lumbar spine bone mineral density (L2-4 BMD) and femoral neck BMD were made using dual-energy X-ray absorptiometry. The fracture groups were significantly older and had more years since menopause than the control groups. Logistic regression showed that measurements of UTV, STF and BUA discriminated between fracture and non-fracture subjects for both the hip (p < 0.001) and spine (p < 0.05). Femoral neck BMD discriminated both hip and vertebral fractures from controls (p < 0.001 and p < 0.01, respectively). Spinal BMD discriminated between subjects with vertebral fractures and those without (p < 0.01), but not hip fractures (p = 0.64). For hip fracture, areas under receiver-operating characteristic (ROC) curves were 0.85 for UTV, 0.83 for STF, 0.79 for BUA, 0.78 for femoral neck BMD and 0.53 for spinal BMD. For vertebral fracture, areas under the ROC curve were 0.68 for UTV, 0.70 for STF, 0.66 for BUA, 0.66 for femoral neck BMD and 0.67 for spinal BMD.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Better discrimination of hip fracture using bone density, geometry and architecture.

Bone density predicts the risk of hip fracture. Because hip strength is determined by bone geometry and architecture as well as density, we tested which variables in geometry and architecture were independent discriminators of hip fracture and, if combined with density, improved the discrimination of fracture from non-fracture over bone density alone. The design was a case-control study. The subjects were Caucasian women over the age of 60 years who had sustained a hip fracture after the age of 58 years (n = 22), and controls matched for age and weight (n = 43) and unmatched controls (n = 317) with no history of hip fracture. Variables in density, geometry and architecture were obtained from dual-energy X-ray absorptiometry images and from radiographs of the upper end of the femur. In a univariate model, of the measures of bone mass, the best discriminator of hip fracture was bone mineral density of the neck of femur; of the geometric measurements, it was hip axis length; and of the measurements of bone architecture, it was Singh grade. In a multivariate model, these three variables were shown to be independent discriminators of hip fracture. When hip axis length was combined with bone mineral density, there was significant improvement in discrimination of hip fracture (p = 0.014), and when Singh grade was combined with hip axis length and bone mineral density there was a further significant improvement (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1995

High frequency components of bone strain in dogs measured during various activities.

Rubin et al. [J. Biomechanics 23, 43-54 (1990)] proposed that high frequency bone strains in the 15-30 Hz range might have significant influence on the morphological adaptation of bone tissue. We sought to further their findings by determining the magnitude of high frequency strains during various activities. We measured strains in the forelimbs of dogs during walking, standing and with their limbs unweighted. As negative controls, we measured strains while the dogs were tranquilized and after sacrifice. Strains in the 15-30 Hz range were not significantly greater than controls for any activity except walking, in which they were less than 4% as large as in the 0-15 Hz range. The high frequency strains observed during walking seemed to occur prior to footfall, suggesting that they were not the result of foot strike. The biological significance of high frequency bone strains has yet to be determined, but may be less than originally proposed because of the relatively small magnitude of these strains.

Adaptation, Physiological↗
PubMed1995

The anisotropy of osteonal bone and its ultrastructural implications.

The anisotropic elastic symmetry of osteonal bone reflects the ultrastructural organization of collagen fibrils and mineral crystals within the osteons as well as the lamellar microstructure. Until recently, reported values for bone's anisotropic elastic properties were limited in their interpretation by poor precision and resolution of measurement techniques. Here, we report measurements of bone anisotropy using high precision acoustic microscopy. The elastic properties of canine femoral bone specimens, taken from 23 femora, were measured at 10 degrees increments from the long axis of the bone. Half of the bone specimens subsequently were demineralized in EDTA solution, the other half were decollagenized in sodium hypochlorite solution, and the acoustic measurements were repeated. We found the elastic symmetry of osteonal bone deviates significantly from orthotropic theory supporting the hypothesis that the lamellar microstructure forms a "rotated plywood" (Weiner and Traub, FASEB J 6:879-885; 1992). The principal orientation of bone mineral was along the long axis of the bone, while bone collagen appeared to be aligned at a 30 degrees angle to the long axis. The misalignment between the mineral and the collagen suggests that (1) a substantial percentage of the mineral is extrafibrillar, and (2) the alignment of extrafibrillar mineral is governed by external influences, e.g., mechanical stresses.

Acoustics↗
PubMed1995

Skeletal adaptations to mechanical usage: results from tibial loading studies in rats.

Wolff's law defines a static relationship between stress trajectories and trabecular architecture. More recent theories have attempted to describe the dynamic relationship between the form of bone and its mechanical environment. Frost's mechanostat theory is unique among these in its distinction between modeling and remodeling processes, lamellar and woven bone formation, mechanical usage windows for activation and its application to disorders of bone and mineral metabolism. Our studies suggest that lamellar and woven bone formation are very different not only in histological appearance, but in the temporal characteristics of their formation. Thus, it is important to distinguish these two histological types when interpreting studies of adaptive bone formation. Studies using the in vivo 4-point bending model in rat tibiae show that static loads do not play a role in mechanotransduction and that bone formation is threshold-driven and dependent on strain rate, amplitude and duration of loading. They have also provided strong indirect evidence that mechanical strains cause interstitial fluid flow that, in turn, activates the bone cell response. Based on these observations, we hypothesize that strain rate determines the vigor of osteoblastic activity and the regularity of loading bouts determines osteoblast recruitment in a "quantum" fashion.

Adaptation, Physiological↗
PubMed1995

Elastic properties of osteoporotic bone measured by scanning acoustic microscopy.

A combination of low bone mass and decreased bone quality underlies osteoporotic fracture. We used scanning acoustic microscopy, a nondestructive method for assessing bone elasticity at a resolution of about 60 microns, to estimate the quality of biopsied iliac bones. We compared the acoustic velocities and bone volumes among premenopausal normal (n = 10), osteoporotic (n = 20), and postmenopausal normal (n = 10) subjects, the latter age-matched to the osteoporotic subjects. The acoustic measurements were highly reproducible (coefficient of variation = 0.32%). Bone volume of osteoporotic subjects (BV/TV = 13.3%) was lower than that of premenopausal and age-matched normals (BV/TV = 22.8%, p = 0.0007; BV/TV = 24.8%, p = 0.0004, respectively). Acoustic velocity of osteoporotic bone was 6.2% lower than that of age-matched normal bone (p < 0.02), but 3.4% higher than that of bone from premenopausal normal women. The lower acoustic velocity of osteoporotic bone than that of age-matched normal subjects implies that osteoporosis involves altered tissue elasticity. However, the lowest acoustic velocities were measured in premenopausal normal subjects. This unexpected result may indicate a complex relationship between tissue level properties and fragility in bone.

Aged↗
PubMed1995

Mechanotransduction in bone: role of strain rate.

Bone tissue can detect and respond to its mechanical environment, but there is no consensus for how bone cells detect mechanical loads. Some think that cells sense tissue deformation (strain) and respond when strain is abnormally high. However, strains in bone tissue are usually very small, and it is questionable whether bone cells are sensitive enough to detect them. Another theory suggests that mechanical loads are coupled to the bone cells by stress-generated fluid flow within the bone tissue, which is dependent on the rate of change of bone strain. We applied bending loads to the tibiae of adult rats to create equivalent peak strains in the bone tissue but with varied rates of strain. Bone formation was significantly increased in the two experimental groups when the highest strain rates were compared with lower strain rates (P < 0.01), and the amount of new bone formation was directly proportional to the rate of strain in the bone tissue. These results suggest that relatively large strains alone are not sufficient to activate bone cells. High strain rates and possibly stress-generated fluid flow are required to stimulate new bone formation.

Adaptation, Physiological↗
PubMed1995

Fluoride reduces bone strength in older rats.

In response to recent concerns about the effect of water fluoridation on hip fracture rates, we studied the influence of fluoride intake on bone strength. Four groups of rats were fed a low-fluoride diet ad libitum and received 0, 5, 15, or 50 ppm of fluoride in their drinking water. Animals were euthanized after 3, 6, 12, or 18 months of treatment. Mechanical strength of the right femur was measured by three-point bending. Fluoride content for the left femur was measured, and static histomorphometric measurements were made on a lumbar vertebra. Femoral failure load was not significantly decreased in rats treated for 3 and 6 months, but was decreased as much as 23% in rats treated 12 and 18 months at 50 ppm fluoride. Extrapolation from regression equations predicted that older rats lose 36% of femoral bone strength when bone fluoride content is increased from 0 to 10,000 ppm, while younger rats will lose only 15%. Thus, the decreased strength appeared to be due to the combined effects of fluoride intake and age on bone tissue and was not associated with a decrease in bone density or mineralization defects. There were only small effects of fluoride on bone histomorphometry. Fluoride intake at high levels had no negative effects on bone mineralization. Fluoride intake was associated with slight increases in trabecular bone volume and trabecular thickness, but these effects could not be demonstrated consistently. The mechanism by which large amounts of fluoride affect bone strength more severely in older animals is unknown.

Aging↗
PubMed1995

Effect of disc lesion on microdamage accumulation in lumbar vertebrae under cyclic compression loading.

A relationship between disc lesion and microdamage accumulation in adjacent vertebrae during fatigue loading was investigated in a canine model. Eighteen functional spinal units obtained from 6 skeletally mature mongrel dogs were divided into 3 groups: I, control (without loading) (n = 6); II, loading with normal disc (n = 6); and III, loading with disc lesion created by nucleotomy (n = 6). Physiologic cyclic compression was performed for 10(5) cycles, and fractional trabecular bone area and microcrack density in the vertebrae were measured. There was a significant difference in microcrack density among groups and regions (p < 0.0001) with significantly more microdamage in functional spinal units with disc lesions than in the other 2 groups (p < 0.0001). The microcracks were distributed predominantly in the vertebral region adjacent to the nucleotomized disc (p < 0.005). There was a negative association of microcrack density with fractional trabecular bone area (R2 = 0.236, p < 0.02). These results support the hypothesis that disc degeneration contributes to vertebral fragility by causing microdamage accumulation, especially in vertebrae with low bone mass.

Animals↗
PubMed1994

Mechanical loading thresholds for lamellar and woven bone formation.

Bone formation was measured in rat tibiae after 12 days of applied loading. Bending forces were applied using a four-point loading apparatus. Sham loads were applied at the same magnitudes as bending forces but the loading pads were arranged so that bending was minimized. Bending and sham loading were applied to the right tibiae of rats and the left tibiae served as contralateral controls. Loading was applied as a sine wave with a frequency of 2 Hz for 18 s (36 cycles) per day. The peak magnitude of applied load was 27, 33, 40, 52, and 64 N. Woven bone was observed on the periosteal surface in all animals subjected to loads of 40 N or greater. Periosteal woven bone formation occurred in both bending and sham loading groups. Woven bone formation on the periosteal surface was either absent or responded at a maximal rate if the stimulus threshold was surpassed. The amount of new woven bone and the woven bone-forming surface were independent of the magnitude of applied strain. Bone formation on the endocortical surface was exclusively lamellar. Lamellar bone formation was stimulated by applied bending of the tibia but not by sham loading. Bending strains above a loading threshold of 40 N or about 1050 mu strain increased both bone-forming surface and the mineral apposition rate and subsequently increased the bone formation rate as much as sixfold. No evidence of increased bone formation was seen for applied strains below 1050 mu strain. Examination of bulk stained sections from animals exposed to the highest applied loads showed no evidence of microcracks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dual-energy x-ray absorptiometry of raloxifene effects on the lumbar vertebrae and femora of ovariectomized rats.

A new potential therapeutic agent for postmenopausal osteoporosis, raloxifene, previously known as keoxifene, was evaluated by x-ray densitometry and more traditional techniques in quantitating the short-term (4-5 weeks) effects of ovariectomy on bones from 6-month-old rats. A Hologic QDR 1000/W and, to a limited extent, a Lunar DPXL, was used to quantitate ovariectomy, estrogen replacement, and raloxifene effects on vertebrae, femora, and tibiae. Both instruments performed well with precisions of 1.6% (Hologic) and 0.9% (Lunar) for anesthetized rats, which improved to 0.4% (Hologic) and 0.5% (Lunar) when the same rats were frozen. The lumbar vertebrae L1-4 showed a 12% decrease in bone mineral density 4 weeks after ovariectomy, compared with a 9% decrease for femora. Tibiae were also examined, but edge-detection problems prevented reproducible analysis of this site in vivo. The decrease in bone mineral density postovariectomy, especially for femora, was found to include both an increase in the projected area and a slight but not significant decrease in the bone mineral content of L1-4 and femora. These changes in density parameters of femora were supported by a decrease in dry weight and volume and a marginal increase in the second moment of inertia I for the identical femora examined ex vivo. Examination of individual lumbar vertebrae L1-5 suggested that the bone mineral density of L3 changes most dramatically in response to ovariectomy, but present techniques lack the spatial resolution and precision to quantitate bone changes reliably in individual vertebrae. 17 beta-Estradiol administered at 100 micrograms/kg/day subcutaneously inhibited ovariectomy effects on L1-4 bone mineral density, femoral moment of inertia, dry weight, and volume and to a lesser extent, femoral bone mineral density. A nonsteroidal compound, raloxifene HCl, at 1 mg/kg/day per os, had bone effects and effects on body weight that were largely indistinguishable from those of 17 beta-estradiol; however, raloxifene did not produce the uterotrophic effects observed with estrogen. The half-maximal efficacious dose of raloxifene on L1-4 bone mineral density was between 0.1 and 1.0 mg/kg/day per os. These data show that dual-energy x-ray absorptiometry compares favorably with traditional methods in quantitating bone changes caused by ovariectomy in small rodents, that L1-4 is a more sensitive region than whole femora in evaluating the effect of estrogen deficiency on bone loss, and the raloxifene may have promise as a treatment for conditions characterized by excessive bone loss after ovariectomy.

Absorptiometry, Photon↗
PubMed1994

Geometric structure of the femoral neck measured using dual-energy x-ray absorptiometry.

An algorithm was developed to estimate the strength of the femoral neck from data generated by the dual-energy x-ray absorptiometry (DXA). This algorithm considers shape of the proximal femur as well as cross-sectional moment of inertia (CSMI) in the estimate. Proximal femora (10) from cadavers of white adults and an aluminum step wedge were scanned with the Lunar DPX to validate the calculation of CSMI. After scanning, each femoral neck was sectioned at its narrowest portion for direct measurement of CSMI. Three healthy young women were scanned five times each to evaluate the reproducibility of geometric measurements using DXA. There was a strong linear association between the CSMI measured directly and using DXA in both cadaver bones (r2 = 0.96) and the aluminum step wedge (r2 = 0.99). The coefficient of variation for CSMI from repeated measurements using DXA was less than 3%. This indicates that it is possible to estimate reproducibly the bending rigidity of bone from DXA measurements. The data from 306 normal subjects were analyzed to investigate geometric changes in the femoral neck with age. Although there was no strong correlation between CSMI and age in normal subjects of either sex, safety factor (SF, an index of strength of the femoral neck during walking) and fall index (FI, an index of the strength of the femoral neck during a fall) decrease with age in both sexes. We observed an alteration of the geometric structure of the femoral neck with age that may increase the stress on the femoral neck and decrease SF and FI.

Absorptiometry, Photon↗
PubMed1994

Do variations in hip geometry explain differences in hip fracture risk between Japanese and white Americans?

Despite lower femoral neck bone mass, Japanese women have a substantially lower incidence of hip fracture than North American whites. Reasons for this discrepancy were sought in a study of 57 Japanese and 119 white American women aged 50-79. All women were in good health. Bone mineral content (BMC) in the femoral neck, femoral neck length (NL), femoral neck angle (theta), cross-sectional moment of inertia (CSMI), safety factor (SF), and fall index (FI) were calculated using dual x-ray absorptiometry. Height and weight were greater in Americans than in Japanese (1.62 versus 1.52 m; p < 0.0001 and 66.0 versus 49.4 kg; p < 0.0001, respectively). Mean BMC in the femoral neck and CSMI were greater in Americans than in Japanese (3.91 versus 3.02 g; p < 0.0001 and 0.99 versus 0.57 cm4; p < 0.0001, respectively). NL was longer in Americans (5.6 versus 4.4 cm; p < 0.0001) and theta was larger in Americans (130 versus 128 degrees; p < 0.01), whereas SF and FI were less in Americans than in Japanese (3.41 versus 5.12; p < 0.0001 and 1.00 versus 1.40; p < 0.0001, respectively). These results indicate that despite lower bone mass, Japanese women have lower risks of structural failure in the femoral neck, attributable primarily to shorter femoral necks and, to a lesser degree, a smaller femoral neck angle. Geometric characteristics of the femoral neck in Japanese women are associated with their lower hip fracture risk, and the measurement of proximal femoral geometry, combined with bone mass, may provide further clinical information about the risk of hip fracture.

Absorptiometry, Photon↗
PubMed1994

Contribution of collagen and mineral to the elastic anisotropy of bone.

It has long been thought that collagen fibers within the bone matrix are deposited in an aligned pattern that channels mineral growth. If this model of bone structure is correct, both organic and inorganic phases of bone should have similar elastic anisotropy. Using an acoustic microscope, we measured longitudinal and transverse acoustic velocities of cortical specimens taken from 10 dog femurs before and after removal of either the mineral (using 10% EDTA) or collagen phases (using 7% sodium hypochlorite) and calculated longitudinal (CL) and transverse (CT) elastic coefficients. The anisotropy ratio (CL/CT) decreased significantly after demineralization (1.61 before versus 1.06 after, P < 0.0001, paired t-test). However, there was no significant change after decollagenization (1.51 before versus 1.48 after, P = 0.617, paired t-test). We conclude that the orientation of mineral crystals is the primary determinant of bone anisotropy, and the collagen matrix within osteonal bone has little directional orientation.

Acoustics↗