Updated: 6/16/2021

Normal Bone Metabolism

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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 in hip 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 D3 and 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
  • 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 theproliferative zoneof the growth plate
  • 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
  • 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)

(OBQ08.171) 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?

QID: 557
FIGURES:
1

Figure A

3%

(103/3236)

2

Figure B

89%

(2891/3236)

3

Figure C

2%

(75/3236)

4

Figure D

1%

(22/3236)

5

Figure E

4%

(126/3236)

L 1 C

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

QID: 443
1

Testosterone

16%

(276/1728)

2

Progesterone

2%

(36/1728)

3

Growth Hormone

11%

(185/1728)

4

Estrogen

70%

(1206/1728)

5

Cortisol

1%

(22/1728)

L 2 D

Select Answer to see Preferred Response

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