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On the Horizon From the ORS

Silva, Matthew J. PhD; Burr, David B. PhD; T. Nelson, Fred R. MD; Flynn, Michael PhD

JAAOS - Journal of the American Academy of Orthopaedic Surgeons: January 2009 - Volume 17 - Issue 1 - p 56–59

Topics from the frontiers of basic research presented by the Orthopaedic Research Society.

Dr. Burr or a member of his immediate family has received research or institutional support and nonincome support (such as equipment or services), commercially derived honoraria, or other non-research-related funding (such as paid travel) from Eli Lilly and the Alliance for Better Bone Health; has received royalties from Springer and CRC press; and is a consultant to or an employee of Eli Lilly, the Alliance for Better Bone Health, and PharmaLegacy. Dr. Nelson or a member of his immediate family has received research or institutional support from Stryker, is an unpaid consultant for IVIVI, and has received other financial or material support from the publisher Elsevier. None of the following authors or a member of their immediate families has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Silva and Dr. Flynn.

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How Stress Fractures Heal: The Role of the Periosteum

The sequence of events that leads to a stress fracture is not precisely known. Clearly, repetitive loading that generates high bone strains and produces bone damage is a prerequisite condition. It is reasonable to postulate that a stress fracture will develop if the rate of damage removal does not keep pace with the rate of damage accumulation.1 This supposition focuses on intracortical events in the development of a stress fracture, but it does not address how a stress fracture heals.

Clinicians are well aware that a healed stress fracture exhibits a hard periosteal callus. A series of recent studies in the rat provides insight into the regulation of this periosteal callus formation. These studies rely on an in vivo loading model by which the rat forelimb is repetitively loaded in axial compression until the ulna develops an acute stress fracture, the severity of which can be controlled by limiting the forelimb displacement.2,3 Within 7 days after generation of an ulnar stress fracture, periosteal woven bone forms in proportion to the severity of the stress fracture.4 Bones that sustain a relatively minor stress fracture (˜10% loss of strength) exhibit a small woven bone response; bones that sustain a severe stress fracture (˜60% strength loss) exhibit a much greater woven bone response. This modulation of the bone formation response results in strength recovering within 14 days, regardless of initial stress fracture severity. These findings support the concept that periosteal woven bone formation provides rapid stabilization of the bone structure, which enables function while the slower process of intracortical remodeling repairs the internal bone damage.

A critical component of this healing response is a proportional increase in periosteal vascularity before bone deposition.5 The vasculature may serve as a template for bone formation, as it does in intramembranous bone formation in distraction osteogenesis. Given the robust vascular response seen in this model of a healing stress fracture, it is not surprising that clinical cases of problematic stress-fracture healing are often associated with compromised vascularity.

The molecular factors that coordinate the angiogenic-osteogenic response to a stress fracture have been recently described.6 As expected, there is early upregulation (within 1 hour) of genes associated with angiogenesis (eg, vascular endothelial growth factor). One to 3 days after stress fracture, genes associated with osteogenesis (eg, osterix, bone sialoprotein) are significantly upregulated and localized to subperiosteal bone-lining cells. Intriguingly, bone morphogenetic protein-2 (BMP-2) is upregulated within 1 hour after stress fracture and is initially localized to neurovascular bundles in the periosteum, followed by localization to subperiosteal bone-lining cells on day 1. Thus, BMP-2 may be an important early response gene in the initiation of periosteal woven bone formation in a healing stress fracture. Many of the histologic and molecular features of the healing stress fracture are similar to the intramembranous portion of fracture repair, suggesting that woven bone repair of a stress fracture may be an abbreviated fracture healing response that does not involve endochondral ossification.

Matthew J. Silva PhD

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Is Bisphosphonate Therapy a Risk Factor for Subtrochanteric Femoral Fractures?

Recently, several groups have reported an apparent increase in the incidence of subtrochanteric femoral fractures, especially in osteopenic women who are being treated with alendronate for osteoporosis.7-10 These femoral fractures do not seem to be associated with high-energy trauma, but they have the radiologic appearance of stress fractures. There is evidence from some radiographs of periosteal woven bone formation along the medial or lateral cortex of the femur, indicative of an attempt at repair before the frank fracture. Although epidemiologic data on subtrochanteric femoral fractures is not extensive (and although the terminology used to describe femoral fractures is often confusing and inconsistent), low-energy subtrochanteric fractures are not infrequent in postmenopausal women. Estimates place the prevalence without bisphosphonate treatment at about 7 per 100,000 person-years in women aged 55 to 74 years and at 34 to 74 per 100,000 person-years in women older than age 75 years.11

Nevertheless, concern exists that there is an association between long-term treatment with alendronate and these fractures. A fair amount of circumstantial evidence supports an association between bisphosphonates (BPs) and subtrochanteric femoral fractures. Suppression of bone remodeling by BPs prevents the repair of microdamage and may allow accumulation and coalescence of microcracks to the point of frank fracture. The radiologic signs of periosteal reaction at the fracture site, which must have occurred before fracture, is putative evidence that there was damage to the bone and an attempt at repair before fracture. Studies in animal models have shown that remodeling suppression by BPs can result in a four- to sevenfold increase in microdamage in some bones (eg, vertebrae, ribs, iliac crest) and that this increase is associated with a 20% to 40% reduction in the energy required to fracture.12-15

Analysis of human iliac crest biopsies have also suggested that microdamage will accumulate following an average 5-year treatment period with alendronate,16 especially in patients with low bone mineral density. The average length of treatment with alendronate in women who presented with subtrochanteric femoral fractures was about 4 years.8,10 However, animal studies have not been able to demonstrate cause and effect between microdamage accumulation and reduced energy to fracture.15,17 The latest studies in an animal model show that changes in tissue mechanical properties occur without a change in microdamage accumulation after 3 years of BP treatment.15

However, it is well known that as bone tissue ages (a natural consequence of remodeling suppression), it accumulates advanced glycation end products (AGEs), which are the products of processes leading to nonenzymatic glycation of the bone tissue. It is also well known that glycation of bone tissue will make the tissue brittle18 and can reduce the deformation that bone undergoes before fracture.19,20 Glycation of bone tissue is a common problem in diabetes and is one reason for the increased risk of fracture in persons with type II diabetes, even though these individuals often do not have low bone mass. Animal studies have shown that BP treatment results in greater AGE accumulation in both cancellous21 and cortical bone22 and have demonstrated that this is associated with more brittle mechanical behavior.

The rate of bone turnover in the femoral shaft is normally quite low (<3% per year, and probably lower); it is difficult to believe that a small further reduction in turnover could have very serious consequences unless alendronate treatment was directly affecting preexisting bone. Some of the case reports describe biochemical markers and biopsy data, although there is nothing approaching what could be called a statistically valid sample of either.23,24 What clearly emerges from these studies is that remodeling is low, which is not surprising, given that the patients were being treated with alendronate. But in some patients, the remodeling rate may have been excessively low, with no indication of active osteoclasts, little osteoid, and no fluorescent labels that would indicate active mineralizing surfaces. This excessively low remodeling rate suggests that before a patient is given a BP, biomarkers related to bone resorption and formation should be measured from serum and urine, with periodic follow-up assessments done of the biomarkers to determine that some bone turnover is occurring.

The first step toward understanding this problem may be to ensure that the reported cases of subtrochanteric fracture truly represent something out of the ordinary. The fact that, in one study,10 36% of the fracture patients were on alendronate is not surprising given that nearly all of the patients (84%) were female; understandably, many of them were taking a BP. What is unclear in this study is how many patients on BPs were seen at this site over the same retrospective period. Knowing this number might allow some estimate to be made of the actual incidence. One difficulty with the data is that significant confounding morbidities exist that are known to be related to cortical bone fractures. Some of the subjects in the study who presented with fractures also had diabetes, which could confound the problem of glycation, as discussed above. Others were being treated with glucocorticoids for various conditions; glucocorticoids are known to suppress osteoblastic bone formation and can be associated themselves with osteoporotic conditions. This makes it impossible to separate out the role BPs may play in these patients.

Therefore, before we spend too much time considering the possible pathogenesis of these fractures, it is necessary to determine both the actual extent of the problem and the true prevalence of subtrochanteric fractures in women who are taking anticatabolic medications for osteoporosis. These data should be accompanied by serum and urine biomarker data, iliac crest biopsies (when possible), and a description of comorbid conditions accompanying the fracture.

David B. Burr PhD

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Tomosynthesis in Musculoskeletal Care

In the 1930s, conventional geometric tomography was used to help define nonunions and other bone changes that were hard to image. The x-ray tube and image receptor moved in synchrony on opposite sides of the patient to produce an image of structures in relatively sharp focus at the plane containing the fulcrum of the motion. Structures above and below the fulcrum plane were blurred and less visible. Typically, the slices were 0.5-cm thick, and the in-plane picture had considerable scatter.25 The lack of accuracy for determining nonunion versus delayed union limited the value of the study.

Computed tomography (CT), which became popular in the 1970s, records the x-ray attenuation for multiple beams of radiation. By doing this in a complete circle of 360°, CT allows us to reconstruct the material attenuation coefficient, a material property dependent on density and composition, for numerous points in a two-dimensional plane image. This reduces scatter and allows for thinner slices. However, the radiation exposure is far greater than that of conventional radiographs.

Tomosynthesis significantly improves on conventional geometric tomography by allowing an arbitrary number of in-focus planes to be generated retrospectively from a sequence of projection radiographs that are acquired during a single motion of the x-ray tube. Using computerized reconstruction methods similar to CT, tomosynthesis allows specific planes to be reconstructed in good detail and with minimal out-ofplane artifacts.25 Early applications of tomosynthesis included angiography, chest imaging, mammography, dental imaging, and orthopaedic imaging.

Mermuys et al26 note that, in 2003, tomosynthesis was used to determine the presence of a scaphoid fracture not seen on conventional radiographs. In their study,26 the authors used tomosynthesis to image a healing fracture of the scaphoid with a surgical fixation screw in place. Normally the scatter of standard CT would obliterate that detail. Tomosynthesis is now being used in the investigation of knee osteoarthritis in which insufficiency fractures, early bone matrix changes, and contour deformities may occur rapidly.27 The protocol has been refined so that there is depth localization, improved conspicuity of structures, and improved contrast of local structures. The advantages over CT include improved spatial resolution, lower radiation dose, and avoidance of metal artifacts. Advantages over magnetic resonance imaging include better spatial resolution of bone detail and reduced cost. All of these may allow for improved and more efficient diagnosis of skeletal pathology.

As the technique is refined for musculoskeletal imaging, it will allow for quantification of bone changes associated with osteoarthritis. This improvement will make tomosynthesis a powerful tool that can be used to define the relationships of metabolic changes in cartilage with those in bone, as well as the relationship of bone changes to cartilage. This will be particularly true in circumstances in which both magnetic resonance and tomosynthesis images are concurrently available.

Fred R. T. Nelson MD

Michael Flynn PhD

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5. Matsuzaki H, Wohl GR, Novack DV, Lynch JA, Silva MJ: Damaging fatigue loading stimulates increases in periosteal vascularity at sites of bone formation in the rat ulna. Calcif Tissue Int 2007;80:391-399.
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27. Ksar J, Flynn M, Lange K, Nelson F, van Holsbeeck M: Digital tomosynthesis: A new radiographic technique for orthopedic imaging. AJR Am J Roentgenol 2007;188:A172.
© 2009 by American Academy of Orthopaedic Surgeons