Aging Clinical and Experimental Research
Bone healing and osteoporosis Umberto Tarantino1, Irene Cerocchi1, Alessandro Scialdoni1, Luca Saturnino1, Maurizio Feola1, Monica Celi1, Federico Maria Liuni1, Giovanni Iolascon2 and Elena Gasbarra1 1Orthopaedics and Traumatology, PTV Foundation, University of Tor Vergata, Rome, 2Department of Orthopaedics, Traumatology, Rehabilitation and Plastic-Surgery, Second University of Naples, Naples, Italy ABSTRACT. A correct fracture healing depends on the synergy between biomechanical, molecular and cellular factors. Focusing on different stages, fracture hematoma represents the starting point of the inflammatory process, with a critical role in triggering the process of fracture healing. The essential factors for bone repair are the activation of mesenchymal stem cells and the release of growth and regulatory factors. Moreover, the efficacy of fracture healing is determined by three ideal conditions: adequate blood supply, good contact between bone fragments and good stability. It is remarkable how the implant choice influences fracture healing after surgical treatment. In osteoporosis, bone quality adversely affects the tissue structural competence, increasing the risk of a complicated fracture healing. The qualitative and quantitative alterations established at the cellular level during osteoporosis explain the progressive deterioration of bone tissue healing ability. (Aging Clin Exp Res 2011; 23 (Suppl. to No. 2): 66-68) ©2011,
Editrice Kurtis
INTRODUCTION The healing of the fracture is one of the most remarkable repairing processes in the body, since it results not in scar, but in the actual reconstruction of the injured tissue in something very similar to its original form. It involves the coordinated contribution of hematopoietic and immune cells in a continuous process where all stages follow one another, often overlapping. Knowledge of the various factors involved in this process is essential for understanding the pathophysiology of fracturehealing, and the influence of osteoporosis and aging on the duration and efficacy of the repairing process. PHYSIOLOGICAL FRACTURE HEALING Bone healing throughout fracture repair is a repairing process that follows a well-defined spatial and temporal order. We can recognize two distinct processes: an anabol-
ic phase, characterized by tissue formation, and a catabolic phase, characterized by remodeling of woven bone into trabecular and cortical bone. Anabolic and catabolic phases follow each other and overlap in the repairing process. There is an initial extravasation of cells (macrophages, granulocytes, lymphocytes, monocytes) from the blood stream, capable of releasing pro-inflammatory cytokines able to recruit other inflammatory cells, and facilitate the migration of mesenchymal cells. This phase is followed by fibrous callus formation: growth factors stimulate the differentiation and proliferation of mesenchymal cells into chondroblasts and fibroblasts, resulting in fibro-cartilage soft callus production. Afterwards, angiogenic factors stimulate neoangiogenesis. Following processes are represented by endochondral ossification, characterized by bone formation, with intense osteoblastic periosteal activity, sustained by bone morphogenetic proteins (BMPs). Subsequently, mineralized matrix gradually replaces the soft-callus, and, finally, osteoblast differentiation is facilitated by massive angiogenesis. The last stage is bone remodeling, when osteoblasts secrete factors that promote osteoclasts differentiation and control the resorption and apposition processes (i.e. RANK-L); these events lead to mineralized callus remodeling and reorganization into cortical and trabecular bone (1). The role of fracture hematoma and of the inflammatory response during fracture repair are still unclear. Fracture hematoma represents the starting point of the inflammatory process that triggers bone repair. Experimental studies showed that premature hematoma removal from the fracture site results in delayed callus formation and mineralization, suggesting a crucial role of inflammation in triggering the fracture healing process (2). Abilities of fracture hematoma such as the induction of angiogenesis and periosteal cell proliferation, and the initiation of intramembranous bone formation, develop over time. This hypothesis was confirmed in a study on 2-day-old rat fracture hematoma, that produces new bone only coupled with the periosteum, whereas a 4-day-old fracture hematoma is capable of
Key words: Bone healing, fracture healing, osteoporosis. Correspondence: Umberto Tarantino, Orthopaedics and Traumatology, PTV Foundation, University of Tor Vergata, Viale Oxford 81, 00133 Rome, Italy. E-mail:
[email protected]
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Bone healing and osteoporosis
forming ectopic bone when implanted in muscle (3). Respect of inflammatory hematoma during surgery could be useful in order to enhance the physiological fracture healing. This can be achieved by using less invasive surgical techniques, such as intramedullary nailing, which avoids wide exposure thus preserving fracture hematoma. The complex scheme of interaction of inflammatory cytokines, that characterizes the context of fracture hematoma, follows a time course in which pro-inflammatory and immunosuppressive agents interact. In the first 6 hours after fracture, monocytes and granulocytes (ratio 2:1 compared to lymphocytes) predominate and produce pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6). Within 24 hours, lymphocytes (specific immunity) appear, with production of immunosuppressive cytokines (IL-10, IL-4) which regulate the inflammatory phase, inhibiting and interacting with osteoprogenitor cells, and promoting osteoclast activity. Thus, the immune system plays an important role both in modulating inflammation and directly intervening in bone formation (4). Clarifying the role of inflammation in triggering fracture healing could lead to the development of new and more specific treatment strategies to enhance fracture healing. Conditions for "Ideal Fracture Healing" Physiological bone repair depends on three essential factors: activation of mesenchymal stem cells, release of growth factors and production of regulatory factors. It is also determined by three ideal conditions: adequate blood supply, good contact between the bone fragments and good stability at the fracture site. If these criteria are met, they can lead to full recovery. Adequate blood supply is essential to ensure the recruitment of inflammatory and mesenchymal cells at the fracture site. Furthermore, it can improve the circulation of systemic and local signaling molecules and assure oxygen and other nutrients, essential for cellular metabolism. Good contact between fragments and good reduction at the fracture site may affect bone callus progression. Therefore, in long bone fractures, a correct reduction of bone axis and rotation is needed; the gap between bone fragments should be less than 2 mm. Experimental studies have shown how a major gap can reduce periosteal callus formation, resulting in impaired ossification. Stability at the fracture site is another necessary condition for physiological bone repair. An extremely rigid fixation limits bone callus formation, while a too flexible device can lead to vicious consolidation. On the other hand, proper synthesis allows load transfer to the fracture site without transmitting excessive stresses. Fixation devices strongly influence fracture-healing process: it is already known how tension and compression micromovements can stimulate bone callus formation. Intermittent tensile forces elicit endochondral bone formation, while intermittent compression eases intramembranous ossification. Conversely, transversal movements can
determine reduced periosteal callus formation and delayed bone formation, with lower mechanical stability. Bone implant choice influences fracture healing: intramedullary fixation induces increased chondrocyte proliferation and production of pro-inflammatory cytokines, while too rigid fixation increases macrophage activity. Therefore, intramedullary nailing, compared to external fixation, induces the formation of a bigger bone callus. Greater bone mineral density and mineral content result in better biomechanical properties (5). BONE HEALING AND OSTEOPOROSIS Analyzing fracture healing in osteoporosis models, many authors evaluated the influence of this disease on fracture repair. Alterations characterizing poor bone quality could delay fragility fracture healing. Physiologically impaired fracture healing Age-related changes in bone metabolism, in postmenopausal women or in elderly people, could negatively affect fracture repair, leading to a "physiologically impaired fracture healing". The real pathway by which these alterations influence bone-healing progression, remains still unclear. Animal study on ovariectomized fractured mice, showed how estrogen deficiency negatively affects all stages of fracture healing, particularly the mineralization and remodelling phases, as it promotes osteoclastic activity. These results suggest that estrogen deficiency in post-menopausal women could be an important factor in the development of non-unions and delayed fracture healing. Elderly mice with iatrogenic fracture showed delayed periosteal reaction, cell differentiation, cartilage vascularization and endochondral ossification (6). Experimental studies documented cellular alterations in osteoporotic conditions, including: decreased number of MSCs (mesenchymal stem cells) with consequent gradual replacement of red marrow by adipose tissue; impaired ability of MSC response to humoral stimuli (with diminished proliferation capacity and reduced osteogenic differentiation); reduced osteoblastic response to mechanical stimuli (lower production of TGF-β, resulting in reduced fibroblast, chondroblast and osteoblast proliferation). Moreover, in senile osteoporosis, it has been established that mesenchymal stem cells tend to differentiate towards adipose tissue, with consequent reduction in osteogenesis (7). Recent experimental studies in elderly rats showed that systemic and local impairment of the inflammatory response leads to delayed fracture healing. Although a local and well controlled inflammation seems to be essential for bone repair, increased or prolonged local and systemic inflammation negatively affects fracture healing. Systemic inflammation has been shown to induce hypertrophic and immature callus formation, with reduced bone mechanical properties. The main mecha-
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nisms leading to this result are: neutrophil over-activation, chronic activation of macrophage subpopulations and proliferation of hypo-responsive T lymphocytes (8). Pathological conditions impairing fracture healing Frequently, comorbidities or drug therapies in patients who sustain a fragility fracture may influence the fracture healing process at different levels. The most common comorbidities are diabetes and hypertension. Diabetes mellitus and, in particular, Type 1 diabetes (T1DM) has been associated with impaired osseous wound healing properties. The currently available evidence shows that the main mechanisms underlying diabetic bone pathophysiology may be hyperglycaemia and/or hypoinsulinaemia, in the case of T1DM. Insulin plays a critical role in directly promoting the fracture healing potential, and impaired diabetic osseous healing may be associated with reduced local insulin levels, as a result of decreased systemic insulin levels in the diabetic state. The accumulation of advanced glycation end-products (AGEs) in bone as a result of non-enzymatic glycosylation has been implicated in the pathogenesis of diminished bone formation, in a fracture healing model with experimental diabetes (9). Clinical and experimental studies have demonstrated some negative effect of hypertension on bone mineral density. Experimental studies support the clinical investigations documenting an association between low bone mineral density (BMD) and high blood pressure. Angiotensin II is the major mediator of the maintenance of extracellular fluid volume and blood pressure. Although the effect of angiotensin II on osteoblastic cells is still controversial and predominantly based on in vitro studies, there is some evidence to suggest that this mediator is a potent suppressor of the differentiation of osteoblastic cells and, consequently, of bone formation. Individuals with essential hypertension could be a risk group for bone disorders (10). Many drugs could impair fracture healing. The most common drugs involved in delayed fracture repair are antiblastic agents, corticosteroids, antibiotics, NSAIDs and anticoagulants. They all compromise chondroblastic and osteoblastic proliferation, thus impairing bone callus formation and mineralization (11). DISCUSSION In conclusion, fracture healing is a sequence of physiological events which, if supported by appropriate biomechanical, cellular and humoral conditions, is able to completely restore bone tissue, with its original structural and functional characteristics. A negative influence of osteoporosis on fracture repair, with lower callus miner-
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alization and thinning and perforation of bridging structures within the callus, results in lower tensile and compressive strength. This implies worse stabilization by bone callus, loss of fracture reduction and, consequently, prolonged fracture healing. Possible modulation of anabolic and catabolic processes through the administration of antiosteoporotic drugs opens new perspectives for their use in fracture healing. The proven effectiveness of antiosteoporotic drugs in increasing biomechanical properties of bone tissue and in reducing fracture risk, suggests a possible role in promoting and/or accelerating fracture healing, while improving implant fixation (12, 13). Disclosure statement The authors have nothing to disclose.
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