Normal structure of

bone
&
Biology of fracture
healing

Dr. Aashish Chaudhry

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Normal structure of bone

Bone is a specialized connective tissue with a mineralized collagenous
framework for skeletal support of the body. The tensile strength of the bone
is nearly equal to that of the cast iron but it is three times lighter and ten
times more flexible than the later. Bone first appears after the seventh
embryonic week. It develops from condensation of mesenchyme (embryonic
connective tissue). This mesenchyme may undergo ossification directly
(Intramembranous ossification or membrane bone formation) or the
mesenchyme is initially replaced by dense cellular cartilage which
subsequently becomes ossified by Intra-cartilaginous ossification
(Enchondral ossification).
There are three basic shapes of the bones:
1. Short bones ( Tarsals, carpals, vertebrae)
- Measure approx. same in all directions
2. Flat bones ( Cranial vault, Scapula, Iliac wing )
- One dimension is much shorter or longer than the other two
3. Long bones
- Expanded metaphysis & epiphysis at either end

Parts of a typical long bone

1. Diaphysis : Ossified from primary centre
2. Epiphysis : Minimum of one epiphysis at either end of diaphysis
3. Epiphysial cartilage : Lies b/w epiphysis & end of diaphysis

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Responsible for longitudinal growth of the bone

4. Metaphysis : Part abutting on the epiphysial plate
Peculiarities
1. Area of greatest growth activity in the bone
2. Extremely profuse blood supply ( a.k.a ‘Lake of blood’ ) arranged
in ‘hair pin loop’ patterns thus leading to stasis of blood
3. Site of attachment of various muscles, tendons or joint capsules,
thus a likely site to suffer strains (micro fractures)
4. It is partly intracapsular thus responsible for spread of infection in
either direction
5. This region has least number of phagocytes

5. Periosteum: Consists of two layers:

a. Outer fibrous layer
b. Inner cambium/ osteogenic layer
Responsible for appositional growth
Deep layer blends with epiphysial cartilage
(Pus b/w bone & periosteum can’t spread beyond)

Sharpey’s fibers
Thick bundles of collagenous fibers that pass from the periosteum
into the basic external circumferential lamellae. They fix the periosteum
firmly to the surface of the bone especially at the junction of epiphysis &
shaft of the long bones.

Ossification of long bones

According to the law of ossification, where a bone has an epiphysis at
either end, the epiphysis which is the first to appear is the last to join and
the epiphysis which is the last to appear is the first to join.( Except fibula).
Growth continues longest at shoulder & wrist in upper limbs and longest at
knee in lower limbs. Thus epiphysis of:
- U/E Humerus
- L/E Radius
- L/E Ulna
- U/E Tibia
- L/E Femur
……unite later than the epiphysis at the other ends of these bones.

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Nutrient foramina of limb bones are directed according to the rhyme ‘To the
elbow I go, from the knee I flee’. (Reverse situation to start with, reversal
due to selective growth pattern)

Blood supply of bone (Typical long bone)

Mature bones have an elaborate vascular system that supplies the cells
of the marrow, bone tissue and periosteum. Even within the densest bone
tissue, the organization of vascular canals ensures that no cell lies > 300
micrometers from a blood vessel. Disruptions of blood supply to the bone
due to injury, disease or operative procedures can cause necrosis & impair
healing (esp. in regions like scaphoid, tibial diaphysis, femoral head, talus
etc.). Long bones have two circulatory systems:
A. The periosteal-diaphyseal-metaphyseal system
B. The epiphyseal-physeal system

A. Periosteal-diaphyseal-metaphyseal system
a. Diaphyses & metaphyses of have three sources of blood supply:
1. Nutrient Artery
2. Arteries penetrating epi- & metaphysis
3. Periosteal arteries
Together these vessels form ‘medullary vascular system’ and thus
supplies most of periosteum covered bone (centrifugal blood flow)
b. Periosteum also has an elaborate vascular system. A vascular
plexus lies over the surface of the outer fibrous layer &
anastamose with vessels in skeletal muscles and with vessels in
cambium layer. In children these vessels communicate with intra-
osseous vessels. Under certain circumstances periosteal vessels
form an important source of blood supply to skeletal muscle.
Thus crush injuries of muscle are less likely to cause ischemic
damage if muscle- periosteal vascular connections remain intact.

The anastomosis b/w the medullary vascular and periosteal system gives the
diaphysis & metaphysic a ‘Dual blood supply’. This is important in various
clinical conditions (bone /soft tissue injuries, reaming of medullary canal
etc.).
B. Epiphyseal- Physeal blood supply

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The blood supply to most epiphyses is more precarious than the

supply to other parts. During skeletal growth, very few vessels cross the
cartilaginous portion of the physis leaving the epiphysis & the epiphyseal
pole of the physis dependent on blood vessels that penetrate the epiphysis.
After closure of the physis, vascular channels penetrate the physeal scar but
functional importance is uncertain. (E.g. capital femoral epiphysis, epiphysis
of 2nd metatarsal & epiphysis of humeral capitellum).

Compact and Spongy bone

Cortex of bone is composed of compact bone while medulla contains

spongy/cancellous bone. Both cortical and the cancellous bone have the
same matrix composition and structure but the mass of cortical bone matrix
per unit of volume is much greater i.e. cortical bone has greater density or
less porosity ( approx. 10 % porosity) than cancellous bone (50-90 %
porosity). As the ‘compression strength’ of bone is proportional to the square
of its density, the modulus of elasticity and the ultimate compression
strength of cortical bone may be as much as ‘ten times’ greater than those of
a similar volume of cancellous bone.

Woven and lamellar bone

Cortical or cancellous bone may consist of woven (fiber or primary) or

lamellar (secondary) bone. Woven bone forms the embryonic skeleton and is
then resorbed and replaced by mature bone as the skeleton develops.
Fracture callus follows the same sequence. Small amounts of woven bone
may form permanent parts of tendon and ligament attachments, the suture
margins of cranial bones, & the ossicles of the ear & woven bone formed in
the growth plates. With these exceptions woven bone rarely is present in the
normal human skeleton after the age of 4-5 years. It can however appear at
any age in response to osseous or soft tissue injury, metabolic and neoplastic
diseases or inflammation.

Haversian system: The functional unit of mature cortical bone. Also

known as ‘an osteon’ a cylindrical structure about 250 microns wide by 1 to
5cm long composed of concentric layers of lamellar bone surrounding a
central haversian canal.

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Woven & lamellar bone differs with regard to their formation, composition,
organization and mechanical properties.

S No. Woven bone Lamellar bone

1. Turnover Rapid Slow (less active)

Pattern of collagen
2. Irregular & random Regular
fibrils
No. of osteocytes
3. Four times --
(Per unit vol.)
Variable size, orientation Uniform size, parallel
4. Osteocytes
& distribution orientation
Irregular pattern Uniform
5. Mineralization (Homogenous X- ray
(Irregular x-ray appearance)
appearance)

Because of its irregular collagen fibril orientation, relatively high cell and
water content and irregular pattern of mineralization, woven bone is more
flexible, more easily deformed, and weaker than lamellar bone. The almost
random alignment of the collagen fibrils makes the mechanical properties of
woven bone similar regardless of the orientation of the applied forces i.e. it
behaves isotropically when loaded. In contrast, lamellar bone behaves
anisotropically; its mechanical properties differ depending on the orientation
of the applied forces.

For these reasons, restoration of normal mechanical properties to bone

tissue at the site of a healing fracture requires the eventual replacement of
the woven bone of the fracture callus with mature lamellar bone.

Bone cells

They originate from two cell lines: a mesenchymal stem cell line and
a hematopoietic stem cell line.
1. Mesenchymal stem cell line
a. Undifferentiated cells (Pre-osteoblasts)
b. Osteoblasts
c. Bone linig cells

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d. Osteocytes
2. Hematopoietic stem cell line
a. Circulating or marrow monocytes
b. Pre-osteoclasts
c. Osteoclasts

Undifferentiated mesenchymal cells (osteoprogenitor cells, OPC’s)

- Reside in bony canals, endosteum, periosteum & marrow
- Surrounding tissues & vascular pericytes are other sources
- Differentiate into osteoblasts only after stimulation
Osteoblasts
- Lines the surfaces of bone & packed tightly against each other
- Functions: a). Synthesis & secretion of the organic matrix of bone in discrete
layers (lamellae) with collagen at 900 to adjacent layer (plywood
structure)*
b). Control electrolyte fluxes b/w ECF & osseous fluid
c).Release mediators to activate osteoclasts (PTH/cytokine
controlled)
- Fates : Assume flatter form as bone lining cells
Become osteocytes (gets surrounded by matrix)
Disappear from site of bone formation
- These cells don’t have power of cell division (c.f. OPC’s)
- Contain high levels of alkaline phosphatase (marker)
* In injury & repair, bone forming tumors, Paget’s disease osteoblasts initially
secrete woven bone in which collagen fibrils have a random orientation.
Bone lining cells
- Lie directly against the bone matrix
- A.k.a. resting osteoblasts or surface osteocytes
- They contract & secrete enzymes that remove thin layer of mineralized matrix
(PTH stimulated) thus permitting osteoclasts to attach to the surface of the
bone and to begin resorption of bone.
Osteocytes
- Forms > 90 % of bone cells in the mature human skeleton
- Surround themselves with an organic matrix that can mineralize
- Interconnected with other osteocytes, osteoblasts and bone lining cells to
sense deformation of bone and co-ordinate the formation & resorption of bone
Osteoclasts
- Hematopoietic stem cell precursor
- Typically have 3-20 nuclei & numerous mitochondria and lysosomes
- Proton pump in plasma membrane to acidifies the region b/w cell & bone
surface, thus dissolving the mineral phase
- Found occasionally on endosteal, haversian & periosteal bone surfaces

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- On cancellous/periosteal surfaces, they create characteristic depressions called

as Howship’s lacunae.
- In dense cortical bone, they lead osteonal cutting cones that tunnel through
bone, creating resorption cavities
- Most distinctive microscopic feature is the complex folding of the cytoplasmic
membrane where it is applied to the site of resorption of bone matrix.(Ruffled
border)
- Bone formation & resorption are locally coupled with osteoblasts always
following the osteoclastic activity & replacing the resorbed bone with lamellar
bone. Coupling factors include TGF-Beta & BMP’s are activated by acidic
environment of osteoclasts & then attract and stimulate OPC’s

- Contains glycolytic enzymes, collagenases, acid hydrolases and acid

phosphatases (marker)
- Osteopetrosis demonstrates the adverse effects of inadequate or ineffective
osteoclast function. Principal defect is that the osteoclasts fail to resorb
calcified cartilage and bone. The bone is extremely dense, hard and white. A
mixture of calcified cartilage, bone and fibrous tissue occupies most of the
marrow leaving little normal marrow space.(sever anemia, infection and
death)

Bone matrix
It has great durability and stability. Matrix makes up > 90% of total
volume of the lamellar bone (remainder is cells, cell processes, blood

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vessels). Composed of Organic & Inorganic component (Organic 20%,

inorganic 65% & water 10-15 %). Organic component (Collagen) gives the
bone its form and ability to resist tension. Inorganic or mineral component
primarily resists compression. (Demineralized bone, like a tendon or
ligament is flexible, pliable, and resistant to fracture. A demineralized long
bone like fibula can be bent or even tied in a knot without fracturing. In
contrast removal of the organic matrix makes the bone rigid and brittle; even
slightest deformation fractures it and a sharp blow shatters it.

Organic matrix
- Collagens, mainly Type I ( small amounts of type V & XII)…90%
- Non collagenous glycoproteins & proteoglycans……………..10%
- Also contain growth factors like TGF-Beta, FGF, IGF & BMP’s
- These proteins & growth factors incorporated into the matrix of bone are
responsible for the maintenance of normal bone remodeling process & they
give bone matrix its osteogenic potential which make bone grafting possible
- Heritable abnormalities of Type I collagen leads to Osteogenesis Imperfecta

Inorganic matrix
- Consists of hydroxyapatite, a crystal form of calcium & phosphate and water
- Constitutes 8-9% of bone
- 99% Ca, 85% Ph., 40-60% Na and Mg are associated with bone mineral
crystals
- Hydroxyapatite crystals are deposited in the ‘hole zones’ formed within
overlapping regions of type I collagen molecules & later are spread along the
fibers by secondary nucleation
- Osteonectin (glycopr. in org. matrix) binds hydroxyapatite to the collagen
- Osteopontin (phosphopr. in org. matrix) binds cells to bone
- Osteocalcin (glycopr. in org. matrix) is involved in osteoclast recruitment for
resorption of bone matrix
- Function: Ion reservoir & give bone its strength and stiffness

Biology of fracture healing

A fracture occurs whenever the upper limit of bone strain is exceeded, and
this local injury sets into motion a sequence of generalized systemic &
specific tissue responses, which conclude when the biomechanical
competence of the tissue is restored. It is Wolff’s law in the-extreme since a

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change in the functional state of bone causes structural or architectural

changes in the tissue.
The basic mechanism for the initiation of wound healing and bone
regeneration is the same. The bone healing process normally unites
fractures, arthrodesis, osteotomies and bone grafting operations. The
osteoclast and osteoblast cells that make intercellular substances of each
stage don’t exist in sufficient numbers to heal the bone at the moment of
fracture or operation. They are made available by local multicellular
mediator mechanisms under influence of local & systemic agents.

Stages of fracture healing

(Healing by external callus; secondary/spontaneous healing)
1. The fracture
2. Granulation tissue production (Temporary soft healing tissue)
3. Callus formation ( Temporary hard tissue)
4. The remodeling stage (Lamellar bone formation )
5. The modeling stage
An accompanying ‘Regional tissue reaction’ accelerates these processes
(Without this local reaction, healing takes 2-10 times longer)

1. The fracture stage

Fracture injures local marrow, periosteum, adjacent soft tissues and

living bone itself. As a result some cells in these tissues die while
others are perturbed. This leads to:
a. Sensitization of perturbed cells so that they can respond better
to special local & systemic messengers and stimuli
b. Release of local & labile biochemical & biophysical
messengers (guide the differentiation & organization of daughter cells).
and mitogens (cause proliferation of precursor cells).
Essential part of the first stage biologic response finish within 7 days
of injury.

2. The granulation tissue stage

Sensitized precursor cells begin to produce new cells that differentiate

and organize to produce new vessels, fibroblasts, intercellular
materials, supporting cells etc. Collectively they form a Soft
granulation tissue in the space b/w the fracture fragments. When a

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hematoma clot is present, the macrophages, giant cells and other

wandering cells arise in the granulation tissue to invade and remove it.
This stage lasts about 2 weeks. Some osteoclasts appear at this
time and erode some of the fracture surfaces.

3. The callus (External)

Further cell proliferation, differentiation & organization begin to

create new chondroblasts & osteoblasts in the granulation tissue. They
synthesize the extra cellular organic matrices of cartilage and woven
bone which gets mineralized starting a week later. Mineralization
finishes few weeks further with formation of ‘the fracture Callus’,
revealed on X-rays because of the calcium it contains.
Its organization usually ignores the orientation of the local
mechanical strains & loads, rather it reflects the orientation of new
capillaries that are created before the trabeculae & that nourishes the
latter afterwards. Callus is cartilaginous at periphery (away from
bone) and bony near the viable fracture ends. The common
determining factor is the Low O2 tension. Cartilage provides a suitable
material (less demanding of O2) when callus outgrows its blood
supply, thus temporarily bridging the gap until the blood supply
catches up.
Healing by external callus can be considered as two separate
but inter-related phases. There is an initial ‘Primary callus response’
which is largely independent of environmental circumstances & which
almost certainly arises from predetermined cells in the bone tissues
themselves. This leads subsequently to ‘Phase of bridging callus
formation’, the speed of which is likely to depend on the recruitment
of cells from the surrounding tissues by a process of ‘osteogenic
induction’. This phase is susceptible to environmental influences.
This process usually takes 4-16 weeks (adults vs. children &
Compact vs. spongy).

4. The remodeling stage

Some enigmatic property of the mineralized callus makes the ‘packet

style’ bone remodeling process begin inside it to replace the callus

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with packets of new bone (The remodeling-basic multicellular unit,

BMU). Remodelling does the following:
1. Replaces any mineralized cartilage with woven bone
2. Replaces the woven bone with packets of new lamellar bone
3. Replaces callus b/w the ends of the compacta with new
secondary osteons made of lamellar bone ( in accordance with
Wolff’s law)
4. Remove any callus plugging the marrow cavity, restoring the
cavity.

The remodeling-Basic multicellular Unit (BMU)

The BMU is a particular mediator mechanism that contains
many kinds of cells, intercellular materials & capillaries, all
specially organized in space & time and communication with
each other. A BMU first produces osteoclasts that remove a
packet of pre-existing hard tissue and then produces osteoblasts
that replace it with packet of newly made bone (activation-
resorption-formation sequence) that consumes 3-4 months per
BMU.
Complete replacement of the callus with functionally competent
lamellar bone by the remodeling BMU consumes 1-4 years. Failure
of the callus to mineralize can block the above process.

There are differences in remodeling process depending on whether it is

occurring in compact or cancellous bone. In remodeling of cancellous
or endosteal/periosteal surfaces, the cells are never very far away from
the blood vessels and so the whole process of bone apposition or
replacement can take place on the surface of the trabeculae. The
osteoclasts lie on surface of the bone and excavate a cavity called as
‘How-ship’s Lacunae’. When osteoclasts have completed their
resorptive activity they move away from the site of resorption or
breakdown into mononuclear cells. Thereafter active osteoblasts cover
the resorbed surface with osteoid seams. Mineralization of these seams
completes the remodeling process. This process is known as ‘Creeping
Substitution’
In compact bone, Internal or osteonal remodeling occurs in which the
more deeply placed cells require presence of Haversian systems which
must be replaced & thus a more orderly sequence is observed. First the
osteoclasts ream out a tunnel in the dead bone, often passing through
the old osteonal systems. These ‘Cutting cones’ create large resorption

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cavities that are visible on plain radiographs as lucent areas within the
cortical bone. Cement line mark the sites where resorption by a cutting
cone stopped & new bone formation began. Within the cutting cone,
group of spindle cells, osteoblasts & small blood vessels follow the
advancing group of osteoclasts.
Examination of cutting cone cell population suggest that
approximately 50 osteoblasts are required to replace the amount of
bone resorbed by one osteoclast in one day.

Gap healing v/s Contact healing

Gap healing: Gaps present b/w the fracture surfaces are invaded by
new capillaries & OPC’s grow in from the edges and new bone is laid
down on the exposed surface. Where the crevices are very narrow (less
than 200 micrometers) osteogenesis produce lamellar bone; wider gaps
are filled first by woven bone which is then remodeled to lamellar bone.

Contact healing : When the exposed fracture surfaces are in intimate

contact & held rigidly from the outset internal bridging occur without
any intermediate stages.

5. The modeling stage

After the callus formation, bone resorption & formation, the process of
modeling starts on endosteal & periosteal surfaces of the compact bone
thus recontours its gross shape towards normal. This process of reshaping
or sculpturing can reach completion in young children and nearly so in
young adolescents but never in adults.
The process requires one or more years and goes on concurrently with the
remodeling process.

Modeling refers to alterations in shape of the bone whereas remodeling

refers to turnover of bone that doesn’t alter the shape; however the two
processes often occurs simultaneously & the distinction b/w them may not
be readily apparent.

Regional acceleratory phenomenon (RAP)

First described in 1983 in relation to the fracture healing. It is known
that some how the original injury accelerates these normal regional
processes. This acceleration is called Regional acceleratory phenomenon.

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RAP doesn’t seem to provide new processes but by increasing the rapidity
but by increasing the rapidity of other healing stages it makes healing occur
2-10 times quickly than otherwise. RAP is not well appreciated as it
normally occurs after fractures, arthrodesis, osteotomies or bone graft
procedures and it is not exhibited in < 3% of fracture cases (rarely absent).
Also RAP due to its bone density effects is usually dismissed as disuse
osteoporosis roentgenographically.
It begins within few days of the fracture, peaks at 1-2 months and may
take 6 to > 24 months to subside. The increased intracortical bone
remodeling it causes produces tunneling within the cortex.

Other healing processes

1. Healing by medullary callus

Not only it is different from external callus in its location but

also the cartilage formation is much less prominent in
medullary callus. It may unite directly with external callus in a
displaced fracture. Mechanical stability doesn’t hinder its
formation. Also total immobility is not essential in its formation
as is the case with primary bone healing.

2. Primary bone healing

It is not really a separate method of union. Instead it is the

remodeling process which normally occurs very late in the normal
fracture healing process and thus requires the artificial stability to be
maintained for many months or even years. It is seen when fracture
ends are stabilized with total immobility. Dead fracture ends are not
resorbed but are recanalized by new haversian systems and when the
fragments are in direct contact; these systems actually cross from one
fragment into the other.

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Ability
Tolerance Tolerance Importance
to
S No. Type of healing Speed of of total of external
bridge
movements rigidity* soft tissues
gaps

Primary callus
1. ++++ + ++++ ++++ --
healing

External bridging
2. +++ +++ +++ -- ++++
callus

Late medullary ++++

3. ++ ++ +++ --
callus (slow)

4. Primary cortical + -- -- ++++ --

* Implies Stable fixation in present times

It is likely that all the above processes are involved to a greater or lesser
extent in the healing of every fracture, the special circumstances imposed by
particular methods of clinical management usually means that one or other
of them will preponderate. Thus the treatment should be planned in such a
way as to facilitate a particular mechanism or more importantly not interfere
with it.

Effect of various mechanical stresses on healing pattern

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It is a now known that bone formation mechanisms respond differently

under different types of mechanical stresses.

1. Intermittent compressive or shear stresses

Enchondral ossification

2. Tensile stress
Intramembranous ossification

3. Constant compressive stresses (hydrostatic stress)

Inhibits enchondral ossification, cartilage formation

4. High shear stresses

Fibrous tissue formation

Bone healing in patients with associated head injury

Head injury patients not only have increased heterotopic ossification
but also undergo abundant callus formation & progress to union rapidly.
Various mechanisms cited for this are:
1. These patients are frequently ventilated with high respiratory rates in order
to lower arterial CO2 concentrations, in an attempt to decrease intracranial
pressure. This leads to relatively alkalotic blood pH which promotes calcium
precipitation & early bone union
2. Central hormone response or induction of an unknown local factor acts as an
anabolic stimulator of osteoblasts
3. High serum prolactin levels during 5th week post injury coincide with
appearance of heterotopic ossification
4. FGF levels rose to 7 times in fracture pts with head injury (c.f. 3 times
without head injury)
5. IL-6, which is abundantly secreted by osteogenic cells, is significantly
increased in head injury patients
6. BMP receptors are upregulated following head injury
7. Head injury pts with uncontrollable seizures causes to increased movements
of the fracture fragments thus increasing callus formation

Bone healing problems

These can be divided into:
1. Technical failure

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Impairment of normal biologic potential due to treatment

problem
2. Biologic failures
Biologic malfunctions making correct treatment ineffective
3. Combination of the two

Technical failures

In this situation, the biologic processes had normal potentials but

treatment problems kept them from functioning properly. These problems
include infection, poor reduction, distraction, repeated gross motion of the
fragments (esp. pistoning & shear) and loss of local blood supply due to
injury and/or surgical procedures.

Technical problems cause or contribute to about 70-80% of all

delayed unions and non unions of the fractures, bone grafting operations,
osteotomies & arthrodeses. They affect cortical bone more often than spongy
bone. Roentgenograms of a technical failure of a long bone fracture shows
adequate callus formation on the ends of each major fragment separated by a
pseudoarthrosis of some kind, thus called hypertrophic non union. These
failures seldom need bone grafting to promote healing. Eliminating
excessive motion and infection & improving reduction usually leads to
union. An exception is synovial pseudoarthrosis which requires resection of
the cartilage covered ends of the non union because of a special tissue
‘gating barrier’ effect that prevents ossification across cartilage layers
separated by synovial fluid.

Treatment of technical failures: Correcting the treatment problem usually

leads to satisfactory union.

Biologic failures

In this situation, abnormalities in the biology of the healing processes

delay or prevent union even with proper treatment. They account for about
20% of all non unions & in combination with technical problems, contribute

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another 20%. They occur mostly in cortical bone and seldom in spongy
bone.
a. Failure to make callus: This involves malfunctioning of the
mediator mechanisms that produce the callus. Such a
malfunction occurs in about 80% of all biologic failures. The
underlying cause is either inability of local biology to produce
adequate callus or a systemic metabolic abnormality preventing
chondral & bone matrices from mineralization or both.
Therapeutic radiation, cytotoxins, regional denervation and
some NSAID’s can cause this failure.
Treatment: Fresh autogenous cancellous bone is an excellent
graft material in this problem as it delivers varied labile
biologic messangers to the tissues & mediator mechanisms in
the recipient site.

b. Inadequate RAP: It leads to slow callus formation and

replacement by lamellar bone. Inadequate RAP occurs in <5%
of all biologic delayed and non unions and happens more often
in cortical bone than spongy bone. Three or four months after
the injury, clinical roentgenograms provide a clue to an absent
RAP. There is absent or minimal longitudinal tunneling of the
local compacta and/or trabecular osteopenia in adjacent
metaphyses. Longitudinal tunneling and metaphyseal
osteopenia stem from greatly increased local BMU based
remodeling and an associated increase in remodeling space.
Both acute mechanical disuse & the RAP can cause these
increases and their effects can combine in normal healing
fractures. Another clue to a poor or absent RAP is a ‘cold or
cool regional scintigram’. Some medical problems like DM,
peripheral neuropathies, major regional sensory denervation,
diphosphate intoxication, sever radiation damage and severe
malnutrition are associated with inadequate RAP.
Inadequate RAP seldom occurs in children & spongy bone.
Treatment: Prolonging immobilization of the fracture, internal
fixation operation (which creates its own new RAP thereby
improving subsequent healing), electrical treatment & PGE2
administration helps in achieving union in these cases.

c. Failure to mineralize callus: This occurs mostly in

osteomalacia and rickets (seldom in Vitamin D resistant rickets)

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thereby leading to pseudo fractures and non unions of traumatic

fractures, surgical osteotomies, grafting operations and
arthrodeses. Subsequent modeling and BMU based remodeling
stages cannot occur until the callus mineralizes suggesting that
mineral plays role in enabling these processes. This contributes
to <3% all delayed & non unions.
Treatment: Treating the underlying metabolic abnormality

d. Maldifferentiation: If the initial tissue reaction of

sensitization- stimulus- proliferation occurs properly but
produces fibroblasts and/ or lipoblasts instead of chondroblasts
and/ or osteoblasts, the fracture space fills with scar tissue and
fat instead of callus. Some metastatic tumours & treatment
problems can cause such failures (esp. distraction). Unusual
causes include chronic primary hyperparathyroidism,
neurofibromatosis, diabetic neuropathy, total local denervation
and congenital pseudoarthrosis of tibia. Maldifferentiation
problem contribute to <10% of all biologic delayed and non
unions.

e. Remodeling stage malfunction: They can delay replacement

of apparently normal callus by lamellar bone. Callus doesn’t
produce a mechanically durable structural material for, unless it
is replaced by lamellar bone, it breaks down with mechanical
usage. Thus early healing proceeds normally but later callus
becomes plastic & deformity begins to develop. This is a very
rare problem.

Treatment: Prolonging immobilization by 2-4 times can

facilitate remodeling.

f. Modeling stage malfunction: Seen in children with

osteogenesis imperfecta. As a result, the deformities of multiple
fractures can persist & accumulate and require surgical
correction. These patients usually form callus rapidly and
replace it normally with lamellar bone. Their modeling defect is
usually partial. Imperfecta children with total or near total
inability to replace woven with lamellar bone or to model bone
usually die at or shortly after birth. Modeling stage

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malfunctions can also occur in osteomalacia and rickets. The

ability to model bone usually becomes ineffective after skeletal
maturity. In contrast the BMU based remodeling actually
continues for life!

Secondary injury phenomenon: It implies that fractures fixated a

week or more after the fracture heal more rapidly than other fractures.
The stimulation is called ‘booster type’ of mechanism. The delayed
fixation means a refracture of callus (which has already formed) in a
stage when some of the injuries of the soft tissues have healed i.e. the
release of biochemical mediators from the soft tissue wound has
faded. The method implies a greater risk of pulmonary complications.
Various methods of bone lengthening by osteotomy and distraction
with a frame like Wagner’s method and Ilizarov’s method work on
this principle. Thus micromanipulations of callus help in prolonging
the time of active stimulation by the fracture exudate, thereby
enhancing healing process. Second injury phenomenon becomes
operational when two conditions are met:

1. A biologic failure would have followed the first injury had a

second injury not happened.

2. The second injury should occur more than a few days but less
than 2-3 months after the first one.

An On-Off Phenomenon: Bone grafting & internal fixation

procedures of some biologic failures done many months or more than
a year after the original fracture leads to prompt and occasionally
exuberant subsequent healing. It is suggested that some biologic
failures may reflect an only temporary & local inability to heal
normally, a kind of ‘Off state’ of the local mediator mechanisms. An
injury may occur during such stage, but a subsequently successful
operation may be done after that inability has resolved and so during
an ‘On state’.

To conclude, the healing of a fracture is one of the most remarkable of

all the repair processes in the body since it results, not in a scar, but

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in the actual reconstitution of the injured tissue in something very like

its original form.

References
1. Mc Kibbin B. The biology of fracture healing in long bones; JBJS
Vol. 60-B, No 2, May 1978 (150-162).
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supply, cells, matrix and mineralization; JBJS Vol 77-A(8), Aug
1995 (1256-1275)
3. Buckwalter, J.A. et al. Bone biology. Part II: Formation, form,
modeling, remodeling, and regulation of cell function; JBJS Vol
77-A(8), Aug 1995 (1276-1289)
4. Frost H.M. The biology of fracture healing; an overview for
clinicians. Part I. CORR No 248, Nov 1989 (283-293)
5. Frost H.M. The biology of fracture healing; an overview for
clinicians. Part II. CORR No 248, Nov 1989 (294-306)
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249, Dec 1989 (265-283)
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mechanical and surgical intervention. CORR No 355S, Oct
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8. Edmund Y.S. et al. The effect of rigidity on fracture healing in
external fixation. CORR No 241, April 1989 (24-35)
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Feb 1979 (175-195)
10. Simmons D.J. Fracture healing perspectives. CORR No 200,
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callus formation in patients with femoral fracture and head
injury. Injury (2006) 375, S18-S24
13. Solomon Louis et al. Apley’s system of orthopaedics and
fractures, Eighth Ed. Pg. 540-543

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14. Watson- Jones. Fractures and joint injuries. Sixth Ed. Pg. 14-
28
15. Campbell’s operative orthopaedics Tenth Ed. Vol. 3. Pg. 2686-
2687
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