Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Graves’ Disease and Bone Metabolism Sun Wook Cho & Young Joo Park Department of Internal Medicine Seoul National University College of Medicine Seoul,"— Presentation transcript:

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

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

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 - Vestergaard & Mosekilde, Thyroid, 2003:13:585 Bone mineral density (Z-score)Fracture risk (relative risk) Age (years)

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

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 Oikawa, Hamamatsu University School of Medicine, Japan. Clin Endocrinol 1999:50:171 Hyper Eu

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

9 Bone, 2008:43:418 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

10 TSH itself may play a role in the preservation of bone Bone 2007:40:1128 Clin Endocrinol 2006:64: postmenopausal women Health Promotion Centre Asan Medical Centre, Korea Positive association between serum TSH and BMD in euthyroid subjects : 2 large scaled cross sectional studies 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 Ann Intern Med 2001:134:561

11 Hyperthyroid-associated osteoporosis can be exacerbated by the loss of TSH signaling J Clin Invest 2012 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 several in vitro studies. >> WT TSHR KO Euthyroid Hyperthyroid

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

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

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 : 1 st generation TBII methods –Serum Bone-specific alkaline phosphatase(ALP), osteocalcin, C-telopeptide –PTH, Ca/P, Prot/alb, 25-OH Vit. D3

15 TBII with stimulating activity (TSAb) TBII with blocking activity Men Premenopausal women Postmenopausal women n (all female) Age (years)40±1232±956±646±14 T3 (ng/dl)395.9± ± ± ±122.7 Free T4 (ng/dl)3.17± ± ± ±0.93 TBII (%)48.2± ± ± ±22.0 Calcium (mg/dl)9.7±0.49.6±0.49.5±0.49.6±0.7 Phosphrous (mg/dl)4.3±1.14.4±1.04.6±0.54.2± OH Vit D3 (ng/ml)18.4± ± ± ±6.9 PTH (pg/ml)14.9± ± ± ±7.5 BS-ALP (U/L)59.4± ± ± ±15.7 Osteocalcin (ng/ml)54.0± ± ± ±18.5 C-telopeptide (ng/ml)0.87± ± ± ±13.29 Clinical characteristics and serum parameters related with bone metabolism in subgroups

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

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

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. Bone turn- over marker Men Premenopausal women Postmenopausal women Age40±12 yrs32±9 yrs56±6 yrs UnivariateMultivariateUnivariateMultivariateUnivariateMultivariate Bone specific ALP Osteocalcin C-telopeptide The positive association suggests that TSAb may have osteoblastogenic effects. TSAb has 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? TSAb Men Premenopausal women Postmenopausal women UnivariateMultivariateUnivariateMultivariateUnivariateMultivariate T FT 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 Men Premenopausal women Postmenopausal women TSAb UnivariateMultivariateUnivariateMultivariateUnivariateMultivariate Bone specific ALP Osteocalcin C-telopeptide T3 Bone specific ALP Osteocalcin C-telopeptide Free T4 Bone specific ALP Osteocalcin C-telopeptide

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

22 Osteoclast marker is correlated with thyroid hormone levels, while osteoblat markers is more with TSAb activities T3 Men Premenopausal women Postmenopausal women UnivariateMultivariateUnivariateMultivariateUnivariateMultivariate Bone specific ALP Osteocalcin C-telopeptide TSAb Men Premenopausal women Postmenopausal women UnivariateMultivariateUnivariateMultivariateUnivariateMultivariate Bone specific ALP Osteocalcin C-telopeptide TSAb shows a positive correlation with osteoblast markers T3 shows a positive correlation both with osteoclast marker and osteoblast marker

23 CalciumCorrected CaIntact PTH25OH-VitD3 TSAb Total Men PreMP women PostMP women PTH Men Premenopausal women Postmenopausal women UnivariateMultivariateUnivariateMultivariateUnivariateMultivariate Bone specific ALP Osteocalcin C-telopeptide Multivariate analysis: Age, TSI, T3, FT4, PTH is involved. * Log-transformed value was used. 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

24 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 TSAb in Graves' disease would protect against bone loss. Summary

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

26 C3H10T1/2 cell

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

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

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

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

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 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 TSAb in Graves' disease would compensatory protect against bone loss. These results implicate a possibe therapeutic application of TSH analogues for several diseases including osteoporosis. Summary

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

35 Rev Endocr Metab Disord 2010:11:219–227

36  =0.006 P=0.941  =0.245 P=0.003  =0.320 P<0.001  =0.069 P=0.481  =0.325 P<0.001  =0.363 P<0.001 Free T4 Serum C-telopeptideOsteocalcin Bone specific ALP T3 Serum C-telopeptide Osteocalcin Bone specific ALP Correlation between thyroid hormone and serum bone turnover markers

37 Stimulating activity Blocking activity Men Normal ref. PreMP women Normal ref. PostMP women Normal ref. Calcium (mg/dl)9.7 ± ± ± ±0.7 Phosphrous (mg/dl) 4.3 ± ± ± ±1.2 Adjusted-Ca9.5 ± ± ± ± OH Vit D3 (ng/ml) 18.4 ± ± ± ±6.9 PTH (pg/ml)14.9 ± ± ± ±7.5 BS-ALP (U/L)59.4 ± ± ± ±15.7 Osteocalcin (ng/ml) 54.0 ± ± ± ±18.5 C-telopeptide (ng/ml) 0.87 ±0.44 < ±0.35 < ±0.42 < ±13.29 BS-ALP : men ≥25years C-telopeptide : men years 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 Serum parameters related with bone metabolism in the subjects

38

39


Download ppt "Graves’ Disease and Bone Metabolism Sun Wook Cho & Young Joo Park Department of Internal Medicine Seoul National University College of Medicine Seoul,"

Similar presentations


Ads by Google