Structure of Bone Tissue
Division of the Skeleton
Bone Growth
Classification of Bones
Long bones
Short bones
Flat bones
Irregular bones
1
Compact Bone Histology
Compact Bone
Spongy Bone
Osteoblasts, Osteoclasts,
and Osteocyes
Compact Bone (continued)
2
Regulation
Cell linage
Estrogen
PTH
1,25(OH)2 vitamin D
Calcitonin
http://courses.washington.edu/bonephys/physiology.html
Cortisol
GH/IGF-1
Thyroid hormone
Vitamin A
Cytokines and others
http://courses.washington.edu/bonephys/physiology.html
Basic Multicellular Unit (BMU)
Calcium Physiology: Blood Calcium
• Calcium Flux into and out of Blood
–“IN”factor: Intestinal absorption, Bone resorption
–“OUT”factor: Renal excretion, Bone Formation
(Ca incorpation into bone)
–Balance between “IN”and “
OUT”factors
•Organ physiology of gut, bone, and kidney
•Hormone function of PTH and vitamin D
Bone remodeling
CALCIUM HOMEOSTASIS
DIETARY CALCIUM
THE ONLY “
IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
ORGAN,
ENDOCRINE
BLOOD CALCIUM
INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY
ENDOCRINE PHYSIOLOGY
KIDNEYS
ORGAN PHYS.
ENDOCRINE PHYS.
http://courses.washington.edu/bonephys/physremod.html
URINE
THE PRINCIPLE “
OUT”
3
FUNCTION OF VITAMIN D
• TISSUE SPECIFICITY
– GUT
•STIMULATE TRANSEPITHELIAL TRANSPORT OF CALCIUM
AND PHOSPHATE IN THE SMALL INTESTINE (PRINCIPALLY
DUODENUM)
– BONE
•STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS
•STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO
MOBILIZE CALCIUM
– PARATHYROID
CALCIUM, PTH, AND VITAMIN D FEEDBACK
LOOPS
BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION
RISING BLOOD Ca
NORMAL BLOOD Ca
FALLING BLOOD Ca
• INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK
REGULATION)
BONE RESORPTION
STIMULATE PTH
URINARY LOSS
1,25(OH)2 D PRODUCTION
PARATHYROID HORMONE (PTH)
PHYSIOLOGY
• PTH FUNCTIONS TO PRESERVE NORMAL BLOOD
CALCIUM (AND PHOSPHATE)
–PTH STIMULATES BONE RESORPTION AND,
THUS, INCREASES BLOOD CALCIUM
–PTH STIMULATES RENAL TUBULAR
REABSORPTION OF CALCIUM, AND THUS,
INCREASES BLOOD CALCIUM
–PTH STIMULATES RENAL 1a-HYDROXYLATION
OF 25(OH)VITAMIN D, THUS INDIRECTLY
STIMULATING INTESTINAL ABSORPTION OF
CALCIUM
BONE MASS AS A FUNCTION
OF AGE; PERTURBATIONS
PEAK BONE MASS
NORMAL
FAILURE TO REACH PEAK
ACCELERATED LOSS
BONE
MASS
THEORETICAL
FRACTURE
THRESHOLD
AGE
PTH PHYSIOLOGY
• PTH SECRETION IS INCREASED IN RESPONSE TO
FALLING CALCIUM LEVEL, TO HELP KEEP CALCIUM
NORMAL BY THE ABOVE MECHANISMS
• RISING CALCIUM FEEDS BACK TO THE
PARATHYROIDS TO SUPPRESS PTH SECRETION IN
A CLASSIC ENDOCRINE FEEDBACK LOOP
• THIS LOOP IS MUCH LIKE OTHER ENDOCRINE
FEEDBACK LOOPS YOU’
RE FAMILIAR WITH SUCH
AS GLUCOSE AND INSULIN, THYROID HORMONE
AND TSH, ETC.
RICKETS AND
OSTEOMALACIA
• DISEASES OF DEFECTIVE BONE MINERALIZATION
• THESE DISEASES ARE PATHOPHYSIOLOGICALLY RELATED,
AND DIFFER MAINLY IN THE AGE AT WHICH THEY BECOME
MANIFEST
– RICKETS IS A DISEASE OF CHILDHOOD
– OSTEOMALACIA IS A DISEASE OF ADULTHOOD
• WIDE RANGING CATEGORY OF DISEASE
– DISORDERS OF VITAMIN D
– PHOSPHATE DEFICIENCY
– CHRONIC RENAL FAILURE (ALSO RENAL OSTEODYSTROPHY)
– PRIMARY DISORDERS OF BONE METABOLISM
4
RICKETS AND
OSTEOMALACIA: CAUSES
• NUTRITIONAL DEFICIENCY OF VITAMIN D AND/OR
INADEQUATE SUNLIGHT EXPOSURE:
– EASILY TREATED WITH DIETARY SUPPLEMENTATION
• FORTIFIED MILK - PROVIDES VITAMIN D AND CALCIUM
• MULTIPLE VITAMIN - PROVIDES VITAMIN D ONLY
• EITHER WAY, MUST ASSURE ADEQUATE CALCIUM WITH THE VITAMIN
D
• DEFECTIVE RENAL 1-HYDROXYLATION OF 25(OH) VIT. D
– AUTOSOMAL RECESSIVE
– CHARACTERIZED BY HYPOCALCEMIA, HYPOPHOSPHATEMIA,
SECONDARY HYPERPARATHYROIDISM, LOW 1,25(OH)2D, AND
INCREASED ALKALINE PHOSPHATASE
– TREATMENT IS BY GIVING 1,25(OH)2D AND CALCIUM
RICKETS AND OSTEOMALACIA:
CAUSES, cont.
• TISSUE RESISTANCE TO 1,25(OH)2D
– AUTOSOMAL RECESSIVE, OR ACQUIRED
– DEFECT IN NUCLEAR RECEPTOR FOR VITAMIN D
•DEFECTIVE SYNTHESIS OF RECEPTOR
•DEFECTIVE AFFINITY OF RECEPTOR FOR 1,25(OH)2D
•DEFECTIVE ABILITY OF 1,25(OH)2D/VITAMIN D RECEPTOR
COMPLEX TO INTERACT WITH DNA OR ACTIVATE
TRANSCRIPTIONAL MACHINERY PROPERLY
– TREATMENT IS WITH 1,25(OH)2D AND CALCIUM
•RESPONSE TO THERAPY IS VARIABLE GIVEN DIVERSITY OF
MOLECULAR DEFECTS (ABOVE)
Bone Mass Loss
Bone strength (Quality)
Reduction of Bone Mineral Density
Osteoporosis: 2.5 standard deviations below peak bone mass (20-year-old
person standard) as measured by Dual energy X-ray absorptiometry(DEXA), or
any fragility fracture
Causes
Sarcopenia (aging), Malnutrition, Diseases, Genetics, Smoking,
Low physical activities
Involved Ca 2+ , vitamin D, sex steroids, glucocortocoid, thyroid hormone,
parathyroid hormone,
The most critical and susceptible population is postmenopausal women
5
Main pathways for extragonadal synthesis of
active androgens (boxes) and potent estrogens
(circles) in humans
Model for mediation of effects of E on osteoclast
formation and function by cytokines in bone
marrow microenvironment
Three-dimensional reconstruction by microcomputed
tomography of a lumbar spine sample from a youngadult normal woman and from a woman with
postmenopausal osteoporosis
Schematic of mechanism of E interaction with
biomechanical strain to regulate bone mass
A Hypothetical Model of Bone Loss Associated
with Age-related Declines of Sex Steroids
Schematic representation in cortical bone of the
differential effects of gender on growth and maturation
and on bone loss with aging
Adrenopause,
DHEA and T 
Menpause, E 
IGF 
Bone formation 
Bone mass
Adrenopause,
DHEA and T 
Menpause, E 
IL-6 
Bone resorption 
6
Patterns of age-related
changes in serum values for
SHBG, Bio E, and Bio T
among men and women
Model for causation
of increases in serum
SHBG in aging people
7