Grafting is also necessary in cases where the bone defect is significantly too large to allow for natural healing. Six to eight million fractures occur in the United States annually, and approximately 10% will require orthopedic intervention due to disrupted patterns of healing (Einhorn, 1995, in Hadjiargyrou M, Lombardo F, Zhao S, Ahrens W, Joo J, Ahn H, et al. , 2002; Thompson, 2003). Global figures, as of 2005, reach approximately 2. 2 million, according to Giannoudis and associates (in Laurencin, 2006). The economic impact of impaired fracture healing is immense.
Fracture repair through bone graft implantation amount to anywhere between $2. 5 billion to $15 billion annually (Laurencin; Hing, 2004). In addition, income and productivity of patients suffering from fractures are also impaired because of the over 30,000,000 days lost annually to disability or confinement (Hadjiargyrou, et al. ). Apart from the economic burden of fractures, the supply of bone tissue that can be harvested and then used in grafting is also limited, not to mention the probability of pain, infection, and inflammation in cases of bone autografts, which is the gold standard (Cornell, 2004).
Barriga and associates, as well as McCann and companions, also contended in 2004 that there is no assurance of freedom from disease, while Togawa at al argued that healing can be inconsistent with autografts (in Hing). Bone allografts, on the other hand, also carry with them the risk of transmission of infection despite the availability of rigorous screening techniques, and cases of death and disability have been documented extensively by Tomford, and Conrad and companions, both in 1995; Boyce and associates in 1999; and most recently by the US Centers for Disease Control and Prevention in 2001 and 2002 (in Laurencin).
Because of these risks for morbidity and mortality with the conventional methods, there was a need to develop synthetic substitutes for bone that would address both the complications of conventional grafting, as well as the problem of supply, while at the same time assuring optimal restoration of form and function of the damaged skeleton. * The expansion of knowledge in bone physiology addressed this problem, and has significantly increased the armamentarium of the surgeon dealing with fractures.
Today, a heterogeneous group of devices made from various materials”termed osteobiologics (discussed below)”are being marketed as bone graft substitutes. In addition pharmaceutical products that would facilitate the healing process have been developed, or have been identified from drugs previously marketed for a different indication. In this paper, we briefly review some of the devices and drugs that have been developed for fracture healing. Specifically, we focus on the composition, utility, efficacy, and safety of bone graft substitutes, and pharmacological agents used to facilitate fracture healing.
It must be emphasized, however, that because of the limited space, the restricted amount of data and knowledge circulating in the scientific circles, and the continuously expanding list of agents for bone repair, this paper is not an exhaustive dissertation on the topic. Prior to discussing the agents however, it is of paramount importance to discuss first the physiology of bone healing. Bone Organization Bone is a mineralized connective tissue, which comprise the skeletal system.
It mainly functions for mechanical support (protection of viscera, determination of body size and shape, movement), mineral homeostasis (99% of the bodys calcium, 85% of phosphorus, and 65% of sodium and magnesium are stored in bone), and hematopoiesis (progenitor cells are found in the bone marrow) (Cameron, 1972, in Hing; Rosenberg). Histologically, two types of tissue could be identified in bone. The greater part (i. e. 75% to 80%) consists of the dense cortical bone, which comprise the outer layers of the long bones, as well as the flat bones (Hing).
The remainder is composed of trabecular or cancellous bone”a network of spicules that surround interconnected spaces”which make up the inner portion of the axial skeleton, as well as the interior of the shafts of the long bones (Genuth, 2004). Biochemically, bone could be described as being a dense, multi-phase material composed of both inorganic elements and organic matrix (Hing). The inorganic component of bone is primarily calcium hydroxyapatite (HA) [10Ca:6(PO4):(OH)2], although carbonates, sodium, magnesium and ? uoride salts are also found (Rosenberg).
Hydroxyapatite provides bone its characteristic hardness and strength, and is the primary storehouse of the bodys minerals (Hing). The organic component of bone, on the other hand, is made up of cells of the bone and proteins in the matrix (Rosenberg). Four major cell types are found in bone, but three are of paramount significance: osteoblasts, osteocytes, and osteoclasts (Rosenberg). Osteoblasts arise from pleuripotent mesenchymal stem cells (osteoprogenitor cells) through the action of bone morphogenetic proteins and other growth factors (Hing).
Osteoblasts act primarily to produce, transport, and organize matrix proteins; initiate mineralization; and bind hormones (such as parathyroid hormone) and growth factors (such as bone morphogenetic protein) for appropriate function (Rosenberg). Once mineralization is completed, and the osteoblast is fully surrounded by bone, it is converted into the osteocyte, which functions for the maintenance of bone through transfer of nutrients or substrates among and between osteocytes (Hing). Finally, osteoclasts function for bone resorption, and is derived from hematopoietic progenitor cells (Rosenberg).
Proteins of bone is a composite of type 1 collagen and noncollagenous proteins derived primarily from osteoblasts (Rosenberg). Noncollagenous proteins include a number of sulphated and acid mucopolysaccharides, such as osteocalcin (binds HA), bone sialoprotein (promotes osteoblast differentiation and bone resorption), osteopontin (inhibits HA formation, through inhibition of crystallite growth), and osteonectin (binds HA when complexed with collagen), which regulate bone mineralization and remodeling (Hing; Genuth).
Essential to the proper functioning of bone cells are growth factors, which function to regulate cellular growth, operation, and motility (Rosenberg). Within the bone matrix are multiple growth factors (i. e. vascular endothelial growth factor, VEGF; insulin-like growth factors I & II, IGF-I, IGF-II; transforming growth factor beta, TGF-b, etc. ) that either act on osteoblasts to regulate cell growth, or induce neovasculariztion or osteogenesis. Principal among these is bone morphogenetic protein, which is discussed in the succeeding pages.
The structure and composition of bone varies according to age, since it is involved in a constant process of remodeling”a coupling of bone formation and resorption”primarily influenced by mechanical load (Genuth; Springfield, 2005). A persons skeletal mass increases until age 25 to 30, after which it goes on a process of decline, with women experiencing a greater loss of skeletal mass after menopause, presumably because of the drop in the circulating levels of estrogen (Genuth; Springfield; Mishell, 2001). Physiology of Bone Healing Bone, as in any component of the human body, is endowed with the natural capacity to heal itself.
Unlike other body parts, however, where post-injury repair is primarily formed by connective tissue that compose the scar, the result of reparative process in bone is the formation (or regeneration) of new bone (McKibbin; Hing). The process of bone healing following a fracture parallels the process of embryologic bone development (through intramembranous and endochondral ossification), and could be described as proceeding in three distinct, sequential, but overlapping phases, occurring simultaneously at the biomolecular, cellular and organ levels (McKibbin; Menkes, 1996; Hadjiargyrou, et al; Genuth; Rosenberg; Springfield).
Inflammatory phase Following a fracture, there is disruption of the periosteal and surrounding soft tissue vasculature, resulting in hematoma formation, which essentially fills the fracture gap and surrounds the area of bone injury (Rosenberg). This disruption in blood supply causes osteocytes nearest the fracture to die, as evidenced by empty lacunae surrounding the fracture site, and initiates a classic inflammatory response, the aim of which is to remove devitalized tissue, stabilize the damaged area, and prepare the bone for repair (McKibbin).
Platelet activation causes hemostasis through fibrin mesh production. At the same time, it creates a framework for the ingrowth of fibroblasts, neovascularization, and the influx of inflammatory cells (specifically macrophages), which subsequently remove tissue debris (Hing). Growth factors and cytokines released by platelets and inflammatory cells activate the osteoprogenitor cells in the periosteum, medullary cavity, and surrounding soft tissues to differentiate, and thus, stimulate osteoclastic and osteoblastic activity in the bone (Rosenberg).
The end result of this brief phase”where there is an organizing hematoma, remodeling of bone ends, and modulation of adjacent tissue for matrix production”is a microenvironment conducive for the reparative phase of fracture healing (Menkes). Reparative Phase The reparative phase constitutes one of the most conspicuous stages in fracture healing, the end result of which is the formation of callus.
The activated progenitor cells adjacent to undamaged bone transform into osteoblasts, and initiate osteogenesis, whereas those located farther away transform into chondroblasts and initiate chondrogenesis, to produce cartilage (fibrocartilage and hyaline cartilage) and bone, both of which constitute the callus (Hing). This specialized tissue acts to stabilize the fractured ends, especially with endochondral ossification of the cartilage following angiogenesis (Hing; Rosenberg). Concurrent with bone formation, osteoclasts are also activated at this phase to remove necrotic edges of the damaged fragments (Menkes).
The callus thus formed serves as a bridge between the fractured bone fragments. Remodeling phase This phase of fracture healing, as implied by its name, aims to restore bone to its former size, shape, and outline. Excess fibrous tissue, bone, and cartilage produced in the formation of the callus are gradually resorbed (Menkes). This process is a direct function of weight-bearing, such that redundant portions of the callus are resorbed, while new bone is laid down along natural lines of stress (Rosenberg).
Finally, the medullary cavity is restored (Springfield). The final phase of fracture healing, consequent to the processes involved in this phase, is accomplished several years after the injury (Menkes). Pharmacologic Agents for Fracture Repair Fracture healing, as was already discussed, is a dynamic process akin to tissue regeneration, which involves multiple cell types and chemical mediators, although it takes quite some time for the bone to be restored to its full natural configuration and function.
This has led to a search for modalities and techniques that would considerably shorten the time for fracture healing to be achieved, and Wahlstrom in 1984, and Kristiansen and associates in 1997, have been successful in this regard using electromagnetism and ultrasound, respectively (Aspenberg, 2005). Pharmacological agents have been extensively studied, and will be the focus of this section. Specifically, the pharmacologic properties of parathyroid hormones, bisphosphonates, bone morphogenetic protein, and selective prostaglandin agonists (Cox inhibitors) will be discussed.
Among the three, only bone morphogenetic protein has received approval from the Food and Drugs Administration (FDA) for use in fracture healing. Bisphosphonates Bisphosphonates have a marked inhibitory reaction to osteoclast mediated bone resorption and some studies suggest it may increase bone mineral density (BMD) which may help in fracture repair by enhancing the healing process and limiting disuse osteoporosis. However, the clinical relevance of increasing BMD within the fracture callous is uncertain.
Since bisphosphonates possess an inhibitory osteoclastic effect, they may potentially have a prophylactic use in preventing stress fractures by suppressing initial bone turnover. Transient bone weakness associated with stress fractures may also be bypassed. Parathyroid Hormone Parathyroid hormone (PTH) plays a significant role in both intra- and extra-cellular calcium homeostasis. PTH appears to have an effect secondary to the activation of resting osteoblasts which results in an increased number of circulating cells. PTH may not have a role in the treatment of non-unions because of the need for viable osteoblasts cells.
However, it may play a role in the treatment of slowly resolving stress fractures. Parathyroid hormone (PTH) is a single chain protein, composed of 84 amino acids (molecular weight = 9500 daltons) secreted by the parathyroid glands (Genuth). Biologic activity of the hormone resides in the N-terminal portion, especially within amino acids 1 to 27 (Marcus, 2001). It is initially derived from a precursor molecule, prepro-PTH, whose N-terminal signal sequence have been enzymatically cleaved at the ribosomes, and further processed at the Golgi apparatus (Genuth).
Secretion of PTH is regulated by plasma calcium levels, such that hypocalcemia stimulates synthesis and secretion of the hormone (Marcus). The half-life of PTH in plasma is 2 to 5 minutes, and clearance is primarily a function of the kidney and the liver (Marcus). Parathyroid hormone mainly functions to maintain at physiologic levels the amount of extracellular calcium ions, specifically to increase calcium concentrations and decrease phosphate levels by acting directly on bone and kidney, and indirectly on the gastrointestinal tract (Hardy, Conlan, Hay, & Gregg, 1993; Aleksyniene, & Hvid, 2004).
This action is mediated by activation of adenylyl cyclase through G-protein-coupled-receptors, which results to increased levels of cyclic adenylyl monophosphate (cAMP), and finally, phosphorylation of proteins necessary for enhancement of transport of calcium and related ions (Genuth). PTH has both catabolic and anabolic functions (as demonstrated in multiple animal studies), such that continuous administration results in the former, while intermittent administration results in the latter, and it is the anabolic function that is of interest in fracture healing (Aleksyniene, et al. Andreassen, Fledelius, Ejersted, & Oxlund, 2001; Chiba, Okada, Lee, Serge, & Neer, 2001; Wang, Canaff, Davidson, Corluka, Liu, Hendy, et al. , 2001).
The mechanisms for this action of parathyroid hormone has not been fully elucidated, but is thought to be mediated by multiple receptor cites. For instance, osteoblasts and osteoprogenitor cells possess PTH receptors, and it was hypothesized that the result of the binding of this hormone to the cellular receptor site is the expression of multiple growth factors, cytokines, and hormones essential for cellular growth (Aleksyniene, et al. ).