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Biomedical subjects

D B Kimmel

Publications and source records attributed to D B Kimmel.

At least 55 records · Page 3Linked to original sources
PubMed1992

Change in bone mass immediately before menopause.

A group of 75 healthy women nearing menopause were entered into a longitudinal study of bone mass and bone cell function. All were at least 46 years, were still menstruating, and had premenopausal levels of follicle stimulating hormone (FSH) and estradiol (E2). Bone density measurements of the spine (dual-photon absorptiometry, DPA) and total-body (DPA) and forearm (single-photon absorptiometry, SPA) were made at 6 month intervals along with measurements of FSH and E2 over an average of 2.04 +/- 0.45 years. The annual rate of change in bone mass was determined for each individual by regressing the bone mass measurement at each site at the time of observation. The slopes were pooled, and the percentage annual change was calculated as the mean slope divided by the initial mean bone mass value. The mean rates of change in bone mass were calculated with and without weighting by length of observation. No meaningful differences in the results were seen in the weighted values compared to the unweighted values, and none of the sites showed a slope significantly different from zero. Demonstrated reproducibility and sample size provided sufficient power to detect annual weighted rates of change of 0.81% for spine BMC, 0.69% for spine BMD, 1.31% for forearm BMC, 1.55% for forearm BMC/BW, and 1.09% for total body bone mineral. We conclude that if changes in bone mineral are occurring in women at this age, they are substantially less than 1%/year for spine and not much more for the forearm or total skeleton.

Absorptiometry, Photon↗
PubMed1992

Restoring and maintaining bone in osteopenic female rat skeleton: I. Changes in bone mass and structure.

This experiment contains the crucial data for the lose, restore, and maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (+/- phase). The purpose of this study was to learn whether switching to an agent known chiefly for its ability to maintain existing bone mass preserves new bone induced by PGE2 in osteopenic, estrogen-depleted rats. The current study had three phases, the bone loss (-), restore (+), and maintain (+/-) phases. We ovariectomized (OX) or sham ovariectomized (sham-OX) 5.5-month-old female rats (- phase). The OX rats were treated 5 months postovariectomy with 1-6 mg PGE2 per kg/day for 75 days to restore lost cancellous bone mass (+ phase), and then PGE2 treatment was stopped and treatment began with 1 or 5 micrograms/kg of risedronate, a bisphosphonate, twice a week for 60 days (+/- phase). During the loss (-) phase, the cancellous bone volume of the proximal tibial metaphysis in the OX rat fell to 19% of initial and 30% of age-matched control levels. During the restore (+) phase, the cancellous bone volume in OX rats doubled. When PGE2 treatment was stopped, however, and no special maintenance efforts were made during the maintain (+/-) phase, the PGE2-induced cancellous bone disappeared. In contrast, the PGE2-induced cancellous bone persisted when the PGE2 treatment was followed by either a 1 or 5 micrograms treatment of risedronate per kg given twice a week for 60 days during the maintain (+/-) phase. The tibial shaft demonstrated very little cortical bone loss during the loss (-) phase in OX rats. The tibial shaft cortical bone fell some 8%. During the restore (+) phase, new cortical bone in OX rats increased by 22%. When PGE2 treatment was stopped and nothing was given during the maintain (+/-) phase, however, all but the PGE2-induced subperiosteal bone disappeared. In contrast, when PGE2 treatment was stopped and 1 micron risedronate per kg twice a week for 60 days was administered during the maintenance (+/-) phase, the PGE2-induced subperiosteal bone and some of the subendocortical bone and marrow trabeculae persisted.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1992

Effects of long-term daily administration of prostaglandin-E2 on maintaining elevated proximal tibial metaphyseal cancellous bone mass in male rats.

The effects of long-term prostaglandin E2 (PGE2) on cancellous bone in proximal tibial metaphysis were studied in 7-month-old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3, and 6 mg PGE2/kg/day and sacrificed after 60, 120, and 180 days. Histomorphometric analyses were performed on double fluorescent-labeled undecalcified bone specimens. After 60 days of treatment, PGE2 produced diffusely labeled trabecular bone area, increased trabecular bone area, eroded and labeled trabecular perimeter, mineral apposition rate, and bone formation rate at all dose levels when compared with age-matched controls. In rats given PGE2 for longer time periods (120 and 180 days), trabecular bone area, diffusely labeled trabecular bone area, labeled perimeter, mineral apposition, and bone formation rates were sustained at the elevated levels achieved earlier at 60-day treatment. The eroded perimeter continued to increase until 120 days, then plateau. The observation that continuous systemic PGE2 administration to adult male rats elevated metaphyseal cancellous bone mass to 3.5-fold of the control level within 60 days and maintained it for another 120 days indicates that the powerful skeletal anabolic effects of PGE2 can be sustained with continuous administration.

Animals↗
PubMed1992

Characterization of in vivo strain in the rat tibia during external application of a four-point bending load.

This paper describes a technique for characterizing strains and stresses induced in vivo in the rat tibia during application of an external four-point bending load. An external load was applied through the muscle and soft tissue with a four-point bending device, to induce strain in a 11 mm section of the right tibiae of ten adult female Sprague-Dawley rats. Induced strains were measured in vivo on the lateral surface of the tibia. Inter-rat difference, leg positioning and strain gage placement were evaluated as sources of variability of applied strains. Beam bending theory was used to predict externally induced in vivo strains. Finite element analysis was used to quantify the magnitude of shear stresses induced by this type of loading. There was a linear relationship between applied load and induced in vivo strains. In vivo strains induced by external loading were linearly correlated (R2 = 0.87) with the strains calculated using beam bending theory. The finite element analysis predicted shear stresses at less than 10% of the longitudinal stresses resulting from four-point bending. Strains predicted along the tibia by finite element analysis and beam bending theory were well-correlated. Inter-rat variability due to tibia size and shape difference was the most important source of variation in induced strain (CV = 21.6%). Leg positioning was less important (CV = 9.5%).

Animals↗
PubMed1992

Long-term effect of naproxen on cancellous bone in ovariectomized rats.

Previous work shows that at 42 d post-ovariectomy (OX) in aged rats, naproxen, a nonsteriodal anti-inflammatory drug (NSAID) prevents cancellous bone loss. The purpose of this study was to evaluate the effects of naproxen on cancellous bone of aged OX and sham-OX rats, at 90 days post-OX. Six-month-old Sprague-Dawley retired breeder female rats underwent either sham-OX (n = 49) or OX (n = 65). Sham-OX rats were randomized into five groups and OX rats into six groups. The first five groups of both were given ad lib access to water containing 0, 4, 10, 25, or 62.5 mg/l of naproxen sodium. The sixth group of OX rats was given water containing 156.25 mg naproxen sodium/l. After ninety days, the rats were killed following in vivo dual calcein labeling. Terminal serum naproxen was measured by HPLC. In the proximal tibial metaphysis, trabecular bone volume, trabecular thickness, trabecular number, mineralizing surface (double label), osteoclast surface, and bone formation rate were measured. Sham-OX and OX rats were compared by t-test of means. Kruskal-Wallis tests and, as necessary, Dunnett's t-tests, were applied separately to the groups of Sham-OX and OX rats. Dose-related serum levels of naproxen up to 9.4 mcg/ml were achieved in the 156.25 mg/ml group. OX rats had significantly lower bone volume, trabecular thickness, and trabecular number than Sham-OX groups (p less than .001). OX rats had significantly higher mineralizing surface, formation rate, and osteoclast surface than sham-OX rats (p less than .001). No differences related to naproxen treatment existed in sham-OX rats. Naproxen treatment producing a serum level of 9.4 mcg/ml reduced bone volume in OX rats consuming water with 156.25 mg/l (p less than .05). At 90 days post-OX, naproxen, at serum levels of 9.4 mcg/ml or less, did not diminish estrogen-depletion cancellous bone loss in rats. Naproxen lacks lasting ability to halt estrogen-depletion bone loss in aged OX rats.

Animals↗
PubMed1991

Rapid determination of cancellous bone mineral loss in ovariectomized rats by a subtraction technique.

We present a rapid technique for determining cancellous bone mineral changes in small experimental animals. We used the distal centimeter of the right femur from ovariectomized (OX) (N = 30) and shamovariectomized (ShOX) (N = 28) rats, aged 90 days at surgery and killed at times from 125-540 days postsurgery. We used dual photon absorptiometry to scan the segment three times: intact, after parasagittal splitting, and after removing all cancellous bone. We equated the difference between the second and third scans to cancellous bone mineral content (Cn.BMC). To validate this, we compared it with histomorphometrically determined bone volume (BV/TV) of the proximal tibial metaphysis of the same rat. Parasagittally splitting the segment removed no detectable mineral. OX rats had 40% less Cn.BMC than ShOX rats. However, OX rats had 80% lower BV/TV than ShOX rats. The subtraction technique not only makes a rapid, reasonable assessment of cancellous bone loss in OX rats but permits a smaller sample size than histomorphometry. The histomorphometric technique finds a greater difference between OX and ShOX rats because it examines a region where cancellous bone loss is more marked than does the scanning technique. The current technique measures bone of not only the central secondary spongiosa but also the juxtacortical region and the primary spongiosa, where OX-related differences are less prominent. The principles of this subtraction technique proved workable. However, for the future, we recommend a two-scan technique using a dual energy X-ray scanner. It is likely to take only 20-30 min per specimen to assess cancellous bone mineral.

Absorptiometry, Photon↗
PubMed1991

A histomorphometric study of cortical bone activity during increased weight-bearing exercise.

To quantify cortical bone response to weight-bearing exercise, bone size, mineral content, and formation were measured at the femoral midshaft in swine. Bone formation was measured histomorphometrically on the periosteal, endosteal, and osteonal surfaces. Sedentary adult crossbred sows (3 years, 229 kg) were randomly assigned to basal (B, n = 6), control (C, n = 7), or trained (T, n = 7) groups. The basal and control groups did not exercise and were killed initially (B) or after 20 weeks (C). The trained group walked on a treadmill 20 minutes/day at 5 km/h and 5% grade, 5 days/week for 20 weeks. Bone length, area, or fat-free dry weight was not different with time (B versus C) or with training (C versus T). Periosteal modeling was stimulated by walking. Periosteal formation surface and mineral apposition rate (MAR) were greater in trained than control femora. No effects of walking were measured on the endosteal surface. Intracortical remodeling was not affected by walking. The number of labeled osteons (22.4 cm-2) was not different among groups, but osteonal MAR was greater in trained (1.18 microns/day) than control (0.96 mu/day) femora. Walking for 20 weeks in the previously sedentary sows was not a sufficient stimulus to create differences in gross measures of bone size or mineral content but did increase periosteal and intracortical MAR. The primary effect of increased exercise appeared to be osteoblast activation.

Animals↗
PubMed1991

The effect of dietary consistency on bone mass and turnover in the growing rat mandible.

Hard and soft diets were fed to weanling rats for up to 8 weeks. Some animals were switched after 4 weeks to the opposite diet. A histomorphometric study of bone formation activity at the mandibular ramus, body, and condyle was made after in vivo fluorochrome labelling. Mineral apposition rates at the lateral and inferior periosteal surfaces of the ramus were lower in the soft diet than in the hard diet animals. The rate of bone formation at the lateral periosteal surface of the ramus was significantly lower in soft than in hard diet animals. The medial periosteal surface of the ramus sometimes changed to bone formation in the soft diet groups. Condylar cartilage zones were somewhat thinner in soft diet groups. In the mandibular body, differences due to dietary consistency were less marked than near the gonial angle. Adaptation of periosteal bone and condylar cartilage to a new dietary consistency occurred within 4 weeks of switching. These results suggest that lateral and inferior periosteal bone growth of the ramus and condylar elongation were slowed in rats consuming soft diets. Decreased functional force during rapid mandibular bone growth causes changes in shape. The changes are due to regional decreases in osteoblast function, realignment of bone formation surfaces in the ramus area, and slowed growth in the condylar cartilage.

Animals↗
PubMed1991

A noninvasive, in vivo model for studying strain adaptive bone modeling.

We present a noninvasive, in vivo model for strain application in the tibiae of rats. The hind limb of each animal was placed into a device that applied four point bending to the tibia. Bending was applied in the medial-lateral direction causing compression on the lateral surface of the tibia and tension on the anteromedial surface. The peak strain magnitudes were estimated to be between 1600 and 3500 mu strain. In this pilot work, data were collected from 12 rats. The rats received either one cycle per day, four cycles per day, 12 cycles per day, 36 cycles per day, or 108 cycles per day of bending. The experimental (right) tibiae from all of the rats showed new bone formation after 12 days. The control (left) tibiae showed no new bone formation over this period. A better organized, dense bony reaction occurred in regions of lesser strains than in regions of higher strains, where there was a large accumulation of bone easily identified as woven. The organization and density of the newly formed bone appeared to be inversely related to the peak strains in the region. After 40 days of daily loading, the new bone area appeared to be more compact and better mineralized. However, bone formation was still occurring after 40 days. The results of this study suggest that woven bone formation occurred due to the bending stimulus and not due to pathology.

Adaptation, Physiological↗
PubMed1990

Effect of naproxen on cancellous bone in ovariectomized rats.

Nonsteroidal anti-inflammatory drugs (NSAIDs) affect bone metabolism in vitro and in vivo. They delay but do not alter the outcome of healing processes in bone. In some bone loss models, they block bone resorption and slow the rate of loss. We studied the effect of naproxen, a potent NSAID, on cancellous bone of the proximal tibial metaphysis of 6-month-old adult female ovariectomized rats. Animals were ovariectomized, divided into groups, and fed standard diets differing only in naproxen content for 42 days. The rats of the groups ate 2.0, 5.5, 12.7, and 32 mg naproxen per kg body weight per day, respectively. Serum levels of naproxen were determined. Bone volume, mineralizing surface, osteoblast activity, osteoclast surface, and bone resorption rate were determined by bone histomorphometric techniques. The rats' dose-related serum naproxen levels ranged from 4 to 28 micrograms/ml. Naproxen inhibited up to 70% of the bone loss occurring after ovariectomy at a serum level of 4 micrograms/ml. We deduced that naproxen blocked bone resorption in ovariectomized rats by slowing osteoclast activity at all doses. In contrast, naproxen slowed bone formation only at serum levels greater than 20 micrograms/ml in ovariectomized rats. These findings may have clinical relevance in helping to prevent postmenopausal bone loss in women.

Animals↗
PubMed1990

Nondestructive measurement of bone mineral in femurs from ovariectomized rats.

One hundred ninety-eight rats were ovariectomized (OX) or sham-ovariectomized (shOX) at 100 days of age. Groups were killed at 35, 70, 100, 125, 180, 270, 360, and 540 days postsurgery. Bone mineral content (BMC) of the right femur was assayed on a dual photon absorptiometer (DPA) optimized for human spine and whole body measurements. Three regions were studied: the distal measuring 0.8 cm, the proximal measuring 0.88 cm, and the diaphysis, the remainder. The DPA technique accurately showed the ash content (r = 0.96), with a precision error of 3-5%. Whole femoral BMC was 4.3-11.1% lower in OX than shOX rats, with significant differences from 35-180 days. By 35 days, distal femoral BMC declined 6% in OX rats and rose 12% in shOX rats. Distal femoral BMC was 11.3-17.5% lower in OX than shOX rats, with significant differences at all times except 540 days. Femoral diaphyseal BMC of OX and shOX rats did not differ at any time. The relative distal femoral osteopenia which appeared by 35 days in OX rats did not worsen during the next 17 months. A DPA suited for human BMC studies is also accurate for BMC determination in bones with 250-500 mg of mineral. It is less precise for this purpose than dedicated instruments using single photon absorptiometry. However, enough precision exists to monitor the development of relative osteopenia in OX rats. Osteopenia in OX rats is confined to a region containing appreciable cancellous bone. Its self-limiting nature suggests the existence of an estrogen-dependent quantum of cancellous bone in female rats. The adult rat model is accurate for cancellous bone of the adult human, but inaccurate for cortical bone.

Absorptiometry, Photon↗
PubMed1990

A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects.

Transilial bone biopsies following in vivo fluorochrome labeling were obtained from 90 women with postmenopausal osteoporosis and 34 healthy post-menopausal women. Standard histomorphometric data were collected from undecalcified sections. The distribution of values for both structural and remodelling indices was the same for each group. Bone volume was 35% lower (P less than 0.001), wall thickness was 12% lower (P less than 0.001), and trabecular thickness was 11% lower (P less than 0.02) in osteoporotics. Trabecular separation was 34% greater (P less than 0.001) and trabecular number was 36% lower (P less than 0.001) in osteoporotics. Biopsy core width was 11% less (P less than 0.02) and cortical width was 35-50% less (P less than 0.001) in osteoporotics. Static indices of remodelling, mineralizing surfaces, and mineral apposition rate were similar in the two groups. The absolute values for bone histomorphometric variables for both groups are similar to most published data. Osteoporotics had poorer bone structure, marked by decreased trabecular connectivity and thin cortices. There were no major differences in dynamic indices of remodelling. Since the histomorphometric data were distributed the same in both groups, special subsets of osteoporotic subjects not in the normal population did not exist.

Aged↗
PubMed1990

Effects of prostaglandin E2 on production of new cancellous bone in the axial skeleton of ovariectomized rats.

The effects of prostaglandin E2 (PGE2) were histomorphometrically evaluated in cancellous bone of the axial skeleton of ovariectomized, osteopenic rats. Four months following bilateral ovariectomy (OVX) and sham-ovariectomy (SHAM) at 3 months of age, rats received daily subcutaneous injections of PGE2 at 0, 0.3, 1.0, 3.0 and 6.0 mg/kg/day for 30 days. The undecalcified fourth lumbar vertebral bodies (LVB) were processed for static and dynamic bone histomorphometry. The OVX rats possessed a slightly osteopenic LVB (17% vs. 24% cancellous bone mass). In rats given PGE2 at 3 and 6 mg/kg/day for 30 days, bone turnover, lamellar bone mass, and formation of new woven bone trabeculae were increased. Observations supported the conclusion that PGE2 activates bone modeling and remodeling, and shifts bone balance in favor of formation. In OVX rats given 6 mg PGE2/kg/day, cancellous bone mass and trabecular numbers were restored to levels found in untreated SHAM rats. Cancellous bone mass in the LVB of SHAM rats given 3 and 6 mg PGE2/kg/day increased by 16% and 30% over that of control rats. In addition, PGE2 stimulated longitudinal bone growth in both OVX and SHAM rats, a response that differed from male rats.

Aging↗
PubMed1988

Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females.

Transilial bone biopsies were obtained from 34 healthy postmenopausal women following in vivo fluorochrome labeling. Stained and unstained undecalcified sections were evaluated using a Merz grid. Standard histomorphometric data from cancellous bone tissue were collected and the results were evaluated and presented as variables commonly used in bone histomorphometry. The normal ranges, medians, means, and standard deviations for the group of 34 are presented in tabular form for structural, surface, basic dynamic, and derived dynamic data. Similar data for individuals grouped by ages 45-54, 55-64, and 65-74 are also presented. Secular trends for the whole group are evaluated. The structural and surface data are not much different from previous reports of sudden-death accident victims, when methodologic differences are considered. The mineral apposition rate (MAR) was 0.53 +/- 0.08 micron/day, similar to previous reports in cancellous bone, but one-third less than in cortical bone. MAR showed a marked decline with age. In contrast, the extent of tetracycline-labeled surfaces varied widely without a secular trend. Double-label surface (dLS/BS) ranged from 0.5 to 8.0% and single-label surface (sLS/BS), from 0.5 to 10.5%. Mineralizing osteoid surface (MS/OS) varied from 2 to 64%. Using only double-label surface to represent mineralizing surface, volume-based bone formation rate (BFR/BV) ranged from 0.7 to 28%/yr, and the remodeling period (Rm.P) varied from 0.28 to 4.5 years. Calculations using other representations of mineralizing surface [double plus one-half single label (MS/BS"); all label (MS/BS')] are also presented. These bone histomorphometric data are important because: (1) they come from a cohort of living subjects that was recruited solely for the purpose of establishing normal bone histomorphometry; (2) they represent the age range of patients with postmenopausal osteoporosis; and (3) they markedly expand the bone histomorphometric database of healthy persons given in vivo fluorochrome labeling prior to transilial biopsy.

Aged↗
PubMed1987

The proportion of trabecular bone in human vertebrae.

The proportion of trabecular bone in human cadaver vertebrae was assessed by anatomic dissection. Thirty-two whole thoracic and lumbar vertebrae were obtained from 10 normal human postmenopausal female cadavers, 14 from 4 normal adult human male cadavers of similar age, and 8 from one female osteoporotic cadaver. Each vertebra was opened by saw cuts and separated into four tissue types: (1) body trabecular bone and marrow; (2) body cortical bone; (3) vertebral arch trabecular bone and marrow; and (4) vertebral arch cortical bone. Calcium was determined in each tissue type for each vertebra by ashing and atomic absorption spectrophotometry. Trabeculae accounted for 24.4 +/- 4.5% of the total calcium in whole female vertebrae, and 18.8 +/- 4.4% in whole male vertebrae (p less than 0.001). The body averaged 41.8% trabecular bone in females and 33.5% in males. The arch averaged 9.7% trabecular bone in females and 4.9% in males. The proportion of trabecular bone in the whole vertebrae in the single osteoporotic spine was 28.5 +/- 3.2%, a value not significantly different from the trabecular fraction in normal females. These data indicate that whole human thoraco-lumbar vertebrae are composed of a substantially lower proportion of trabecular bone than is usually assumed, and they suggest that cortical and trabecular bone are eventually lost in equal proportion from the vertebrae during the development of spinal osteoporosis. These results are important for the interpretation of data from noninvasive bone measurement techniques that evaluate the spine, and they suggest that studies of this type are important for any site where noninvasive bone mass measurement is done.

Analysis of Variance↗
PubMed1987

The role of bone cells in increasing metaphyseal hard tissue in rapidly growing rats treated with prostaglandin E2.

The skeletal effects of graded doses of prostaglandin E2 (PGE2) given to weanling Sprague-Dawley rats for 3 weeks were investigated to elucidate the role of bone cells in increasing hard tissue mass. Decalcified (3 micron) sections were quantified in the light microscope by point hit and intersect counting using a Merz grid. Hard tissue mass (bone and calcified cartilage) and osteoblast, osteoclast and osteoprogenitor cell numbers were counted in metaphyseal tissue bands 0.24, 0.48, 0.72, 1.20, 1.68, 2.16, 2.64, 3.12, 3.60 and 4.08 mm from the growth plate metaphyseal junction. Changes were different and more marked in the secondary spongiosa than the primary spongiosa of the proximal tibial metaphysis of treated rats. In the primary spongiosa of rats treated with 3 or 6 mg PGE2/kg/d (1) an increase in bone and hard tissue masses and (2) a decrease in osteoclasts, osteoprogenitor cell numbers and surface to volume ratio was observed. In the secondary spongiosa (lower metaphysis) of rats treated with 2 same dose levels (1) an increase in bone mass, calcified cartilage cores, and hard tissue mass and perimeter, an elevation of osteoprogenitor cell and osteoblast numbers, a depression of osteoclast, osteoclast nuclei numbers and surface to volume ratio and new sites of intramembranous ossification (woven bone formation) originating from the cortico-endosteal envelope was observed. In this growing rat skeletal model, we showed that PGE2 increases metaphyseal calcified tissue mass by depressing hard tissue resorption and stimulating the replication and differentiation of osteoblast precursors to form new foci of woven bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of ovariectomy on iliac trabecular bone in baboons (Papio anubis).

Biopsies were collected from the left iliac crest of six adult female baboons, after which three of the animals were ovariectomized. Biopsies were collected from the right iliac crest six months later. Histomorphometric evaluation of the biopsies revealed consistent increases in fractional forming surface, appositional rate, and volume-based bone formation rate after ovariectomy. The data indicate that bone turnover is increased following ovariectomy in the baboon.

Animals↗