|
http://upload.orthobullets.com/topic/9009/images/fractue healing.jpg
Introduction
  •  Fracture healing involves a complex and sequential set of events to restore injured bone to pre-fracture condition  
    • stem cells are crucial to the fracture repair process
      • the periosteum and endosteum are the two major sources
  • Fracture stability dictates the type of healing that will occur
    • the mechanical stability governs the mechanical strain
    • when the strain is below 2%, primary bone healing will occur
    • when the strain is between 2% and 10%, secondary bone healing will occur
  • Modes of bone healing
    • primary bone healing (strain is < 2%)
      • intramembranous healing
        • occurs via Haversian remodeling
      • occurs with absolute stability constructs
    • secondary bone healing (strain is between 2%-10%)
      • involves responses in the periosteum and external soft tissues. 
        • enchondral healing
          • occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating, intramedullary nailing, etc. 
    • bone healing may occur as a combination of the above two process depending on the stability throughout the construct 
 
Type of Fracture Healing with Treatment Technique
Cast treatment Secondary: enchondral ossification
External fixation Secondary: enchondral ossification
IM nailing Secondary: enchondral ossification
Compression plate Primary: Haversian remodeling
 
Secondary Bone Healing

Stages of Fracture Healing
Inflammation
  • Hematoma forms and provides source of hemopoieitic cells capable of secreting growth factors.
  • Macrophages, neutrophils and platelets release several cytokines
    • this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12
    • they may be detected as early as 24 hours post injury
    • lack of TNF-Alpha (ie. HIV) results in delay of both enchondral/intramembranous ossification
  • Fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around fracture ends 
    • during fracture healing granulation tissue tolerates the greatest strain before failure 
  • Osteoblasts and fibroblasts proliferate
    • inhibition of COX-2 (ie NSAIDs) causes repression of runx-2/osterix, which are critical for differentiation of osteoblastic cells
Repair
  • Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft callus forms.
    • the mechanical environment drives differentiation of either osteoblastic (stable enviroment) or chondryocytic (unstable environment) lineages of cells
  • Enchondral ossification converts soft callus to hard callus (woven bone). Medullary callus also supplements the bridging soft callus
    • cytokines drive chondocytic differentiation. 
    • cartilage production provides provisional stabilization 
  • Type II collagen (cartilage) is produced early in fracture healing and then followed by type I collagen (bone) expression
  • Amount of callus is inversely proportional to extent of immobilization 
    • primary cortical healing occurs with rigid immobilization (ie. compression plating)
    • enchondral healing with periosteal bridging occurs with closed treatment
Remodeling
  • Begins in middle of repair phase and continues long after clinical union
    • chondrocytes undergo terminal differentiation
      • complex interplay of signaling pathways including, indian hedgehog (Ihh), parathyroid hormone related peptide (PTHrP), FGF and BMP
      • these molecules are also involved in terminal differentiation of the appendicular skeleton
    • type X collagen types is expressed by hypertrophic chondrocytes as the extraarticular matrix undergoes calcification 
    • proteases degrade the extracellular matrix 
    • cartilaginous calcification takes place at the junction between the maturing chondrocytes and newly forming bone
      • multiple factors are expressed as bone is formed including BMPs, TGF-Betas, IGFs, osteocalcin, collagen I, V and XI
    • subsequently, chondrocytes become apoptotic and VEGF production leads to new vessel invasion
    • newly formed bone (woven bone) is remodeling via organized osteoblastic/osteoclastic activity 
  • Shaped through
    • Wolff's law: bone remodels in response to mechanical stress
    • piezoelectic charges : bone remodels is response to electric charges: compression side is electronegative and stimulates osteoblast formation, tension side is electropostive and simulates osteoclasts

Variables that Influence Fracture Healing
  • Internal variables
    • blood supply (most important)
      • initially the blood flow decreases with vascular disruption
      • after few hours to days, the blood flow increases 
        • this peaks at 2 weeks and normalizes at 3-5 months
      • un-reamed nails maintain the endosteal blood supply
        • reaming compromises of the inner 50-80% of the cortex
        • looser fitting nails allow more quick reperfusion of the endosteal blood supply versus canal filling nails 
    • head injury may increase osteogenic response
    • mechanical factors
      • bony soft tissue attachments
      • mechanical stability/strain 
      • location of injury
      • degree of bone loss
      • pattern (segmental or fractures with butterfly fragments)
        • increased risk of nonunion likely secondary to compromise of the blood supply to the intercalary segement
  • External variables
    • Low Intensity Pulsed Ultrasound (LIPUS)
      • exact mechanism for enhancement of fracture healing is not clear
        • alteration of protein expression
        • elevation of vascularity
        • development of mechanical strain gradient
      • accelerates fracture healing and increases mechanical strength of callus (including torque and stiffness) 
        • the beneficial ultrasound signal is 30 mW/cm2 pulsed-wave   
      • healing rates for delayed unions/nonunions has been reported to be close to 80%
    • bone stimulators
      • four main delivery modes of electrical stimulation
        • direct current
          • decrease osteoclast activity and increase osteoblast activity by reducing oxygen concentration and increasing local tissue pH 
        • capacitively coupled electrical fields (alternating current, AC)
          • affect synthesis of cAMP, collagen and calcification of carilage
        • pulsed electromagnetic fields
          • cause calcification of fibrocartilage
        • combined magnetic fields
      • they lead to elevated concentrations of TGF-Beta and BMP
    • COX-2
      • promotes fracture healing by causing mesenchymal stem cells to differentiate into osteoblasts 
    • radiation (high dose)
      • long term changes within the remodeling systems  
      • cellularity is diminished
  • Patient factors
    • diet
      • nutritional deficiencies
        • vitamin D and calcium
        • as high as 84% of patients with nonunion were found to have metabolic issues
          • greater than 66% of these patients had vitamin D deficiencies
      • in a rat fracture model 
        • protein malnourishment decreases fracture callus strength
        • amino acid supplementation increases muscle protein content and fracture callus mineralization
      • gastric bypass patients
        • calcium absorption is affected because of duodenal bypass with Roux-en-Y procedure
          • leads to decreased Ca/Vit D levels, hyperparathyroidism (secondary) & increased Ca resportion from bone
        • treat these patients with Ca/Vit D supplementation 
        • gastric banding does not lead to these abnormalities because the duodenum is not bypassed
    • diabetes mellitus
      • affects the repair and remodeling of bone
        • decreased cellularity of the fracture callus
        • delayed enchondral ossification 
        • diminished strength of the fracture callus
      • fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients
    • nicotine
      • decreases rate of fracture healing
      • inhibits growth of new blood vessels as bone is remodeled
      • increase risk of nonunion (increases risk of pseudoarthrosis in spine fusion by 500%)
      • decreased strength of fracture callus
      • smokers can take ~70% longer to heal open tibial shaft fractures versus non-smokers
    • HIV
      • higher prevalence of fragility fractures with associated delayed healing
      • contributing factors
        • anti-retroviral medication
        • poor intraosseous circulation
        • TNF-Alpha deficiency
        • poor nutritional intake
    • medications affecting healing
      • bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage
        • recent studies demonstrated longer healing times for surgically treated wrist fractures in patients on bisphosphonates
        • long term usage may be associated with atypical subtrochanteric/femoral shaft fractures
      • systemic corticosteroids 
        • studies have shown a 6.5% higher rate of intertrochanteric fracture non unions 
      • NSAIDs
        • prolonged healing time becaue of COX enzyme inhbition
      • quinolones
        • toxic to chondrocytes and diminishes fracture repair
 
 

Please rate topic.

Average 4.0 of 53 Ratings

Questions (9)

(OBQ10.41) In rat models looking at the effect of malnutrition on fracture healing, amino acid supplementation in a nutritionally deprived rat increases all of the following EXCEPT Review Topic

QID:3129
1

Serum albumin

3%

(76/2246)

2

Body mass

14%

(304/2246)

3

Quadriceps total protein content

8%

(182/2246)

4

Fracture callus mineralization

39%

(868/2246)

5

Insulin-like growth factor 1 (IGF-1) mRNA expression

35%

(789/2246)

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

The study by Hughes et al found that essential amino acid supplementation (glutamine, arginine, and taurine) following femoral fracture in a protein-malnourished rat model increases serum albumin, body mass, quadriceps total protein content, and fracture callus mineralization. Expression of IGF-1 and IGF-2, myosin, actin, and VEGF mRNA were all significantly decreased in the amino acid supplemented group compared to the malnourished group. The malnourished group is thought to have upregulation of mRNA expression in attempt to increase the amount of protein product that is translated, however the lack of amino acid building blocks in the malnutrition group was a barrier to appropriate protein synthesis.

The study by Day et al created a malnourished rat femur fracture model by administering a 6% protein diet. They found that administering a 20% protein diet in the post-fracture period yielded a greater cross-sectional area of the fracture callus and callus stiffness compared to the 6% protein malnourished group.


Please rate question.

Average 1.0 of 101 Ratings

Question COMMENTS (5)

(OBQ10.273) Level 1 evidence has shown Low-intensity Pulsed Ultrasound Stimulation (LIPUS) decreased the time to fracture union in all of the the following injuries EXCEPT? Review Topic

QID:3361
1

Radius shaft fracture

8%

(159/1911)

2

Distal radius fracture

10%

(200/1911)

3

Tibia shaft fracture treated with casting

9%

(168/1911)

4

Tibia shaft fracture treated with reamed intramedullary nailing

55%

(1052/1911)

5

Scaphoid fracture

17%

(328/1911)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

Tibia shaft fractures treated with reamed intramedullary nailing do not have Level 1 evidence supporting adjunctive LIPUS treatment. Low-intensity pulsed ultrasound (LIPUS) "bone stimulators" deliver 30mW/cm2 pulsed-waves via an external device over the fracture site.

The meta-analysis by Busse et al found 6 randomized, controlled trials evaluating LIPUS. They concluded that low-intensity pulsed ultrasound treatment may significantly reduce the time to fracture healing for fractures treated nonoperatively.

The metanalysis cites that Emami et al found no benefit to LIPUS treatment on intramedullary fixed tibial fractures. Injuries described in the metaanalysis as having positive benefits from LIPUS include radius shaft(Cook et al), distal radius(Kristiansen et al), scaphoid(Mayr et al), and tibia treated with casting (Heckman et al).

The Level 1 study by Heckman et al of 67 patients found a significant decrease in the time to clinical healing in tibia fractures treated with casting and no serious complications with its use.


Please rate question.

Average 1.0 of 65 Ratings

Question COMMENTS (2)

(OBQ09.84) What is the mechanism of action of capacitive coupling (CC) stimulation when used as an adjunctive therapy for bone healing? Review Topic

QID:2897
1

Reduces oxygen concentration and increases local tissue pH

8%

(145/1857)

2

Stimulates transmembrane calcium translocation via voltage-gated calcium channels

65%

(1211/1857)

3

Upregulates TNF alpha

1%

(25/1857)

4

Transmits mechanical energy to stimulate bone formation

24%

(439/1857)

5

Upregulates osteoclast activity

1%

(25/1857)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Adjunctive therapies for bone healing are widely used and the mechanism of action is slowly being elucidated. Capacitive coupling involves externally placed electrodes with an alternating current which creates an electrical field. This stimulates calcium translocation which then activates calmodulin and upregulates many factors involved in bone healing (BMP, cyclic adenosine monophosphate (cAMP), and TGF-beta1).

Direct current(DC) stimulates an inflammatory-like response during fracture repair while . Pulsed electromagnetic fields (PEMFs) cause calcification of fibrocartilage but not calcification of fibrous tissue.

Answer 1 describes the mechanism of action of direct current stimulation. Answer 4 describes ultrasound stimulation. Otter et al present a nice review of electromagnetic fields and their influence of fracture healing.


Please rate question.

Average 2.0 of 33 Ratings

Question COMMENTS (1)

(OBQ08.44) Which of the following statements regarding COX-2 is FALSE? Review Topic

QID:430
1

It causes mesenchymal stem cells to differentiate into osteoblasts

28%

(736/2621)

2

COX-2 knockout mice heal fractures more quickly than control mice

58%

(1524/2621)

3

COX-2 is an enzyme which converts arachidonic acid to prostaglandin endoperoxide H2

4%

(97/2621)

4

Most NSAIDS non-specifically inhibit both COX-1 and COX-2 enzymes

6%

(158/2621)

5

The expression of COX-2 is upregulated in several human cancers

4%

(92/2621)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Cycloxygenase-2 (COX-2,aka prostaglandin-endoperoxide synthase 2) is an enzyme which converts arachidonic acid to prostaglandin endoperoxide H2. COX-2 is not expressed under normal conditions, but elevated levels are found during general states of inflammation. Zhang et al and Simon et al have both studied the role of COX-2 with regard to fracture healing. Zhang et al created a COX-2 knockout mouse (one which does not express the COX-2 gene). This COX-2 knockout mouse has been shown to heal fractures more slowly than COX-1 knockout mice or normal controls, thus identifying the role of COX-2 in general inflammation and bone repair. Zhang et al hypothesize that COX-2 causes mesenchymal progenitor cells to differentiate into osteoblasts, thus promoting new bone formation. Simon et al showed the delayed effects of fracture healing when animals were treated with COX-2 inhibitors. Gerstenfeld et al. studied the reversibility of COX-2 inhibition on the short term bone healing in an animal model. They found that COX-2 inhibitors block fracture healing more than NSAIDS and the magnitude of this effect is related to the duration of treatment. While specific inhibitors of COX-2 exist, traditional NSAIDs non-specifically inhibit both COX-1 and COX-2 enzymes. In addition to its role in inflammation, COX-2 has been shown to be upregulated in many human cancers such as gallbladder carcinoma.


Please rate question.

Average 3.0 of 36 Ratings

Question COMMENTS (8)

(OBQ06.27) The nonunion as seen in Figure A will most likely unite by what intervention? Review Topic

QID:138
FIGURES:
1

Increased mechanical stability

94%

(1592/1699)

2

Decreased mechanical stability

2%

(30/1699)

3

Increased biology at the fracture site

2%

(37/1699)

4

Decreased biology at the fracture site

0%

(6/1699)

5

Antibiotics and resection of pseudoarthrosis

1%

(15/1699)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

As described in the review by Rodriguez-Merchan and Forriol, hypertrophic nonunions result from motion at the fracture site and generally unite once the mechanical stability is increased. Atrophic and oligotrophic nonunions, while multi-factorial, result from poor biology at the fracture site (poor vascularity, lack of mesenchymal stem cells, bone loss). Treatment of atrophic nonunions then entails takedown of the nonunion and bone grafting (to improve the biology) with stabilization to initiate a healing response.


Please rate question.

Average 3.0 of 20 Ratings

Question COMMENTS (0)

(OBQ06.262) Which of the following is a mechanism by which low-intensity pulsed ultrasound is reported to stimulate fracture healing? Review Topic

QID:273
1

decreasing intracellular calcium concentration

5%

(24/492)

2

decreasing temperature

1%

(4/492)

3

produces nanomotion at the fracture site

91%

(448/492)

4

decreases proteoglycan synthesis

1%

(6/492)

5

inhibits integrins

1%

(5/492)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Despite various reports documenting effects of low intensity ultrasound on living tissues, the exact mechanism of ultrasound on biological tissues remains largely unknown. It is most likely due to the mechanical energy of the sound waves that are transferred to tissues. Low frequency ultrasound in the region of 1.0 kHz may be capable of producing vibration and therefore strain across the cell wall (aka nanomotion at the fracture site).

The study by Parvizi et al observed that rat chondrocytes were stimulated by an ultrasound signal. They found that intracellular Ca++ concentration increased and proteoglycansynthesis increased in response to stimulation. When intracellular calcium was chelated in their experiment, the increase in proteoglycan synthesis reduced significantly, indicating that the rising intracellular Ca++ concentration as a result of ultrasound stimulation functioned as an intracellular signal to increase proteoglycan synthesis.

Authors:

Please rate question.

Average 2.0 of 19 Ratings

Question COMMENTS (1)

(OBQ05.1) What type of fracture healing occurs in a femoral shaft fracture treated with an intramedullary nail? Review Topic

QID:38
1

Primary fracture healing

5%

(77/1693)

2

Secondary fracture healing

91%

(1546/1693)

3

Extramembranous ossification

2%

(34/1693)

4

Haversian remodelling

1%

(9/1693)

5

"Cutting cone" remodelling

1%

(13/1693)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Intramedullary nails function as internal splints that allow for secondary fracture healing.

Secondary bone healing involves responses in the periosteum and external soft tissues. Here both committed osteoprogenitor cells and uncommitted undifferentiated mesenchymal cells contribute to the process of fracture healing by recapitulation of embryonic intramembranous ossification and endochondral bone formation. The response from the periosteum is a fundamental reaction to bone injury and is enhanced by motion and inhibited by rigid fixation.

Bong et al. reviewed the biomechanics and biology of long bone fracture healing with Intrameduallary nailing. They showed that reaming and the insertion of intramedullary nails can have early deleterious effects on endosteal and cortical blood flow initially. However, the canal reaming appears to have an overall positive effect at the fracture site as it increases extra osseous circulation and applies bone graft to the fracture site.

Illustration A shows a series of radiographs of a fracture healed by secondary intention with an IM nail.

Incorrect Answers:
Answer 1,4,5: Primary fracture healing (aka haversian remodelling or cutting cone remodelling) involves a direct attempt by the cortex to reestablish itself. In order for a fracture to become united, bone on one side of the cortex must unite with bone on the other to reestablish mechanical continuity. This process seems to occur only when there is anatomic restoration of the fracture fragments and when stability of the fracture reduction is ensured by rigid internal fixation and a substantial decrease in interfragmentary strain.
Answer 3: Secondary bone healing involves the ecapitulation of embryonic INTRAmembranous ossification and endochondral bone formation. EXTRAmembranous ossification is not believed to be a process involved in the healing of bone.

ILLUSTRATIONS:

Please rate question.

Average 3.0 of 29 Ratings

Question COMMENTS (3)

(OBQ05.64) Which of the following is most often implicated as an etiology for a hypertrophic nonunion? Review Topic

QID:950
1

Malreduction with open plating

2%

(9/568)

2

Smoking

2%

(10/568)

3

Inadequate mechanical stability

93%

(531/568)

4

Open injury with significant soft tissue stripping

1%

(3/568)

5

Infection

2%

(11/568)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Hypertrophic nonunions are caused by inadequate stability, with callus formation by an appropriate biological response. Lack of biology leads to an atrophic nonunion. Hypertrophic nonunions should be treated with a fixation construct that lends appropriate stability without creating a poor biological environment.


Please rate question.

Average 4.0 of 19 Ratings

Question COMMENTS (0)

(OBQ04.109) Type X collagen expression by hypertrophic chondrocytes is characteristic of which of the following aspects of fracture healing? Review Topic

QID:1214
1

Inflammation

1%

(4/424)

2

Granulation tissue formation

10%

(44/424)

3

Cartilage callus formation and calcification

80%

(339/424)

4

Bone deposition

1%

(6/424)

5

Bone remodeling

5%

(22/424)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

There are three phases to fracture healing: 1) Reactive, 2) Reparative, and 3) Remodeling. The reactive phase is characterized by inflammation and granulation tissue formation. The reparative phase is marked by cartilage callus formation and bone deposition. Finally, the bone deposited during the reparative phase is remodeled during the remodeling phase. Type X collagen is a homotrimeric collagen found in hypertrophic cartilage expressed during the cartilage callus calcification phase of fracture healing. After fracture, inflammation and clot formation occurs where type I and II collagen are found. Type III collagen is expressed by fibroblasts and type V is found in areas of fibrous tissue formation. In the soft tissue callus/chondroid phase, types II and IX predominate, with type II being deposited in areas of mature cartilage production and type IX stabilizing the fibrils of type II. In the callus calcification phase type X collagen is expressed by proliferating chondrocytes as the extracellular matrix undergoes calcification. In the osteogenic bone deposition phase, there is a progressive shift from primary to secondary spongiosa and type I collagen predominates.


Please rate question.

Average 3.0 of 33 Ratings

Question COMMENTS (4)
Sorry, this question is available to Virtual Curriculum members only.

Click HERE to learn more and purchase the Virtual Curriculum today!


This is a Never-Been-Seen Question that can only be seen in Milestone Exams
for Virtual Curriculum members.

Click HERE to learn more and purchase the Virtual Curriculum today!


CASES (1)
VIDEOS (1)
POSTS (1)
EVIDENCE & REFERENCES (33)
Topic COMMENTS (32)
Private Note