My research career as an epidemiologist or “disease detective” began with an investigation of the effect of thyroid hormone on bone, working with Dr. Elizabeth Barrett-Connor in the early 1990s. Starting in 1972, she spearheaded a study designed to follow the residents of Rancho Bernardo, California, a community just northeast of San Diego. The original study focused on factors that might increase one's risk for heart disease. Dr. Barrett-Connor continued the study and expanded it to include other diseases and problems. The first osteoporosis-focused clinic visit started in 1989, when one of the first bone density machines, a central DXA, was made available for research purposes.
My first research project was to study the effect of thyroid hormone on bone density. My intellectual curiosity about this topic came from a group of patients that I referred to as “thyroid junkies.” These were patients who had been on thyroid hormone for many years yet did not feel well unless they were taking higher than the needed replacement doses. Each time I lowered their doses in an effort to get their blood test results into the normal range, they would complain about how sluggish the lower doses made them feel. As a result, they would just resume a higher dose of thyroid hormone on their own. I kept telling them that this was not good for their health. They were putting themselves at risk for bad effects on their heart, such as irregular heart rhythms, and for damage to their bone.
Their response was, “Prove it to us!” When I looked into the literature on thyroid and bone, the information was primarily about the effects on bone from an overactive thyroid, or hyperthyroidism. Little information was available about replacement doses of thyroid hormone and bone. As a result, we did a systematic study of the women in the Rancho Bernardo Study. Our findings were novel. We hit the publication “jackpot”—the lead article in an issue of the Journal of the American Medical Association (JAMA) with an accompanying editorial. My research publication career started at the top!
THYROID DISEASE
When the thyroid goes awry, it either accelerates or puts on the brakes. A more sensitive blood test now helps doctors discover over or under activity of the thyroid earlier in the course of disease. Obvious presentations of overactive “hyperthyroidism” or underactive “hypothyroidism” are seen much less frequently in doctors' offices today. Thyroid disease is more common in women than in men.
Thyroid Hormones
The master gland, the pituitary, produces thyroid-stimulating hormone or TSH. As the name suggests, it stimulates the thyroid to produce thyroid hormones. Thyroxine, abbreviated T4 for its chemical structure, is the principal hormone. T3 or triiodothyronine is the other. A synthetic version of thyroxine T4 is the most common “replacement” for hypothyroidism. The thyroid hormones send feedback both to the hypothalamus (a region of the brain that produces hormones to control multiple functions, including thyroid-releasing hormone to activate the pituitary gland) and the pituitary.
If too large a quantity of thyroid hormone is produced, as in hyperthyroidism, or you are taking too much thyroid hormone medicine, the pituitary stops producing TSH. This is termed “suppression,” and the TSH level will be low to undetectable.
If too small a quantity of thyroid hormones is circulating, the pituitary produces more and more TSH, trying to get the thyroid to make more thyroid hormones. The TSH level in this case will be high, indicating an underactive thyroid status or hypothyroidism.
HYPERTHYROIDISM
Thyroid hormones play a major role in your body's metabolism and also influence bone metabolism. Hyperthyroidism revs up bone turnover, just as it revs up the whole body. Bone loss is a result of increased bone turnover. Too much thyroid hormone appears to be more detrimental to the dense cortical bone found in the hip and forearm than to the spongy trabecular bone found in the spine.
The main causes of hyperthyroidism are Graves' disease, toxic multinodular goiter, and toxic thyroid nodules. Hyperthyroidism is more common in women, and risk of hyperthyroidism increases with age.
The majority of studies of hyperthyroidism and bone have focused on postmenopausal women. Bone breakdown activity by the osteoclasts is increased out of proportion to bone formation by the osteoblasts. In addition, the normal duration of the bone remodeling cycle is shortened. These changes lead to a net loss of bone and increased fracture risk at the hip, spine, wrist, and foot.
An increased risk for hip fracture is reported in women with a history of hyperthyroidism. Other studies report that the risk of spine and forearm fractures is increased as well. The effect of this condition may worsen with agerelated bone loss. After successful treatment of hyperthyroidism, small increases in bone density have been observed in postmenopausal women. However, complete reversibility is not usually possible.
In contrast, hyperthyroidism does not have an effect on the bone density of premenopausal women and men. Estrogen may provide bone protection to younger women who have not yet reached menopause. Few men have been systematically studied.
Fortunately, with the development of sensitive TSH assays and more frequent screening, hyperthyroidism is generally identified early.
HYPOTHYROIDISM
Bone metabolism slows down with hypothyroidism. In the early months of giving thyroxine (T4) replacement to normalize function, a transient increase in bone loss may be observed. This is “catch-up” loss of bone that would have been lost had the thyroid been functioning normally. Fortunately, this transient increase in bone loss is followed by resumption of a normal rate of bone loss. Today, an underactive thyroid condition is usually found by blood testing if hypothyroidism is mild, with few if any symptoms. However, those who never or rarely see doctors may be diagnosed from obvious signs of the disease.
THYROID HORMONE TREATMENT
The brand name Synthroid® (levothyroxine sodium) is the most common thyroid hormone prescribed for hypothyroidism. Synthroid is usually one of the top ten prescriptions dispensed in the US each year. The data from 2010 show that name or generic levothyroxine ranked fourth with a total of 70.5 million prescriptions dispensed. More than 10 percent of postmenopausal women take thyroid hormones.
The correct thyroid hormone replacement dose is the dose that maintains a normal TSH level. Up to 20 percent of postmenopausal women are estimated to be “over replaced.” Younger adults usually require a higher dose of thyroid hormone replacement than older adults. This is related to the amount of lean body mass. With age, lean body mass, or muscle mass, decreases. Therefore, smaller doses may be required for replacement with aging.
However, it is all too common to be on the same dose without change over many years, even though the measured TSH may drop lower and lower. This is a sign that your thyroid hormone prescription probably needs an adjustment to a smaller dose. Advances in the measurement of TSH with more sensitive assays have contributed to lowering the doses of thyroid hormone over the last fifteen years.
The best way to monitor your dose of thyroid hormone replacement is to have your T4 and TSH levels checked each year as part of your annual laboratory evaluation. In that way, you will not run into the problem of “over replacement.” Clinically, this is referred to as “subclinical hyperthyroidism.” Subclinical hyperthyroidism is the term used for normal levels of thyroid hormone, T3 and T4, with a TSH below the normal reference range. With “over replacement,” bone loss is greater at the hip than at the spine. Irregular heart rhythms are more common, particularly atrial fibrillation. The replacement dose of thyroxine should maintain normal thyroid hormone and TSH levels. Blood levels are followed to individualize and adjust your dose as needed.
What we found in the Rancho Bernardo Study on thyroid hormone and bone was interesting. In this population of older postmenopausal women, those who were taking more than “replacement doses” had lower bone density than those on appropriate doses of thyroid hormone. This finding confirmed other studies. The new observation was that those women who were “over replaced” and taking estrogen therapy had been spared the harmful bone effects. Their bone densities were higher at all sites, including the hip, spine, and forearm. Estrogen appeared to protect the bones when too much thyroid hormone was given.
Limited information is available on premenopausal women. Similar to what was observed in the Rancho Bernardo women, estrogen may provide premenopausal women with protection against acceleration of bone turnover and bone loss.
Thyroid disease is much less common in men than in women. Therefore, fewer studies have been conducted and less information is available. However, it appears that the influence of thyroid hormone on bone in men is less impressive than the influence of thyroid hormone on bone in women. In our evaluation of men in the Rancho Bernardo Study, we found that bone mineral density was not decreased in those taking thyroid hormone. This observation has been consistent in other studies as well.
As long as the levels of TSH remain in the normal range so that thyroid hormone is truly “replaced,” bone density is not affected and, most importantly, fracture risk does not increase.
SUPPRESSIVE DOSES OF THYROID HORMONE
Thyroid hormone tablets are also prescribed to thyroid cancer patients to prevent recurrence of cancer. Larger amounts of thyroid hormone are given to “suppress” TSH to basically “undetectable” levels. Several other thyroid problems, such as a single benign thyroid nodule or an enlarged thyroid, called a “goiter,” with multiple nodules, may require suppressive thyroid hormone therapy. These doses are not as high as those used for cancer.
In premenopausal women, thyroid hormone suppression does not cause any significant decrease in bone mineral density. On the other hand, bone loss is observed in postmenopausal women. The amount of bone loss is related to the number of years a person has been on suppressive thyroid hormone doses. This effect is not observed in women taking estrogen therapy. A few studies in men observed no effect of thyroid hormone on bone density.
PREVENTION AND TREATMENT OF THYROID HORMONE-ASSOCIATED BONE LOSS
The best approach is to prevent bone loss by identifying an overactive thyroid as early as possible and by taking the lowest possible thyroid hormone dose to maintain a normal range of TSH. Hyperthyroidism can adversely affect bone, and it is associated with higher risk of fracture in postmenopausal women. Therefore, assessment of bone mass is recommended for all hyperthyroid patients.
Thyroid hormone replacement that results in normal TSH levels has no effect on bone. Since maintaining normal TSH levels with this therapy does not have a significant negative effect on bone, recommendations for bone health and DXA screening follow those for the general population.
Thyroid hormone suppression of TSH for thyroid cancer, goiter, or nodules may have an adverse effect on bone that is greatest in postmenopausal women. Assessment of bone mass is recommended along with use of the lowest effective dose to minimize bone loss and fracture risk.
Adequate calcium intake and vitamin D supplementation are general measures for everyone. Estrogen therapy has fallen out of favor even though it can effectively protect postmenopausal women from thyroid hormone-associated bone loss. Bisphosphonates are the preferred choice if prescription treatment of low bone density is needed.
In summary, the harmful effects of excessive thyroid hormone on bone are observed only in postmenopausal women, not in premenopausal women or men even with suppressive doses. However, in postmenopausal women receiving both estrogen and thyroid hormone, bone appears to be protected. This does not mean that it is okay to take too much thyroid hormone as long as you are on estrogen therapy! Thyroid hormone has other possible harmful effects, especially on your heart. Also, keep in mind that these observations of estrogen therapy were done when estrogen was still “in vogue,” prior to the Women's Health Initiative findings. This brings me back to my “thyroid junkies.” The Rancho Bernardo research findings ultimately helped convince my patients to follow doctor's orders.
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The Bare Bones
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