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J Bone Miner Res. Dec 2008; 23(12): 2018–2024.
Published online Aug 4, 2008. doi:  10.1359/JBMR.080803
PMCID: PMC2686925

Dynamic and Structural Properties of the Skeleton in Hypoparathyroidism

Abstract

Hypoparathyroidism, a disorder in which PTH is absent, is associated with BMD that is above average. We studied associated structural and dynamic properties of the skeleton in hypoparathyroidism. Thirty-three subjects with hypoparathyroidism and 33 age- and sex-matched control subjects with no known metabolic diseases underwent percutaneous iliac crest bone biopsies after double-labeling with tetracycline. The main outcome was histomorphometric assessment of structural and dynamic skeletal parameters. Subjects with hypoparathyroidism had greater cancellous bone volume (mean ± SD; BV/TV: 23.5 ± 8 versus 19.7 ± 5%, p = 0.02), trabecular width (Tb.Wi: 136.1 ± 37 versus 119.3 ± 21 μm, p = 0.03), and cortical width (Ct.Wi: 923.4 ± 420 versus 753.5 ± 246 μm, p = 0.05) than control subjects. Dynamic skeletal indices, including mineralizing surface (MS: 0.85 ± 1.58 versus 4.27 ± 3.32%, p < 0.0001) and bone formation rate (BFR/BS: 0.006 ± 0.014 versus 0.032 ± 0.028 μm3/μm2/d, p < 0.0001), were profoundly suppressed in the hypoparathyroid subjects. We conclude that hypoparathyroidism is characterized by markedly unusual structural and dynamic properties of bone.

Key words: hypoparathyroidism, bone histomorphometry, bone densitometry, parathyroid

INTRODUCTION

Hypoparathyroidism is caused by deficient or absent PTH. It occurs after thyroid or parathyroid surgery, if all parathyroid tissue is removed; as a consequence of autoimmune disorders, such as antibodies that activate the calcium sensing receptor of the parathyroid glands(13); and, more rarely, as a congenital disorder of parathyroid dysgenesis, such as DiGeorge syndrome.(47) Independent of etiology, the typical biochemical constellation in untreated hypoparathyroidism includes low circulating PTH levels, hypocalcemia, relatively high urinary calcium excretion, hyperphosphatemia, and reduced levels of 1,25-dihydroxyvitamin D.(8,9)

In the absence of PTH, bone remodeling is reduced.(1012) Chronically low bone turnover in patients with hypoparathyroidism typically leads to bone mass that is higher than age- and sex-matched controls.(1316) This study was designed to provide a detailed description of the structural and dynamic features of the skeleton in hypoparathyroidism. Our findings provide new evidence for the fundamental importance of PTH in the maintenance of skeletal structure and function.

MATERIALS AND METHODS

Subjects

Thirty-three subjects with documented hypoparathyroidism were compared with 33 age- and sex-matched historical control subjects. The diagnosis of hypoparathyroidism was established by the simultaneous presence of serum calcium and PTH concentrations below the lower limits of normal on at least two prior occasions separated by an interval of at least 30 days. Hypoparathyroidism had to have been present for at least 3 yr, to establish a chronic state of PTH deprivation. Patients were excluded if they had been on a bisphosphonate within 5 yr before study entry or for >6-mo duration at any time or if they were women within 5 yr of onset of menopause. Patients were also excluded if they used any of the following medications: estrogens, progestins, raloxifene, calcitonin, systemic corticosteroids, fluoride, bisphosphonates, lithium, statins, loop diuretics, or methotrexate. Potentially confounding disorders were also exclusionary criteria, if present: Paget's disease of bone, diabetes mellitus, chronic liver or renal disease, acromegaly, Cushing's syndrome, rheumatoid arthritis, or multiple myeloma.

Patients were recruited from the Metabolic Bone Diseases Unit of Columbia University Medical Center and from the Hypoparathyroidism Association. A total of 146 patients were screened from August 2004 until February 2007. Any of the following criteria were cause for exclusion: documented hypoparathyroidism <3y r (n = 31); menopause within 5 yr (n = 15); teriparatide (n = 7) or bisphosphonate (n = 8) therapy; other metabolic bone disease (n = 5); history of malignancy other than thyroid cancer (n = 12); current thyroid cancer (n = 9); renal insufficiency (n = 6); glucocorticoid use (n = 4); and planning a pregnancy (n = 2). Of the 47 subjects who met inclusion criteria, 14 did not participate because of difficulty with travel or committing to the schedule of the visits. Twenty of the 33 enrolled patients were on thyroid replacement; thyroid-stimulating hormone (TSH) indices indicated overtreatment in 7 and undertreatment in 2 patients.

Thirty-three sex- and age-matched control subjects were randomly selected from four individual studies, which included 10 postmenopausal women,(17) 14 premenopausal women,(18,19) and 9 men.(20) There was no history of low-trauma fractures in any of the controls, as well as no history of medical illness or drug therapy known to affect bone metabolism.

Protocol

Patients were referred to the Metabolic Bone Diseases Unit at Columbia University Medical Center. All patients were screened for study eligibility criteria before enrollment. Blood and urine were collected for biochemical analysis, BMD was measured twice within 1 mo, and the mean values were used. All patients underwent a percutaneous iliac crest bone biopsy.

Serum calcium, phosphorus, and alkaline phosphatase activity were measured by automated techniques (Technicon Instruments, Tarrytown, NY, USA). The average value of the two serum calcium determinations was used. Serum PTH was measured by immunoradiometric assay (IRMA),(21) urinary calcium by atomic absorption spectrophotometry, and serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D as previously described.(22)

Bone mineral densitometry

BMD of the lumbar spine, total hip, and distal one-third radius was measured by DXA. The short-term in vivo precision error (root-mean-square SD) was 0.026 g/cm2 for L1–L4; 0.032 g/cm2 for the total hip; 0.041 g/cm2 for the femoral neck, and 0.033 g/cm2 for the forearm.

Histomorphometry

Before the procedure, all patients were labeled twice with tetracycline in a 3 days on:12 days off:3 days on sequence. Two different tetracyclines were used (tetracycline hydrochloride and declomycin) to distinguish between the two labels. Biopsy specimens were processed and subjected to histomorphometric analysis as previously described in detail from our laboratory.(23) Histomorphometry was performed using a digitizing image-analysis system OsteoMeasure (OsteoMetrics, Atlanta, GA, USA). Cancellous and cortical bone structure were assessed by measuring cancellous bone volume (BV/TV), trabecular width (Tb.Wi), trabecular number (Tb.No), trabecular separation (Tb. Sp), cortical width (Ct.Wi), and cortical porosity area (Ct. Po. Ar). Bone remodeling activity was evaluated on cancellous, endocortical, or intracortical bone surfaces and expressed by the variables of osteoid surface (O.S), osteoid width (O.Wi), mineralizing surface (MS), mineral apposition rate (MAR), adjusted apposition rate (Aj.AR), bone formation rate (BFR), and eroded surface (ES). Bone resorption rate (BRs.R) was calculated as (BFR/BS)/(E.Pm/BS). All indices are expressed according to the recommendations of the ASBMR nomenclature committee.(24)

Statistical analysis

All statistical analyses were performed using SPSS for Windows (version 11.0; SPSS, Chicago, IL, USA). All continuous data are presented as mean value ± SD, and all categorical data are reported as percentage or absolute number. Student's t-tests were used to assess differences between groups for normally distributed data and the Mann-Whitney U-test/Wilcoxon rank sum test were used to determine significance for non-normally distributed data. A Pearson's correlation coefficient was used to assess the relationship between variables. To account for and to correct for multiple comparisons, an α level of 0.01 was required to be considered significant.

The study was approved by the Institutional Review Boards of Columbia University Medical Center and Helen Hayes Hospital. All subjects gave written informed consent.

RESULTS

Characteristics of the study population

The demographics of the hypoparathyroid population reflected a predominance of women (Table 1). The two major etiologies of the disease were post-thyroid surgery and idiopathic disease. Duration of hypoparathyroidism ranged from 3 to 45 yr. Although none of the subjects had classic fragility fractures, one quarter sustained mild fractures in adulthood. Basal ganglia calcifications were found on prior radiologic imaging in the four subjects with suggestive neurological symptoms; the presence of calcifications was not investigated in the other patients. Baseline biochemical values are shown in Table 2. All subjects were receiving calcium and vitamin D, and on this replacement therapy most had normal calcium values; a few subjects had serum calcium levels below the lower limits of normal. All patients had previously been well documented to have hypoparathyroidism by concomitant hypocalcemia and low PTH levels.

Table 1
Demographics of the Hypoparathyroid Population
Table 2
Biochemistries and BMD of the Hypoparathyroid Population

BMD by DXA

BMD was normal or above average (Table 2; Fig. 1). We used Z-scores for comparisons because of the wide age distribution of the patients. Measurements tended to be the highest at the lumbar spine (Z-score +2.2 ± 2.2) but were exceedingly well maintained at the total hip (Z-score +1.1 ± 1.3), femoral neck (Z-score +1.3 ± 1.3), and distal one-third radius (Z-score +0.64 ± 0.94) as well (Fig. 1). There was a positive correlation between lumbar spine BMD (g/cm2) and duration of hypoparathyroidism (r = +0.58, p = 0.01). BMD did not differ significantly at any site between subjects with postsurgical hypoparathyroidism compared with those with idiopathic hypoparathyroidism.

FIG. 1
Bone densitometry in hypoparathyroidism. Z-scores are used because of the wide age distribution of the patients. Four different sites (lumbar spine, total hip, femoral neck, and distal one-third radius) are shown (mean ± SD). Although BMD data ...

Bone histomorphometry: structural analysis

Results were compared with data from 33 age-and sex-matched normal subjects. The structural analyses showed more bone in both cancellous and cortical compartments in the hypoparathyroid subjects. A representative photomicrograph of a biopsy from a hypoparathyroid subject compared with a normal control is shown in Fig. 2. Hypoparathyroid subjects had greater cancellous bone volume (BV/TV, p = 0.02; Table 3), as well as greater trabecular width (Tb.Wi, p = 0.03). There was a trend for cortical width (Ct.Wi) to be increased (p = 0.05) and cortical porosity (Ct.Po.Ar, p = 0.13) to be decreased in the hypoparathyroid subjects. These abnormalities in bone structure were present regardless of the etiology of the hypoparathyroidism (data not shown). The duration of hypoparathyroidism correlated positively with both trabecular width (r = +0.41, p = 0.02) and cortical width (r = +0.40, p = 0.02).

Table 3
Histomorphometric Variables of Bone Structure in 33 Subjects With Hypoparathyroidism and Controls
FIG. 2
A representative photomicrograph of a biopsy from a hypoparathyroid subject (right) compared with a normal control (left). The hypoparathyroid subject is a 32-yr-old premenopausal woman; the control is a 22-yr-old premenopausal woman. In the hypoparathyroid ...

Bone histomorphometry: assessment of bone turnover

Analyses of cancellous, endocortical, and intracortical surfaces showed significantly reduced osteoid width (O.Wi) and osteoid surface (OS) at all three bone envelopes (Table 4). Mineral apposition rate (MAR) was also significantly lower in all three envelopes. The percentage of bone surface that was mineralizing (MS) was also significantly reduced in all three envelopes, as was the bone formation rate (BFR). The adjusted apposition rate (Aj.AR) was significantly lower in the hypoparathyroid subjects in the cancellous and endocortical envelopes. Eroded surface (ES) did not differ between hypoparathyroid subjects and controls in any of the envelopes. However, bone resorption rate (BRs.R) was significantly lower in the hypoparathyroid subjects in all three compartments. As with static histomorphometric abnormalities, the alterations in dynamic indices were not dependent on the etiology of hypoparathyroidism (data not shown). Representative biopsies from a patient and a control subject (Fig. 3) showed that the double tetracycline labels, readily seen in the normal subject, are absent in the hypoparathyroid subject. These dynamic indices are consistent with profoundly reduced bone turnover in hypoparathyroidism. When subjects whose TSH values were below or above normal were excluded from the analysis, neither the static nor the dynamic indices differed significantly.

Table 4
Histomorphometric Variables of Bone Remodeling in Subjects With Hypoparathyroidism (n = 33) and Conrols (n = 33)
FIG. 3
Reduced tetracycline uptake in a hypoparathyroid bone biopsy (right) compared with a control (left). The hypoparathyroid subject is a 61-yr-old postmenopausal woman; the control is a 63-yr-old postmenopausal woman. Double labels are visualized in the ...

DISCUSSION

This study of 33 patients with hypoparathyroidism, the largest cohort ever studied with this disease, showed that the PTH deficiency state has clear consequences on the skeleton. Independent of etiology and well-maintained BMD notwithstanding, bone structure and skeletal dynamics were markedly atypical. Cancellous bone volume and cortical bone width were both markedly increased, whereas bone turnover was substantially decreased. These data suggest that bone quality in hypoparathyroidism seems to be unusual and that the ways in which bone is anomalous might be a consequence of PTH deficiency.

The central anomaly that may well form the basis for all the others is the markedly reduced bone turnover, an observation previously made in a much smaller study of hypoparathyroidism.(10) In that study, as in this study, subjects were treated with varying amounts of vitamin D. The data from both studies suggest that even with vitamin D repletion, the skeleton still shows characteristics of a PTH deficiency state. In our study, subjects with hypoparathyroidism had greater cancellous bone volume, trabecular width, and cortical width than control subjects. Dynamic skeletal indices, including mineralizing surface, bone formation rate, and bone resorption rate, were markedly suppressed in our hypoparathyroid subjects. Similarly, compared with euparathyroid age- and sex-matched controls, hypoparathyroid patients in the study of Langdahl et al.(10) also had a prolonged quiescent period, along with markedly reduced resorption and formation rates and reduced activation frequency. Reduced indices of bone turnover were also reported in a study on hypoparathyroid dogs.(25) In all of these studies, it seems that the increases in BMD and bone volume were associated with both decreased bone formation and bone resorption rates, theoretically leading to the accumulation of unremodeled or hypermature bone. The common use of vitamin D in both the animal and the human studies permits the conclusion that, without PTH, vitamin D cannot, by itself, restore structure or dynamic properties to the usual state in hypoparathyroidism. These findings illustrate the unique actions of PTH on these skeletal dynamics. This model, in fact, could be regarded, in a way, as an acquired human “knockout” of PTH. The influence of the duration of PTH deficiency on skeletal structure is not well defined, but our observation of a positive correlation between the duration of hypoparathyroidism and both trabecular and cortical width suggests that these anomalies become more advanced with time.

It has been shown in other settings, particularly therapeutic ones, that several aspects of bone quality in addition to BMD contribute to fracture risk.(2428) The therapeutic effects of antiresorptive and anabolic agents in osteoporosis can be accounted for only incompletely by changes in BMD.(26) In situations where BMD is abnormally high, such as the experience with fluoride as a treatment for osteoporosis, increases in BMD may not be beneficial at all.(27) Some of the other factors that contribute to bone quality include bone turnover, geometry, material properties, and microarchitecture.(2830) It is possible that all these properties in the hypoparathyroid skeleton are influenced by the lack of PTH and have an impact on bone quality in hypoparathyroidism. Ongoing studies will help to address these points.

If reduced bone turnover is a central finding in hypoparathyroidism, how could it potentially contribute to a change in bone quality? One proposed salutary function of the remodeling process is to maintain bone strength by repairing microdamage or replacing overly mature bone. Thus, it is plausible that in bone that is not remodeling or is remodeling very slowly, microdamage is not easily repaired and that bone becomes hypermature. With increasing maturity, another problem may develop: bone may lose its characteristically heterogeneous mineral distribution. Such heterogeneity is thought to obstruct the propagation of microcracks into larger defects. Without this normal remodeling process, the reduced bone turnover state could theoretically lead to bone that is more stiff than tough and thus more likely to fracture.(31,32) Hypoparathyroidism might also affect modeling and remodeling of the growing skeleton, as suggested by the finding that patients with congenital hypoparathyroidism or parathyroidectomy in childhood might not achieve normal height.(3335)

Despite scattered reports in the literature, there are no data on fracture incidence in hypoparathyroidism. This is because the epidemiology of fracture incidence is confounded by the exceedingly small numbers of patients with this disease. Nevertheless, the importance of bone turnover in the assessment of fracture risk is widely accepted. Heaney(36) has described a U-shaped relationship in which both high and low bone turnover are both associated with increased fracture risk. It is postulated by Heaney that, in hypoparathyroidism, very low bone turnover is associated with the left upstroke of the U-shaped relationship describing bone turnover and fracture risk. Although the types of fractures found in our group were not typical fragility fractures, it is noteworthy that 24% of our cohort had a history of some form of fracture.

It seems paradoxical that both a deficiency and surfeit of PTH, as exemplified by hypoparathyroidism and primary hyperparathyroidism, respectively, are apparently associated with preserved or improved cancellous bone microarchitecture. Moreover, BMD is also lowest at the cortical-enriched distal radius in both disorders. Presumably, the paradox is explained by mechanisms that differ by whether there is an excess or deficiency of PTH.

It is also possible that the increased bone mass in hypoparathyroidism is at least partially caused by PTH-related peptide (PTHrP). A mouse model of complete PTH deficiency (PTH−/−) alone has been associated with high trabecular and cortical bone volume,(37) whereas mice that also have PTHrP haploinsufficiency (PTH−/− and PTHrP+/−) have been shown to have low bone mass.(38) Moreover, studies of osteoblast-specific Pthrp knockout mice suggested that PTHrP regulates both bone formation and resorption.(39,40) It is unknown whether these mouse genetics are applicable to the model that we are studying, namely acquired hypoparathyroidism in the mature human subject. Future studies will be necessary to investigate whether and to what extent PTHrP might be contributing to the observations in human subjects with hypoparathyroidism.

In conclusion, our data suggest that bone structure and turnover are markedly atypical in hypoparathyroidism, despite increased BMD. It is possible that these anomalies are primarily caused by the lack of PTH and its effects on bone turnover and other aspects of bone quality. Future studies will focus in more detail on these other aspects of bone quality and how they may contribute to skeletal integrity. Treatment of these subjects with PTH and restoration of these atypical findings would be a compelling test of this hypothesis.

ACKNOWLEDGMENTS

This study was supported by DK067619, DK069350, and FD-R-02525.

Footnotes

Dr Bilezikian states financial conflicts with Mercy & Co., Eli Lilly & Co., and Novartis Pharmaceuticals. All other authors state that they have no conflicts of interest.

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