Abstract
Wang et al. (1) report a cohort study of patients who underwent thyroidectomy due to differentiated thyroid carcinoma. They conclude based on their data set that thyrotropin (TSH) suppression significantly increases the risk of postoperative osteoporosis without changing tumour recurrence in low- and intermediate-risk patients.
Although the number of patients is impressively large and the results are conclusively presented, we do not share their approach of the osteoporosis risk assessment. Although it was shown that age had a major impact, it remains unclear whether the density values were weight and height adjusted and how they where used to define osteoporosis according to a −2.5 T score threshold. Were these values measured on different densitometer units, and if yes, were they cross-calibrated? It is known that changes in body composition might affect the apparent density calculated by a DXA device. Such changes may occur in the course of thyroid-related metabolic changes in cancer patients. That would hamper the validity of the WHO score system, which is related to noncancer subjects.
It appears to us that no retrospective information is provided on assessment of bone density changes during the follow-up time of 6.5 years and the subsequent risk of bone fragility, which might define a higher risk of osteoporosis. The Supplementary Data S1 also do not really illuminate the definition of the osteoporosis risks in relation to density or architectural parameters. It is our understanding that the “risk” should rather be provided as bone density changes as assessed at the beginning and the end of the follow-up time. A density loss would be synonymous to an increased fragility.
Such considerations led us to a prospective cohort study (2), which was obviously not considered and discussed by the authors. The main aspect of our controlled study included baseline and one-year follow-up measurements to assess the changes in bone density and numerous other parameters during the study period. The reasons for our longitudinal design were limitations of several foregoing cross-sectional studies, which concluded similar findings as the ones reported by Wang et al. The follow-up time of 1.1 years in our study was powered to detect a 2% change of density parameters in relation to the precision of the devices at a significance level of 0.01, requiring a minimum of 23 participants per group.
Our results showed little evidence of adverse effects on bone due to TSH suppression by levothyroxine at the lumbar spine and the hip-bone density, as measured with DXA, neither during follow-up nor between patients and control groups. However, we found a risk of BMD reduction due to levothyroxine suppression therapy in women, as measured at the peripheral skeleton by pQCT. Yet, a longer follow-up might have been more conclusive either in confirming our observation or in resulting in a different outcome. The study of Wang et al. and our study did not assess all potentially bone relevant parameters, such as the vitamin D status. The vitamin D status was beyond the scope of our study. We also did not address adverse effects of levothyroxine suppression on cardiovascular outcomes.
It is difficult to compare the degree of TSH suppression in the patients studied by Wang et al., which were divided into two groups by a median TSH threshold, with ours, showing mean TSH values of 0.04 and 0.05 in men and women in comparison with controls, respectively. Our study was restricted to premenopausal women and to men of comparable age to exclude hormonal and/or ageing effects. We tried to evaluate clinical risk factors (CRFs) with tools provided by two systems, including the WHO-FRAX system and a German guideline system (3). There was a considerably divergent number of patients identified as treatment candidates. We concluded that our findings deserved further investigation of some CRFs. Moreover, our analysis revealed that a TSH level of <0.3 mIU/L as a clinical risk factor in one of the risk assessment models was particularly dominating the model without sufficient justification supported by the literature.
As suggested by Wang et al. and several other studies, suppression therapy can also have an impact beyond bone on patients at risk of cardiovascular disease. Therefore, we agree with the ATA recommendation 49 in cautioning against excessive suppression therapy in low- and intermediate-risk patients, as long as there are no prospective long-term studies existing to clarify this issue further.