6-1998

Thyroid and Bone

P.L.A. van Daele, H.A.P. Pols, Rotterdam, the Netherlands 

Contents

Introduction

Effect of thyroid hormones on bone tissue

Effects of thyroid function on bone mineral density and fractures

Conclusion

References

Authors

Introduction

Bone is a metabolically highly active tissue. Various factors are necessary to ensure normal skeletal growth, maturation and turnover. Well known calciotropic hormones include parathyroid hormone (PTH), calcitonin (CT) and 1,25-dihydroxyvitamin D. They act together with locally produced factors to regulate the activity of bone cells and calcium metabolism. Apart from these, sufficient levels of thyroid hormones are also important for normal skeletal development, a fact which was already recognised over 100 years ago by von Recklinghausen. The most dramatic example of the importance of thyroid hormone for skeletal development is seen in untreated congenital hypothyroidism. Findings include shortness of stature, infantile skeletal proportions, with relatively short extremities, retarded "bone age" and epiphyseal dysgenesis. On the other hand, hyperthyroidism is one of the causes of secondary osteoporosis.

In the following, we will discuss the effects of thyroid hormone on bone at cellular and tissue level. Furthermore, we will review the effects of both hyper- and hypothyroidism on markers of bone turnover, bone mineral density and fractures.

Effect of thyroid hormones on bone tissue

In order to understand the effect of thyroid hormones on bone it is important to describe in some detail the normal process of bone turnover. In adults, there is a continuous process of both bone resorption and bone formation which are tightly coupled, so that the net activity of bone resorbing cells equals the net activity of bone forming cells. This process of bone resorption followed by bone formation is called remodelling (see also figure page 4). It provides a mechanism for self repair and adaptation to stress. Bone remodelling is a cyclic process, occurring dyssynchronously at thousands of sites in the human skeleton at all times. Because of its high surface to volume ratio, many more remodelling sites are to be found per unit volume of trabecular than cortical bone. Therefore, disorders of remodelling become earlier manifest in trabecular than in cortical bone.

Remodelling starts with activation, the attraction of bone resorbing cells (osteoclasts) to a locus on the bone surface. Activation frequency describes the frequency with which activation events occur on bone surfaces, in other words "how often a given site on the bone surface undergoes resorption and subsequent formation". The osteoclasts create a resorption cavity, a process which takes 4 to 12 days. The depth of the cavity is approximately 40–60 µm. After a reversal phase, osteoblasts start to invade the area and begin bone formation. First an osteoid matrix is formed, which is later mineralised. The total remodelling sequence takes approximately 200 days. Normally, the amount of bone formed, equals the amount which was first resorbed. The end product of the remodelling sequence is the bone structural unit (BSU).

Figure: Remodeling Sequence

Bone remodelling in cancellous bone as seen in longitudinal sequence and cross sections. Five different phases can be distinguished over time: (1) osteoclastic resorption, (2) reversal, (3) preosteoblastic migration and differentiation into osteoblasts, (4) osteoblastic matrix (osteoid) formation, and (5) mineralization. The endproduct of remodelling in cancellous bone is the completed cancellous bone structural unit (BSU) covered by lining cells (6) (From: Eriksen EF, Axelrod DW, Melsen F. Bone Histomorphometry. Raven Press, New York, pp 3–12, 1994.

Thyroid hormones exert their effect on the activation frequency such that higher levels of thyroid hormone lead to a higher activation frequency. In other words, there is an increase in the total number of activated BSUs. In addition, both the resorption and the formation phase of the remodelling sequence are shortened. In thyrotoxicosis, the surface area of unmineralised matrix (osteoid) is increased. Although both osteoblast and osteoclast activity are increased by elevated levels of thyroid hormone, the net result is loss of bone mass. The final resorption depth is normal, but the amount of bone formed is decreased, leading to a negative balance of approximately 10 µm per remodelling cycle. Apparently, the shortening of the formation phase predominates. The latter, together with the increase in total ongoing BSUs lead to an increase in the remodelling space (i.e. the space corresponding to the amount of bone resorbed by osteoclasts but not yet reformed by osteoblasts). When thyroid hormone levels are decreased, the activation frequency is reduced, and the resorption and formation phases are prolonged. In states of hypothyroidism, the resorption depth is reduced, but the amount of bone that is formed is near normal, despite a reduction in osteoblastic activity. This leads to a positive balance of approximately 15 µm per remodelling cycle.

Although thyroid hormone stimulates both osteoblasts and osteoclasts, stimulation of the latter appears to be indirect. The exact mechanism by which thyroid hormones increase osteoclast activity remains unknown, but in vitro experiments show that the presence of (activated) osteoblasts is a prerequisite for stimulation of osteoclasts. Unlike osteoclasts, osteoblasts possess nuclear receptors for T3, based on biochemical binding studies and detectable mRNA levels for thyroid hormone receptors. How stimulated osteoblast increase osteoclast activity is still unsolved. It has been suggested that the effect is mediated by a soluble factor, termed osteoclast resorption-stimulating activity, which appears to be associated with the osteoblast cell surface or the extracellular matrix.

During the various stages of bone turnover, markers of this process are released are released. These biomarkers provide the possibility of assessment of bone resorption and formation. The rate of formation and resorption of bone can be assessed by measuring enzymatic activity related to bone-forming (alkaline phosphatase) or resorbing (acid phosphatase) cells. An alternative is to measure bone matrix components released into the circulation, either after their secretion by osteoblasts (osteocalcin, procollagen type I) or after their release (as breakdown products) during osteoclastic bone resorption (urinary hydroxyproline, pyridinoline crosslinks), see also the table.

In hyperthyroidism, as a result of coupling, both markers of bone formation and of bone resorption are increased. In fact, there is a significant correlation between serum alkaline phosphatase and thyroid function. On the other hand, most markers of bone turnover are decreased in patients with hypothyroidism.

As a result of increased bone resorption, serum calcium is also slightly higher in subjects with hyperthyroidism, although serum levels above the upper level of normal are rare. This increase in serum calcium will lead to suppression of PTH-secretion and to a decreased formation of 1,25-dihydroxyvitamine D. Subsequently, calcium excretion by the kidney is enhanced and calcium resorption by the intestines is decreased. Tubular reabsorption of phosphate is increased. The increased renal calcium loss and the decreased intestinal calcium resorption prevent further hypercalcaemia, at the expense of a negative calcium balance. In hypothyroidism the opposite is seen, although abnormalities in serum calcium are even more uncommon than in hyperthyroidism.

Table: Markers of bone turnover

Effects of thyroid function on bone mineral density and fractures

Although some studies suggest differently, it is generally accepted that bone mass is reduced in thyrotoxicosis, and overt osteoporosis occurs in long-standing hyperthyroidism. For this reason, many incorporate measurements of thyroid hormones or thyroid-stimulating hormone (TSH) in the evaluation of elderly subjects with osteoporosis. It has been reported that the negative effect of thyroid hormone on bone occurs more frequently in female patients.

The effects on bone mass appears to be reversible after effective treatment of the thyroid disease. Normalisation of the thyroid function tests, leads to a substantial increase in bone mineral density measured both at the lumbar spine and proximal femur. Grant et al reported however, that previous hyperthyroidism remained a risk factor for osteoporosis in patients who were treated with radio-active iodine and who were currently euthyroid. Whether "subclinical" hyperthyroidism, i.e. a decreased TSH with normal values for thyroid hormones, has any effect on bone mass is still matter of debate. Subjects with subclinical hyperthyroidism have a slight increase in bone turnover and might have a reduced bone mass. Faber et al found that bone density decreased by approximately 2% per year in postmenopausal women with subclinical hyperthyroidism who were untreated. Treatment with radio-active iodine, resulting in normalisation of TSH, prevented this bone loss at a faster rate. Similar results were reported by Mudde et al, who found that in postmenopausal women with endogenous subclinical hyperthyroidism, treatment with methimazol prevented excessive bone loss. On the other hand, in a study by Folder et al, there was no difference in bone mass in premenopausal women with subclinical hyperthyroidism compared to an euthyroid control group, although they did find a slight and not statistically significant lower bone mass in postmenopausal women with subclinical hyperthyroidism. The results of the various studies on this matter, suggest that bone loss in subclinical hyperthyroidism is primarily a problem in postmenopausal women. The difference between pre- and postmenopausal women might be explained by the fact that bone turnover is already increased in the latter. High levels of thyroid hormone accelerate this process further with subsequently an increase in the rate of bone loss.

Although on theoretical grounds (see above), one would expect that in hypothyroidism, bone mass might be elevated, it appears to be similar to that of euthyroid subjects. Subsequent treatment of hypothyroidism with thyroid hormone has been reported to decrease or to have no effect on bone mineral density. For instance, in a study by Hanna et al, there was no effect on bone mass by adequate thyroid replacement therapy. Schneider et al, found that a replacement dose of thyroxin of 1.6 µg/kg or less, had no effect on bone mass, whereas higher doses led to a decrease in bone mineral density. In order to suppress TSH-secretion, subjects with thyroid carcinoma and nontoxic goitre, receive supraphysiologic doses of thyroid hormone. In a meta-analysis, Raber et al examined the effect of supraphysiologic doses of thyroid hormone on bone mass. After on average 8.5 years, subjects had 2.67% lower bone mass than controls. However, Franklyn et al found no effect of suppressive doses of thyroid hormone on bone density in subjects who had undergone thyroidectomy for differentiated thyroid cancer, despite long-term thyroxin therapy. As with subclinical hyperthyroidism, it has been suggested that supraphysiologic doses of thyroid hormone leads to bone loss primarily in postmenopausal women, and not in premenopausal women or in men. However, the size of the studies addressing this matter are too small to draw definite conclusions. Several studies have shown that the negative effects of thyroid hormone on bone can be negated by either bisphosphonates or (in women) maybe by estrogen replacement therapy. Calcitonin has not proven to be effective.

Few studies have addressed the question whether thyroid disease increases fracture risk and the results of these studies are inconsistent. In a retrospective study, Solomon et al found no enhanced prevalence of hip, vertebral or forearm fractures in subjects with thyroid disease. However, they did observe a propensity for fractures to occur earlier in women with a history of hyperthyroidism. Leese et al observed no excess of fractures in patients on thyroxin treatment even when TSH was suppressed. In contrast, Franklyn et al recently reported an excess mortality (standardised mortality ratio 2.9) as a consequence of hip fractures in a large group of women treated with radioactive iodine for hyperthyroidism.

Conclusion

Thyroid hormone is essential for normal bone turnover. Excessive thyroid hormone levels, either of endogenous origin or by thyroid hormone replacement, resulting in TSH-suppression, leads to bone loss. The latter appears partially reversible after adequate treatment, yet an increased risk for osteoporosis may persist. Therefore, it appears prudent to assess bone mineral density in subjects with thyrotoxicosis and subjects on hormone replacement therapy with suppressed TSH. Bisphosphonates and estrogen replacement therapy may prevent the detrimental effects of excessive thyroid hormone on bone.

Hypothyroidism itself seems to have little (clinically significant) effect on the skeleton.

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Authors

Paul L.A. van Daele, MD is resident in Internal Medicine at the Department of Internal Medicine III, University Hospital "Dijkzigt", Rotterdam, The Netherlands.
From 1992–1996 he worked as a research fellow at the department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam. He wrote his thesis on the ultrasonic evaluation of osteoporosis and the value of biochemical markers of bone turnover in the prediction of osteoporotic fractures. Currently he is involved in studies on endocrine determinants of osteoporosis.

Huibert A. P. Pols, MD is Professor of Medicine at the Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands. During the 15 years his research was focused on calcium and bone metabolism, especially the mechanisms of action of vitamin D and metabolic bone diseases. Since 1992 he is also involved in epidemiogical research as principal investigator of the Rotterdam Study (endocrine determinants of diseases in the elderly). He was one of the organizers of the World Congress on Osteoporosis 1996 in Amsterdam. He is also a member of the board of the Dutch Endocrine Society. His current interests are focused on the genetic aspects of osteoporosis.