and differentiation of chondroprogenitor cells into chondrocytes. Cartilage callus provides immediate mechanical stability and promotes sites for cell attachment and new bone formation.
Fig. 8.3 Receptor activator of nuclear factor kappa-B ligand pathway and mechanism of action for bisphosphates.
1. Factors influencing callous phase of fracture healing (▶Fig. 8.1).
a. TGF-β activates fibroblasts to induce collagen formation, endothelial cells for angiogenesis, chondroprogenitor cells, and mesenchymal cells.
b. PDGF stimulates cellular replication (mitogenesis), increasing cell populations of mesenchymal and osteoprogenitor cells.
c. PDGF activates macrophages resulting in further debridement and triggers a second source of growth factors released from the host tissues by macrophages.
2. Mature callous phase involves mineralization of the cartilaginous callus matrix. Chondrocyte proliferation declines and hypertrophic chondrocytes predominate. Chondroclasts remove the calcified cartilage, and blood vessels develop with perivascular mesenchymal stem cells that differentiate into bone-forming osteoblasts.
3. Remodeling phase (▶Fig. 8.1).
a. Osteoclasts are responsible for fracture callus remodeling.
b. Interaction between osteoblastic and osteoclastic function leads to successful remodeling.
4. Juvenile osteoblasts secrete factors that induce fully differentiated osteoblasts to express ligands that regulate the activity of osteoclasts.
5. Receptor activator of nuclear factor kappa-B ligand (RANKL), found on osteoblasts, activates osteoclasts (▶Fig. 8.3).
a. Osteoclastic activity is triggered by osteoblasts’ surface-bound RANKL activating the osteoclasts’ surface-bound RANK.
b. Activation of RANK by RANKL promotes the maturation of preosteoclasts into osteoclasts.
6. RANKL inhibitor, denosumab prevents maturation of osteoclasts by binding to and inhibiting RANKL.
Fig. 8.4 Radiograph of a patient with a complete atypical femoral fracture. Note the substantially transverse orientation of the fracture line at the lateral cortex, the medial spike, and the generalized cortical thickening.
7. Estrogen inhibits the formation and activation of the bone-resorbing osteoclasts via suppression of RANKL signaling within the osteoclast.
8. Parathyroid hormone (PTH) binds to osteoblasts (osteoclasts do not have a receptor for PTH) stimulating them to increase expression of RANKL.
a. PTH also inhibits osteoblast expression of osteoprotegerin (OPG).
b. The binding of RANKL to RANK stimulates osteoclast precursors to fuse, forming new osteoclasts, which enhances bone resorption.
c. Teriparatide (Forteo) is the recombinant form of PTH. Intermittent use activates osteoblasts more than osteoclasts and leads to an overall increase in bone.
d. Teriparatide is used in the treatment of some forms of osteoporosis.
9. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis which leads to slowing of bone loss (▶Fig. 8.3).
a. There are two classes of bisphosphonates: the N-containing and non-N-containing bisphosphonates.
i. Non-nitrogenous bisphosphonates (diphosphonates) are metabolized and replace terminal pyrophosphate moiety of adenosine triphosphate (ATP), forming a nonfunctional molecule. It competes with ATP for cellular energy metabolism. ATP loss causes osteoclast death, with decrease in the breakdown of bone.
ii. Nitrogenous bisphosphonates promote inhibition of osteoclast ruffled border with dysfunction of resorption.
b. Long-term bisphosphonate use can result in oversuppression of bone turnover (atypical femoral fractures; ▶Fig. 8.4).
III. Categories of Available Biologic Adjuvants for Clinical Use
A. Autogenous cellular materials (osteogenic) (▶Table 8.1).
1. Autogenous iliac crest bone graft (AICBG, gold standard)—other sites include posterior iliac crest, proximal tibia, distal femur, calcaneus, and distal radius. Rapid revascularization occurs and performs best in well-vascularized beds.
a. Approximately 30 mL of graft reliably harvested from an anterior iliac crest.
b. Complications related to the harvest and limited availability.
2. Reamer Irrigator Aspirator (RIA; Synthes, Paoli, PA)—the medullary canal of the femur or tibia is reamed with a collection device and delivers 30 to 90 mL for grafting.
a. Elevated osteoinductive growth factors, osteoprogenitor/endothelial progenitor cell types are used compared to AICBG.
b. Cell viability and osteogenic potential is equal in both RIA and AICBG.
3. Bone marrow aspirate concentrate (BMAC; ▶Fig. 8.5).
a. BMAC has a high concentration of viable connective tissue progenitors for grafting.
b. Bone formation is dependent on the number of cells available in the graft.
i. Technologies include methods for harvest and concentration of bone-forming cells.
ii. Implanted BMAC combined with bioactive scaffold matrix allow differentiation into an osteoblastic cell lineage for bone repair.
iii. Allogeneic human undifferentiated mesenchymal “stem cell grafts” from cadaver donors are clinically available. There is limited clinical data available for these, therefore use with caution.
4. Platelet concentrates (PC)—platelet activation following injury or surgical insult. Platelets release protein content (degranulation) of more than 30 bioactive proteins. Primary factors include PDGF and TGF-β.
a. The PDGF
i. Primary function of PDGF is to stimulate cellular replication (mitogenesis).
ii. It increases cell populations of mesenchymal stem cells and osteoprogenitor cells.
iii. It also activates macrophages resulting in debridement of the surgical or traumatic site.
b. Transforming growth factor β (TGF-β)
i. It stimulates proliferation of osteoblast precursor cells and collagen.
ii. Increases osteoblast cell line, and the upregulation of osteoblasts.
Fig. 8.5 (a, b) The aspiration technique is