Types of bone formation 

Types of bone formation 

• Enchondral

  • Examples:

    • Embryonic formation of long bones

    • Longitudinal growth (physis)

    • Fracture callus

  • Bone formed with demineralized bone matrix

  • Undifferentiated cells secrete cartilaginous matrix and differentiate into chondrocytes.

  • Matrix mineralizes and is invaded by vascular buds that bring osteoprogenitor cells.

  • Osteoclasts resorb calcified cartilage; osteoblasts form bone.

  • Bone replaces the cartilage model; cartilage is not converted to bone.

  • Embryonic formation of long bones (Figs. 1.7 and

    1.8)

     

  • Physis

 

• These bones are formed from the mesenchymal anlage at 6 weeks’ gestation.

• Vascular buds invade the mesenchymal model, bringing osteoprogenitor cells that differentiate into osteoblasts and form the primary ossification centers at 8 weeks.

• Differentiation stimulated in part by binding of Wnt protein to the lipoprotein receptor–related protein 5 (LRP5) or LRP6 receptor

• Marrow forms through resorption of the central cartilage anlage by invasion of myeloid precursor cells that are brought in by capillary buds.

• Secondary ossification centers develop at bone ends, forming the epiphyseal centers (growth plates) responsible for longitudinal growth.

• Arterial supply is rich during development, with an epiphyseal artery (terminates in the proliferative zone), metaphyseal arteries, nutrient arteries, and perichondrial arteries (Fig. 1.9).

   

• Two types of growth plates exist in immature long bones: (1) horizontal (the physis) and (2) spherical (growth of the epiphysis).

  • The spherical plate is less organized than the horizontal plate.

• Perichondrial artery—major source of nutrition of growth plate

• Delineation of physeal cartilage zones is based on growth (see Fig. 1.9) and function (Figs. 1.10 and 1.11).

   

  Table 1.4

   

  Types of Bone Formation

   

   

  Type of Ossification	Mechanism	Examples of Nor Mechanisms
  Enchondral	Bone replaces a cartilage model	Embryonic formation long bones Longitudinal growth (physis) Fracture callus Bone formed with the us of deminerali bone matri
  Intramembranous	Aggregates of undifferentiated mesenchymal cells differentiate into osteoblasts, which form bone	Embryonic fla bone formation Bone formatio during distraction osteogenes Blastema bone
  Appositional	Osteoblasts lay down new bone on existing bone	Periosteal bon enlargeme (width) The bone formation phase of b remodelin

   

   

  FIG. 1.7 Enchondral ossification of long bones. Note that phases F through J often occur after birth.

  From Moore KL: The developing human,

  Philadelphia, 1982, Saunders, p 346.

   

  • Reserve zone: cells store lipids, glycogen, and proteoglycan aggregates; decreased oxygen tension occurs in this zone.

    • Lysosomal storage diseases (e.g., Gaucher disease) can affect this zone.

  • Proliferative zone: growth is longitudinal, with stacking of chondrocytes (the top cell is the dividing “mother” cell), cellular proliferation, and matrix production; increases in oxygen tension and proteoglycans inhibit calcification.

    • Achondroplasia causes defects in this zone (see Fig. 1.11 ).

    • Growth hormone exerts its effect in the proliferative zone.

  • Hypertrophic zone:

    • Divided into three zones: maturation, degeneration, and provisional calcification

    • Normal matrix mineralization occurs in the lower hypertrophic zone: chondrocytes increase five times in size, accumulate calcium in their mitochondria, die, and release calcium from matrix vesicles.

    • Chondrocyte maturation is regulated by systemic hormones and local growth factors (PTH-related peptide inhibits chondrocyte maturation; Indian hedgehog protein is produced by chondrocytes and regulates the expression of PTH-related peptide).

    • Osteoblasts migrate from sinusoidal vessels and use cartilage as a scaffolding for bone formation.

    • Low oxygen tension and decreased proteoglycan aggregates aid in this process.

    • This zone widens in rickets (see Fig. 1.11), with little or no provisional calcification.

       

       

      FIG. 1.8 Development of a typical long bone: formation of the growth plate and secondary centers of

      ossification.

      From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 136.

       

       

       

      FIG. 1.9 Structure and blood supply of a typical growth plate.

      From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 166.

       

       

      FIG. 1.10 Zone

      structure, function, and physiologic features of the growth plate.

      From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 164.

       

       

       

      FIG. 1.11 Zone

      structure and pathologic defects of cellular metabolism. From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 165.

       

    • Mucopolysaccharide diseases (see Fig. 1.11) affect this zone, leading to chondrocyte degeneration.

    • Physeal fractures

      probably traverse several zones, depending on the type of loading ( Fig. 1.12 ).

Slipped capital femoral epiphysis (SCFE) occurs here.

• Except renal osteodystrophy (through metaphyseal spongiosa)

• Metaphysis

  • Adjacent to the physis and expands with skeletal growth

  • Osteoblasts from osteoprogenitor cells align on cartilage bars produced by physeal expansion.

  • Primary spongiosa (calcified cartilage bars) mineralizes to form woven bone and remodels to form secondary spongiosa and a “cutback zone” at the metaphysis.

  • Groove of Ranvier: supplies chondrocytes to the periphery for lateral growth (width)

  • Perichondrial ring of La Croix: dense fibrous tissue, primary membrane anchoring the periphery of the physis

  • Intramembranous ossification

    • Occurs without a cartilage model

    • Undifferentiated mesenchymal cells aggregate into layers (or membranes), differentiate into osteoblasts, and deposit an organic matrix that mineralizes.

    • Examples:

      • Embryonic flat bone formation

      • Bone formation during distraction osteogenesis

      • Blastema bone (in young children with amputations)

  • Appositional ossification

    • Osteoblasts align on the existing bone surface and

      lay down new bone.

    • Examples:

 

• Bone remodeling

  • General

• Periosteal bone enlargement (width)

• Bone formation phase of bone remodeling

   

• Cortical bone and cancellous bone are continuously remodeled throughout life by osteoclastic and osteoblastic activity (Fig. 1.13).

• Wolff’s law: remodeling occurs in response to mechanical stress.

  • Increasing mechanical stress increases bone gain.

  • Removing external mechanical stress increases bone loss, which is reversible (to varying degrees) on remobilization.

  • Piezoelectric remodeling occurs in response to electric charge.

  • The compression side of bone is electronegative, stimulating osteoblasts (formation).

  • The tension side of bone is electropositive, stimulating osteoclasts (resorption).

• Hueter-Volkmann law: remodeling occurs in small packets of cells known as basic multicellular units (BMUs).

  • Such remodeling is modulated by hormones and cytokines.

     

     

    FIG. 1.12 Histologic zone of failure varies with the type of loading applied to a specimen.

    From Moen CT, Pelker RR: Biomechanical and histological correlations in growth plate failure, J Pediatr Orthop 4:180–184, 1984.

     

    • Compressive forces inhibit growth; tension stimulates it.

    • Suggests that mechanical factors influence longitudinal growth, bone remodeling, and fracture repair

    • May play a role in scoliosis and Blount disease

    • Cortical bone remodeling

      • Osteoclastic tunneling (cutting cones; Fig. 1.14)

        • The head of the cutting cone is made up of osteoclasts followed by capillaries and osteoblasts.

        • Followed by layering of osteoblasts and successive deposition of layers of lamellae

    • Cancellous bone remodeling

      • Osteoclastic resorption followed by deposition of

new bone by osteoblasts

• Bone injury and repair

  • Fracture repair (Table 1.5)

    • Stages of fracture repair

      • Inflammation

        • Fracture hematoma provides hematopoietic cells capable of secreting growth factors.

        • Subsequently, fibroblasts, mesenchymal cells, and osteoprogenitor cells form granulation tissue around the fracture ends.

        • Osteoblasts (from surrounding osteogenic precursor cells) and fibroblasts proliferate.

      • Repair

 

• Primary callus response within 2 weeks

• For bone ends not in continuity, bridging (soft) callus occurs.

  • Soft callus is later replaced through enchondral ossification by woven bone (hard callus).

  • Medullary callus supplements the bridging callus, forming more slowly and later.

• Fracture healing varies with treatment method (Table 1.6).

  • In an unstable fracture, type II collagen is expressed early, followed by type I collagen.

  • Amount of callus is inversely proportional to extent of immobilization.

• Progenitor cell differentiation

  • High strain promotes

     

  • Remodeling

development of fibrous tissue.

• Low strain and high oxygen tension promote development of woven bone.

• Intermediate strain and low oxygen tension promote development of cartilage.

  • Remodeling begins in middle of repair phase and continues long after clinical healing (up to 7 years).

  • Allows bone to assume its normal configuration and shape according to stress exposure (Wolff ’s law)

  • Throughout, woven bone is replaced with lamellar bone.

  • Fracture healing is complete when the marrow space is repopulated.

  • Biochemistry of fracture healing (Table 1.7)

    • Growth factors of bone (Table 1.8)

      • BMP-2: acute open tibial fractures

      • BMP-3: no osteogenic activity

      • BMP-4: associated with fibrodysplasia ossificans progressiva

      • BMP-7: tibial nonunions

      • BMPs activate intracellular signal molecules called SMADs to cause osteoblastic differentiation

    • Endocrine effects on fracture healing (Table 1.9)

      • Head injury

        • Can increase the osteogenic response to fracture

      • Nicotine (smoking)

        • Increases time to fracture healing

        • Increases risk of nonunion (particularly in the tibia)

        • Decreases strength of

          fracture callus

        • Increases risk of pseudarthrosis after lumbar fusion by up to 500%

      • Nonsteroidal antiinflammatory drugs

        • Have adverse effects on fracture healing and healing of lumbar spinal fusions

        • Cyclooxygenase-2 (COX-2) activity is required for normal enchondral ossification

          during fracture healing.

      • Quinolone antibiotics

        • Toxic to chondrocytes and inhibit fracture healing

      • Ultrasound and fracture healing

        • Low-intensity pulsed ultrasound (30 mW/cm 2 ) accelerates fracture healing and increases the mechanical strength of callus

        • A cellular response to the mechanical energy of ultrasound has been postulated.

      • Effect of radiation on bone

        • High-dose irradiation causes long-term changes within the haversian system and decreases cellularity.

      • Diet and fracture healing

      • Protein malnutrition results in negative effects on fracture healing:

      • Decreased periosteal and external callus

      • Decreased callus strength and stiffness

      • Increased fibrous tissue within callus

      • In experimental models, oral supplementation with essential amino acids improves bone mineral density in fracture callus.

         

         

         

        FIG. 1.13 Bone remodeling. Osteoclasts dissolve the mineral from the bone matrix. Osteoblasts produce new bone (osteoid) that fills in the resorption pit.

        Some osteoblasts are left within the bone matrix as osteocytes.

        From Firestein GS et al, editors: Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2008, Saunders.

         

Electricity and fracture healing

• Definitions

  • Stress-generated potentials

    • Piezoelectric effect: tissue charges are displaced secondary to mechanical forces.

    • Streaming potentials: occur when electrically charged fluid is forced over a cell membrane that has a fixed charge

    •  

Transmembran potentials: generated by cellular metabolism

 

 

FIG. 1.14 Cortical bone remodeling. (A) Longitudinal and cross sections of a time line illustrating formation of an osteon.

Osteoclasts cut a cylindrical channel through bone.

Osteoblasts follow, laying down bone on the surface of the channel until matrix surrounds the central blood vessel of the newly formed osteon (closing cone of a new osteon). (B) Photomicrograph of a cutting cone. (C) Higher-magnification photomicrograph; osteoclastic resorption can be more clearly appreciated.

A from Standring S et al,

editors: Functional anatomy of the musculoskeletal system. In Gray’s anatomy, ed 40, London, 2008, Elsevier,

Fig. 5-19.

 

Table 1.5

 

Biologic and Mechanical Factors Influencing Fracture Healing

 

 

Biologic factors	Patient age Comorbid medical conditions Functional level Nutritional status Nerve function Vascular injury Hormones Growth factors Health of the soft tissue envelope Sterility (in open fractures) Cigarette smoke Local pathologic conditions Level of energy imparted Type of bone affected Extent of bone loss
Mechanical factors	Soft tissue attachments to bone Stability (extent of immobilization) Anatomic location Level of energy imparted Extent of bone loss

 

 

 

Table 1.6

 

Type of Fracture Healing Based on Type of Stabilization

 

 

 

Compression plate

Periosteal bridging callus and interfragmentary enchondral ossification

Type of

Stabilization

Predominant Type of

Healing

Cast (closed treatment)

 

Primary cortical healin (cutting-cone type

	haversian remodeling)
Intramedullary nail	Early: periosteal bridging callus; enchondral ossification Late: medullary callus and intramembran ossification
External fixator	Dependent on extent rigidity:   Less rigid: periosteal bridging callus; enchondral ossification   More rigid: primary cortical healing; intramembranous ossification
Inadequate immobilization with adequate blood supply	Hypertrophic nonuni (failed enchondral ossification); type I collagen predominates
Inadequate immobilization without adequate blood supply	Atrophic nonunion
Inadequate reduction with displacement at the fracture site	Oligotrophic nonunio

 

• Types of electrical stimulation

  • Direct current: stimulates an inflammatory-like response, resulting in decreased oxygen concentrations and

    increase in tissue pH (similar to effects of an implantable bone stimulator).

  • Alternating current: “capacity-coupled generators”; affects cyclic AMP (cAMP) synthesis, collagen synthesis, and calcification during repair stage

  • Pulsed electromagnetic fields (PEMFs): initiate calcification of fibrocartilage (but not fibrous tissue)

Table 1.9

 

Endocrine Effects on Fracture Healing

 

 

Hormone Effect Mechanism
Cortisone	–	Decreased callus proliferation
Calcitonin	+?	Unknown
Thyroid hormone, PTH	+	Bone remodeling
Growth hormone	+	Increased callus volume

 

 

• Types of bone formation (Table 1.4)

  • Enchondral

    • Examples:

      • Embryonic formation of long bones

      • Longitudinal growth (physis)

      • Fracture callus

    • Bone formed with demineralized bone matrix

    • Undifferentiated cells secrete cartilaginous matrix and differentiate into chondrocytes.

    • Matrix mineralizes and is invaded by vascular buds that bring osteoprogenitor cells.

    • Osteoclasts resorb calcified cartilage; osteoblasts form bone.

    • Bone replaces the cartilage model; cartilage is not converted to bone.

    • Embryonic formation of long bones (Figs. 1.7 and

      1.8)

       

    • Physis

 

• These bones are formed from the mesenchymal anlage at 6 weeks’ gestation.

• Vascular buds invade the mesenchymal model, bringing osteoprogenitor cells that differentiate into osteoblasts and form the primary ossification centers at 8 weeks.

• Differentiation stimulated in part by binding of Wnt protein to the lipoprotein receptor–related protein 5 (LRP5) or LRP6 receptor

• Marrow forms through resorption of the central cartilage anlage by invasion of myeloid precursor cells that are brought in by capillary buds.

• Secondary ossification centers develop at bone ends, forming the epiphyseal centers (growth plates) responsible for longitudinal growth.

• Arterial supply is rich during development, with an epiphyseal artery (terminates in the proliferative zone), metaphyseal arteries, nutrient arteries, and perichondrial arteries (Fig. 1.9).

   

• Two types of growth plates exist in immature long bones: (1) horizontal (the physis) and (2) spherical (growth of the epiphysis).

  • The spherical plate is less organized than the horizontal plate.

• Perichondrial artery—major source of nutrition of growth plate

• Delineation of physeal cartilage zones is based on growth (see Fig. 1.9) and function (Figs. 1.10 and 1.11).

   

  Table 1.4

   

  Types of Bone Formation

   

   

  Type of Ossification	Mechanism	Examples of Nor Mechanisms
  Enchondral	Bone replaces a cartilage model	Embryonic formation long bones Longitudinal growth (physis) Fracture callus Bone formed with the us of deminerali bone matri
  Intramembranous	Aggregates of undifferentiated mesenchymal cells differentiate into osteoblasts, which form bone	Embryonic fla bone formation Bone formatio during distraction osteogenes Blastema bone
  Appositional	Osteoblasts lay down new bone on existing bone	Periosteal bon enlargeme (width) The bone formation phase of b remodelin

   

   

  FIG. 1.7 Enchondral ossification of long bones. Note that phases F through J often occur after birth.

  From Moore KL: The developing human,

  Philadelphia, 1982, Saunders, p 346.

   

  • Reserve zone: cells store lipids, glycogen, and proteoglycan aggregates; decreased oxygen tension occurs in this zone.

    • Lysosomal storage diseases (e.g., Gaucher disease) can affect this zone.

  • Proliferative zone: growth is longitudinal, with stacking of chondrocytes (the top cell is the dividing “mother” cell), cellular proliferation, and matrix production; increases in oxygen tension and proteoglycans inhibit calcification.

    • Achondroplasia causes defects in this zone (see Fig. 1.11 ).

    • Growth hormone exerts its effect in the proliferative zone.

Hypertrophic zone:

• Divided into three zones: maturation, degeneration, and provisional calcification

• Normal matrix mineralization occurs in the lower hypertrophic zone: chondrocytes increase five times in size, accumulate calcium in their mitochondria, die, and release calcium from matrix vesicles.

• Chondrocyte maturation is regulated by systemic hormones and local growth factors (PTH-related peptide inhibits chondrocyte maturation; Indian hedgehog protein is produced by chondrocytes and regulates the expression of PTH-related peptide).

• Osteoblasts migrate from sinusoidal vessels and use cartilage as a scaffolding for bone formation.

• Low oxygen tension and decreased proteoglycan aggregates aid in this process.

• This zone widens in rickets (see Fig. 1.11), with little or no provisional calcification.

   

   

  FIG. 1.8 Development of a typical long bone: formation of the growth plate and secondary centers of

  ossification.

  From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 136.

   

   

   

  FIG. 1.9 Structure and blood supply of a typical growth plate.

  From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 166.

   

   

  FIG. 1.10 Zone

  structure, function, and physiologic features of the growth plate.

  From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 164.

   

   

   

  FIG. 1.11 Zone

  structure and pathologic defects of cellular metabolism. From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 165.

   

  • Mucopolysaccharide diseases (see Fig. 1.11) affect this zone, leading to chondrocyte degeneration.

  • Physeal fractures

    probably traverse several zones, depending on the type of loading ( Fig. 1.12 ).

• Slipped capital femoral epiphysis (SCFE) occurs here.

  • Except renal osteodystrophy (through metaphyseal spongiosa)

  • Metaphysis

  • Adjacent to the physis and expands with skeletal growth

    • Osteoblasts from osteoprogenitor cells align on cartilage bars produced by physeal expansion.

    • Primary spongiosa (calcified cartilage bars) mineralizes to form woven bone and remodels to form secondary spongiosa and a “cutback zone” at the metaphysis.

  • Groove of Ranvier: supplies chondrocytes to the periphery for lateral growth (width)

Perichondrial ring of La Croix: dense fibrous tissue, primary membrane anchoring the periphery of the physis

• Intramembranous ossification

  • Occurs without a cartilage model

Undifferentiated mesenchymal cells aggregate into layers (or membranes), differentiate into osteoblasts, and deposit an organic matrix that mineralizes.

• Examples:

  • Embryonic flat bone formation

  • Bone formation during distraction osteogenesis

  • Blastema bone (in young children with amputations)

• Appositional ossification

  • Osteoblasts align on the existing bone surface and

    lay down new bone.

  • Examples:

 

• Bone remodeling

  • General

• Periosteal bone enlargement (width)

• Bone formation phase of bone remodeling

   

• Cortical bone and cancellous bone are continuously remodeled throughout life by osteoclastic and osteoblastic activity (Fig. 1.13).

• Wolff’s law: remodeling occurs in response to mechanical stress.

  • Increasing mechanical stress increases bone gain.

  • Removing external mechanical stress increases bone loss, which is reversible (to varying degrees) on remobilization.

  • Piezoelectric remodeling occurs in response to electric charge.

  • The compression side of bone is electronegative, stimulating osteoblasts (formation).

  • The tension side of bone is electropositive, stimulating osteoclasts (resorption).

• Hueter-Volkmann law: remodeling occurs in small packets of cells known as basic multicellular units (BMUs).

  • Such remodeling is modulated by hormones and cytokines.

     

     

    FIG. 1.12 Histologic zone of failure varies with the type of loading applied to a specimen.

    From Moen CT, Pelker RR: Biomechanical and histological correlations in growth plate failure, J Pediatr Orthop 4:180–184, 1984.

     

    • Compressive forces inhibit growth; tension stimulates it.

    • Suggests that mechanical factors influence longitudinal growth, bone remodeling, and fracture repair

    • May play a role in scoliosis and Blount disease

    • Cortical bone remodeling

      • Osteoclastic tunneling (cutting cones; Fig. 1.14)

        • The head of the cutting cone is made up of osteoclasts followed by capillaries and osteoblasts.

        • Followed by layering of osteoblasts and successive deposition of layers of lamellae

    • Cancellous bone remodeling

      • Osteoclastic resorption followed by deposition of

new bone by osteoblasts

• Bone injury and repair

  • Fracture repair (Table 1.5)

    • Stages of fracture repair

      • Inflammation

        • Fracture hematoma provides hematopoietic cells capable of secreting growth factors.

        • Subsequently, fibroblasts, mesenchymal cells, and osteoprogenitor cells form granulation tissue around the fracture ends.

        • Osteoblasts (from surrounding osteogenic precursor cells) and fibroblasts proliferate.

      • Repair

 

• Primary callus response within 2 weeks

• For bone ends not in continuity, bridging (soft) callus occurs.

  • Soft callus is later replaced through enchondral ossification by woven bone (hard callus).

  • Medullary callus supplements the bridging callus, forming more slowly and later.

• Fracture healing varies with treatment method (Table 1.6).

  • In an unstable fracture, type II collagen is expressed early, followed by type I collagen.

  • Amount of callus is inversely proportional to extent of immobilization.

• Progenitor cell differentiation

  • High strain promotes

     

  • Remodeling

development of fibrous tissue.

• Low strain and high oxygen tension promote development of woven bone.

• Intermediate strain and low oxygen tension promote development of cartilage.

  • Remodeling begins in middle of repair phase and continues long after clinical healing (up to 7 years).

  • Allows bone to assume its normal configuration and shape according to stress exposure (Wolff ’s law)

  • Throughout, woven bone is replaced with lamellar bone.

  • Fracture healing is complete when the marrow space is repopulated.

  • Biochemistry of fracture healing (Table 1.7)

    • Growth factors of bone (Table 1.8)

      • BMP-2: acute open tibial fractures

      • BMP-3: no osteogenic activity

      • BMP-4: associated with fibrodysplasia ossificans progressiva

      • BMP-7: tibial nonunions

      • BMPs activate intracellular signal molecules called SMADs to cause osteoblastic differentiation

    • Endocrine effects on fracture healing (Table 1.9)

      • Head injury

        • Can increase the osteogenic response to fracture

      • Nicotine (smoking)

        • Increases time to fracture healing

        • Increases risk of nonunion (particularly in the tibia)

        • Decreases strength of

          fracture callus

        • Increases risk of pseudarthrosis after lumbar fusion by up to 500%

      • Nonsteroidal antiinflammatory drugs

        • Have adverse effects on fracture healing and healing of lumbar spinal fusions

        • Cyclooxygenase-2 (COX-2) activity is required for normal enchondral ossification

          during fracture healing.

      • Quinolone antibiotics

        • Toxic to chondrocytes and inhibit fracture healing

      • Ultrasound and fracture healing

        • Low-intensity pulsed ultrasound (30 mW/cm 2 ) accelerates fracture healing and increases the mechanical strength of callus

        • A cellular response to the mechanical energy of ultrasound has been postulated.

      • Effect of radiation on bone

        • High-dose irradiation causes long-term changes within the haversian system and decreases cellularity.

      • Diet and fracture healing

      • Protein malnutrition results in negative effects on fracture healing:

      • Decreased periosteal and external callus

      • Decreased callus strength and stiffness

      • Increased fibrous tissue within callus

In experimental models, oral supplementation with essential amino acids improves bone mineral density in fracture callus.

 

 

 

FIG. 1.13 Bone remodeling. Osteoclasts dissolve the mineral from the bone matrix. Osteoblasts produce new bone (osteoid) that fills in the resorption pit.

Some osteoblasts are left within the bone matrix as osteocytes.

From Firestein GS et al, editors: Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2008, Saunders.

 

• Electricity and fracture healing

  • Definitions

    • Stress-generated potentials

      • Piezoelectric effect: tissue charges are displaced secondary to mechanical forces.

      • Streaming potentials: occur when electrically charged fluid is forced over a cell membrane that has a fixed charge

      •  

Transmembran potentials: generated by cellular metabolism

 

 

FIG. 1.14 Cortical bone remodeling. (A) Longitudinal and cross sections of a time line illustrating formation of an osteon.

Osteoclasts cut a cylindrical channel through bone.

Osteoblasts follow, laying down bone on the surface of the channel until matrix surrounds the central blood vessel of the newly formed osteon (closing cone of a new osteon). (B) Photomicrograph of a cutting cone. (C) Higher-magnification photomicrograph; osteoclastic resorption can be more clearly appreciated.

A from Standring S et al,

editors: Functional anatomy of the musculoskeletal system. In Gray’s anatomy, ed 40, London, 2008, Elsevier,

Fig. 5-19.

 

Table 1.5

 

Biologic and Mechanical Factors Influencing Fracture Healing

 

 

Biologic factors	Patient age Comorbid medical conditions Functional level Nutritional status Nerve function Vascular injury Hormones Growth factors Health of the soft tissue envelope Sterility (in open fractures) Cigarette smoke Local pathologic conditions Level of energy imparted Type of bone affected Extent of bone loss
Mechanical factors	Soft tissue attachments to bone Stability (extent of immobilization) Anatomic location Level of energy imparted Extent of bone loss

 

 

 

Table 1.6

 

Type of Fracture Healing Based on Type of Stabilization

 

 

 

Compression plate

Periosteal bridging callus and interfragmentary enchondral ossification

Type of

Stabilization

Predominant Type of

Healing

Cast (closed treatment)

 

Primary cortical healin (cutting-cone type

	haversian remodeling)
Intramedullary nail	Early: periosteal bridging callus; enchondral ossification Late: medullary callus and intramembran ossification
External fixator	Dependent on extent rigidity:   Less rigid: periosteal bridging callus; enchondral ossification   More rigid: primary cortical healing; intramembranous ossification
Inadequate immobilization with adequate blood supply	Hypertrophic nonuni (failed enchondral ossification); type I collagen predominates
Inadequate immobilization without adequate blood supply	Atrophic nonunion
Inadequate reduction with displacement at the fracture site	Oligotrophic nonunio

 

• Types of electrical stimulation

  • Direct current: stimulates an inflammatory-like response, resulting in decreased oxygen concentrations and

    increase in tissue pH (similar to effects of an implantable bone stimulator).

  • Alternating current: “capacity-coupled generators”; affects cyclic AMP (cAMP) synthesis, collagen synthesis, and calcification during repair stage

  • Pulsed electromagnetic fields (PEMFs): initiate calcification of fibrocartilage (but not fibrous tissue)

    Table 1.7

     

    Biochemical Steps of Fracture Healing

     

     

    Step	Collagen Type
    Mesenchymal	I, II, III, V
    Chondroid	II, IX
    Chondroid-osteoid	I, II, X
    Osteogenic	I

     

     

     

    Table 1.8

     

    Growth Factors of Bone

     

     

    Growth Factor Action Notes
    Bone morphogenetic protein	Osteoinductive; stimulates bone formation Induces metaplasia of mesenchymal cells into osteoblasts	Target cells of BMP are the undifferentiated perivascular mesenchymal cells; signals through serine-threonine kinase receptors Intracellular molecules called SMADs serve as signaling mediators for BMPs
    Transforming growth factor–β	Induces mesenchymal cells to produce type II collagen and proteoglycans Induces osteoblasts to synthesize collagen	Found in fracture hematomas; believed to regulate cartilage and bone formation in fracture callus; signals through serine/threonine kinase receptors Coating porous implants with TGF-β enhances bone ingrowth
    IGF-2	Stimulates type I collagen, cellular proliferation, cartilage matrix synthesis, and bone formation	Signals through tyrosine kinase receptors
    Platelet-derived growth factor	Attracts inflammatory cells to the fracture site (chemotactic)	Released from platelets; signals through tyrosine kinase receptors

Table 1.9

 

Endocrine Effects on Fracture Healing

 

 

Hormone Effect Mechanism
Cortisone	–	Decreased callus proliferation
Calcitonin	+?	Unknown
Thyroid hormone, PTH	+	Bone remodeling
Growth hormone	+	Increased callus volume