Biomedical subjects

N Binkley

Publications and source records attributed to N Binkley.

At least 19 recordsLinked to original sources

PubMed2004

Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.

Endemic hypovitaminosis D contributes to osteoporosis development. However, variation in 25-hydroxyvitamin D (25OHD) measurement is reported and confounds the diagnosis of vitamin D insufficiency/deficiency. This report emphasizes the marked variability observed in serum 25OHD measurements between laboratories.Initially, postmenopausal women had serum 25OHD determinations: 42 in laboratory A, 20 in laboratory B. Their mean (sem) serum 25OHD concentrations were 46 (2.1) and 21 (2.3) ng/ml in laboratories A and B, respectively. Furthermore, there was little overlap in serum 25OHD among these clinically similar individuals. Specifically, 17% of those measured in laboratory A but 90% in laboratory B were below an arbitrary threshold value of 32 ng/ml.Subsequently, serum was obtained from 10 healthy adults. Two aliquots from each individual, one of which was spiked with 20 ng/ml 25OHD, were sent to six laboratories. Substantial variability was noted between these six laboratories. The mean serum 25OHD concentration ranged from 17.1-35.6 ng/ml. Similarly, the mean increase produced by spiking with 20 ng/ml ranged from 7.7-18.0 ng/ml.In conclusion, 25OHD assays yield markedly differing results; whether an individual is found to have low or normal vitamin D status is a function of the laboratory used. If the medical community is to make progress in correcting widespread hypovitaminosis D, 25OHD measurement must be standardized.

Aged↗

PubMed2003

Bone loss detection in rats using a mouse densitometer.

Estrogen-depletion bone-loss studies often use ovariectomized (ovx) rats and measure bone mineral density in vivo or ex vivo using DXA. Recently, a portable densitometer (PIXImus) was developed for mouse research; however, its use in rats is unclear. This study compared the ability of PIXImus and a standard densitometer (DPXL) to detect ovx-induced bone loss in rats both in vivo and ex vivo. Additionally, instrument accuracy was assessed by comparing measured bone mass with ash weight. Finally, the use of two distal femur regions of interest (ROI) to detect ovx-induced bone loss was evaluated. Twenty-three 6-month-old nulliparous female Sprague-Dawley rats were randomly assigned to sham or ovx groups. Distal femur bone mineral density was assessed at baseline and at 1 and 2 months postoperatively, using a PIXImus and DPXL densitometer. At 3 months postoperatively, all animals were killed, and ex vivo femur scans obtained. Distal femur bone loss was demonstrable by 1 month post-ovx using either densitometer. With the PIXImus, a 4-mm ROI demonstrated greater bone loss (p < 0.05) than an 8-mm ROI. Using the 4-mm ROI, similar amounts of bone loss were detected by the PIXImus and DPXL: 22.2% and 22.4%, respectively, at 2 months post-ovx. Total femur bone mineral content was overestimated by the PIXImus but highly correlated with the DPXL measurement (r = 0.988) and ash weight (r = 0.998). Given its comparability to standard DXA plus its rapid scan speed and portability, the PIXImus is useful in evaluating ovx-induced osteopenia in rats.

Animals↗

PubMed2002

Vitamin K supplementation does not affect ovariectomy-induced bone loss in rats.

Vitamin K may be important in bone metabolism. Notably, high-dose menaquinone-4 (menatetrenone, MK4) has been reported to reduce ovariectomy (ovx)-induced bone loss in rats and to decrease osteoporotic fracture in postmenopausal women. However, it is unclear whether these beneficial effects reflect a physiologic effect of vitamin K, or indicate direct pharmacologic activity of MK4. To further evaluate this, 60 6-month-old nulliparous Sprague-Dawley rats were randomized by distal femur bone mineral density (BMD) in a 3:1 ratio to ovx or sham groups. The sham and one ovx group's diet contained 1% calcium and 1300 microg/kg of vitamin K1, phylloquinone. Diets of the other two ovx groups were supplemented with 882 mg phylloquinone or MK4 per kilogram chow. Distal femur bone mineral density (DFBMD) in an 8 mm region of interest was measured at baseline, 1 and 3 months postoperatively, utilizing dual-energy X-ray absorptiometry (DXA). All animals were killed at 3 months, their right femurs excised, ex vivo BMD measured by DXA, and biomechanical testing performed. No effect of phylloquinone or MK4 supplementation on ovx-induced bone loss was observed. Specifically, DFBMD declined 10.5%, 9.2%, and 11.2% at 1 month and 14.4%, 10.6%, and 13.9% at 3 months in the ovx control, high phylloquinone, and high MK4 groups, respectively. In addition, serum osteocalcin was elevated by ovx; this was not altered by phylloquinone or MK4. Finally, femoral biomechanical properties were not affected by phylloquinone or MK4. To conclude, in this study, neither high-dose phylloquinone nor MK4 reduced the ovx-associated increase in bone turnover or decline in DFBMD.

Animals↗

PubMed2000

Dietary content may prevent secondary hyperparathyroidism in female rhesus monkeys (Macaca mulatta).

Macaque laboratory chows provide relatively more calcium (Ca) and vitamin D (D) than human diets; this may influence skeletal aging. To evaluate this possibility, parameters of skeletal relevance in premenopausal and naturally postmenopausal rhesus monkeys were measured in a cross-sectional study. Serum osteocalcin (Oc) was elevated in the postmenopausal group (P < 0.01), but levels of parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) were not different. Subsequently, in premenopausal animals, dietary Ca and/or D intake was reduced to optimal human levels for 8 weeks prior to the evaluation of the skeletal parameters. Serum 25OHD concentration was reduced (P < 0.01) and a trend (P=0.10) towards increased PTH was observed in both low D groups. In addition, serum alkaline phosphatase (ALP) levels were increased in the low Ca group (P < 0.01). In conclusion, skeletal turnover, as measured by serum Oc, was increased in naturally postmenopausal rhesus monkeys in the absence of hyperparathyroidism. Dietary D reduction causes a decline in serum 25OHD and an upward trend in PTH.

Alkaline Phosphatase↗

PubMed2000

Hypervitaminosis A and bone.

Animal, human, and in vitro data all indicate that excess vitamin A stimulates bone resorption and inhibits bone formation. This combination would be expected to produce bone loss and to contribute to osteoporosis development and may occur with relatively low vitamin A intake. It is possible that unappreciated hypervitaminosis A contributes to osteoporosis pathogenesis.

Animals↗

PubMed2000

Diet- or warfarin-induced vitamin K insufficiency elevates circulating undercarboxylated osteocalcin without altering skeletal status in growing female rats.

To further characterize the skeletal role of vitamin K (K), markers of bone turnover, density, and strength were evaluated in rats with diet- or warfarin (W)-induced K insufficiency. One hundred two, 7-week-old, female rats were randomly assigned to low K (phylloquinone [K1], 20 microg/kg diet), control K (K1, 1300 microg/kg diet), low-dose W (W, 1.5 mg/kg control diet), or high-dose W plus K (W/K1, 10/100 mg/kg diet). Femur bone mineral content (BMC) and bone mineral density (BMD), plasma prothrombin time (PT) and prothrombin concentration (PC), and serum total alkaline phosphatase (ALP) and skeletal alkaline phosphatase (sALP) were measured at baseline and days 20, 40, 60, and 80. Serum total osteocalcin (OC) and undercarboxylated osteocalcin (ucOC) and femur length (FL) were measured at baseline and day 80. Left femur OC was measured and biomechanical testing of the right femur and third lumbar vertebral body was performed at day 80. Low dietary K elevated circulating ucOC (17% higher than control; p < 0.0001) at day 80. Furthermore, in both W groups, essentially all circulating OC was undercarboxylated and femur OC was lower than control (p < 0.0001). However, there was no change in femur percent ucOC, suggesting deposition of less newly synthesized OC. No between group differences were observed in PT, ALP, sALP, FL, BMC, BMD, or bone strength. In conclusion, skeletal K insufficiency can be induced by W or diet manipulation. This does not hinder peak bone mass attainment in female rats; however, W causes less newly synthesized OC to be deposited in bone.

Absorptiometry, Photon↗

PubMed1999

Central region-of-interest analysis of lumbar spine densitometry demonstrates lower bone mass in older rhesus monkeys.

Osteoarthritis (OA) spuriously elevates spine bone mineral density (BMD) as measured by dual-energy X-ray absorptiometry (DXA). This study documents spinal OA prevalence in adult female rhesus monkeys, and evaluates a custom central region-of-interest (CROI) analysis technique designed to minimize OA effects on BMD measurement. Lumbar spine radiographs were obtained on 71 animals, age 10-37 years. OA degree was blindly scored as none, minimal, or moderate/severe. Moderate/severe OA was not observed before age 19, but was present in 66% of older animals. Subsequently, lumbar spine (L2-4) BMD was determined by standard DXA analysis and manual placement of 0.92 cm2 CROIs in two groups of female rhesus monkeys. One group (eight control, eight postovariectomy, ages 10-19 years) was assessed longitudinally, the second (n = 90, ages 10-37) cross-sectionally. Measured bone loss following ovariectomy (8.1% standard analysis, 11.5 % CROI) was comparable with both techniques. By contrast, CROI demonstrated lower bone mass with age (p < 0.0001), whereas only a trend (p = 0.06) was observed with standard analysis. When World Health Organization criteria were applied, 42% of animals > or = age 19 years were classified as osteopenic/osteoporotic by standard analysis compared with 67% by CROI. All "normal" animals reclassified as osteopenic/osteoporotic by CROI had OA. In conclusion, female rhesus monkeys often develop spinal OA with advancing age. CROI analysis demonstrated lower bone density in older monkeys and was as sensitive to estrogen-depletion bone loss as standard methodology. This suggests that alternative analysis techniques, such as CROI, may be more appropriate to evaluate bone density in nonhuman primates, and potentially in people.

Absorptiometry, Photon↗

PubMed1999

Skeletal effects of aging in male rhesus monkeys.

Age-related bone loss in men is receiving increased attention. In light of this, animal models for male bone loss are desirable. This study examined the effects of age and osteoarthritis (OA) on bone mineral content (BMC), bone mineral density (BMD), and markers of bone turnover and skeletal relevance in 56 male rhesus monkeys 4-34 years of age. BMC and BMD increased at all sites from 4 to 10 years of age. Male rhesus monkeys reach peak bone mass at approximately 10 years of age after which bone mass is lower at the lateral spine and distal radius. Markers of bone turnover (osteocalcin and carboxyterminal telopeptide of type I collagen [ICTP]) decreased with age. There was no relationship between PTH, 25-hydroxyvitamin D, FSH, or testosterone and age. With advancing age, the prevalence of lumbar spine OA increases dramatically, masking decreases in posteroanterior spine bone mass that are clear in the lateral projection. These data suggest that male rhesus monkeys sustain age-related bone loss in the absence of nutritional or gonadal steroid deficiencies. These animals may prove useful in studying the mechanisms of age-related bone loss.

25-Hydroxyvitamin D 2↗

PubMed1999

Skeletal effects of aging and menopausal status in female rhesus macaques.

To further define the nonhuman primate as a model of the adult human skeleton, we explored the impact of growth, natural menopause, and osteoarthritis on bone mass, serum markers of bone turnover (osteocalcin and C-terminal telopeptide of type I collagen) and measures of skeletal relevance (PTH, 25-hydroxyvitamin D, total alkaline phosphatase, calcium, phosphorus, creatinine, and albumin). Fifty-eight female (aged 4-30 yr) rhesus macaques were defined as growing (G; n = 12; < or = 10 yr old), adult premenopausal (APre; n = 30; > 10 yr old; eumenorrheic, high serum estradiol and low FSH), or postmenopausal (Post; n = 16; amenorrheic for at least 1 yr, with low serum estradiol and high FSH). Total body and posterior-anterior spinal bone masses were lower in G than APre animals (P < 0.05). Post females had lower total body, distal radius, and spinal bone mass than premenopausal animals (P < 0.05). Osteocalcin was higher in Post than APre animals (P < 0.01). Other measures showed no relationship with menopausal status. In older monkeys, spinal osteoarthritis became common, causing increased dual-energy x-ray absorptiometry-measured bone mass in the lumbar spinal posterior-anterior projection. In conclusion, after natural menopause, rhesus monkeys have lower bone mass and higher skeletal turnover without alteration of the calcium-vitamin D axis. As such, they are an excellent model of human estrogen-depletion bone loss.

Absorptiometry, Photon↗

PubMed1999

Rib biopsy technique for cortical bone evaluation in rhesus monkeys (Macaca mulatta).

Old World primates are often studied to model human skeletal physiology. An important advantage of monkeys over other animal models (i.e., rodents) is the presence of cortical bone Haversian remodeling. Seventy-five female rhesus monkeys (Macaca mulatta) were subjected to bone biopsy. With monkeys in lateral decubitus position, the tenth rib was surgically exposed and freed from periosteum by use of careful sharp and blunt dissection. The rib section was resected, using bone cutters, and the surgical wound was closed. This procedure was repeated for the contralateral rib at a later time point in 65 monkeys. There was no mortality or appreciable morbidity. The bone specimens were (mean +/- SD) 2.50 +/- 0.25 cm long, with 5.5 +/- 1.0 mm2 total cross-sectional area. They were adequate for histologic, immunohistochemical, and quantitative histomorphometric examinations. Prevalence of pneumothorax was approximately 8.0% for the 140 procedures. This complication was immediately and successfully corrected by insertion of a small thoracic tube, evacuation of pneumothorax, and closure of the incision. This well-tolerated, repeatable procedure yields excellent specimens for performance of cortical bone histologic examination without euthanasia, allowing longitudinal evaluation.

Animals↗

PubMed1998

Zoledronate prevents the development of absolute osteopenia following ovariectomy in adult rhesus monkeys.

This study assessed effects of the bisphosphonate zoledronate (ZLN) on bone density and biochemical markers of bone turnover in ovariectomized (OVX) adult female rhesus monkeys. Forty monkeys were randomly assigned to one control or four OVX groups. The control and one OVX group received saline, and the other three OVX groups received ZLN (0.5, 2.5, or 12.5 microg/kg) by a single weekly subcutaneous injection for 69 weeks. Bone mass of the total body (TB), lumbar spine (LS), distal and central radius (dual-energy X-ray absorptiometry), and skeletal turnover markers were measured at baseline and at 13, 26, 39, 52, and 69 weeks of treatment. Increased skeletal turnover and decreased bone mass (LS and TB) were demonstrable by 13 weeks post-OVX. Maximal bone loss (7-8%) at these sites occurred by 39 weeks after OVX and persisted for the study duration. Long-term ZLN treatment was well tolerated and prevented increased skeletal turnover and bone loss in a dose-dependent fashion. Progressive turnover suppression was not observed with any ZLN dose. In conclusion, after OVX, adult rhesus monkeys develop persistent increased bone turnover and absolute osteopenia of the LS and TB, making them an outstanding model of skeletal behavior in perimenopausal women. These OVX-related skeletal changes are dose-dependently blocked by ZLN.

Absorptiometry, Photon↗

PubMed1997

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and L-carnitine levels in oophorectomized rats.

Alteration in energy metabolism of postmenopausal women might be related to the reduction of dehydroepiandrosterone sulfate (DHEAS). DHEA and DHEAS decline with age, leveling at their nadir near menopause. DHEA and DHEAS modulate fatty acid metabolism by regulating carnitine acyltransferases and CoA. The purpose of this study was to determine whether dietary supplementation with DHEAS would also increase tissue L-carnitine levels, carnitine acetyltransferase (CAT) activity and mitochondrial respiration in oophorectomized rats. Plasma L-carnitine levels rose following oophorectomy in all groups (P < 0.0001). Supplementation with DHEAS was not associated with further elevation of plasma L-carnitine levels, but with increased hepatic total and free L-carnitine (P = 0.021 and P < 0.0001, respectively) and cardiac total L-carnitine concentrations (P = 0.045). In addition, DHEAS supplementation increased both hepatic and cardiac CAT activities (P < 0.0001 and P = 0.05 respectively). CAT activity positively correlated with the total and free carnitine levels in both liver and heart (r = 0.764, r = 0.785 and r = 0.700, r = 0.519, respectively). Liver mitochondrial respiratory control ratio, ADP:O ratio and oxygen uptake were similar in both control and supplemented groups. These results demonstrate that in oophorectomized rats, dietary DHEAS supplementation increases the liver and heart L-carnitine levels and CAT activities. In conclusion, DHEAS may modulate L-carnitine level and CAT activity in estrogen deficient rats. The potential role of DHEAS in the regulation of fatty acid oxidation in postmenopausal women is worthy of investigation.

Animals↗

PubMed1997

Influence of fat intake and caloric restriction on bone in aging male rats.

Caloric and fat intake may have important skeletal consequences. To evaluate this possibility, skeletal effects of adult-onset caloric restriction (CR) at differing fat intakes were assessed in male Lobund-Wistar rats. At age 17 months, two groups of animals received an anti-obesity diet, restricted approximately 35% from individual ad libitum baseline calorie consumption, and two groups received a diet approximately 50% restricted. Dietary fat concentrations were 5, 15, 15, and 25% by weight, respectively. At ages 20, 24, 28, 30, and 32 months, ex vivo femoral bone densitometry and serum biochemical analyses were performed. Body weight (BW) decreased with time on CR in each group (p < .005), declining faster at the more severe restriction (p = .001). Femoral bone mineral contents (BMC) were also reduced. After adjusting for bone area and BW differences among groups, the only significant difference was a reduction in distal femur BMC in the 25% fat group subjected to more severe CR (p = .02). No differences were observed in serum parathyroid hormone, calcium, phosphorus, or creatinine. Femoral bone loss occurred with CR. This was entirely accounted for by reduction in BW. Higher dietary fat content did not affect BW in CR animals, but did result in lower distal femur BMC.

Aging↗

PubMed1996

The effect of advancing age on bone mineral content of female rhesus monkeys.

Dual-energy X-ray absorptiometry (DXA) can be used to assess bone mass in nonhuman primates; however, the changes in bone mineral across the lifespan have not been well described. The purpose of this cross-sectional study was to evaluate the effect of maturation and subsequent aging on bone mineral content (BMC) and bone size (two dimensional bone area) in female rhesus monkeys at sites analogous to those commonly evaluated in humans. Total body (n = 178) and lumbar spine (n = 167) DXA scans were performed on female rhesus monkeys aged 2.8 to 34.6 years. Radius scans (n = 86) were performed on monkeys aged 9.7 to 34.6 years. Measurement precision was comparable to that reported for humans. At all sites, BMC was highly correlated with bone area (p = 0.0001), which was positively correlated with both body weight (p < or = 0.002) and age (p < or = 0.08). Total body and lumbar spine BMC and bone area increased with maturation (p < 0.0001) until age 11 and then remained stable with further advancing age. There was little change in total body and lumbar spine area-adjusted BMC across the lifespan. At the radial sites, there were no significant changes in BMC or bone area with age, but the area-adjusted BMC and the weight- and area-adjusted BMC declined in older animals (p < 0.05). In conclusion, the female rhesus monkey does not attain peak bone mass until age 11. Significant bone loss at later ages was observed only at radial sites.

Absorptiometry, Photon↗

PubMed1995

Interleukin-6 causes hypocholesterolemia in middle-aged and old rhesus monkeys.

BACKGROUND: Hypocholesterolemia is a risk factor for morbidity and mortality in older people. We have hypothesized that hypocholesterolemia in older people is due to the chronic effect of proinflammatory cytokines on lipoprotein metabolism. METHODS: To test the effects of the chronic administration of interleukin-6 (IL-6) on lipoprotein levels in middle-aged and old rhesus monkeys, five middle-aged and five old rhesus monkeys received a subcutaneous injection of recombinant human IL-6 (15 micrograms/kg) for 28 days. Lipid, apolipoprotein, and albumin levels were measured at 0, 28, and 42 days after injection. RESULTS: Total and HDL cholesterol levels fell by 16 and 23%, respectively, after IL-6 injections. The concentrations of apolipoproteins A1 and B also decreased. The changes in lipoprotein levels were accompanied by a decrease in albumin levels and body weight. Levels of lipids and plasma proteins returned toward normal 2 weeks after injections were stopped. There was no difference in response between middle-aged and older animals. CONCLUSIONS: Chronic IL-6 injections cause acquired hypocholesterolemia, hypoalbuminemia, and weight loss in nonhuman primates. These changes are similar to those seen in older persons with acquired hypocholesterolemia.

Aging↗

PubMed1995

Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density.

OBJECTIVE: To determine if plasma levels of Interleukin-6 (IL-6) across the lifespan correlate with bone density or plasma osteocalcin. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-five healthy community-dwelling volunteers aged 25-74 years. Exclusion criteria were smoking use of medications known to affect bone metabolism (corticosteroids, heparin, thyroxine, thiazides, and anticonvulsants), and presence of chronic inflammatory disease. MEASUREMENTS: Bone density was measured by dual-energy X-ray absorptiometry at the femoral neck and lumbar spine. Plasma levels of IL-6 and osteocalcin were determined by ELISA and RIA, respectively. RESULTS: Plasma levels of IL-6 increased with advancing age (P < .0001) and correlated with postmenopausal status (P < .0001). No correlation was observed between plasma IL-6 level and bone mineral density at either the lumbar spine or femoral neck, and none was observed with plasma osteocalcin. CONCLUSIONS: The elevation of plasma IL-6 observed following menopause is consistent with the proposed importance of estrogen in the regulation of IL-6. These findings do not provide support for a role of IL-6 in determination of peak bone density or subsequent development of osteoporosis. However, it is possible that plasma levels of IL-6 differ from those in the bone microenvironment.

Absorptiometry, Photon↗

PubMed1994

The role of interleukin-6 in certain age-related diseases.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a wide range of functions. Perhaps the most important physiologically is its role as a mediator of the acute phase inflammatory response. Normally, there is little measurable IL-6 in the circulation, but levels increase abruptly to nanogram amounts during an inflammatory process. During aging, it has been proposed that the tight regulation of IL-6 gene expression becomes less effective and levels are measurable even when there is no evidence for inflammation. Several investigators have identified this cytokine as being involved in the pathogenesis of various disease processes and we have suggested that certain age-associated diseases are directly related. Among these are late-life lymphoma and myeloma, osteoporosis and possibly Alzheimer's disease.

Aging↗

PubMed1993

Sensitivity and positive predictive value of clinical signs of hypogonadism in elderly men.

One hundred three ambulatory elderly men had serum free testosterone (FT) assessed as part of a study of bone loss. The FT was analyzed using radioimmunoassay. Each participant was questioned regarding the presence of erections adequate for sexual activity and the presence of sexual desire. Each was examined for decreased axillary and pubic hair. A FT of less than 9.0 pg/mL was found in eight subjects. The sensitivity of the clinical predictors as an indicator of a low FT value ranged from 43% to 86%, while positive predictive value ranged from 12% to 19%. The abnormal clinical signs and symptoms investigated in this study obviously have mechanisms in addition to hypogonadism. A history of adequate erections ruled out a low FT value in all but 1 of 44 cases.

Aged↗