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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1562-1566
Copyright © 1999 by The Endocrine Society

Original Studies

On the Mechanism of Cancellous Bone Preservation in Postmenopausal Women with Mild Primary Hyperparathyroidism1

D. W. Dempster, M. Parisien, S. J. Silverberg, X.-G. Liang, M. Schnitzer, V. Shen, E. Shane, D. B. Kimmel, R. Recker, R. Lindsay and J. P. Bilezikian

Regional Bone Center, New York State Department of Health, Helen Hayes Hospital (D.W.D., M.P.,X.-G.L., M.S., V.S., R.L.), West Haverstraw, New York 10993; the Departments of Pathology (D.W.D., M.P., V.S.), Medicine (S.J.S., E.S., R.L., J.P.B.), and Pharmacology (J.P.B.), College of Physicians and Surgeons of Columbia University, New York, New York 10032; and the Department of Medicine, Creighton University (D.B.K., R.R.), Omaha, Nebraska 68131

Address all correspondence and requests for reprints to: David W. Dempster, Ph.D., Regional Bone Center, Helen Hayes Hospital, Route 9W, West Haverstraw, New York 10993. E-mail: daviddempster{at}mindspring.com


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Several studies have demonstrated that cancellous bone mass and architecture are preserved in postmenopausal women with primary hyperparathyroidism (PHPT). To investigate the mechanism(s) that could account for this observation, we analyzed features of bone formation in 19 postmenopausal women with PHPT by bone histomorphometry. The results were compared with those from a comparable group of 34 healthy, postmenopausal women. Patients with PHPT were similar to control subjects in cancellous bone area as well as in trabecular width, separation, and number. However, in PHPT, elevations were observed in indexes of bone turnover, such as eroded surface, osteoid surface, mineralizing surface, bone formation rate at the tissue level, and activation frequency. At the level of the bone-remodeling unit, women with PHPT had significantly higher values for the wall width of trabecular bone packets (40.26 ± 0.36 vs. 34.58 ± 0.45 mm), the adjusted apposition rate (0.40 ± 0.04 vs. 0.29 ± 0.03 mm/day), and the active formation period (67.8 ± 5.1 vs. 57.3 ± 2.3 days). These findings are consistent with a stimulatory action of elevated PTH levels on the duration of the active bone formation phase in individual remodeling units and may account at least in part for the preservation of cancellous bone in postmenopausal women with mild PHPT.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WE AND OTHERS have reported previously that cancellous bone mass and structure are preserved in patients with mild primary hyperparathyroidism (PHPT) (1, 2, 3, 4, 5, 6). This appears to be the case even among postmenopausal women, in whom estrogen deficiency would be expected to result in an accelerated rate of cancellous bone loss (5, 7, 8). There is a paucity of information related to mechanisms of cancellous bone preservation in PHPT, and there are conflicting data in the literature. Delling and colleagues (1, 9) reported an increase in trabecular width in patients with PHPT, whereas others have reported either normal (3) or reduced trabecular width (5). Charhon et al. (7) found a reduction in cancellous bone volume, accompanied by decreased wall width of trabecular bone packets, in women with PHPT who were less than 50 yr of age and normal values for both variables in women over that age. The finding of reduced wall width in premenopausal women was confirmed by Christiansen et al. (5), who also reported a reduction in the adjusted apposition rate, an index of bone formation. Wall width was normal in postmenopausal women, but no conclusion can be made about the adjusted apposition rate in postmenopausal women as control values were not available. On the other hand, Vogel et al. (9) found elevated values for wall width in both pre- and postmenopausal women, but the mechanism underlying this observation was not considered.

In the present investigation we explored the mechanism(s) responsible for cancellous bone preservation in postmenopausal women with PHPT by comparing static and dynamic histomorphometric variables of bone formation with those from a comparable group of healthy postmenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
This study was approved by the institutional review boards of Helen Hayes Hospital, Columbia-Presbyterian Medical Center, and Creighton University. All subjects gave informed consent.

Subjects

The patient group comprised 19 postmenopausal women who were derived from a cohort of 137 patients enrolled in a prospective study of mild PHPT and included all postmenopausal women who were not receiving hormone replacement therapy and who consented to an iliac bone biopsy. The clinical, biochemical, and densitometric characteristics of the cohort have previously been described (2, 10). Data on several histomorphometric variables, cancellous bone volume, bone formation rate at tissue level, total trabecular strut length, and the lengths of its component strut types, have previously been reported for 16 of these women (8). None of the patients had vertebral fractures or radiological evidence of bone disease. The bone mineral density (BMD) values for the lumbar spine, femoral neck, and distal radius were measured on a Hologic QDR 1000 as previously described (10, 11). Women were prelabeled with tetracycline hydrochloride (250 mg, four times daily) and demethylchlortetracycline (150 mg, four times daily) after a 3 days on, 14 days off, 3 days on, 5–7 days free schedule before the biopsy. Transiliac bone biopsy was performed according to standard technique (12), with no significant postoperative complications occurring in any of the subjects.

The control group consisted of 34 postmenopausal women who have previously been described in detail (13). The control subjects were prelabeled with tetracycline using the same protocol as that for the patients. Biopsies from control subjects were reanalyzed by the same observer who analyzed the patient biopsies using identical methods.

Biochemistry

Intact PTH and biochemical indices (serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, and urinary calcium and creatinine) were measured as previously described (2).

Bone histomorphometry

All histomorphometric indexes were designated in accordance with the nomenclature recommended by the American Society for Bone and Mineral Research (14). Indexes of bone structure were evaluated using Goldner-stained, 7-µ thick sections. Before the measurements, the outer margins of the cancellous space were defined as the distance from the inner surface of the cortex equal to twice the thickness of the thickest subcortical trabecula (15) Cancellous bone area as a percentage of the total cancellous tissue area, trabecular number, trabecular width, and trabecular separation were derived from automated measurements (Optomax V AMS system, Optomax, Inc., Hollis, NH) of the bone area and perimeter (x31 magnification); they were defined previously (14, 16).

All static indexes of remodeling activity were measured on 7-µ thick sections, with the Eriochrome Cyanin R stain used for osteoid parameters and the Goldner’s Trichrome stain used for eroded perimeter. Twenty-micron unstained sections were used to measure all dynamic indexes of bone formation. Perimeter indexes were expressed as percentages of the total trabecular perimeter. Osteoid perimeter, eroded perimeter, and mineralizing perimeter, i.e. the extent of all double labels plus half the extent of single labels, were measured by the point-counting method at x125 magnification, and the proportion of mineralizing osteoid perimeter was calculated. The mineral apposition rate was calculated from the semiautomated measurement of interlabel distance (Optomax VIDS V) and the interval in days between the two labels. The bone formation rate and adjusted apposition rate were calculated and expressed in cubic micrometers per mm2/day (14).

The wall width of completed trabecular bone packets was measured semiautomatically (VIDS IV, Optomax) at x160 magnification on 3–8 sections/biopsy following the method of Kragstrup et al. (17); the mean number of intercept measurements per biopsy was 78, with a range of 14–384. Osteoid width was measured semiautomatically (VIDS IV, Optomax) at four equidistant points on each seam at x400 magnification. The mineralization lag time and osteoid maturation time were calculated2 (14).

The active formation period of the bone structural unit (FP[A]) assumes that bone formation is continuous and therefore does not take into account the resting periods in the life span of osteoblasts ("off" periods) (18, 19, 20). The total formation period of the bone structural unit (FP[T]) represents the total time spent by the osteoblasts in completing the bone structural unit including off periods. FP[A] and FP[T] were calculated using standard formulas (14). Resorption period, remodeling period, and activation frequency were calculated using FP[T].

Statistical analysis

All indexes are reported as the mean ± SEM. The significance of differences between the two groups was evaluated by unpaired, two-tailed Student’s t tests for normally distributed values and by Wilcoxon rank sum test for abnormally distributed values, using SAS software (SAS Institute, Inc., Cary, NC). The significance of the relationship between variables was assessed by calculating Pearson’s correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The biochemical and densitometric characteristics of the patients are shown in Table 1Go. Serum calcium levels were elevated, and PTH-(1–84) was almost double the upper limit of normal. Serum phosphorus approached the lower limit of normal. Serum 25-hydroxyvitamin D was normal, whereas 1,25-dihydroxyvitamin D was at the upper limit of normal. Serum alkaline phosphatase activity and the urinary calcium/creatinine ratio were both mildly elevated. The BMD data revealed preservation of cancellous bone relative to cortical bone, as evidenced by the increasing decrements in BMD as we move from a cancellous bone-enriched site (lumbar spine) to a cortical bone-enriched site (distal radius). The patient and control groups were comparable in terms of age (PHPT, 59.8 ± 1.5 yr; control, 60.0 ± 1.3 yr; P = NS) and years since menopause (PHPT, 12.5 ± 1.9 yr; control, 13.4 ± 1.5 yr; P = NS).


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  		Table 1. Biochemical and bone density characteristics of the PHPT patients

 
Mean values for structural variables are provided in Table 2Go. There were no differences between the PHPT group and the control group in cancellous bone area, or trabecular number width or separation. Results for variables related to bone remodeling are given in Table 3Go. Static and dynamic indexes of bone turnover, including eroded perimeter, osteoid perimeter, bone formation rate, and activation frequency, were all significantly elevated in the PHPT patients. Osteoid width and wall width of cancellous bone packets were also higher in the PHPT group than in the control group. There was no significant difference between groups in the total formation period, but the active formation period and the adjusted apposition rate were both elevated in the PHPT group.


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  		Table 2. Structural variables in PHPT and control groups

 

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  		Table 3. Wall width and remodeling variables in PHPT and control groups

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
After the menopause in normal women, both bone resorption and bone formation are increased. However, the two are not coupled with net resorption exceeding formation, and as a result, the rate of bone loss increases. Yet studies in several laboratories have shown that postmenopausal women with mild PHPT display preservation of cancellous bone mass and structure (1, 2, 3, 4, 5, 6, 7, 8, 9), suggesting that the excess PTH has in some way restored the balance between resorption and formation. The present study offers at least a partial explanation for this. We have found that the wall width of cancellous bone packets in postmenopausal women with PHPT is greater than that in normal postmenopausal women. In this regard, the elevated endogenous PTH level or some other factor associated with the hyperparathyroid state appears to be having the same anabolic action at the level of the bone-forming unit as that observed with daily administration of PTH in postmenopausal osteoporotic women (21). The increase in wall width in the patients with PHPT was accompanied by increases in osteoid width, osteoid maturation time, and adjusted apposition rate. The adjusted apposition rate is the mineral apposition rate averaged over the entire osteoid surface and is thought to be the best estimate of the mean rate of matrix apposition (22, 23). The increase in adjusted apposition rate and wall width could be the result of an increase in the number of osteoblasts recruited into each bone-forming unit and/or an increase in the volume of matrix synthesized by each osteoblast (22). In vitro studies have shown that PTH can stimulate collagen formation both by enhancing osteoblast number through enhanced replication of precursors (24) and by stimulating the activity of the differentiated osteoblast (25). These effects appear to be mediated by enhanced osteoblastic production of growth factors, such as insulin-like growth factor I, under the influence of PTH (25). Release of growth factors (e.g. transforming growth factor-ß) from bone matrix will also be increased as a result of PTH-stimulated resorption (26).

We have previously reported an increase in the bone formation rate at the tissue level in this group of postmenopausal women with PHPT (8). The present study demonstrates a significant increase in several other variables that reflect or influence bone formation, including osteoid perimeter, osteoid width, active formation period, activation frequency, and wall width. Measurements of these variables allow further characterization of the physiology underlying the increase in mineralizing perimeter in these patients. This could be due to increased number of bone-remodeling units (BRUs) as a result of increased activation frequency, increased active formation period, increased life span of BRUs, and/or de novo synthesis of bone matrix under the influence of PTH. The latter has been suggested to explain the increase in bone formation seen immediately after the initiation of daily PTH injections in osteoporotic patients (27, 28, 29). The present data indicate that the increase in mineralizing surface is the result of an increase in both activation frequency and the active formation period. It is not possible at present to distinguish completely between the number and life span of BRU and the extent to which formation was either de novo or remodeling based.

Although there was no significant difference between the patients and control subjects with respect to the total formation period, the active formation period was significantly longer in the patients with PHPT, reflecting the higher ratio of mineralizing (i.e. tetracycline-labeled) perimeter/osteoid perimeter. According to traditional histomorphometric theory (18, 19, 20), a greater value for the active formation period indicates that the osteoblast team spent less of the total formation period in an inactive or off mode. An alternative explanation (23) is that rather than switching off completely, toward the end of the formation period osteoblasts slow down the rate of matrix synthesis to the extent that insufficient tetracycline is captured to produce a detectable label. In this scenario, the present data would be interpreted to indicate that the osteoblast team in patients with PHPT spends less of its total life span working at this low rate.

Our finding of increased wall width in postmenopausal women with PHPT is in agreement with the results of an earlier study involving 24 women of 50 or more yr of age (9), but differs from the findings of Christiansen et al. (5), who showed normal wall width in a group of 29 women 50 or more yr of age with PHPT. The reason for this difference is unclear. Furthermore, it is difficult to compare our results for dynamic variables of bone formation, such as adjusted apposition rate and formation periods, with those of Christiansen et al. (5), as normal values for these variables in postmenopausal women were not available in their study. The disparity in the wall width results could be due to differences between the two study populations. As has been previously noted, the Danish patients had higher serum calcium levels and, possibly, more severe PHPT than the cohort studied here. There may also be differences between the two groups of patients in the average age and time from menopause, characteristics that are not provided in the report by Christiansen et al. (5). Finally, the number of postmenopausal control subjects for the static variables, including wall width, in the Danish study (5) was small (10), and an unspecified number of these control samples was obtained at autopsy rather than from healthy volunteers as in the present study.

The finding of increased wall width of trabecular bone packets in postmenopausal women with PHPT was unexpectedly not associated with increased trabecular width and bone area. There are at least two possible explanations. First, as a result of the higher activation frequency in the PHPT group, the remodeling space would be higher, and this would tend to counteract the positive effect of increased wall width on bone area. Second, the increased wall width may be counterbalanced by increased resorption depth, so that there is little or no net gain in bone area. There are very few studies of resorption depth in hyperparathyroid states. In a study of 19 patients with PHPT (6 males and 13 females; mean age, 47 yr), Eriksen et al. (30) found a 20% reduction in final resorption depth. This was accompanied by an 8.8% decrease in wall width. The bone balance, i.e. the difference between wall width and resorption depth, was calculated to be zero or slightly positive depending on whether a measured or an estimated value was used for wall width. Christiansen et al. (5) reported normal values for resorption depth in a group of 23 women aged 50 yr or older. Wall width was also normal in these women and so, therefore, was the bone balance. Parfitt et al. (31) also found resorption depth to be normal on the cancellous surface of 18 postmenopausal women, whereas it was increased on the endocortical surface.

In conclusion, we have demonstrated increased width of trabecular bone packets in postmenopausal women with mild PHPT. This is apparently the result of increments in the adjusted apposition rate and the active formation period of the BRU. This finding may account at least in part for the preservation of cancellous bone mass and architecture that occurs in postmenopausal women with mild PHPT.


   Footnotes
 
1 Presented in part at the 18th Annual Meeting of the American Society for Bone and Mineral Research, Seattle, WA, September 1996. This work was supported in part by NIH Grants AR-31991 and DK-32333. Back

2 These formulas were used for the calculation of bone remodeling indexes: M.Pm/B.Pm = (dL.Pm + sL.Pm/2)/B.Pm; BFR/B.Pm = (M.Pm/B.Pm) x MAR; FP[A] = W.Wi/MAR; Aj.AR = [(M.Pm/B.Pm) x MAR]/(O.Pm/B.Pm); FP[T] = W.Wi/MAR; Omt = O.Wi/MAR; Rs.P = FP[T] x (E.Pm/O.Pm); Mlt = O.Wi/Aj.AR; Rm.P = FP[T] + Rs.P; M.Pm/O.Pm = (M.Pm/B.Pm)/(O.Pm/B.Pm); Ac.F = {1/FP[T] x (B.Pm/O.Pm)} x 365. Abbreviations: M.Pm/B.Pm, mineralizing perimeter; B.Pm, total trabecular perimeter; MAR, mineral apposition rate; W.Wi, wall width; O.Pm/B.Pm, osteoid perimeter; Omt, osteoid maturation time; Mlt, mineralization lag time; Aj.AR, adjusted apposition rate; Rs.P, resorption period; M.Pm/O.Pm, proportion of mineralizing osteoid perimeter; Ac.F, activation frequency; O.Wi, osteoid width. Back

Received June 17, 1998.

Revised October 27, 1998.

Accepted January 25, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Delling G. 1987 Bone morphology in primary hyperparathyroidism–a qualitative and quantitative study of 391 cases. Appl Pathol. 5:147–159.
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