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
Keeping Your Bones Pumped Up
This post 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.
While a reasonable amount of “pumping iron” exercise has proven beneficial for musculoskeletal health, long-term use of acid-suppressing proton pump inhibitors (PPIs) may have the opposite effect on bone. Many people are currently taking PPIs, most commonly for gastrointestinal disorders such as heartburn and gastroesophageal reflux. Fortunately, many are occasional PPI users, taking the drugs only when symptoms arise. However, PPIs are often prescribed long term for preventive reasons.1
The same proton-pump mechanism present in the GI tract is seen in the vacuolar H+-ATPases that are present in high concentrations on the ruffled border of osteoclasts.2 Years of PPI use may therefore interfere with normal and essential bone remodeling. PPIs are also prescribed in the pediatric population for reflux symptoms. The effect of PPIs on future fracture or long-term osteoporosis in these very young patients is not clear.
The consequences for adult and elderly patients are clearer. Femoral bone mineral density is significantly decreased in PPI users. Also, patients with peptic ulcer disease using PPIs have a higher risk for osteoporosis than peptic ulcer patients not using PPIs. Among younger adults, the risk of fracture was significantly higher in those using PPIs than in those not using PPIs.
In 2010, the FDA issued a communication alerting healthcare professionals that users of PPIs have a possible increased risk of fractures of the hip, wrist, and spine, and that they should weigh the known benefits against the potential risks when recommending use of these medications. In 2011, the FDA refined its language somewhat: “Following a thorough review of available safety data, FDA has concluded that fracture risk with short-term, low dose PPI use is unlikely.” Still, when fractures are the outcome of interest, the data implicates long-term use of PPIs in having deleterious effects on bone.
Although data on human fracture healing in association with PPI use are sparse, animal studies do show that PPIs have a negative impact on normal fracture healing, with a decrease in the expression of important markers of bone formation, including bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich angiogenic inducer (CYR)61.
It is time to question the need for chronic use of PPIs by our patients. Orthopaedists should encourage their patients who take PPIs to discuss this matter with their primary care physician.
References
- Eom CS, Park SM, Myung SK, Yun JM, Ahn JS. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med. 2011 May-Jun;9(3):257-67. doi: 10.1370/afm.1243. PMID: 21555754
- Wagner SC. Proton Pump Inhibitors and Bone Health: What the Orthopaedic Surgeon Needs to Know. JBJS Rev. 2018 Dec 18. doi: 10.2106/JBJS.RVW.18.00029. [Epub ahead of print] No abstract available. PMID: 30562209
When Is a Fracture Good to Go?
This post 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.
Determining when a fracture has healed enough for functional use can be difficult. The Radiographic Union Score for Tibia fractures (RUST) assesses fracture healing on a continuous scale from 4 to 12 points. Based on an evaluation of anteroposterior and lateral radiographs, RUST accounts for callus without visible fracture line (3 points), callus with visible fracture line (2 points), or absence of any callus (1 point) for each of four cortices. The modified RUST (mRUST) score subdivides the second parameter into two categories (callus present and bridging callus), creating a score ranging from 4 to 16 points. This tool has demonstrated high intraclass correlation coefficients (ICCs). However, until now, the correlation of these scores to mechanical properties of healed bone had not been demonstrated.
Cooke et al.1 evaluated both scores against the physical properties of bone healing by using a model of closed, stabilized femur fractures in 8- to 12-week-old male mice. Control mice received a normal diet and an experimental group received a phosphate-restricted diet. The physical properties of bone healing were determined with micro-computed tomography (µCT) and torsion testing on postoperative days 14, 21, 35, and 42. There were 10 to 16 mice in each group at any given time-point.
RUST scores from five raters were determined from anteroposterior and lateral radiographic views constructed from the µCT scans. ICCs were 0.71 (mRUST) and 0.63 (RUST). Both RUST scores were positively correlated with callus bone mineral density, bone volume fraction, callus strength, and rigidity. Radiographically healed calluses with an mRUST score of ≥13 and a RUST score of ≥10 had excellent relationships to structural and biomechanical metrics.
Mechanical properties revealed the effects of delayed healing due to phosphate dietary restrictions at later time points, but no such distinctions were found in the RUST scores. Both the RUST and mRUST scores have high correlation to physical properties of bone healing, but this tool may not be reliable for detecting poor bone quality due to nutrient deficiencies.
Reference
- Cooke ME, Hussein AI, Lybrand KE, Wulff A, Simmons E, Choi JH, Litrenta J, Ricci WM, Nascone JW, O’Toole RV, Morgan EF, Gerstenfeld LC, Tornetta P 3rd. Correlation between RUST assessments of fracture healing to structural and biomechanical properties. J Orthop Res. 2018 Mar;36(3):945-953. doi: 10.1002/jor.23710. Epub 2017 Sep 20. PMID: 28833572 PMCID: PMC5823715 DOI: 10.1002/jor.23710
Guest Post: Is There a Role for LIPUS in Bone Healing?
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from E. Scott Paxton, MD, in response to a recent “Rapid Recommendation” in The BMJ.
An international panel convened by The BMJ recently issued a “Rapid Recommendation” that strongly recommends against using low-intensity pulsed ultrasound (LIPUS) in patients with fracture or osteotomy because the treatment doesn’t improve functional recovery or pain.1
The systematic review on which the recommendation was based reviewed 26 trials of nearly 1600 patients with fracture or osteotomy who were randomized to either LIPUS or sham/no device.2 The authors concluded with moderate to high levels of certainty that the treatment had little effect on the time patients could return to work, time to full weight-bearing activity, pain levels, future operations, or time to radiographic healing.
In 2009, Busse et al. performed a similar meta-analysis, concluding that “evidence for the effect of low intensity pulsed ultrasonography on healing of fractures is moderate to very low in quality and provides conflicting results.”3 This analysis only included 13 trials, however. Then, in 2016, Busse et al. published results from the TRUST study,4 a blinded, randomized controlled trial of 501 patients from 43 North American academic trauma centers who had a fresh tibial shaft fracture treated with intramedullary nailing. The authors based their sample size calculations on the minimal clinically important difference on the SF-36 PCS, as this was a co-primary outcome. The authors found no improvement in radiographic healing time or functional recovery with the use of LIPUS. However, the authors noted that only 1 nonunion occurred among 195 sham-treated patients, demonstrating that this group was at extremely low risk for nonunion at baseline.
Including the TRUST trial in the 2017 meta-analysis of LIPUS led Schandelmaier et al. to the aforementioned conclusions and informed the strong BMJ Rapid Recommendation against the use of LIPUS for patients with any bone fracture or osteotomy. However, this recommendation was based in large part on the TRUST trial, which was unable to directly assess the effectiveness of LIPUS on reducing nonunion rates because of the almost universal healing of the fractures studied.
The BMJ Rapid Recommendation states “there was high quality evidence showing a lack of benefit in accelerating healing for fresh fractures; thus it is unlikely that LIPUS would improve outcomes in patients with non-union.” However, the effect of LIPUS on preventing nonunions in fractures known to have high nonunion rates or on treating established nonunions will require further high-quality studies looking at those patients specifically.
Scott Paxton, MD is an assistant professor in the Department of Orthopaedic Surgery at the Warren Alpert Medical School at Brown University and a fellowship-trained shoulder and elbow surgeon at University Orthopedics in Providence, Rhode Island.
References
- Poolman RW, Agoritsas T, Siemieniuk RAC, et al. Low intensity pulsed ultrasound (LIPUS) for bone healing: a clinical practice guideline. BMJ. February 2017:j576-j576. doi:10.1136/bmj.j576.
- Schandelmaier S, Kaushal A, Lytvyn L, et al. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ. 2017;356:j656. doi:10.1136/bmj.j656.
- Busse JW, Kaur J, Mollon B, et al. Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials. BMJ. 2009;338:b351. doi:10.1136/bmj.b351.
- TRUST Investigators writing group, Busse JW, Bhandari M, et al. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. BMJ. 2016;355:i5351. doi:10.1136/bmj.i5351.
JBJS Classics: Sarmiento Pioneered Weight-Bearing Fracture Healing
OrthoBuzz 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 JBJS articles have had on the practice of orthopaedics. Please feel free to join the conversation about these classics by clicking on the “Leave a Comment” button in the box to the left.
Prior to the innovative work of Gus Sarmiento in the 1960s, most orthopaedic surgeons treated tibial shaft fractures with a prolonged period of immobilization, in a long-leg non-weight bearing cast. While the fracture usually healed, knee joint stiffness and atrophy of the entire limb usually resulted as well.
In this 1967 JBJS classic, Sarmiento extended the concept of early weight-bearing treatment of these fracture as advocated by Dehne and others by incorporating the limb in a below-the-knee total-contact plaster cast, a technique that had recently been developed for the early rehabilitation of a below-the-knee amputation. The skin-tight plaster cast was applied over a single layer of stockinette one to two weeks after the acute swelling had subsided. It was molded proximally to contain the muscles of the proximal leg, and it had medial and lateral condylar flares, similar to a patellar-tendon-bearing (PTB) prosthesis.
Sarmiento encouraged early weight bearing in the cast, as he believed that doing so stimulated fracture healing. His confidence was borne out by this report of 100 consecutive tibial shaft fractures treated with a PTB cast. All 100 fractures healed, and healing occurred with minimal deformity or shortening. This success soon led to Sarmiento’s development of a functional below-the-knee tibial fracture brace made of Orthoplast®, a thermoplastic material which, when heated in a water bath, could be molded easily to the injured limb.
While today most tibial shaft fractures are treated with intramedullary nails, the principles developed by Sarmiento still apply, as the nail acts much like the fracture brace to maintain alignment during the healing process. Fracture healing is enhanced by weight bearing, and joint stiffness and muscle atrophy are avoided by early motion.
Sarmiento’s concept of functional treatment was later extended to the treatment of humeral and ulnar shaft fractures, which commonly continue today to be managed effectively with fracture braces that he developed. This emphasis upon early functional restoration while the fracture is healing has allowed many patients to achieve faster healing and to resume full function much sooner.
James D. Heckman, MD
JBJS Editor Emeritus
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.
Try Clinical Classroom
Recent Comments