Subclinical Hyperthyroidism Increases Risk of Hip and Other Fractures

Hip fractureSubclinical hyperthyroidism was associated with an increased risk of hip fracture and other fractures in an observational study involving data from more than 70,000 participants. The study, which was reported in the May 26 issue of JAMA, did not find a link between subclinical hypothyroidism and fracture risk.

“After several conflicting findings over these last years, our results from pooling individual participant data of all available prospective cohorts, show increased fracture risk in subclinical hyperthyroidism, with particularly higher risk for participants with TSH <0.10 mIU/L,” said senior author Nicolas Rodondi, MD, MAS, Head of Ambulatory Care, Department of General Internal Medicine, Inselspital, Bern University Hospital, Switzerland.

“There is a wealth of literature suggesting low bone density in patients with subclinical hyperthyroidism,” commented Douglas S. Ross, MD, Professor of Medicine, Harvard Medical School, and Co-Director, Thyroid Associates, Massachusetts General Hospital, Boston. “This study is important because it demonstrates an increase fracture risk, especially hip fracture. A randomized controlled trial that demonstrates reduced fracture rates with treatment is desperately needed,” Dr. Ross said. (See below for Dr. Ross’ full commentary on this study.)

Data Evaluated from Over 70,000 Patients
The authors evaluated data from 70,298 participants (age ≥18 years; median age, 64 years; 61% were women) enrolled in 13 prospective cohorts who were followed for a median of 12 years. Of these participants, 2,219 participants (3.2%) had subclinical hyperthyroidism (ie, thyroid-stimulating hormone [TSH] <0.45 mIU/L) and 4,098 (5.8%) had subclinical hypothyroidism (ie, TSH ≥ 4.50-19.99 mIU/L with normal thyroxine levels). The primary outcome was the risk of hip fracture.

Over 762,401 person-years of follow-up, 2,975 participants (4.6%) experienced hip fracture, 2,528 participants (9.0%) experienced any fracture, 2,018 participants (8.4%) experienced nonspine fracture, and 296 participants (1.3%) experienced spine fracture.

Fracture Risk Increased in Patients With Subclinical Hyperthyroidism
As shown in the Table, participants with subclinical hyperthyroidism were at increased risk for hip, spine, and other fractures compared with participants with normal TSH levels in age- and sex-adjusted analyses. The risk was greatest in patients with the lowest TSH levels (<0.10 mIU/L) and in participants whose subclinical hyperthyroidism was endogenous vs exogenous (eg, taking too much levothyroxine). For example, the hazard ratio for spine fracture in patients with a TSH <0.10 mIU/L was 3.57 and for patients with endogenous subclinical hyperthyroidism was 1.74Hazard ratio for fracture; hyperthyroidism“Our results are consistent with current guidelines recommending that treatment of subclinical hyperthyroidism should be strongly considered if TSH is persistently <0.1 mIU/L in all individuals ≥65 years old, and that treatment should also be considered if TSH is low but ≥0.1 mIU/L in individuals ≥65 years old,” Dr. Rodondi said.

“As there is currently no ongoing large trial on subclinical hyperthyroidism, we unfortunately have to rely on observational studies to decide on treatment of this condition,” Dr. Rodondi said. “Therefore, this study pooling and analyzing individual participant data of all available prospective cohorts represents the current best evidence on this association to guide clinical decisions,” he said.

Commentary by Douglas S. Ross, MD

Dr. Ross is Professor of Medicine, Harvard Medical School, and Co-Director, Thyroid Associates, Massachusetts General Hospital, Boston. Dr. Ross was a member of the American Thyroid Association/American Association of Clinical Endocrinologists Taskforce that developed the 2011 management guidelines on hyperthyroidism and other causes of thyrotoxicosis.

It is clear that overt hyperthyroidism is associated with fractures. In the early 20th century before anti-thyroid drugs were available to treat hyperthyroidism, long-bone fractures and rib fractures were common even in young patients with overt hyperthyroidism. Subclinical hyperthyroidism is defined biochemically as a subnormal TSH with normal levels of thyroid hormone. It represents very mild hyperthyroidism.

Numerous small studies have suggested reduced bone density associated with subclinical hyperthyroidism. A recent large population-based study found an increased risk of hip fracture associated with a low TSH in women, and the risk increased with the duration of hyperthyroidism.1 The current study in JAMA extracted participant data from 13 studies, with 70,298 participants, and compared 2,219 participants with subclinical hyperthyroidism to euthyroid individuals.2 The study confirmed a significant risk of hip fracture, as well as other fractures, especially among participants whose TSH values were less than 0.1 mIU/L or who had endogenous subclinical hyperthyroidism (ie, the hyperthyroidism was not due to exogenous ingestion of thyroid hormone).

These data support the recommendations that high-risk patients with subclinical hyperthyroidism receive treatment. Small non-controlled trials have shown improvement in bone density comparing treated to non-treated patients with endogenous subclinical hyperthyroidism. The authors of the JAMA article emphasized that randomized controlled trials assessing the benefits and risks of treatment are critically needed.

Subclinical hyperthyroidism has been traditionally divided into mild (TSH ≥ 0.1mIU/L), or more severe (TSH < 0.1 mIU/L) hyperthyroidism. Patients have been divided into high risk (elderly, underlying cardiac disease, osteoporosis, and postmenopausal women not taking estrogens or bisphosphonates) or low risk (younger patients without the preceding risk factors). The American Thyroid Association/American Association of Clinical Endocrinologists guidelines strongly suggest treatment in high-risk patients with TSH values under 0.1 mIU/L.3 This study confirms that those patients are at increased risk for hip and other fractures. Younger patients also were at risk, and this supports the guideline's suggestion that treatment be considered in low-risk patients with TSH under 0.1 mIU/L. The study also found an increased but smaller risk for TSH values between 0.1-0.45 mIU/L, but did not determine whether the risk differed in patients with underlying osteoporosis or other risk factors.

Until better data are available, especially results from randomized controlled treatment trials, controversy will remain as to whether low-risk patients with minimal subclinical hyperthyroidism require intervention. However, this study indirectly supports a more aggressive stance towards high-risk patients with minimal subclinical hyperthyroidism.

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