Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model.

The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.

Osteotomy Site Venting Enhances Femoral Bone Consolidation With Magnetic Intramedullary Lengthening Nails.

BACKGROUND: Magnetic intramedullary lengthening nailing has demonstrated benefits over external fixation devices for femoral bone lengthening. These include avoiding uncomfortable external fixation and associated pin site infections, scarring, and inhibition of muscle or joint function. Despite this, little has changed in the field of biologically enhanced bone regeneration. Venting the femoral intramedullary canal at the osteotomy site before reaming creates egress for bone marrow during reaming. The reamings that are extruded from vent holes may function as a prepositioned bone graft at the distraction gap. The relationship between venting and the consolidation of regenerating bone remains unclear. QUESTIONS/PURPOSES: (1) Do bone marrow reamings extruded through venting holes enhance the quality of bone regeneration and improve healing indices and consolidation times? (2) Is venting associated with a higher proportion of complications than nonventing? METHODS: We performed a retrospective study of femoral lengthening performed at one hospital from December 2012 to February 2022 using a magnetic intramedullary lengthening nail with or without venting at the osteotomy site before reaming. This was a generally sequential series, in which the study groups were assembled as follows: Venting was performed between July 2012 and August 2016 and again from November 2021 onward. Nonventing was used between October 2016 and October 2021 because the senior author opted to create drill holes after the reaming procedure to avoid commitment to the osteotomy level before completing the reaming procedure. Outcomes were evaluated based on bone healing time, time to achieve full weightbearing, and complications. Sixty-one femoral lengthening procedures were studied (in 33 male and 28 female patients); two patients were excluded because of implant breakage. The mean age was 17 ± 5 years. The mean amount of lengthening was 55 ± 13 mm in the venting group and 48 ± 16 mm in the nonventing group (mean difference 7 ± 21 [95% CI 2 to 12]; p = 0.07). The healing index was defined as the time (in days) required for three cortices to bridge with new bone formation divided by the length (in cm) lengthened during the clinical protocol. This index signifies the bone formation rate achieved under the specific conditions of the protocol. Full weightbearing was allowed upon bridging the regenerated gap on three sides. Consolidation time was defined as the total number of days from the completion of the lengthening phase until adequate bone union (all three cortices healed) was achieved and full weightbearing was permitted. This time frame represents the entire healing process after the lengthening is complete divided by the amount of lengthening achieved (in cm). Patient follow-up was conducted meticulously at our institution, and we adhered to a precise schedule, occurring every 2 weeks during the distraction phase and every 4 weeks during the consolidation phase. There were no instances of loss to follow-up. Every patient completed the treatment successfully, reaching the specified milestones of weightbearing and achieving three cortexes of bone bridging. RESULTS: The mean healing index time in the venting group was faster than that in the nonventing group (21 ± 6 days/cm versus 31 ± 22 days/cm, mean difference 10 ± 23 [95% CI 4 to 16]; p = 0.02). The mean consolidation time was faster in the venting group than the nonventing group (10 ± 6 days/cm versus 20 ± 22 days/cm; mean difference 10 ± 23 [95% CI 4 to 15]; p = 0.02). No medical complications such as deep vein thrombosis or fat or pulmonary embolism were seen. Two patients had lengthy delays in regenerate union, both of whom were in the nonventing group (healing indexes were 74 and 62 days/cm; consolidation time was 52 and 40 days/cm). CONCLUSION: Femoral lengthening with a magnetic intramedullary lengthening nail healed more quickly with prereaming venting than with nonventing, and it allowed earlier full weightbearing without any major associated complications. Future studies should evaluate whether there is a correlation between the number of venting holes and improvement in the healing index and consolidation time. LEVEL OF EVIDENCE: Level III, therapeutic study.

Infection rates and risk factors with magnetic intramedullary lengthening nails.

Introduction: Surgical site infection (SSI) related to magnetic intramedullary lengthening nails (MILNs) can lead to delayed consolidation or loss of limb function, resulting in deleterious effects to a patient's quality of life. With the rise of MILNs, we sought to determine the incidence rate and risk factors for infection during limb lengthening with MILNs. Methods: We reviewed a consecutive series of patients who underwent femoral and/or tibial lengthening with an MILN at a single institution between 2012 and 2020 (n = 420). SSI was defined according to CDC-NHSN criteria (including superficial and deep infections) with postoperative surveillance time of 12 months. Demographic, health metrics, comorbidities, limb- and surgery-related factors, were assessed as potential risk mediators of SSI. Results: Incidence of SSI was 3.3 % (14/420). This was divided into superficial (0.5 %,2/420) and deep (2.9 %, 12/420) infections. Of deep infections, 75 % (9/12) were osteomyelitis. Of the 14 limbs that developed SSI, 57 % (8/14) had a history of prior external fixation in the same limb and 38 % (5/14) had a previous infection of the same limb. A subanalysis of patients with a history of prior external fixation in the same bone was associated with SSI, as compared to those without previous external fixation. None of the surgery-related infection risk factors reached statistical significance. Discussion and conclusion: The total incidence of infection with MILNs was 3.3 % at 24 months follow-up. The risk of deep infection was 2.9 %. Patients with a history of previous external fixation and prior infection show an independent association with increased rate of infection recurrence in the same bone. These patients could be considered a high-risk group for developing deep tissue infection. Potential algorithms include prolonged oral antibiotics after MILN insertion or simultaneous injection of absorbable antibiotic at the time of the nail insertion.

Treatment of External Fixator Pin Tract Deep Infections With an Antibiotic "Sparkler".

Pin tract infections are virtually universal complications with the use of external fixation. While most are superficial and respond to oral antibiotics and local care, septic loosening may occur at the bone-pin interface, which may lead to instability of the fixator, catastrophic failure, fracture, and long-term osteomyelitis. Classification systems and prevention protocols have been developed to address this ubiquitous complication. Treatment of severe pin tract infections often requires debridement, parenteral antibiotics, and removal of the offending pin or the entire external fixator. In cases of osteomyelitic pin tracks, a sizable cavity is often present. We describe a simple technique for treatment of deep bone pin tract infection through the use of debridement, irrigation, and an antibiotic "sparkler," which is a specially prepared percutaneous implant of antibiotic laden bone cement.Levels of Evidence: Level 5.

Chronic knee pain following infrapatellar/suprapatellar magnetic intramedullary lengthening nails versus external fixators in limb length discrepancy: A retrospective review.

Aims & objectives: Prior to the popularization of magnetic intramedullary nails (MILNs), gradual deformity correction using external fixation was the norm in limb lengthening. Trauma literature has shown MILN via a suprapatellar approach (SP) to be associated with less knee pain than either an infrapatellar entry (IP) or external fixation. Yet, no research has investigated chronic knee pain and MILNs. We assessed differences in chronic knee pain following lengthening via an IP or SP approach with an MILN versus external fixation. Materials & methods: We reviewed 147 limbs (55 MILN/IP, 22 MILN/SP, 71 external fixator) in 124 patients who underwent tibial lengthening with ≥12 months follow-up between February 2012 and July 2020. Knee pain was assessed pre- and postoperatively at 6 and 12 months, with the Lysholm Knee Scoring Scale (LKSS) and numeric pain scale (0-10). Differences in knee pain outcomes were compared across methods, with subgroup analysis of MILN/SP and MILN/IP. Results: Mean LKSS was 96.3 for external fixation and 88.5 for MILN (P = .011). In the MILN subgroups, mean LKSS was 91.7 for IP and 85.3 for SP. The IP group reported a lesser mean pain score (0.6 versus 2.1) at 12 months. Bilateral nail recipients demonstrated no knee pain differences versus unilateral. At 12 months postoperative, external fixation had better knee outcomes. Conclusion: Tibial lengthening with external fixation was associated with less chronic anterior knee pain and better functional outcomes than MILN overall. In terms of MILN approach, IP surpassed SP on subjective pain scores. Larger tibial lengthening and knee pain studies are warranted.