Subclinical hyperthyroidism may increase the risk of hip, spine, and other fractures, especially among those with low thyroid-stimulating-hormone (TSH) levels, according to a study published in the May 26 issue of the Journal of the American Medical Association.
The study included over 70,000 patients and is the largest study to date to examine possible links between subclinical hyperthyroidism and fracture risk in adults.
“[In our study], people with subclinical hyperthyroidism had an increased risk of all types of fractures, particularly when the TSH was very low [< 0.1 mIU/L], showing that subclinical hyperthyroidism is a risk factor for fractures,” commented senior author Nicolas Rodondi, MD, of the department of general internal medicine, Bern University Hospital, Switzerland.
Subclinical hyperthyroidism refers to abnormal TSH levels in a person without clinical symptoms and with normal free thyroxine. Thyroid function can affect fracture risk through direct effects of thyroid hormones on osteoclasts and osteoblasts, resulting in increased rates of bone turnover and bone loss. Moreover, the effects of hyperthyroidism on muscle strength and coordination may put these patients at increased risk for falls. Thyroxine medication may also play a role, the authors suggest.
While the link between overt hyperthyroidism and increased risk for osteoporosis and fractures has long been established, the associations between subclinical hyperthyroidism and fracture risk have been difficult to study. Currently, no randomized controlled trials are looking at this issue, and there is not likely to be one anytime soon, according to Dr Rodondi. Because of the rarity of subclinical hyperthyroidism, recruiting enough participants for a large trial poses a problem, he explained. In addition, patients usually receive prompt treatment once the condition is detected, which excludes these patients from trials.
Therefore, Dr Rodondi and colleagues performed a pooled analysis of large prospective cohort studies that looked at the association between thyroid function and fractures. They searched MEDLINE and EMBASE to identify articles published from inception to March 2015, regardless of language. They also manually searched bibliographies in key articles. They defined euthyroidism as TSH between 0.45 and 4.49 mIU/L, subclinical hyperthyroidism as TSH < 0.45 mIU/L with normal thyroxine levels, and subclinical hypothyroidism as TSH ≥ 4.50-19.99 mIU/L with normal thyroxine concentrations.
The authors identified prospective cohort studies from the United States, Europe, Australia, and Japan. The studies covered 70,298 participants (median age, 64 years; 61.3% women), of which 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism.
Compared with patients with euthyroidism, those with subclinical hyperthyroidism had an increased risk for fracture, after adjustment for age and sex.
Risk for Fracture for Subclinical Hyperthyroidism vs Euthyroidism
| Fracture Type | HR (95% CI) |
| Hip | 1.36 (1.13 – 1.64) |
| Any | 1.28 (1.06 – 1.53) |
| Nonspine | 1.16 (0.95 – 1.41) |
| Spine | 1.51 (0.93 – 2.45) |
Patients with a TSH below 0.10 mIU/L had the greatest risk for fractures.
Risk for Fracture With TSH < 0.10 mIU/L
| Fracture Type | HR (95% CI) |
| Hip | 1.61 (1.21 – 2.15) |
| Any | 1.98 (1.41 – 2.78) |
| Nonspine | 1.61 (0.96 – 2.71) |
| Spine | 3.57 (1.88 – 6.78) |
Patients with endogenous subclinical hyperthyroidism who were not on thyroid medication also had increased risk for fractures, except for nonspine fractures.
Risk for Fracture With Endogenous Subclinical Hyperthyroidism Not on Thyroid Medication
| Fracture Type | HR (95% CI) |
| Hip | 1.52 (1.19-1.93) |
| Any | 1.42 (1.16-1.74) |
| Spine | 1.74 (1.01-2.99) |
By contrast, the investigators found a low association between subclinical hypothyroidism and increased risk for fractures.
Risk for Fracture With Subclinical Hypothyroidism
| Fracture Type | HR (95% CI) |
| Hip | 0.96 (0.83 – 1.10) |
| Any | 1.02 (0.89 – 1.18) |
| Nonspine | 1.06 (0.90 – 1.24) |
| Spine | 0.96 (0.59 – 1.55) |
Dr Rodondi and colleagues noted that their results are “consistent” with current guidelines.
“The current guidelines recommend treating subclinical hyperthyroidism particularly if the TSH is below 0.1 mIU/L and particularly if the age of the patient is over 65, because these people are at increased risk for fractures, compared with younger people,” Dr Rodondi mentioned.
“Until this study, there were very little data to support the guidelines, particularly [concerning the] possible risk of fractures. This was not clear because of conflicting data,” Dr Rodondi continued. “Now we add, with our study, that there is an increased risk of fractures after pooling a large number of studies. So we move from having something like an expert opinion to having data to support the guidelines, although randomized trials are lacking.”
Dr Rodondi and colleagues emphasized the need for more studies to determine whether treating subclinical hyperthyroidism can decrease the risk for fractures.
Dr Rodondi reports receipt of funding for a randomized controlled trial on subclinical hypothyroidism (TRUST trial) from the European Commission. Disclosures for the coauthors are listed in the article.
— Veronica Hackethal, MD
