Peter Evangelista

Recombinant Human Platelet-Derived Growth Factor-BB and Beta-Tricalcium Phosphate (rhPDGF-BB/β-TCP): An Alternative to Autogenous Bone Graft

BACKGROUND Joint arthrodesis employing autogenous bone graft (autograft) remains a mainstay in the treatment of many foot and ankle problems. However, graft harvest can lead to perioperative morbidity and increased cost. We tested the hypothesis that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) homodimer combined with an osteoconductive matrix (beta-tricalcium phosphate [β-TCP]) would be a safe and effective alternative to autograft. METHODS A total of 434 patients were enrolled in thirty-seven clinical sites across North America in a prospective, randomized (2:1), controlled, non-inferiority clinical trial to compare the safety and efficacy of the combination rhPDGF-BB and β-TCP with those of autograft in patients requiring hindfoot or ankle arthrodesis. Radiographic, clinical, functional, and quality-of-life end points were assessed through fifty-two weeks postoperatively. RESULTS Two hundred and sixty patients (394 joints) underwent arthrodesis with use of rhPDGF-BB/β-TCP. One hundred and thirty-seven patients (203 joints) underwent arthrodesis with use of autograft. With regard to the primary end point, 159 patients (61.2% [262 joints (66.5%)]) in the rhPDGF-BB/β-TCP group and eighty-five patients (62.0% [127 joints (62.6%)]) in the autograft group were fused as determined by computed tomography at six months (p < 0.05). Clinically, 224 patients (86.2%) [348 joints (88.3%)]) in the rhPDGF-BB/β-TCP group were considered healed at fifty-two weeks, compared with 120 patients (87.6% [177 joints (87.2%)] in the autograft group (p = 0.008). Overall, fourteen of sixteen secondary end points at twenty-four weeks and fifteen of sixteen secondary end points at fifty-two weeks demonstrated statistical non-inferiority between the groups, and patients in the rhPDGF-BB/β-TCP group were found to have less pain and an improved safety profile. CONCLUSIONS In patients requiring hindfoot or ankle arthrodesis, treatment with rhPDGF-BB/β-TCP resulted in comparable fusion rates, less pain, and fewer side effects as compared with treatment with autograft.

Prospective, randomized, multi-center feasibility trial of rhPDGF-BB versus autologous bone graft in a foot and ankle fusion model.

Background: The increased morbidity and surgical time associated with harvesting autologous bone graft (ABG) have encouraged surgeons to develop synthetic orthobiologic alternatives. The recombinant form of platelet-derived growth factor (rhPDGF-BB), an angiogenic, mitogenic, and chemotactic cytokine, has been shown to significantly enhance bone formation in human periodontal osseous defects when combined with a tricalcium phosphate carrier (β-TCP). The purpose of this prospective, controlled, randomized, multi-center feasibility clinical trial was to compare the safety and efficacy of this biosynthetic bone graft substitute (Augment™ Bone Graft) to ABG during ankle and hindfoot fusion. Materials and Methods: Twenty adult subjects requiring ankle or hindfoot fusion from three U.S. centers were enrolled and randomized in a 2:1 ratio to receive Augment™ or ABG, respectively. Surgical approach and fixation techniques were standardized, and minimum followup was 9 months. The primary endpoint was radiographic osseous union, evaluated by a blinded independent radiologist. Secondary endpoints included assessment of clinical success, union rate by serial computed tomography (CT) examination, time to full weightbearing, AOFAS Ankle-Hindfoot Score (AOFAS), Foot Function Index (FFI), Short Form-12 (SF-12), and Visual Analog pain assessment Scale (Pain VAS). Results: At 36 weeks, 77% (10/13) of the Augment™ and 50% (3/6) of the ABG patients were fused based on radiographic criteria. There were two nonunions in the Augment™ group (9%, 2/14). Healing rates based on 12 week CT scanning (50% osseous bridging) were 69% (9/13) in the Augment™ and 60% (3/5) in the ABG groups, respectively. All functional outcome measures (FFI, AOFAS, SF-12), as well as the VAS pain scores, improved in both groups over time. Surgical procedure times lasted an average 26 minutes longer for the ABG as compared to the Augment™ populations. There were no device related serious adverse events in this study. Conclusion: Based on the available data, the rate of radiographic union, time to full weightbearing, and outcomes scores between the Augment™ and ABG subjects appear comparable. Augment™ may represent a safe and efficacious treatment alternative to ABG during foot and ankle arthrodesis. Level of Evidence:

Establishing the Relationship Between Clinical Outcome and Extent of Osseous Bridging Between Computed Tomography Assessment in Isolated Hindfoot and Ankle Fusions

Background: Determining the success of joint fusion operations is often a diagnostic dilemma, and many factors may be considered. Most would agree that the broad categories of clinical success and radiographic success are likely most useful to determine the overall success of a joint fusion operation. Very little evidence exists to assist the surgeon in determining what constitutes a successful radiographic fusion. The aim of this study was to determine the extent of osseous bridging as measured by computed tomography (CT) that was associated with a good clinical outcome as measured by the 12-Item Short Form (SF-12), Foot Function Index (FFI), and American Orthopaedic Foot & Ankle Society (AOFAS) clinical outcomes questionnaires at 24 weeks. Methods: Patients who had isolated joint fusions were evaluated (n = 275) to determine the correlation of extent of osseous bridging with clinical outcome. The extent of osseous bridging across the joint in question was categorized as absent (0%-24%), minimal (25%-49%) moderate (50%-74%), or complete (75%-100%). Clinical outcome scores included the SF-12, FFI, and AOFAS outcomes score. Results: Patients evaluated to have at least minimal osseous bridging at fusion sites (25%-49%) on CT reported a clinically important improvement in SF-12, FFI, and AOFAS, whereas those with “absent” osseous bridging (0%-24%) did not report a clinically important improvement in outcome scores. Conclusion: This study suggests that osseous bridging of greater than 25% to 49% at the fusion site measured by CT may be necessary to consider a hindfoot or ankle fusion clinically successful. Level of Evidence: Level IV, case series.

Prospective Randomized Controlled Trial of Hindfoot and Ankle Fusions Treated With rhPDGF-BB in Combination With a β-TCP-Collagen Matrix

Background: Ankle and hindfoot arthrodesis is often supplemented with autograft to promote bony union. Autograft harvest can lead to increased perioperative morbidity. Purified recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB) has stimulated bone formation in mandibular defects and hindfoot fusion. This randomized controlled trial evaluated the efficacy and safety of rhPDGF-BB combined with an injectable, osteoconductive beta-tricalcium phosphate (β-TCP)–collagen matrix versus autograft in ankle and hindfoot fusions. Methods: Seventy-five patients requiring ankle or hindfoot fusion were randomized 5:1 for rhPDGF-BB/β-TCP-collagen (treatment, n = 63) or autograft (control, n = 12). Prospective analysis included 142 autograft control subjects from another clinical trial with identical study protocols. Standardized operative and postoperative protocols were used. Patients underwent standard internal fixation augmented with autograft or 0.3 mg/mL rhPDGF-BB/β-TCP-collagen. Radiologic, clinical, and quality-of-life outcomes were assessed over 52 weeks. Primary outcome was joint fusion (50% or more osseous bridging on computed tomography) at 24 weeks. Secondary outcomes included radiographs, clinical healing status, visual analog scale pain score, American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale score, Foot Function Index score, and Short Form-12 score. Noninferiority P values were calculated. Results: Complete fusion of all involved joints at 24 weeks as indicated by computed tomography was achieved in 53 of 63 (84%) rhPDGF-BB/β-TCP-collagen-treated patients and 100 of 154 (65%) autograft-treated patients (P < .001). Mean time to fusion was 14.3 ± 8.9 weeks for rhPDGF-BB/β-TCP-collagen patients versus 19.7 ± 11.5 weeks for autograft patients (P < .01). Clinical success at 52 weeks was achieved in 57 of 63 (91%) rhPDGF-BB/β-TCP-collagen patients and 120 of 154 (78%) autograft patients (P < .001). Safety-related outcomes were equivalent. Autograft controls had 2 bone graft harvest infections. Conclusions: Application of rhPDGF-BB/β-TCP-collagen was a safe, effective alternative to autograft for ankle and hindfoot fusions, eliminating the pain and morbidity associated with autograft harvesting. Level of Evidence: Level I, prospective randomized study.

Pain syndrome with stress fractures in transplanted patients treated with calcineurin inhibitors

Bone disease remains a major cause of morbidity after renal transplantation. Post-transplant osseous complications include osteoporosis and osteonecrosis, both historically associated with glucocorticoids, and a newer syndrome of bone pain associated with calcineurin inhibitors. Calcineurin inhibitor-induced pain syndrome (CIPS) is a reversible etiology of lower extremity bone pain and bone marrow edema reported in patients receiving cyclosporine or tacrolimus after solid organ or bone marrow transplantation. While the syndrome’s pathophysiology is unclear, bone insufficiency and epiphyseal impaction may play a role. We review the literature on this increasingly important post-transplant entity and describe a case illustrating the syndrome’s key features.

Clinical Outcomes of Nonunions of Hindfoot and Ankle Fusions.

BACKGROUND While nonunion after foot and ankle fusion surgery has been associated with poor outcomes, we are not aware of any longitudinal study on this subject. Thus, we prospectively evaluated the impact of nonunion on clinical outcomes of foot and ankle fusions and identified potential risk factors for nonunion after these procedures. METHODS Using data from a randomized clinical trial on recombinant human platelet-derived growth factor-BB (rhPDGF-BB; Augment Bone Graft, BioMimetic Therapeutics), union was defined either by assessment of computed tomography (CT) scans at 24 weeks by a reviewer blinded to the type of treatment or by the surgeons composite assessment of clinical and radiographic findings at 52 weeks and CT findings at 24 or 36 weeks. The nonunion and union groups (defined with each assessment) were then compared in terms of clinical outcome scores on the American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), Foot Function Index (FFI), and Short Form-12 (SF-12) as well as age, sex, body mass index (BMI), smoking status, diabetes status, work status, and arthrodesis site. RESULTS Blinded CT assessment identified nonunion in 67 (18%) of 370 patients, and surgeon assessment found nonunion in 21 (5%) of 389 patients. Postoperatively, the nonunion group scored worse than the union group, regardless of the method used to define the nonunion, on the AOFAS-AHS and FFI, with mean differences of 10 and 12 points, respectively, when nonunion was determined by blinded CT assessment and 19 and 20 points when it was assessed by the surgeon. The nonunion group also had worse SF-12 Physical Component Summary scores. Differences between the union and nonunion groups were clinically meaningful for all outcome measures, regardless of the nonunion assessment method. The concept of an asymptomatic nonunion (i.e., imaging indicating nonunion but the patient doing well) was not supported. Patients with nonunion were more likely to be overweight, smokers, and not working. CONCLUSIONS This prospective longitudinal study demonstrated poorer functional outcomes in patients with a nonunion after foot and ankle fusion, regardless of whether the diagnosis of nonunion was based on CT only or on combined clinical, radiographic, and CT assessment. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Burn scar regeneration with the “SUFA” (Subcision and Fat Grafting) technique. A prospective clinical study

Summary Background Treatment of burn scars with traditional surgical techniques is challenging due to recurrent contractures. Fat grafting has been previously used in small clinical series and results are often biased by lack of scientific validating methods. Fat grafting in clinical practice is often evaluated for its filler properties and rarely scientifically validated for its potential in dermal regeneration. Animal studies have shown dermal regeneration with new deposition and reorientation of the collagen fiber. Our study aims to apply the validity of in vitro studies to clinical practice. Methods Our study prospectively evaluated outcomes in 12 patients treated with the “SUFA” technique (Subcision and Fat Grafting) for debilitating contracted burns scars limiting range of motion. Results were evaluated clinically with the Vancouver scale and by range of motion at 1, 3, 6 and 12 months. Dermal regeneration was evaluated by looking at dermis thickening using high definition ultrasound and scar remodeling looking at reorientation and new deposition of collagen fibers with hematoxylin-eosin histology and monoclonal antibodies against collagen type 1 and 3. Results Statistically significant clinical improvements in range of motion of the affected joints was observed (P<0.05). Fat reabsorption occurred with a mean of 40%. Thickening of dermis and redistribution and reorientation of the collagen fibers within the dermis was also demonstrated. Conclusions Our results present the first clinical scientific evidence of dermal regeneration in fat grafting. Using monoclonal antibodies and high definition ultrasounds, we demonstrate the first evidence of dermis regeneration in a clinical scenario.

Rapid-Onset Diffuse Skeletal Fluorosis from Inhalant Abuse

Case: A thirty‐year‐old man presented with severely debilitating left hip pain and stiffness. Radiographs demonstrated diffuse osteosclerosis and heterotopic bone formation with near ankylosis of the left hip. The patient underwent successful joint‐preserving surgery to restore hip range of motion. After disclosing a history of inhalant abuse, which was confirmed by elevated serum fluoride levels, he was diagnosed with diffuse skeletal fluorosis. Conclusions: To the best of our knowledge, we present the first reported case of diffuse skeletal fluorosis caused by inhalant abuse of 1,1‐difluoroethane. Skeletal fluorosis is uncommon in the United States but is important to consider in the differential diagnosis when a patient presents with otherwise unexplained joint pain and osteosclerosis.