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.
Pulsatile Lavage Harms Muscle in Rat Model of Blast Injury
Basic 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
Histology Yields Clues to HO in Injured Service Members
Between 2000 and 2014, 1573 wounded US service members sustained one or more major amputations, and nearly two-thirds of those individuals developed posttraumatic heterotopic ossification (HO). Deciding when to excise HO (which can cause pain and interfere with rehabilitation programs and prosthetic limbs) requires careful consideration, and findings from a study by Isaacson et al. in the April 20, 2016 JBJS may help surgeons and patients faced with that decision.
Using sophisticated microscopy techniques to analyze symptomatic heterotopic bone excised from 33 service members following combat-related trauma, Isaacson et al. determined that mineral apposition rates in the HO specimens averaged 1.7 μm/day, which is 1.7 times higher than the 1.0 μm/day rate typically found in non-pathological human bone. The authors also found a direct relationship between mineral apposition rates and clinical predictors of HO, such as traumatic brain injury. The findings further suggested that mineral apposition rates correlate with the severity of HO recurrence.
Although the mineral apposition rates increased along with the time from injury to excision, the authors concluded that “the optimal time to resect symptomatic HO must still be a clinical decision,” and they call for further investigation into correlations between mineral apposition rates and HO development and recurrence.
Naproxen Effective for Preventing HO after Hip Arthroscopy
Heterotopic ossification (HO) is a known complication of hip arthroplasty. A double-bl
ind, randomized, placebo-controlled trial by Beckmann et al. in the December 16, 2015 Journal of Bone & Joint Surgery showed that prophylaxis with naproxen dramatically reduced the prevalence of HO after hip arthroscopy, without serious medication-related side effects. These findings bolster findings from previous retrospective investigations that showed large reductions in HO prevalence among those taking nonsteroidal anti-inflammatory drugs (NSAIDs).
The patients in the study took naproxen (500 mg) or a placebo twice a day for three weeks following arthroscopic surgery for femoroacetabular impingement. After one year, the prevalence of radiographically determined HO in patients randomized to the naproxen group was 4% versus 46% in the patients randomized to the placebo group, an 11-fold difference. While the potential for serious GI and renal side effects with NSAIDs is well-documented, in this study only minor adverse reactions to study medication were reported in 42% of those taking naproxen and in 35% of those taking placebo.
Noting that the clinical consequences of HO following hip arthroscopy are “largely undetermined,” the authors still suggest a role for HO prophylaxis “because it could reduce the risk of developing symptomatic HO or requiring revision surgery for HO excision.”
In an accompanying commentary, Sverre Loken praises the authors for the well-designed study, but he cautions that “clinically relevant HO is uncommon, and this has to be weighed against the risk of serious side effects caused by NSAIDs.” He also emphasizes the observation Beckmann et al. make in the last paragraph of their study: that “the lowest dose and shortest duration of NSAID prophylaxis that still prevent HO remain to be determined.”
JBJS Reviews Editor’s Choice–Femoral Head Fractures
Fractures of the femoral head are uncommon. Typically associated with hip dislocations, they are found in association with high-energy trauma. They occur more commonly in men than women. Because of their relatively rare occurrence, large series with validated outcomes have not been reported. As noted by Marecek et al. in the November 2015 issue of JBJS Reviews, the goals of treatment are to achieve early and safe reduction and fixation and, in doing so, avoid complications, including osteonecrosis and heterotopic ossification.
To accomplish these goals, it is important to identify any associated life-threatening injuries and to achieve prompt reduction. A distinction is made between infrafoveal and suprafoveal fractures and the presence of associated femoral neck or acetabular fractures. Operative treatment is usually accomplished through the direct anterior or surgical hip dislocation approach, depending on the associated injury patterns. The use of mini-fragment lag screw fixation is generally preferred.
The initial treatment of femoral head fractures follows advanced trauma life support (ATLS) protocols. If hip dislocation is present, urgent reduction is performed in conjunction with skeletal relaxation to decrease the risk of osteonecrosis of the hip. Nonoperative treatment is reserved for patients with infrafoveal fractures with a concentric hip joint and no intra-articular debris and patients in whom operative intervention carries a morbid risk of complications. The timing of intervention for femoral head fractures remains controversial, and at least one randomized controlled trial demonstrated significantly worse outcomes for patients who had closed manipulative reduction and delayed open reduction and internal fixation compared with patients who received immediate operative reduction and fixation.
In summary, femoral head fractures are uncommon but severe. After prompt reduction of hip dislocations, a thorough evaluation is required to detect all associated injuries and to formulate an appropriate operative plan. Treatment should be directed toward achieving a stable, concentrically reduced hip with anatomic reduction of the fracture or excision of comminution and removal of articular debris. Arthroplasty should be reserved for patients who are older, those who have degenerative changes of the hip, and those who have complex injuries, the treatment of which would be more detrimental or risky than immediate arthroplasty.
Thomas A. Einhorn, MD
Editor, JBJS Reviews
Fibrin No Friend of Fracture Repair
Researchers at Vanderbilt University Medical Center have concluded that fibrin, a protein involved in blood clotting and found abundantly around the site of new bone fractures, impedes rather than supports fracture healing.
Their recent study in The Journal of Clinical Investigation looked at mice that had experimentally induced deficits in either fibrin production or fibrin clearance. Researchers found normal fracture repair in mice without fibrin and impaired vascularization and fracture healing in mice with inhibited fibrin clearance. They also saw increased heterotopic ossification in the mice unable to remove fibrin.
In a Vanderbilt press release, study coauthor Jonathan Schoenecker, MD, commented that “any condition associated with vascular disease and thrombosis will impair fracture healing.” These findings, he suggested, may explain why obesity, diabetes, smoking, and old age—all of which are associated with impaired fibrin clearance—are also associated with impaired fracture healing. Dr. Schoenecker went on to speculate that anti-clotting drugs commonly used to treat cardiovascular conditions may find new applications in enhancing fracture repair.
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