Caution Appropriate as We Investigate New Approaches to Pain Management
The dangers of chronic opioid use have rightly been at the forefront of orthopaedic practice considerations in recent years. The widespread use of regional anesthesia and periarticular-injection cocktails, targeted NSAID utilization, and strict limitations on opioid use have become standard approaches for postoperative pain management.
With the availability of cannabinoids in numerous state jurisdictions, attention has now turned to the potential of these compounds to enhance patient comfort in the postoperative period. However, as we contemplate their use, it’s imperative that we also evaluate the impact of these compounds on clinically important outcomes such as bone-healing and fusion. The track record of nicotine, NSAIDs, and other compounds in terms of the impact on bone-healing is enough to suggest caution.
In the June 2, 2021 issue of JBJS, Yun et al. provide new insight into this topic. Specifically, they evaluated the impact of cannabinoid receptor agonist WIN55 on osteogenic differentiation in vitro and bone regeneration and spinal fusion in a preclinical rat model.
They found that WIN55 had no adverse impact on osteogenic differentiation of primary bone marrow stem cells in vitro. As noted by the authors, “mRNA expression levels of Runx2 and Alp were similar among cells treated with vehicle alone and WIN55. Likewise, exposure to WIN55 did not inhibit ALP [Alkaline phosphatase] activity or bone matrix mineralization.”
In addition, no adverse impact of WIN55 on spinal fusion or bone regeneration was found. Forty-five rats (15 per group) underwent L4-L5 posterolateral spinal fusion with bilateral placement of collagen scaffolds soaked with rhBMP-2. The rats were treated with vehicle alone or 0.5 or 2.5 mg/kg WIN55 by way of daily intraperitoneal injections for 5 days. Radiography, manual palpation-based fusion scoring, microCT, and histology were used for assessment. No significant differences among the groups in the mean fusion score, fusion rate, and new bone volume were demonstrated.
These findings are intriguing, and such research helps set the stage for carefully designed in vivo research projects, eventually moving toward randomized controlled trials, before recommending widespread use of cannabinoids for post-surgical pain management.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
A New Venue for Dr. Nelson’s Basic Science Tips
Based on page-view data, the monthly basic science posts from Fred Nelson, MD have been hugely popular on OrthoBuzz over the last 4-plus years.
Now, OrthoBuzz readers can sign up to receive Dr. Nelson’s insights on a weekly basis. The “ORS Connects” e-newsletter, a publication of the Orthopaedic Research Society, has kindly agreed to email OrthoBuzz readers Dr. Nelson’s weekly basic science tips. If you are interested, please email Amber Blake at blake@ors.org with your first and last name and email address.
Because Dr. Nelson’s tips are now available to a wider audience on a more frequent basis, we will no longer be including them in OrthoBuzz. The OrthoBuzz team has thoroughly enjoyed engaging with Dr. Nelson and his fascinating basic-science content. We thank him for his outstanding contributions.
Trimming the Fat (Pad) in Knee OA
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. It has been sent to >3,000 members of the Orthopaedic Research Society (ORS). For more information about the ORS, visit http://www.ors.org.
The knee joint is comprised of cartilage, fibrocartilage, bone, synovium, ligaments, a fibrous capsule, and adipose tissue, the last of which includes the large anterior infrapatellar fat pad (IFP). The role of synovial inflammatory cells and cytokines in knee osteoarthritis (OA) has been well studied. The IFP is also rich in stem cells and inflammatory cells. Because Hartley guinea pigs naturally develop a form of knee OA that is similar to human disease, researchers recently used them as a model for elucidating a possible role of the IFP in knee OA.1
Ten 3-month-old guinea pigs had a unilateral IFP excision from one knee, with sham surgery performed on the opposite knee. Hartley guinea pigs typically develop OA after three months, and this intervention sought to determine whether IFP excision protected against OA. Gait analysis data were collected prior to surgery and then monthly until the animals were harvested at 7 months of age, at which point researchers performed microcomputed tomography (microCT) and histopathology on all 20 knee joints.
In knees with IFP resection, fibrous connective tissue replaced the adipose tissue. Stride length was not statistically different for either hindlimb throughout the study. Joints with resected IFPs had a decreased microCT score compared to contralateral intact knees (p <0.0001), indicating healthier cartilage. Histopathologically, the mean modified Mankin score of knees with IFPs removed was 2.556 versus 12.56 in contralateral knees (p <0.0004).
Surgeons commonly resect the fat pad during reconstructive knee surgery in humans, with no known reports of adverse effects beyond decreased range of motion due to local fibrosis. A recent review of the contribution of the IFP and synovium to knee OA pain2 suggests that synovial tissue and adipose tissue may act as a “functional unit” and have a combined effect on OA pathogenesis and, in all probability, OA pain and progression.
References
- Afzali MF, Radakovich LB, Pixler ZC, Campbell MA, Sanford JL, Marolf AJ, Donahue T, Santangelo, Kelly S. Early removal of the infrapatellar fat pad beneficially alters the pathogenesis of primary osteoarthritis in the Hartley guinea pig ORS 2020 Annual Meeting Paper No.0166
- Belluzzi E, Stocco E, Pozzuoli A, Granzotto M, Porzionato A, Vettor R, De Caro R, Ruggieri P, Ramonda R, Rossato M, Favero M, Macchi V. Contribution of Infrapatellar Fat Pad and Synovial Membrane to Knee Osteoarthritis Pain. Biomed Res Int. 2019 Mar 31;2019:6390182. doi: 10.1155/2019/6390182. eCollection 2019.PMID: 31049352
Micromotion Followed by Rigid Fixation Boosts Fracture Healing
Mechanical factors undoubtedly play a role in the rate and quality of fracture healing. For example, the seminal work on fracture strain by the late Stephan Perren, MD helped us understand that the larger the overall fracture area, the lower the fracture strain—and that less strain encourages fracture union.
But with the variety of fracture planes and orientations, different energies imparted to produce the fracture, and multiple patient factors such as bone density, the best approaches by which to positively influence fracture-healing mechanics are still being investigated. We do know that motion mechanics come into play for nonsurgically stabilized fractures in our patients.
In the February 3, 2021 issue of The Journal, Glatt et al. provide more data on the role of micromotion in fracture healing. The authors created a 2-mm transverse tibial osteotomy in 18 goats and then used an external fixator to achieve static, rigid fixation in 6 of the osteotomized tibiae. Six other tibiae were treated with a fixator that allowed 2 mm of controlled axial micromotion for the 8-week duration of the experiment. (This so-called dynamization technique was championed more than 30 years ago by Fred Behrens, MD, who established that inducing micromotion helps stimulate maturation of fracture callus.) The remaining 6 tibiae were initially treated with dynamization, followed by rigid fixation during weeks 4 through 8—a technique known as reverse dynamization. The experimental groups simulated 3 different versions of cast or brace immobilization without surgery.
Using radiographs, micro-CT data, and torsion testing, the investigators found that, after 8 weeks, bones in the reverse-dynamization group were significantly stronger and showed more characteristics of intact, contralateral tibiae than the treated bones in the other 2 groups. I agree with the authors’ conclusion that their results “may have important consequences regarding our understanding of the optimum fixation stability necessary to maximize the regenerative capacity of bone-healing clinically.” With this experiment, Glatt et al. have added another important piece to the puzzle that Drs. Perren and Behrens started solving many years ago.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
T-Scores for Diagnosing Osteoporosis: 3 Are Better Than 1
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.
The World Health Organization (WHO) and the International Society for Clinical Densitometry (ISCD) define osteoporosis based on (DXA) measures of bone mineral density that are translated into T-scores. A T-score ≤ -2.5 at any 1 of the 3 commonly measured sites (lumbar vertebrae, femoral neck, and total hip) is considered diagnostic for osteoporosis, and a T-score between -2.5 and -1 is indicative of osteopenia. University of Pennsylvania investigators1 proposed that combining all 3 T-scores in a multivariate analysis would be “potentially more informative” than the common practice of using the single lowest T-score.
The investigators applied multivariate statistical theory to T-scores from a sample of 1,000 65-year-old white women. When both real data and simulation models were analyzed, the researchers found that more patients were diagnosed with osteoporosis using the multivariate version of the WHO/ISCD guidelines than with the current WHO/ISCD guidelines. The diagnoses of osteoporosis using this method were also associated with higher Fracture Risk Assessment Tool (FRAX) probabilities of major osteoporotic fractures (P=0.001) and hip fractures (P=2.2×10−6). The FRAX tool combines a patient’s history of fracture with age, sex, race, height, weight, and social habits such as smoking and drinking to determine the risk of a major facture in the next 10 years.
This study shows that statistically considering all 3 T-scores may reveal more cases of osteoporosis than using the single lowest T-score. The trick will be getting this insight into the hands—and minds—of those making radiologic interpretations of DXA findings.
Reference
- Sebro R, Ashok S. A Statistical Approach regarding the Diagnosis of Osteoporosis and Osteopenia from DXA: Are we underdiagnosing osteoporosis? J. Bone Mineral Res Plus. In press
Knee OA: Does It Start with Stiff Menisci or Soft Cartilage?
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.
As an orthopaedic surgeon, I often noticed the rigidity of the meniscus as I excised it during a total knee replacement. Focused on the job at hand, however, I never closely considered the involvement of menisci in degenerative joint disease. But German researchers recently hypothesized that early biomechanical changes in meniscal tissue occur before articular cartilage changes in knee osteoarthritis.1
To test their hypothesis, they dissected 12 cadaver knees with Kellgren-Lawrence (KL) scores between 1 and 2 and 12 knees with KL scores between 3 and 4. The menisci were carefully embedded in a cast of polymethylmethacrylate using bony attachments to hold the specimens for Einst testing at the anterior horn, pars intermedia, and posterior horn. (Instantaneous modulus of elasticity [Einst] is the measure of the initial response of a viscoelastic material to an initial load before long-term deformity occurs.) The exposed tibial surface was then cut 10 mm below the joint for Einst testing at the same zones, and the researchers also measured the articular cartilage-to-cartilage contact area.
Mann-Whitney U-testing revealed higher meniscal Einst values with increasing degeneration for both lateral and medial menisci, while the underlying tibial articular cartilage showed a decrease in Einst in the medial compartment. These findings suggest that knee joint degeneration might very well begin with a stiffening of the menisci, followed by articular cartilage softening.
The wide variation in Einst values uncovered in this study leaves open the possibility there is more than one pathway by which the biochemical response to meniscal cytokine expression would lead to subsequent articular cartilage breakdown. Nevertheless, the authors suggest that their findings might prompt the treatment and diagnostic paradigms of knee osteoarthritis to change, “focusing on the degeneration detection of the menisci instead of the articular cartilage.”
Reference
- Seitz AM, Osthaus F, Ignatius A, Dürselen L. Degeneration alters first the biomechanical properties of human menisci before affecting the tibial cartilage. ORS 2020 Annual Meeting Paper No.0687
What’s New in Musculoskeletal Basic Science 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 all such OrthoBuzz specialty-update summaries.
This month, co-author Philipp Leucht, MD selected the most compelling findings from the 15 studies summarized in the December 2, 2020 “What’s New in Musculoskeletal Basic Science.”
Spine: Annulus Fibrosus Findings
The relatively high prevalence of repeat discectomies has caused researchers to focus on characteristics of the annulus fibrosus, the healing of which often remains incomplete after disc herniation.
–Knowing that the neonatal annulus fibrosus shows regenerative capacity, researchers recently identified Scleraxis-lineage cells as the main contributors to those regenerative properties.1 They discovered that the neonatal cellular programming that results in complete functional restoration of the annulus fibrosus is completely absent in the adult annulus fibrosus after injury. Knowledge of this regenerative mechanism could help scientists develop new treatments for annulus fibrosus regeneration in adults.
–Related research demonstrated that the residual strain of the healthy nucleus pulposus generates pre-strain in the outer annulus fibrosus, and that the loss of residual strain, as seen in disc herniation, results in short-term apoptosis and the emergence of a fibrotic cell phenotype in the annulus fibrosus.2 Blocking cell contractility pathways may therefore offer a viable target to prevent post-injury fibrosis.
Spine: Somitogenesis
–The somitogenesis process in vertebrate development is believed to be controlled by an oscillating genetic “clock.” Researchers developed an in vitro modeling system to recapitulate the human segmentation clock,3 determining that the clock causes a new somite to be formed every 5 hours. This model allowed investigators to assess the function of mutations involved in segmentation defects such as congenital spondylocostal dysostosis. This easily manipulated model could provide the framework for discoveries of the gene oscillations and molecular underpinnings in both normal and abnormal vertebral development.
Osteoarthritis
–Transforming growth factor beta (TGF-β) signaling has been revealing in studying osteoarthritis. Researchers found that mice lacking in Prx1 osteochondral progenitors during development showed joint developmental defects.4 They further found that both postnatal ablation of Tgfbr2 in osteochondral progenitors and pharmacological inhibition of TGF-β receptor 2 led to an osteoarthritis phenotype with accompanied upregulation of the receptor antagonist IL-36α. They then discovered that an IL-36Ra intra-articular injection attenuates osteoarthritis progression in both Tgfbr2-deletion and posttraumatic arthritis models, confirming the IL-36 family as a viable target in fighting osteoarthritis.
Bone Regeneration
–Skeletal stem and progenitor cells migrate to sites of damage after an injury to participate in the repair process. Researchers recently discovered that the quiescent CXCL12-expressing perisinusoidal bone marrow stromal cells also participate in the repair process5 by converting into a skeletal stem-cell-like state after injury. These CCXL12-positive cells are highly malleable and long-living and thus represent an ideal source for bone tissue regeneration.
References
- Torre OM, Mroz V, Benitez ARM, Huang AH, Iatridis JC. Neonatal annulus fibrosus regeneration occurs via recruitment and proliferation of Scleraxis-lineage cells. NPJ Regen Med.2019 Dec 20;4:23.
- Bonnevie ED, Gullbrand SE, Ashinsky BG, Tsinman TK, Elliott DM, Chao PG, Smith HE, Mauck RL. Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss. Nat Biomed Eng.2019 Dec;3(12):998-1008. Epub 2019 Oct 14.
- Matsuda M, Yamanaka Y, Uemura M, Osawa M, Saito MK, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen TL, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C. Recapitulating the human segmentation clock with pluripotent stem cells. 2020 Apr;580(7801):124-9. Epub 2020 Apr 1.
- Li T, Chubinskaya S, Esposito A, Jin X, Tagliafierro L, Loeser R, Hakimiyan AA, Longobardi L, Ozkan H, Spagnoli A. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci Transl Med.2019 May 8;11(491):eaan2585.
- Matsushita Y, Nagata M, Kozloff KM, Welch JD, Mizuhashi K, Tokavanich N, Hallett SA, Link DC, Nagasawa T, Ono W, Ono N. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat Commun.2020 Jan 16;11(1):332.
How Much Radiation Does a Surgeon’s Brain Receive during Femoral Nailing?
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Impact Science, in response to a recent article in JBJS.
Surgeon exposure to ionizing radiation during C-arm fluoroscopy is common during many orthopaedic procedures, including fracture reduction and fixation-implant positioning. With increased exposure, concern about potential health risks to staff also increases.
A new study in the November 18, 2020 issue of The Journal of Bone & Joint Surgery estimates how much radiation a surgeon’s brain is exposed to while performing short cephalomedullary (SC) nailing over a 40-year career. Ramoutar et al. used two cadaveric specimens (one representing the patient and one head-and-neck specimen representing the surgeon) during a simulated fluoroscopic-guided femoral-nailing procedure.
The dose of radiation to the brain was measured with sensors implanted in the cadaver brain and placed superficially on the skull. Measurements were made with the surgeon specimen set up with different configurations of personal protective equipment (PPE) to test their effectiveness at shielding the brain from radiation.
Ramoutar et al. calculated that the overall extrapolated lifetime dose over 40 working years for surgeons performing 16 SC nailing cases per year without PPE was 2,146 µGy, which is comparable to the radiation exposure during a 1-way flight from London to New York. The authors also found that the use of a thyroid shield was very effective in reducing the radiation exposure to the brain, although the use of additional PPE (e.g., leaded glasses and lead cap) did not add any significant reduction in brain exposure to radiation.
In addition to concluding that the lifetime brain dose of radiation from SC nailing is low, the authors say the findings should encourage surgeons performing this procedure to use thyroid shields. This study also provides a repeatable methodology for future studies investigating brain-radiation doses during other common orthopaedic procedures.
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.
Balancing Antibiotic Perfusion and Tourniquet Usage
Antibiotics are an integral part of infection prophylaxis in orthopaedic surgery, and tourniquets are widely used during many of those same surgeries. The timing of antibiotic administration in relation to tourniquet use has long been debated. Hanberg et al. explore this “balancing act” in the November 4, 2020 issue of The Journal in a carefully performed animal study.
The researchers anesthetized 24 female pigs and surgically exposed both of their hind calcanei. They then placed microdialysis catheters through drill holes in each calcaneus and also into the subcutaneous adipose tissue in the hind feet. Tourniquets were applied to one hind leg on each animal, and each pig was then randomized into 1 of 3 groups, based on when the animal received 1.5 gm of cefuroxime intravenously:
- Group A –15 minutes prior to tourniquet inflation
- Group B – 45 minutes prior to tourniquet inflation
- Group C – At the time of tourniquet release
Hanberg et al. inflated the tourniquets for 90 minutes in all 3 groups, and then they measured the concentrations of cefuroxime and ischemic markers at regular intervals between the time of tourniquet inflation and up to 480 minutes afterward.
The authors found that in both Groups A and B, cefuroxime concentrations were maintained above the minimum inhibitory concentration (MIC) for Staphylococcus aureus in cancellous bone and adipose tissue throughout the 90 minutes of tourniquet inflation. In addition, injecting cefuroxime at the time of tourniquet deflation (Group C) kept the tissue-antibiotic levels above the MIC on the tourniquet side for 3.5 hours after tourniquet release.
There were no differences in the time above MIC in bone or adipose tissue between the 3 groups, but the researchers noted a trend toward shorter time above MIC in bone in Group A vs. Group C (p=0.08). There was also a tendency toward higher time above MIC in bone on the tourniquet side compared to no-tourniquet side in Group B (p=0.08) and Group C (p=0.06). The researchers also found that, in all the animals, tissue ischemia persisted for 2.5 hours after tourniquet deflation in bone, while the adipose tissue recovered immediately.
This animal study provides useful data and prompts us to ponder ideas for further investigation regarding the interplay between tourniquets and antibiotic perfusion. For example, I think the prolonged ischemia in cancellous bone is a topic that warrants further investigation, and I am also curious whether adding antibiotics at the time of tourniquet release might help combat the potentially negative effects of that ischemia.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
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.
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