• Cells involved
  • Osteoclasts: degrade bone tissue by secreting collagenase and H⁺
    • Regulation
      • RANKL: Stimulates differentiation, fusion, activation, and prevents apoptosis (via binding to RANK).
      • OPG (Osteoprotegerin): Inhibits activity (by blocking RANKL).
      • M-CSF: Stimulates proliferation and differentiation of precursor cells.
      • Lack of Mechanical Load: Stimulates activity (leading to decreased bone mass).
      • PTH (High Levels): Stimulates activation.
      • PTH (Low Levels): Stimulates apoptosis.
      • Estrogen: Inhibits activity (stimulates apoptosis).
      • Vitamin D: Stimulates differentiation.
      • Bisphosphonates: Inhibit activity.
      • Glucocorticoids: Stimulate activity (increase lifespan).
      • IL-1: Leads to an increase in RANK ligand signaling and subsequent osteoclast-mediated bone resorption
  • Osteoblasts
    • Build bone tissue by secreting type I collagen
    • Activity assessed by an increase in bone ALP, osteocalcin, and type I procollagen propeptides
    • Regulation
      • Mechanical Load: Stimulates activity (leading to increased bone mass).
      • Growth Factors (Released by Osteoclasts): Stimulates activity.
      • PTH (Low Levels): Stimulates bone formation.
      • Estrogen: Stimulates activity/survival (inhibits apoptosis).
      • Vitamin D: Stimulates differentiation and activation.

Bone remodeling in cortical bone

Degradation

• Osteoclasts organize in a basic multicellular unit (BMU) and excavate a tunnel in the cortical bone.
• Connective tissue vessels and unmyelinated nerves grow in the tunnel.

Formation

• Osteoclasts are followed by osteoblasts → deposition of the first osteoid layer in the tunnel
• Additional osteoblasts follow and deposit osteoid onto the first osteoid layer → osteoblasts of the first layer are walled in → osteoblasts become osteocytes
  • Osteocyte function relies on the presence of gap junctions that connect the cytoplasmic processes between osteocytes. These junctions facilitate cell-to-cell communication, allowing intracellular signals (eg, calcium, cyclic AMP) to propagate to neighboring cells.
• The deposition process is repeated until the tunnel is almost full → central Haversian canal remains open
• The innermost (i.e., last) generation of osteoblasts is no longer walled in → cells return to their resting state and form the endosteum

Mineralization: occurs successively

• Osteoblasts secrete collagen and vesicles into the extracellular matrix.
• Vesicles contain enzymes (e.g., alkaline phosphatase), which increase local phosphate levels (e.g., by cleavage of pyrophosphate).
• Calcium-binding molecules in the vesicles most likely serve as a focal point.
• Initial formation of hydroxyapatite crystals around the focal point in the vesicles
• Independent growth of the crystals until penetration of the vesicle membrane
• Release of crystals in the extracellular matrix
• Growth of crystals in the extracellular matrix and accumulation of collagen fibrils

Regulation of bone remodeling

• RANK (receptor activator of nuclear factor κB): receptor on osteoclasts and osteoclast precursors, for interaction with osteoblasts
• RANKL (receptor activator of nuclear factor κB ligand)
  • Membrane-bound protein of osteoblasts that stimulates osteoclasts by interacting with RANK
  • Ensures fusion and differentiation into activated osteoclasts and prevents their apoptosis
• Osteoprotegerin (OPG)
  • A regulatory protein secreted by osteoblasts that binds RANKL
  • Inhibits RANK-RANKL interaction, leading to decreased osteoclast activity
• Mechanical load (Wolff's law)
  • Load on the bone leads to increased bone mass.
  • Absence of load (e.g., due to being confined in bed) results in decreased bone mass.
  • Sensed by osteocytes via extracellular attachments (eg, integrins) to the canalicular walls, resulting in the release of mediators—such as soluble receptor activator of nuclear factor-kappa B (RANKL) and sclerostin—that orchestrate bone remodeling
• Hormones
  • PTH effects
    • At low levels: increased bone formation and increased apoptosis of osteoclasts → decreased bone resorption (anabolic effects)
    • At high levels (e.g., primary hyperparathyroidism): activation of osteoclasts → increased bone resorption (catabolic effects) → osteoporosis or osteitis fibrosa cystica
  • Estrogen effects
    • Inhibits apoptosis of osteoblasts, leading to increased bone formation
    • Stimulates apoptosis of osteoclasts, leading to decreased bone resorption
    • Stimulates closure of the epiphyseal plate in puberty
    • Estrogen deficiency (e.g., postmenopausal or after bilateral oophorectomy) leads to increased bone resorption, which can result in osteoporosis.
  • Thyroid hormone
    • In long-standing hyperthyroidism, T3 stimulates osteoclast differentiation, increased bone resorption, and release of calcium.