Activations of immune cells and mediators is a physiological cascade normally involved into a bone fracture healing process, which somewhat overlaps with all processes involving bone me tabolism, including lack of unions, heterotopic ossifications and osteoporosis.
Clinical observa tions regarding the healing behavior of the in jured elbow were firstly collected founding that the elbow has great potential for fracture healing but is very sensitive to prolonged immobilization which can easily lead to intraarticular adher ences and stiffness. In addition, when both radius and ulna are fractured, the interosseus mem brane facilitates communication between the re generative environments. Such extensive injuries around the proximal forearm can lead to hetero topic ossifications and synostosis which decreas es sagittal range of motion through impingement and even block the rotational movement through bone bridges.
The inflammatory phase is one of the initiating factors for bone healing. The exact role of the various cytokines involved in bone healing on osteoblast biology is not entirely clari fied.
The understanding of the molecular and cellular mechanism of fracture healing can facili tate the fracture management and the treatment of impaired bone healing2. System wide inflam matory conditions also modulate the primary processes of fracture management which could explain the shock induction in polytraumatic pa tients, as well as increased ossifications associat ed with head injuries. We aimed to review and describe this intricate process of bone metabo lism, with particular focus on abnormal function and exemplifying it with a series of clinical cases that will justify their practical importance.
Methods
Scope of the present review is to analyze all the recent literature focused on the immuno pathological pathways around the elbow joint in order to identify relevant topics which could be useful to improve clinical practice. In addition, we searched on the electronic database of our clinic, over a period of 5 years, in order to obtain a broad view of the surgically treated elbow fractures/dislocations. At the end we refined the results in order to discard multiple or inappropri ate coding. Virtually, all simple radial head frac tures and elbow dislocations were treated as out patients and, thus, not included in our results. We then pursued to identify the surgical treat ment for any complication of the elbow joint re gardless its etiology and providing evidence for relevant cases. Results Three directions of clinically relevant im munepathological researches were identified: “fracture healing and nonunion”, “induced membranes technique” and “heterotopic ossifica tions”.
Out of 106 admissions for traumatic in juries about the elbow, the majority were olecra non fractures, followed by fractures of the distal humerus.Virtually all osteosynthesis for the ole cranon were performed using K wires and figure eight cerclage, with a trend towards bicortical fixation. This construct was also the most frequent to require removal and had favorable out comes.
The distal humerus fractures, on the other hand, often led to ROM limitations and ossifica tions which persisted even after implant removal. A total of 14 cases were surgically treated for im portant residual functional limitations: 6 distal humerus fractures, 4 unstable dislocations (terri ble triad), one distal humerus non union, one ra dioulnar proximal synostosis, one bad connected proximal ulna fracture and one extended tumoral resection of the proximal ulna. Fracture Healing and Lack of Union Whenever a fracture occurs, bone and sur rounding soft tissues are ruptured. The immedi ate consequence is the release of inflammatory mediators and the formation of an hematoma.
This is deemed the acute inflammatory phase; it peaks within 24 hours and develops under hy poxic conditions.
The tumor necrosis factorα (TNFα) and interleukins 1 and 6 (IL1, IL6) are the major regulators3. Then, the callus fills with cartilage formed from specialized mature mes enchymal stem cells recruited by stromal cellde rived factor1 and Gproteincoupled receptor CXCR44. Vascular endothelial growth factor (VEGF)dependent pathway is the responsible for revascularization and neoangiogenesis at the fracture site. The cartilage then calcifies and is replaced with woven bone which confers rigidity3. In an animal model, a study by Toben et al5 compared the healing process of a fracture be tween normal and imunodeficient hosts. Recom bination of activated gene 1 deprived (RAG1/) organisms showed more bone and less cartilage with an accelerated endochondral ossification. In addition, they had less lymphocytes and reduced expression of inflammatory cytokines apart from IL10.
Nam et al6 performed a similar research using immunodeficient (recombination activating gene 2) mice as a model of impaired injury re pair. IL17F was determined to be an important contributor for the cellular response in osteogen esis and supposed to be produced by Th17 subset of Tlymphocytes. General administration of prostaglandin (Pg) E receptor 4 ligands, such as prostaglandin E2, appears to support fracture healing. In a study by Tanaka et al7, the total vol ume of cortical bone, as well as the mineral con tent, increased proportionally with the Pg dose by accelerating the local turnover.
A skeletogene sis regulator, the betacatenin pathway, activates T cell factor dependent transcription and posi tively regulates osteoblasts. Chen et al8 demon strated that, in early stages of fracture repair, be tacatenin differentiates pluripotent mesenchymal cells to either osteoblasts or chondrocytes. After wards, betacatenin continues to exert a positive regulation on osteoblasts. Sclerostin is a glyco protein secreted by osteocytes which inhibits os teoblastogenesis via Wnt signaling. Furthermore, sclerostin neutralizes antibodies leading to in creased bone mineralization in animal models of osteoporosis. Systemic administration of SclAb III also results in an increased mineral density and histological bone deposition in a noncritical size defect as early as the first week.
These find ings might provide its potential use in complicat ed fractures and nonunions9,10. Osteoclasts cross presents antigens to induce transcription factor Scurfin (also known as forkhead box P3 and en coded by Foxp3) in CD8+ Tcell.
In an animal model for hormonal osteoporosis, this process was showed to limite bone loss while to increase bone density11 (Figure 1). Induced Membranes Technique Inducement of foreignbody granulation tissue is a promising aid treatment for large bony defects repair. Masquelet and Begue12 found that, when a segmental bone loss is temporarily occupied by a polymethylmethacrylate (PMMA) spacer, a reactive inflammatory membrane cre ates around it in as little as 6 weeks. In a second step, when the cement block is removed and re placed by cancellous bone, this membrane acts, somewhat, like a periost, preventing resorption and secreting growth factors.
A literature review by Taylor et al13 detailed the benefits of foreign body induced membranes in the staged treatment of segmental bone defects. They point out that PMMA cement induces a biologic membrane that will nurture the definitive bone graft. One to two months after spacer placement the protective shell matures. This prevents graft dispersal and resorption, promotes revascularization and in duces growth factors that lead to excellent clini cal results being reported.
The inductive potential of such membranes has been histological proved in animal models14,15 with better results in com parison to recent artificial bioresorbable polylac tide membranes that boast single step procedures16.
Many authors15,17 have now showed that production of growth (VEGF, TGFβ1) and osteoinductive factors (BMP2) will peak as ear ly as one month.
This well correlated with the ex pression of VEGF, IL6 and typeI collagen, as well as typeI procollagen production in aminoterminal propeptide, ionic calcium concen tration increase and alkaline phosphatase in creased activity when cocultured on mesenchy mal cells15. Such immunochemistry analysis can support and confirm a more rapid conversion to bone grafting15,17 (Figure 2).