Seeking Molecular Signatures of Ectopic Bone Formation
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Impact Science, in response to an article in the November 4, 2020 JBJS.
Among military personnel who sustain blast-related injuries, physicians have observed a dramatic increase in the incidence of heterotopic ossification (HO), a pathology in which bone grows abnormally within soft tissues. This condition is frequently observed in association with burns and nonmilitary orthopaedic trauma, and combat-related HO is now occurring at an exceptionally high frequency of approximately 60%.
HO can range from an asymptomatic, incidental finding to a debilitating condition causing chronic pain and impaired movement. Although symptomatic HO is usually treated with surgical excision, identifying HO early in its development could go a long way toward improving quality of life for those with combat injuries.
Previous studies have suggested that certain microRNAs (miRNAs) play an important role in the formation of post-traumatic HO. A group of US researchers recently hypothesized that specific miRNA “signatures” might be present in the tissues of military personnel soon after a blast injury.
The authors collected 10 tissue samples from injured servicemembers during the surgical debridement of their wounds, about 8 days after the initial injuries occurred. The miRNA profiling of the samples, performed using a real-time polymerase chain reaction array, revealed that the tissues from patients who developed HO had upregulated levels of 6 miRNAs previously thought to take part in various bone-formation processes. Moreover, when some of those miRNAs were introduced into cultures of mesenchymal progenitor cells, the researchers found that 2 specific miRNAs (miR-1 and miR-206) were the most robust osteogenic “enhancers.” Interestingly, those same 2 miRNAs were found to target the downstream transcription factor SOX9, a deficiency of which can lead to a skeletal malformation syndrome.
These findings show that there are indeed early molecular signatures in the tissues of patients whose injuries progress to HO. While these novel insights into the molecular mechanisms underlying the development of HO may open doors to new therapeutic possibilities, Takamitsu Maruyama, PhD, in a commentary on the findings, cautions that modulating miR-1 and miR-206 “could affect not only HO formation but also the bone-healing process.”
Impact Science is a team of highly specialized subject-area experts (Life Sciences, Physical Sciences, Medicine & Humanities) who collaborate with authors, societies, libraries, universities, and various other stakeholders for services to enhance research impact. Through research engagement and science communication, Impact Science aims at democratizing science by making research-backed content accessible to the world.
Cannabis Users Should Disclose Prior to Surgery
Although many patients believe marijuana is an effective agent to treat chronic and nerve pain, the effect of cannabis on acute musculoskeletal pain has been questioned. In an OrthoBuzz post from 2019, we reported findings published in JBJS indicating that, compared with “never users,” patients who reported using marijuana during recovery from a traumatic musculoskeletal injury experienced increases in both total prescribed opioids and duration of opioid use.
At the 2020 annual meeting of the American Society of Anesthesiologists, researchers reported parallel findings. Among 118 patients who underwent open reduction and internal fixation to repair a tibial fracture, 25% reported using cannabis prior to surgery. When researchers compared the patients who had used cannabis with those who had not, they found the following perioperative and postoperative results among the users:
- A higher intraoperative requirement for inhalation anesthetic
- Higher reported pain scores while in the postacute care unit after surgery
- Higher in-hospital postoperative opioid consumption
In a press release about this study, lead author Ian Holmen, MD is quoted as saying, “…it is important for patients to tell their physician anesthesiologist if they have used cannabis products prior to surgery to ensure they receive the best anesthesia and pain control possible.”
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
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
Less Drinking/Smoking Associated with Fewer Hip Fractures
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Shahriar Rahman, MS in response to a recent study in JAMA Internal Medicine.
Hip fractures are an important cause of morbidity and mortality among the elderly population worldwide. However, age-adjusted hip fracture incidence has decreased in the US over the last 2 decades. While many attribute the decline to improved osteoporosis treatment, the definitive cause remains unknown. A population-based cohort study of participants in the Framingham Heart Study prospectively followed a cohort of >10,000 patients for the first hip fracture between 1970 and 2010.
The age-adjusted incidence of hip fracture decreased by 4.4% per year during this study period. That decrease in hip fracture incidence was coincident with a decrease over those same 4 decades in rates of smoking (from 38% in 1970 to 15% by 2010) and heavy drinking (from 7% to 4.5%), with subjects born more recently having a lower incidence of hip fracture for a given age. Meanwhile, during the study period, the prevalence of other hip-fracture risk factors–such as being underweight, being obese, and experiencing early menopause–remained stable.
This study’s findings should be interpreted in light of 2 major limitations. First of all, there was a lack of contemporaneous bone mineral density data across the study period; secondly, all the study subjects were white. Nevertheless, these findings should encourage physicians to continue carefully managing patients who have osteoporosis and at the same time caution them against smoking and heavy drinking.
Shahriar Rahman, MS is an assistant professor of orthopaedics and traumatology at the Dhaka Medical College and Hospital in Bangladesh and a member of the JBJS Social Media Advisory Board.
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
What’s New in Orthopaedic Trauma 2020
Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of OrthoBuzz summaries of these “What’s New” articles. This month, co-author Niloofar Dehghan, MD, selected the 5 most clinically compelling findings from the >20 studies summarized in the July 1, 2020 “What’s New in Orthopaedic Trauma.”
Hip Fracture
—An international randomized controlled trial (RCT) of hip fracture patients ≥45 years of age1 compared outcomes among 1,487 who underwent an “accelerated” surgical procedure (within 6 hours of diagnosis) and 1,483 who received “standard care” (surgery within 24 hours of diagnosis). Mortality and major complication percentages were similar in both groups, but it is important to note that even the standard-care group had a relatively rapid median time-to-surgery of 24 hours.
—An RCT of nearly 1,500 patients who were ≥50 years of age and followed for 2 years2 compared total hip arthroplasty (THA) with hemiarthroplasty for the treatment of displaced femoral neck fractures. There was no between-group difference in the need for secondary surgical procedures, but hip instability or dislocation occurred in 4.7% of the THA group versus 2.4% of the hemiarthroplasty group. Functional outcomes measured with the WOMAC index were slightly better (statistically, but not clinically) in the THA group. Serious adverse events were high in both groups (41.8% in the THA group and 36.7% in the hemiarthroplasty group). Although the authors conclude that the advantages of THA may not be as compelling as has been purported, THA’s benefits may become more pronounced with follow-up >2 years.
—A preplanned secondary analysis of data from the FAITH RCT examined the effect of posterior tilt on the need for subsequent arthroplasty among older patients with a Garden I or II femoral neck fracture who were treated with either a sliding hip screw or cannulated screws. Patients with a posterior tilt of ≥20° had a significantly higher risk of subsequent arthroplasty (22.4%) compared with those with a posterior tilt of <20° (11.9%). In light of these findings, instead of internal fixation, primary arthroplasty may be an appropriate treatment for older patients who have Garden I and II femoral neck fractures with posterior tilt of >20°.
Ankle Syndesmotic Injury
—An RCT that compared ankle syndesmosis fixation using a suture button with fixation using two 3.5-mm screws3 found a higher rate of malreduction at 3 months postoperatively with screw fixation (39%) than with suture button repair (15%). With the rate of reoperation also higher in the screw group due to implant removal, these findings add to the preponderance of recent evidence that the suture button technique is preferred.
Wound Management
—A 460-patient RCT examining the cost-effectiveness of negative-pressure wound therapy4 for initial wound management in severe open fractures of the lower extremity found the technique to be associated with higher costs and only marginal improvement in quality-adjusted life-years for patients.
References
- HIP ATTACK Investigators. Accelerated surgery versus standard care in hip fracture (HIP ATTACK): an international, randomised, controlled trial. Lancet.2020 Feb 29;395(10225):698-708. Epub 2020 Feb 9.
- Bhandari M, Einhorn TA, Guyatt G, Schemitsch EH, Zura RD, Sprague S, Frihagen F, Guerra-Farfán E, Kleinlugtenbelt YV, Poolman RW, Rangan A, Bzovsky S, Heels-Ansdell D, Thabane L, Walter SD, Devereaux PJ; HEALTH Investigators. Total hip arthroplasty or hemiarthroplasty for hip fracture. N Engl J Med.2019 Dec 5;381(23):2199-208. Epub 2019 Sep 26.
- Sanders D, Schneider P, Taylor M, Tieszer C, Lawendy AR; Canadian Orthopaedic Trauma Society. Improved reduction of the tibiofibular syndesmosis with TightRope compared with screw fixation: results of a randomized controlled study. J Orthop Trauma.2019 Nov;33(11):531-7.
- Petrou S, Parker B, Masters J, Achten J, Bruce J, Lamb SE, Parsons N, Costa ML; WOLLF Trial Collaborators. Cost-effectiveness of negative-pressure wound therapy in adults with severe open fractures of the lower limb: evidence from the WOLLF randomized controlled trial. Bone Joint J.2019 Nov;101-B(11):1392-401.
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
JBJS Announces 2019 EST Award Winners
JBJS Essential Surgical Techniques (EST) and The Journal of Bone and Joint Surgery (JBJS) give out two annual awards–one for the best Subspecialty Procedure (SP) article, and the other for the best Key Procedures (KP) video published during each calendar year.
We are pleased to announce the winners for 2019:
- Editor’s Choice Technique Award:
Patellofemoral Arthroplasty
by Anders Odgaard, MD, DMSc, FRCS; Jonathan Eldridge, MD, FRCS; and Frank Madsen, MD - Editor’s Choice Video Award:
Repair of Tibial Plateau Fracture (Schatzker II)
by Dylan T. Lowe, MD; Michael T. Milone, MD; Leah J. Gonzalez, BS; and Kenneth A. Egol, MD
Both articles are freely available online until the end of August 2020.
Submissions for the 2020 EST Awards are currently being accepted.
Preop Nerve Blocks for Hip Fractures – Sooner Is Better
The benefits of peripheral nerve blocks for pain control and decreased use of opioids has been well-established for several orthopaedic procedures. In the May 20, 2020 issue of The Journal, a prospective cohort study by Garlich et al. shows that administering such a block earlier rather than later significantly benefits elderly patients awaiting surgery for a hip fracture.
The authors looked at whether the time to block (TTB) with a fascia iliaca nerve block (FIB) in a cohort of 107 patients who sustained a hip fracture affected preoperative opioid consumption and postoperative pain scores. They also examined the relationship between TTB and length of stay and adverse events related to opioids. All FIBs were performed between the time of emergency department arrival and ≥4 hours prior to surgery. Those parameters allowed time for the block to work and also time for the patients in this cohort to request pain medication.
Preoperatively, 72% of all opioid consumption took place prior to block placement. Patients experiencing a faster TTB consumed fewer opioids preoperatively and also on postoperative days 1 and 2, although the day-2 differences were not statistically significant. More specifically, Garlich et al. found a 63.7% reduction in the median preoperative opioid consumption in those with a TTB <8.5 hours from the time of arrival, relative to those whose TTB was ≥8.5 hours.
In addition, patients with a TTB <8.5 hours had significantly lower pain scores on postoperative day 1, and their hospital stays were significantly shorter than those who received blocks ≥8.5 hours after arrival (4.0 days versus 5.5 days). There were no differences in opioid-related adverse events between the TTB groups, although commentator Dr. Patrick Schottel notes that the study was underpowered to definitively discern those between-cohort differences.
Overall, this important study shows that early preoperative FIB reduces perioperative opioid consumption in geriatric patients with hip fractures, in addition to decreasing their pain scores and length of hospital stay. Further investigation is needed to determine the optimal timing for administering preoperative blocks in this vulnerable population.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
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