Description of the condition
Bone fractures (broken bones) are a common injury that affect people worldwide. A recent study found around 3% of white adults aged 50 years or over sustain a fracture each year in the USA (estimated incidence 2704 per 100,000 persons/year) (Amin 2014). Most often, bones are broken as a consequence of trauma; though sometimes they are broken as part of a treatment, such as osteotomy, where the bone is cut usually to facilitate realignment. Overall, bones tend to heal after surgical or non-surgical treatment. However, in approximately 1 in 10 cases they fail to heal normally, resulting in either nonunion or delayed union (Einhorn 2014). The risk of nonunion, which represents a failure of the bone healing process, varies according to the bone involved. An epidemiological study of the nonunion in 18 types of bones reported an overall nonunion rate of 4.9%, with the highest nonunion rates occurring in the scaphoid (15.5%), tibia and fibula (14%) and femur (13.9%), and the lowest in the metacarpal (1.5%) and radius (2.1%) bones (Zura 2016).
Bone healing requires multiple factors including: 1) an adequate mechanical environment; 2) osteogenic progenitor cells (cells that can make bone); 3) growth factors and inflammatory mediators (signalling molecules); 4) vascular supply; and 5) an osteoconductive scaffold. This process demonstrates a remarkable potential for regeneration. Bone healing follows most instances in which there is bone discontinuity (i.e. bone fracture or defect), usually taking several weeks or months (Loi 2016). For example, nondisplaced distal radius fractures in adults typically require six weeks of short-arm cast immobilisation to achieve bone union (Roth 2013). Humeral fractures, treated conservatively with functional bracing, take an average of 10 weeks to heal (Papasoulis 2010). The time taken for the bone to heal can represent an opportunity to enhance and optimise treatments in order to allow patients to resume their activities sooner.
Furthermore, as indicated above, fractures may take longer to heal (delayed union) or fail to heal. These are often associated with risk factors including: 1) patient-related factors, such as medical comorbidities, smoking, metabolic disease and nutritional deficiency; and 2) injury-related factors, such as complex fracture pattern, open fracture, high energy trauma, displacement, soft tissue injury and bone loss (Hak 2014). Zura 2016 narrowed down the main risk factors to "fracture severity, fracture location, disease comorbidity, and medication use". The treatment of these challenging conditions embraces a multimodal approach where surgical treatment to achieve mechanical stabilisation is partnered with host optimisation and biological supplementation to the nonunion site (Dimitriou 2011).
Nonunion and delayed union represent a substantial clinical challenge and cause considerable comorbidity for patients, prolonging their disability and pain (Einhorn 2014; Antonova 2013). Additionally, these conditions are difficult to treat and consume substantial healthcare resources (Antonova 2013). Strategies targeted to enhancing bone healing would allow patients to resume their daily life activities and return to work, thus improving their health outcomes while reducing the direct and indirect costs.
Description of the intervention
Tissue engineering strategies, which include the combined use of cells, scaffolds and biologically-active signalling molecules, are becoming increasingly available technologies to augment bone healing (Muschler 2004). When cells or tissues are obtained and used in the same individual, they are called autologous therapies, and they present the benefit of not having the risk of being rejected by the recipient's immune system. The two categories of autologous interventions covered in this Cochrane Review are bone marrow-derived products and autologous blood-derived products. Both therapies can be applied as percutaneous injections or during surgical procedures, alone or in combination with scaffolds, and in a single or a series of applications (Patterson 2008).
Bone marrow-derived products
Whole bone marrow contains multiple active components including plasma, red blood cells, platelets, nucleated cells including white blood cells, hematopoietic stem cells, connective tissue progenitor cells, growth factors and cytokines. Bone marrow samples are obtained through percutaneous or open harvest, and the sample is processed by centrifugation to obtain bone marrow concentrate (BMC). This is believed to increase the concentration of components of bone marrow aspirate that are believed to have a beneficial effect in bone healing. In a further attempt to increase the number of progenitor cells, since they only make up to approximately 0.01% of nucleated cells in the bone marrow, harvested cells can be cultured in-vitro and expanded to obtain bone marrow mesenchymal stromal/stem cells (BM-MSC) at higher concentrations (Hoch 2014).
Autologous blood-derived products
Whole blood and relevant fractions of blood obtained by separating its components have been used to enhance bone healing. Platelet-rich plasma (PRP) therapies are the most often employed, which consist of a concentration of platelets in a small volume of plasma, and can be easily isolated from freshly-drawn peripheral whole blood (Amini 2012; Piuzzi 2017a). The PRP can be obtained at the bedside both by centrifugation or filtering of extracted whole blood mixed with an anti-coagulant. Depending on the preparation protocol employed, different types of PRP can be obtained, which all contain a supra-physiological concentration (above whole blood baseline value) of platelets: leukocyte-poor PRP (LP-PRP), leukocyte-rich PRP (LR-PRP), or leukocyte- and platelet-rich fibrin (LR-PRF) or Choukroun’s PRF. These types of PRP vary on the presence of cell content (mostly leukocytes) and the fibrin architecture (Dohan Ehrenfest 2009).
How the intervention might work
Osteogenic stem cells and progenitor cell populations involved in bone healing are present in the bone (marrow, endosteum and periosteum) and local soft tissues (muscle and fat) (Marcucio 2015). In the clinical setting where bone fails to heal, there may be an underlying deficiency of cellular activity contributing to the delayed healing or nonunion. Therefore harvesting cells from a different healthy source, such as bone marrow from an alternative anatomical site, and transplanting these, whether as they are or in concentrated form, at the fracture or nonunion site is a plausible way of enhancing bone healing. The rationale supporting the transplantation of osteogenic stem and progenitor cells (in bone marrow and related concentrated products) to the site of bone healing is based on the understanding that these cells are required to form bone (Connolly 1998). These bone marrow-derived cell-based therapies could potentially enhance bone healing by different mechanisms: 1) repopulating of osteogenic stem and progenitor cells at the nonunion site; 2) modulation of the nonunion environment, either by secretion of signalling molecules or through cell-to-cell interactions; and (3) by homing of cells to the nonunion site (Patterson 2008). Furthermore, these stem and progenitor cells can be cultured in the attempt to increase the number of cells delivered (mesechnymal stromal/stem cells (MSC)), with the intention of increasing their effect on bone healing.
Regulation and legislation even in the use of autologous cell-based therapies is complex. Research continues to assess the feasibility and safety of many autologous cellular therapies, and many challenges must be overcome in order for them to become safely, effectively and routinely used in the clinical setting (Halme 2006).
Growth factors are mediators of the inflammatory process and, during different phases of tissue healing, they constitute a key element in promoting tissue regeneration (Roffi 2017). Platelets, which are a component of whole blood, are an important source of these growth factors and play a crucial role in the pathway signalling required for successful bone healing. A more detailed rationale in support of the use of autologous whole blood and derived fractional products, such as PRP, as a therapy in bone healing is that multiple bioactive molecules (e.g. transforming growth factor beta (TGF-β1), platelet-derived growth factor BB (PDGF-BB), vascular endothelial growth factor A (VEGF-A) and insulin-like growth factor 1 (IGF-1)) released by platelets, when activated, can ultimately promote bone healing by mechanisms of cellular recruitment (chemotaxis), cell proliferation or growth, morphogenesis and immunomodulation (Piuzzi 2017a; Roffi 2017). To date, different formulations of PRP have been shown to be a safe treatment with only minor adverse events, including transient mild pain and local swelling (Imam 2017; Piuzzi 2017a).
Why it is important to do this review
Despite widespread marketing, cellular (also referred as ‘stem cell–based') interventions remain unproven and their efficacy for musculoskeletal applications is yet to be established (Chahla 2016; Piuzzi 2017c; Srivastava 2016). Nevertheless, commercial ‘stem-cell' clinics worldwide offer cell therapies for a wide array of conditions, of which musculoskeletal are the most frequent (Turner 2016). Many of these clinics are currently delivering autologous cells, such as bone marrow-derived or blood-derived products, and market such interventions directly to consumers (Piuzzi 2017b; Rachul 2017; Ramkumar 2017).
So called ‘stem cell' therapies, which oftentimes are bone marrow-derived cellular therapies, have raised substantial hope and enthusiasm regarding their therapeutic potential. However, to date, their treatment effect remains uncertain. A systematic review, with a narrower scope to this Cochrane Review, reported on a substantial number of human clinical studies that investigated on the use of BMC; it suggested benefit with this therapy (Imam 2017). However, there were limitations in terms of the review methodology and the low quality and heterogeneity of the included studies (Piuzzi 2018).
While positive preclinical findings on the biological potential of PRP favouring bone healing have been reported, the overall available literature in clinical trials has been reported to have major limitations in terms of low quality and heterogeneity, which have limited the reliability of estimates of any treatment effect (Chahla 2017; Griffin 2012; Roffi 2017). Griffin 2012 concluded in a previous Cochrane systematic review on the use of PRP for long bone healing in adults that, although potential clinical benefit could not be ruled out, the available evidence was insufficient to support the routine use of this intervention in clinical practice.
Our review seeks to evaluate the available up to date evidence on the use of autologous bone marrow-derived and blood-derived products for enhancing bone healing in adults and, where possible, provide a reliable estimate of their treatment effects.