Endocrine PEndocrine PPhysiology ofPhysiology of Bone and ...of Endocrinologyof Endocrinology 5, 2010. Outline o ... more parathyroid gland Primary Hyperparathyr with hypercalcemia

Endocrine PEndocrine PBone and Calc

John P. BileProfessor of Medicin

Chief Division oChief, Division oMarch 1

Physiology ofPhysiology of cium Disorders

ezikian, M.D.e and Pharmacology

of Endocrinologyof Endocrinology15, 2010

Outline oOutline o

• Normal calcium ho• Normal calcium ho• Useful indices of c• Hypercalcemia• Hypocalcemiayp• Osteoporosis

of Lectureof Lecture

omeostasisomeostasiscalcium metabolism

Two Major Calcium-R

• Parathyroid

• 1,25-dihydro

Regulating Hormones

d hormone

oxyvitamin D

Regulation of Para

• Ionized cal

•• 1,251,25--dihydrdihydr

athyroid Hormone

cium

roxyvitamin Droxyvitamin D

The Calcium-Se••Type I ligands:Type I ligands:

Direct receptor bindingDirect receptor binding

P1 2 3 4

ensing ReceptorNH2

SP

HS

outside••Type II ligands:Type II ligands:

P

PP

inside5 6 7

yp gyp gallosteric allosteric

modulationmodulation

P

HOOC

Ca2+Ca2+

Regulation of Para

• Ionized cal

• 1,25-dihydr

athyroid Hormone

cium

roxyvitamin D

Major Functions of P

• Regulation of serum c

B d li• Bone remodeling

• Regulation of 1 25 dih• Regulation of 1,25-dih

Parathyroid Hormone

calcium and phosphate

hydroxyvitamin D levelshydroxyvitamin D levels

Two Major Calcium-R

• Parathyroid

• 1,25-dihydr

Regulating Hormones

d hormone

roxyvitamin D

Major Functions of 1,2

•• GI absorption of caGI absorption of ca

•• Bone remodelingBone remodeling

• Regulation of parat

25-dihydroxyvitamin D

alcium and phosphatealcium and phosphate

thyroid hormone

Relationship between 25Relationship between 25--hyhy

Thomas MKThomas MK

ydroxyvitamin D and PTHydroxyvitamin D and PTH

K et al. N Eng J Med 1998;338:778K et al. N Eng J Med 1998;338:778--783783

HOW PTH AND 1,25(OHTO CONTROL THE SERUM C

H)2D WORK TOGETHERCALCIUM CONCENTRATION

Other Circulating HorBone MeBone Me

• Parathyroid hormone • 1,25 (OH)2 vitamin D• Gonadal steroids (estro• Corticosteroids• Thyroid hormone• Growth hormone

rmones that Influence etabolismetabolism

ogens and androgens)

Local Regulators o

• IGFs and IGF binding p• IGFs and IGF binding p• TGF-β• Bone morphogenic pro• Bone morphogenic pro• Platelet-derived growth

growth factorgrowth factor• Prostaglandins• Interleukins (IL 1 IL 6)• Interleukins (IL-1, IL-6)• RANKL/osteoprotegeri

Raisz LG. Clin Chem 1999;45:1353-8.

of Bone Metabolism

proteinsproteins

oteinoteinh factor, fibroblast

))n

Outline oOutline o




Useful indices of caas gleaned from the mu

“THE HOLY TRINI“THE HOLY TRINICalciumCalciumCalciumCalciumPhosphorousPhosphorousAlkaline phosphaAlkaline phospha

alcium metabolism ultichannel autoanalyzer

ITY”ITY”

ataseatase

4.0

Useful Indices of ca

• Calcium phosphorus• Calcium, phosphorus• Dynamic markers of

Bone formation Bone resorptionp

alcium metabolism

ssbone metabolism

Bone turnover in tBone turnover in t

Resorpt

Revers

Formati

Activation

Formati

Resting phFROM: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism; 2nd Ed.

the adult skeletonthe adult skeleton

ion

sal

ionion

hase

Useful indices of cabiochemical marke

Bone resorptionN telopeptide (NTx)• N-telopeptide (NTx)

• C-telopeptide (CTx)• Deoxypyridinoline (free, total)

alcium metabolism: ers of bone turnover

Bone formationBone specific alkaline • Bone-specific alkaline phosphatase

• Osteocalcin• Propeptides type I collagen (P1NP)

1. Sornay-Rendu E. J Bone Miner Res. 2005;20:1813-19.


• Calcium phosphorus• Calcium, phosphorus• Dynamic markers of b• Calciotropic hormone• Calciotropic hormone

– Parathyroid hormone– Vitamin DVitamin D

• 25-hydroxyvitamin • 1,25-dihydroxyvitamin

alcium metabolism

ssbone metabolismeses

DD

Storage form: inStorage form: insufficiency or

ndex of vitamin Dndex of vitamin D r insufficiency

VITAMIN D DEFICIENCY IN M

Thomas MK et al.

MEDICAL INPATIENTS

N Eng J Med 1998;338:778-783


• Calcium phosphor• Calcium, phosphor• Dynamic markers o

t b limetabolism• Calciotropic hormo• Measurement of bo

alcium metabolism

rusrusof bone

onesone mass

REDUCED BONERISK FACTOR F

E MASS IS A KEY FOR FRACTURE

Relationship BetFracture Risk in U

R d d b

30

35Reduced bone

risk factor for the

15

20

25

Relative Risk

of 2 x

0

5

10ofFracture

-1SD

2 x

-5 -4 -3 -2

Bone dens

tween BMD and ntreated Patients

i ke mass is a key

e fragility fracture

2 -1 0

sity (SD units)

Dual Energy X-Ray A

Hologic

Absorptiometry (DXA)

GE Lunar

Features of bone deFeatures of bone de(dual energy X-ray

• Safe• Accurate• Accurate• Precise• Normative popu• Correlates with • A diagnostic staosteoporosisosteoporosis

ensitometry by DXAensitometry by DXAy absorptiometry)

ulation databases fracture riskandard for

Bone loss as a fBone loss as a f

1

0

-11

-2

3ore

-3

-4T= -2.5T-

sco

20 25 30 35 40 45 50

-5

-6

Faulkner KG, et al. J Clin Densitom 1999;2:343-50.

20 25 30 35 40 45 50

function of age function of age gg

PA spinePA spinePA spinePA spine

55 60 65 70 75 80 85 90 9555 60 65 70 75 80 85 90 95

Age

Referents for of bone mass mof bone mass m

• Z score:: a measure• Z-score: : a measure standard deviations frosex-matched cohortssex matched cohorts

T score• T-score: : a measure ostandard deviations frobone mass (25-30 yeabone mass (25-30 yea

comparisons measurementsmeasurements

of bone density inof bone density in om normal age- and

f b d it iof bone density in om cohorts at peak rs old)rs old)

BMD gm/cm2 Spine: L1-

1 20

1.32

T1.20

1.08Z0.96

0 84T= - 2 Z= - 0.5

0.84

0.72

20 40 6

Age

T-Score-L4

+1

0

-1

-2

3-3

-4

60 80 100

e

Diagnosticg

T-SC

c Standard

CORE

Interpreting T-scores (Wo

Correlates with life time fract

OsteoporosisLow

Bone M(Osteop

--4.0 -3.5 -3.0 -2.5 -2.0

T-

orld Health Organization)

ture risk for Caucasian Women

Normal Bone Mass

w Masspenia)

-1.5 -1.0 -0.5 0 +0.5 +1.0

score

Outline oOutline o




CAUSES OF HY

• Primary H h idiHyperparathyroidism

• Malignancy• Other endocrinopathy

HyperthyroidismHyperthyroidismPheochromocytomaVIPomaAdrenal insufficiency

• Medications• Medicationslithiumthiazide diureticsthyroid hormone Vitamin AVitamin AVitamin D

YPERCALCEMIA

• Vitamin DToxicityGranulomatous disease

– Tuberculosis– Sarcoidosis– Any other

• Lymphomay p• FHH• Immobilization• Acute or chronic renal cute o c o c e a

disease

MAJOR CAUSES O

# OF PATI# OF PATI# OF PATI# OF PATI

Primary H th idi

111Hyperparathyroidism

Malignancy 7272

Others (sarcoid, thyroid, vit D, etc

12

Unknown 12

OF HYPERCALCEMIA(From Mundy and Martin)(From Mundy and Martin)

IENTSIENTS % OF TOTAL% OF TOTALIENTSIENTS % OF TOTAL% OF TOTAL

1 54

22 3535

2 6

2 6

PRIMARY HYPERPPRIMARY HYPERP

A common endocrine dA common endocrine dby incompletely regulatsecretion of parathyroidp ymore parathyroid gland

Primary Hyperparathyrwith hypercalcemia andparathyroid hormone.

PARATHYROIDISMPARATHYROIDISM

disorder characterizeddisorder characterized ted, excessive d hormone from one or ds.

roidism is associated d elevated levels of

Human ParathyHuman Parathy

GluSer1

Ser Val Ile Gln LH N GluSer

20

Ser Val Ile Gln L

ASerMetGluArgValGluTrp

H2N

30

TrpLeu

Arg Lys Lys Leu Gln Asp V

yroid Hormoneyroid Hormone

His10

Leu Met AsnHis

Gly

Leu Met AsnLeu

LysHisLeuAsnGly

Val His Asn Phe

-COOH

Hypoparathyroidism

PRIMARY HYPERPPRIMARY HYPERP

Before 1970: A disand g

PARATHYROIDISMPARATHYROIDISM

ease of bone, stones, groans

Emergence of the Moof Primary Hypeof Primary Hype

Cope et al.Cope et al. Heath e19301930--19651965 1965-19

NephrolithiasisNephrolithiasis 57%57% 51%51%

HypercalciuriaHypercalciuria Not Not reportedreported

36%36%reportedreported

Overt Skeletal Overt Skeletal DiseaseDisease

23%23% 10%10%DiseaseDisease

AsymptomaticAsymptomatic 0.6%0.6% 18%18%

odern Clinical Profile erparathyroidismerparathyroidism

et al. Mallette et Silverberg, 974 al.

1965-1974Bilezikian et al.1984-2010

%% 37%37% 17%17%

%% 40%40% 39%39%

%% 14%14% 1.4%1.4%

%% 22%22% 80%80%

Biochemical andBiochemical andBiochemical and Biochemical and in Primary Hypein Primary Hype

Index Pa

•• Calcium (mg/dl)Calcium (mg/dl) 1010•• Phosphorus (mg/dl)Phosphorus (mg/dl) 2.2.•• Alk Phos (IU/l)Alk Phos (IU/l) 1111•• PTH (pg/ml)PTH (pg/ml) 1212•• 2525--OH Vit D (ng/ml)OH Vit D (ng/ml) 22•• 1 251 25 OHOH Vit D (pg/ml) 5•• 1,251,25--OHOH2 2 Vit D (pg/ml) 5• Urinary calcium (mg) 24•• DPD (nmol/mmol Cr)DPD (nmol/mmol Cr)DPD (nmol/mmol Cr)DPD (nmol/mmol Cr)

hormonal profilehormonal profilehormonal profile hormonal profile erparathyroidism erparathyroidism

atients nl range

0.70.7±±0.10.1 8.48.4--10.210.2.9.9±±0.10.1 2.52.5--4.54.51414±±44 <100<1002121±±77 1010--65652121±±11 99--525259±2 15 6059±2 15-6048 + 12 250-3001717 ++ 66 44--212117 17 66 44 2121

PRIMARY HYPERPPRIMARY HYPERPPRIMARY HYPERPPRIMARY HYPERP

Before 1970: A disease o

Since 1970: A disease p(i d l i ) d d(increased calcium) and deindices

PARATHYROIDISMPARATHYROIDISMPARATHYROIDISMPARATHYROIDISM

of bone, stones, and groans

primarily of biochemical it t i (b DXA)ensitometric (by DXA)

BONE MASS MEAPRIMARY HYPERP

ASUREMENTS IN PARATHYROIDISM

Bone and stone dBone and stone dhyperparathyroid

Mallette, BilezikHeath & Aurbach

1965-1972n=57

Nephrolithiasis Nephrolithiasis 37%37%

Bone disease 14%(Radiological)

isease in primaryisease in primary dism: 1965-2010

kian Silverberg, h Bilezikian et al.

1984-2010n=121n=121

17%17%

1.4%

BMD in PostmenopBMD in PostmenopPrimary HyperpPrimary HyperpPrimary HyperpPrimary Hyperp

100

sity:

d

*

90

iner

al De

nsf E

xpec

ted

80

Bone

Mi

% o

f

70Lumbar Spine

Silverberg, Bilezikian et al.Silverberg, Bilezikian et al.JBMR, 1989JBMR, 1989

pausal Women With pausal Women With parathyroidismparathyroidismparathyroidismparathyroidism

** Differs from radius,p<.05

Femoral Neck Radius

Normal Bone

Cancellous

Skeletal Site Cancellous CorticalSkeletal Site Cancellous CorticalLumbar spineT t l Hi

*****

***Total HipFemoral neckRadius (1/3 site) *

****

***Radius (1/3 site) * ***

Cortical

Densitometric and Densitometric and Characteristics oCharacteristics oCharacteristics oCharacteristics o

HyperparaHyperpara

• Cancellous bone (lu(relatively well preser

• Cortical bone (distal preferentially affectepreferentially affecte

Histomorphometic Histomorphometic of Bone in Primaryof Bone in Primaryof Bone in Primary of Bone in Primary athyroidismathyroidism

mbar spine): p )rved

radius): ed (i e reduced)ed (i.e. reduced)

TO CUT ITTO LEAVTO LEAV

A key clinicaP im H pPrimary Hyper

T OUT OR VE IT INVE IT IN…

al dilemma in p th idi mrparathyroidism

Guidelines for Pa(Bilezikian et al., 3rd In

J Clin Endocri

• Hypercalcemia (> • Stone or overt bon• Reduced bone den• Age: <50 years old• Age: <50 years old

arathyroid Surgeryy g ynternational Workshop, nol Metab, 2009)

1 mg/dL above normal)ne diseasensity: T-score <-2.5dd

Hypoparathyroidism

Humoral Hypercalce

Malignant tumors sMalignant tumors sMalignant tumors sMalignant tumors ssecrete humors thasecrete humors thaosteoclastosteoclast--mediatemediate

emia of Malignancy

synthesize andsynthesize andsynthesize and synthesize and at stimulate at stimulate d bone resorptiond bone resorption

Parathyroid Hormoas an Etioloas an Etiolo

CritCrit

• Produced by the tumor

• Blood level correlates w

• Mimics the clinical synd

• Reducing the PTHRP “b• Reducing the PTHRP bhypercalcemia

one-Related Proteinogy of HHMogy of HHM

teriateria

with hypercalcemia

rome

burden” reversesburden reverses

Circulating PTHypercalcemiaHypercalcemia

MalignancyMalignancy

•• HTLVHTLV--1 T1 T--cell lymphomacell lymphoma•• Classical squamous cell carcinomaClassical squamous cell carcinomaqq•• AdenocarcinomaAdenocarcinoma•• Breast carcinomaBreast carcinoma•• Myeloma and other hematological mMyeloma and other hematological m•• Myeloma and other hematological mMyeloma and other hematological m

Budayr et al. AnBudayr et al. AnyyIkeda et al. J Clin Ikeda et al. J Clin

THRP Levels ina of Malignancya of Malignancy

% Elevated% Elevated

99%99%85%85%58%58%50%50%

malignanciesmalignancies 21%21%malignanciesmalignancies 21%21%

nals Int Med, 1989nals Int Med, 1989,,Endo & Metab, 1994Endo & Metab, 1994

Potential Physiologica

•• LactationLactation

•• Placental Calcium TranPlacental Calcium Tran

N t l C l i M tN t l C l i M t•• Neonatal Calcium MetaNeonatal Calcium Meta

•• Proliferation and DifferProliferation and Differ

•• Bone GrowthBone Growth

•• Chondrocyte DevelopmChondrocyte DevelopmChondrocyte DevelopmChondrocyte Developm

•• Smooth Muscle FunctioSmooth Muscle Functio

al Functions of PTHRP

nsportnsport

b lib liabolismabolism

entiation of the Skinentiation of the Skin

mentmentmentment

onon

CAUSES OF HY

•• Primary HyperparathyroidismPrimary Hyperparathyroidism•• MalignancyMalignancy• Other endocrinopathy

HyperthyroidismPheochromocytomaVIPomaAdrenal insufficiency

• Medications• Medicationslithiumthiazide diureticsthyroid hormonethyroid hormone Vitamin AVitamin D

YPERCALCEMIA

• Vitamin DtaToxicityGranulomatous disease

Tuberculosis– Tuberculosis– Sarcoidosis– Any other

• Lymphoma• FHH• Immobilization• Acute or chronic renal

disease

Symptoms, signSymptoms, signof hypercof hyperc

To be discuss

s, and treatment s, and treatment calcemiacalcemia

sed tomorrow!

Outline oOutline o




Hypocay

• Hypoparathyroidis• Hypoparathyroidis– Deficient secretion

hormonehormone• Secondary hyperp

A i t– Appropriate responstimulus

Oth• Other causes

alcemia

smsmn of parathyroid

arathyroidismt h l inse to hypocalcemic

HypocaHypoca

• Autoimmune hypopHypoparathyroidism - Deficient s

Autoimmune hypop– Multiple end-organ e– Isolated parathyroidp y

•• Familial hypoparathyFamilial hypoparathy–– Defective processing Defective processing –– Defective cellular trafDefective cellular traf–– Developmental ageneDevelopmental agene

A ti ti t tiA ti ti t ti•• Activating mutations Activating mutations •• Congenital (DeGeorgCongenital (DeGeorg

•• PostPost--surgical hypopsurgical hypop

alcemiaalcemia

parathyroidismsecretion of parathyroid hormoneparathyroidismendocrine gland insufficiencyd gland deficiencyg yyroidismyroidism

of PTH gene productof PTH gene productfficking of PTH gene productfficking of PTH gene productesis (Xesis (X--linked)linked)

f th l i tf th l i tof the calcium receptorof the calcium receptorge Syndrome)ge Syndrome)

parathyroidismparathyroidism

HypocaHypoca

• Vitamin D d

Secondary Hyperparathyroidism - Approp

Vitamin D d– Nutritional – Malabsorpt– Liver disea– Liver disea– Renal disea

•• Vitamin D reVitamin D reVit i DVit i D–– Vitamin D reVitamin D re

–– Vitamin D dVitamin D d•• DrugsDrugsgg

–– FoscarnetFoscarnet–– PentamidinePentamidine–– KetaconazoKetaconazoKetaconazoKetaconazo

•• PseudohypoPseudohypo

alcemiaalcemia

eficiency

priate response to hypocalcemic stimulus

eficiency

tionaseaseasesistant statessistant states

i t t i k ti t t i k tesistant ricketsesistant ricketsdependent ricketsdependent rickets

eeoleoleoleoleoparathyroidismoparathyroidism

Symptoms, signs, Symptoms, signs, hypocahypoca

To be discuss

and treatment of and treatment of alcemiaalcemia

sed tomorrow!

Outline oOutline o




PostmenopauPostmenopaupp

• OsteoporosisOsteoporosis6 to 8 million US wom

• Low bone mass20 to 24 million20 to 24 million

• Fractures40% will suffer an ostlif tilifetime

Vertebral: 15.6%Hip: 17.5%Forearm: 16 0%Forearm: 16.0%

• 2.0 million fractures

Melton LJ, et al. J Bone Miner Res 1992;7:1005-10. Looker AC, et al. J Bone Miner Res 1997;12:1761-8.National Osteoporosis Foundation. 1998, 2002, 2005.

sal Osteoporosissal Osteoporosispp

men age ≥ 50

teoporotic fracture in their

annually

Human Costs oHuman Costs o•• Impaired function, dImpaired function, d•• More bone loss due tMore bone loss due t•• More bone loss due tMore bone loss due t•• Compressed abdomeCompressed abdome

reduced appetitereduced appetitereduced appetitereduced appetite•• Reduced pulmonaryReduced pulmonary

functionfunctionfunctionfunction•• Sleep disordersSleep disorders

Shortened s r i alShortened s r i al

Ross PD et al Ann Intern Med 1991;114-23

•• Shortened survivalShortened survival•• Poor self esteemPoor self esteem

Ross PD et al. Ann Intern Med 1991;114-23.Silverman SL. Bone 1992;13 (suppl 2):S27-31. Cooper C, et al. Am J Epidem 1993;137:1001-5.Lyles et al. Am J Med 1993;94:595-601. Schlaich C, et al. Osteoporos Int 1998;8:261-7.

of Osteoporosisof Osteoporosisdecreased mobilitydecreased mobilityto decreased activityto decreased activityto decreased activityto decreased activityen, en,

y y

Photo courtesy of the National Osteoporosis Foundation

Incidence of Osteopo

28-32,000,000

Women

28 32,000,000

National Osteoporosis Foundation, 2002.

orosis and Osteopenia

Men10-12,000,000

Osteoporosis: def

“A skeletalA skeletal disordercharacterized bycharacterized by compromised bone strengthgpredisposing to an increased risk of fracture.”

NIH Consensus Development Conference on Osteoporosis, 2000.

fining the Problem

Osteoporotic bone

Healthy bone

8080

Healthy bone

Independent Riskin Older

Major Risk Factors OMajor Risk Factors• Bone Density• Age

O

••GG• Age• Fragility fracture• Family history

••SS••AA••LLy y

• The menopause (i.e. estrogen deficiency)

LL••FF••BB

Cummings SR, et al. Cummings SR, et al. N Engl J MedN Engl J Med 1995;23:332:7671995;23:332:767--73.73.Garnero P, et al. Garnero P, et al. J Bone Miner ResJ Bone Miner Res 1996;11:15311996;11:1531--8.8.

ks for Hip Fracturer WomenOther Important Risk FactorsOther Important Risk Factors

GlucocorticoidsGlucocorticoidsSmokingSmokingAlcohol abuseAlcohol abuseLow body weight (<127 lbs)Low body weight (<127 lbs)Low body weight (<127 lbs)Low body weight (<127 lbs)Fall RiskFall RiskBone TurnoverBone Turnover

Independent RisksIndependent Risksin Older Woin Older Woin Older Woin Older Wo

••Minor Risk FactorsMinor Risk FactorsMinor Risk FactorsMinor Risk Factors–– Tallness at age 26Tallness at age 26–– Fair to poor selfFair to poor self--rated rated

healthhealth–– Previous hyperthyroidismPrevious hyperthyroidism

LL ii–– LongLong--acting acting benzodiazepinesbenzodiazepines

–– Excessive caffeine intakeExcessive caffeine intakeExcessive caffeine intakeExcessive caffeine intake–– Not walking for exerciseNot walking for exercise

Cummings SR et al. Cummings SR et al. N Engl J MedN Engl J Med 1995;23:332:71995;23:332:7Garnero P, et al. Garnero P, et al. J Bone Miner ResJ Bone Miner Res 1996;11:15311996;11:1531--

s for Hip Fracture s for Hip Fracture omen (cont)omen (cont)omen (cont)omen (cont)

–– Weight loss since age Weight loss since age 25 25

–– <4 hours/day on feet<4 hours/day on feet–– Inability to rise from a Inability to rise from a

chair without using chair without using armsarms

–– Poor depth perceptionPoor depth perception–– Poor contrast sensitivityPoor contrast sensitivity–– Tachycardia at restTachycardia at rest

6767--73.73.--8.8.

Therapeu

Bone Remodeling

Stabilize or increase BMD

Maintain trabecular hit tarchitecture

Increase mineralization density of bone matrix

utic Goals

Therapeutic Goals

THERAPEUTIC COTHERAPEUTIC CO

• HOW TO PREVENT• HOW TO PREVENT• HOW TO TREAT?

ONSIDERATIONSONSIDERATIONS

T?T?

Diagnosis, evaluatioosteop

To be discuss

on and treatment of porosis

sed tomorrow!

Documents

Endocrine PEndocrine PPhysiology ofPhysiology of Bone and ...of Endocrinologyof Endocrinology 5, 2010. Outline o ... more parathyroid gland Primary Hyperparathyr with hypercalcemia