Bone structure in postmenopausal hyperparathyroid, osteoporotic, and normal women.

The purpose of this study was to test the hypothesis that patients with mild primary hyperparathyroidism are protected against postmenopausal (PM) loss of cancellous bone architecture. To achieve this, we compared bone structure and turnover in iliac bone biopsies from three groups: 16 women with mild primary hyperparathyroidism (PHPT; 58.2 +/- 2.2 years, 11.5 +/- 1.7 years PM), 17 women with untreated primary osteoporosis (OP; 65.1 +/- 2.0 years, 17.2 +/- 2.3 years PM), and 31 healthy women (N; 59.8 +/- 1.4 years, 13.4 +/- 1.5 years PM). The bone formation rate was significantly higher in PHPT than in either OP or N, and not different between OP and N. Cancellous bone volume, total strut length, and indices of connectivity (node number, node to node strut length, and node to terminus ratio) were significantly lower in OP than in either PHPT or N but were the same or higher in PHPT than in N. Indices of disconnectivity were significantly lower in PHPT than in N, whereas they were the same or higher in OP than N. The data were also analyzed in subgroups matched by years PM with no changes in the results. These findings indicate that osteoporotic patients with normal bone turnover have low bone volume and microarchitectural deterioration, while patients with mild PHPT have normal bone volume and normal or greater trabecular connectivity despite higher bone turnover. These findings suggest that mild PHPT protects against the loss of cancellous bone structure that normally follows menopause.

Relationships between bone structure in the iliac crest and bone structure and strength in the lumbar spine.

The purpose of this study was to examine the relationship between histomorphometric variables of cancellous bone structure and ultimate compressive strength (UCS) in the second lumbar vertebra (L2) and to determine whether structural variables in the iliac crest are predictive of the same variables and of UCS in L2. At autopsy, 7.5 mm diameter cores were removed from the iliac crest and from L2 of 29 subjects who had died suddenly without bone disease. Cancellous bone volume (BV/TV, %) was significantly lower in L2 than in iliac crest due to lower trabecular number (Tb.N, per mm) and thickness (Tb.Th, microns). There were significant correlations between iliac crest and L2 for BV/TV, Tb.N and trabecular separation (Tb.Sp, microns), but not for Tb.Th. BV/TV was negatively correlated, and Tb.Sp was positively correlated with age at both sites. Tb.Th was not significantly correlated with age in the iliac crest, but a significant negative correlation was observed in L2. The UCS of vertebral cores was negatively correlated with age. BV/TV and Tb.Th in L2 were positively correlated with UCS in L2.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis.

We previously demonstrated an increase in cancellous bone volume and trabecular number in patients with mild primary hyperparathyroidism (PHPT). To test the hypothesis that this increase is due to preservation of cancellous bone architecture, we conducted a trabecular strut analysis using a new method that measures trabecular connectivity. Iliac crest biopsies from 37 patients with PHPT, 14 men (28-68 years) and 23 women (26-68 years), were examined histomorphometrically and compared to cadaveric samples from 24 age-matched subjects, 17 men and 7 women. Two-dimensional indices of cancellous structure--node number (N.Nd), terminus number (N.Tm), node to node (Nd.Nd), node to terminus (Nd.Tm), and terminus to terminus (Tm.Tm) strut lengths, and total strut length (TSL)--were measured and the ratio of node number to terminus number (N.Nd/N.Tm) calculated. TSL, N.Nd, and Nd.Nd were significantly higher in patients than in controls. TSL and Nd.Nd, but not N.Nd or Nd/Tm, decreased significantly with age in PHPT, indicating that age-related bone loss in PHPT occurs without significant loss of trabecular connectivity. Two-dimensional indices reflecting connectivity or the amount of bone, that is, N.Nd, Nd.Nd, N.Nd/N.Tm, and TSL, correlated positively with cancellous bone volume (BV/TV) and trabecular number (Tb.N) and negatively with trabecular spacing (Tb.Sp) in both PHPT and controls. Trabecular thickness (Tb.Th) correlated positively with Nd.Nd and Tb.N and negatively with Tm.Tm in PHPT but not in controls. The present data show that in PHPT there is not only greater cancellous bone volume and trabecular number but preserved trabecular connectivity as well. The data further support the hypothesis that in PHPT cancellous bone architecture is maintained.

Effects of combined and separate intermittent administration of low-dose human parathyroid hormone fragment (1-34) and 17 beta-estradiol on bone histomorphometry in ovariectomized rats with established osteopenia.

To evaluate the potential use of a combination of parathyroid hormone (PTH) and estrogen as therapy for osteoporosis, we examined the effects of combined and separate administration of low-dose PTH and estradiol in ovariectomized rats with established osteopenia. Ovariectomized rats were untreated for 5 weeks after surgery and then injected s.c. with vehicle (Ovx + V), 1-34 hPTH (2.5 micrograms/kg/day) (Ovx + P), 17 beta-estradiol (50 micrograms/kg/day) (Ovx + E), or a combination of these (Ovx + P + E), for a further 4 weeks. We found no differences in serum calcium, tubular reabsorption of phosphate, or 25OHD. 1,25(OH)2D levels were significantly higher in Ovx + P and lower in Ovx + E, when compared with Ovx + V. Though there was no change in bone mineral density (BMD) in the diaphysis region of femurs, reduction of BMD in the distal region of the femurs in Ovx + V was reversed in Ovx + E and Ovx + P + E. Compared with Ovx + V, Ovx + P and Ovx + P + E had significantly higher cancellous bone volume (Cn-BV/TV) whereas Ovx + E showed a nonsignificant increase. When indices of bone turnover were examined, PTH alone showed a small but not significant improvement in bone formation rate (BFR). Increased osteoclast surface (OCS), as the result of ovariectomy, was inhibited in Ovx + E and Ovx + P + E. Estrogen alone (Ovx + E) severely inhibited BFR, but co-administration of PTH and estrogen (Ovx + P + E) showed an impressive reversal of such inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of changes in histomorphometric, bone mass, and biochemical parameters in ovariohysterectomized dogs.

A predictable animal model with skeletal remodeling characteristics similar to those of humans is needed to facilitate the understanding of the mechanism of postmenopausal osteoporosis. We have utilized the ovariohysterectomized (Ovh) dog to examine cellular and biochemical responses to estrogen depletion and PTH stimulation. Histomorphometric measurements of bone biopsies taken prior to (first biopsy) and five months after the operation (second biopsy) showed no significant differences in static and dynamic parameters. Bone mineral density of the excised vertebrae displayed the same values between the two groups six months after surgery. Between the second biopsy and sacrifice, two infusion studies were performed. A two-hour infusion of EDTA followed by a two-hour recovery period elicited a rapid response in PTH production, highly correlated to the changes in ionized calcium, but no significant difference in response was observed between Sham and Ovh groups. A short-term (24-h) infusion of 1-34 hPTH increased circulating ionized calcium and 1,25-(OH)2-D levels to a similar extent in both groups. The levels of alkaline phosphatase were constant and both groups showed a small but nonsignificant increase in osteocalcin. The lack of sizable responses in histomorphometric, bone mass, and biochemical parameters may limit the utility of dogs for the study of cancellous bone loss in ovarian-dysfunction osteoporosis.

Age-related changes in resorption cavity characteristics in human trabecular bone.

The depth of resorption cavities in trabecular bone is an important determinant of bone structure and has implications relevant to the cellular pathophysiology of bone loss in osteoporosis. However, assessment of resorption depth has proved difficult and few data are available; in this study we report age-related changes in iliac crest trabecular bone obtained from 41 normal healthy subjects (21 female, 20 male) aged 22-80 years. Using 8-microns undecalcified sections stained with toluidine blue, resorption cavities were quantitatively assessed by a computerized technique in which the eroded bone surface is reconstructed and measurements made interactively. Maximum and mean cavity depth showed no significant correlation with age in either sex. The absolute length of eroded surface was unrelated to age but the eroded surface/BS (%) and the number of cavities/BS (/mm) showed a significant positive correlation with age (r = 0.384 and 0.386 respectively, p less than 0.05). No significant correlation was found between age and either cavity area or density. These results suggest that increased resorption depth does not contribute to age-related bone loss, although the possibility that deeper resorption cavities occur which result in trabecular penetration and are therefore unrecognizable cannot be discounted. The age-related increase in eroded surface/BS (%) reflects a decreased available trabecular surface and/or increased number of cavities rather than a greater surface length of individual cavities; alternatively it may indicate an increased resorption period. No evidence of increased resorption depth at the time of the menopause was found in this study.

A new manual method for assessing two-dimensional cancellous bone structure: comparison between iliac crest and lumbar vertebra.

We have developed a simple method for the direct analysis of two-dimensional trabecular structure. Using this method, we have compared the structure of the left and right iliac crest and the second lumbar vertebra and studied the relationship between two-dimensional trabecular structure and the ultimate compressive stress of bone samples from the second lumbar vertebra. Transverse cores were taken from the left and right iliac crests and second lumbar vertebrae of 35 subjects (12 females) who died suddenly. The trabecular structure was subdivided into nodes (node count) and free ends (free end count), which were expressed per square millimeter of cancellous space. A node was defined as the point of junction between two or more trabeculae; a free end was defined as the end of a trabecula that was unconnected in the plane of the section to any other trabecular element. The following struts were defined by drawing a line between the nodes and the free ends: node to node, node to free end, free end to free end, and cortex-derived struts. Strut lengths were measured and expressed as a percentage of the total strut length and per square millimeter of cancellous space. Intraobserver variation was generally low, with coefficients of variation for repeat measurements in the range 3.9-17.8%. There was no statistically significant difference between left and right iliac crests for any of the variables measured. With the exception of cortex-derived struts, there was no statistically significant correlation between crests for any variable.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between spinal trabecular bone mineral content and iliac crest trabecular bone volume.

The relationship between spinal trabecular bone mineral density and iliac crest trabecular bone volume has been studied in 84 patients, 23 with primary osteoporosis, 19 with osteoporosis secondary to inflammatory bowel disease, and 42 with nonsteroid-treated rheumatoid arthritis. Spinal trabecular bone mineral density was measured in the first three lumbar vertebrae by quantitative computed tomography, and iliac crest trabecular bone volume was assessed histomorphometrically in sections from trans-iliac biopsies using computerized techniques. In all 84 patients, there was a significant positive correlation between the two measurements (r = 0.60, P less than 0.001). However, when the three patient groups were analyzed separately, a significant correlation was found in the group with secondary osteoporosis (r = 0.65, P less than 0.01) but not in the patients with primary osteoporosis (r = 0.07) or rheumatoid arthritis (r = 0.19). These results indicate that the relationship between spinal trabecular bone mineral density and iliac crest trabecular bone volume differs according to the underlying disease process, these differences possibly reflecting variations in skeletal patterns of bone loss in different types of osteoporosis.

The relationship between resorption depth and mean interstitial bone thickness: age-related changes in man.

The amounts of bone resorbed and formed in each bone remodelling unit are important determinants of bone mass. The mean wall thickness (MWT), which indicates the amount formed, decreases with age; less is known about changes in resorption depth although two studies have reported some evidence in favor of an age-related decrease. We have calculated mean intersitial bone thickness (MIBT), which is indirectly related to resorption depth, from measurements of MWT and mean trabecular plate thickness (MTPT) in 48 normal subjects, aged 19-80 years. No significant age-related changes in MIBT were found in either sex, or in both sexes grouped together, whereas MWT and MTPT showed a significant decrease with age (P less than 0.001 and less than 0.05 respectively). Detailed analysis of possible relationships between MIBT and resorption depth revealed that, assuming formation never exceeds resorption, a decreased MIBT may be associated with an increased, constant, or decreased resorption depth; an increased MIBT can only result from a decreased resorption depth. A constant MIBT may indicate either an unchanged or decreased resorption depth; in the former case, MTPT is unchanged whereas a decreased resorption depth is associated with a decreased MTPT. In view of the age-related reduction in MTPT, our results are therefore consistent with earlier reports of an age-related decrease in resorption depth. No evidence for an increased resorption depth during the menopause was found in this study.

Age-related changes in trabecular width and spacing in human iliac crest biopsies.

Age-related changes in trabecular width and spacing have been examined in iliac crest bone obtained from 96 normal subjects. The mean trabecular plate density and separation were calculated from values of trabecular bone volume and mean trabecular plate thickness. There was an age-related decrease in mean trabecular plate thickness with age in both sexes; this was statistically significant in males (P less than 0.02) but not in females. In females, there was a significant decrease in mean trabecular plate density (P less than 0.001) and increase in mean trabecular plate separation (P less than 0.001); similar but non-significant trends were observed in the males. These results demonstrate that trabecular thinning contributes to age-related bone loss in both sexes. Loss of trabeculae also occurs in both sexes, but to a greater extent in females than in males.

Structural mechanisms of trabecular bone loss in man.

The relationship between trabecular thinning and loss of connectedness of the trabecular bone pattern has been studied in iliac crest bone samples from 89 normal subjects in order to determine the structural mechanisms underlying age-related bone loss. Trabecular width and structure were quantitatively assessed using computerized techniques. Highly significant negative correlations were found between the mean trabecular plate thickness and number of free ends/mm2 both in males (r = -0.571) and in females (r = -0.667) (P less than 0.001). Mean trabecular plate thickness also showed significant negative correlations with other structural indices indicating reduced connectedness, whereas positive correlations were found with those indices representing preservation of connectedness. Examination of the relative frequency of trabecular widths less than 100 microns revealed that only 2-5% of the trabecular surface would be susceptible to erosion by a resorption cavity of normal depth. These results indicate that trabecular thinning and erosion are interdependent processes in age-related bone loss. Since only a small percentage of the trabecular surface is susceptible to erosion, and resorption cavities normally occupy only 1-5% of the total trabecular surface, these findings imply that the site of activation of new BMUs may not be randomly distributed but may instead be preferentially located at sites of lower trabecular width.

Reduced bone formation in non-steroid treated patients with rheumatoid arthritis.

The cellular basis of trabecular bone loss in rheumatoid arthritis was investigated in 45 non-steroid treated patients. Mean wall thickness, an indicator of the amount of bone formed per remodelling unit, mean interstitial bone thickness, which is related to resorption depth, and the extent of trabecular surface covered by osteoid, which reflects the number of remodelling units, were assessed in iliac crest biopsy specimens. The mean wall thickness was significantly reduced in the patient group when compared with controls matched for age and sex (mean (SD) 39.8 (5.4) v 51.6 (9.7) microns). There was no significant difference between patients and controls in the mean interstitial bone thickness (51.0 (26.4) v 61.4 (31.9) microns) or osteoid surface (16.7 (11.4) v 21.0 (10.5)%). These results show that reduced bone formation at the remodelling unit level is the predominant mechanism of bone loss in rheumatoid arthritis.

Bone turnover and 1,25-dihydroxycholecalciferol during treatment with phosphate binders.

The effect of dietary phosphate restriction with high-dose aluminum hydroxide or calcium carbonate on bone disease assessed by histomorphometry and on the plasma levels of 1,25-dihydroxycholecalciferol was investigated in 12 children with chronic renal failure (GFR 8 to 45 ml/min/1.73 m2, age 5 to 15 years) over a one year period. Prior to treatment patients had biochemical and histological hyperparathyroidism with greatly increased bone formation rates. During treatment, plasma phosphate levels decreased from the upper to the lower limit of normal for age (pre, 1.69 +/- 0.06 mmol/liter; 6 months, 1.28 +/- 0.06 mmol/liter; 1 year, 1.34 +/- 0.06 mmol/liter; P less than 0.01). Circulating 1,25-dihydroxycholecalciferol rose to supranormal levels within three months and remained high throughout the period of study (pre, 96 +/- 32 pmol/liter; 6 months, 144 +/- 46 pmol/liter; 1 year, 169 +/- 53 pmol/liter; P less than 0.001). Significant falls in bone formation rate at tissue and cellular levels (P less than 0.005) and in total resorption surface (P less than 0.005) were observed. A mild mineralization defect present before treatment worsened, with a decrease in mineral appositional rate (P less than 0.01) and increase in mineralization lag time (P less than 0.01). Staining for aluminum in post-treatment biopsies was positive in 9 of 11 cases. Phosphate restriction produced suppression of biochemical and histological hyperparathyroidism and sustained elevation of circulating 1,25-dihydroxycholecalciferol. The adverse changes in bone mineralization may be related to aluminum hydroxide therapy; calcium carbonate is therefore recommended.

Iliac crest trabecular bone mass and structure in patients with non-steroid treated rheumatoid arthritis.

Iliac crest trabecular bone volume and structure have been studied in bone biopsy specimens from 48 patients with classical or definite rheumatoid arthritis, none of whom had received steroids. Results were compared with those obtained from healthy controls matched for age and sex. The mean trabecular bone volume in female patients aged 34-50 years was significantly lower than in controls (p less than 0.01); in male patients aged 34-50 years values were also lower than those in controls (mean (SD) 17.8 (3.2) v 22.4 (5.6)% total medullary volume), though this difference was not statistically significant. Values in older patients were similar to those of controls. The mean trabecular plate thickness was significantly lower in female patients in all three age groups when compared with the controls (p less than 0.005, 0.05, and 0.005). Similar but non-significant changes were seen in male patients. The mean trabecular plate density, an index of trabecular number, and the mean trabecular plate separation showed no age related change in either male or female patients, in contrast with the female control group, in whom the mean trabecular plate density decreased and separation increased with age. These results suggest that non-steroid treated rheumatoid arthritis is associated with premature bone loss, the structural basis of which is trabecular thinning.

Age-related changes in iliac crest trabecular microanatomic bone structure in man.

Age-related changes in the microanatomic structure of human iliac crest trabecular bone have been investigated in biopsies from 90 subjects, using a new computerised method which automatically identifies and quantifies nodes, free ends and a number of topologically defined struts. In both sexes there was a significant age-related decrease in the number of nodes and of trabecular struts, corrected for section area. In females, there was also a significant age-related decrease in the node to free end ratio (P less than 0.001), and the combined node-to-node and node-to-loop strut length, expressed as a percentage of total strut length (P less than 0.001) and a significant increase in free end to free end strut length (P less than 0.001). In males, the only additional age-related change was a significant increase in the cortex to free end strut length (P less than 0.005). These results indicate that loss of trabeculae resulting in decreased interconnectedness of the normal trabecular bone structural pattern, plays an important role in age-related bone loss in females. Removal of trabeculae also occurs in males but in less prominent, implying that trabecular thinning makes a greater contribution to age-related bone loss in males.

Measurement of mean trabecular plate thickness by a new computerized method.

Mean trabecular plate thickness (MTPT) has been measured by a new direct computerised method on an IBAS II image analyser in iliac crest bone from 56 normal subjects. The new method has been shown to be accurate and reproducible; apart from some initial editing of the image, it is carried out automatically without any need for observer interaction. A close correlation was found between values for MTPT obtained using the new direct method and values obtained by calculation based on area and perimeter measurements made on the IBAS II (r = 0.98).

A new method for the two-dimensional analysis of bone structure in human iliac crest biopsies.

A new method is described for the analysis of the two-dimensional structural pattern of trabecular bone in human iliac crest biopsies. 8 microns thick undecalcified sections stained with the von Kossa technique were examined at a magnification of X 9. Using an Ibas II image analyser, the ratio of nodes to free ends and the length of different strut types (cortex to free end, node or cortex, free end to free end and node to node, loop or free end) expressed as a percentage of total strut length were assessed. The reproducibility of the method was good for most of the measured indices but inter-observer and inter-section variation were greater. Comparison of biopsy sections obtained from eleven young healthy control subjects and eleven patients with hepatic osteoporosis revealed a significantly higher node to free end ratio, node to loop and node to node strut length and significantly lower cortex to free end and free end to free end strut length in the controls. No significant differences were seen in node to free end, cortex to cortex or cortex to node strut length. This approach to trabecular bone structure analysis should prove useful in determining patterns of bone loss in health and disease and in examining the effects of treatment on bone structure in osteoporosis.

Resolution of prolonged neonatal apnea with hernia repair.

Three cases of hernia repair and simultaneous resolution of prolonged neonatal apnea are reported. An association has been made between vagal overactivity and apnea. Protrusion of a large hernia at times of vagal stimulation is suggested as a possible mechanism resulting in sustained inhibition of the respiratory control center by increasing vagal afferent traffic to this center. Consideration should be given to repair of hernias in the premature infant with neonatal apnea rather than wait for resolution of the apneic episodes.