Nontraumatic Osteonecrosis: An Early Target for Gene Therapy
As osteonecrosis of the femoral head (ONFH) progresses, it can impair a patient’s ability to walk, and hip arthroplasty is often the only effective long-term option. Other interventions to relieve the pain of ONFH include surgical decompression of the femoral head, which is generally effective but often does not change the natural history of the process. Once the femoral head collapses and loses sphericity, degenerative arthritis of the hip follows quickly. Well-documented risk factors for ONFH include excessive alcohol consumption and corticosteroid use. But why do some patients with these risk factors develop osteonecrosis, while others do not.
In the September 16, 2020 issue of The Journal, Zhang et al. address that clinical quandary with a genomewide association study on a chart-reviewed cohort of 118 patients with ONFH and >56,000 controls. The findings shed light on what is obviously a condition with multifactorial etiology and complex gene-environment interactions. The case-control study identified 1 gene (PPARGC1B) and 4 single nucleotide variants associated with ONFH overall, and with 2 subgroups—those exposed to corticosteroids and those with femoral head collapse. Steroid intake was highly prevalent in both cohorts—90.7% of the ONFH patients had at least one 3-week course of corticosteroids, compared with 68.3% of controls.
For readers interested in the detailed genetic bases for osteonecrosis, this study offers a treasure trove of data. But for all of us, these findings, after they are verified in other populations, may very well form the basis for pharmacologic and gene-modifying strategies in patients at risk for ONFH. Moreover, osteonecrosis of the femoral head is just one of many musculoskeletal conditions that can probably be addressed with this type of genome-based research strategy.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
What Affects Symptoms in Kids with Flatfoot?
Pes planovalgus (flatfoot) is a common condition seen in the pediatric orthopaedic clinic. We who help manage this condition differentiate it from adult acquired flatfoot deformity, primarily in that most child and adolescent patients remain asymptomatic or minimally symptomatic and rarely require surgical intervention. However, it would be nice to have data to share with young patients and their parents regarding factors associated with flatfoot symptoms.
Min et al. provide some of that data in the September 2, 2020 issue of The Journal. The authors retrospectively evaluated factors affecting the symptoms of idiopathic pes planovalgus among 123 patients (mean age of 10.1 ± 3.2 years) using the 4-domain Oxford Ankle Foot Questionnaire (OxAFQ) administered to patients and their parents. They compared questionnaire scores to 3 radiographic measurements─anteroposterior (AP) talo-first metatarsal angle, lateral talo-first metatarsal angle, and hallux valgus angles. They also analyzed the scores in relation to patient age and sex.
Min et al. found that the physical domain score for the child-reported OxAFQ decreased by 0.74 with each 1° increase in the AP talo-first metatarsal angle. Because that angle is a surrogate for forefoot abduction, this finding portends worse patient-reported outcomes in kids with greater severity of that component of flatfoot. Female sex was also associated with lower physical domain scores, with the authors postulating that this might be attributable to culturally influenced sex differences.
In addition, age was a significant factor in 3 domains of the OxAFQ. Compared with scores from younger kids, children ≥10 years old and their parents reported statistically worse outcomes with regard to school/play, emotional well-being, and footwear. In other words, at or beyond the age of 10, flatfoot deformity seems to significantly affect the patient’s choice of footwear, interferes with the ability to participate in sports and play, and may cause personal distress, such as that which comes from being teased about foot appearance.
Orthopaedists can help manage most cases of pediatric flatfoot with sound footwear recommendations and reassurance. But it appears that in the setting of increased forefoot abduction, female sex, and symptoms that persist past the age of 10 years, further investigation may be warranted. Although this study has weaknesses, it shows that there may be detriments─both physical and emotional─associated with pes planovalgus in pediatric patients that should not be ignored.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
New Surgical Approaches Still Welcome
JBJS has long promoted the use of high-level studies to facilitate evidence-based decision making. Still, each year only approximately 10% to 12% of published articles provide Level-I evidence. Although that percentage is increasing, the slope of the upward curve is gentle, largely because of the difficulty in designing and conducting randomized controlled trials (RCTs), and in gathering enough data from existing RCTs to conduct Level-I meta-analyses. The challenge of designing and conducting Level-I studies in orthopaedic surgery is compounded by our need to treat many conditions that are not common enough to make a controlled trial feasible. Consequently, there will always be room for Level-III and Level-IV research in the pages of The Journal (see related JBJS Editorial).
A Level-IV study that focuses on a surgical approach is rare, but in the September 2, 2020 issue of JBJS, Liu et al. describe preliminary results from a new concealed-incision, extrapelvic surgical approach to the anterior pelvic ring. This so-called “Fu-Liu approach” was investigated to treat pubic symphysis diastasis and parasymphyseal fractures, including those of the anterior column. Among the advantages of this approach over the more traditional Pfannenstiel approach are the following:
- Easier protection of the spermatic cord in males and the round ligament of the uterus in females
- Less risk to peritoneal internal organs, iliac blood vessels, and femoral nerves
- Improved aesthetic outcomes (The 2 small incisions are ultimately covered under perineal hair.)
- Relatively short learning curve
As our field continues to innovate toward less-invasive surgical interventions, such creative approaches are welcome. What we need now are comparative trials focused on this surgical approach versus the time-honored Pfannenstiel approach to convince surgeons and assure patients that the Fu-Liu approach yields limited complications and equal or better radiographic and patient-reported functional outcomes.
Because the conditions to which this approach can be applied are quite variable, such a trial would likely have to be multicenter and focused on pure, open-book, isolated pelvic fractures. We look forward to receiving and reviewing the manuscript describing an adequately powered trial that directly compares these two approaches.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Sustained Fevers After Spinal Fusion: A Sentinel for Infection?
Postoperative fevers occur frequently. During the first 2 to 3 days after surgery, these fevers are often due to atelectasis or the increased inflammatory response that arises from tissue injury during surgery. However, persistent postoperative fevers should be cause for concern. In the August 19, 2020 issue of The Journal, Hwang et al. examine the relationship between sustained fevers after spine instrumentation and postoperative surgical site infection.
The authors retrospectively reviewed 598 consecutive patients who underwent lumbar or thoracic spinal instrumentation. They excluded patients who underwent surgery to treat tumors or infections and those with other identified causes of fever, such as a urinary tract infection or pneumonia. Sustained fevers were defined as those that began on or after postoperative day (POD) 4 and those that started on POD 1 to 3 if they persisted until or beyond POD 5.
Sixty-eight patients (11.4%) met the criteria for a sustained fever after spinal instrumentation. Nine of those 68 (13.2%) were diagnosed with a surgical site infection. Of the 530 patients who did not have a sustained fever, only 5 (0.9%) developed a surgical site infection (p<0.001 for the between-group difference).
Further analysis revealed 3 diagnostic clues for surgical site infections among the patients with sustained fevers:
- Continuous fever (rather than cyclic or intermittent)
- Levels of C-reactive protein (CRP) >4 mg/dL after POD 7
- Increasing or stationary patterns of CRP level and neutrophil differential
In addition, the authors found that CRP levels >4 mg/dL between PODs 7 and 10 had much greater sensitivity for discriminating surgical site infection than gadolinium-enhanced magnetic resonance imaging data obtained within 1 month of the surgical procedure.
Although a vast majority (87%) of patients with sustained postoperative fevers in this study did not develop an infection, persistent fever after spine instrumentation surgery is something to be mindful of. The authors describe their findings as “tentative” and advise readers to interpret them with caution. Those caveats notwithstanding, I consider this information to be valuable because it might help prevent delays in the diagnosis of a potentially serious perioperative complication.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
Drug to Improve Tibial Shaft Fracture Healing Fizzles
In our ongoing attempt to identify pharmacologic interventions that improve fracture healing, the sclerostin inhibitor romosozumab is a logical candidate, as it has been shown to decrease bone resorption, improve bone healing in animal and human studies, and reduce the prevalence of some fragility fractures in postmenopausal women. In the August 19, 2020 issue of The Journal, Bhandari et al. present the results of a randomized trial comparing romosozumab to placebo in the healing of tibial diaphyseal fractures treated with intramedullary (IM) nails. Tibial shaft fractures are common in adults, but even after IM nail fixation there is a significant rate of healing failure and subpar functional outcomes with this fracture type.
The study by Bhandari et al. was very well designed and conducted with high-quality data collection. In terms of the primary outcome—median time to radiographic healing—there was no significant difference between the placebo group (n=100) and 9 romosozumab groups (n=293 total, testing 3 different dose levels and 3 different frequencies). Additionally, analysis revealed no differences between placebo and romosozumab groups in median time to clinical healing or in changes in physical function from baseline. (See related OrthoBuzz post about a recent randomized trial investigating romosozumab for hip fractures.)
Kudos to Amgen for funding the trial and for allowing the 66-center, international academic consortium that conducted it to publish the results, warts and all. Such negative findings appropriately inform decisions about which compounds to investigate and about study designs for retesting the same compounds. For example, Bhandari et al. encourage further study of romosozumab in tibial-fracture patients at high risk of poor fracture healing, such as those with diabetes or patients undergoing treatment with corticosteroids.
We are likely to see many such “failures” in the search for pharmacological adjuncts to improve fracture healing, but it seems our orthopaedic community has laid out a clear roadmap for studying this important question further.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Treating Developmental Hip Dislocations Diagnosed after Walking Age
There is a wry saying in academic medicine that “nothing ruins good results like long-term follow-up.” But long-term follow-up helps us truly understand how our orthopaedic interventions affect patients. This is especially important with procedures on children, and the orthopaedic surgeons at the University of Iowa have been masterful with long-term outcome analysis in pediatric orthopaedics. They demonstrate that again in the August 5, 2020 issue of The Journal, as Scott et al. present their results comparing outcomes among 2 cohorts of patients who underwent treatment for developmental hip dislocations between the ages of 18 months and 5 years—and who were followed for a minimum of 40 years.
Seventy-eight hips in 58 patients underwent open reduction with Salter innominate osteotomy, and 58 hips in 45 patients were treated with closed reduction. At 48 years after reduction, 29 (50%) of the hips in the closed reduction cohort had undergone total hip arthroplasty (THA), compared to 24 (31%) of hips in the open reduction + osteotomy group. This rate of progression to THA nearly doubled compared to previously reported results at 40 years of follow-up, when 29% of hips in the closed reduction group and 14% of hips in the open reduction group had been replaced.
In addition, the authors found that patient age at the time of reduction and presence of unilateral or bilateral disease affected outcomes. Patients with bilateral disease who were treated at 18 months of age had a much lower rate of progression to THA when treated with closed reduction, compared to those treated with open reduction—but the opposite was true among patients with bilateral disease treated at 36 months of age. Treatment type and age did not seem to substantially affect hip survival among those with unilateral disease.
I commend the authors for their dedication to analyzing truly long-term follow-up data to help us understand treatment outcomes among late-diagnosed developmental hip dislocations in kids. Long-term follow-up may “ruin” good results, but it gives us more accurate and useful results. And, in this case, the findings reminded us how important it is to diagnose and treat developmental hip dislocations as early in a child’s life as possible.
Read the JBJS Clinical Summary about this topic.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
Validity of Non-English PROMs to Assess TKA
Patient-reported outcome measures (PROMs) have become increasingly important tools in the 30 years since the orthopaedic community began embracing the movement toward the “patient perspective.” Clinical findings such as range of motion and imaging results remain important, but we have come to understand that pain and function–as reported by the patient–are the most crucial data points. And we are not alone. Insurance companies, registries, scholarly publications, and research review panels now often require PROMs as part of their core evaluations.
But not all PROMs are created equal. For clinicians to trust the output from these instruments, validation of the measures is required. This entails reliability testing and assessment of face, construct, and criterion validity. Furthermore, translating PROMs validated in English into other languages involves not only linguistic translation, but also cultural components in order to capture the full patient perspective.
In the August 5, 2020 issue of The Journal, Bin Sheeha et al. report their work in evaluating the responsiveness, reliability, and validity of the Arabic-language version of the Oxford Knee Score (OKS-Ar). After painstaking statistical analysis of OKS-Ar questionnaires completed by 100 Arabic-speaking patients (80 of whom were female) before and after total knee arthroplasty (TKA), the authors concluded that the OKS-Ar is a valid, sensitive, and easy-to-use instrument to assess pain and function in TKA-treated individuals whose main language is Arabic.
To be truthful, this is not very glamorous research to conduct or very exciting to read about. However, it is absolutely fundamental to ensuring the validity of multicenter, international trials and registry studies. In essence, Bin Sheeha et al. have dug a conduit that facilitates the flow of reliable data and that will help improve future patient care worldwide. As such, it deserves our attention, understanding, and appreciation.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Complex Reconstructions Call for Creative Solutions
Metastatic disease around the acetabulum often leads to patients needing total hip arthroplasty (THA), plus supplementary acetabular reconstruction. Traditional methods such as the Harrington reconstruction technique have shown good short-term outcomes, but there are concerns that a cemented acetabular component in this setting is at risk for failure in the longer term. Newer approaches, such as using cementless tantalum acetabular components with augments, have also shown promise. Houdek et al. compared these 2 approaches and report the findings in the July 15, 2020 issue of The Journal.
The authors followed 115 patients who underwent THA for metastatic disease at 2 tertiary sarcoma centers, with a mean 4-year follow-up among surviving patients. They compared the outcomes of 78 Harrington reconstructions with those of 37 tantalum reconstructions, with surgeons at each center exclusively performing 1 of the 2 techniques. The cohorts were comparable at baseline regarding age, sex, severity of systemic disease and acetabular defects, and pelvic discontinuity. Functional outcomes improved in both groups, but there were no significant between-group differences. The main statistical finding of the study was that a higher percentage of patients in the Harrington reconstruction group (27%) needed a reoperation than those in the tantalum group (8%), with a hazard ratio of 4.59 (p=0.003).
Historically, there has been an understandable lack of long-term follow-up in this fragile patient population; 94 of the 115 patients in this study died of systemic disease progression at an average of 16 months after surgery. Overall patient survival was only 34% at 2 years and 15% at 10 years. Despite these grim mortality numbers, Houdek et al. claim that with advances in treatments for metastatic cancer, patients are living longer and therefore may benefit from more durable acetabular reconstructions.
This study leaves unanswered the question of whether the theoretic advantage of bony ingrowth with tantalum is what accounted for the decreased reoperation rates. As Albert Aboulafia, MD notes in his Commentary on this study, the authors did not review radiographs or postmortem histology to look for evidence of osseointegration. But Houdek et al. do present a potential avenue for further investigation. And what remains clear is that metastatic disease around the hip is a complex problem, and that we as surgeons should continue to investigate promising treatment strategies to improve patient outcomes (even if only palliative) and enhance biological fixation.
Click here for a 4-minute video in which co-author Matthew Houdek explains the rationale for this study.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
The NSAID-Fracture Nonunion Debate Continues
Many animal studies have investigated the impact of nonselective NSAIDs and selective COX-2 inhibitors on fracture healing. Nearly all those experiments focused on chronic drug administration following simulated long-bone fractures. One concern regarding the clinical relevance of those animal studies is that the “fractures” are often created by open means, which results in cortical devascularization and which may not accurately simulate the most common long-bone fracture pathophysiology in humans. Nevertheless, many orthopaedic surgeons have used the results of those animal studies to limit—or even stop—their use of NSAIDs to treat postfracture pain.
In the July 15, 2020 issue of The Journal, George et al. use a large private-insurance database to investigate the association between postfracture prescriptions filled for NSAIDS (both selective COX-2 inhibitors and nonselective types) and the subsequent diagnosis of a nonunion at 1 year postinjury. Administrative database research is more useful for generating hypotheses than for proving or disproving them, and these authors (along with Commentary writer Willem-Jan Metsemakers, MD, PhD) rightly point out that adequately powered randomized trials are needed to more fully address this issue.
Still, I was a bit surprised by the finding that nonselective NSAIDs were not associated with the diagnosis of nonunion while selective COX-2 inhibitors were. It seems to me that, given the sparse and conflicting clinical evidence today, a brief course of NSAIDs for fracture-related pain management should be included for patients while we await answers from studies with more robust research designs.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Patients as Teachers: Surgeons as Students
In the July 1, 2020 issue of The Journal, Dr. C. McCollister Evarts, writes an illuminating “What’s Important” essay about learning from his most difficult cases. He recounts an event early in his career as a medical officer aboard an aircraft carrier, when a fat embolism caused the untimely death of a young adult patient he treated for a closed tibial fracture. This event spurred a lifelong quest for knowledge about surgery-associated emboli, about which cases and literature were sparse at the time (mid-1960s). My quick search of Dr. Evarts’ long list of publications shows that more than 20 of them are related to embolic events, no doubt a direct result of the experience with that seaman many years ago, and with another one of his early-career patients who died of a pulmonary embolism a week after undergoing hip surgery.
We should all look toward our patients to teach us ways to improve our craft. Not every procedure goes as planned, and the day a surgeon stops trying to get better should likely be the day he or she starts contemplating retirement. Dr. Evarts states that “each and every encountered complication should be carefully examined with the goal of ultimately providing better care.”
Instead of fearing complications, orthopaedic surgeons should carefully analyze the root causes of complications as part of their career-long effort to learn and improve. Our patients can be our teachers in these difficult situations, and we should be willing and open students. This teacher-student approach might require a difficult conversation with the patient or their family to understand why the procedure didn’t go as planned or the outcomes weren’t what was envisioned. As Dr. Evarts points out in his essay, “Most family members do not understand what has happened when a complication occurs, and they appreciate an explanation in a face-to-face meeting.”
The adage that “you learn something new every day” is more likely to come true if you pay extra attention to your most difficult cases. As practicing surgeons, we are never “finished.” We should strive to remain teachable students, always learning from our patient-teachers.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
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