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