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Radiology in the Study of Bone Physiology
Original Investigation
Radiology in the Study of Bone Physiology Michael V. Kushdilian, MS, Lauren M. Ladd, MD, Richard B. Gunderman, MD, PhD Rationale and Objectives: In this article, we review the core principles of bone physiology alongside imaging examples that demonstrate such principles. Materials and Methods: The core principles of bone physiology are reviewed and further solidified with a corresponding abnormal pathophysiologic example. The key principles of bone physiology to be reviewed include the following: (1) formation and growth, (2) maintenance and repair, (3) metabolism and regulation, and (4) neoplastic disease. Lastly, a collection of secondary bone diseases is presented to demonstrate the skeletal manifestations of numerous systemic diseases. With this integrative method, we hope to emphasize the value of using radiology to teach physiology within a clinical context. This is especially relevant now, as many US medical schools undergo curricular reform with more emphasis on integrative interdisciplinary learning. Ultimately, we intend to provide a paradigm for incorporating radiology into the pre-clinical medical curriculum through a review of basic science physiology that underlies key radiographic findings of the skeletal system. Results: Radiology is known for its role in helping make diagnoses and clinical decisions. However, radiology is also well suited to enhance medical education by offering the ability to visualize physiology in action. This is especially true in skeletal radiology, where radiographic osseous changes represent a wide range of physiological processes. Therefore, skeletal radiology can be a useful tool for illustrating concepts of physiology that underlie the normal and abnormal radiologic appearances of bone. Conclusion: Radiology is an important but underutilized tool for demonstrating concepts in bone physiology. Key Words: medical education; physiology; radiology; medical students; curricular reform. © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
INTRODUCTION AND BACKGROUND
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ne of the greatest underappreciated opportunities in medical education is the use of radiologic images to teach the basic medical sciences. Too often, medical students learn such subjects as anatomy, physiology, and pathology from text, diagrams, cadavers, and animal models rather than from living human subjects. Radiology makes it possible to visualize living human structure, function, disease, and injury in ways that can help learners gain a much deeper understanding of the material, creating indelible images that they carry with them into practice for many years. Nonetheless, radiology is underutilized in this regard. Despite the explosion of diagnostic imaging utilization in clinical practice, estimated to be nearly twice the rate of laboratory and pharmaceutical usage (1), the role of radiology in medical education has remained stagnant across allopathic and osteopathic medical schools for decades (2). If available, a formal radiology clerkship is typically offered to medical students as a fourth-year elective, long after the basic science coursework has ended. This approach isolates radiology from Acad Radiol 2016; 23:1298–1308 From the Department of Radiology and Imaging Sciences, School of Medicine, Indiana University, 550 N. University Blvd. Rm 0663, Indianapolis, IN 46202. Received February 26, 2016; accepted June 1, 2016. Address correspondence to: M.V.K. e-mail: [email protected] © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.acra.2016.06.001
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its foundation in the basic sciences and may put students at a disadvantage in their future clinical practices. Although radiology has been used in a piecemeal fashion throughout the preclinical curricula for decades with subjects like anatomy (3,4), radiology can also be an effective tool for teaching the basic sciences not traditionally amenable to visual or anatomic applications. Physiology, in particular, is a vital basic discipline of medicine that guides diagnosis and therapeutic approaches in clinical practice (5–7), which may be more effectively taught when concepts are paired with radiologic cases of normal and abnormal physiology, a strategy that has been proposed for general medical physiology courses previously (8). This case-based approach is especially relevant now in the face of national curricular reforms focusing on more “vertical” integration of basic sciences and their clinical applications (9). Some schools adopting these curricular changes have also incorporated radiographic studies into their preclinical curricula, receiving high praise from their students and educators (10) and producing objective improvements in physiology comprehension (11). Whether a particular school has undergone this reform, it is imperative that radiology education be used for more than basic image interpretation skills. Therefore, we will demonstrate the untapped potential of radiology in fortifying basic science concepts to medical students, focusing on the skeletal system. As an extremely dynamic tissue, the radiologic appearance of normal and abnormal bone acts as a biological signature, representing underlying physiological processes in action. By
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Figure 1. X-rays from three different patients show progressive intramembranous ossification in the cranium. (a) Radiolucent fibrous tissue of the coronal (solid arrows) and lambdoid (dashed arrows) sutures from a 28-day-old. (b) At 6 months of age, sutures have narrowed via osseous replacement. (c) By 13 years of age, the sutures have been completely replaced with bone leaving only thin radiolucent lines.
maintenance and repair, (3) metabolism and regulation via the endocrine system, and (4) bone neoplasia. Radiologic manifestations of secondary bone disorder, such as metastatic disease, also help learners understand how bone reacts to systemic diseases. Overall, we hope this integrated approach of teaching basic science and radiology together will improve clinical acumen and solidify an understanding of physiology.
BONE DEVELOPMENT AND GROWTH
Figure 2. A benign osteoma of an adult skull on axial computed tomography. Excessive focal osteoid deposition during intramembranous ossification results in a densely calcified osseous prominence in or extending from a membranous bone as shown here at the squamo-mastoid suture line (arrows).
contrasting key imaging components of normal physiologic and abnormal pathophysiologic appearances of bone, we will review and illustrate the core physiology principles of this system including (1) bone growth and development, (2)
Bone development and growth requires understanding of two different processes: intramembranous ossification, as seen in flat bones such as the skull, and endochondral ossification, as occurs in long bones. The former begins when groups of mesenchymal stem cells cluster into a nidus (the primary ossification centers) within fibrous connective tissue. These clustered immature mesenchymal cells differentiate into osteoblasts that secrete unmineralized bone matrix (osteoid), which mineralizes as it becomes infused with calcium and phosphorous. Radiographs of the infant and adolescent skull provide an opportunity to visualize progressive intramembranous ossification as the radiolucent sutures, representing the unmineralized fibrous connective tissue, progressively decrease in width with progressive ossification of the skull bones (Fig 1). Osteomas, on
Figure 3. Endochondral ossification in a 4-year-old boy. (a) Normal knee radiograph demonstrates open, lucent physes (arrowheads) and secondary ossification centers of the physes (asterisks) and patella (arrow), which appear radiodense after ossification. (b) T1-weighted sagittal magnetic resonance imaging from the same patient depicts the ossified metaphyses, intermediate signal intensity physeal cartilage (arrowheads), and partially ossified epiphyseal (asterisks) and patellar (arrow) secondary ossification centers. A portion of the unossified secondary ossification center cartilage will remain as articular cartilage.
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Figure 4. Axial computed tomography of an enchondroma in the distal femur of an adult patient. This well-circumscribed lucent lesion in the medial metaphysis (solid arrows) displays the classic appearance of chondroid matrix: relatively hypodense with small internal ring-and-arc calcifications (dashed arrow). Although it is eccentrically located, there is no significant endosteal scalloping, cortical reaction, or soft tissue mass to suggest a more aggressive malignant cartilage lesion.
the other hand, are a pathological example of abnormal intramembranous ossification (12). These benign tumors are formed when a focal overabundance of osteoblasts secretes excess osteoid into a membranous bone (Fig 2). Endochondral ossification is the mechanism of bone development for long bones and utilizes a hyaline cartilage template. Primary ossification begins within the central diaphysis where the cartilaginous model is resorbed and replaced by bone due to a complex cascade of osteoblast and osteoclast stimulation and maturation. Later, secondary centers of ossification develop within the epiphyseal cartilage. As ossification proceeds at these sites, a band of physeal cartilage remains trapped between these mineralizing ossification centers,
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otherwise known as the growth plate, which determines the rate of bone growth and final adult height. The steps of endochondral ossification can be clearly demonstrated with magnetic resonance (MR) imaging of skeletally immature bones in children, giving learners the opportunity to see this dynamic process in action (Fig 3). MR imaging is best for visualizing both the ossified bone and the nonossified structures such as cartilage. Furthermore, MR imaging can depict less prominent features of bone physiology including specific zones of the physeal cartilage that enable bone growth, as well as the normal conversion of hematopoietic to fatty marrow (13). Diseases associated with abnormal endochondral ossification often produce characteristic radiologic features that reflect their pathophysiology. An enchondroma, for example, is a benign cartilaginous bone tumor formed by a segment of physeal cartilage that fails to ossify normally (Fig 4). In this case, a rest of chondrocytes becomes nested in the bone marrow and continues to produce cartilage (chondroid matrix). Cartilage, being mostly water and collagen, is less dense on X-ray and computed tomography imaging than the surrounding mineralized bone and appears hyperintense on fluid-sensitive MR imaging. This benign cartilage lesion often partially calcifies, producing a distinctive radiographic pattern that helps differentiate it from more ominous osseous lesions such as malignant bone tumors or metastases (14). Another disorder of abnormal endochondral ossification is Blount’s disease, where regional inhibition of endochondral ossification in the tibial physes causes bony deformation and growth disturbance. It is associated with childhood obesity, in which extreme compressional forces that occur with walking inhibit endochondral ossification in the physeal cartilages around the knee. The growth plate dysfunction is most pronounced medially, resulting in the classic radiographic appearance of short, wide, and medially-sloped tibial metaphyses and epiphyses compared to the lateral sides (Fig 5) (15). Without surgery or bracing to unload the affected physes and allow resumption of normal endochondral ossification, the patient can suffer permanent disfigurement (varus and procurvatum deformity), gait abnormalities, and premature arthritis (16).
Figure 5. A 4-year-old child with Blount’s disease. (a) Radiographic long-leg study demonstrates bilateral varus deformities (dashed arc). (b) Magnified view of the knee shows the classic “bird’s beak” appearance of the proximal metaphysis (arrow) as a result of excessive medial compressive force.
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fication in their leg musculature or adjacent soft tissues from crush injury (football) or repetitive trauma (horseback riding). BONE MAINTENANCE AND REPAIR
Figure 6. Myositis ossificans adjacent to the proximal femur of a 28-year-old man on axial computed tomography. The inflammatory response within damaged muscle causes deposition of reparative fibrous tissue (asterisk) and subsequent peripheral ossification (arrows) by a rim of fibroblast-derived osteoblasts.
Ossification can also occur in abnormal locations, such as soft tissues following injury due to metaplasia of the reparative cells. This is referred to as heterotopic ossification and occurs when native fibroblasts or endothelial cells are erroneously transformed into osteogenic cells similar to osteoblasts (17). This can be isolated to the muscle when trauma initiates inflammation of muscle tissue, resulting in myositis ossificans (Fig 6). Athletes may develop this kind of heterotopic ossi-
Skeletal maintenance and repair rely on a dynamic balance between bone formation and resorption. The ongoing process of remodeling involves osteoclasts that dissolve old or damaged bone, osteoblasts that secrete unmineralized osteoid, and the process of osteoid mineralization to form new bones. Even though there is minimal net change in bone mass, these opposing forces of bone formation and resorption are simultaneously active during physiological remodeling (18). Perhaps this is why many physiology students erroneously conceptualize bone to be a relatively static tissue in the human body when, in reality, bone is quite dynamic and highly metabolically active. Direct visualization in surgery or in cadaveric dissection does not do this remarkable process enough justice. Students are often amazed by the sheer vigor of this process upon learning that remodeling provides them with an entirely new skeleton every 10 years (19). However, the opportunity to visualize this process in action with the gradual disappearance of an old fracture is probably the most indelible demonstration of remodeling and its continuous tenacity in maintaining bone structure and function. This balance, however, is disrupted under certain physiologic or pathologic conditions that uncouple the remodeling process. When this occurs, a surplus of bone formation or resorption may occur, ultimately producing a net change in bone mass. This is easily understood from radiographic images. In osteoporosis, bone mass and density are decreased to a pathologic degree, which is highlighted radiographically by the overall radiolucency of osteoporotic bones or by consequent fractures of the weakened bone (Fig 7). The pathophysiology involves accelerated bone resorption by osteoclasts with simultaneous osteoblastic senescence that contribute to a state
Figure 7. Osteoporosis in two patients. (a) Hand radiographs of a 65-year-old woman and (b) spine radiographs of a different elderly patient, both of which demonstrate abnormally lucent bones (asterisks) and thin cortices (arrows) due to demineralization of osteoporosis. Demineralization leads to weak bones that are susceptible to compression fractures (outlined) as seen in (b).
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Figure 8. Axial computed tomography images of the proximal femora of two 22year-old men, a professional football player (a) and a nonathlete (b), demonstrate the chronic adaptation and cortical thickening of bone with anabolic bone remodeling in response to repeated stress (Wolff’s law). The athlete’s bone (a) demonstrates 50% increase in cortical thickness, which provides greater mechanical strength and injury protection.
of net osseous catabolism (20,21). On the other hand, bone mass and density may be increased in certain athletes who experience repeated mechanical stresses. This mechanobiological adaptation, known as Wolff’s law, is thought to be mediated by extracellular fluid and electrical current shifts between osteocytes that signal osteoprogenitor differentiation into active osteoblasts (Fig 8) (22). Besides mechanical and hormonal influences, abnormal remodeling can also occur with diseases of the bone cells themselves. If the activity of one cell type is pathologically altered (increased or decreased), the radiologic appearance can
Figure 9. Frontal radiograph of a 3-year-old with osteopetrosis demonstrates densely sclerotic pelvic and proximal femoral bones (arrows), replacing the marrow space, and undertubulation (Erlenmeyer flask deformity) of the distal metadiaphysis (outlined). As the marrow space is replaced with unopposed bone formation, pancytopenia and organomegaly from extramedullary hematopoiesis often occur.
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reflect the compensatory activity of the other bone cells. For example, there is excessive bone formation in osteopetrosis (“marble bone disease”) due to a genetic defect that impairs carbonic anhydrase, the enzyme required by osteoclasts to acidify and dissolve bone matrix (23). Because osteoblasts are unaffected, bone formation proceeds without osteoclastic opposition (23). The radiographic appearance of this disease provides a striking representation of this pathophysiology: very dense, sclerotic, and deformed bones without the normal resorptive activity to maintain an appropriate balance of bone tissue (Fig 9). Paget’s disease, on the other hand, offers a more dynamic illustration of disrupted remodeling. It begins as an osteolytic disease in which osteoclasts are hyperstimulated to a pathologic degree (24). These overactive osteoclasts resorb exorbitant amounts of bone, which stimulates an intense osteoblastic response with rapid deposition of disorganized bone (presumably as compensation for the loss) among the lytic foci. Eventually both cell types will “burn out” to leave bone with patches of immature woven bone, causing thickening and expansion of the cortex in the final sclerotic phase (Fig 10).
Figure 10. Pelvis radiograph of a 56-year-old man with Paget’s disease of the right hemipelvis. Patchy lucencies are sequelae of the initial osteoclastic activity, followed by a robust osteoblastic response causes coarsening and distortion of the trabeculae (arrows) and thickening of the cortex (outline).
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Figure 11. Radiographs of primary and secondary fracture repairs. (a–c) A 17-yearold man with a transverse scaphoid waist fracture (solid arrows) demonstrating primary fracture repair. The fragments are anatomically aligned (a), and the fracture gap is bridged directly (b, c) with new woven bone (dashed arrows) and without callus formation. (d–f) Secondary fracture repair of a 4-year-old with transverse fractures of the radius and ulna (solid arrows). Progressive healing (e) demonstrates new bone formation via ossification of a fibrous callus (dashed arrows) to stabilize the fracture. Remodeling continues for months to years after reapproximation, and the medullary cavity and cortices are eventually restored (f).
More run-of-the-mill examples further illustrate the dynamic balance between bone production and bone resorption. Every fracture, if observed radiographically over time, provides a superb opportunity to visualize this physiologic concept. Immediately after a fracture, the inflammatory stage of healing begins. In the reparative phase, a soft fibrocartilaginous callus is formed from mesenchymal cells of the periosteum to bridge the bone fragments, seen as indistinctness of the fracture margins and, at times, widening of the fracture gap. Next, the soft callus hardens as fibrocartilage is replaced with mineralized osteoid by a process resembling endochondral ossification (23), resulting in callus
formation on radiographs. In the months and years that follow, the bony callus remodels to reconstitute the medullary cavity and cortical bone (Fig 11d–f). A different mechanism of fracture repair occurs when there is minimal interfragmentary strain, displacement, or comminution between the fragments. In this case, no callus is formed because it is not needed. Rather, osteoclast-driven cutting cones containing osteoblasts traverse the fracture gap and then initiate osteosynthesis across the gap (Fig 11a–c) (25). If the fracture site is reimaged years later, the healed fracture may completely remodel and appear “good as new” with few or no radiographic clues of prior trauma. 1303
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Figure 12. A 66-year-old woman with nonunion of oblique distal tibial and fibular fractures. (a) Radiographs demonstrate a persistent fracture gap, displacement, and angulation with a large nonbridging callus (arrow) that has attempted to stabilize the fragments without success. (b) Computed tomography reveals the hypodense, nonossifying fibrous tissue within the fracture gap (asterisks).
Unfortunately, not all fracture repairs are adequate or complete. A number of local factors, if present, can undermine the repair response, which leaves a persistent fracture line. These include instability (insufficient immobilization or improper fixation method), poor vascularization, or infection (26), just to name a few. Diabetes, smoking, and anti-inflammatory medications are also associated with inadequate fracture repair by interfering with callus formation or ossification (27–30). Regardless of the cause, the results of failed fracture repair can be devastating. Fractures may heal slowly (delayed union) or stop healing altogether, perhaps in the wrong position (non-
union), which can lead to permanent disfigurement and disability (Fig 12). BONE METABOLISM AND REGULATION Metabolism is another important topic in bone physiology. In this context, metabolism refers to the balance of anabolic and catabolic remodeling in relation to systemic mineral requirements and regulation by the endocrine system. The vital role of the skeletal system in calcium and phosphorous homeostasis can be conceptualized when physiology students learn
Figure 13. Bone resorption and abnormal mineralization in hyperparathyroidism. (a) Radiograph of the index finger shows severe bone resorption of the tufts (arrow), or acroosteolysis, in this 32-year-old man. (b) Sagittal computed tomography of the lumbar spine of a 52-year-old man demonstrates linear bands of subchondral endplate sclerosis (arrows), known as a “rugger jersey spine,” with alternating bands of lucency (asterisks) in the central vertebral bodies due to osteopenia.
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Figure 14. Rickets and osteomalacia. (a) Frontal radiograph from a 3-year-old girl with rickets disease demonstrates diffusely demineralized, radiolucent bones (asterisks) with flared metaphyses (arrows) due to poorly mineralized osteoid at the periphery of the metaphyses. This also results in pliable bones with resultant lateral bowing (genu varum). (b) Lateral distal femoral radiograph of a 58-year-old demonstrates the radiolucent and bowed appearance of a long bone (dashed arrows) from osteomalacia and defective mineralization in a skeletally mature patient.
that bone is mostly composed of extracellular mineralized matrix (65%), which stores 99% of the body’s calcium and 85% of its phosphorous (31). However, students may gain a deeper understanding and enduring appreciation for this concept with radiographic images of normal and abnormal bones. Factual information can then be reconciled with the corresponding radiologic appearances which clearly depict bone mineral composition and density. Two endocrine hormones primarily regulate bone metabolism: parathyroid hormone (PTH) and vitamin D. These hormones influence systemic calcium and phosphorous levels through many pathways, including regulation of osteoblast and osteoclast activity. Other notable, albeit less prominent, endocrine regulators of bone metabolism include calcitonin, estrogen, growth hormone, thyroid hormone, and glucocorticoids (20). Consequently, endocrinopathies often produce characteristic radiographic signs in bone. Therefore, radiology offers the opportunity to visualize disease processes and highlight the integrated relationship between body systems. A common example is hyperparathyroidism (HPTH), a condition of excess PTH secretion, originating from a parathyroid adenoma in its primary form or from hyperstimulation by persistent hypocalcemia in the secondary form (32). PTH stimulates osteoclastic bone resorption and calcium reabsorption in the kidneys (among other effects), which raise the plasma calcium level. Accordingly, the skeletal effects of HPTH on radiographs show excessive resorption of subperiosteal bone, especially in the phalanges (Fig 13a, b). The finding of subperiosteal resorption with diffuse osteopenia on radiographic images is almost pathognomonic for HPTH (33). Chronic renal disease also produces perturbations in bone and mineral homeostasis, producing a constellation of radiologic effects collectively known as renal osteodystrophy (Fig 13). In this secondary form of HPTH, there are osteolytic lesions from excessive bone resorption, but with the puzzling addition of osteosclerotic foci and calcinosis in soft tissues. However, these seemingly contradictory skeletal findings help explain the underlying renal pathophysiology: declining renal function causes undersecretion of phosphate,
and the result is hyperphosphatemia. Combined with hypercalcemia from secondary HPTH, phosphate and calcium precipitate and produce widespread calcinosis and osteosclerosis (34). Another important regulatory hormone that raises calcium and phosphate levels is the active form of vitamin D (D3). In bone, D3 promotes osteoid mineralization. Osteomalacia is a skeletal disease characterized by soft bones that are poorly mineralized when D3 is inadequate due to poor nutrition or a genetic mutation. Osteomalacia in children is referred to as rickets and is often more severe than the adult form because of the delayed growth and abnormal mineralization that occur in skeletally immature children (Fig 14a). Radiographically, bones appear osteopenic and bend easily as they lack adequate mineral content. In adults, osteomalacia is a discrete disease entity that is also apparent radiographically, but unlike rickets, does not affect the growth plates (Fig 14b). Often, the only finding is diffusely osteopenic bone, similar to osteoporosis, except that (histologically) the mineralization ratio is decreased in osteomalacia (35). Finally, as mentioned earlier, estrogen plays an important role in inhibiting osteoclasts and preventing bone loss, which occurs in osteoporosis (Fig 7a, b). Therefore, the postmenopausal hypoestrogenic state is a major contributing factor of osteoporosis (36). NEOPLASTIC DISEASE Despite their rarity, primary bone neoplasms provide a particularly memorable opportunity to watch bone pathophysiology in action. For example, enchondromas and chondrosarcomas demonstrate what it looks like when cartilage formation goes awry (Fig 15). Both are tumors of chondrocytes that produce abnormal deposition of hyaline cartilage with the former being benign and the latter being malignant. Because the chondroid (cartilage matrix) tends to mineralize peripherally, they produce a characteristic “ring-and-arc” calcification pattern on radiographic images (37). Osteosarcomas, on the other hand, demonstrate the effects of unregulated bone production with a distinct “fluffy” cloud-like matrix pattern when 1305
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teum from the underlying cortex at a leading edge (Fig 16c). Although subtle at times, this reaction of cortical bone to insult (commonly tumor or infection) occurs as a direct response to the aggressiveness of the underlying pathologic process and often serves as a harbinger of serious disease, especially in children who have a loosely attached periosteum (38).
SECONDARY DISORDERS OF BONE
Figure 15. Frontal radiograph of a chondrosarcoma from an 81year-old man. There is a large mixed lytic and sclerotic intramedullary lesion with characteristic “ring-and-arc” pattern (solid arrows) of chondroid matrix. Unlike the previously described benign chondroid lesion (enchondroma), this lesion is large, spanning the entire medullary space of the mid and distal femoral metadiaphysis. Other notable features include indistinct margins, endosteal scalloping (dashed arrow), and periosteal thickening (arrowheads).
the excessive osteoid that is produced by tumorous osteoblasts becomes mineralized (Fig 16a, b) (37). Also of interest is the variety of forms periosteal reaction, from the very solid and laminated appearance of benign processes, to the Codman triangle of highly aggressive processes that lift the perios-
Numerous secondary disorders of bone show how bone reacts to external insults. In osteomyelitis, for example, there is inflammation of cortex and marrow from an infection. The bone may be infiltrated by infectious and inflammatory cells, resulting in replacement of the normal marrow fat (Fig 17). If present long enough, the bone may even attempt to sequester the infection, by forming a sclerotic bony rim around the infectious focus or attempt to expel the infection through the formation of a cloaca where pus can drain. Alternatively, bone metastases from nonskeletal cancers display a wide range of radiographic phenotypes that demonstrate different behaviors of various cancers through the bony reactions they incite. A well-known example is the lytic appearance of renal and breast carcinomas that metastasize to bone (Fig 18a). The metastatic deposits appear lytic in bone because they produce osteolytic factors like PTH-related protein, which activates osteoclasts to resorb normal bone surrounding the cancer cells (39). Prostate metastases, on the other hand, usually render a sclerotic appearance because they secrete proosteoblastic cofactors like bone morphogenetic proteins and endothelin-1 (Fig 18b) (40). Arthritides are also highly illustrative. Osteoarthritis (OA) provides a marvelous illustration of the role of normal cartilage in joints and of how bone responds to its destruction. In OA, degradation of the articular cartilage exposes the
Figure 16. Two adolescent patients with osteosarcomas. (a) Frontal radiograph of the distal femur with an aggressive periosteal reaction (arrows) and “cloudlike” mineralization of osteoid matrix. (b) Nuclear medicine bone scan from the same patient shows intense radiotracer uptake where the malignant cells are producing bone at an accelerated rate. (c) A second patient with another aggressive pattern of periosteal reaction, known as Codman triangle (dashed arrow). Note the tumor expansion into adjacent soft tissues (asterisks).
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Figure 17. A 55-year-old man with a large posterior heel soft tissue ulcer (solid arrows) and osteomyelitis of the posterior calcaneal tubercle (asterisk) on sagittal Short T1 Inversion Recovery (STIR) MRI. There are abnormal areas of edema appearing as high fluid signal, which is consistent with acute osteomyelitis. Small susceptibility foci are seen in the soft tissues and tracking cranially along the Achilles tendon (dashed arrows), which are gas foci indicating extensive spread of soft tissue infection.
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underlying bony surfaces. The pathologic sequelae can be seen radiographically as asymmetric joint space narrowing, osteophytosis, eburnation, and sclerosis of affected bones (Fig 19a). Rheumatoid arthritis, an inflammatory arthritis, also features joint damage, but it is secondary to autoimmune disease. White blood cells and autoreactive antibodies incite an intraarticular inflammatory response that triggers destruction of cartilage and bone, best seen first at the “bare areas” of the joint margins where there is a small zone of bone not covered by articular cartilage. Radiographs demonstrate dissimilar (although sometimes overlapping) features compared to OA (Fig 19b), including periarticular osteopenia from the hyperemic inflammatory response, marginal erosions, and symmetric joint space narrowing as the cartilage is damaged diffusely and simultaneously. Similarly, septic arthritis also provides a visual testimony of the effects of abnormal, infectious synovial fluid on articular cartilage and the underlying bone. Because many systemic diseases affect the form and function of bone, radiology can not only teach future clinicians to recognize diagnostic clues, but also reinforce the integrated relationships between body systems.
Figure 18. Metastatic bone disease in two patients. (a) Axial computed tomography image of the head in a 73-year-old man with metastatic renal cell cancer. Note that the metastasis has eroded the calvarium, leaving a lytic lesion and an associated soft tissue mass (arrows). (b) Sagittal computed tomography of the lumbar spine in a 73-year-old man with multifocal sclerotic lesions (arrows) due to the osteoblastic response of prostate cancer metastasizing to bone.
Figure 19. Hand radiographs from different patients with arthritis. (a) Hand radiograph demonstrates features of osteoarthritis as irregular damage to articular cartilage, resulting in asymmetric joint space loss in the distal interphalangeal joints (white arrows), osteophyte formation, and subchondral sclerosis (black arrows). (b) Rheumatoid arthritis demonstrates symmetric joint space narrowing with a more proximal distribution (white arrowheads). Sequelae of synovial inflammation are seen as periarticular erosions (arrow) and osteopenia from hyperemia-stimulated accelerated bone resorption. Ulnar deviation of the phalanges results from subluxation of the metacarpophalangeal joints (lines).
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CONCLUSION Radiology is an underappreciated and underutilized tool in medical education. Despite its growth in clinical practice, its use in medical curricula has not advanced apace, even amidst widespread curricular reform. This is a shame, given its ability to portray anatomy, physiology, and pathology, especially in the skeletal system. Perhaps this explains, at least in part, why many nonradiology residency program directors consider interpretation of bone and joint radiographs to be an “essential” skill for medical graduates (41). Through a concise yet thorough review of core physiologic principles of bone and their associated radiographic manifestations, we have laid out a blueprint for embedding radiologic cases within existing curricula. In this way, radiologists can expand their role in educating future physicians by clarifying basic science principles through integration of physiology and radiology. Importantly, radiologic cases can be implemented as courseware with varying depth or coverage of the basic sciences to fit the needs of medical students and educators. Ultimately, the use of radiology to reinforce an understanding of physiology enables medical students to provide better care for their patients. REFERENCES 1. Hendee WR, Becker GJ, Borgstede JP, et al. Addressing overutilization in medical imaging. Radiology 2010; 257:240–245. 2. Poot JD, Hartman MS, Daffner RH. Understanding the US medical school requirements and medical students’ attitudes about radiology rotations. Acad Radiol 2012; 19:369–373. 3. Phillips AW, Smith SG, Straus CM. The role of radiology in preclinical anatomy: a critical review of the past, present, and future. Educ Issue 2013; 20:297–304, e1. 4. Bassett LW, Squire LF. Anatomy instruction by radiologists. Invest Radiol 1985; 20:1008–1010. 5. Tufts MA, Higgins-Opitz SB. What makes the learning of physiology in a PBL medical curriculum challenging? Student perceptions. Adv Physiol Educ 2009; 33:187–195. 6. Sefton AJ. Charting a global future for education in physiology. Adv Physiol Educ 2005; 29:189–193. 7. Michael JA, Richardson D, Rovick A, et al. Undergraduate students’ misconceptions about respiratory physiology. Am J Physiol 1999; 277:S127– S135. 8. Nay JW, Aaron VD, Gunderman RB. Using radiology to teach physiology. J Am Coll Radiol 2011; 8:117–123. 9. Finnerty EP, Chauvin S, Bonaminio G, et al. Flexner revisited: the role and value of the basic sciences in medical education. Acad Med 2010; 85:349–355. 10. Eisenstein A, Vaisman L, Johnston-Cox H, et al. Integration of basic science and clinical medicine: the innovative approach of the cadaver biopsy project at the Boston University School of Medicine. Acad Med 2014; 89:50– 53. 11. Bell FE, 3rd, Wilson LB, Hoppmann RA. Using ultrasound to teach medical students cardiac physiology. Adv Physiol Educ 2015; 39:392–396. 12. Boffano P, Roccia F, Campisi P, et al. Review of 43 osteomas of the craniomaxillofacial region. J Oral Maxillofac Surg 2012; 70:1093–1095. 13. Laor T, Jaramillo D. MR imaging insights into skeletal maturation: what is normal? Radiology 2009; 250:28–38.
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14. Marco RA, Gitelis S, Brebach GT, et al. Cartilage tumors: evaluation and treatment. J Am Acad Orthop Surg 2000; 8:292–304. 15. Birch JG. Blount disease. J Am Acad Orthop Surg 2013; 21:408–418. 16. Sabharwal S. Blount disease. J Bone Joint Surg Am 2009; 91:1758– 1776. 17. Walczak BE, Johnson CN, Howe BM. Myositis ossificans. J Am Acad Orthop Surg 2015; 23:612–622. 18. Andersen TL, Sondergaard TE, Skorzynska KE, et al. A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol 2009; 174:239–247. 19. Parfitt AM. Misconceptions (2): turnover is always higher in cancellous than in cortical bone. Bone 2002; 30:807–809. 20. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem 1999; 45:1353–1358. 21. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci 2006; 1092:385–396. 22. Chen J-H, Liu C, You L, et al. Boning up on Wolff’s law: mechanical regulation of the cells that make and maintain bone. J Biomech 2010; 43:108– 118. 23. Del Fattore A, Teti A, Rucci N. Bone cells and the mechanisms of bone remodelling. Front Biosci (Elite Ed) 2012; 4:2302–2321. 24. Mee AP, Dixon JA, Hoyland JA, et al. Detection of canine distemper virus in 100% of Paget’s disease samples by in situ-reverse transcriptasepolymerase chain reaction. Bone 1998; 23:171–175. 25. Schindeler A, McDonald MM, Bokko P, et al. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol 2008; 19:459– 466. 26. Gaston MS, Simpson AHRW. Inhibition of fracture healing. J Bone Joint Surg Br 2007; 89-B:1553–1560. 27. Forslund JM, Archdeacon MT. The pathobiology of diabetes mellitus in bone metabolism, fracture healing, and complications. Am J Orthop (Belle Mead NJ) 2015; 44:453–457. 28. Gullihorn L, Karpman R, Lippiello L. Differential effects of nicotine and smoke condensate on bone cell metabolic activity. J Orthop Trauma 2005; 19:17–22. 29. Raikin SM, Landsman JC, Alexander VA, et al. Effect of nicotine on the rate and strength of long bone fracture healing. Clin Orthop 1998; 231– 237. 30. Giannoudis PV, MacDonald DA, Matthews SJ, et al. Nonunion of the femoral diaphysis: The influence of reaming and non-steroidal antiinflammatory drugs. J Bone Joint Surg Br 2000; 82-B:655–658. 31. Kumar V, Stanley L. Robbins basic pathology. 8th ed. Saunders/Elsevier., 2007. 32. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343:1863–1875. 33. Genant HK, Heck LL, Lanzl LH, et al. Primary hyperparathyroidism. A comprehensive study of clinical, biochemical and radiographic manifestations. Radiology 1973; 109:513–524. 34. Jevtic V. Imaging of renal osteodystrophy. Eur J Radiol 2003; 46:85– 95. 35. Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006; 92:4–8. 36. Pacifici R. Cytokines, estrogen, and postmenopausal osteoporosis – the second decade. Endocrinology 1998; 139:2659–2661. 37. Wodajo FM, Gannon F, Murphey MD. Visual guide to musculoskeletal tumors: a clinical-radiologic-histologic approach. Elsevier Health Sciences, 2010. 38. Rana RS, Wu JS, Eisenberg RL. Periosteal reaction. AJR Am J Roentgenol 2009; 193:W259–W272. 39. Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 2005; 12:549–583. 40. Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem 2004; 91:718–729. 41. Kondo KL, Swerdlow M. Medical student radiology curriculum: what skills do residency program directors believe are essential for medical students to attain? Educ Issue 2013; 20:263–271.
Radiology in the Study of Bone Physiology Michael V. Kushdilian, MS, Lauren M. Ladd, MD, Richard B. Gunderman, MD, PhD Rationale and Objectives: In this article, we review the core principles of bone physiology alongside imaging examples that demonstrate such principles. Materials and Methods: The core principles of bone physiology are reviewed and further solidified with a corresponding abnormal pathophysiologic example. The key principles of bone physiology to be reviewed include the following: (1) formation and growth, (2) maintenance and repair, (3) metabolism and regulation, and (4) neoplastic disease. Lastly, a collection of secondary bone diseases is presented to demonstrate the skeletal manifestations of numerous systemic diseases. With this integrative method, we hope to emphasize the value of using radiology to teach physiology within a clinical context. This is especially relevant now, as many US medical schools undergo curricular reform with more emphasis on integrative interdisciplinary learning. Ultimately, we intend to provide a paradigm for incorporating radiology into the pre-clinical medical curriculum through a review of basic science physiology that underlies key radiographic findings of the skeletal system. Results: Radiology is known for its role in helping make diagnoses and clinical decisions. However, radiology is also well suited to enhance medical education by offering the ability to visualize physiology in action. This is especially true in skeletal radiology, where radiographic osseous changes represent a wide range of physiological processes. Therefore, skeletal radiology can be a useful tool for illustrating concepts of physiology that underlie the normal and abnormal radiologic appearances of bone. Conclusion: Radiology is an important but underutilized tool for demonstrating concepts in bone physiology. Key Words: medical education; physiology; radiology; medical students; curricular reform. © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
INTRODUCTION AND BACKGROUND
O
ne of the greatest underappreciated opportunities in medical education is the use of radiologic images to teach the basic medical sciences. Too often, medical students learn such subjects as anatomy, physiology, and pathology from text, diagrams, cadavers, and animal models rather than from living human subjects. Radiology makes it possible to visualize living human structure, function, disease, and injury in ways that can help learners gain a much deeper understanding of the material, creating indelible images that they carry with them into practice for many years. Nonetheless, radiology is underutilized in this regard. Despite the explosion of diagnostic imaging utilization in clinical practice, estimated to be nearly twice the rate of laboratory and pharmaceutical usage (1), the role of radiology in medical education has remained stagnant across allopathic and osteopathic medical schools for decades (2). If available, a formal radiology clerkship is typically offered to medical students as a fourth-year elective, long after the basic science coursework has ended. This approach isolates radiology from Acad Radiol 2016; 23:1298–1308 From the Department of Radiology and Imaging Sciences, School of Medicine, Indiana University, 550 N. University Blvd. Rm 0663, Indianapolis, IN 46202. Received February 26, 2016; accepted June 1, 2016. Address correspondence to: M.V.K. e-mail: [email protected] © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.acra.2016.06.001
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its foundation in the basic sciences and may put students at a disadvantage in their future clinical practices. Although radiology has been used in a piecemeal fashion throughout the preclinical curricula for decades with subjects like anatomy (3,4), radiology can also be an effective tool for teaching the basic sciences not traditionally amenable to visual or anatomic applications. Physiology, in particular, is a vital basic discipline of medicine that guides diagnosis and therapeutic approaches in clinical practice (5–7), which may be more effectively taught when concepts are paired with radiologic cases of normal and abnormal physiology, a strategy that has been proposed for general medical physiology courses previously (8). This case-based approach is especially relevant now in the face of national curricular reforms focusing on more “vertical” integration of basic sciences and their clinical applications (9). Some schools adopting these curricular changes have also incorporated radiographic studies into their preclinical curricula, receiving high praise from their students and educators (10) and producing objective improvements in physiology comprehension (11). Whether a particular school has undergone this reform, it is imperative that radiology education be used for more than basic image interpretation skills. Therefore, we will demonstrate the untapped potential of radiology in fortifying basic science concepts to medical students, focusing on the skeletal system. As an extremely dynamic tissue, the radiologic appearance of normal and abnormal bone acts as a biological signature, representing underlying physiological processes in action. By
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Figure 1. X-rays from three different patients show progressive intramembranous ossification in the cranium. (a) Radiolucent fibrous tissue of the coronal (solid arrows) and lambdoid (dashed arrows) sutures from a 28-day-old. (b) At 6 months of age, sutures have narrowed via osseous replacement. (c) By 13 years of age, the sutures have been completely replaced with bone leaving only thin radiolucent lines.
maintenance and repair, (3) metabolism and regulation via the endocrine system, and (4) bone neoplasia. Radiologic manifestations of secondary bone disorder, such as metastatic disease, also help learners understand how bone reacts to systemic diseases. Overall, we hope this integrated approach of teaching basic science and radiology together will improve clinical acumen and solidify an understanding of physiology.
BONE DEVELOPMENT AND GROWTH
Figure 2. A benign osteoma of an adult skull on axial computed tomography. Excessive focal osteoid deposition during intramembranous ossification results in a densely calcified osseous prominence in or extending from a membranous bone as shown here at the squamo-mastoid suture line (arrows).
contrasting key imaging components of normal physiologic and abnormal pathophysiologic appearances of bone, we will review and illustrate the core physiology principles of this system including (1) bone growth and development, (2)
Bone development and growth requires understanding of two different processes: intramembranous ossification, as seen in flat bones such as the skull, and endochondral ossification, as occurs in long bones. The former begins when groups of mesenchymal stem cells cluster into a nidus (the primary ossification centers) within fibrous connective tissue. These clustered immature mesenchymal cells differentiate into osteoblasts that secrete unmineralized bone matrix (osteoid), which mineralizes as it becomes infused with calcium and phosphorous. Radiographs of the infant and adolescent skull provide an opportunity to visualize progressive intramembranous ossification as the radiolucent sutures, representing the unmineralized fibrous connective tissue, progressively decrease in width with progressive ossification of the skull bones (Fig 1). Osteomas, on
Figure 3. Endochondral ossification in a 4-year-old boy. (a) Normal knee radiograph demonstrates open, lucent physes (arrowheads) and secondary ossification centers of the physes (asterisks) and patella (arrow), which appear radiodense after ossification. (b) T1-weighted sagittal magnetic resonance imaging from the same patient depicts the ossified metaphyses, intermediate signal intensity physeal cartilage (arrowheads), and partially ossified epiphyseal (asterisks) and patellar (arrow) secondary ossification centers. A portion of the unossified secondary ossification center cartilage will remain as articular cartilage.
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Figure 4. Axial computed tomography of an enchondroma in the distal femur of an adult patient. This well-circumscribed lucent lesion in the medial metaphysis (solid arrows) displays the classic appearance of chondroid matrix: relatively hypodense with small internal ring-and-arc calcifications (dashed arrow). Although it is eccentrically located, there is no significant endosteal scalloping, cortical reaction, or soft tissue mass to suggest a more aggressive malignant cartilage lesion.
the other hand, are a pathological example of abnormal intramembranous ossification (12). These benign tumors are formed when a focal overabundance of osteoblasts secretes excess osteoid into a membranous bone (Fig 2). Endochondral ossification is the mechanism of bone development for long bones and utilizes a hyaline cartilage template. Primary ossification begins within the central diaphysis where the cartilaginous model is resorbed and replaced by bone due to a complex cascade of osteoblast and osteoclast stimulation and maturation. Later, secondary centers of ossification develop within the epiphyseal cartilage. As ossification proceeds at these sites, a band of physeal cartilage remains trapped between these mineralizing ossification centers,
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otherwise known as the growth plate, which determines the rate of bone growth and final adult height. The steps of endochondral ossification can be clearly demonstrated with magnetic resonance (MR) imaging of skeletally immature bones in children, giving learners the opportunity to see this dynamic process in action (Fig 3). MR imaging is best for visualizing both the ossified bone and the nonossified structures such as cartilage. Furthermore, MR imaging can depict less prominent features of bone physiology including specific zones of the physeal cartilage that enable bone growth, as well as the normal conversion of hematopoietic to fatty marrow (13). Diseases associated with abnormal endochondral ossification often produce characteristic radiologic features that reflect their pathophysiology. An enchondroma, for example, is a benign cartilaginous bone tumor formed by a segment of physeal cartilage that fails to ossify normally (Fig 4). In this case, a rest of chondrocytes becomes nested in the bone marrow and continues to produce cartilage (chondroid matrix). Cartilage, being mostly water and collagen, is less dense on X-ray and computed tomography imaging than the surrounding mineralized bone and appears hyperintense on fluid-sensitive MR imaging. This benign cartilage lesion often partially calcifies, producing a distinctive radiographic pattern that helps differentiate it from more ominous osseous lesions such as malignant bone tumors or metastases (14). Another disorder of abnormal endochondral ossification is Blount’s disease, where regional inhibition of endochondral ossification in the tibial physes causes bony deformation and growth disturbance. It is associated with childhood obesity, in which extreme compressional forces that occur with walking inhibit endochondral ossification in the physeal cartilages around the knee. The growth plate dysfunction is most pronounced medially, resulting in the classic radiographic appearance of short, wide, and medially-sloped tibial metaphyses and epiphyses compared to the lateral sides (Fig 5) (15). Without surgery or bracing to unload the affected physes and allow resumption of normal endochondral ossification, the patient can suffer permanent disfigurement (varus and procurvatum deformity), gait abnormalities, and premature arthritis (16).
Figure 5. A 4-year-old child with Blount’s disease. (a) Radiographic long-leg study demonstrates bilateral varus deformities (dashed arc). (b) Magnified view of the knee shows the classic “bird’s beak” appearance of the proximal metaphysis (arrow) as a result of excessive medial compressive force.
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fication in their leg musculature or adjacent soft tissues from crush injury (football) or repetitive trauma (horseback riding). BONE MAINTENANCE AND REPAIR
Figure 6. Myositis ossificans adjacent to the proximal femur of a 28-year-old man on axial computed tomography. The inflammatory response within damaged muscle causes deposition of reparative fibrous tissue (asterisk) and subsequent peripheral ossification (arrows) by a rim of fibroblast-derived osteoblasts.
Ossification can also occur in abnormal locations, such as soft tissues following injury due to metaplasia of the reparative cells. This is referred to as heterotopic ossification and occurs when native fibroblasts or endothelial cells are erroneously transformed into osteogenic cells similar to osteoblasts (17). This can be isolated to the muscle when trauma initiates inflammation of muscle tissue, resulting in myositis ossificans (Fig 6). Athletes may develop this kind of heterotopic ossi-
Skeletal maintenance and repair rely on a dynamic balance between bone formation and resorption. The ongoing process of remodeling involves osteoclasts that dissolve old or damaged bone, osteoblasts that secrete unmineralized osteoid, and the process of osteoid mineralization to form new bones. Even though there is minimal net change in bone mass, these opposing forces of bone formation and resorption are simultaneously active during physiological remodeling (18). Perhaps this is why many physiology students erroneously conceptualize bone to be a relatively static tissue in the human body when, in reality, bone is quite dynamic and highly metabolically active. Direct visualization in surgery or in cadaveric dissection does not do this remarkable process enough justice. Students are often amazed by the sheer vigor of this process upon learning that remodeling provides them with an entirely new skeleton every 10 years (19). However, the opportunity to visualize this process in action with the gradual disappearance of an old fracture is probably the most indelible demonstration of remodeling and its continuous tenacity in maintaining bone structure and function. This balance, however, is disrupted under certain physiologic or pathologic conditions that uncouple the remodeling process. When this occurs, a surplus of bone formation or resorption may occur, ultimately producing a net change in bone mass. This is easily understood from radiographic images. In osteoporosis, bone mass and density are decreased to a pathologic degree, which is highlighted radiographically by the overall radiolucency of osteoporotic bones or by consequent fractures of the weakened bone (Fig 7). The pathophysiology involves accelerated bone resorption by osteoclasts with simultaneous osteoblastic senescence that contribute to a state
Figure 7. Osteoporosis in two patients. (a) Hand radiographs of a 65-year-old woman and (b) spine radiographs of a different elderly patient, both of which demonstrate abnormally lucent bones (asterisks) and thin cortices (arrows) due to demineralization of osteoporosis. Demineralization leads to weak bones that are susceptible to compression fractures (outlined) as seen in (b).
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Figure 8. Axial computed tomography images of the proximal femora of two 22year-old men, a professional football player (a) and a nonathlete (b), demonstrate the chronic adaptation and cortical thickening of bone with anabolic bone remodeling in response to repeated stress (Wolff’s law). The athlete’s bone (a) demonstrates 50% increase in cortical thickness, which provides greater mechanical strength and injury protection.
of net osseous catabolism (20,21). On the other hand, bone mass and density may be increased in certain athletes who experience repeated mechanical stresses. This mechanobiological adaptation, known as Wolff’s law, is thought to be mediated by extracellular fluid and electrical current shifts between osteocytes that signal osteoprogenitor differentiation into active osteoblasts (Fig 8) (22). Besides mechanical and hormonal influences, abnormal remodeling can also occur with diseases of the bone cells themselves. If the activity of one cell type is pathologically altered (increased or decreased), the radiologic appearance can
Figure 9. Frontal radiograph of a 3-year-old with osteopetrosis demonstrates densely sclerotic pelvic and proximal femoral bones (arrows), replacing the marrow space, and undertubulation (Erlenmeyer flask deformity) of the distal metadiaphysis (outlined). As the marrow space is replaced with unopposed bone formation, pancytopenia and organomegaly from extramedullary hematopoiesis often occur.
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reflect the compensatory activity of the other bone cells. For example, there is excessive bone formation in osteopetrosis (“marble bone disease”) due to a genetic defect that impairs carbonic anhydrase, the enzyme required by osteoclasts to acidify and dissolve bone matrix (23). Because osteoblasts are unaffected, bone formation proceeds without osteoclastic opposition (23). The radiographic appearance of this disease provides a striking representation of this pathophysiology: very dense, sclerotic, and deformed bones without the normal resorptive activity to maintain an appropriate balance of bone tissue (Fig 9). Paget’s disease, on the other hand, offers a more dynamic illustration of disrupted remodeling. It begins as an osteolytic disease in which osteoclasts are hyperstimulated to a pathologic degree (24). These overactive osteoclasts resorb exorbitant amounts of bone, which stimulates an intense osteoblastic response with rapid deposition of disorganized bone (presumably as compensation for the loss) among the lytic foci. Eventually both cell types will “burn out” to leave bone with patches of immature woven bone, causing thickening and expansion of the cortex in the final sclerotic phase (Fig 10).
Figure 10. Pelvis radiograph of a 56-year-old man with Paget’s disease of the right hemipelvis. Patchy lucencies are sequelae of the initial osteoclastic activity, followed by a robust osteoblastic response causes coarsening and distortion of the trabeculae (arrows) and thickening of the cortex (outline).
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Figure 11. Radiographs of primary and secondary fracture repairs. (a–c) A 17-yearold man with a transverse scaphoid waist fracture (solid arrows) demonstrating primary fracture repair. The fragments are anatomically aligned (a), and the fracture gap is bridged directly (b, c) with new woven bone (dashed arrows) and without callus formation. (d–f) Secondary fracture repair of a 4-year-old with transverse fractures of the radius and ulna (solid arrows). Progressive healing (e) demonstrates new bone formation via ossification of a fibrous callus (dashed arrows) to stabilize the fracture. Remodeling continues for months to years after reapproximation, and the medullary cavity and cortices are eventually restored (f).
More run-of-the-mill examples further illustrate the dynamic balance between bone production and bone resorption. Every fracture, if observed radiographically over time, provides a superb opportunity to visualize this physiologic concept. Immediately after a fracture, the inflammatory stage of healing begins. In the reparative phase, a soft fibrocartilaginous callus is formed from mesenchymal cells of the periosteum to bridge the bone fragments, seen as indistinctness of the fracture margins and, at times, widening of the fracture gap. Next, the soft callus hardens as fibrocartilage is replaced with mineralized osteoid by a process resembling endochondral ossification (23), resulting in callus
formation on radiographs. In the months and years that follow, the bony callus remodels to reconstitute the medullary cavity and cortical bone (Fig 11d–f). A different mechanism of fracture repair occurs when there is minimal interfragmentary strain, displacement, or comminution between the fragments. In this case, no callus is formed because it is not needed. Rather, osteoclast-driven cutting cones containing osteoblasts traverse the fracture gap and then initiate osteosynthesis across the gap (Fig 11a–c) (25). If the fracture site is reimaged years later, the healed fracture may completely remodel and appear “good as new” with few or no radiographic clues of prior trauma. 1303
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Figure 12. A 66-year-old woman with nonunion of oblique distal tibial and fibular fractures. (a) Radiographs demonstrate a persistent fracture gap, displacement, and angulation with a large nonbridging callus (arrow) that has attempted to stabilize the fragments without success. (b) Computed tomography reveals the hypodense, nonossifying fibrous tissue within the fracture gap (asterisks).
Unfortunately, not all fracture repairs are adequate or complete. A number of local factors, if present, can undermine the repair response, which leaves a persistent fracture line. These include instability (insufficient immobilization or improper fixation method), poor vascularization, or infection (26), just to name a few. Diabetes, smoking, and anti-inflammatory medications are also associated with inadequate fracture repair by interfering with callus formation or ossification (27–30). Regardless of the cause, the results of failed fracture repair can be devastating. Fractures may heal slowly (delayed union) or stop healing altogether, perhaps in the wrong position (non-
union), which can lead to permanent disfigurement and disability (Fig 12). BONE METABOLISM AND REGULATION Metabolism is another important topic in bone physiology. In this context, metabolism refers to the balance of anabolic and catabolic remodeling in relation to systemic mineral requirements and regulation by the endocrine system. The vital role of the skeletal system in calcium and phosphorous homeostasis can be conceptualized when physiology students learn
Figure 13. Bone resorption and abnormal mineralization in hyperparathyroidism. (a) Radiograph of the index finger shows severe bone resorption of the tufts (arrow), or acroosteolysis, in this 32-year-old man. (b) Sagittal computed tomography of the lumbar spine of a 52-year-old man demonstrates linear bands of subchondral endplate sclerosis (arrows), known as a “rugger jersey spine,” with alternating bands of lucency (asterisks) in the central vertebral bodies due to osteopenia.
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Figure 14. Rickets and osteomalacia. (a) Frontal radiograph from a 3-year-old girl with rickets disease demonstrates diffusely demineralized, radiolucent bones (asterisks) with flared metaphyses (arrows) due to poorly mineralized osteoid at the periphery of the metaphyses. This also results in pliable bones with resultant lateral bowing (genu varum). (b) Lateral distal femoral radiograph of a 58-year-old demonstrates the radiolucent and bowed appearance of a long bone (dashed arrows) from osteomalacia and defective mineralization in a skeletally mature patient.
that bone is mostly composed of extracellular mineralized matrix (65%), which stores 99% of the body’s calcium and 85% of its phosphorous (31). However, students may gain a deeper understanding and enduring appreciation for this concept with radiographic images of normal and abnormal bones. Factual information can then be reconciled with the corresponding radiologic appearances which clearly depict bone mineral composition and density. Two endocrine hormones primarily regulate bone metabolism: parathyroid hormone (PTH) and vitamin D. These hormones influence systemic calcium and phosphorous levels through many pathways, including regulation of osteoblast and osteoclast activity. Other notable, albeit less prominent, endocrine regulators of bone metabolism include calcitonin, estrogen, growth hormone, thyroid hormone, and glucocorticoids (20). Consequently, endocrinopathies often produce characteristic radiographic signs in bone. Therefore, radiology offers the opportunity to visualize disease processes and highlight the integrated relationship between body systems. A common example is hyperparathyroidism (HPTH), a condition of excess PTH secretion, originating from a parathyroid adenoma in its primary form or from hyperstimulation by persistent hypocalcemia in the secondary form (32). PTH stimulates osteoclastic bone resorption and calcium reabsorption in the kidneys (among other effects), which raise the plasma calcium level. Accordingly, the skeletal effects of HPTH on radiographs show excessive resorption of subperiosteal bone, especially in the phalanges (Fig 13a, b). The finding of subperiosteal resorption with diffuse osteopenia on radiographic images is almost pathognomonic for HPTH (33). Chronic renal disease also produces perturbations in bone and mineral homeostasis, producing a constellation of radiologic effects collectively known as renal osteodystrophy (Fig 13). In this secondary form of HPTH, there are osteolytic lesions from excessive bone resorption, but with the puzzling addition of osteosclerotic foci and calcinosis in soft tissues. However, these seemingly contradictory skeletal findings help explain the underlying renal pathophysiology: declining renal function causes undersecretion of phosphate,
and the result is hyperphosphatemia. Combined with hypercalcemia from secondary HPTH, phosphate and calcium precipitate and produce widespread calcinosis and osteosclerosis (34). Another important regulatory hormone that raises calcium and phosphate levels is the active form of vitamin D (D3). In bone, D3 promotes osteoid mineralization. Osteomalacia is a skeletal disease characterized by soft bones that are poorly mineralized when D3 is inadequate due to poor nutrition or a genetic mutation. Osteomalacia in children is referred to as rickets and is often more severe than the adult form because of the delayed growth and abnormal mineralization that occur in skeletally immature children (Fig 14a). Radiographically, bones appear osteopenic and bend easily as they lack adequate mineral content. In adults, osteomalacia is a discrete disease entity that is also apparent radiographically, but unlike rickets, does not affect the growth plates (Fig 14b). Often, the only finding is diffusely osteopenic bone, similar to osteoporosis, except that (histologically) the mineralization ratio is decreased in osteomalacia (35). Finally, as mentioned earlier, estrogen plays an important role in inhibiting osteoclasts and preventing bone loss, which occurs in osteoporosis (Fig 7a, b). Therefore, the postmenopausal hypoestrogenic state is a major contributing factor of osteoporosis (36). NEOPLASTIC DISEASE Despite their rarity, primary bone neoplasms provide a particularly memorable opportunity to watch bone pathophysiology in action. For example, enchondromas and chondrosarcomas demonstrate what it looks like when cartilage formation goes awry (Fig 15). Both are tumors of chondrocytes that produce abnormal deposition of hyaline cartilage with the former being benign and the latter being malignant. Because the chondroid (cartilage matrix) tends to mineralize peripherally, they produce a characteristic “ring-and-arc” calcification pattern on radiographic images (37). Osteosarcomas, on the other hand, demonstrate the effects of unregulated bone production with a distinct “fluffy” cloud-like matrix pattern when 1305
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teum from the underlying cortex at a leading edge (Fig 16c). Although subtle at times, this reaction of cortical bone to insult (commonly tumor or infection) occurs as a direct response to the aggressiveness of the underlying pathologic process and often serves as a harbinger of serious disease, especially in children who have a loosely attached periosteum (38).
SECONDARY DISORDERS OF BONE
Figure 15. Frontal radiograph of a chondrosarcoma from an 81year-old man. There is a large mixed lytic and sclerotic intramedullary lesion with characteristic “ring-and-arc” pattern (solid arrows) of chondroid matrix. Unlike the previously described benign chondroid lesion (enchondroma), this lesion is large, spanning the entire medullary space of the mid and distal femoral metadiaphysis. Other notable features include indistinct margins, endosteal scalloping (dashed arrow), and periosteal thickening (arrowheads).
the excessive osteoid that is produced by tumorous osteoblasts becomes mineralized (Fig 16a, b) (37). Also of interest is the variety of forms periosteal reaction, from the very solid and laminated appearance of benign processes, to the Codman triangle of highly aggressive processes that lift the perios-
Numerous secondary disorders of bone show how bone reacts to external insults. In osteomyelitis, for example, there is inflammation of cortex and marrow from an infection. The bone may be infiltrated by infectious and inflammatory cells, resulting in replacement of the normal marrow fat (Fig 17). If present long enough, the bone may even attempt to sequester the infection, by forming a sclerotic bony rim around the infectious focus or attempt to expel the infection through the formation of a cloaca where pus can drain. Alternatively, bone metastases from nonskeletal cancers display a wide range of radiographic phenotypes that demonstrate different behaviors of various cancers through the bony reactions they incite. A well-known example is the lytic appearance of renal and breast carcinomas that metastasize to bone (Fig 18a). The metastatic deposits appear lytic in bone because they produce osteolytic factors like PTH-related protein, which activates osteoclasts to resorb normal bone surrounding the cancer cells (39). Prostate metastases, on the other hand, usually render a sclerotic appearance because they secrete proosteoblastic cofactors like bone morphogenetic proteins and endothelin-1 (Fig 18b) (40). Arthritides are also highly illustrative. Osteoarthritis (OA) provides a marvelous illustration of the role of normal cartilage in joints and of how bone responds to its destruction. In OA, degradation of the articular cartilage exposes the
Figure 16. Two adolescent patients with osteosarcomas. (a) Frontal radiograph of the distal femur with an aggressive periosteal reaction (arrows) and “cloudlike” mineralization of osteoid matrix. (b) Nuclear medicine bone scan from the same patient shows intense radiotracer uptake where the malignant cells are producing bone at an accelerated rate. (c) A second patient with another aggressive pattern of periosteal reaction, known as Codman triangle (dashed arrow). Note the tumor expansion into adjacent soft tissues (asterisks).
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Figure 17. A 55-year-old man with a large posterior heel soft tissue ulcer (solid arrows) and osteomyelitis of the posterior calcaneal tubercle (asterisk) on sagittal Short T1 Inversion Recovery (STIR) MRI. There are abnormal areas of edema appearing as high fluid signal, which is consistent with acute osteomyelitis. Small susceptibility foci are seen in the soft tissues and tracking cranially along the Achilles tendon (dashed arrows), which are gas foci indicating extensive spread of soft tissue infection.
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underlying bony surfaces. The pathologic sequelae can be seen radiographically as asymmetric joint space narrowing, osteophytosis, eburnation, and sclerosis of affected bones (Fig 19a). Rheumatoid arthritis, an inflammatory arthritis, also features joint damage, but it is secondary to autoimmune disease. White blood cells and autoreactive antibodies incite an intraarticular inflammatory response that triggers destruction of cartilage and bone, best seen first at the “bare areas” of the joint margins where there is a small zone of bone not covered by articular cartilage. Radiographs demonstrate dissimilar (although sometimes overlapping) features compared to OA (Fig 19b), including periarticular osteopenia from the hyperemic inflammatory response, marginal erosions, and symmetric joint space narrowing as the cartilage is damaged diffusely and simultaneously. Similarly, septic arthritis also provides a visual testimony of the effects of abnormal, infectious synovial fluid on articular cartilage and the underlying bone. Because many systemic diseases affect the form and function of bone, radiology can not only teach future clinicians to recognize diagnostic clues, but also reinforce the integrated relationships between body systems.
Figure 18. Metastatic bone disease in two patients. (a) Axial computed tomography image of the head in a 73-year-old man with metastatic renal cell cancer. Note that the metastasis has eroded the calvarium, leaving a lytic lesion and an associated soft tissue mass (arrows). (b) Sagittal computed tomography of the lumbar spine in a 73-year-old man with multifocal sclerotic lesions (arrows) due to the osteoblastic response of prostate cancer metastasizing to bone.
Figure 19. Hand radiographs from different patients with arthritis. (a) Hand radiograph demonstrates features of osteoarthritis as irregular damage to articular cartilage, resulting in asymmetric joint space loss in the distal interphalangeal joints (white arrows), osteophyte formation, and subchondral sclerosis (black arrows). (b) Rheumatoid arthritis demonstrates symmetric joint space narrowing with a more proximal distribution (white arrowheads). Sequelae of synovial inflammation are seen as periarticular erosions (arrow) and osteopenia from hyperemia-stimulated accelerated bone resorption. Ulnar deviation of the phalanges results from subluxation of the metacarpophalangeal joints (lines).
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CONCLUSION Radiology is an underappreciated and underutilized tool in medical education. Despite its growth in clinical practice, its use in medical curricula has not advanced apace, even amidst widespread curricular reform. This is a shame, given its ability to portray anatomy, physiology, and pathology, especially in the skeletal system. Perhaps this explains, at least in part, why many nonradiology residency program directors consider interpretation of bone and joint radiographs to be an “essential” skill for medical graduates (41). Through a concise yet thorough review of core physiologic principles of bone and their associated radiographic manifestations, we have laid out a blueprint for embedding radiologic cases within existing curricula. In this way, radiologists can expand their role in educating future physicians by clarifying basic science principles through integration of physiology and radiology. Importantly, radiologic cases can be implemented as courseware with varying depth or coverage of the basic sciences to fit the needs of medical students and educators. Ultimately, the use of radiology to reinforce an understanding of physiology enables medical students to provide better care for their patients. REFERENCES 1. Hendee WR, Becker GJ, Borgstede JP, et al. Addressing overutilization in medical imaging. Radiology 2010; 257:240–245. 2. Poot JD, Hartman MS, Daffner RH. Understanding the US medical school requirements and medical students’ attitudes about radiology rotations. Acad Radiol 2012; 19:369–373. 3. Phillips AW, Smith SG, Straus CM. The role of radiology in preclinical anatomy: a critical review of the past, present, and future. Educ Issue 2013; 20:297–304, e1. 4. Bassett LW, Squire LF. Anatomy instruction by radiologists. Invest Radiol 1985; 20:1008–1010. 5. Tufts MA, Higgins-Opitz SB. What makes the learning of physiology in a PBL medical curriculum challenging? Student perceptions. Adv Physiol Educ 2009; 33:187–195. 6. Sefton AJ. Charting a global future for education in physiology. Adv Physiol Educ 2005; 29:189–193. 7. Michael JA, Richardson D, Rovick A, et al. Undergraduate students’ misconceptions about respiratory physiology. Am J Physiol 1999; 277:S127– S135. 8. Nay JW, Aaron VD, Gunderman RB. Using radiology to teach physiology. J Am Coll Radiol 2011; 8:117–123. 9. Finnerty EP, Chauvin S, Bonaminio G, et al. Flexner revisited: the role and value of the basic sciences in medical education. Acad Med 2010; 85:349–355. 10. Eisenstein A, Vaisman L, Johnston-Cox H, et al. Integration of basic science and clinical medicine: the innovative approach of the cadaver biopsy project at the Boston University School of Medicine. Acad Med 2014; 89:50– 53. 11. Bell FE, 3rd, Wilson LB, Hoppmann RA. Using ultrasound to teach medical students cardiac physiology. Adv Physiol Educ 2015; 39:392–396. 12. Boffano P, Roccia F, Campisi P, et al. Review of 43 osteomas of the craniomaxillofacial region. J Oral Maxillofac Surg 2012; 70:1093–1095. 13. Laor T, Jaramillo D. MR imaging insights into skeletal maturation: what is normal? Radiology 2009; 250:28–38.
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