Vertebral fracture and cortical bone changes in corticosteroid-induced osteoporosis.

Despite an intriguing understanding of trabecular bone dynamics, little is known about corticosteroid-induced cortical bone loss and fractures. Recently, we verified a steroid-induced decrease in cortical bone volume and density using peripheral quantitative computed tomography (pQCT) in adult asthmatic patients given oral corticosteroids. Subsequently, the pQCT parameters and presence of vertebral fractures were investigated to further clarify the role of cortical bone quality in fractures in 86 postmenopausal (>5 years after menopause) asthmatic patients on high-dose oral steroid (>10 g cumulative oral prednisolone) (steroid group) and 194 age-matched controls (control group). Cortical and trabecular bone was subjected to measurement of various parameters using pQCT (Stratec XCT960). Relative Cortical Volume (RCV) was calculated by dividing the cortical area by the total bone area. Strength Strain Index (SSI) was determined in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. Patients treated with high doses of oral steroid (>10 g cumulative oral prednisolone) were found to have an increased risk of fracture compared with control women receiving no steroid medication (odds ratio, 8.85; 95% CI, 4.21-18.60) after adjustment was made for years since menopause, body mass index and RCV. In both groups, the diagnostic and predictive ability of the pQCT parameters for vertebral fracture was assessed by the areas under their receiver operating characteristic (ROC) curves. All parameters were found to be significant predictors ( p<0.0001) in the control group. In the steroid group, however, the cortical bone mineral density (BMD) ( p = 0.001), RCV ( p<0.0001) and SSI ( p = 0.001) were found to be significant predictors, but not trabecular BMD ( p = 0.176). For comparison between the two groups, thresholds of all parameters for vertebral fracture were also calculated by the point of coincidence of sensitivity with specificity in ROC testing and the 90th percentile value. Although a rise in fracture threshold in the steroid group was suggested, considerable difference in the values obtained by the two methods of calculation precluded any conclusion. High-dose oral steroid administration was associated with an increased risk of fracture. Cortical bone parameters obtained by pQCT could play a role as good predictors of future corticosteroid-induced vertebral fractures.

Cytoplasmic microtubular system implicated in de novo formation of a Rabl-like orientation of chromosomes in fission yeast.

Chromosomes are not packed randomly in the nucleus. The Rabl orientation is an example of the non-random arrangement of chromosomes, centromeres are grouped in a limited area near the nuclear periphery and telomeres are located apart from centromeres. This orientation is established during mitosis and maintained through subsequent interphase in a range of species. We report that a Rabl-like configuration can be formed de novo without a preceding mitosis during the transition from the sexual phase to the vegetative phase of the life cycle in fission yeast. In this process, each of the dispersed centromeres is often associated with a novel Sad1-containing body that is contacting a cytoplasmic microtubule laterally (Sad1 is a component of the spindle pole body (SPB)). The Sad1-containing body was colocalized with other known SPB components, Kms1 and Spo15 but not with Cut12, indicating that it represents a novel SPB-related complex. The existence of the triplex structure (centromere-microtubule-Sad1 body) suggests that the clustering of centromeres is controlled by a cytoplasmic microtubular system. Accordingly, when microtubules are destabilized, clustering is markedly reduced.

Oral glucocorticoid-induced fall in cortical bone volume and density in postmenopausal asthmatic patients.

Despite a deepening understanding of the influence of glucocorticoids (GC) on trabecular bone, little is known about GC-induced cortical bone loss. To elucidate the mechanism of GC-induced loss of cortical bone strength with particular reference to cortical bone loss, changes in cortical density, relative cortical volume, and the Strength Strain Index (SSI) based on biomechanical analyses of the geographic distribution of cortical bone material were measured. These parameters were compared, using peripheral quantitative computed tomography (pQCT), among the following age-matched groups: 68 postmenopausal asthmatic patients receiving high-dose oral GC in addition to inhaled GC (oral GC group), 68 postmenopausal asthmatic patients receiving only inhaled GC (inhaled GC group) and 69 postmenopausal controls without asthma or GC therapy (control group). Cortical bone mineral density (BMD) was measured, relative cortical volume was obtained by dividing the cortical area by the total bone area using pQCT (Stratec XCT960), and the Strength Strain Index (SSI) was calculated in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. The number of vertebral fractures per patient correlated highly with cortical BMD, relative cortical volume and SSI values at the radius. The number of vertebral fractures per patient and the number of patients with fracture were similar between the control and inhaled GC group, both being significantly lower than those in the oral GC group. Total BMD, trabecular BMD, cortical BMD, relative cortical volume and SSI were similar between the first two, being significantly higher than in the last group. The slopes of cortical volume-density relationship, however, were identical among the three groups, indicating the persistence of cortical bone remodeling and a similar degree of calcification regardless of GC administration.

Peripheral computed tomography (pQCT) detected short-term effect of AAACa (heated oyster shell with heated algal ingredient HAI): a double-blind comparison with CaCO3 and placebo.

Trabecular bone density at the distal radius and cortical bone density at the midradius were measured in four randomized groups of women before and after 4 months administration of AAACa, oyster shell heated under reduced pressure with addition of heated algal ingredient (HAI) (group A); AACa, the same preparation without HAI (group B); CaCO3 (group C); and placebo (group D) in a double-blind system using peripheral quantitative computed tomography (pQCT) with lumbar spine density measurement by dual-energy X-ray absorptiometry (DXA). Groups A, B, and C received 900 mg/day elemental calcium and D received none. In subjects of group A, but not B, C, and D, radial trabecular bone density increased significantly, to 106.2% +/- 2.1% of the initial value (mean +/- SEM). The increase of trabecular bone density was significantly different from the placebo group (D) only in AAACa (group A) and not in AACa (group B) and the calcium carbonate (group C). Cortical bone density increase was also greater in group A (but not in B and C) than in D. Lumbar spine density did not change significantly. AAACa was apparently more effective, increasing trabecular bone density more than AACa and CaCO3 containing the same amount of elemental calcium.

Increase of intestinal calcium absorption and bone mineral density by heated algal ingredient (HAI) in rats.

Active absorbable calcium (AAACa) produced by adding HAI (heated algal ingredient) to oyster shell calcium (AACa) is quite efficiently absorbed from the intestine and can increase bone mineral density in elderly osteoporotic patients. HAI was produced by heating the seaweed Cystophyllum fusiforme under reduced pressure, extracting with 6N HCL, and partially neutralizing it. Butanol-ethanol extraction then yielded active HAI fraction A, corresponding to about 1% in weight. The active HAI fraction increased intestinal Ca absorption as shown by a dose-dependent increase of plasma Ca in young male parathyroidectomized rats maintained on a low-Ca diet by administration through a stomach tube with a constant dose of AACa. The action of the active fraction A to maintain bone mass was then tested in young male rats kept on a low-Ca diet for 2 weeks. Bone weight, trabecular bone density, and strength-strain index as indices of bone strength measured by peripheral computed tomography (pQCT) tended to increase when the active HAI fraction was given along with Ca. HAI increased intestinal Ca absorption and prevented the decrease of bone density in rats kept on a low-Ca diet.

Measurement of forearm bone in children by peripheral computed tomography.

By means of peripheral computed tomography (pQCT), adult cortical bone density and volume was shown to be under a fixed rectilinear relationship regardless of age, sex, and presence or absence of osteoporosis. In children, however, the density-volume regression line followed a clearly different slope from that for adults (P < 0. 001), indicating a difference in property and composition of the cortical bone between growing bone of children and grown-up bone of adults. Although both relative cortical volume and density increased with age in both boys and girls, no significant increase of trabecular bone was noted in either during the growth period. When the same technique was applied to the bone of rats known to continue growing with indefinite modeling without remodeling, the regression line between cortical bone density and volume was different from that of adult humans and similar to that of growing human children. Growing bone in a constant process of modeling and mineralization thus seems to have cortical bone possibly with less complete mineralization somewhat different from those of grown-up bone only undergoing remodeling. Selective cortical bone measurement by pQCT appears to be useful in characterizing the unique properties of the cortex of the growing bone.

Comparison of trabecular bone density at vertebral and radial sites using quantitative computed tomography.

Trabecular volumetric bone mineral density (VMD) was measured at the lumbar spine using quantitative computed tomography (QCT) and at the distal radius using peripheral QCT (pQCT) in 60 Japanese women aged 21-86 years. The age-dependent decrease between age 20 and 80 years was found to be almost identical between vertebral trabecular VMD and radial trabecular VMD, averaging 2.5 +/- 0.26 (SE) and 2.5 +/- 0.30 mg/cm3 per year, respectively. A highly significant correlation was found between vertebral and radial trabecular VMD (r = 0.806, p < 0.001) with a prediction error of +/- 9.6% (+/- SD/mean). In the present study, a relatively constant trabecular VMD ratio was found between the vertebral and distal radial sites, despite the relatively small study population. This may indicate a close parallelism between vertebral and radial trabecular bone.

Transmenopausal change of trabecular bone density and structural pattern assessed by peripheral quantitative computed tomography in Japanese women.

Trabecular bone pattern, related to connectivity, was analyzed along with a separate measurement of cortical and trabecular bone mineral density (BMD) at the distal radius by peripheral quantitative computed tomography (pQCT) in 48 perimenopausal women, consisting of 25 premenopausal women aged 41 to 52 (mean 46.6 +/- 2.9 years) and 23 early postmenopausal women aged 46 to 59 (mean 53.2 +/- 3.2 years) within 5 years of the menopause (mean 2.7 +/- 1.5 years). No significant difference was found in either cortical or trabecular bone density between premenopausal and postmenopausal women despite a significant difference in age (premenopause vs postmenopausal: 46.7 +/- 2.9 years vs 53.2 +/- 3.1 years, p < 0.00001), including a slow change of BMD, if any, before and within 5 years of the menopause. However, analysis of trabecular fragments and perforation revealed a significant increase of the number of perforations in postmenopausal compared with premenopausal women (premenopausal vs postmenopausal: 0.9 +/- 1.6 vs 2.9 +/- 2.3, p < 0.002), indicating that disconnectivity has already increased before a significant reduction of BMD. Furthermore, chi-square analysis showed that even postmenopausal women with trabecular BMD more than 160 mg/cm3 were about 11 times more likely to have three or more perforations than premenopausal ones (odds ratio: 11.42, F = 0.030). These data suggest that trabecular bone connectivity is more sensitive that BMD in the detection of the early changes of postmenopausal osteoporosis.

Ultrasound transmission as a sensitive indicator of bone change in Japanese women in the perimenopausal period.

Apparent velocity of ultrasound (AVU) through the patella was measured in 160 Japanese women without specific diseases affecting the skeletal system. AVU averaged 1955 +/- 64 m/s (mean +/- S.D.) in healthy premenopausal women. Twenty patients with postmenopausal osteoporosis over the age of 50 years with at least one atraumatic vertebral fracture had significantly lower average AVU (1757 +/- 89.6 m/s) than that of the same age group without compression fracture (1838 +/- 78.0 m/s, P < 0.05). Perimenopausal women without vertebral fracture in their 50s were divided into two groups, premenopausal (n = 11) and postmenopausal (n = 28), and both AVU through the patella and spinal BMD (L-2-4) using DXA were measured. A significant difference was found in AVU between the two groups (premenopausal, 1953 +/- 58 m/s; postmenopausal, 1885 +/- 73 m/s, P < 0.01), in the absence of a difference either in the mean age (premenopausal, 52.7 +/- 2.0; menopausal, 54.2 +/- 2.4) or in the spinal BMD as assessed by DXA (premenopausal, 0.930 +/- 0.080 g/cm2; postmenopausal, 0.851 +/- 0.148 g/cm2). The apparent difference in AVU without corresponding difference in BMD suggests that perhaps AVU measures something about the bone that is not reflected in BMD in women in their 50s in the immediate postmenopausal period. When AVU of our test subjects was compared with that in Caucasians reported by Heaney RP et al. (Osteoporotic bone fragility: detection by ultrasound transmission velocity. J Am Med Assoc 1989;261:2986-2990) no difference was found in AVU between Japanese and Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of growth hormone by vasoactive intestinal polypeptide in acromegaly.

Vasoactive intestinal polypeptide (VIP) was administered as an iv bolus of 1 micrograms/kg BW to 8 acromegalic patients and in doses of 0.5 and 1 microgram/kg BW to 15 normal volunteers. Both systolic and diastolic blood pressures decreased, and pulse rate increased transiently after VIP injection. VIP stimulated PRL release from the anterior pituitary in normal subjects. Plasma PRL responses to VIP in women were dose dependent and larger than those in men. On the other hand, plasma GH levels rose markedly after VIP injection in all 6 patients with untreated acromegaly. In 2 patients studied after transsphenoidal microadenomectomy, there was no plasma GH response to VIP. In 2 other patients with inactive acromegaly as well as in normal subjects, VIP failed to affect plasma GH levels. In all 6 patients with active acromegaly, LRH (1-2 micrograms/kg BW, iv) did not increase plasma GH levels, but TRH (5-10 micrograms/kg BW, iv) caused significant increases in plasma GH, the magnitude of which was not similar to that of increases seen after VIP injection. Paradoxical GH responses to TRH were not observed in patients in the inactive phase after transsphenoidal surgery. These findings suggest that VIP stimulates GH release in vivo in acromegalic patients. A VIP test as well as a TRH test offer promise as simple and reliable techniques to evaluate the activity of acromegaly, particularly after transsphenoidal surgery.

Effect of long term bromocriptine treatment on glucose intolerance in acromegaly.

Blood glucose, plasma GH, insulin and glucagon levels during oral glucose tolerance test before and after treatment with bromocriptine (5-20 mg daily for 2-9 months) were investigated in eleven acromegalic patients with glucose intolerance. Nine out of 11 patients showed improvement or normalization in glucose tolerance after bromocriptine therapy. Basal levels of plasma GH were markedly decreased in 7 of 11 patients treated, although the improved glucose tolerance was not always associated with a drop of basal plasma GH levels. In contrast, basal plasma glucagon level showed a distinct fall in all the patients whose glucose tolerance was improved, but unchanged in whom glucose tolerance was not ameliorated. The mean values of plasma GH and glucagon after oral glucose load were significantly lower during bromocriptine therapy than those before the treatment, respectively. Basal levels of plasma insulin and its response to glucose load did not change after bromocriptine treatment. Bromocriptine thus appears to be a good alternative in the treatment of glucose intolerance in acromegalic patients and the improvement of glucose tolerance by bromocriptine may be related to the reduction in plasma glucagon levels. The possibility, however, is not excluded that a decrease by bromocriptine in the total daily GH secretion is a cause of the improved glucose tolerance.