The document discusses the multiple factors affecting fracture healing, which can be categorized into local and systemic factors. Key local factors include blood supply, mechanical stability, and infection, while systemic factors involve age, obesity, hormonal influences, and nutritional status. It highlights the importance of understanding these factors for achieving ideal fracture healing, as well as elaborating on treatments like bone grafts and electrical stimulation methods.

1. Dr. BHOSALE SUMIT
Junior Resident-1
Dept. of Orthopedics
Dr . PRAMOD SARKELWAD DR.DEEPAK AGRAWAL
ASSO. Professor and HOU PROF. and HOD
Dept. of Orthopaedics Dept. Of Orthopaedics
DUPMC & H DUPMC & H

2. FACTORS AFFECTING FRACTURE
HEALING AND REMODELING

3. Aspiration for ideal fracture healing necessitates a comprehensive
knowledge and understanding of all the factors that directly or
indirectly influence the healing process. The main pillars of fracture
healing are a good biological environment with adequate blood supply
and a good mechanical environment with adequate stability.
The AO has set four principles for ideal fracture healing. This includes
fracture reduction to restore the anatomy, fracture fixation to achieve
absolute or relative stability, preservation of the blood supply to the
bone and surrounding soft tissues, and early and safe mobilization.
The list of factors that affect fracture healing is exhaustive; however,
it can broadly be categorized into local and systemic categories.

4. Local Factors
•The blood supply and the biological environment are the most important local factors affecting
the fracture healing process. Immediately after the fracture, the blood vessels in the surrounding
area get disrupted with resultant low blood. This improves over the next few hours to days after the
fracture and reaches its highest at two weeks, then declines back to normal between 3 to 5 months.
Reduced blood supply to the fracture site can lead to delayed union or non-union. Bone blood
supply should also be considered in the operative treatment of fractures and the used prosthesis. For
example, reaming for intramedullary nailing would compromise 50% to 80% of the endosteal
circulation. Also, canal tight-fitting nails compromise the endosteal blood supply compared to
looser-fitting nails, which allow better endosteal reperfusion.
•Fracture Characteristics and the mechanical environment: Excessive movement and
malalignment. Extensive soft tissue damage and soft tissues caught within the fracture site can lead
to delayed union or non-union, as well as the amount of bone comminution and loss. Additionally,
specific fracture patterns have more probabilities of developing non-union or delayed union, such
as segmental fractures or fractures with butterfly fragments.
•Infection: can significantly compromise the healing process with a consequent non-union or
delayed unions.

5. Systemic Factors
•Advanced age: elderly have a lower capacity for fracture healing when compared to their
younger population. Aging influences the inflammatory response during fracture healing.
With aging, there is a weakness in the immune response and increased systemic pro-
inflammatory status.
•Obesity: In animal studies, lower levels of FGF and TGF-β, and higher levels of TNF-α,
were reported more in obese mice and contributed to delayed fracture healing.
•Anemia
•Endocrine conditions: diabetes mellitus affects the fracture healing process in multiple
aspects; fracture callus would have low cellular content with resultant weak callus.
Endochondral ossification is delayed, and fracture healing is generally prolonged compared to
the general population. Menopause and parathyroid problems also compromise the fracture-
healing process.
•Steroid administration.
•Malnutrition: a high proportion of the patients developing delayed union or non-union were
reported to have metabolic compromise, especially of vitamin D. Calcium deficiency is
another compromising factor of the bone union. Calcium deficiency can be secondary to
gastrointestinal malabsorption or endocrinal problems such as secondary
hyperparathyroidism.

6. •Smoking: nicotine inhibits angiogenesis and forms weak calluses
with an overall delay in the fracture healing process.
•Medications: Certain medications can directly or indirectly affect
the fracture healing process. NSAIDs can result in delayed union
due to COX enzyme inhibition. For example, systemic
corticosteroids have been reported to increase the non-union rate of
intertrochanteric femur fracture. Conversely, long-term use of
bisphosphonates has been associated with osteoporotic fractures
such as subtrochanteric femoral insufficiency fractures. Quinolones
have been reported to be toxic to chondrocytes with the consequent
compromise of the fracture healing process.

7. •Dietary supplements - calcium, protein, vitamins C and D.
•Bone stimulators - which can be electrical, electromagnetic, and ultrasound. The current
effectiveness of these methods is still equivocal, and this area requires further research. There
are four principal modes of electrical stimulation; the direct current reduces osteoclast
activity and increases osteoblast activity by creating an alkaline tissue environment and
reducing oxygen concentration. In contrast, the alternating current (AC) affects collagen
synthesis and cartilage calcification. The other two types are magnetic, either pulsed
electromagnetic fields that result in the calcification of fibrocartilage or combined magnetic
fields that increase the concentrations of transforming growth factor beta and bone
morphogenic proteins. Ultrasound such as (LIPUS) low-intensity pulsed ultrasound has been
reported to augment fracture healing and increase the strength of the formed callus, with
healing rates in non-union and delayed unions approaching 80%. LIPUS improves fracture
healing by increasing chondrocytes, soft callus formation, and, consequently, earlier
endochondral ossification.
•A bone graft involves using bone to help provide a scaffold to the newly forming bone. This
graft can be from the patient's body (autograft) or a deceased donor (allograft).

8.  I. SYSTEMIC FACTORS OR PATIENT VARIABLES
 II.LOCAL FACTORS OR TISSUE VARIABLES
a.Factors independent of injury, treatment, or
complications
b. Factors dependent of injury or injury variables
 III. Factors depending on treatment or treatment variables
 IV. Factors associated with complications

9.  I. Systemic factors or patient variables
A. Age
B. Activity level including
1. Immobilization
C. Nutritional status
1. Sufficient carbohydrates and protein
2. Anaemia
3. Vitamin deficiencies: C, D, K
D. Hormonal factors
1. Growth hormone
2. Corticosteroids
3. Others (thyroid, oestrogen, androgen,
calcitonin, parathyroid hormone,
prostaglandins)

10. E. Diseases: Diabetes, neuropathies, Tabesdorsalis,
PVD, malignancies,
immunocomprised states(hiv& aids)
F. Drugs: NSAIDs, Steroids, statins,anticoagulants,
Antibiotics like Fluroquinolones
G. Smoking & alcohol abuse
H. Hyperoxia
I. Systemic growth factors
J. Central nervous system trauma

11. Changes in fracture healing caused by diabetes
Changes at the tissue level
Reduced bone formation
Reduced cartilage formation
Accelerated loss of cartilage
Reduced vascularity and reduced angiogenesis
Changes at the molecular level
Reduced expression of growth factors
Reduced expression of matrix proteins
Increased expression of proinflammatory genes
Increased expression of pro-osteoclastogenic factors
Increased expression of proapoptotic genes

13. II. Local factors or tissue variables
A. Factors independent of injury, treatment, or
complications
1. Type of bone
cortical or cancellous
2. Abnormal bone
a. Radiation necrosis
b. Infection
c. Tumours and other
pathological conditions
3. Denervation

14. B. Factors depending on injury or injury variables
1. Degree of local damage
a. Compound fracture
b. Comminution of fracture
c. segmental fractures
d. Velocity of injury
2. Extent of disruption of vascular supply to
bone, its fragments (macro vascular
osteonecrosis), or soft tissues;
3. Type and location of fracture (one or two
bones, e.g., tibia and fibula or tibia alone
4. Loss of bone
5. Soft-tissue interposition
6. Local growth factors
7. Intra articular fractures

15. C. Factors depending on treatment
or treatment variables
1. Extent of surgical trauma (blood supply, heat)
2. Implant-induced altered blood flow
3. Degree and kind of rigidity of internal or
external fixation and the influence of timing
4. Degree, duration, and direction of load-
induced deformation of bone and soft tissues
5. Apposition of fracture fragments (gap,
displacement, over distraction
6. Factors stimulating posttraumatic
osteogenesis (bone grafts, bone
morphogenetic protein, electrical stimulation,
surgical technique, intermittent venous stasis .

16.  D. Factors associated with complications
1. Infection
2. Venous stasis
3. Metal allergy

17. Local Regulation of Bone Healing
 Growth factors
Transforming growth factor
Bone morphogenetic proteins
Fibroblast growth factors
Platelet-derived growth factors
Insulin-like growth factors
 Cytokines
Interleukin-1,-4,-6,-11, macrophage and
granulocyte/macrophage (GM) colony-stimulating factors
(CSFs) and Tumor Necrosis Factor
 Prostaglandins/ Leukotrienes
 Hormones
 Growth factor antagonists

18. Specific Factor Stimulation of
Osteoblasts and Osteoclasts
 Cytokine Bone Formation Bone Resorption
 IL-1 + +++
 TNF-α + +++
 TNF-β + +++
 TGF-α -- +++
 TGF-β ++ ++
 PDGF ++ ++
 IGF-1 +++ 0
 IGF-2 +++ 0
 FGF +++ 0

19. Timing and Function of Growth Factors

20. Transforming Growth Factor
 Super-family of growth factors (~34 members)
 Acts on serine/ threonine kinase cell wall
receptors
 Promotes proliferation and differentiation of
mesenchymal precursors for osteoblasts,
osteoclasts and chondrocytes
 Stimulates both enchondral and
intramembranous bone formation
 Induces synthesis of cartilage-specific proteoglycans
and type II collagen
 Stimulates collagen synthesis by osteoblasts

21. Bone Morphogenetic Proteins
 These are included in the TGF-β family
 Except BMP-1
 Sixteen different BMP’s have been identified
 BMP2-7,9 are Osteoinductive
 BMP2,6, & 9 may be the most potent in osteoblastic
differentiation
 Involved in progenitor cell transformation to pre-
osteoblasts
 Work through the intracellular Smad pathway
 Follow a dose/response ratio

22. Bone Morphogenetic Proteins
 Induce cell differentiation
 BMP-3 (osteogenin) is an extremely potent inducer
of mesenchymal tissue differentiation into bone
 Promote endochondral ossification
 BMP-2 and BMP-7 induce endochondral bone
formation in segmental defects
 Regulate extracellular matrix production
 BMP-1 is an enzyme that cleaves the carboxy
termini of procollagens I, II and III

23. Clinical Use of BMP’s
 Used at doses between 10x & 1000x native levels
 rhBMP-2 used in “fresh” open fractures to enhance
healing and reduce need for secondary procedures after
unreamed IM nailing
 BMP-7 approved for use in recalcitrant nonunions in
patients for whom auto grafting is not a good option
(i.e. medically unstable, previous harvesting of all iliac
crest sites, etc.)

24. BMP Future Directions
 BMP-2
 Increased fusion rate in spinal fusion
 BMP-7 equally effective as ICBG in
nonunions (small series: need larger
studies)
 Must be applied locally (insert them
surgically in the fracture site) because of
rapid systemic clearance.

25. BMP Antagonists
 May have important role in bone formation
 Noggin
 Extra-cellular inhibitor
 Competes with BMP-2 for receptors
 BMP-13 found to limit differentiation of mesenchymal
stromal cells
 Inhibits osteogenic differentiation

26. Fibroblast Growth Factors
 Both acidic (FGF-1) and basic (FGF-2) forms
 Increase proliferation of chondrocytes and
osteoblasts
 Enhance callus formation
 FGF-2 stimulates angiogenesis

27. Platelet-Derived Growth Factor
 A dimer of the products of two genes, PDGF-A and PDGF-B
 PDGF-BB and PDGF-AB are the predominant forms found
in the circulation
 Stimulates bone cell growth
 Increases type I collagen synthesis by increasing the
number of osteoblasts
 PDGF-BB stimulates bone resorption by increasing the
number of osteoclasts

28. Insulin-like Growth Factor
 Two types: IGF-I and IGF-II
 Synthesized by multiple tissues
 IGF-I production in the liver is stimulated by
Growth Hormone
 Stimulates bone collagen and matrix synthesis
 Stimulates replication of osteoblasts
 Inhibits bone collagen degradation

29. Cytokines
 Interleukin-1,-4,-6,-11, granulocyte/macrophage (GM)
colony-stimulating factors (CSFs) and Tumor Necrosis
Factor
 Stimulate bone resorption
 IL-1 is the most potent
 IL-1 and IL-6 synthesis is decreased by estrogen
 May be mechanism for post-menopausal bone
resorption
 Peak during 1st
24 hours of fracture healing then again
during remodeling
 Regulate endochondral bone formation

30. Prostaglandins / Leukotrienes
 Effect on bone resorption is species dependent and their
overall effects in humans unknown
 Prostaglandins of the E series
 Stimulate osteoblastic bone formation
 Inhibit activity of isolated osteoclasts
 Leukotrienes
 Stimulate osteoblastic bone formation
 Enhance the capacity of isolated osteoclasts to form
resorption pits

31. Hormones
 Estrogen
 Stimulates fracture healing through receptor mediated
mechanism
 Modulates release of a specific inhibitor of IL-1
 Thyroid hormones
 Thyroxine and triiodothyronine excess stimulate
osteoclastic bone resorption
 Glucocorticoids
 Inhibit calcium absorption from the gut causing increased
PTH and therefore increased osteoclastic bone resorption

32. Hormones (cont.)
 Parathyroid Hormone
 Intermittent exposure stimulates
Osteoblasts
Increased bone formation
 Growth Hormone
 Mediated through IGF-1 (Somatomedin-C)
 Increases callus formation and fracture strength

33. Vascular Factors
 Metalloproteinases
 Degrade cartilage and bones to allow invasion of vessels
 Angiogenic factors
 Vascular-endothelial growth factors
Mediate neo-angiogenesis & endothelial-cell specific
mitogens
 Angiopoietin (1&2)
Regulate formation of larger vessels and branches

34. Electromagnetic Field
 Electromagnetic (EM) devices are based on Wolff’s
Law that bone responds to mechanical stress: In vitro
bone deformation produces piezoelectric currents
and streaming potentials.
 Exogenous EM fields may stimulate bone growth and
repair by the same mechanism
 Clinical efficacy very controversial
 No studies have shown PEMF to be effective in
“gap healing” or pseudarthrosis

35. Types of EM Devices
 Microamperes
 Direct electrical current
 Capacitively coupled electric fields
 Pulsed electromagnetic fields (PEMF)

36. PEMF
 Approved by the FDA for the treatment of non-unions
 Efficacy of bone stimulation appears to be frequency
dependant
 Extremely low frequency (ELF) sinusoidal electric fields in
the physiologic range are most effective (15 to 30 Hz
range)
 Specifically, PEMF signals in the 20 to 30 Hz range
(postural muscle activity) appear more effective than
those below 10 Hz (walking)

37. Ultrasound
 Low-intensity ultrasound is approved by the FDA for
stimulating healing of fresh fractures
 Human clinical trials show a decreased time of healing in
fresh fractures treated non-operatively
 Four level 1 studies show a decrease in healing time up to
38%
 Has also been shown to decrease the healing time in smokers
potentially reversing the ill effects of smoking

38. DETERMINANTS OF FRACTURE
HEALING
1.METHOD OF TREATMENT:
- Stability of the fracture site determines the
differentiation of progenitor cells and the amount of -
callus formation.
- With absolute stability, rigid fixation and low
strain environment, there is no movement(500-2000
micro strain)at the fracture site and fracture heals
with “primary fracture repair”

40. 2.ENDOCRINE INFLUENCE AND EFFECT OF
LOCAL GROWTH FACTORS :

41. 3. EFFECT OF AGE:
Faster in younger patients by a factor of 1.5-2 times
when compared to elderly.
Causes of delay in old age:
-Delay in onset of periosteal reaction(due to-
periosteal and its cambial layer atrophy)
-Delay in cell proliferation(due to aging effect-
on cells)
-Decreased bone formation( due to lower-
osteo-inductuve capacity of bone matrix.)
-Delayed angiogenic invasion of cartilage (due to
decreased expression of VEGF, PDGF, Hypoxia-
inducible factor-1 alpha)

42. 4.LOCATION OF THE FRACTURE:
-Metaphyseal fractures heal faster than Diaphyseal.
-Upper limb fractures heals faster than Lower limb
fractures.

43. 5. LOSS OF BONE:
decreases fracture healing
6. INTERPOSITION OF SOFT TISSUES:
decreases fracture healing
7. IMPLANT INDUCED ALTERED BLOOD FLOW:
decreases fracture healing process.

44. 8. DRUGS:
Drugs disrupting bone healing are,
-Corticosteroids, Immunosuppressants, NSAIDS,
Fluoroquinolones, Tetracyclines
Rifampicin, Gentamicin, Povidone Iodine

46. 9. SMOKING AND ALCOHOLISM:
-Nicotine decreases Osteoblast activity
-It inhibits revascularization of bone grafts
-It inhibits expression of wide range of cytokines
-Induces Osteoporosis
-Reduces estrogen effectiveness
-Counter the antioxidant property of Vit.C and E

47. 10. CHEMICAL OR THERMAL BURNS:
Decreases fracture healing
11. ANAEMIA AND HYPOXIA:
Decreases fracture healing
12. DENERVATION AND NEUROPATHIES:
Decreases fracture healing

48. 13. INFECTIONS:
Delays healing
14. VENOUS STASIS:
Delays healing
15. METAL ALLERGY:
Delays healing

49. 16. EFFECTS OF RADIATION:
-Causes long term suppressive effect on Haversian
system by reducing vascularity and cellularity.
-Post operative Radiations reduces bone graft
incorporation and should be delayed for 3 weeks.
-It may lead to Osteo-radionecrosis, Fractures, Bone
growth changes, Radiation induced Cancers

51. SOME FACTS TO NOTE
 Fracture repair and consolidation are inversely proportional to the amount of
mobility at fracture site.
 Compression at fracture;
-physiological compression stimulate bone
formation
-compression is useful for spongy bone while its
harmful for diaphyseal bones

52. METHODS TO ENHANCE FRACTURE HEALING
 ELECTRICAL STIMULATION;
-Direct current
-Inductive coupling
-Capacitive coupling
 EXTRA CORPOREAL SHOCK WAVE THERAPY
 MECHANICAL STIMULATION
 BIOLOGICAL METHODS
-Bone morphogenic proteins
-Prostacyclins
-Platelet concentrate and Bone marrow injections
-Parathyroid hormone
-Ultra concentrate of centrifuged blood
-Anabolic supplementations and minerals
-Bone grafts and substitutes

53. FACTORS INFLUENCING/AFFECTING
FRACTURE HEALING
 These factors can be subdivided into systemic and local factors.
 Systemic factors present at the time of injury with exception of trauma to the
CNS.
 Local factors subdivided according to their nature such as mechanical ,
chemical ,physical, or environmental. Such classification has little clinical
importance.

54. SYSTEMIC FACTORS
A. Age
B. Activity level including---
1. General immobilization
2. space flight
C. Nutritional status
D. Hormonal factors
1.GH
2.Corticosteroids(microvascular AVN)
3. others- thyroid, estrogen , androgen,
calcitonin, PTH,PG

55. E. Diseases:- anemia, neuropathies,tabes
F. Vitamin defcncy: A,D,E,K
G. Drugs : NSAIDs, anticoagulants ,CCB, sodium fluride, tetracycline.
H. Nicotine, alcohol
I. Hyperoxia
J. Systemic growth factors
K. Environmental temperature
L. CNS trauma

56. LOCAL FACTORS
A. Factors independent of injury, treatment, or complications
1. Type of bone
2. Abnormal bone
-- radiation necrosis
--- infection
--- tumours and other pathologic conditions.
3. Denervation

57. B. Factors depending on injury
1. Degree of local damage
a.compound #
b. communition of #
c. velocity of injury
d. low circulation levels of vit.K

58. 2. Extent of disruption of vascular supply to bone, it,s fragments, soft tissue or
severity of injury.
3. Type and location of fracture( one /2 bones ie tibia and fibula or tibia
alone.
4. Loss of bone
5. soft tissue interposition
6. Local growth factors.

59. C. Factors depending on treatment___
1. Extent of surgical trauma( bld supply, heat)
2. Implant induced altered bld flow
3. Degree and kind of rigidity of external/internal
fixation and influence of timing.
4. Degree, duration and direction of load- induced
deformation of bone and soft tissue
5. Extent of contact b/w fragments
6. Factors stimulating post traumatic osteogenesis
----- bone graft, BMPs, electrical stimulation ,surgical
technique ,intermittent venous stasis.

60. D. Factors associated with complications
1. infection
2. venous stasis
3. metal allergy

61. VARIABLES THAT INFLUENCE FRACTURE
HEALING
 Cruess and Buck Walter have devided the varibles into 4 Groups
1. INJURY VARIABLES
2. PATIENT VARIABLES
3. TISSUE VARIBLES
4. TREATMENT VARIABLES

62. 1. INJURY VARIABLE
A) Open #s---- causes soft tissue destruction and disturbe blood suply prevent
haematoma fornation and delayed repair
B) Severity of injury----- severe injury lead to extensive soft tissue damage
and bone communition with displacement ,leading to retardation of fracture
healing.
C. Intra-articular #s ----
synovial fluid hinders the fracture healing as it contains collagenases which
degrade the matrix of initial # callus. So intra-articular #s require
reconstruction of joint, stable fixation of fragments and early mobilisation.

63. D) Soft tissue interposition----
compromise # healing
E) Segmental fracture------ of long bone impairs the intramedullary blood suply
of middle fragment resulting in delayed union/non union.
F) Damage to blood supply----
lead to delay/ prevent # healing.

64. PATIENT VARIBLES
1. Age:- infants and childrn have rapid rate of healing where as healing
declines significantly with age advances.
2. Nutrition :- poor nutritional status decreases synthesis of large volumes of
collagens, polyglycans and other matrix macromolecules, hence affect
fracture healing and can lead to mortality.
3. Systemic hormones:-- corticosteroids, NSAIDs , anticoagulants inhibit fracture
healing. Where as GH, TH,insulin,and anabolic steroids enhance fracture
healing.
4. Nicotine :-- cigarette smoking inhibit # healing by inhibiting vascularisation of
cancellous bone graft.

65. TISSUE VARIABLES
1. Form of bone ( cancellous/ cortical):
cancellous bone healing rapid because of larger surface area per unit
volume,and rich blood supply.
2. Bone necrosis :-- leads to decreased bone healing.
3. Bone diseases :- osteoporosis, osteomalacia, primary malignant tumors,
osteogenesis imperfecta etc all cause pathological # and delay in healing
process.
4. Infection :- slow down / prevents healing. Infection will cause necrosis of
normal tissue, edema and thrombosis of blood vessels, threby retarding or
prevent healing.

66. TREATMENT VARIABLES
1. Apposition of fracture fragments :- Decreasing the # gap decreases volume
of repair tissue needed to heal a fracture. Anatomical reduction causes
rapid healing as compared to displaced fragments.
2. Loading and micromotion:-- Loading a # site stimulate bone formation while
decreased loading slows fracture healing. Immediate controlled loading and
limb movement, including induced micromotion at long fracture sites,
promotes fracture healing but too much movement cause nonunion.
3. Stabilization of fracture :- will prevent repeated disruption of repair tissue
and speed up the fracture callus.
4. Rigid fixation :-- Plate like LC-DCP leads to primary union of fracture, stable
fixation allows early mobilization of joints and hence prevents stiffness.

67. 5. Bone grafting :-- It is osteo inductive as well as osteoconductive. BMP stimulates healing.
Autograft and allograft of cancellous , cortical or cortico-cancellous bone are used to
stimulate # healing and replace lost bone.
6. Ultrasound:- low intensity pulsed USG accelerate # healing. It increases the concentration
of intracellular calcium in fracture callus chondrocytes.
7 . Demineralized mone marrow :--- The factors in bone marrow stimulate bone formation,
by migration of undifferentiated mesenchymal cells to the implanted matrix and
differentiation into chondrocytes.

68. Electrical and electromagnetic stimulation
The fibrous union can be converted into a fibrocartilage which then
undergoes enchondral ossification by using cathode electrodes,each
delivering an optimal osteogenic current of 20micro.amp
At least 3 electrical and electromagnetic methodes are available.
1. Invasive
2. Semi-invasive
3. Non-invasive

69. Invasive method
 A self powered, self contained and totally implantable electrical stimulation
is used.
 Union is achieved in more than 85% 0s cases within 12-36 weeks.

70. Semi-invasive method
 Consists of insertion of cathodes percutaneously into the nonunion site and
continous application of small amount of direct current. Early osteogenesis
can be detected in 12 weeks.

71. Non-invasive method
 Weak electric currents are induced by pulsating elctromagnetic fields.
 radiograph made after 4-6 wks interval shows evidence of healing.

72. REFERENCES
CAMPBELL’S OPERATIVE ORTHOPEDICS
ROCKWOOD AND GREEN
ESSENTIAL ORTHOPEDICS-VARSHNEY

73. THANK YOU