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Introduction
  • Normal bone metabolism is the complex sequence of bone turnover (osteoclastogenesis) and bone formation (osteoblastogenesis)
    • Physiology of bone metabolism
      • bone has structural and metabolic functions
      • metabolic functions of bone largely involve the homeostasis of calcium and phosphate
      • release of calcium, or absorption of calcium, by bone is largely regulated by hormones and, less so, by steroids
    • Regulators of bone metabolism
      • Hormones
        • PTH
        • Calcitonin
        • Sex Hormones (eg. estrogen, androgens)
        • Growth Hormone
        • Thyroid Hormones
      • Steroids
        • Vitamin D 
        • Glucocorticosteroids 
    • Properties of bone metabolism
      • Bone mass
        • bone mass is the measure of bone tissue present at the end of skeletal maturity
        • represents both its volume and size, as well as the density of the mineralized tissue
        • peak bone mass occurs between ages 16 and 25 
        • greater in men and African Americans
      • Bone loss
        • bone mass decreases by 0.3 to 0.5% per year after skeletal maturity
        • further decreases by 2-3% per year for untreated women during the 6th-10th years after menopause
        • rate of bone loss can be modulated by structural and metabolic factors
Calcium
  • Location
    • bone (99%)
    • blood and extracellular fluid (0.1%)
    • intracellular (1%)
  • Function
    • calcium has a wide range of function including
      • muscle cell contraction
      • nerve conduction
      • clotting mechanisms
  • Forms of calcium
    • bone
      • majority is hydroxyapatite
    • serum
      • Ca++ bound to protein (45%)
      • free-ionized Ca++ (45%)
      • bound to various anions, eg. citrate, bicarbonate (10%)
  • Regulation
    • absorption from the digestive tract
    • resorption from bone
    • resorption in the kidneys
  • Dietary requirements
    • 2000 mg/day for lactating women
    • 1500 mg/day for pregnant women, postmenopausal woman, and patients with a healing bone fracture
    • 1300 mg/day for adolescents and young adults
    • 750 mg/day for adults
    • 600 mg/day for children
  • Dysfunction
    • hypercalcemia 
    • hypocalcemia 
Phosphate
  • Location
    • bone  (86%)
    • blood and extracelluar fluid (0.08%)
    • intracellular (14%)
  • Function
    • key component of bone mineral
    • important in enzyme systems and molecular interactions
  • Forms of phosphate
    • bone
      • majority is hydroxyapatite
    • serum
      • mostly inorganic phosphate (H2PO4-)
  • Regulation
    • plasma phosphate is mostly unbound and reabsorbed by the kidney
    • may be excreted in urine
    • elevated serum phosphate can lead to increased release of PTH and bone resorption
  • Dietary intake
    • 1000-1500 mg/day
PTH
  • Structure
    • 84 amino acid peptide
  • Origin
    • synthesized and secreted from chief cells in the four parathyroid glands
  • Net effect
    • increases serum calcium
    • decreases serum phosphate
  • Mechanism
    • bone
      • PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines to activate osteoclasts and increase resorption of bone
      • Increases osteoblast production of M-CSF (macrophage colony-stimulating factor) and RANKL, which increases number of osteoclasts.
      • Paradoxically, osteoclasts do not express receptor for PTH
    • kidney
      • stimulates enzymatic conversion of 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form) which:
        • increases resorption of Ca++ in kidney (increasing serum Ca++)
        • increases excretion of PO4- from kidney (decreasing serum phosphate)
    • intestine
      • no direct action
      • indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3
  • Dysfunction
    • PTH-related protein and its receptor have been implicated in metaphyseal dysplasia
  • Parathyroid hormone-related protein (PTHrP) has related effects to PTH as it binds to the same receptors on osteoblasts and renal cells to increase serum calcium
Calcitonin
  • Structure
    • 32 amino-acid peptide hormone
  • Origin
    • produced by clear cells in the parafollicles of the thyroid gland (C cells)
  • Net effect
    • limited role in calcium homeostasis
    • inhibit number and activity of osteoclasts 
  • Function
    • bone
      • inhibits osteoclastic bone resorption by decreasing number and activity of osteoclasts
      • osteoclast have receptor for calcitonin
      • Inc. serum Ca > secretion of calcitonin > inhibition of osteoclasts > dec. Ca (transiently) 
  • Dysfunction
    • secreted by medullary thyroid tumors and mulitple endocrine neoplasia type II tumors
    • Recombinant calcitonin used to treat Paget disease, osteoporosis, and hypercalcemia in malignancy
Vitamin D
  • Structure
    • fat soluble secosteroid (steroid with a 'broken ring')
  • Origin
    • produced by skin when exposed to sunlight (UV B-generated Vitamin D)
    • dietary intake (lipid-soluble vitamin D3)
    • active metabolite 1,25-(OH)2-vitamin D3 formed by two hydroxylations in the liver and kidney, respectively
  • Net effect
    • maintains normal serum calcium levels by activating osteoclasts for bone resorption and increasing intestinal absorption of calcium (increase serum Ca++)
    • promotes the mineralization of osteoid matrix
  • Function
    • liver
      • activated-vitamin D3 converted to 25-(OH)-vitamin D3
    • kidney
      • 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form)
        • activated by
          • increased levels of PTH
          • decreased levels of serum Ca++, P
      • 1,25-(OH)2-vitamin D3 (active hormone form)can be inactivated to 24,25-(OH)2-vitamin D3
        • inactivity occurs with:
          • decreased levels of PTH
          • increased levels of serum Ca++, P
      • vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys 
    • bone
      • 1,25-(OH)2-vitamin D3 stimulates terminal differentiation of osteoclasts
      • when osteoclasts mature they do not respond to 1,25-(OH)2-vitamin Dand respond mostly to cytokines released by osteoblasts
      • 1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by osteoblasts
  • Dysfunction
    • Vitamin D deficiency causes osteomalacia and rickets 
    • phenytoin (dilantin) causes impaired metabolism of vitamin D
Estrogen
  • Structure
    • D ring steroid hormone
  • Origin
    • predominantly in the ovaries
    • synthetic forms available
  • Net effect
    • prevents bone loss by decreasing the frequency of bone resorption and remodeling
  • Function
    • alone, because bone formation and resorption are coupled, it also indirectly decreases bone formation
    • leads to an increase in bone density of the femoral neck and reduces the risk of hip fracture
    • most important sex-steroid for peak bone mass attainment in both men and women
  • Therapeutic estrogen
    • outcomes
      • decreases bone loss if started within 5-10 years after onset of menopause
      • significant side effects so risk/benefit ratio must be evaluated
      • gains in bone mass usually limited to an annual increase of 2-4% for the first 2 years of therapy
    • secondary effects 
      • increases risk of
        • heart disease
        • breast cancer
      • decreases risk of
        • hip fracture
        • endometrial cancer (if combined with cyclic progestin)
    • laboratory
      • will see a decreases in
        • urinary pyridoline
        • serum alkaline phosphatase
Thyroid Hormone
  • Function
    • regulates skeletal growth at the physis by stimulating
      • chondrocyte growth
      • type X collagen synthesis
      • alkaline phosphatase activity
    • thyroid hormones increase bone resorption and can lead to osteoporosis
      • large doses of therapeutic thyroxine can mimic this process and cause osteoporosis
Growth Hormone
  • Function
    • increases serum calcium by
      • increased absorption in intestine
      • decreasing urinary excretion
    • function is interdependent with insulin, somatomedins, and growth factors (TGF-B, PDGF, mono/lyphokines)
  • Gigantism
    • oversecretion or increased response to growth hormone effecting the proliferative zone of the growth plate  
Steroids
  • Function
    • increase bone loss by
      • decreasing Ca++ absorption in intestine through a decrease in binding proteins
      • decreasing bone formation (cancellous more so than cortical bone) by
        • decreasing collagen synthesis
        • inhibiting osteoblast activity
 

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Questions (3)

(OBQ08.57) Peak bone mass attainment in both men and women is most dependent on which sex-steroid? Review Topic

QID:443
1

Testosterone

17%

(228/1364)

2

Progesterone

2%

(24/1364)

3

Growth Hormone

9%

(117/1364)

4

Estrogen

72%

(977/1364)

5

Cortisol

1%

(15/1364)

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PREFERRED RESPONSE 4

Estrogen has been shown to be important for both men and women in attaining peak bone mass.

Risk factors for osteoporosis are: increasing age, female sex, early menopause, fair-skinned, family history of hip fracture, low body weight, smoking, glucocorticoid use, excessive alcohol, low protein intake, and anticonvulsant or antidepressant use.


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(OBQ08.171) Which of the following Figures represents a disease process that is caused by over-secretion of hormone that preferentially affect the proliferative zone of the growth plate? Review Topic

QID:557
FIGURES:
1

Figure A

3%

(59/2191)

2

Figure B

91%

(1986/2191)

3

Figure C

2%

(44/2191)

4

Figure D

1%

(12/2191)

5

Figure E

4%

(78/2191)

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PREFERRED RESPONSE 2

Figure B shows a picture of a male with Gigantism (over-secretion of growth hormone) who had a final height of nearly 9 feet. Longitudinal bone growth occurs at the growth plate by a process called endochondral ossification in which cartilage is first formed and then remodeled into bone tissue. The growth plate consists of three principal layers: the resting zone, proliferative zone, and hypertrophic zone. Growth hormone acts preferentially at the proliferative zone where it stimulates longitudinal bone growth.
Figure A represents Spondyloepiphyseal dysplasia (SED) where there is disproportionate dwarfism, spinal involvement, and a barrel chest from a COL2A1 mutation. Figure C represents diastrophic dysplasia with a "hitch-hikers" thumb, "cauliflower ear", cleft palate, and short-limbed dwarfism due to a sulfate transport mutation. Figure D represents cleidocranial dysplasia due to defect in core-binding factor alpha 1 (CBFA-1) causing dwarfism and absent clavicles. Figure E represents Multiple epiphyseal dysplasia (MED) causing disproportionate dwarfisim with multiple epiphyses involved, shortened metacarpals, valgus knees, but no spinal involvement, all of which are due to a COMP mutation.


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Question COMMENTS (9)

(OBQ07.67) You are counseling a 40-year-old woman about her future risk of osteoporosis. During what age do most people achieve their peak bone mass? Review Topic

QID:728
1

0-5 years

0%

(1/733)

2

6-15 years

1%

(6/733)

3

16-25 years

73%

(534/733)

4

26-35 years

25%

(182/733)

5

36-45 years

1%

(7/733)

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PREFERRED RESPONSE 3

Peak bone mass is the greatest amount of bone an individual will have in his/her lifetime. Most individuals attain their peak level of bone mass sometime between the ages of 16 and 25 years. There is a correlation between one's peak bone mass and that person's likelihood of developing osteoporosis. Women tend to experience minimal change in total bone mass between acquisition of peak bone mass and menopause. Bone mass then decreases 2-3% per year for untreated women during the years after menopause.


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