Graves’ Disease and Bone Metabolism Sun Wook Cho & Young Joo Park Department of Internal Medicine...

Graves’ Disease and Bone Metabolism

Sun Wook Cho & Young Joo Park

Department of Internal Medicine

Seoul National University College of Medicine

Seoul, Korea

Untreated or persistentGraves’ Ds

Increasedbone turn-over

Fractures

Normal → Osteopenia Osteporosis

Changes of Bone in Graves’ Patients

Resorption > Formation

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;13:274-281• Chang Gung Memorial Hospital, Taiwan

• University of Yamanashi Medical School, Japan

Zhonghua Yi Xue Za Zhi. 1998 Sep;78(9):682-4• Beijing Tongren Hospital, China

Clin Endocrinol (Oxf). 1993 Mar;38(3):283-6

The decrement of BMD or the increment of fracture risk in Graves’ disease is larger in aged or post-

menopausal 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) Age (years)

The decreased BMD or the increased fracture riskin 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 Dx

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 DenmarkCalcif Tissue Int 2005:77:139

BMD was normalized in patients who reached euthyroid sta-tus after treatment, but decreased in persistently hyperthy-

roid patients

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

Hyper

Eu

Bone resorption > formationNormal → Osteopenia → Osteporosis

What induces the changes of bone in thyroid disease?

?TSH

Thyroid H Fractures

Both in osteoblasts & osteoclasts

Bone, 2008:43:418

Thyroid hormone (T3) increases both oesteoblasto-genesis and osteoclastogenesis

The osteoclastogenesis is greater than the osteoblastogenesis, and the uncoupling of osteoclast and osteoblast activitiesresults in a ~10% net loss of bone per remodeling cycle

TSH itself may play a role in the preservation of bone

Bone 2007:40:1128Clin Endocrinol 2006:64:86

3172 postmenopausal womenHealth Promotion CentreAsan Medical Centre, Korea

• Positive association between serum TSH and BMD in euthyroid sub-jects : 2 large scaled cross sectional studies

581 postmenopausal womenSubsamples of National Health and Nutrition Exam-ination 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 womenStudy of Osteoporotic Fractures Research Group. US Ann Intern Med 2001:134:561

Hyperthyroid-associated osteoporosis can be exacer-bated by the loss of TSH signaling

J Clin Invest 2012

TSHR-knockout mice have greater bone loss than wild-type mice with in-tact 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

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

stimulatingantibody

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 os-teoblastogenic or osteoclastogenic ac-

tivities in Graves’ patients?

Rakuwakai Otowa Hospital, Japan, Osteoporos Int, 2006:17:1103

• Positive association between TSAb activities and urine N-telopeptide levels

J Clin Endocrinol Metab1990;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 associa-tion between TSAb and bone markers

Study about an association between serum TSAb activ-ities 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; sponta-

neously developed hypothyroid status with persistent high serumTBII levels.

• Measurements– T3, free T4, TSH– TSAb : 1st generation TBII methods– Serum Bone-specific alkaline phosphatase(ALP), osteocal-

cin, C-telopeptide– PTH, Ca/P, Prot/alb, 25-OH Vit. D3

TBII with stimulating activity (TSAb)TBII with block-

ing activityMen Premenopausal women

Postmenopausal women

n 25 83 19 12 (all female)

Age (years) 40±12 32±9 56±6 46±14

T3 (ng/dl) 395.9±205.1 430.9±183.0 343.4±123.8 209.7±122.7

Free T4 (ng/dl) 3.17±1.09 3.63±1.54 3.08±1.02 1.56±0.93

TBII (%) 48.2±25.6 53.7±23.5 41.3±24.6 75.0±22.0

Calcium (mg/dl) 9.7±0.4 9.6±0.4 9.5±0.4 9.6±0.7

Phosphrous (mg/dl) 4.3±1.1 4.4±1.0 4.6±0.5 4.2±1.2

25-OH Vit D3 (ng/ml) 18.4±10.8 16.7±8.7 17.3±9.0 17.0±6.9

PTH (pg/ml) 14.9±8.2 12.8±7.9 15.8±6.7 14.3±7.5

BS-ALP (U/L) 59.4±28.7 58.2±27.2 67.7±33.7 41.2±15.7

Osteocalcin (ng/ml) 54.0±29.5 45.9±19.6 41.1±27.4 31.8±18.5

C-telopeptide (ng/ml) 0.87±0.44 0.78±0.35 0.85±0.42 4.22±13.29

Clinical characteristics and serum parameters related with bone metabolism in subgroups

TB

II (%

) :

Sti

mu

lati

ng

=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-telopeptideOsteocalcinBone specific ALP

TSAb activities show a positive correlation with serum bone turnover markers indepen-

dent of thyroid hormone levels

The correlation seems stronger in osteoblst makers than in osteoclast marker

* P-value are from Partial correlation adjusting free T4


=0.253 P=0.453

=-0.541 P=0.086

=-0.555 P=0.076

TB

II (%

) :

Blo

ckin

g

No correlation or borderline negative correla-tion between TSHR blocking antibody and

serum bone turnover markers

Serum obsteoblastic activities were positively associated with TSAb activities in premenopausal female and male

Graves’ patients

Log-transformed value was usedCorrelation efficient (Pearson, Spearman); age, TSAb, T3, and FT4 were used for multivariate analysis.

Bone turn-over

markerMen

Premenopausal women

Postmenopausal women

Age 40±12 yrs 32±9 yrs 56±6 yrs

Univariate Multivariate Univariate Multivariate Univariate Multivariate

Bone specific ALP 0.360 0.491 0.313 0.362 0.259 0.376

Osteocalcin 0.466 0.680 0.296 0.443 0.380 0.380

C-telopeptide 0.348 0.348 0.107 0.392 0.082 0.469

• The positive association suggests that TSAb may have osteoblastogenic ef-fects.

• TSAb has little osteoblastogenic effects, thus little protective effects in post-menopausal women.

• The difference of TSAb effects on osteoblast among subgroups could be a pos-sible reason why the risk of osteoporosis is larger in postmenopausal women.

How can the effects of thyroid hormone levels be excluded from the effects of TSAb on bone

turn-over markers?

TSAb MenPremenopausal

womenPostmenopausal

women


T3 0.392 0.392 0.339 0.427 0.173 0.173

FT4 0.192 0.027 -0.006 0.427 0.152 0.173

• No association between thyroid hormone levels and TSAb

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

MenPremenopausal

womenPostmenopausal

women

TSAb Univariate Multivariate Univariate Multivariate Univariate Multivariate


Osteocalcin 0.466 0.680 0.296 0.443 0.380 0.380

C-telopeptide 0.348 0.348 0.107 0.392 0.082 0.469

T3


Osteocalcin 0.381 0.006 0.410 0.401 0.027 0.055

C-telopeptide 0.279 0.033 0.388 0.388 0.072 0.145

Free T4


Osteocalcin 0.100 0.008 0.177 0.003 0.200 0.014

C-telopeptide 0.177 0.001 0.246 0.001 0.236 0.236

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

Osteoclast marker is correlated with thyroid hormone levels, while osteoblat markers is more with TSAb activities

T3 MenPremenopausal

womenPostmenopausal

women



Osteocalcin 0.381 0.006 0.410 0.401 0.027 0.055

C-telopeptide 0.279 0.033 0.388 0.388 0.072 0.145

TSAb MenPremenopausal

womenPostmenopausal

women



Osteocalcin 0.466 0.680 0.296 0.443 0.380 0.380

C-telopeptide 0.348 0.348 0.107 0.392 0.082 0.469

TSAb shows a positive correlation with osteoblast markers

T3 shows a positive correlation both with osteoclast marker and osteoblast marker

Calcium Corrected Ca Intact PTH 25OH-VitD3

TSAb

Total 0.041 -0.046 0.057 0.166

Men 0.100 -0.189 0.031 0.037

PreMP women 0.060 0.090 0.113 0.211

PostMP women -0.179 -0.103 0.062 0.230

PTH MenPremenopausal

womenPostmenopausal

women



Osteocalcin 0.087 0.050 0.130 0.117 0.322 0.367

C-telopeptide 0.919 0.932 0.732 0.634 0.328 0.241

Multivariate analysis: Age, TSI, T3, FT4, PTH is in-volved.

* Log-transformed value was used.

The effects of TSAb on bone metabolism is not re-lated with PTH, a osteoblastogenic factor

• No correlation between TSAb and PTH

• No correlation between PTH and bone turn-over markers

• Serum TSAb activities were associated with an increased bone

turn-over (osteoblastogenesis >> osteoclastogenesis), indepen-

dent of thyroid hormone levels in Graves’ patients.

• The TSAb-related increments of osteoblastic activities were ob-

served in premenopausal women and men, but not in post-

menopausal 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 thy-

roid hormone levels, the presence of TSAb in Graves' disease

would protect against bone loss.

Summary

Inhibition No physiologic effect Stimulation

Cell, 2003:115:151

JBMR, 2007:22:849Mol Endocrinol, 2008:22:501

Is it real that TSH/TSAb can increase the os-teoblastogenesis?

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

C3H10T1/2 cell

ALP/GAPDH

Ost

eo

calc

in/G

AP

DH

• Osteoblast marker gene

VEHTSH

TSAbVEH

TSHTSAb

VEH

osteogenic medium

VEHTSH

TSAbVEH

TSHTSAb

VEH

osteogenic medium

VEHTSH

TSAbVEH

TSHTSAb

VEH

osteogenic medium

Osteocalcin/GAPDH Collagen type I /GAPDH

• Alkaline phosphatase (ALP) activity

none TSH M22 OM OM (+) TSH

OM (+) M22

0

0.1

0.2

0.3

0.4

0.5

0.6

AL

P a

ctiv

ity

VEH TSH TSAb VEH TSH TSAb

osteogenic medium

The expression of ostoeblastogenic gene or osteoblas-togenic activity was not increased by treatment of

TSH or TSAb

β-Catenin

γ-tubulin

γ-tubulin

Smad

VEHTSH

TSAbVEH

TSHTSAb

wnt3A

VEHTSH

TSAbVEH

TSHTSAb

BMP

• No change in Wnt- catenin signals

• No change in BMP-Smad signals

p-ERK

γ-tubulin

ERK

VEHTSH

TSAb

• Increased phosphorylation of ERK

Changes of the signals in ostogenic pathway after treatment of TSH/TSAb

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

TSAb Protective or compenstory effects

Correlation in Graves’ patients :Osteoblastogenic effect > osteoclastogenenic effect

In vitro data :? Osteoblastogenic effect, inhibitory effect on osteoclastogenesis

Possible therapeutic applicationof TSHR analogues

Summary

• Thyrotoxicosis is an established cause of high-bone-turnover osteoporosis, which results from a net increase in bone re-sorption.

• 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.

• 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 os-teoblastic 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 pres-ence 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

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

Rev Endocr Metab Disord 2010:11:219–227

=0.006P=0.941

=0.245P=0.003

=0.320P<0.001

=0.069P=0.481

=0.325P<0.001

=0.363P<0.001

Fre

e T

4


T3


Correlation between thyroid hormone and serum bone turnover markers

Stimulating activityBlocking activityMen Normal

ref.PreMPwomen

Normal ref.

PostMPwomen

Normal ref.

Calcium (mg/dl)

9.7±0.4 8.8-10.5 9.6±0.4 9.5±0.4 9.6±0.7

Phosphrous (mg/dl)

4.3±1.1 2.5-4.5 4.4±1.0 4.6±0.5 4.2±1.2

Adjusted-Ca 9.5±1.4 9.8±0.4 9.7±0.4 9.6±0.7

25-OH Vit D3 (ng/ml)

18.4±10.8

9.0-37.6 16.7±8.717.3±9.

017.0±6.9

PTH (pg/ml) 14.9±8.2 10-66 12.8±7.915.8±6.

714.3±7.5

BS-ALP (U/L)59.4±28.

715.0-41.3

58.2±27.2

11.6-29.6

67.7±33.7

14.2-42.7

41.2±15.7

Osteocalcin (ng/ml)

54.0±29.5

14-4645.9±19.

611-43

41.1±27.4

15-49 31.8±18.5

C-telopeptide (ng/ml)

0.87±0.44

<0.5840.78±0.3

5<0.573

0.85±0.42

<1.0084.22±13.2

9• 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 pre-

menopausal women ,15–46 in postmenopausal women

Serum parameters related with bone metabo-lism in the subjects

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Graves’ Disease and Bone Metabolism Sun Wook Cho & Young Joo Park Department of Internal Medicine...

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