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A. Structuresnavigator

  1. Epiphysis
  2. Epiphyseal Plate
  3. Metaphysis
  4. Diaphysis

B. Cells and Layersnavigator

  1. Periosteum
  2. Endosteum
  3. Osteoblasts
  4. Osteocytes
  5. Osteoclasts
  6. Spicules (found in cancellous bone)
  7. Marrow
  8. Fatty Tissue

C. Bone as Dynamic Tissue [1,14] navigator

  1. Remodels
  2. Repairs
  3. Atrophy occurs without use or in reduced gravity
  4. Infarction
  5. Infection
  6. Alterations in environment
  7. Markers of Bone Synthesis and Breakdown
    1. Alkaline Phosphatase (Heat Labile) - bone formation
    2. Osteocalcin (serum) - marker for bone formation
    3. Collagen Degradation Products are markers for bone destruction (remodeling)
  8. Bone Composition
    1. Bone is composed of type I collagen stiffened by crystals of calcium hydroxyapatite
    2. Increases in hydroxyapatite increase stiffness but reduce flexibility
    3. Human bone is ~60% mineralized
    4. Triple helix structure of type I collagen confers strength and tension
    5. These helices are cross linked to keep the helices fastened
    6. Bone fabric woven at submicroscopic, microscopic, macroscopic levels to resist cracking
  9. Bone Formation
    1. Requires Vitamins C and D
    2. Bone morphogenic proteins (BMPs) stimulate new bone formation
    3. Prominent bone growth during puberty with growth hormone and IGF-1 increases
    4. Bone use generates pizioelectric currents which stimulates remodeling
    5. Bone atrophy occurs from lack of use
    6. Endochondral bone is formed by calcification of cartilage
    7. Periosteal appositional bone is formed by addition of new bone on top of older bone
  10. Bone Types
    1. Cortical Bone - consists of overlapping parallel osteons; used to build long bones
    2. Long bones are levers for loading and movement, rigidity favored over flexibility
    3. Long bones grow in length by endochondral apposition on inner surface periosteal apposition on outer surface
    4. Trabecular Bone - vertebral bodies, function like a spring which can absorb energy
    5. Trabecular bone deforms more, but tolerates less loading, than long bones
    6. Interconnecting trabecular plates achieve lightness and flexibility over stiffness
  11. Bone Changes (ABCs)
    1. Alignment
    2. Bone Density
    3. Cartilage
    4. Soft Tissues

D. Cartilage and Osteoblasts [2,3] navigator

  1. Cartilage [4]
    1. Formed by chondrocytes
    2. Cartilage an avascular tissue with poor repair / healing properties
    3. Induction of cartilage production by chondrocytes involves soluble factors
    4. Parathyroid hormone related peptide (PTH-RP) induce chondrocyte proliferation and blocks chondrocyte differentiation
    5. Indian hedgehog protein induces PTH-RP protein in perichondrial cells
  2. Osteoblasts [2,5,14]
    1. Responsible for deposition of new cartilage (new collagen type) and mineralization
    2. Derived from pluripotent mesenchymal stem cells and preosteoblastic cells
    3. Circulate in small numbers in serum, increasing numbers during rapid bone growth [6]
    4. Differentiation to osteoblasts requires Runx-2 (core binding factor alpha, CBFA1)
    5. Main stimulators are Insulin-like growth factor 1 (IGF-1), BMPs and Wnt [14]
    6. IGF-1 stimulates various proteins including BMPs and osteocalcin in osteoblasts
    7. IGF-1 mediates the effects of growth hormone on long bone growth
    8. Wnt and BMP have similar stimulatory effects, but signal through different pathways
    9. A matrix based on Type 1 collagen is laid down and osteoblasts mineralize it
    10. Play a central role with osteoclasts in bone remodeling
    11. Parathyroid hormone (PTH) stimulates osteoblast production

E. Osteoclastsnavigator

  1. Derived from marrow cells similar to monocyte/macrophage precursors
  2. Osteoclast Development [5,7,8,9]
    1. Development of osteoclasts requires M-CSF, GM-CSF, IL-6 and IL-11
    2. Receptor activator for NF-kB (RANK) ligand (RANKL) stimulates osteoclast formation [8]
    3. RANKL also induces proliferation, differentiation, and activation of osteoclasts [12]
    4. Osteoprotegerin (OPG) functions as decoy receptor for RANKL
    5. OPG blocks osteoclast development, suppresses coupled process of skeletal turnover
    6. RANKL/OPG ratio is altered in many bone disorders [12]
    7. Blockade of RANKL with monoclonal antibody increases bone mass, reduces turnover [13]
    8. Mutations in OPG cause some cases of Juvenile Paget's Disease
    9. Low levels of RANKL associated with increased risk of nontraumatic fracture [10]
    10. Glucocorticoids, hyperparathyroidism, post-menopausal osteoporosis increase RANKL/OPG
    11. Many tumors which home to bone express RANKL in various forms
  3. Osteoclast Stimulation [5]
    1. Activation of osteoclasts is critical to normal bone turnover
    2. Interleukin (IL-), IL 1, and tumor necrosis factor alpha (TNFa) stimulate osteoclasts
    3. Pulsatile (normal physiologic) PTH primarily stimulates osteoblasts
    4. Chronic constant PTH stimulates osteoclasts
    5. Osteoblasts can make some of these mediators stimulating osteoclasts
    6. Osteoclasts use integrin alpha V beta 3 (aVß3) for binding to bone
    7. Estrogen (and androgens) both inhibit interleukin 6 (IL-6) production
  4. Osteoclast Histology
    1. Osteoclasts form lines of remodeling which increase with age [9]
    2. Apical surface is ruffled and eats bone by secreting protons (H+)
    3. Protons are created by carbonic anhydrase and pumped out by ATPase
    4. Basolateral surface performs exocytosis and secretes bicarbonate (HCO3-)
  5. Osteoclast Activity [9,11]
    1. Resorption of bone is carried out by activated, multinucleated osteoclasts
    2. Apical surface responsible for "eating" hydroxyapatite from bone using acid (H+)
    3. Also secrete collagenase, tissue plasminogen activator, metalloproteinases, other proteins
    4. Increased, unbalanced osteoclast activity is major contributor to bone loss in peri-menopausal women
    5. This is a rapid process just after menopause begins and continues for up to 3 years
    6. Osteoblast activity also increases due to coupling, but is not sufficient for balance

F. Bone Remodeling [2,3,11,14] navigator

  1. Remodeling of bone occurs throughout life in osteoclast-osteoblast cycle
  2. Temporally regulated process of coordinated resorption and formation of skeletal tissue
  3. Resorption by osteoclasts initiates remodeling process
    1. Once bone is resorbed (3-5 weeks), osteoblasts are attracted
    2. Osteoblast attraction by local increased calcium, TGF-ß, others which inhibit osteoclasts
    3. Inhibited osteoclasts separate from bone
    4. Eventually they undergo apoptotic cell death
    5. Estrogen inhibits osteoclasts
    6. Calcitonin can inhibit osteoclasts
    7. Bisphosphonates are the most potent inhibitors of osteoclasts known
    8. Denosomab, a monoclonal against RANKL, is also a potent inhibitor [13]
  4. In general, amount of new bone formed is slightly smaller than that which was resorbed
  5. Bone Reactions to Injury
    1. Fast: little calcification
    2. Slower: more calcification

References navigator

  1. Seeman E and Delmas PD. 2006. NEJM. 354(21):2250 abstract
  2. Canalis E. 2005. NEJM. 352(19):2014 abstract
  3. Weinstein RS and Manolagas SC. 2000. Am J Med. 108(2):153 abstract
  4. Strewler GJ. 2000. NEJM. 342(3):177 abstract
  5. Roodman GD. 2004. NEJM. 350(16):1655 abstract
  6. Eghbali-Fatourechi GZ, Lamsam J, Fraser D, et al. 2005. NEJM. 352(19):1959 abstract
  7. Whyte MP, Obrecht SE, Finnegan PM, et al. 2002. 347(3):175 abstract
  8. Hofbauer LC and Schoppet M. 2004. JAMA. 292(4):490 abstract
  9. Tolar J, Teitelbaum SL, Orchard PJ. 2004. NEJM. 351(27):2839 abstract
  10. Schett G, Kiechl S, Redlich K, et al. 2004. JAMA. 291(9):1108 abstract
  11. Khosla S. 2003. NEJM. 349(13):1277 abstract
  12. Whyte MP. 2006. NEJM. 354(8):860 abstract
  13. McClung MR, Lewiecki M, Cohen SB, et al. 2006. NEJM. 354(8):821 abstract
  14. Canalis E, Giustina A, Bilezikian JP. 2007. NEJM. 357(9):905 abstract