Activity-Related Bone Stress Injury of the Pubis

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 fractures^1,2; 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 bone^1,2. 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 weakening^1,2. 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 accumulation^4,5.

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 fracture^1,4.

 

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 morbidity^6,7.

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 injury^6-10: 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 system^6,8,10 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 bone^7,8. Arterial bleeding contributes to most of the haemorrhage in pelvic fractures which comes from the iliac vessels and branches^6,7; 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 respectively^7-9.

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 mortality^7,11; 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 process^16,17; mechanotransduction is where cells sense and respond to mechanical stimuli^17-20. In bone tissue, osteocytes are the mechanosensor which directs osteogenesis and initiates the process of targeting bone remodeling^18,19,21. 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 level^18,21.

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 ability^19,20,23.

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 outcomes^6,9,10, several studies suggest using external fixators to stabilise an unstable pelvis reduces shock and mortality^7,24,25. 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 inhibited^16,18.

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

1. Kiuru MJ, Pihlajamäki HK, Ahovuo JA. Bone stress injuries. Acta Radiologica. 2004; 45(3):000-000.  DOI:doi:10.1080/02841850410004724.

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

5. Ferry AT, Graves T, Theodore GH, Gill TJ. Stress Fractures in Athletes. The Physician and Sportsmedicine. 2010; 38(2):109-116.  DOI:10.3810/psm.2010.06.1788.

6. Dimitriou R, Giannoudis PV. Pelvic fractures. Surgery (Oxford). 2012; 30(7):339-346.  DOI:http://doi.org/10.1016/j.mpsur.2012.05.009.

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.

8. Slater SJ, Barron DA. Pelvic fractures—A guide to classification and management. European Journal of Radiology. 2010; 74(1):16-23.  DOI:http://doi.org/10.1016/j.ejrad.2010.01.025.

9. Shivji FS, Quah C, Forward DP. Pelvic fractures. Surgery (Oxford). 2015; 33(6):257-263.  DOI:http://doi.org/10.1016/j.mpsur.2015.03.006.

10. Hammel J. Pelvic fracture. In: Legome E, Shockley LW, editors. Trauma: A Comprehensive Emergency Medicine Approach. Cambridge: Cambridge University Press; 2011. p. 251-271.

11. Osterhoff G, Scheyerer MJ, Fritz Y, Bouaicha S, Wanner GA, Simmen H-P, et al. Comparing the predictive value of the pelvic ring injury classification systems by Tile and by Young and Burgess. Injury. 2014; 45(4):742-747.  DOI:https://doi.org/10.1016/j.injury.2013.12.003.

12. Loi F, Córdova LA, Pajarinen J, Lin T-h, Yao Z, Goodman SB. Inflammation, fracture and bone repair. Bone. 2016; 86:119-130.  DOI:https://doi.org/10.1016/j.bone.2016.02.020.

13. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nature Reviews. Rheumatology. 2012; 8(3):133-143.  DOI:http://dx.doi.org/10.1038/nrrheum.2012.1.

14. Medzhitov R. Origin and physiological roles of inflammation. Nature [10.1038/nature07201]. 2008; 454(7203):428-435. Available from: http://dx.doi.org/10.1038/nature07201.

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.

17. Boccaccio A, Pappalettere C. Mechanobiology of Fracture Healing: Basic Principles and Applications in Orthodontics and Orthopaedics. In: Klika V, editor. Theoretical Biomechanics. Rijeka: InTech; 2011. p. Ch. 02.

18. Iolascon G, Resmini G, Tarantino U. Mechanobiology of bone. Aging Clinical and Experimental Research [journal article]. 2013; 25(1):3-7.  DOI:10.1007/s40520-013-0101-2.

19. Khan KM, Scott A. Mechanotherapy: how physical therapists’ prescription of exercise promotes tissue repair. British Journal of Sports Medicine. 2009; 43(4):247-252.  DOI:10.1136/bjsm.2008.054239.

20. Thompson WR, Scott A, Loghmani MT, Ward SR, Warden SJ. Understanding Mechanobiology: Physical Therapists as a Force in Mechanotherapy and Musculoskeletal Regenerative Rehabilitation. Physical Therapy. 2016; 96(4):560-569.  DOI:10.2522/ptj.20150224.

21. Oftadeh R, Perez-Viloria M, Villa-Camacho JC, Vaziri A, Nazarian A. Biomechanics and Mechanobiology of Trabecular Bone: A Review. Journal of Biomechanical Engineering. 2015; 137(1):0108021-01080215.  DOI:10.1115/1.4029176.

22. McMahon LA, O’Brien FJ, Prendergast PJ. Biomechanics and mechanobiology in osteochondral tissues. Regenerative Medicine. 2008; 3(5):743-59.  DOI:http://dx.doi.org/10.2217/17460751.3.5.743.

23. Terlouw TJA. Roots of Physical Medicine, Physical Therapy, and Mechanotherapy in the Netherlands in the 19(th) Century: A Disputed Area within the Healthcare Domain. The Journal of Manual & Manipulative Therapy. 2007; 15(2):E23-E41. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2565611/.

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.

25. Burgess AR, Eastridge BJ, Young JWR, Ellison TS, Ellison PSJ, Poka A, et al. Pelvic Ring Disruptions: Effective Classification System and Treatment Protocols. Journal of Trauma and Acute Care Surgery. 1990; 30(7):848-856. Available from: http://journals.lww.com/jtrauma/Fulltext/1990/07000/Pelvic_Ring_Disruptions__Effective_Classification.15.aspx.

26. Augat P, Simon U, Liedert A, Claes L. Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone. Osteoporosis International [journal article]. 2005; 16(2):S36-S43.  DOI:10.1007/s00198-004-1728-9.

27. Major NM, Helms CA. Pelvic stress injuries: the relationship between osteitis pubis (symphysis pubis stress injury) and sacroiliac abnormalities in athletes. Skeletal Radiology. 1997; 26(12):711-717.  DOI:10.1007/s002560050316.

28. Bodle JC, Hanson AD, Loboa EG. Adipose-derived stem cells in functional bone tissue engineering: lessons from