| Background & objectivePrevious results on the effects of levothyroxine(L-T4)suppression therapy on bone metabolism have been inconsistent.The purpose of this study was to investigate the potential effects of L-T4 supplementation or suppression therapy on bone mineral density and bone metabolism parameters in patients with thyroid disease and the timeeffect relationship,and then to investigate the effects of different concentrations of LT4 and TSH on osteoblast proliferation and differentiation ability.Methods(1)Clinical observation: A total of 40 patients with subclinical hypothyroidism,40 patients with differentiated thyroid carcinoma and 40 patients with benign thyroid nodules who visited the Endocrinology Clinic of the First Hospital of Lanzhou University from December 2017 to December 2019 were selected.The general data of patients in each group were collected in detail.Cubital venous blood was collected in the morning under fasting state to determine the levels of FT3,FT4,TSH,BALP,Ca,P,PTH,25-OHVD,BGP,PINP and other laboratory parameters.Lunar i DXA dualenergy X-ray absorptiometry was utilized to detect the bone mineral density of the anteroposterior lumbar spine(L1 ～ 4)and proximal femur of the patients.Patients with subclinical hypothyroidism were given individualized physiological doses of levothyroxine(12.5 to 50 μg/day)replacement therapy.Supra-physiological doses of levothyroxine(100 to 300 μg/day)and low doses of levothyroxine(25 to 100 μg/day)were given to patients with differentiated thyroid carcinoma and benign thyroid nodules,respectively.The above serological parameters and bone mineral density were also reexamined at 3,6,and 9 months after treatment.(2)Experimental part: Ten neonatal(< 24 h)SD rats were used to cut the calvaria for cell culture and osteoblast subculture.Different concentrations of L-T4(0,10,50,100,1000 μg/m L)and TSH(0,0.1,0.4,4.0,10,100 ng/ml)were added,respectively,and the changes of osteoblast proliferation ability treated with different concentrations of L-T4 and TSH were observed by MTT assay,and the activity of alkaline phosphatase was determined by mineralized nodule staining and PNPP assay to analyze the osteoblast differentiation ability.Statistical analysis was performed using SPSS 26.0software,respectively.Results(1)After L-T4 treatment,TSH levels in patients with subclinical hypothyroidism were normal at the 6th month,and the difference was statistically significant(p < 0.05);BGP gradually increased during treatment,and the difference was statistically significant(p < 0.05);however,there was no significant effect on the bone mineral density of L1 ～ L4 lumbar vertebrae and femur as a whole(p > 0.05).(2)After high-dose L-T4 treatment in postoperative patients with differentiated thyroid carcinoma,FT3 and FT4 showed a significant upward trend,with significant differences from those before treatment(p < 0.05);TSH levels were inhibited at 0.13 ±0.05 u IU/m L at 9 months,with p < 0.05 compared with those before treatment;osteogenic markers such as BALP,BGP and PINP continued to rise,with statistically significant differences(p < 0.05);in contrast,PTH showed a slow downward trend(p< 0.05).With prolonged treatment,both lumbar spine and total hip bone mineral density decreased from 6th month of treatment,and the decrease was significant at 9th month(p < 0.05),with a more significant decrease in bone mineral density at the hip than at the lumbar spine(0.074 vs 0.134).(3)TSH in patients with benign thyroid nodules was successfully inhibited at a lower level within the normal range at the 9th month,with a statistically significant difference compared with that before treatment(p < 0.05);BGP also gradually and slowly increased within the normal range,with a statistically significant difference(p< 0.05);Similarly,PINP level also increased significantly,with a statistically significant difference(p < 0.05).Exogenous L-T4 had no significant effect on lumbar and femoral bone mineral density during treatment(p > 0.05).(4)In the L-T4 intervention group,the proliferation promotion rate and differentiation promotion rate of osteoblasts gradually increased with the increase of LT4 concentration,and the proliferation promotion rate and differentiation promotion rate of osteoblasts were the highest in the 100 μg/m L group,and then showed a gradually decreasing trend with the increase of L-T4 concentration.(5)In the TSH intervention group,the osteoblast proliferation promotion rate and differentiation promotion rate also showed a dose-dependent increase,reaching the highest point when the TSH concentration was 4 ng/m L,and then although the TSH concentration increased,the osteoblast proliferation promotion rate and differentiation promotion rate did not increase significantly.Conclusion(1)Clinical observation reveals that physiological doses of L-T4 can be safely used in patients with thyroid nodules and subclinical hypothyroidism without significant effects on bone mineral density.When TSH-suppressive therapy for differentiated thyroid carcinoma is performed,supraphysiological doses of L-T4 accelerate the rate of bone turnover and reduce bone mineral density.It is suggested that the changes of bone mineral density should be monitored during the follow-up of the diseases,and timely intervention should be performed to prevent the occurrence of osteoporosis and even fracture.(2)The experiment results showed that exogenous L-T4 was positively correlated with osteoblast proliferation and differentiation in a certain concentration range(0 ～100 μg/m L),and the effect of L-T4 > 100 μg/m L on osteoblasts was reduced.TSH was positively correlated with osteoblast proliferation and differentiation within a certain concentration range(0 ～ 4 ng/m L),and TSH > 4 ng/m L was shown to reduce the proliferation and differentiation ability of osteoblasts.Changes in L-T4 and TSH concentrations may affect the proliferation and differentiation of osteoblasts leading to changes in bone metabolism. |
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