Regardless of its etiology, the effects of chronic PTH deficiency on the human skeleton are profound. In normal adults, bone mass is regulated by a delicate balance between bone resorption and formation in a tightly regulated process termed remodeling. PTH is one of the key regulators of the rate of bone remodeling. A reduction or absence of circulating PTH leads initially to a decrease in bone resorption and then to a coupled reduction in bone formation. However, the balance between resorption and formation favors the latter as, over time, bone mass increases. This effect is manifested in both cancellous and cortical bone compartments.(90-94)
Greater insight into the architectural basis of the increase in bone mass can be obtained by peripheral quantitative computed tomography (pQCT). Using this technique, Chen et al compared volumetric bone mineral density (vBMD) and geometry of the distal radius and midradius among postmenopausal women with postsurgical or idiopathic hypoparathyroidism, PHPT, and normal controls.(93)
At the 4% distal radius site, which is enriched in cancellous bone, trabecular vBMD was higher in the rank order hypoparathyroidism>control>PHPT. At the 20% midradius site, cortical vBMD was also greater in the same rank order. The BMD differences among these 3 groups could be explained by differences in bone geometry. At both radial sites, total bone area and both periosteal and endosteal surfaces were greater in PHPT than in hypoparathyroidism, and controls and cortical thickness and area were higher in the rank order hypoparathyroidism>control>PHPT. Increased cancellous bone volume has been shown by high-resolution pQCT and increased mechanical strength has been suggested by microfinite element analysis ().(95)
FIG. 3 Images showing tissue stress levels under axial loading generated by microfinite element analysis based on microcomputed tomography of iliac crest bone biopsies (A, C, E) and high-resolution peripheral quantitative computed tomography (B, D, F) of the (more ...)
Although there are only two studies available, the most comprehensive information on the effects of hypoparathyroidism on the skeleton has come from histomorphometric analysis of the iliac crest bone biopsy. In the first of these studies, biopsies were obtained from 4 men and 8 women with vitamin D-treated hypoparathyroidism and 13 age- and gender-matched controls.(96)
Nine of the subjects suffered from postoperative hypoparathyroidism of 2-53 years’ duration, and 3 had idiopathic disease. Ten of the patients were treated with 1-α-hydroxylated vitamin D (0.5-3.9 μg/d), and 2 received calciferol oil. There was a nonsignificant trend toward an increase in cancellous bone volume in the hypoparathyroid subjects, but the structural indexes, marrow star volume, trabecular star volume, and trabecular thickness were not different from controls. Bone forming surface and bone formation rate (BFR) were significantly reduced by 58% and 80%, respectively, in the hypoparathyroid subjects, and remodeling activation frequency was 0.13 per year, compared to 0.6 per year in controls. Initial mineral apposition rate was also lower, by a factor of 5, in the hypoparathyroid subjects, but this difference was not statistically significant. The total resorption period was prolonged from 26 to 80 days in the hypoparathyroid subjects and the resorption depth was reduced. The reconstructed remodeling cycles derived from these data are shown in . The balance between the resorption depth and wall thickness of cancellous bone packets was slightly positive, by approximately 5 μm, in the hypoparathyroid subjects compared to the controls.
FIG. 4 Reconstructed remodeling cycles in hypoparathyroid (upper) and normal (lower) subjects. Note the marked elongation of all phases of the remodeling cycle in hypoparathyroidism. Reproduced with permission.(95)
A more recent larger histomorphometric study involved 33 subjects (24 women and 9 men) with hypoparathyroidism treated with vitamin D and 33 age- and sex-matched control subjects.(94)
The etiologies of the hypoparathyroid state were post-thyroid surgery (n=18), autoimmune (n=13), and DiGeorge syndrome (n=2), and the mean duration of the disease was 17±13 (SD) years. Vitamin D intake varied between 400 and 100,000 IU/d and calcium supplementation varied between 0 and 9 g/d. Ten of the 33 hypoparathyroid subjects were receiving thiazide diuretics. In contrast to the earlier smaller study,(96)
cancellous bone volume was elevated in the hypoparathyroid subjects ( and ). The structural basis for the higher cancellous bone volume in hypoparathyroidism was an increase in trabecular width; trabecular number and trabecular spacing were both similar to controls. Cortical width was also significantly greater in the hypoparathyroid subjects, and cortical porosity was 17% lower than in controls, but this difference was not statistically significant. Remodeling activity was assessed separately on cancellous, endocortical, and intracortical skeletal envelopes. Osteoid surface and width were reduced in the hypoparathyroid subjects on all 3 envelopes. The tetracycline-based BFR was significantly lower on all 3 envelopes in the hypoparathyroid subjects with the most profound reduction (more than fivefold) seen on the cancellous envelope (). The reduction in BFR was due to significant decreases in both mineralized surface and mineral apposition rate on all 3 envelopes. The eroded surface did not differ between the hypoparathyroid and normal subjects, but the bone resorption rate was significantly lower in the hypoparathyroid subjects on all 3 envelopes. As in the earlier study,(96)
these findings are all indicative of a profound reduction in the bone turnover rate in hypoparathyroidism accompanied by an increase in bone mass in both cancellous and cortical compartments.
FIG. 5 Low-power view of iliac crest bone biopsies from a control subject (left) and a subject with hypoparathyroidism (right). Goldner trichrome stain. Note the increase in cancellous bone volume and cortical thickness in the hypoparathyroid subject. Reproduced (more ...)
FIG. 6 Cancellous and cortical bone parameters obtained by histomorphometry in subjects with hypoparathyroidism (hatched bars) and controls (open bars). Values are mean±SD. Drawn from data from Rubin et al.(94)
Tetracycline labels in a hypoparathyroid (left) and control subject (right). Tetracycline uptake was markedly reduced in the hypoparathyroid subject, reflecting the low turnover rate.
The effects of PTH deficiency on cancellous and cortical bone mass, which were initially observed by noninvasive imaging and by 2-dimensional histomorphometry, were recently confirmed by the 3-dimensional analytical capability afforded by microcomputed tomography.(97)
Results from this study confirmed the increase in cancellous bone volume and trabecular thickness in hypoparathyroid subjects and demonstrated higher trabecular number and trabecular connectivity in comparison to matched control subjects. In addition, the structural model index was lower in hypoparathyroidism, indicating that the trabecular structure was more plate-like than rod-like ().
FIG. 8 Reconstructed microcomputed tomographic images of cancellous bone from a hypoparathyroid (left) and a control subject (right). Note the dense trabecular structure in hypoparathyroidism. Reproduced with permission.(97)
Rubin and colleagues have also recently begun to explore the material composition of the bone matrix in hypoparathyroidism. Using backscatter electron imaging, they found that the mean mineralization density in iliac bone from subjects with hypoparathyroidism was similar to controls, although there was greater interindividual variation in mineralization parameters in the hypoparathyroidism subjects than in the controls.(98)
This result is surprising as one might have expected that mineralization density would be enhanced in hypoparathyroidism because of the low turnover and the attendant increase in mineralization as the bone “ages.” It suggests that mineralization density is controlled by other factors, in addition to the degree of secondary mineralization, and indicates that the higher bone mineral density (BMD) by densitometry in hypoparathyroidism is due in large part to the increase in bone tissue volume rather than an increase in the amount of mineral within the tissue.
As evidenced by the work cited here, application of new research techniques to the study of hypoparathyroidism is leading to new insights regarding the skeletal abnormalities in this disease. We expect that this progress will continue at an even greater pace over the next 5 years and will lead to a much better understanding of the pathophysiology, as well as the biomechanical and metabolic effects, of a disease that has, until recently, received little attention.