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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3155-3159
Copyright © 2003 by The Endocrine Society

Increased Bone Mineral Density in Patients with Chronic Hypoparathyroidism

Fredriech K. W. Chan, Sau-Cheung Tiu, Kin-Lam Choi, Cheung-Hei Choi, Alice P. S. Kong and Chi-Chung Shek

Departments of Medicine (F.K.W.C., S.-C.T., K.-L.C., C.-H.C., A.P.S.K.) and Pathology (C.-C.S.), Queen Elizabeth Hospital, Hong Kong SAR, China

Address all correspondence and requests for reprints to: Dr. Fredriech K. W. Chan, Department of Medicine, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, HKSAR, China. E-mail: chankwf{at}netvigator.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Bone mineral density (BMD) has been shown to be increased in postmenopausal females with postthyroidectomy hypoparathyroidism, but it is not known whether similar gains occur in patients with idiopathic hypoparathyroidism. In this study, we measured the BMD of lumbar spine and proximal femur in 14 patients, 8 with idiopathic hypoparathyroidism and 6 with postthyroidectomy hypoparathyroidism, using dual-energy x-ray absorptiometry. Their age ranged from 23–57 yr old, with a mean of 42.5 yr. The results showed that patients with hypoparathyroidism had a higher BMD than the normal age- and sex-matched population. This was particularly evident at the lumbar spine (L2–L4), with positive Z-score of 1.93 ± 1.03, whereas Z-score at the femoral neck was 1.14 ± 0.62 SD. Subgroup analysis showed that those with postthyroidectomy hypoparathyroidism had a mean lumbar spine BMD of 1.434 g/cm2 and femoral neck BMD of 1.026 g/cm2, compared with a mean BMD of 1.364 g/cm2 and 1.022 g/cm2 at spine and hip, respectively, for those with idiopathic hypoparathyroidism. Statistical analysis did not reveal any significant difference in the BMD, T-score, and Z-score of the bone, at these two sites, between the two groups. In conclusion, the state of chronic hypoparathyroidism is associated with increased BMD, especially at the lumbar spine. Those with idiopathic hypoparathyroidism have a similar degree of increase in BMD as those with postthyroidectomy hypoparathyroidism.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PTH PLAYS AN IMPORTANT ROLE in the regulation of bone metabolism. It regulates calcium homeostasis by affecting intestinal calcium absorption, renal calcium excretion, and the rate of bone resorption. Secondary hyperparathyroidism is involved in the pathogenesis of age-related cortical bone loss and hip fractures (1). Patients with mild asymptomatic primary hyperparathyroidism have preferential reduction in cortical bone mass, with relative preservation of cancellous bone (2). Parathyroidectomy for primary hyperparathyroidism has been associated with an increase in bone mineral density (BMD) (3).

Only a limited number of studies have investigated the impact of hypoparathyroidism on bone mass. In 1993, Abugassa et. al (4) used photon absorptiometry to measure the skeletal mass in 13 females with hypoparathyroidism secondary to thyroid surgery for thyroid carcinoma at 10–13 yr after surgery. Bone mass in this cohort was 21–28% above that of a control group of 13 patients who had normal parathyroid function after thyroid surgery. Two years later, another study showed that hypoparathyroidism retarded the rate of postmenopausal bone loss, as measured by dual-energy x-ray absorptiometry (DXA), in 33 postmenopausal females with postthyroidectomy hypoparathyroidism (5). These studies were confined to postmenopausal females and postsurgical hypoparathyroidism. The purpose of this study is to investigate whether the same increase in BMD occurs in patients with idiopathic hypoparathyroidism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 14 patients, 8 female and 6 male, with the diagnosis of hypoparathyroidism, in a local regional hospital. Their age ranged from 23–57 yr, with a mean of 42.5 yr. The mean height of the patients was 156.7 ± 8.2 cm, and their mean weight was 59.6 ± 10.3 kg. Eight patients suffered from idiopathic hypoparathyroidism, and six had postthyroidectomy hypoparathyroidism. Five of the 8 female subjects were premenopausal. The duration of treatment for hypoparathyroidism was 3–27 yr, with a median duration of follow-up of 14 yr. Their calcium levels at diagnosis were low, with a mean of 1.49 mM and a range of 1.13–1.85 mM. PTH levels at diagnosis ranged from undetectable to 1.9 pM (normal range being 1.1–6.5 pM). All were treated with calcitriol at doses of 0.25–0.75 µg daily and calcium carbonate at doses of 600-1800 mg daily to maintain serum calcium and phosphate within the lower limits of normal ranges. The mean daily dietary calcium intake was assessed by food frequency questionnaires and was found to be 495 mg/d. Calcium levels were normalized to a mean of 2.18 mM (range, 1.95–2.36 mM). Five patients required T4 replacement after thyroidectomy. Indications for thyroidectomy included Grave’s disease and multinodular goiter. All patients had normal thyroid function tests, with a mean TSH level of 1.38 mIU/liter. Of those with idiopathic hypoparathyroidism, 6 patients had basal ganglia calcification. Two patients suffered from mild mental retardation, and 3 patients had a history of epilepsy. Only 1 patient with epilepsy was still taking carbamazepine during the study. One patient had hypertension treated with nifedipine. One patient had alopecia, cataract, and dystrophic nails; and the other patient had a double uterus and single kidney. Subjects were excluded if they had any concomitant disease that might affect BMD (such as Paget’s disease, diabetes mellitus, chronic liver, or renal disease) or were taking any medication that can influence bone mass (such as estrogens, progestins, steroids, or bisphosphonates). No subject had a history of fractures. All subjects gave informed consent.

Measurement of BMD

BMD of the lumbar spine (L2–L4, posteroanterior scanning), femoral neck, and total hip was measured by DXA (model DPX-L; Lunar Corp., Madison, WI). The coefficient of variation at these sites ranged from 1.5–2.4%. T-score and Z-score were obtained by comparing the BMD of the patient to the peak young normal BMD and the sex- and age-matched normal BMD of the Asian population, respectively. The normative reference data were built in the computer software of the machine. It was based on Japanese data taken by Hamamatsu University according to the U.S. Food and Drug Administration guideline and protocol (personal communication with Lunar Corp. Asia & Pacific, Tokyo, Japan). These data were collected from the patients numbered more than 200 per decade of patient age. Data have been updated from time to time since those beginning in 1989. The lumbar spine BMD was expressed as the mean of the BMD of L2–L4, excluding deformed vertebrae. A vertebra was designated as abnormal if its posterior vertical height was 20% lower than that of the adjacent vertebrae or if the height ratio of its central portion vs. the anterior or posterior cortex was less than 0.8.

Blood and urine analysis

Liver and renal function tests, serum calcium, and phosphorus and urinary calcium concentration were measured using an autoanalyzer (Modular Analytics; Roche/Hitachi, Mannheim, Germany), using standard automated techniques. The serum PTH concentration was measured by immunochemiluminometric assay (IMMULITE; Diagnostic Products, Los Angeles, CA), and TSH level was measured by a fluoroimmunometric assay (Elecsys 170; Roche/Hitachi).

To evaluate the effect of hypoparathyroidism on the biochemical markers of bone turnover, serum bone-specific alkaline phosphatase (BAP) level was measured by one-step immunoenzymatic essay using a mouse monoclonal antibody specific to BAP (Access Ostase; Beckman Coulter, Inc., Chaska, MN). The level was then compared with the mean of 17 control subjects who were matched with the hypoparathyroid patients with respect to sex and age.

Statistical analyses

All results were expressed as the mean ± SEM. One-sample t tests were used to determine whether Z-scores differ from zero. Statistical differences between means of the parameters were tested by nonparametric Mann-Whitney U test. P values were two-tailed. P < 0.05 was considered statistically significant. Statistical analyses were performed with the Statistical Package for Social Sciences for Windows, version 9.0.1 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In this cross-sectional analysis, BMD of the lumbar vertebra and the femoral neck were higher in patients with hypoparathyroidism, when compared with the corresponding BMD of the sex- and age-matched population. Results for each vertebra were reported. It showed uniform increase in BMD down the level of lumbar spine. Any vertebral deformity, collapse, or calcifications were ruled out. The mean BMD of lumbar spine and femoral neck of the study subjects were, respectively, 1.394 ± 0.107 g/cm2 and 1.023 ± 0.064 g/cm2 (Table 1Go). Relative to the peak BMD of young normal individuals, BMD of the lumbar spine of subjects with hypoparathyroidism was 2.06 ± 1.07 SD higher by PA scanning, and BMD of the femoral neck was higher by 0.83 ± 0.58 SD. The BMD at lumbar spine and femoral neck was higher by 1.93 ± 1.03 SD and 1.14 ± 0.62 SD (P < 0.001), respectively, when compared with the age- and sex-matched population (Fig. 1Go). Statistical analysis showed that patients with hypoparathyroidism had significantly higher bone mass at the vertebra than at the femoral neck (P < 0.001). Regression analysis showed that BMD did not significantly correlate with the duration of treatment.


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  		TABLE 1. BMD of the lumbar spine and proximal femur in patients with hypoparathyroidism

 


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  		FIG. 1. Mean Z-scores for the BMD of lumbar vertebra, femur neck, and total hip in patients with hypoparathyroidism (P < 0.001).

 
Serum BAP level of the patients with hypoparathyroidism was significantly lower at 9.35 ± 0.52 µg/liter, compared with a mean of 12.46 ± 0.99 µg/liter for the control subjects (P = 0.018). This reflected the low rate of bone remodeling in patients with hypoparathyroidism, and the level was not significantly different between the groups with idiopathic hypoparathyroidism and postthyroidectomy hypoparathyroidism.

Table 2Go shows the characteristics and BMD of patients with idiopathic hypoparathyroidism (group 1) and postthyroidectomy hypoparathyroidism (group 2). There was no significant difference in the age and disease duration between these two groups. Patients with idiopathic hypoparathyroidism presented with significantly lower calcium levels than those with postthyroidectomy hypoparathyroidism at diagnosis. Although there was a trend toward higher lumbar spine Z-scores in patients with postthyroidectomy hypoparathyroidism, statistical analysis did not reveal any significant difference in BMD, T-scores, and Z-scores of the lumbar spine and proximal femur between the two groups (Fig. 2Go).


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  		TABLE 2. Age, sex, disease duration, calcium level at diagnosis and after treatment, urinary calcium excretion, BMD of the spine and hip in patients with idiopathic hypoparathyroidism (group 1), and postthyroidectomy hypoparathyroidism (group 2)

 


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  		FIG. 2. Stem-and-leaf plots showing the distribution of (A) lumbar spine BMD, (B) lumbar spine Z-score, (C) femoral neck BMD, and (D) femoral neck Z-score for the two groups of patients (group 1, idiopathic hypoparathyroidism; group 2, postthyroidectomy hypoparathyroidism).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our results showed that BMD of the lumbar spine and proximal femur was increased in patients with hypoparathyroidism. This is in agreement with other studies that used photon absorptiometry to measure BMD in females with postthyroidectomy hypoparathyroidism (4). Duan et. al. (6) also showed that BMD in postmenopausal females with postthyroidectomy hypoparathyroidism was higher, compared with age-predicted mean, at the lumbar spine and the proximal femur but not at the distal radius, by using DXA. All these studies, including the present one, are admittedly cross-sectional studies. Longitudinal studies comparing BMD pre- and posthypoparathyroidism are difficult to perform with idiopathic hypoparathyroidism, because the exact time of onset of disease is often not well defined. Postsurgical hypoparathyroidism has a well-defined point of onset. However, because parathyroidectomies are generally performed either for primary hyperparathyroidism or in the course of total or subtotal thyroidectomy, longitudinal changes in BMD may be confounded by factors such as changes in thyroid, parathyroid, and calcium status.

Because most other studies (4, 5, 6) investigated bone mass in female patients with postsurgical hypoparathyroidism, it remains unknown whether the same occurs in patients with idiopathic hypoparathyroidism in whom there is no prior history of thyroid function abnormalities and in whom the onset of hypoparathyroidism may be more insidious. This study included eight patients with idiopathic hypoparathyroidism. Six of them were male. The mean BMD Z-scores were elevated at both the lumbar spine and femoral neck, which were 1.68 SD and 1.02 SD above the sex- and age-matched normal, respectively. Although there was a trend toward higher lumbar spine and femoral neck Z-score in patients with postthyroidectomy hypoparathyroidism, statistical analysis did not reveal any significant difference in BMD, T-scores, and Z-scores of the lumbar spine and proximal femur between the two groups. Possible caveats are the small sample size and the difference in sex distribution between the two groups. The latter is unlikely to be significant, because areal BMD of the male skeleton is higher than that of the female because of the greater size of bones in men (7); yet, this study showed a trend toward higher BMD in the female-predominant postthyroidectomy hypoparathyroidism group. Apparently, the transient period of high bone turnover caused by thyrotoxicosis before surgery does not jeopardize bone mass. Indeed, it may even expand the remodeling space for osteoblastic bone formation after surgery.

The observed effects on BMD may either be attributable to hypoparathyroidism itself or to continuous treatment with calcitriol and calcium. The effects of the latter on bone mass are, however, still controversial. Some researchers reported positive results (8, 9), whereas other studies showed decreased bone mass (10, 11) and even increased fracture incidences (12). Moreover, it has been postulated that the protective effects of vitamin D in osteoporosis can be explained by the suppression of PTH secretion, leading to reduced bone turnover. In patients with idiopathic or postthyroidectomy hypoparathyroidism, PTH secretion is already defective, and whether calcium and vitamin D treatment can increase bone mass in these circumstances is not certain.

Hypoparathyroidism per se seems to be the most important factor that contributes to a markedly increased BMD. The effects and mechanisms of action of PTH on bone have intrigued many researchers working in this field. PTH is believed to have an anabolic effect on bone (13). PTH/PTH-related peptide receptors, located on osteoblasts, are coupled to dual intracellular signaling pathways: the adenylate cyclase activating G protein-coupled protein (Gs) and the phospholipase C-activating Gq protein (14, 15). PTH action on bone cells leads to induction of several growth factor genes, including those for IGF-I, IGF-II, and TGF (16, 17). PTH enhances the recruitment of preosteoblasts from marrow stromal cells, induces the maturation of lining osteoblasts, reduces osteoblastic apoptosis, and increases collagen synthesis (18). Significant increases in cancellous bone thickness have been observed with intermittent exposure to PTH in ovariectomized animal models (19, 20), and randomized double-blind studies have shown that intermittent injection of aminoterminal fragments of human PTH increased BMD in both males (21, 22) and females (23, 24) and reduced fracture rates in postmenopausal females (25).

On the other hand, primary hyperparathyroidism has been well documented to be associated with lower cortical BMD (26, 27), and hypoparathyroidism is shown to be associated with gains in BMD in this and other studies (4, 5, 6). As a principal regulator of calcium homeostasis, PTH also has acute effects in mobilizing skeletal calcium. It is likely that the overall biological action of PTH on the bone will depend on the balance between activation of the cAMP/protein kinase A and the protein kinase C pathways and on the balance between its differential effects on osteoblasts and osteoclasts (28). Because PTH secretion is pulsatile, the skeletal effects of PTH may also be dependent on pulse frequencies as well as pulse amplitudes (29). Whereas intermittent administration of human PTH(1–34) increases cancellous bone mass, chronic sustained PTH treatment results in catabolic effects at cortical sites (30). To our knowledge, there are, as yet, no studies on pulse periodicity patterns in hypoparathyroidism. A study on pulse amplitude and frequency modulation in primary hyperparathyroidism, however, showed no significant difference in PTH pulse rhythms between subjects and normal postmenopausal controls (31).

Another interesting observation in our study is that the increase in BMD was greater at the lumbar spine (a site rich in trabecular bone) than at the femoral neck (a site richer in cortical bone). The BMD at the lumbar spine and femoral neck of the hypoparathyroid patients was at 1.93 SD and 1.14 SD above the sex- and age-matched normal, respectively. Because hyperparathyroidism is known to cause significantly more bone loss at the cortical bone, with relative preservation of spinal bone mass (26, 27), one may be tempted to infer that the protective effect of hypoparathyroidism on bone loss would be more prominent at the hip. The opposite was, however, evident from our study. In mild asymptomatic primary hyperparathyroidism, hypoparathyroidism, and with intermittent PTH administration the trabecular bone seems to be relatively better protected.

In conclusion, our study in a small group of patients with either idiopathic or postthyroidectomy hypoparathyroidism showed that the state of hypoparathyroidism is associated with increased BMD, most notably at the spine. The increase in BMD may be attributable to an increase in bone mineralization secondary to suppressed bone turnover, as supported by the lower level of BAP in patients with hypoparathyroidism. It is also consistent with the bone histomorphometry, which showed virtual absence of detectable cell-based remodeling in patients with hypoparathyroidism (32). Because intermittent injection of PTH is anabolic on bone and increases the bone mass, a state of hypoparathyroidism after hyperparathyroidism may optimize the bone mineralization and further increase the BMD.


   Footnotes
 
Abbreviations: BAP, Bone-specific alkaline phosphatase; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.

Received August 30, 2002.

Accepted March 26, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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