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Graves’ Disease and Bone Metabolism

Graves’ Disease and Bone Metabolism. Sun Wook Cho & Young Joo Park Department of Internal Medicine Seoul National University College of Medicine Seoul, Korea. Changes of Bone in Graves’ Patients. Untreated or persistent Graves’ Ds. Resorption > Formation. Normal → Osteopenia

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Graves’ Disease and Bone Metabolism

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  1. Graves’ Disease and Bone Metabolism Sun Wook Cho & Young Joo Park Department of Internal Medicine Seoul National University College of Medicine Seoul, Korea

  2. Changes of Bone in Graves’ Patients Untreated or persistent Graves’ Ds Resorption > Formation Normal → Osteopenia Osteporosis Fractures Increased bone turn-over

  3. BMD was low in Graves’ patients, especially more in aged over 50 or postmenopausal subjects - Studies in East-Asia - • Seoul National University Hospital, Korea J Clin Endocrinol Metab 1990;70:766–770 • Chang Gung Memorial Hospital, Taiwan Changgeng Yi XueZaZhi 1990;13:274-281 • University of Yamanashi Medical School, Japan Clin Endocrinol (Oxf). 1993 Mar;38(3):283-6 • Beijing TongrenHospital, China Zhonghua Yi XueZaZhi. 1998 Sep;78(9):682-4

  4. The decrement of BMD or the increment of fracture risk in Graves’ disease is larger in aged or postmenopausal subjects- A meta-analysis about the risk of osteoporosis in Graves’ patients - Bone mineral density (Z-score) Fracture risk (relative risk) Age (years) Age (years) Vestergaard & Mosekilde, Thyroid, 2003:13:585

  5. The decreased BMD or the increased fracture riskin Graves’ patients is normalized after treatment Bone mineral density (Z-score) Fracture risk (relative risk) Dx Dx Thyroid, 2002:12:585 ClinEndocrinol, 2004:61:466 A meta-analysis, Vestergaard& Mosekilde, Thyroid, 2003:13:585

  6. The increased risk of fracture persists for at least 3~5 years after initial diagnosis and treatment of Graves’ disease A large population-based study in Denmark Calcif Tissue Int 2005:77:139

  7. BMD was normalized in patients who reached euthyroid status after treatment, but decreased in persistently hyperthyroid patients Eu Hyper Oikawa, Hamamatsu University School of Medicine, Japan. ClinEndocrinol 1999:50:171

  8. What induces the changes of bone in thyroid disease? ? Both in osteoblasts & osteoclasts TSH Bone resorption > formation Normal → Osteopenia → Osteporosis Thyroid H Fractures

  9. Thyroid hormone (T3) increases both oesteoblastogenesis and osteoclastogenesis The osteoclastogenesis is greater than the osteoblastogenesis, and the uncoupling of osteoclast and osteoblast activities results in a ~10% net loss of bone per remodeling cycle Bone, 2008:43:418

  10. TSH itself may play a role in the preservation of bone • Positive association between serum TSH and BMD in euthyroid subjects : 2 large scaled cross sectional studies 3172 postmenopausal women Health Promotion Centre Asan Medical Centre, Korea 581 postmenopausal women Subsamples of National Health and Nutrition Examination Survey, NHANES III, US • Increased risk for fracture in women with low serum TSH levels 686 women older than 65 years of age from a cohort of 9704 women Study of Osteoporotic Fractures Research Group. US ClinEndocrinol 2006:64:86 Bone 2007:40:1128 Ann Intern Med 2001:134:561

  11. Hyperthyroid-associated osteoporosis can be exacerbated by the loss of TSH signaling TSHR-knockout mice have greater bone loss than wild-type mice with intact TSH signaling after thyroxine treatment, which induces hyperthyroid status. TSH inhibits osteoclastogenesis, while increases osteoblastogenesis in severalin vitro studies. WT TSHR KO Euthyroid >> Hyperthyroid >> J ClinInvest 2012

  12. Graves’ disease ; a condition of disruption of an inverse relationship between thyroid hormone and TSH  Thyroid hormone +  TSH +  TSHR stimulating Ab (TSAb) Is there any association between serum TSAb activities and serum osteoblastogenic or osteoclastogenic activities in Graves’ patients? Net TSH action may be increased Effects ? If TSH is an important negative regulator of bone remodeling, the presence of TSAb in Graves' disease would protect against bone loss! TSHR stimulating antibody Osteoblast & osteoclast

  13. A few studies has been reported about the association between TSAb and bone markers • Positive association between TSAb activities and urine N-telopeptide levels RakuwakaiOtowa Hospital, Japan, OsteoporosInt, 2006:17:1103 • The other few reports showed that TSAb or bone turn-over markers werenegatively association with BMD. • It is hard to discriminate the effects of TSAb from those of thyroid hormone on BMD. OsteoporosInt2006:17:1103 J Clin Endocrinol Metab 1990;70:766–770

  14. Study about an association between serum TSAb activities and serum bone markers • Subjects • 139 newly diagnosed Graves’ patients at SNUH • 127 patients had TSHR Ab with stimulating activity (TSAb) • 12 patients had TSHR Ab with blocking activity (TBAb) • Blocking activities were defined according to the clinical courses; spontaneously developed hypothyroid status with persistent high serumTBII levels. • Measurements • T3, free T4, TSH • TSAb : 1st generation TBII methods • Serum Bone-specific alkaline phosphatase(ALP), osteocalcin, C-telopeptide • PTH, Ca/P, Prot/alb, 25-OH Vit. D3

  15. Clinical characteristics and serum parameters related with bone metabolism in subgroups

  16. TSAb activities show a positive correlation with serum bone turnover markers independent of thyroid hormone levels TBII (%) : Stimulating  =0.184 P=0.038  =0.329 P<0.001  =0.305 P<0.001 Bone specific ALP Osteocalcin Serum C-telopeptide * P-value are from Partial correlation adjusting free T4 The correlation seems stronger in osteoblst makers than in osteoclast marker

  17. No correlation or borderline negative correlation between TSHR blocking antibody and serum bone turnover markers TBII (%) : Blocking  =-0.541 P=0.086  =0.253 P=0.453  =-0.555 P=0.076 Bone specific ALP Osteocalcin Serum C-telopeptide * P-value are from Partial correlation adjusting free T4

  18. Serum obsteoblastic activities were positively associated with TSAb activities in premenopausal female and male Graves’ patients Log-transformed value was used Correlation efficient (Pearson, Spearman); age, TSAb, T3, and FT4 were used for multivariate analysis. • The positive association suggests that TSAb may have osteoblastogenic effects. • TSAbhas little osteoblastogenic effects, thus little protective effects in postmenopausal women. • The difference of TSAb effects on osteoblast among subgroups could be a possible reason why the risk of osteoporosis is larger in postmenopausal women.

  19. How can the effects of thyroid hormone levels be excluded from the effects of TSAb on bone turn-over markers? • No association between thyroid hormone levels and TSAb

  20. The correlation of TSAb with bone turn-over markers are different from those of thyroid hormone levels • Different association with bone markers of TSAb with T3 or free T4

  21. Changes in boneturn-over markers during therapy for hyperthyroidism Osteoblast marker Osteoclast marker Relation between TSAb and osteoblast marker Osteoblast markers decreased very slowly contrast to the osteoclast marker Relation between T3 and osteoclast marker TSAb? Similar changes with osteoblast marker The changes of NTx are very similar to those of T3. 13 Graves’ patients, Greece, J Clin Endocrinol Metab 2000;85:1099

  22. Osteoclast marker is correlated with thyroid hormone levels, while osteoblat markers is more with TSAb activities TSAb shows a positive correlation with osteoblast markers T3 shows a positive correlation both with osteoclast marker and osteoblast marker

  23. The effects of TSAb on bone metabolism is not related with PTH, a osteoblastogenic factor • No correlation between TSAb and PTH • No correlation between PTH and bone turn-over markers Multivariate analysis: Age, TSI, T3, FT4, PTH is involved. * Log-transformed value was used.

  24. Summary • Serum TSAb activities were associated with an increased bone turn-over (osteoblastogenesis >> osteoclastogenesis), independent of thyroid hormone levels in Graves’ patients. • The TSAb-related increments of osteoblastic activities were observed in premenopausal women and men, but not in postmenopausal women. These findings might explain the lower BMD and the higher fracture risk in postmenopausal Graves’ women. • Even though a low TSH level may contribute to the bone loss of hyperthyroidism that has been attributed traditionally to high thyroid hormone levels, the presence of TSAbin Graves' disease would protect against bone loss.

  25. Is it real that TSH/TSAb can increase the osteoblastogenesis? Stimulation Inhibition No physiologic effect • Many controversies about the effects of TSH/TSAb on osteoblast! • Recent data strongly suggest a stimulatory effect JBMR, 2007:22:849 Wnt (LRP-5) and VEGF (Flk) signaling MolEndocrinol, 2008:22:501 Cell, 2003:115:151 Wnt5a PNAS, 2011:108:16277

  26. C3H10T1/2 cell

  27. The expression of ostoeblastogenic gene or osteoblastogenic activity was not increased by treatment of TSH or TSAb • Osteoblast marker gene ALP/GAPDH Osteocalcin/GAPDH Collagen type I /GAPDH Osteocalcin/GAPDH • Alkaline phosphatase (ALP) activity ALP activity  VEH VEH VEH TSH TSH TSH TSAb TSAb TSAb VEH VEH VEH TSH TSH TSH TSAb TSAb TSAb VEH VEH VEH VEH TSH TSAb VEH TSH TSAb osteogenic medium osteogenic medium osteogenic medium osteogenic medium

  28. Changes of the signals in ostogenic pathway after treatment of TSH/TSAb • No change in Wnt- catenin signals • Increased phosphorylation of ERK p-ERK β-Catenin γ-tubulin ERK VEH TSH TSAb VEH TSH TSAb γ-tubulin wnt3A VEH TSH TSAb • No change in BMP-Smad signals Smad γ-tubulin VEH TSH TSAb VEH TSH TSAb BMP

  29. The effects of TSH/TSAb on osteoclastogenesis Inhibition No physiologic effect JBMR, 2007:22:849 Cell, 2003:115:151 MolEndocrinol, 2008:22:501 PNAS 2006:103:12849 Thyroid, 2011:21:897

  30. Correlation in Graves’ patients : Osteoblastogenic effect > osteoclastogenenic effect TSAb Protective or compenstory effects Possible therapeutic application of TSHR analogues In vitro data : ? Osteoblastogenic effect, inhibitory effect on osteoclastogenesis

  31. Summary • Thyrotoxicosis is an established cause of high-bone-turnover osteoporosis, which results from a net increase in bone resorption. • In untreated Graves’ patients, BMD was decreased and the risk of fracture was increased, especially more in aged or postmenopausal subjects. • Treatment of Graves’ disease normalizes the levels of bone turnover markers rapidly, but the BMD after about 5 years. • Recent in vitro or animal studies suggest the osteoblastogenic or anti-osteoclastogenic effects of TSH, and as well as thyroid hormone, TSH or TSAb itself may be an important regulator of bone remodeling.

  32. Summary • There remains a concern about that therapeutic suppression of TSH to very low levels may contribute to bone loss in some peatients. • Serum TSAb activities are positively correlated with osteoblastic activities in premenopausal female or male Graves’ patients. • Even though a low TSH level and high thyroid hormone levels may contribute to the bone loss of hyperthyroidism, the presence of TSAbin Graves' disease would compensatory protect against bone loss. • These results implicate a possibe therapeutic application of TSH analogues for several diseases including osteoporosis.

  33. Acknowledgements • Prof. Bo Youn Cho • Prof. Jun-Key Chung • Sun Wook Cho, MD, PhD • Jae Hyun Bae, MD • Sun Kyeong Han, BS • Do Joon Park, MD, PhD • Ka Hee Yi, MD, PhD • Kyung Won Kim, MD, PhD • Jae Hoon Moon, MD, PhD • Hoon Sung Choi, MD, PhD • Jung-A Lim, MD, PhD

  34. Rev EndocrMetabDisord2010:11:219–227

  35. Correlation between thyroid hormone and serum bone turnover markers Free T4 =0.320 P<0.001 =0.006 P=0.941 =0.245 P=0.003 Bone specific ALP Osteocalcin Serum C-telopeptide T3 =0.363 P<0.001 =0.069 P=0.481 =0.325 P<0.001 Bone specific ALP Osteocalcin Serum C-telopeptide

  36. Serum parameters related with bone metabolism in the subjects • BS-ALP : men ≥25years 15.0-41.3 • C-telopeptide : men 30-50 years <0.584, 50-70 years <0.704, >70 years <0.854 • osteocalcin (ng/mL) ; 24–70 in men aged 18–30, 14–46 in men older than 30, 11–43 in premenopausal women ,15–46 in postmenopausal women

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