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Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Address all correspondence and requests for reprints to: Toshitsugu Sugimoto, M.D., Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: sugimot{at}med.kobe-u.ac.jp.
| Abstract |
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| Introduction |
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DXA is used to estimate areal BMD of individual bones. However, the areal BMD measured by DXA is different from true volumetric bone mineral density (vBMD), and PTH affects bone geometry as well as BMD (11), suggesting the possibility that DXA is not appropriate for evaluating the effects of PTH on BMD. However, no reports have examined the effects of an excess or a deficiency of endogenous PTH on vBMD and bone geometry by using peripheral quantitative computed tomography (pQCT) in humans. In the present study, we therefore investigated the effects of an excess and a deficiency of endogenous PTH on bone by employing pQCT in 36 female patients with hyper, nine female patients with idiopathic or postoperative hypo, and 100 normal controls matched to age, gender, and body size (cont).
| Subjects and Methods |
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Thirty-six female patients who were diagnosed as hyper, nine female patients with hypo (six idiopathic and three postoperative), and 100 cont participated in this study. Postmenopausal subjects were 34, seven, and 81 in hyper, hypo, and cont groups, respectively. Years after menopause were 13.0 ± 9.0, 14.6 ± 9.3, and 17.2 ± 8.7 yr in hyper, hypo, and cont groups, respectively. In all hyper patients enrolled in the present study, abnormal parathyroid gland swelling was successfully identified by at least one imaging technique among echography, computed tomography, magnetic resonance imaging, or technetium sestamibi scintigraphy; and the biochemical data were compatible with hyper. The diagnosis of hypo was based on clinical symptoms, hypocalcemia, hyperphosphatemia, low serum concentrations of intact PTH, and increases in tubular reabsorption of phosphate. These patients with postoperative hypo were totally thyroparathyroidectomized for papillary thyroid cancers. The data were taken 616 yr after the operations, and the patients took active vitamin D3 for 616 yr. Idiopathic hypo patients had been receiving active vitamin D3 treatment for more than 3 yr to maintain normal serum concentrations of calcium and phosphorus. Baseline indices are shown in Table 1
in hyper and hypo patients and in cont. Serum levels of intact PTH were significantly elevated in hyper patients. In patients with hypo, serum levels of intact PTH were markedly decreased. Height, body weight, body mass index, and length of radius were not different among the three groups. The study was approved by the ethical review board of Kobe University Hospital. All subjects agreed to participate in the study and gave informed consent.
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Serum concentrations of intact PTH were measured by immunoradiometric assay (Allegro Intact PTH IRMA kit; Nichols Institute Diagnostics, San Juan Capistrano, CA; normal range, 1065 ng/liter) (12, 13). The intact PTH RIA kit reacts with human PTH (hPTH)-(184), whereas hPTH-(134), hPTH-(3984), and hPTH-(3968) were nonreactive (14).
BMD measurements by DXA
BMD values were measured by DXA using QDR-2000 (Hologic Inc., Waltham, MA) at lumbar spine and distal one third of radius. BMD was automatically calculated from the bone area (cm2) and bone mineral content (BMC) (g) and expressed absolutely in g/cm2. The z-score is the number of SD a given measurement differs from the mean for a sex-, age-, and race-matched reference population. The t-score is the number of SD a given measurement differs from the mean for a normal young adult reference population. The coefficients of variation (precision) of measurements of the lumbar spine and radius were 0.9 and 1.9%, respectively.
BMD measurements by pQCT
pQCT analysis was performed at the nondominant forearm using an XCT-960 device (Stratec, Pforzheim, Germany) with a single energy x-ray source, as previously described (15). All computed tomography scans had a slice thickness of 2.5 mm and a vortex size of 0.59 mm. The scanner was positioned at the site of the forearm whose distance from the ulnar styloid process corresponded to 4% and 20% of forearm length, for distal radius and midradius, respectively. To calculate the structural properties of the cortical shell, trabecular and cortical bone had to be separated. To separate the cortical bone, all voxels (0.295 mm x 0.295 mm x 1 mm) of the scanned image with a BMD lower than the threshold (267 mg/cm3) were eliminated. The BMD was calculated for the cortical bone and the trabecular bone separately. Total area (Tt Ar) is the cross-sectional area of the bone after the soft tissue has been peeled off, and cortical area (Ct Ar) is the region with linear attenuation. Cortical thickness (Ct Th) was defined as the mean distance between inner and outer edge of the cortical shell. Polar strength strain index (SSIp) lies within the theory of stability of mechanical structures against bending or torsion. SSIp was calculated by:
(r2 x A x CD/1200)/rmax, where A is the area of a voxel (mm2), r is its distance from the center of gravity, CD is the cortical density (mg/mm3) and is divided by the normal physiological density of cortical bone (1,200 mg/mm3), and rmax is the maximum distance of a voxel from the center of gravity (16). The coefficient of variation was under 1%.
Statistical analysis
All data were expressed as the mean ± SD for each index. Comparisons among the three groups were made with ANOVA. P values < 0.05 were considered significant.
| Results |
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We first examined the effects of endogenous PTH on lumbar and radial BMD by DXA. As shown in Table 1
, lumbar BMD was higher in the order: hypo > cont = hyper, and radius-1/3 BMD was significantly higher in the order: hypo > cont > hyper. Lumbar BMC was also higher in the order: hypo > cont = hyper, and radius-1/3 BMC was higher in the order: hypo > cont = hyper. Among postmenopausal females, the z-score of lumbar BMD was in the order: hypo (1.43 ± 0.60 mg/cm2) > cont (-0.37 ± 0.77 mg/cm2) = hyper (-0.68 ± 1.04 mg/cm2), and that of radial BMD was significantly higher in the order: hypo (1.47 ± 0.80 mg/cm2) > cont (0.30 ± 1.33 mg/cm2) > hyper (-1.10 ± 1.67 mg/cm2). The area of radius-1/3 was significantly higher in hyper than in the cont, although the areas of lumbar vertebrae 24 were not different among the three groups (Table 1
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Comparison of vBMD among hyper, hypo, and cont by pQCT
We next examined the effects of an excess and a deficiency of endogenous PTH on radial vBMD by pQCT. The radius is considered to be rich in trabecular bone at the 4% site and rich in cortical bone at the 20% site. Trabecular vBMD was significantly higher in the order: hypo > cont > hyper at the 4% site. Cortical vBMD was higher in the order: hypo > cont > hyper at 20% site (Table 2
). The state of estrogen affects BMD in females. In postmenopausal females, trabecular vBMD was significantly higher in the order: hypo (151.4 ± 28.3 mg/cm3 in seven) > cont (111.8 ± 39.5 mg/cm3 in 81) > hyper (92.3 ± 33.6 mg/cm3 in 34) at the 4% site. Cortical vBMD in postmenopausal females was significantly higher in the order: hypo (1096.5 ± 27.6 mg/cm3 in seven) > cont (1076.0 ± 70.2 mg/cm3 in 81) > hyper (1029.9 ± 83.8 mg/cm3 in 34) at the 20% site.
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We examined the effects of endogenous PTH excess or deficiency on bone geometry by pQCT. Table 1
shows bone geometry indices among hyper, hypo, and cont by pQCT. Total bone area and endosteal and periosteal circumferences were significantly higher in hyper than in the cont and hypo groups at both the 4 and 20% sites. Ct Ar and Ct Th were higher in the order: hypo > cont > hyper at both the 4 and 20% sites. These results were consistent in the analysis of postmenopausal females (data not shown). On the other hand, SSIp, a bone strength index, was not significantly different among the three groups (Table 1
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| Discussion |
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Previous studies revealed that BMD of patients with postoperative hypo was increased in both trabecular and cortical bones. In our data by pQCT, trabecular vBMD, but not cortical vBMD, was significantly higher in patients with hypo than in cont. The t-score values (division from the young adult means) of trabecular vBMD in pQCT were -1.100 ± 0.678 in postmenopausal hypo patients. Because postmenopausal high bone turnover rate and bone loss were reported to be attenuated in patients with hypo (8, 9), higher trabecular BMD in hypo would be mainly attributable to the prevention of postmenopausal bone loss, presumably through a reduction in bone turnover rate.
pQCT is useful for quantifying geometric properties of long bone because it can be used to estimate area and circumferences of total bone as well as Ct Ar and Ct Th (24). In the present study, the total bone area and endosteal and periosteal circumferences of the total bone in patients with hyper were significantly higher than those in the cont. Moreover, the area of the distal radius in hyper patients was significantly higher than that in cont. These data, therefore, indicated that an excess of endogenous PTH was anabolic for periosteal bone formation. As for cortical bone, the Ct Ar and Ct Th in patients with hyper were significantly lower than those in the cont. These data indicated that an excess of endogenous PTH leads to thin cortical bone. A continuous excess of PTH increases the activation frequency of bone remodeling on both periosteal and endocortical surfaces. The activation magnitude of bone remodeling is increased during the sustained bone balance between periosteal and endocortical surfaces, resulting in increased periosteal bone formation and endosteal bone resorption.
pQCT helps to estimate bone strength by calculating SSIp, which has recently been elaborated to predict bone strength noninvasively (25). In the present study, SSIp of patients with hyper was similar to the SSIp of the cont and hypo groups. These data suggest that the effects of endogenous PTH on bone strength are less significant than its effects on BMD and bone geometry. Bigger bone size is a logical adaptation to enhance the mechanical competence of bone. Consequently, SSIp of patients with hyper was not significantly different from the SSIp values of the cont and patients with hypo. Periosteal bone formation stimulated by an excess of endogenous PTH might partly compensate for a decrease in bone strength induced by decreased BMD. Recent studies have shown that, in hyper patients, the fracture risk of BMD-preserved vertebrae is relatively higher than that of the forearm (26, 27). This might be partly because an increase in bone size enhanced by PTH preserves bone strength.
In conclusion, evaluation of vBMD and bone geometry by pQCT revealed that an excess of endogenous PTH was catabolic for both cortical and trabecular bone, and that bone mass (especially trabecular bone mass) was preserved under conditions of deficient endogenous PTH. An excess of endogenous PTH stimulated periosteal bone formation, which might partly compensate for a decrease in bone strength induced by low BMD.
| Acknowledgments |
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| Footnotes |
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Received March 26, 2003.
Accepted June 24, 2003.
| References |
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