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  • 1

    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

  • 5

    Ca2+

    Regulation of Parathyroid Hormone

    Ionized calcium

    1,25-dihydroxyvitamin D

  • 6

    Major Functions of Parathyroid Hormone

    Regulation of serum calcium and phosphate

    Bone remodelling

    Regulation of 1,25-dihydroxyvitamin D levels

  • 7

    Two Major Calcium-Regulating Hormones

    Parathyroid hormone

    1,25-dihydroxyvitamin D

  • 8

    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

  • 9

    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

  • 10

    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

  • 11

    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

  • 13

    Useful Indices of calcium metabolism

    Calcium, phosphorus

    Dynamic markers of bone metabolism

    Bone formation

    Bone resorption

  • 14

    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

  • 15

    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

  • 16

    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

  • 17

    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

  • 18

    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

  • 19

    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)

  • 20

    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

  • 21

    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

  • 22

    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

  • 23

    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

  • 24

    Hypoparathyroidism

    PRIMARY HYPERPARATHYROIDISMPRIMARY HYPERPARATHYROIDISM

    Before 1970: A disease of bone, stones,

    and groans

  • 25

    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

  • 26

    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

  • 27

    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

  • 28

    Bone and stone disease in

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