Activity-Related Bone Stress Injury of the Pubis

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Activity-related bone stress injury of the pubis (e.g. affecting an athlete in a running-kicking sport such as soccer or AFL) as compared to an acute, high-energy pelvic fracture (e.g. secondary to trauma such as a cycle crash)

Activity-related bone stress injury of the pubis

Pathogenesis

Bone stress injury (BSI) occurs with repetitive and abnormal forces applied to a normal bone which results in fatigue fractures1,2; in this case, abnormal physical forces is placed on the pubic symphysis and parasymphyseal bone3.

Bone requires stress to develop which stimulates remodeling of the internal and external architecture allowing it to withstand new mechanical environment, this is an ongoing dynamic process regulated by cells influenced by the local state of stress within the bone1,2. Initiation of remodeling phase can be due to cellular injury or development of microfractures2; approximately 3 weeks of peak bone loss, osteoclast resorption occurs in response to increase stress resulting in small resorption areas at the microfractures1, full resorption takes about 30 days2; to minimise stress, osteoblast is laid as a replacement matrix of osteoid2. The resorption cavities are then filled with lamellar bone, bone formation takes longer than resorption with a minimum of 90 days; this delay leads to an imbalance between resorption and bone formation resulting in temporary bone weakening1,2. New bone maybe produced by endosteal and periosteal proliferation at the site of microfracture to help the temporary weakened cortex1. This entire process results in the ability of the bone to better adapt with sustained increased stress2.

When a stress occurs in cancellous bone, it could result in microfractures of the trabeculae and microcallus; pathological process occurs as bone repair mechanism is exceeded, an accumulation of microfractures and fatigue stress injury of the cortical or cancellous bone1. Muscles act as a shock absorber and shares load placed on bone tissue, if there is weakness or fatigue, there is reduce shock absorption thus increasing the risk of microdamage accumulation4,5.

Excessive repetitive loading and inadequate recovery time may lead to an overuse injury at the pubic symphysis and parasymphseal bone region3; microfractures on bone tissue have insufficient time to undergo remodeling to adapt to the new mechanical environment4, if left untreated it will become a stress fracture1,4.

 

Acute, high energy pelvic fracture

Pathogenesis

Pelvic fractures are uncommon and usually occur with traumatic injuries6; severity ranges from stable low energy to unstable high energy injuries which could lead to mortality and morbidity6,7.

The degree of instability provides an indication of applied force on the pelvis, and the mechanism provides the direction of force applied through the body7. Classification of pelvic fractures is based on radiological findings (Xrays, CT scans)6,8. Two classifications are used: Young and Burgess, and the tile system. Young and Burgess classify mechanism and severity of injury6-10: Lateral compression either from one or both sides of the pelvis creates vertical compression fractures; Anterior-Posterior forces rotates the iliac wings outward disrupting the pubic symphysis and sacroiliac joints – pelvis opens anteriorly like a book; Vertical shear force occurs as a combined mechanical injury causing complete disruption of the posterior sacroiliac complex – one hemi-pelvis translates superiorly tearing the sacroiliac joint; lastly, combined mechanism. The Tile system6,8,10 classifies fracture into stable, partially unstable and completely unstable.

Three types of bleeding are reported in a pelvic fracture: arterial, venous and bleeding from fractured cancellous bone7,8. Arterial bleeding contributes to most of the haemorrhage in pelvic fractures which comes from the iliac vessels and branches6,7; this is usually identified with pelvic angiography7. Venous bleeding caused by tearing or shearing of the veins usually occurs in the posterior venous plexus7. It is found that bleeding from the bone rarely cause significant blood loss despite having varying severity of pelvic injuries7. There is difficulty determining the proportion of arterial or venous bleeding in pelvic haemorrhage7, therefore these injuries are managed with embolization and tamponade respectively7-9.

It is challenging to correlate fracture pattern with blood loss as patients with high energy trauma often present with associated injuries where they have the most haemorrhage, shock and highest mortality7,11; it is then difficult to know the contribution of mortality caused by pelvic fracture haemorrhage. A study11 compared the differences between the two classification systems with their predictive value on mortality, transfusion/total fluid requirement and concomitant injuries, they found no clinical relevance in this prediction; in a single fracture pattern, both classifications were able to predict transfusion/total fluid and severity of concomitant injuries requirement; using Young-Burgess classification could predict mortality.

Inflammatory response

  Acute, high energy pelvic fracture Activity-related bone stress injury of the pubis
Inducers Acute inflammation

Tissue state activated by high energy trauma injury, tissue stress and para-inflammation response overwhelmed.

Pelvic fracture disrupts bone tissue vasculature, endosteal and periosteal surfaces in bone marrow, and surrounding soft tissue resulting in haematoma (hypoxia, low pH) due to activation of plasma coagulation cascade and platelets exposed to extravascular environment12,13. Angiogenesis needed to remove debris and supply fracture site with cells and mediators13.

Endogenous inducers14 produced by stressed, damaged or malfunctioning tissues: DAMPs or Alarmins liberated when cells damaged/secreted by sensitized cells.

Dysregulated parainflammation

Maladaptive form of para-inflammation due to repetitive and sustained mechanical loading repetitive.

Ongoing pro-inflammatory state develops homeostatic ‘set points’15; Increased reactivity of osteocytes leading to increased risk of pain in bone.

Stressed and distressed chondrocytes and ECM within tissue: DAMPs. Persistent low level noxious inputs result in chronic state of tissue dysfunction.

Sensors Tissue level homeostasis monitored by intercellular sensors.

Activated Hageman factor senses vascular damage and initiates 4 proteolytic cascades which generates inflammatory mediators:

kinin, coagulation, fibrinolytic and complement cascade14.

Tissue resident immune cells: Dendritic cells and macrophage responds to injury and stress; all cells have PRR living within walls of tissue resident immune cells15.

Innate immune response identifies tissue damage mediated by tissue resident immune cells, triggers cascade of pro-inflammatory mediators: cytokines, chemokines, vasoactive amines leading to an inflammatory response15.

Activation of blood coagulation cascade, formation of provisional fibrin matrix for influx of inflammatory cells which are attracted by platelet derived factors, release of danger signal molecules from necrotic cells, damaged ECM, activation of local macrophages12.

First 24 hours, neutrophils at fracture site. Initial fracture haematoma and acute inflammation reaction are essential for fracture healing12.

Macrophages sense pathogens, hypoxia or stressors and produce cytokines, vascular endothelial  growth factory (VEGF) or tissue-level adaptations and defenses15.

– Pattern Recognition Receptors (PRR)

– Tissue resident immune cells (macrophages, mast cells)

– Cells of epithelium, vascular epithelium

– Mesenchymal Cells (MSC), ECM

– Endocrine cells

– Chondrocytes, osteocytes

Mediators Release of cytokines, chemokines, growth factor, bone morphogenetic proteins (BMPs), vascular endothelial  growth factory (VEGF), platelet-driven growth factor (PDGF), fibroblast growth factor-2 (FGF-2)12; Results in initial fracture haematoma and acute inflammation reaction resolution in several days to a week post fracture, replaced by granulation tissue rich in proliferating Mesenchymal cells (MSC) and developing neovasculature embedded in unorganized ECM12,13.

Inflammatory cytokines activates endothelium and leukocytes and induces acute phase response14.

Chemokines control leukocyte extravasation and chemotaxis towards affected tissues14.

Proteolytic enzymes degrades ECM and basement membrane proteins, they host defense, tissue remodeling and leukocyte migration14.

Secretion of inflammatory and chemotactic mediators, IL-6, CCL2, neutrophils recruit second wave of inflammatory cell infiltration to fracture site (monocyte/macrophages)12. Osteomacs in periosteum and endosteum involve in regulation of fracture healing12.

Phagocytosis:

Macrophage removes necrotic cells and provisional fibrin matrix; monocyte-derived osteoclasts resorb necrotic bone fragments and ends of fractured bone12.

Release of cytokines, growth factors, proteases15.

Down regulation: proteoglycans, TIMP, growth factors.

Upregulation: DAMPs, NO, PG2. MMP, proteolytic enzymes.

Effectors Granulation tissue: active proliferation of progenitor cells, deposition of immature fibrotic extracellular matrix, angiogenesis12.

Fracture site hypoxic, chondrocytes produce cartilage, connecting ends of fracture bone several weeks after injury12. Along with fibrotic tissues, cartilage (soft callus) provides initial mechanical stability, act as scaffold for endochondral bone formation12. As soft callus develops, new bone formation advances forming inner layer of periosteum; MSC and periosteal osteoprogenitor cells differentiate into osteoblasts which lay woven bone covering external surface of fibrocartilaginous callus providing mechanical stability12.

Chondrocytes in soft callus hypertrophy go into apoptosis secreting calcium and mediators stimulating vascular ingrowth leaving behind partially calcified cartilage ECM12.

Formation of hard callus: stabilised fracture gap and increased blood flow to healing fracture site, osteoprogenitor cells into osteoblasts and deposit of woven bone on cartilage scaffold12.

Mechanical stability of fracture site improves, ability to carry physiological loads independently; this stage takes several weeks or months after primary injury12.

Sustained stress leads to stress induced premature cell senescence (SIPS), increasing number of senescent cells express senescence associated secretory phenotype (SASP) in chondrocytes.

SASP = increase expression of pro-inflammatory cytokines, growth factors, proteases (increase MMP), increase pro-inflammatory environment within tissue15.

No or reduced activation of vascular system, reduced oedema, non-resident immune cells recruited to a lesser extent.

– Chondrocytes

– Endothelial cells of vessel wall

– Epithelial cells

– Tissue resident mast cells, macrophages

– Cells of HPA axis

Physiological responses Callus formation:

Differentiation of progenitor cells into chondrocytes and production of fibrocartilage, fracture stabilization by fibrocartilage calcification, vascular ingrowth, recruitment of osteoprogenitors cell, woven bone deposition on cartilage scaffold12.

Remodeling: Formation of chondroclasts and osteoclasts, resorption of cartilage and woven bone, restoration of Haversian system12,13.

This process takes several months or years to complete, restoring the normal form and integrity of bone completing the process of fracture healing12.

Programmed cell senescence and SIPS leads to increase SASP in BSI leading to increased pro-inflammatory environment.

Cell senescence: change in phenotype, shift from catabolic to anabolic resulting in expression of SASP; dysregulated apoptosis due to excessive tissue stress.

Para-inflammatory responses are usually short term, adaptive and helpful. However if response is persistent and dysregulated it will lead to chronic inflammation where it is maladaptive and unhelpful.

Mechanobiology

Mechanobiology combines mechanics and biological process16,17; mechanotransduction is where cells sense and respond to mechanical stimuli17-20. In bone tissue, osteocytes are the mechanosensor which directs osteogenesis and initiates the process of targeting bone remodeling18,19,21. Several modalities stimulate osteocytes, depending on the mechanical load applied to the bone tissue and osteocytes; this will induce interstitial fluid movements causing deformations of osteocyte plasma membrane and shear force at cellular level18,21.

In order to maintain homeostasis, bone requires mechanical stimulation22. Loading past the tissue’s set point is a stimulus through mechanotransduction where the body adapts by increasing protein synthesis and add tissue where required19. Mechanotherapy comprises of exercise, manipulations and massage promotes tissue repair or remodelling, with the goal of improving functional ability19,20,23.

Acute management of pelvic fractures is to control haemorrhage and stabilise the pelvis either using wrapping sheet, external fixation device or pelvic clamp with the goal of reducing mortality and improve on clinical outcomes6,9,10, several studies suggest using external fixators to stabilise an unstable pelvis reduces shock and mortality7,24,25. Within 3-7 days post-injury, an open reduction and internal fixation of the pelvic ring is performed to improve on function, plates and screws are used6.

In pelvic fracture, the goal is to restore bone structure, composition and function26. Several factors could impair the healing process, genetics, biological, nutritional and physical factors26. Bone healing requires expression of cytokines and growth factors, and loading16; bone-forming cells are sensitive to mechanical loading and respond by proliferation, matrix synthesis, and modulation of cytokine and growth factor expression26. During initial stages, the fracture site is usually fixated while in the non-injured state, inactive bone for long periods will be resorbed by osteoclast activities and bone formation is inhibited16,18.

In BSI, treatment is usually conservative; reducing in frequency, load or intensity of training to allow the site to heal27; surgical intervention can be considered if conservative treatment is unsuccessful especially in long-standing symptomatic cases with a definite lesion27.

Adipose-derived stem cells (ASC) have been used in bone tissue replacement therapies, they are an alternative to MSC with both having similar phenotype28; it is a rich autologous cell with an ability to regenerate which is involve with mechanical forces, it is understood that ASC can be a likely cell source for future therapeutic constructs28.

Besides the benefits of mechanobiology, as clinicians we should also be aware of the unfavourable conditions such as suggesting the use of NSAIDS prior introduction of a mechanical stimulus (exercise), it has shown to slow down bone formation or impaired skeletal adaptive response20.

References

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2. Miller C, Major N, Toth A. Pelvic Stress Injuries in the Athlete. Sports Medicine. 2003; 33(13):1003-1012.  DOI:10.2165/00007256-200333130-00005.

3. Hiti CJ, Stevens KJ, Jamati MK, Garza D, Matheson GO. Athletic Osteitis Pubis. Sports Medicine. 2011; 41(5):361-376.  DOI:10.2165/11586820-000000000-00000.

4. Astur DC, Zanatta F, Arliani GG, Moraes ER, Pochini AdC, Ejnisman B. Stress fractures: definition, diagnosis and treatment. Revista Brasileira de Ortopedia. 2016; 51:3-10. Available

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7. Dyer GSM, Vrahas MS. Review of the pathophysiology and acute management of haemorrhage in pelvic fracture. Injury. 2006; 37(7):602-613.  DOI:http://doi.org/10.1016/j.injury.2005.09.007.

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15. Chovatiya R, Medzhitov R. Stress, inflammation, and defense of homeostasis. Molecular Cell. 2014; 54:8. Available

16. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Reports. 2017; 6:87-100.  DOI:https://doi.org/10.1016/j.bonr.2017.03.002.

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24. Agolini SF, Shah K, Jaffe J, Newcomb J, Rhodes M, Reed JF. Arterial Embolization Is a Rapid and Effective Technique for Controlling Pelvic Fracture Hemorrhage. Journal of Trauma and Acute Care Surgery. 1997; 43(3):395-399. Available from: http://journals.lww.com/jtrauma/Fulltext/1997/09000/Arterial_Embolization_Is_a_Rapid_and_Effective.1.aspx.

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