Harvey's Garden

Bone remodeling

4 min read

  • 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.
        • 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.

Mnemonic

Blasts Build, Clasts Crumble.

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
      • PTH receptors are on osteocytes & osteoblasts, not osteoclasts. PTH controls osteoclasts indirectly.
      • 1. Continuous/Sustained High Levels (Catabolic):
        • Seen in hyperparathyroidism.
        • Mechanism: PTH acts on osteoblasts to ↑ RANK-L and ↓ OPG.
        • Result: Increased osteoclast activation → bone resorption → ↑ serum Ca2+.
        • Net Effect: Bone breakdown.
      • 2. Intermittent/Pulsatile Low Levels (Anabolic):
        • Physiologic effect.
        • Mechanism: Directly stimulates osteoblast differentiation and activity.
        • Result: Increased bone formation and mass.
        • Net Effect: Bone growth.
        • Clinical Application: Teriparatide (recombinant PTH) for osteoporosis.
    • 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.

Bone composition

FeatureDiaphysis (Shaft)Epiphysis (End)
Outer LayerThick Cortical BoneThin shell of Cortical Bone
InteriorHollow Medullary Cavity with Yellow MarrowNetwork of Cancellous Bone with Red Marrow
CoveringPeriosteumArticular Cartilage (at joint surface), Periosteum elsewhere
High-Yield LesionEwing SarcomaGiant Cell Tumor

Graph View

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