endocrine physiology of bone and calcium .endocrine physiology of bone and calcium disorders

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Endocrine Physiology of

Bone and Calcium Disorders

John P. Bilezikian, M.D.

Professor of Medicine and Pharmacology

Chief, Division of Endocrinology

Wednesday, February 21, 2007

Outline of LectureOutline of Lecture

Normal calcium homeostasis

Useful indices of calcium

metabolism

Hypercalcemia

Hypocalcemia

Osteoporosis

2

3

Two Major Calcium-Regulating Hormones

Parathyroid hormone

1,25-dihydroxyvitamin D

4

Regulation of Parathyroid Hormone

Ionized calcium

1,25-dihydroxyvitamin D1,25-dihydroxyvitamin D

The Calcium-Sensing Receptor

PP

P

P

P

NH2

HOOC

outside

inside

SP

HS

1 2 3 4 5 6 7

Type II Type II ligandsligands::

allostericallosteric

modulationmodulation

Type I Type I ligandsligands::

Direct receptor bindingDirect receptor binding

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Ca2+

Regulation of Parathyroid Hormone

Ionized calcium

1,25-dihydroxyvitamin D

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Major Functions of Parathyroid Hormone

Regulation of serum calcium and phosphate

Bone remodelling

Regulation of 1,25-dihydroxyvitamin D levels

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Two Major Calcium-Regulating Hormones

Parathyroid hormone

1,25-dihydroxyvitamin D

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Major Functions of 1,25-dihydroxyvitamin D

GI absorption of calcium and phosphate

Bone remodelling

Regulation of parathyroid hormone

Major Functions of 1,25-dihydroxyvitamin D

GI absorption of calcium and phosphateGI absorption of calcium and phosphate

Bone Bone remodellingremodelling

Regulation of parathyroid hormone

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Thomas MK et al. N Eng J Med 1998;338:778-783Thomas MK et al. N Eng J Med 1998;338:778-783

Relationship between 25-hydroxyvitamin D and PTH Relationship between 25-hydroxyvitamin D and PTH

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HOW PTH AND 1,25(OH)2D WORK TOGETHER

TO CONTROL THE SERUM CALCIUM CONCENTRATION

Other Circulating Hormones that Influence

Bone Metabolism

Parathyroid hormone

1,25 (OH)2 vitamin D

Gonadal steroids

Corticosteroids

Thyroid hormone

Growth hormone

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

Local Regulators of Bone Metabolism

IGFs and IGF binding proteins

TGF-

Bone morphogenic protein

Platelet-derived growth factor, fibroblast

growth factor

Prostaglandins

Interleukins (IL-1, IL-6)

RANKL/osteoprotegerin

Outline of LectureOutline of Lecture

Normal calcium homeostasis

Useful indices of calcium

metabolism

Hypercalcemia

Hypocalcemia

Osteoporosis

12

Useful indices of calcium metabolism

as gleaned from the multichannel autoanalyzer

THE HOLY TRINITYTHE HOLY TRINITY

CalciumCalcium

PhosphorousPhosphorous

Alkaline Alkaline phosphatasephosphatase

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Useful Indices of calcium metabolism

Calcium, phosphorus

Dynamic markers of bone metabolism

Bone formation

Bone resorption

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Bone turnover in the adult skeleton

Resorption

Reversal

Formation

Resting phase

Activation

FROM: Primer on the Metabolic Bone Diseases

and Disorders of Mineral Metabolism; 2nd Ed.

Useful Indices of calcium metabolism

Calcium, phosphorus

Dynamic markers of bone metabolism

Bone formation:

Alkaline phosphatase (total and

bone-specific), osteocalcin

Bone resorption:

N- or C- telopeptide of collagen

and collagen crosslinks

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Useful Indices of calcium metabolism

Calcium, phosphorus

Dynamic markers of bone metabolism

Calciotropic hormones

Parathyroid hormone

Vitamin D

25-hydroxyvitamin D

1,25-dihyhydroxyvitamin D

Storage form: index of vitamin D

sufficiency or insufficiency

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Thomas MK et al. N Eng J Med 1998;338:778-783

VITAMIN D DEFICIENCY IN MEDICAL INPATIENTS

Normal laboratory reference range

Normal physiologic range

Useful Indices of calcium metabolism

Calcium, phosphorus

Dynamic markers of bone

metabolism

Calciotropic hormones

Measurement of bone mass

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REDUCED BONE MASS IS A KEY

RISK FACTOR FOR FRACTURE

Relationship Between BMD andRelationship Between BMD and

Fracture Risk in Untreated PatientsFracture Risk in Untreated Patients

0

5

10

15

20

25

30

35

-5 -4 -3 -2 -1 0

Relative

Risk

of

Fracture

Bone density (SD units)

-1SD

2 x

Reduced bone mass is a key

risk factor for the fragility fracture

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Dual Energy X-Ray Dual Energy X-Ray AbsorptiometryAbsorptiometry (DXA): (DXA):

Central DevicesCentral Devices

Hologic Delphi

GE Lunar Prodigy

Features of bone densitometry by DXA

(dual energy X-ray absorptiometry)

Safe

Accurate

Precise

Normative population databases

Correlates with fracture risk

A diagnostic standard for

osteoporosis

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Bone loss as a function of ageBone loss as a function of age

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

20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95

1

0

-1

-2

-3

-4

-5

-6

T= -2.5

T-s

core

Age

PA spinePA spine

Referents for comparisons

of bone mass measurements

Z-score: : a measure of bone density instandard deviations from normal age- and

sex-matched cohorts

T-score: : a measure of bone density instandard deviations from cohorts at peak

bone mass (25-30 years old)

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T= - 2 Z= - 0.5

T-Score

0

-1

-2

-3

+1

T

Z

20 40 60 80 100

1.20

0.96

0.84

-40.72

1.08

1.32

BMD gm/cm2 Spine: L1-L4

Age

Diagnostic Standard

T-SCORE

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Correlates with life time fracture risk for Caucasian Women

- -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 +0.5 +1.0

Interpreting T-scores (World Health Organization)

T-score

Osteoporosis

Normal

Bone MassLow

Bone Mass

(Osteopenia)

Outline of LectureOutline of Lecture

Normal calcium homeostasis

Useful indices of calcium

metabolism

Hypercalcemia

Hypocalcemia

Osteoporosis

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CAUSES OF HYPERCALCEMIA

PrimaryHyperparathyroidism

Malignancy Other endocrinopathy

Hyperthyroidism

Pheochromocytoma

VIPoma

Adrenal insufficiency

Medicationslithium

thiazide diuretics

thyroid hormone

Vitamin A

Vitamin D

Vitamin D

Toxicity

Granulomatous disease

Tuberculosis

Sarcoidosis

Any other

Lymphoma

FHH

Immobilization

Acute or chronic renal

disease

MAJOR CAUSES OF HYPERCALCEMIA(From Mundy and Martin)

612Unknown

612Others (sarcoid,thyroid, vit D, etc

35357272Malignancy

54111PrimaryHyperparathyroidism

% OF TOTAL% OF TOTAL# OF PATIENTS# OF PATIENTS

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PRIMARY HYPERPARATHYROIDISMPRIMARY HYPERPARATHYROIDISM

A common endocrine disorder characterized

by incompletely regulated, excessive

secretion of parathyroid hormone from one or

more parathyroid glands.

Primary Hyperparathyroidism is associated

with hypercalcemia and elevated levels of

parathyroid hormone.

HisGluSer

Gly

Human Parathyroid HormoneHuman Parathyroid Hormone

1 10

20

30

Ser Val Ile Gln Leu Met Asn

Leu

LysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

-COOH

H2N

Gly

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Hypoparathyroidism

PRIMARY HYPERPARATHYROIDISMPRIMARY HYPERPARATHYROIDISM

Before 1970: A disease of bone, stones,

and groans

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CHANGING CLINICAL PROFILE OFCHANGING CLINICAL PROFILE OF

PRIMARY HYPERPARATHYROIDISMPRIMARY HYPERPARATHYROIDISM

80%80%22%22%18%18%0.6%0.6%AsymptomaticAsymptomatic

1.4%1.4%14%14%10%10%23%23%Overt Skeletal DiseaseOvert Skeletal Disease

39%39%40%40%36%36%NotNot

reportedreported

HypercalciuriaHypercalciuria

17%17%37%37%51%51%57%57%NephrolithiasisNephrolithiasis

Silverberg,

Bilezikian et al.

1984-2007

Mallette etal.

1965-1974

Heath et al.

1965-1974

Cope et al.Cope et al.

1930-19651930-1965

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Biochemical and hormonal profileBiochemical and hormonal profile

in Primary Hyperparathyroidismin Primary Hyperparathyroidism

Index Patients nl range

Calcium (mg/dl)Calcium (mg/dl) 10.710.70.10.1 8.4-10.28.4-10.2

Phosphorus (mg/dl)Phosphorus (mg/dl) 2.90.1 2.90.1 2.5-4.52.5-4.5

AlkAlk PhosPhos (IU/l) (IU/l) 1144 1144

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PRIMARY HYPERPARATHYROIDISMPRIMARY HYPERPARATHYROIDISM

Before 1970: A disease of bone, stones, andgroans

Since 1970: A disease of asymptomatic hypercalcemia

BONE MASS MEASUREMENTS INBONE MASS MEASUREMENTS IN

PRIMARY HYPERPARATHYROIDISMPRIMARY HYPERPARATHYROIDISM

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Bone and stone disease in