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New Hope for New Bone After Osteomyelitis Debridement

Osteomyelitis Tibia for OBuzzThis basic science tip comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

One clinical frustration following osteomyelitis debridement is poor bone healing. Impaired bone homeostasis provokes serious variations in bone remodeling that involve multiple inflammatory cytokines.

The chemokines CCL2, CCL3, and CXCL2 are known to be strong chemoattractants for neutrophils during inflammatory states, and they play a role during osteoclastogenesis. B cells are also activators of osteoclastognesis and are regulated, in part, by tissue inhibitor of metalloprotease 1 (TIMP-1).

Researchers drilled a 1 mm hole into the proximal tibia of 126 mice. In half of the mice (63), a dose of S. aureus was injected into the canal, while the controls had no bacteria injected. At two weeks, all proximal tibiae were debrided; cultures were taken 3 and 7 days after debridement to assure no residual infection. Cytokine assays and Western blots for CCL2, CCL3, CXCL2, TIMP-1, RANKL, and TNF-α were performed in selected mice in each group. Flow cytometry and histology were also done in selected mice in each group.

In the osteomyelitis group, Western blot analysis identified increased levels of CCL2, CCL3, and CXCL2. Histology revealed increased osteoclastogenesis after osteomyelitis debridement, with calcitonin-receptor and RANKL detection via immunohistochemical and fluorescence staining. There was diminished osteogenesis and proliferation in the osteomyelitis group, but TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Flow cytometry revealed elevated B cell activity in the osteomyelitis group, with subsequent increased osteoclast activity and accelerated bone resorption.

The researchers propose a RANKL-dependent osteoclastogenesis after debridement for osteomyelitis that is associated with elevated B cells and decreased osteogenesis. These findings could lead to new interventions to improve bone healing during the course of osteomyelitis treatment, particularly following debridement.

Reference
Wagner JM, Jaurich H, Wallner C, Abraham S, Becerikli M, Dadras M, Harati K, Duhan V, Khairnar V, Lehnhardt M, Behr B. Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity. J Orthop Res. 2017 Mar 6. doi: 10.1002/jor.23555. [Epub ahead of print] PMID: 28263017

Pulsatile Lavage Harms Muscle in Rat Model of Blast Injury

Rat Limb for OBuzzBasic science investigations into clinically relevant orthopaedic conditions are very common—and often very fruitful. What’s not very common is seeing results from large, multicenter randomized trials published in the same time frame as high-quality in vivo basic-science research on the same clinical topic.

But the uncommon has occurred. In the November 1, 2017 issue of The Journal, Chiaramonti et al. present research on the effects of 20-psi pulsatile lavage versus 1-psi bulb-syringe irrigation on soft tissue in a rat model of blast injuries. With support from the US Department of Defense, Chiaramonti et al. developed an elegant animal study that found radiological and histological evidence that lavage under pressure—previously thought to be critical to removing contamination in high-energy open fractures—results in muscle necrosis and wound complications.

Although none of the rats developed heterotopic ossification during the 6-month study period, the authors plausibly suggest that the muscle injury and dystrophic calcification they revealed “may potentiate the formation of heterotopic ossification by creating a favorable local environment.” Heterotopic ossification is an unfortunately common sequela in patients who suffer blast-related limb amputations.

The aforementioned rare alignment between basic-research findings and clinical findings in people relates to a large multicenter randomized clinical trial recently published in The New England Journal of Medicine. That study found that one-year reoperation rates among nearly 2,500 patients treated surgically for open-fracture wounds were similar whether high, low, or very low irrigation pressures were used. This is a case where the clinical advice from basic-study authors Chiaramonti et al. to keep “delivery device irrigation pressure below the 15 to 20-psi range” when managing open fractures is based on very solid ground.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

“Phenotype” Redefined in Osteoarthritis Research

Osteoarthritis for BSTOTWThis basic science tip comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Over the decades, the meaning of the term “phenotype” has changed. In the past it was solely applied to inherited disorders and was based on physical appearance or clinical presentation. Similarly, the term “penetrance” was applied to the variations in phenotype severity relative to normal. Over time, it has been found that penetrance is usually a reflection of different mutations for the same gene at different parts of the allele, or a mutation in one of several specific genes that could contribute to a similar phenotype.

Now, both terms have been applied to a variety of genetic and environmental circumstances that may affect physical appearance and function. In osteoarthritis research, the term “phenotype” has increasingly been used to define physical, genetic, environmental, and other variables, both past and present.

The authors of a recent abstract use a modern application for the term phenotype to systematically review the literature for studies using knee characteristics relevant for phenotyping osteoarthritis (OA).1 A comprehensive search was performed limited to observational studies of individuals with symptomatic knee OA that identified phenotypes based on OA characteristics, and then the authors assessed phenotypic association with clinically important outcomes.

Based on their abstract, 34 of 2777 citations were included in a descriptive synthesis of the data. Clinical phenotypes were investigated most frequently, followed by laboratory, imaging, and etiologic phenotypes. Eight studies defined subgroups based on outcome trajectories (pain, function, and radiographic progression). Most studies used a single patient or disease characteristic to identify subgroups, while five included characteristics from multiple domains.

Evidence from multiple studies suggested that pain sensitization, psychological distress, radiographic severity, BMI, muscle strength, inflammation, and comorbidities are associated with clinically distinct phenotypes. Gender, obesity and other metabolic abnormalities, the pattern of cartilage damage, and inflammation may delineate distinct structural phenotypes. However, only a few of the 34 studies reviewed investigated the external validity of the chosen phenotypes or their prospective validity using longitudinal outcomes.

While the authors remarked on the heterogeneity of the data included in studies investigating knee OA phenotypes, they say that the phenotypic characteristics identified in their review could form a classification framework for future studies investigating OA phenotypes.

It should be noted that the FRAX score used to calculate fragility fracture risk could be considered a phenotypically based system, the validation of which is continuing.

Reference

  1. Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis 2017 Aug 25. pii: S1063-4584(17)31156-1. doi: 10.1016/j.joca.2017.08.009. [Epub ahead of print].

JBJS Classics: Porous-Coated Hip Components

JBJS Classics Logo.pngOrthoBuzz regularly brings you a current commentary on a “classic” article from The Journal of Bone & Joint Surgery. These articles have been selected by the Editor-in-Chief and Deputy Editors of The Journal because of their long-standing significance to the orthopaedic community and the many citations they receive in the literature. Our OrthoBuzz commentators highlight the impact that these articles have had on the practice of orthopaedics. Please feel free to join the conversation by clicking on the “Leave a Comment” button in the box to the left.

In their classic 1987 publication, Drs. Charles Engh, Dennis Bobyn, and Andrew Glassman described clinical and radiographic results of a series of 307 hips with 2-year follow-up, and 89 hips with 5-year follow-up after total hip arthroplasty in which the patients had received an extensively porous-coated femoral stem. The authors also described histologic evaluation of 11 hips retrieved at autopsy or revision.

By 1987 the same authors as well as other investigators had already published observations concerning the influence of femoral stem size, shape, stiffness, and porosity on clinical and radiographic evidence of fixation and stress shielding in humans and animal models.1,2 But this study, which so far has been cited more than 1500 times, goes “above and beyond” by carefully correlating previous observations with histologic sections obtained through human femora.

Among other achievements, Engh et al. described radiographic criteria for categorizing a femoral implant as either stable by bone ingrowth, stable by fibrous tissue ingrowth, or unstable. Implants thought to be stable by fibrous ingrowth had a prominent radio-opaque line around the stem, separated from the implant by a radiolucent space up to 1 mm in thickness. This line was thought to represent a shell of bone with load-carrying capability. However, histology demonstrated that the space between the shell and the implant was composed of dense fibrous tissue. When the shell was present, there tended to be little hypertrophy or atrophy of the adjacent femoral cortex.

Engh et al. noted that radiographs and histology of hips with extensive ingrowth from the endosteum often showed parallel increased porosity of the adjacent cortex – an early manifestation of stress shielding. Overall, 259 (84%) of the femoral stems had radiographic findings suggestive of bone ingrowth, 42 (13%) had findings interpreted as stable fibrous ingrowth, and 2% were thought to be unstable (but not yet revised at the time of the study). Stress shielding was much more common in larger-diameter stems and those with good bone ingrowth compared to smaller implants or those with stable fibrous fixation.

Why do we consider this manuscript a classic? First, the authors include a careful correlation of histology with radiographic and clinical findings, helping illustrate the importance of tight press fit at the isthmus to achieve proximal fixation. The authors also document intracortical porosity as the morphologic manifestation of stress shielding and emphasize the impact of a small increase in stem diameter on axial rigidity.

Designs of femoral stems have evolved considerably since the 1980s,3 and the findings described in this paper helped validate fundamental principles related to load transmission and bone remodeling4-6 and thus helped advance that evolutionary process.

Thomas W. Bauer, MD, PhD
JBJS Deputy Editor

References

  1. Bobyn JD, Pilliar RM, Binnington AG, Szivek JA. The effect of proximally and fully porous-coated canine hip stem design on bone modeling. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 1987;5:393-408.
  2. Bobyn JD, Pilliar RM, Cameron HU, Weatherly GC. The optimum pore size for the fixation of porous-surfaced metal implants by the ingrowth of bone. Clinical orthopaedics and related research 1980:263-70.
  3. McAuley JP, Culpepper WJ, Engh CA. Total hip arthroplasty. Concerns with extensively porous coated femoral components. Clinical orthopaedics and related research 1998:182-8.
  4. Huiskes R. Validation of adaptive bone-remodeling simulation models. Stud Health Technol Inform 1997;40:33-48.
  5. Huiskes R, Weinans H, Dalstra M. Adaptive bone remodeling and biomechanical design considerations for noncemented total hip arthroplasty. Orthopedics 1989;12:1255-67.
  6. Weinans H, Huiskes R, Grootenboer HJ. Effects of fit and bonding characteristics of femoral stems on adaptive bone remodeling. J Biomech Eng 1994;116:393-400.

JBJS Case Connector Debuts Whole-Slide Images

WSI_Image_2016-10-04.png It is not often that readers of scholarly journals have a “Wow!” moment, a chance to be unexpectedly delighted by a new discovery.1 In the September 14, 2016 edition of JBJS Case Connector, Zhang et al. provide readers of the JBJS family of journals the first of what we hope will be many such moments: the ability to link to and navigate a digital, whole-slide image (WSI) of an entire microscope slide.

Fig_1_for_WSI_OBuzz_2016-10-04_1533.png

Figure 1

Illustrating the histology of tumors and the tissue-level details in basic science studies has long been a challenge. Until recently, readers were usually subjected to the few fields of view that the author chose to photograph. The more senior among you may remember with nostalgia attempting to make sense of fuzzy, black-and-white, circular, histology images viewed as if seen through an antique monocular microscope (Fig. 1).  The advent of color printing (often at the author’s extra expense) and eventually digital photographs improved somewhat the quality of each image, but readers were still required to accept that the author had selected fields of view that were truly representative of the subject matter.

In their case report titled “Morphological Transformation of Giant-Cell Tumor of Bone After Treatment with Denosumab,” Zhang et al. include two links to whole-slide images. In the first, readers can link from a conventional digital photograph of a core needle biopsy to the whole-slide image of the giant cell tumor. The authors also include several conventional photographs of the tumor after resection, along with a link to the corresponding scanned microscope slide.

The use of a viewing algorithm similar to that used by Google Earth allows readers to navigate and zoom in on not just the few isolated fields of view selected by the authors, but the hundreds to thousands of additional fields contained in the original microscope slide of this complicated tumor. While it’s very helpful for illustrating tumor histology, we anticipate that WSI technology will be even more valuable when applied to basic science studies of fracture healing or cartilage, nerve, and tendon repair—as well as many other possible applications.

Thomas Bauer, MD
JBJS Case Connector Co-Editor

Reference

  1. Glassy EF, Rebooting the Pathology Journal. Learning in the Age of Digital Pathology. Archiv Pathol Lab Med 2014;138:728-729.