Resistance to thyroid hormone due to mutations in the THRB gene impairs bone mass and affects calcium and phosphorus homeostasis.

CONTEXT: Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone, which is usually due to mutations in the thyroid hormone receptor ß gene (THRB). Few studies have been conducted to investigate bone and mineral metabolism in RTH. OBJECTIVE: The objective of the study was to evaluate the clinical and biochemical parameters related to bone and mineral metabolism in RTH due to mutations in the THRB gene (RTHß). DESIGN AND PARTICIPANTS: We conducted a cross-sectional study on 14 patients with RTHß (RTHG), eight adults and six children, and 24 control subjects (CG). OUTCOMES: Serum measures included total calcium (TCa), inorganic phosphate (iP), alkaline phosphatase (AP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), osteocalcin (OC), carboxyterminal telopeptide (CTX), and fibroblast growth factor 23 (FGF-23). We estimated the renal threshold phosphate concentration (TmPO4/GFR) and assessed bone mass using dual X-ray absorptiometry. RESULTS: Adults and children with RTH showed higher serum levels of TCa than controls (P=.029 and, P=.018 respectively). However, only children with RTH exhibited lower serum levels of iP than controls (P=.048). FGF-23 was higher in RTHß children (P=.04). RTHß adults had lower whole-body (P=.01) and lumbar spine (P=.01) bone mineral density than control subjects. The same pattern was observed when the results were expressed as Z-scores between groups, with a lower value in RTHG than in CG for the lumbar spine of adults (P=.03). No difference was observed between groups in PTH, 25OHD, AP, OC, and CTX. CONCLUSION: Biochemical abnormalities are seen in children with RTH (Low iP, high FGF23), while high calcium (with normal UCa) is seen in RTH subjects of all ages, and later on, in adult life, low BMD is seen. Considering that the TRα1 isoform is the predominant TR in the skeleton, we hypothesize that probably these patients may exhibit enhanced calcium flux from bone to circulation. Our data represent a challenge for new studies to unveil the control of calcium and phosphorus homeostasis and fracture risk in these patients.