Keywords
bone healing - fracture repair - bone inflammation - osteomyelitis
The human body is made up of 206 bones, representing approximately 15% of an adult's
total body weight. Fracture incidence varies based on age and gender, but ranges from
2 to 5 per 100 person-years.[1]
[2]
[3] More alarmingly, there has been a significant increase in the fracture incidence
over the last several years.[2]
[3]
Fractures not only affect patients quality of life, but also impute a substantial
cost on society.[4] The cost of illness (COI) associated with fractures has been previously reported
across different populations.[4]
[5] Hip fractures have the highest COI with reported numbers over $30,000, mostly due
to long-term morbidity costs.[4] More distressingly, almost one in three patients over 50 years of age who sustain
a hip fracture die within 1 year of the incident.[6]
One way of improving fracture outcomes is by understanding principles of bone growth
and healing. To that end, the primary goal of this paper is to provide a comprehensive
review of bone healing and inflammation. Moreover, we hope to provide an evidence-based
practical approach to bone pathologies such as fractures and osteomyelitis.
Anatomy and Structure of Bone
Anatomy and Structure of Bone
Types of Bone
There are two main types of bone, cortical and cancellous. Cortical bone is dense
and solid; it contains osteons termed Haversian canals.[7] These are cylindrical structures that form a branching network. The walls of these
structures are composed of concentric lamellae that fit inside each other. On the
other hand, cancellous bone (spongy bone) is composed of a network of trabecular plates
and rods in a honey-comb configuration. It also contains osteons called packets which
are semilunar in shape and also composed of concentric lamellae.
The term lamellar bone refers to the orientation of bone where collagen fibrils are
deposited in an alternating fashion, thereby providing increased bone strength. On
the other hand, woven bone is formed when collagen fibrils are deposited in a disorganized
manner (usually present in the formation of primary bone).
Categories of Bone
There are four broad categories of bones. Long bones consist of a long-hollow shaft
(diaphysis), a cone-shaped metaphysis proximal to the growth plate, and a rounded
epiphysis distal to the growth plate. The shaft is mainly composed of compact bone
while the metaphyses and epiphyses are mainly composed of a trabecular bone. Long
bones contain both yellow and red bone marrow and are the principal type of bone that
produces blood cells. Examples of long bones include the femur, humerus, and radius.
The second type is of short bones. These are usually cube shaped with approximately
equal horizontal and vertical dimensions. They are mainly composed of trabecular bone
and covered by a thin layer of cortical bone. Examples of short bones include the
carpal and tarsal bones. The third type are flat bones which are thin bones made up
of a layer of trabecular bone within two layers of cortical bone; examples include
the mandible and calvaria. The last type of bones are irregular bones. They do not
fit in any of the three categories mentioned above. They are made up primarily of
trabecular bone and covered by a thin layer of cortical bone. Examples of irregular
bones include the vertebrae and the hyoid bone.[8]
Bone Composition
Bone is heterogeneously composed of inorganic minerals and an organic matrix. Hydroxyapatite
(Ca10[PO4]6[OH]2) is the main inorganic mineral in bone and makes up the majority of bone material.
It aids in giving bone its rigidity and strength. Calcium is tightly regulated via
different hormones. Parathyroid hormone (PTH) stimulates bone resorption through calcium
release from bone into blood. On the other hand, calcitonin prevents bone breakdown
by inactivating osteoclasts. Finally, calcitriol has many functions including increasing
intestinal absorption of calcium and phosphorous, the main components of the osseus
inorganic matrix.[9]
On the other hand, the organic matrix is mainly composed of collagen type I (approximately
90% of organic matrix), glycosylated proteins (approximately 5% of organic matrix),
and growth factors such as transforming growth factor-beta (TGF-beta), growth hormone
(GH), and insulin-like growth factors (IGF).[10] Collagen has an integral role in maintaining the structure of bone.[10] It also plays an important role in bone function and is involved in processes such
as bone apoptosis, cell proliferation, and differentiation.[11]
[12]
[13] Glycosylated proteins, specifically small leucine-rich proteins, are present in
bone and play an important role in cell proliferation, bone remodeling and mineral
deposition.[14] Finally, growth factors, such as TGF-beta, GH, and IGF, are all important regulators
and signaling markers for bone homeostasis, remodeling, and matrix protein synthesis.[15]
[16]
Bone Modeling and Remodeling
Bone Modeling and Remodeling
Bone modeling is the process by which bones respond to physiologic stress or mechanical
forces, by changing their shape or configuration. It was first described by the German
Surgeon Julius Wolff in 1892 where he postulated that long bones change shape to accommodate
stresses they endure.[17] Over 100 years later, his hypothesis holds true; it is currently believed that strains
within bone tissue are transduced into signals that can control bone deposition and
lead to bone formation.[18] Bones may increase in size or change axis by addition and removal of bone through
osteoblasts and osteoclasts, respectively. Another distinct concept is bone remodeling.
Bone remodeling is the process by which healthy bone is renewed to maintain bone strength,
preserve its mineral composition, and maintain calcium and phosphate homeostasis.
This tightly organized process involves the continuous resorption of old bone and
deposition of newly synthesized proteinaceous matrix which eventually becomes calcified
once again. This process is composed of four main phases.
The first phase of bone remodeling is cell activation which involves recruitment and
activation of monocyte macrophages and osteoclast precursors from circulation.[19] The second phase is resorption which is mediated by osteoclasts and regulated by
a large spectrum of inflammatory markers such as interleukin (IL)-1 and IL-6.[20] Osteoclasts resorb bone through lowering the pH within the bone compartment and
secreting tartrate-resistant acid phosphatase and other enzymes that digest the bone
organic matrix. The third step is reversal, where preosteoblasts are recruited alongside
coupling signals that signal the end of bone resorption and the beginning of bone
formation.[21] The final step, bone formation, is mediated by osteoblasts which synthesize new
collagenous organic matrix.[22] While osteoblasts deposit bone, they become entrapped within the matrix they secrete,
becoming osteocytes which remain in contact and communication through a network that
serves as a functional syncytium. The final result of bone remodeling is production
of a new osteon.
Bone Healing
Primary Healing
Bone healing is the process of rebuilding bone following a fracture. There are two
main types of bone healing, primary and secondary. Primary (direct) healing occurs
when the bony fragments are perfectly reduced, aligned, and fixed under compression
with no motion at the fracture site. If these requirements are achieved, bone can
heal via direct remodeling of lamellar bone and Haversian canals.[23] Bone on one side of the cortex must connect with bone on the other side to reestablish
mechanical and physical continuity. Cutting cones are formed at the ends of the osteons
closest to the fracture site. These cones cross the fracture line and generate longitudinal
cavities (via osteoclasts) which are then filled by bone matrix (via osteoblasts).
This results in generation of bony union and restoration of Haversian systems that
allow for blood supply to be reestablished.[24] Finally, osteons mature and undergo remodeling into lamellar bone, thereby healing
the fracture site without the formation of callus or inflammation.[25]
Secondary Healing
While primary bone healing can be achieved by open reduction and internal fixation
under compression, the more common type of bone healing is secondary (indirect) healing.
Secondary healing consists of both intramembranous and endochondral ossification and
occurs via four main stages. The first stage is the acute inflammatory response which
begins with a hematoma formation. The hematoma coagulates and forms a temporary scaffold
that acts as a template for callus formation.[26] Acute inflammatory markers, such as tumor necrosis factor alpha (TNF-α), IL-1, IL-6,
are then recruited. These markers attract macrophages, monocytes, and lymphocytes
that then serve to remove necrotic tissue and secrete cytokines, such as vascular
endothelial growth factor (VEGF), which stimulate healing and promote angiogenesis.
This stage lasts approximately 5 days. The second stage is the formation of the fibrocartilaginous
network; mesenchymal stem cells are recruited and differentiated into fibroblasts,
osteoblasts, and chondroblasts.[27] This initiates chondrogenesis via deposition of a collagen-rich fibrocartilaginous
network that spans the fracture site (soft callus). Simultaneously, a layer of woven
bone is deposited. The stage usually starts on day 5 postfracture and lasts approximately
5 days. The third stage is the bony callus formation where the cartilaginous callus
(soft callus) undergoes endochondral ossification to form the hard callus (via chondro-
and osteoblasts and clasts). This occurs via resorption of the cartilaginous callus
and deposition of woven bone subperiosteally.[28] This stage usually lasts up until 4 weeks postinjury. It is important to note that
there is significant overlap between the second and third stages (mesenchymal cell
recruitment and hard callus formation). The fourth and final step is bone remodeling
where the bony callus is remodeled via osteoclasts and osteoblasts to form compact
bone centrally, and lamellar bone peripherally.[29] This allows the newly formed bone to achieve the rigidity and biomechanical stability
of normal bone. This stage can last months to years. Understanding the different stages
on bone healing and their timeline allows us to better appreciate treatment protocols
and length of immobilization required.
Inflammation
Inflammation is a key response in bone healing. As previously discussed, proinflammatory
cytokines are initially recruited to initiate the process of secondary healing. However,
increased inflammation could have undesirable effects on bone healing. An experimental
rat model that demonstrated increased proinflammatory activity (via administration
of lipopolysaccharide) impairs bone healing.[30] Another study found that increasing anti-inflammatory IL-10 was found to improve
osseus healing postfractures in rats.[31] In humans, systemic inflammatory conditions, such arthritis, diabetes mellitus,
sepsis, or multiple trauma, increase fracture healing time and impair osseus healing.[32]
While excessive inflammation worsens healing, impaired inflammation can also impede
healing and increase rates of delayed osseus healing. One topic that has been intensely
discussed over the last several years is use of nonsteroidal anti-inflammatory drugs
(NSAIDS) following fractures. These drugs have anti-inflammatory and analgesic properties
and are frequently prescribed postsurgery. However, multiple studies have shown worsening
rates of bony healing, increased nonunions, and weaker bones associated with NSAIDs
use.[33]
[34]
[35] While the underlying pathophysiology of impaired healing due to increased or decreased
states of inflammation remains a debated topic, a tightly regulated inflammatory response
is believed to be critical for adequate osseus healing.
Infection
Osteomyelitis, defined as bone infection, is a dreaded complication that significantly
impairs bone healing and leads to loss of function and even amputation.[36] The incidence of infection after bone fixation varies from 1 to 2% in closed fractures,
to up to 30% in open fractures.[37] Studies have shown that infection impairs callus formation, wherein fibrous tissue
is formed instead, affecting woven bone deposition and thereby decreasing mechanical
stability and overall osseus healing.[38] Neutrophils, one of the main immune cell types present in infected tissues, are
also associated with increased rates of delayed osseous healing.[38]
Osteomyelitis usually presents with nonspecific signs and symptoms such as pain, fever,
chills, and lethargy. Physical examination findings include but are not limited to
cardinal signs of inflammation, decreased range of motion, and point tenderness. Clinicians
should have a low threshold of susception of osteomyelitis in the context of inserted
hardware postreduction.
Blood tests, such a complete blood count (CBC), erythrocyte sedimentation rate (ESR),
and C-reactive protein (CRP) are useful adjuncts in diagnosing this condition. Blood
cultures should always be obtained in cases of query osteomyelitis; however, a negative
blood culture does not exclude the diagnosis.[39] Radiological imaging can be of great value in the diagnosis of osteomyelitis. Whereas
standard X-ray radiography might show signs of bony resorption, bone scans were previously
perceived as the gold-standard radiological study for osteomyelitis; a radioactive
substance, usually technecium-99, accumulates in areas of increased blood flow which
indicates infection. However, recently, magnetic resonance imaging (MRI) has been
hailed as a more accurate radiologic modality (higher sensitivity and specificity),
as it shows greater anatomical details and signs of cortical destruction.[40] However, the gold standard for osteomyelitis diagnosis is bone biopsy and histopathologic
examination.[39]
Treatment of osteomyelitis should not be delayed as it can significantly affect morbidity
and limb salvation. As per infection control principles, the most important treatment
is infection control. This means that any infected hardware should be promptly removed,
and surrounding soft tissue infection drained/debrided and washed out. Staphylococcus aureus is the most common pathogen causing osteomyelitis in adults. However, board spectrum
intravenous (IV) antibiotics should be initiated promptly and stepped down to another
antibiotic with more specific coverage once bacterial cultures and sensitivities are
obtained. Treatment in adults usually consists of 6 weeks of IV antibiotics. Infected
bone has relatively poor blood supply, and therefore require longer duration of treatment
in order for the antibiotic levels to reach sufficient concentration to be able to
penetrate bone.[39]
[41]
[42]
Clinical Significance and Practical Approach
Clinical Significance and Practical Approach
Principles of Reduction and Fixation
In order to strive for optimal fracture healing, it is critical to understand factors
that affect bone healing. For successful bone healing to occur, adequate blood supply
and fracture stability are crucial. There are four principles of fracture fixation
(AO principles)[43] that are integral to optimal fracture fixation and healing. The first of which is
fracture reduction to restore anatomical relationships. The second principle is fracture
fixation to provide absolute or relative stability. The third principle is preservation
of blood supply to soft tissue and bone. The final principle is early and safe mobilization.[44] These principles allow optimal bone healing and the prevention of delayed healing
and nonunion. Nonunion is defined as an arrest in fracture healing or presence of
the fracture 9 months of postinjury, with at least 3 months without radiologic signs
of healing.[45] Delayed union is defined as failure to reach bony union 6 months of postfracture.
There are many different types of bony fixation. An important dichotomy to appreciate
is rigid versus nonrigid fixation. The former achieves absolute fracture stability
and prevents interfragmentary motion across the fracture site, while the latter achieves
relative stability and restores axials, angular, and rotational alignment.[46] Consequently, rigid fixation leads to primary healing (Haversian remodeling) while
nonrigid fixation leads to secondary healing with callous formation. Another important
concept is fracture compression. Fixation modalities that compress the bony fragments
across the fracture site allows for rigid fixation and hence absolute stability. Compression
can be achieved by compression plates, overbending of the plate, lag screws, and external
tension devices. On the other hand, casting, percutaneous Kirschner's wire placement
and external fixation devices are all examples of nonrigid non compression fixation
modalities that lead to secondary healing with callous formation.
There exist other local and systematic factors that affect bone healing which clinicians
should be aware of and attempt to optimize. Factors, such as obesity, steroid administration,
malnutrition, and smoking, are also significantly impair bone healing and need to
be addressed in order to provide holistic patient care.[47]
[48]
[49]
[50]
[51]
[52]
[53]
Bone Stimulators
One emerging technique to treat delayed unions and nonunions is bone stimulation.
This technique consists of delivering an electrical or electromagnetic (EM) field
to a fracture site. While the mechanism of action remains incompletely understood,
it is believed that the EM field acts like a mechanical load which causes a strain
gradient across the bone fracture to stimulate healing.[54] Another novel method of bone stimulation is low-intensity pulsed ultrasound (LIPUS)
which delivers ultrasonic stimuli to the fracture site. LIPUS is believed to improve
osseus healing through increasing chondrocytes, soft callus formation, and therefore
earlier endochondral ossification.[55] While many recent studies have investigated both electrical stimulation, as well
as LIPUS, mixed evidence exists regarding their efficacy and more studies are warranted
before considering a standardized approach in clinical practice.[55]
[56]
[57]
[58]
[59]
Conclusion
Understanding bone healing is vital to provide the best care for patients. Inflammation
is a key response that initiates osseus healing; however, an excess level of an inflammatory
response can impair fracture healing and lead to nonunions. Other factors that significantly
affect bone healing are inadequate blood supply, biomechanical instability, immunosuppression,
and smoking. By understanding the different mechanisms of bone healing, a better application
of principles relating to bony fixation can be implemented which ultimately will lead
to improved patient care.
