Abstract

Hyperthyroidism can alter bone metabolism by increasing both bone resorption and formation. The increase in bone resorption predominates, leading to a decrease in bone mass. To assess the effect of hyperthyroidism on bone and mineral metabolism, we measured bone density using single photon absorptiometry in 30 untreated hyperthyroid patients. Patients were categorized into three groups based on sex and alkaline phosphatase levels: 44 sex- and age-matched subjects were used as controls. Bone densities were significantly lower in all patient groups compared with controls. Alkaline phosphatase was found to be a useful marker for assessing severity of bone disease in hyperthyroid patients as there is significant correlation between the alkaline phosphastase level and degree of bone loss and decrease in bone density among patients with higher alkaline phosphatase value. Hyperthyroidism should be considered in the differential diagnosis of unexplained elevated alkaline phosphatase activity.

Thyroid disorders such as hyperthyroidism have profound effects on bone and mineral metabolism [1]. The skeletal changes in hyperthyroidism can be grouped into two main categories: first, localized changes in the fingers, consisting of periosteal hyperplasia leading to clubbing, a condition known as thyroid acropathy, which has been reported to occur in about 1% of the thyrotoxic patients; and second, a generalized loss of bone mass, taking the form of osteoporosis [2].

There is a negative correlation between the duration of the disorder and the bone mass.

Hyperthyroidism causes increased bone turnover leading to osteopenia and increased incidence of fracture [3].Both osteoblastic and osteoclastic activities are increased, with bone resorption exceeding bone formation.

Bone biopsy usually shows decreased trabecular bone volume and increased cortical porosity [4].

Radiological signs of hyperthyroid bone disease vary between 3.5 and 50% [5], depending on the severity of the disease as well as on the observer, as it is a purely subjective assessment. Bone densitometry devices are used in assessing hyperthyroid bone disease and these often detect the skeletal complications that accompany hyper-thyroidism, even when biochemical or radiological evidence of bone disease is absent [6].

Single photon absorptiometry (SPA) is used to assess appendicular bones only, as tissue composition surrounding the bone mass has to be uniform and minimal. The method was based on the principle described by Cameron et al [7]. SPA was used in this study to examine the effect of hyperthyroidism on bone metabolism.

Methods

Thirty consecutive untreated hyperthyroid patients seen at King Khalid University Hospital in Riyadh were studied. The diagnosis of hyperthyroidism was made based on clinical presentation, I-123 thyroid scan and uptake, and total thyroxine level (T4).

All patients had the following evaluation done: (a) total T4 using Amersham kits with normal range, 51-141 mol/L; (b) serum levels of calcium and alkaline phosphatase were measured by standard methods (autoanalyzer, SMAC Technicon) with normal range for calcium, 2.1 to 2.6 nmol/L, and for alkaline phosphatase, 40 to 130 U/L; (c) bone densitometry measurements were done over the nondominant arm. Measurements were made at two positions: first, at the junction of the proximal two thirds with distal one third (mid-radius) which is predominantly cortical bone; second, at 5 mm from the end of the radius which is predominantly trabecular bone. Bone mineral content (BMC) was expressed as ash weight (in grams) per the axial bone length (in centimeters). Normalization based on the width (BW) of the radius at the measuring site (BMC/BW). This represents the bone mineral density (BMD) expressed as gm/cm².

Forty-four subjects were used as controls; 30 females with age range from 18 to 85 years, with mean of 43.8 ± 17.4 years, 8 of them were post-menopausal; 14 males with age range from 24 to 50 years, with a mean of 37 ± 9.8 years. Their proximal and distal measurements were done over the nondominant arm. The Norland SPA machine was used; reproducibility was 2 to 4% at the proximal site and 2 to 3% at the distal site.

Results

The 30 untreated hyperthyroid patients wereclassified into three groups: Group 1 (18 female patients with high alkaline phosphatase), Group 2 (6 female patients with normal alkaline phosphatase), Group 3 (6 male patients, all were found to have alkaline phosphatase).

Table 1 shows the different groups, the range and mean of age, range and mean of alkaline phosphatase, and range and mean of thyroxine.

No hypercalcemia was found among the patients studied. Serum calcium ranged from 1.96 to 2.56 with a median of 2.42 mmol/L.

Figure 1 shows the BMD of Groups 1 and 2 compared with the control group. In Group 1, the mean of BMD at the proximal end was 0.51 ± 0.10 compared with the mean of the controls which was 0.65 ± 0.06, with P< 0.001. The difference was greater at the distal end, with mean of 0.37 ± 0.07, compared with mean of control of 0.52 ± 0.05, with P<0.001.

In Group 2, the mean of BMD at the proximal end was 0.68 ± 0.02, while the mean of BMD at the distal end was 0.51 ± 0.05, when all hyper-thyroid females were grouped together and compared with control as shown in Figure 2. The mean of BMD at the proximal end was 0.53 ± 0.11, compared with mean of control of 0.651 ± 0.06, with P< 0.001. While at the distal end, the mean of BMD of hyperthyroid patients was 0.4 ± 0.08, compared with control with mean of 0.52 ± 0.04, with P<0.001.

Table 1. Data on all the 3 groups including age, alkaline phosphatase level, thyroxine level. 

Table 2. Correlation of bone mineral density with alkaline phosphatase level.

Figure 3 shows the BMD of the hyperthyroid males, where at the proximal end the mean was 0.55 ± 0.13, compared with controls with a mean of 0.77 ± 0.05( P< 0.001), while at the distal end the mean was 0.4 ± 0.08, compared with controls with a mean of 0.61 ± 0.04 (P< 0.001).

The relationship between BMD and serum alkaline phosphatase was compared. An alkaline phosphatase of 400 U/L was chosen arbitrarily as cut-off between mild to moderate on one hand and severe on the other hand. Seventy-two percent of the patients had an elevated alkaline phosphatase. Table 2 showed 18 patients (15 females, 3 males) had a mild to moderate rise in alkaline phosphatase , who had mean of BMD at the proximal end of 0.56 ± 0.1 while at the distal end this was 0.4 ± compared with 6 patients (3 males, 3 females) with a severe rise in alkaline phosphatase who had a mean BMD at the proximal end of 0.43 ± 0.07 while at the distal end the mean BMD was 0.32 ± 0.04. When these two groups were compared statistically, P was < 0.001 at both sites of measurement.

Discussion

Several aspects of hyperthyroid bone disease were studied. Hypercalcemia was seen in from 5 to 27% of the hyperthyroid patients [6]. When ionized calcium was measured, the frequency and severity of hypercalcemia were even more accentuated [7]. A temporal linear relationship exists between levels of serum calcium and free thyroxine index [8]. Most studies report elevation of serum phosphorus concentration, and an increase of the urinary excretion of phosphate is also frequently encountered [7,9]. In our study, none were found to be hypercalcemic.

Elevated levels of alkaline phosphatase were found in as many as 50% of the hyperthyroid patients studied. Correlation between thyroxine concentration and alkaline phosphatase levels was found. The increase in alkaline phosphatase activity after treatment of hyperthyroidism could be related to increased osteoblastic activity, which is an indicator of bone formation and healing [10]. Therefore, assessing BMD. is a better indicator of bone loss than measurement of alkaline phosphatase activity, which can be elevated at the destruction and healing phases. The study has shown bone loss as shown by the BMD in hyperthyroid patients, even among the subgroup with normal alkaline phosphatase levels.

Parathyroid hormone (PTH) concentration is decreased in hyperthyroid patients and normal or increased in hypothyroid patients. Decreased PTH concentration in hyperthyroid patients would account for the increase in tubular reabsorption of phosphorus and decreased calcium excretion (fractional tubular reabsorption of calcium [11].

Twenty-five hydroxy vitamin D₃ concentration is the same in hyperthyroid and euthyroid subjects; 1.25 dihydroxy vitamin D₃ concentration is decreased among hyperthyroid patients. This is attributed to hypercalcemia, hyperphosphatemia and decreased serum PTH concentrations among hyperthyroid patients [12].

Osteocalcin or bone GLA protein, 49 amino acid, which reflects osteoblastic activity, is increased in hyperthyroid patients [13].

SPA is a sensitive indicator of bone disease among hyperthyroid patients, even among those with normal alkaline phosphatase levels, as shown in this study, where BMD was low, especially at the distal end.

When measurements were made at two sites, it gives a better yield, especially for early osteopenia.

A reverse relationship was shown in this study between the serum alkaline phosphatase level and BMD bone disease, and subsequently the severity of the disease.

Alkaline phosphatase activity is a sensitive indicator of bone disease among hyperthyroid subjects. Hyperthyroidism should be considered among the differential diagnosis Of unexplained elevated levels of serum alkaline phosphatase.

References

1. Erickson EF, Mosekilde L, Nelson F. Trabecular bone remodelling and bone balance in hyperthyroidism. Bone 1985;6:421-8.

2. Meunier PJ, Bianchi GGS, Edouard CM, et al. Bony manifestations of thyrotoxicosis. Orthop Clin North Am 1972;3:745-74.

3. Fraser SA, Smith DA, Anderson SB, Wilson GM. Osteoporosis and fractures following thyrotoxicosis. Lancet 1971;1:981-3.

4. Melsen F, Mosekilde L. Morphometric and dynamic studies of bone changes in «hyperthyroidism. Acta Path Microbiol Scand 1987;85:141-50.

5. Koutras DA, Pandos PG, Koukoulommati AS, Constantes J. Radiological signs of bone loss in hyperthyroidism. Br J Radiol 1973;46:695-8.

6. Linde J, Friis TH. Osteoporosis in hyperthyroidism estimated by photon absorptiometry. Acta Endocrinology 1979;91:437-48.

7. Cameron JR, Mazes B, Sorensen JA. Single photon absorptiometry. Invest Radiol 1968;3:141-8.

8. Baxter JD, Boudy PK. Hypercalcemia of thyrotoxicosis. Ann Intern Med 1966;65:429-42.

9. Burman KD, Monchik JM, Earl JM, Wartoesky L. Ionized and total serum calcium and parathyroid hormone in hyperthyroidism. Ann Intern Med 1976;84:668-71.

10. Daly JG, Greenwood RM, Himsworth RL. Serum calcium concentration in hyperthyroidism at diagnosis and after treatment. Clin Endocrinol 1983;19:387-404.

11. Kleeman CR, Tuttless S, Bassett SH. Metabolic observations in a case of thyrotoxicosis with hypercalcemia. JClin Endocrinol Metab 1958;18:477-91.

12. Cooper DS, Kaplan MM, Rigway EC, et al. Alkaline phosphatase isoenzyme patterns in hyperthyroidism. Ann Intern Med 1979;90:164-8.

13. Bouillon R, De Moor P. Parathyroid function in patients with hyper or hypothyroidism. J Clin Endocrinol Metab 1974;38:999-1004.

14. Macfarlane A, Mawer EB, Berry J, Hann J. Vitamin D metabolism in hyperthyroidism. Clin Endocrinol 1982;17:51-9.

15. Garrel DR, Delmas PD, Malaval L, Fourniare J. Serum bone GLA protein marker of bone turnover in hyperthyroidism. J Clin Endocrinol Metab 1986;62(5):1052-8.