Thomas A. Einhorn

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person‐years. However, long‐term use may be associated with higher risk (∼100 per 100,000 person‐years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

The Cell and Molecular Biology of Fracture Healing

Fracture healing is a complex physiologic process that involves the coordinated participation of several cell types. By using a reproducible model of experimental fracture healing in the rat, it is possible to elucidate the integrated cellular responses that signal the pathways and the role of the extracellular matrix components in orchestrating the events of fracture healing. Histologic characterization of fracture healing shows that intramembranous ossification occurs under the periosteum within a few days after an injury. Events of endochondral ossification occur adjacent to the fracture site and span a period of up to 28 days. Remodeling of the woven bone formed by intramembranous and endochondral ossification proceeds for several weeks. Spatial and temporal expression of genes for major collagens (Types I and II), minor fibrillar collagens (Types IV and XI), and several extracellular matrix components (osteocalcin, osteonectin, osteopontin, fibronectin and CD44) are detected by in situ hybridization. Immunohistochemical studies show that expression of proliferating cell nuclear antigen is both time and space dependent and differentially expressed in the callus tissues formed by the intramembranous and endochondral processes. Chondrocytes involved in endochondral ossification undergo apoptosis (programmed cell death), and early events in fracture healing may be initiated by the expression of early response genes such as c-fos. Additional characterization and elucidation of fracture healing will lay the foundation for subsequent studies aimed at identifying mechanisms for enhancing skeletal repair.

Fracture healing as a post‐natal developmental process: Molecular, spatial, and temporal aspects of its regulation

Fracture healing is a specialized post‐natal repair process that recapitulates aspects of embryological skeletal development. While many of the molecular mechanisms that control cellular differentiation and growth during embryogenesis recur during fracture healing, these processes take place in a post‐natal environment that is unique and distinct from those which exist during embryogenesis. This Prospect Article will highlight a number of central biological processes that are believed to be crucial in the embryonic differentiation and growth of skeletal tissues and review the functional role of these processes during fracture healing. Specific aspects of fracture healing that will be considered in relation to embryological development are: (1) the anatomic structure of the fracture callus as it evolves during healing; (2) the origins of stem cells and morphogenetic signals that facilitate the repair process; (3) the role of the biomechanical environment in controlling cellular differentiation during repair; (4) the role of three key groups of soluble factors, pro‐inflammatory cytokines, the TGF‐β superfamily, and angiogenic factors, during repair; and (5) the relationship of the genetic components that control bone mass and remodeling to the mechanisms that control skeletal tissue repair in response to fracture. J. Cell. Biochem. 88: 873–884, 2003.

The role of growth factors in the repair of bone. Biology and clinical applications.

•: Growth factors (bone morphogenetic protein, transforming growth factor-beta, fibroblast growth factor, platelet-derived growth factor, and insulin-like growth factor) are proteins secreted by cells that act on the appropriate target cell or cells to carry out a specific action. •: Because growth factors are expressed during different phases of fracture-healing, it has been thought that they may serve as potential therapeutic agents to enhance bone repair. •: The selection of an appropriate carrier or delivery system for a particular growth factor is essential in order to induce a specific biologic effect. •: There are a number of potential clinical applications for growth factors in the enhancement of bone repair, including acceleration of fracture-healing, treatment of established nonunions, enhancement of primary spinal fusion or treatment of established pseudarthrosis of the spine, and as one element of a comprehensive tissue-engineering strategy that could include gene therapy to treat large bone-loss problems. Growth factors are proteins that serve as signaling agents for cells. They function as part of a vast cellular communications network that influences such critical functions as cell division, matrix synthesis, and tissue differentiation. The results of experimental studies have established that growth factors play an important role in bone and cartilage formation, fracture-healing, and the repair of other musculoskeletal tissues. Recently, with the advent of recombinant proteins, there has been considerable interest in the use of growth factors as therapeutic agents in the treatment of skeletal injuries. As growth factors become available as therapeutic agents, it is essential that orthopaedic surgeons understand their biological characteristics and clinical potential. The purpose of this review is to define the mechanisms of action, functions, and potential clinical applications of a variety of growth factors that may be used clinically to treat problems associated with the repair of bone. Growth factors are proteins secreted …

Enhancement of fracture-healing.

Fracture-healing is a specialized type of woundhealing response in which the regeneration of bone leads to a restoration of skeletal integrity. While the process of fracture-healing is usually considered to be biologically optimum. the healing of 5 to 10 pen cent of the estimated 5.6 million fractures occurring annually in the United States is delayed or impaired”. The cause of the impaired healing is often unknown. However, problems with operative and non-operative interventions. such as inadequate mobilization of the fracture, distraction of fracture fragments by fixation devices or traction, repeated manipulations or excessive early motion of a fracture, or excessive peniosteal stripping and damage to other soft tissues during operative exposure, intenfene with healing and may cause a delayed union or a non-union. A delayed union on a non-union may also occur if a fracture becomes contaminated at the time of the injury or after an operation or if an acceptable apposition of the fracture fragments on stable fixation is not achieved25. Moreover. specific pants of the skeleton, such as the neck of the talus. the neck of the femur, and the campal scaphoid5, are known to be at increased risk for impaired fracture-healing. and there may be problems related to peculiarities of the local blood supply or difficulties with the control of the mechanical strain environment at these sites. Thus. while most fractures heal without problems. there are several conditions unden which enhancement of the repair process would be of great benefit to ensure the rapid restoration of skeletal function. The ability of injured patients to return to the work force or to recreational activities early would not only have a substantial economic impact on society but would also improve the oven-all physical and mental well-being of the patients. In this article, I will review some of the better descnibed and more extensively tested methods that have been used to stimulate fracture-healing. I will also provide an introduction to certain new technologies that could improve the repair of fractures. The article is organized in two sections. The first section is a discussion

The biology of fracture healing.

The biology of fracture healing is a complex biological process that follows specific regenerative patterns and involves changes in the expression of several thousand genes. Although there is still much to be learned to fully comprehend the pathways of bone regeneration, the over-all pathways of both the anatomical and biochemical events have been thoroughly investigated. These efforts have provided a general understanding of how fracture healing occurs. Following the initial trauma, bone heals by either direct intramembranous or indirect fracture healing, which consists of both intramembranous and endochondral bone formation. The most common pathway is indirect healing, since direct bone healing requires an anatomical reduction and rigidly stable conditions, commonly only obtained by open reduction and internal fixation. However, when such conditions are achieved, the direct healing cascade allows the bone structure to immediately regenerate anatomical lamellar bone and the Haversian systems without any remodelling steps necessary. In all other non-stable conditions, bone healing follows a specific biological pathway. It involves an acute inflammatory response including the production and release of several important molecules, and the recruitment of mesenchymal stem cells in order to generate a primary cartilaginous callus. This primary callus later undergoes revascularisation and calcification, and is finally remodelled to fully restore a normal bone structure. In this article we summarise the basic biology of fracture healing.

Fractures Attributable to Osteoporosis: Report from the National Osteoporosis Foundation

To assess the cost‐effectiveness of interventions to prevent osteoporosis, it is necessary to estimate total health care expenditures for the treatment of osteoporotic fractures. Resources utilized for the treatment of many diseases can be estimated from secondary databases using relevant diagnosis codes, but such codes do not indicate which fractures are osteoporotic in nature. Therefore, a panel of experts was convened to make judgments about the probabilities that fractures of different types might be related to osteoporosis according to patient age, gender, and race. A three‐round Delphi process was applied to estimate the proportion of fractures related to osteoporosis (i.e., the osteoporosis attribution probabilities) in 72 categories comprised of four specific fracture types (hip, spine, forearm, all other sites combined) stratified by three age groups (45–64 years, 65–84 years, 85 years and older), three racial groups (white, black, all others), and both genders (female, male). It was estimated that at least 90% of all hip and spine fractures among elderly white women should be attributed to osteoporosis. Much smaller proportions of the other fractures were attributed to osteoporosis. Regardless of fracture type, attribution probabilities were less for men than women and generally less for non‐whites than whites. These probabilities will be used to estimate the total direct medical costs associated with osteoporosis‐related fractures in the United States.

Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis.

![Graphic][1] Osteoinduction is a process that supports the mitogenesis of undifferentiated mesenchymal cells, leading to the formation of osteoprogenitor cells that form new bone. ![Graphic][2] The human skeleton has the ability to regenerate itself as part of the repair process. ![Graphic][3] Recombinant bone morphogenetic protein has osteoinductive properties, the effectiveness of which is supported by Level-I evidence from current literature sources. ![Graphic][4] Osteoconduction is a property of a matrix that supports the attachment of bone-forming cells for subsequent bone formation. ![Graphic][5] Osteogenic property is a relatively new term that can be defined as the generation of bone from bone-forming cells. Orthopaedic trauma surgery requires the regular use of bone grafts to help provide timely healing of musculoskeletal injuries. The iliac crest autologous graft remains the gold standard. The morbidity associated with the harvest of bone graft has caused practitioners to seek methods of enhancing healing with bone graft substitutes. The term bone graft substitute describes a spectrum of products that have various effects on bone-healing. Unfortunately, there is little information in the literature about when and where to use these devices. In general, we categorize the properties of bone graft substitutes as osteoinductive, osteoconductive, or osteogenic. Going through the operating room storage areas in our institutions, we find many of these products available, with various trade names that can be misleading and confusing. The purpose of this review is to give the practicing surgeon a basic fund of knowledge on the topic of bone graft substitutes as well as an opinion on the levels of evidence in the current literature supporting the use of the various materials. The answers to the most difficult questions regarding bone graft substitutes require multicenter prospective randomized studies. These are extremely difficult to design and execute, with the cost being the most onerous obstacle. Industrial funding has been one of … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif [5]: /embed/inline-graphic-5.gif

Molecular Mechanisms Controlling Bone Formation during Fracture Healing and Distraction Osteogenesis

Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment. In this review, the cellular and molecular mechanisms that regulate fracture repair are contrasted with bone regeneration that occurs during distraction osteogenesis. While both processes have many common features, unique differences are observed in the temporal appearance and expression of specific molecular factors that regulate each. The relative importance of inflammatory cytokines in normal and diabetic healing, the transforming growth factor beta superfamily of bone morphogenetic mediators, and the process of angiogenesis are discussed as they relate to bone repair. A complete summary of biological activities and functions of various bioactive factors may be found at COPE (Cytokines & Cells Online Pathfinder Encyclopedia), http://www.copewithcytokines.de/cope.cgi.

Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double‐blind study of 102 postmenopausal women with distal radial fractures

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 µg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once‐daily injections of placebo (n = 34) or teriparatide 20 µg (n = 34) or teriparatide 40 µg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 µg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 µg and 40 µg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 µg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 µg versus 20 µg (p = .053); however, the time to healing was shorter in teriparatide 20 µg than placebo (p = .006). The primary hypothesis that teriparatide 40 µg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 µg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.