the skeletal response to aging: there’s no bones about it! · the skeletal response to aging:...
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The Skeletal Response to Aging: There’s No Bones About It!
April 7, 2001
Joseph E. Zerwekh, Ph.D.
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Interrelationship of Intestinal, Skeletal, and Renal Systems to theOverall Maintenance of Normal Calcium Homeostasis
Blood Calcium
Absorption(500 mg)
Secretion(300 mg)
Resorption(500 mg)
Formation(500 mg)
Filtration(8000 mg/d)
Reabsorption(7800 mg/d)
Dietary Ca(800 mg/d)
in stool200 mg lost
in urine600 mg lost 800 mg output
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Functions of the Human Skeleton
• Protects soft tissues and organs from injury
• Provides sites for insertion of muscles
• Capable of repair in response to injury
• Storehouse for 99% of body’s cal-cium, 80% of phosphorus, and substantial amounts of magnesium,sodium, and carbonate
• Third line of defense in maintainingacid-base balance
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Distribution of Cortical and Cancellous Bone in a Long Bone
Diaphysis
Metaphysis
Cortical bone
Cancellous boneGrowth plate
% of total skeleton % of total activity
Cortical 80 20 Cancellous 20 80
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Bone Modeling
Denotes sites of bone resorption
Denotes sites of bone formation
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Bone Remodeling
Home Remodeling
Garage to Playroom
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DEMOLITION CREWOSTEOCLAST
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CARPENTEROSTEOBLASTS (Laying down collagen)
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CaP
MINERALIZATION CEMENT CREW
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Sum
mar
y of
Bon
e R
emod
elin
g
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The Role of Parathyroid Hormone in Normal Calcium Homeostasis
• Major calcium-sensing glands inbody
• Secrete parathyroid hormone in re-sponse to low circulating calcium
• Parathyroid hormone increases serum calcium by:
1) Promoting bone resorption2) Diminishing urinary calcium
excretion
3) Indirectly promoting increased dietary calcium absorption via increased renal production of1,25(OH)2D
Parathyroid glands
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Secretion and Metabolism of Human PTH
NH2
HOOCNH2
HOOC
NH2HOOC
HOOCNH2
Intact PTH 1-84Intact PTH 1-84
C-terminal fragments (inactive)
N-terminal fragments (active)
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Physiological Action of Parathyroid Hormone in Raising Blood Calcium Concentration
Ca
Ca Ca 1,25(OH)2D
P
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Cutaneous Production and Systemic Activation of Vitamin D
UV Irradiation
Skin (Vitamin D)
Liver Calcidiol
Kidney Calcitriol
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Physiological Action of 1,25(OH)2D in Raising Blood Calcium Concentration
Ca
Ca
Ca
Ca
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InitialPlasma Condition
PhysiologicalAdjustment
FinalPlasma Condition
LowCirculating
CalciumCa
LowCirculating
PhosphateP
PTH
25OHD3 1,25(OH)2D3(+)(+)
PTH
A.
B.
A.Ca P
P CaB.
Urinary Ca
Ca
P
Ca
P
Central Role of PTH and Vitamin D in the Homeostatic Control of Calcium and Phosphate
Urinary P
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Change in Bone Mineral Density versus Age in Normal Men and Women
Age20 30 40 50 60 70 80 90
Bone
Mas
s
Active Growth
Slow Rapid ContinuingLoss Loss Loss
MEN
OPA
USE ♂
♀
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Model for the Proposed Changes in Calcium Homeostasis and Bone Turnover with Age
Aging
Decreased
25OHD
Decreased
1a-hydroxylaseIntestinal resistance
to 1,25(OH)2D
Decreased bone
formation
Decreased production of 1,25(OH)2D
Decreased calcium absorption
Secondary hyperparathyroidism
Bone loss
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Osteoporosis
Patientat age50...
and25 years
later
Used with permission of the National Osteoporosis Foundation. Osteoporosis: The Silent Disease. National Osteoporosis Foundation. Partners in Prevention Slide Presentation. 1993Used with permission of the National Osteoporosis Foundation. Osteoporosis: The Silent Disease. National Osteoporosis Foundation. Partners in Prevention Slide Presentation. 1993
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Definition of Osteoporosis
“A systematic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures.”
Consensus Development Statement. Osteoporosis Int 1997;7:1-5
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Normal Trabecular Bone Osteoporotic Bone
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Comparative Yearly Incidence
EstimateOsteoporosis-related fractures 1,500,000Breast cancer 184,000Ovarian cancer 26,000Cervical and endometrial cancer 15,000Prostate cancer 317,000
Cancer Facts and Figures 1996
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Osteoporosis is Pervasive
• Afflicts 25 million Americans• 15% of women and 5% of men will
experience a hip fracture in their lifetime• Hip fractures occur as frequently as breast
cancer• Total cost of osteoporosis is estimated at
about $14 billion each year
Ray NF et al. J Bone Miner Res 1997;12:24-35; National Osteoporosis Foundation, 1993; Consensus development Conference. Am J Med 1993;94:646-50
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Annual Costs of Various Chronic Diseases
$ Billions
15
13.811.2
6.2
10
5
0Osteoporosis Congestive Asthma
Heart Failure
Ray NF et al. J Bone Miner Res 1997;12:24-35; DHHS pub. No. PHS 92-1774; Irwin et al. Battelle med Tech Assess Pol Res Cen 1992; Weiss et al. N Engl J Med 1992;326:862
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Medical, Nursing Home and Social Costs of Osteoporotic Fractures
$60 billion$60 billion
$$19951995 20202020
$30 billion$30 billion
$15 billion$15 billion
National Osteoporosis Foundation, 1993; Ray NF et al. J Bone Miner Res 1997;12:24-35
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Established Risk Factors for Osteoporosis
Genetic• Female
• Caucasian or Asian races
• Thin body habitus
• Low peak bone mass
• Family history of fractures
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Established Risk Factors for Osteoporosis
Medical
• Menopause
• Menstrual dysfunction or early menopause
• Glucocorticoids, thyroid, anticonvulsants, benzodiazepines and GnRH use
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Established Risk Factors for Osteoporosis
Nutritional
• Low calcium intake
• Vitamin D deficiency
• Excessive caffeine intake
• Excessive dietary sodium
• Reduced alkali intake
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Established Risk Factors for Osteoporosis
Lifestyle• Excessive smoking
• Excessive alcohol
• Lack of exercise
• Slipping, falling as a result of loose rugs, cords, etc.