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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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