Article

Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Purpose: Total knee arthroplasty (TKA) implanted in patients with secondary osteonecrosis (ON) related to corticosteroids have relatively poor outcome (20% revision rate) at a mean follow-up of only eight years. With the hypothesis that subchondral bone marrow injection might improve knees in these patients, we evaluated 30 patients who had bilateral knee osteoarthritis with severe joint space narrowing and received TKA in one knee and subchondral bone marrow concentrate injection in the contralateral knee. Material and methods: A prospective randomized controlled clinical trial was carried out in 60 knees of 30 patients (mean age 28 years, 18-41) who presented bilateral osteoarthritis secondary to knee ON related to corticosteroids in relation with different severe medical conditions. During the same anesthesia, one knee received TKA; for the other knee, a bone marrow graft containing an average of 6500 MSCs/mL (counted as CFU-F, range 3420 to 9830) was delivered to the subchondral bone of the femur and tibia. The length of anesthesia related to each procedure (bone marrow aspiration and subchondral injection of concentrated bone marrow versus total knee arthroplasty) was measured. Peri-operative outcomes, morbidity, complications, and safety of the two procedures were compared. Subsequent admissions for revision surgery were identified. At the most recent follow-up (average of 12 years, range 8 to 16 years), clinical outcomes of the patient (Knee Society score) were obtained along with radiological imaging outcomes (MRIs for knees with subchondral bone marrow injection). Results: Anesthesia related to the TKA side was longer than for the cell therapy group. Medical and surgical complications were more frequent after TKA. A higher number of thrombophlebitis was observed on the side with TKA (15%) versus none on the side with cell therapy (0%). At the most recent follow-up (average of 12 years, range 8 to 16 years), six (out of 30) TKA knees needed subsequent surgery versus only one with cell therapy. The Knee Score had improved and remained similar in the TKA and cell therapy groups (respectively 80.3 points ± 11 versus 78.3 ± 23); 21 patients preferred the knee with cell therapy and 9 preferred the knee with TKA. Knees with cell therapy had improvement on cartilage and bone marrow lesions observed at the site of bone marrow subchondral injection. Conclusions: Subchondral autologous bone marrow concentrate was an effective procedure for treating young patients with knee osteoarthritis following secondary ON of the knee related to corticosteroids with a lower complication rate and a quicker recovery as compared with TKA.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The ten studies investigating BMAC involved 1710 knees from 1386 patients affected by OA. The concentrate was injected intra-articularly in 8 studies [16][17][18][19][20][21][22][23] and within the tibial and femoral subchondral bones in two other papers [24,25]. The aspirated bone marrow was centrifuged without any other manipulation, expansion, or culture before administering it to the patients. ...
... Regarding the therapeutic protocol, five papers dealt with the administration of BMAC alone: two of these involved subchondral BMAC injections [24,25], whilst in the remaining three, BMAC was injected intra-articularly [16][17][18]. Of these last three papers, one study involved the administration of 4 sequential injections within a 3-month timespan [17]. ...
... In regard to the clinical outcome, the majority of authors employed reliable clinical scores (such as those derived from WOMAC, IKDC, KOOS, or KSS), whereas only a few authors used less known questionnaires, improvement rating scores, or patient satisfaction [17,[20][21][22]. All studies assessed pain through a visual or numerical score such as VAS or NPS, except for two authors [18,25] who included WOMAC and KSS questionnaires, which have sections on patient pain. Finally, three authors performed MRI prior to and following the procedure [19,24,25]. ...
Article
Full-text available
Background: The use of laboratory-expanded mesenchymal stem cells (MSCs) is subject to several restrictions, resulting in "minimal manipulation" methods becoming the current most popular strategy to increase the use of MSCs in an orthopaedic practice. The aim of the present systematic review is to assess the clinical applications of "minimally" manipulated MSCs, either as bone marrow aspirate concentrate (BMAC) or as stromal vascular fraction (SVF), in the treatment of knee osteoarthritis (OA). Methods: A systematic review of three databases (PubMed, ScienceDirect, and Google Scholar) was performed using the following keywords: "Knee Osteoarthritis" with "(Bone marrow aspirate) OR (bone marrow concentrate)" or with "(adipose-derived mesenchymal stem cells) OR (adipose derived stromal cells) OR (stromal vascular fraction) OR (SVF)" as either keywords or MeSH terms. The reference lists of all retrieved articles were further reviewed for identification of potentially relevant studies. Results: Twenty-three papers were included in the final analysis (10 on BMAC and 13 on SVF). Of these, only 4 were randomized controlled trials (RCTs). Bias risk evaluation, performed using a modified Coleman score, revealed an overall poor quality of the studies. In terms of clinical application, despite the apparent safety of minimally manipulated MSCs and the short-term positive clinical outcomes associated with their use, clinicians reported different preparation and administration methods, ranging from single intra-articular injections to intraosseous applications to administration in combination with other surgical procedures. Conclusions: The available literature is undermined by both the lack of high-quality studies and the varied clinical settings and different protocols reported in the few RCTs presently published. This prevents any recommendation on the use of either product in a clinical practice. Nevertheless, the use of minimally manipulated MSCs (in the form of BMAC or SVF) has been shown to be safe and have some short-term beneficial effects.
... However, five studies were excluded being congress abstracts, one study was excluded because it was a case report [25], and one study was excluded because it provided the same data of another included study [26]. Thus, a total of 22 studies were included in the qualitative data synthesis: 4 preclinical studies [27][28][29][30] and 18 clinical studies [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Since the first reports in 2014, the publication trend remarkably increased over time, especially for the clinical studies, with over 50% of the articles published from 2018 (Fig. 2). ...
... Out of the 18 clinical articles found (Table 2), six were retrospective case series, five were retrospective comparative studies, four were randomized controlled trials (RCTs), and three were prospective case series. Eleven studies focused on knee OA [31][32][33][34][35][36][37][38][39][40][41], two focused on hip OA [42,43], two focused on shoulder OA [44,45], while the other three studies described several joints affected by OA [46][47][48]. Intra-articular BMAC injections were performed in 17 studies, while in one study [36], the injection was performed within the tibial and femoral subchondral bone of the knee. ...
... Eleven studies focused on knee OA [31][32][33][34][35][36][37][38][39][40][41], two focused on hip OA [42,43], two focused on shoulder OA [44,45], while the other three studies described several joints affected by OA [46][47][48]. Intra-articular BMAC injections were performed in 17 studies, while in one study [36], the injection was performed within the tibial and femoral subchondral bone of the knee. The most common injection schedule was the single injection (16 articles), while a four injection schedule was studied in two articles [37,42]. ...
Article
Full-text available
PurposeTo investigate the available literature on the use of bone marrow aspirate concentrate (BMAC) and summarize the current evidence supporting its potential for the injective treatment of joints affected by osteoarthritis (OA).MethodsA systematic literature search was conducted on three electronic databases (PubMed, Embase, and Cochrane Library) in April 2020, using the following string: “((bone marrow concentrate) OR (BMC) OR (bone marrow aspirate concentrate) OR (BMAC)) AND (osteoarthritis)”, and inclusion criteria: clinical and preclinical (animal) studies of any level of evidence, written in English language, and evaluating the intra-articular or subchondral use of BMAC for the injective treatment of OA joints.ResultsThe publication trend remarkably increased over time. A total of 22 studies were included in the qualitative data synthesis: four preclinical studies and 18 clinical studies, for a total number of 4626 patients. Safety was documented by all studies, with a low number of adverse events. An overall improvement in pain and function was documented in most of the studies, but the clinical studies present significant heterogeneity, few patients, short-term follow-up, and overall poor methodology.Conclusion There is a growing interest in the field of BMAC injections for the treatment of OA, with promising results in preclinical and clinical studies in terms of safety and effectiveness. Nevertheless, the current knowledge is still preliminary. Preclinical research is still needed to optimize BMAC use, as well as high-level large controlled trials to better understand the real potential of BMAC injections for the treatment of patients affected by OA.
... Surgical interventions include joint-preserving surgery, total knee arthroplasty (TKA), unilateral knee arthroplasty (UKA), core decompression, and high tibial osteotomy [2]. Since the late 1990s, investigations of biologic materials, including autologous bone marrow concentrate (BMC) and platelet-rich plasma (PRP), have shown promise in treating a variety of musculoskeletal pathologies [10][11][12][13][14][15]. For bone marrow lesions and AVN in particular, the proposed therapeutic mechanism of action involves the repopulation of the subchondral microenvironment with healthier mesenchymal signaling cells (MSCs) transferred via concentrated bone marrow aspirated from a different anatomic location [14]. ...
... Since the late 1990s, investigations of biologic materials, including autologous bone marrow concentrate (BMC) and platelet-rich plasma (PRP), have shown promise in treating a variety of musculoskeletal pathologies [10][11][12][13][14][15]. For bone marrow lesions and AVN in particular, the proposed therapeutic mechanism of action involves the repopulation of the subchondral microenvironment with healthier mesenchymal signaling cells (MSCs) transferred via concentrated bone marrow aspirated from a different anatomic location [14]. Over time, procedural techniques for minimally invasive percutaneous applications of these therapies have spawned the novel field of interventional orthopedics to serve as a bridge between traditional conservative care and surgery [16]. ...
... This study included a comparative analysis of MSCs per mL of bone marrow aspirated from the diseased areas of the femurs and tibias to that of the iliac crests, from which aspirate was harvested to produce BMC. The results showed a greater than 10-fold decrease in MSCs per mL in the diseased bone compared with the iliac crest samples [14]. Therefore, the proposed mechanism of action for therapeutic efficacy is the use of bone marrow harvested and concentrated from a healthier location as a method of repopulating MSCs in the diseased ON lesions. ...
Article
Osteonecrosis (ON) is a painful condition involving bony cell death with resultant architectural collapse. This report discusses the case of a 50-year-old Caucasian female who presented to an outpatient musculoskeletal clinic with severe chronic left knee pain. She had a history of ulcerative colitis and resultant chronic corticosteroid exposure with subsequent development of knee ON. She was treated with an intraosseous autologous bone marrow concentrate (BMC), demineralized bone matrix (DBM), and platelet-rich plasma (PRP) injection. At 11 months post-injection, she demonstrated a significant improvement in pain scores, mobility, activity, and decreased narcotic use. Intraosseous orthobiologic injection for the treatment of knee ON is a promising procedure with a reasonable safety profile that warrants further study as an alternative to surgical intervention.
... There were 17 patients with ARDS from influenza A (H7N9) who were treated with 3 to 4 IV doses commonly used MSCs in the United States (68,70). Despite spending billions of dollars, conventional treatment has been uninspiring in treating back pain. ...
... MSC therapy seems to be filling this void and hopefully can mitigate the numerous problems associated with intractable pain, including opioid abuse (71). Early clinical trials have demonstrated that MSCs can be a valuable alternative for joint replacements and spinal fusions (68,70). Because preliminary evidence shows that MSCs have the potential to make strides in recalcitrant back and joint pain, especially in those who have failed conventional therapies, it is worthwhile to explore the role of MSCs in complicated COVID-19 patients, as meaningful alternatives do not currently exist. ...
... These studies have demonstrated that MSCs are capable of improving organ function by regeneration. Bone marrow stem cells have a 30-year history of safety and efficacy in the musculoskeletal arena (68). A meta-analysis of various studies using biologics to treat back pain has been encouraging (69). ...
Article
Background: Although only a small percentage of patients with COVID-19 deteriorate to a critical condition, because of the associated high mortality rate and the sheer number of cases, it imposes a tremendous burden on the society and unprecedented strains the health care resources. Albeit lung is the primary organ involved resulting in acute respiratory distress syndrome (ARDS), many patients additionally present with secondary multiorgan failure. Unfortunately, there is no definitive or curative treatment for this condition, and the management has been predominantly confined to supportive care, which necessitates an urgent need for novel therapies. Mesenchymal stem cell (MSC) therapy has a vast array of preclinical data and early, preliminary clinical data that suggests its potential to regenerate and restore the function of damaged tissues and organs. To date, there has been no review of all the clinical trials that have assessed the safety and efficacy of MSC therapy in organ failure commonly seen in seriously complicated COVID-19 patients. Objectives: To evaluate the effectiveness of MSC therapy in managing multiorgan failure, utilizing currently available literature. Study design: A review of human randomized controlled trials (RCTs) and observational studies assessing the role of MSC therapy in managing multiorgan failure. Methods: PubMed, Cochrane Library, US National Guideline Clearinghouse, Google Scholar, and prior systematic reviews and reference lists were utilized in the literature search from 1990 through May 2020. Studies that included embryonic stem cells, induced pluripotent stem cells, differentiated MSCs into specific lineage cells, and hematopoietic stem cells were excluded. Trials with intraorgan infiltration of MSC were also excluded. Outcome measures: The primary outcome evaluated the improvement in clinical assessment scores and indices of organ function. The secondary outcome assessed the safety of MSC therapy in the clinical trials. Results: Based on search criteria, 12 studies were found for lung, 52 for heart, 23 for liver, 16 for stroke, and 9 for kidney. Among the 6 studies that specifically assessed the effectiveness of MSC therapy in ARDS, 4 showed positive outcomes. Forty-one of the 52 trials that examined ischemic and nonischemic heart failure reported beneficial effects. Twenty of 23 trials for liver failure from different etiologies revealed favorable outcomes. Nine out of the 15 studies evaluating stroke had satisfactory effects. However, only 3 out of the 9 studies for kidney failure showed positive results. Nonexpanded bone marrow mononuclear cells were used in most of the negative studies. The incidence of disease worsening or major complications was extremely rare from MSC therapy. Limitations: Among the studies evaluated, although there were many RCTs, there were also numerous case series. Additionally, most recruited a small number of patients. Conclusions: MSC therapy seems to be promising to treat multiorgan failure from COVID-19. More studies are urgently needed to assess both safety and efficacy.
... Treatments consist of the administration of bone marrow concentrates [14] in the joint or in a scaffold impacted on the subchondral bone [15] or directly in the subchondral bone. The last application [16] has been designed to target the subchondral bone which is frequently affected by the OA processes. The advent of MRI during the two last decades has underlined the role of the subchondral bone in OA pathology [17]. ...
... In a prospective randomized controlled clinical trial [16] carried out in 60 knees of 30 young patients who presented bilateral OA, one knee received a total knee arthroplasty (TKA) and the other knee received a subchondral bone marrow graft. At a follow up of average of 12 years (range 8 to 16 years), six (out of 30) TKA knees needed subsequent surgery versus only 1 with cell therapy. ...
Article
Full-text available
The value of bone marrow aspirate concentrates for treatment of human knee cartilage lesions is unclear. Most of the studies were performed with intra-articular injections. However, subchondral bone plays an important role in the progression of osteoarthritis. We investigated by a literature review whether joint, subchondral bone, or/and scaffolds implantation of fresh autologous bone marrow aspirate concentrated (BMAC) containing mesenchymal stem cells (MSCs) would improve osteoarthritis (OA). There is in vivo evidence that suggests that all these different approaches (intra-articular injections, subchondral implantation, scaffolds loaded with BMAC) can improve the patient. This review analyzes the evidence for each different approach to treat OA. We found that the use of intra-articular injections resulted in a significant relief of pain symptoms in the short term and was maintained in 12 months. However, the clinical trials indicate that the application of autologous bone marrow concentrates in combination with scaffolds or in injection in the subchondral bone was superior to intra-articular injection for long-term results. The tendency of MSCs to differentiate into fibrocartilage affecting the outcome was a common issue faced by all the studies when biopsies were performed, except for scaffolds implantation in which some hyaline cartilage was found. The review suggests also that both implantation of subchondral BMAC and scaffolds loaded with BMAC could reduce the need for further surgery.
... In this manner, a practical regenerative approach for OA is to enhance the performance of the subchondral bone by introducing additional bone marrow derived MSCs, to maintain osteochondral tissue homeostasis and prevent further cartilage loss. Some exciting results from a series of clinical trials have just been released by Hernigou et al. (2018Hernigou et al. ( , 2020a (Table 3), with clinical data of up to 15 years of follow-ups. Patients with different OA conditions (moderate to advanced OA, 60 cases; advanced OA, 140 cases; OA secondary to knee osteonecrosis related to corticosteroids, 30 cases) were recruited. ...
... In the 140-case study, patients scheduled for TKA who were administrated subchondral injection of BMSCs reported good joint preservation results after 15 years of follow up (Hernigou et al., 2020b). In the young osteonecrosis patients, 96% of those who received subchondral bone MSC injection showed postponement of the first TKA for more than 10 years, while a 20% revision rate was found in the TKA treatment group (Hernigou et al., 2018). Subchondral bone MSCs treatment was found to be applicable for both early and late stage OA in terms of subchondral bone remodeling and joint preservation. ...
Article
Full-text available
There is emerging awareness that subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). This review presents recent investigations on the cellular and molecular mechanism of subchondral bone remodeling, and summarizes the current interventions and potential therapeutic targets related to OA subchondral bone remodeling. The first part of this review covers key cells and molecular mediators involved in subchondral bone remodeling (osteoclasts, osteoblasts, osteocytes, bone extracellular matrix, vascularization, nerve innervation, and related signaling pathways). The second part of this review describes candidate treatments for OA subchondral bone remodeling, including the use of bone-acting reagents and the application of regenerative therapies. Currently available clinical OA therapies and known responses in subchondral bone remodeling are summarized as a basis for the investigation of potential therapeutic mediators.
... Although the intra-articular use of these products for the treatment of knee OA provided positive results, the improvement in terms of pain relief and function remains partial and not always satisfactory [1,7]. Thus, a new application has been recently proposed to further exploit the potential of biologic products by also targeting the subchondral bone [21]. This strategy is supported by the substantial evidence revealing that subchondral bone alterations may play a critical role in both the pathophysiology and progression of knee OA [40]. ...
... Vad et al. used tibial BMA for the combined subchondral and intra-articular treatment of ten patients with unicompartmental knee OA, showing improvements in pain and function up to 12 months [42]. The first evidence on the subchondral BMAC injections to address knee OA has been documented in a randomized clinical trial (RCT) by Hernigou et al., which treated 30 young patients (mean age 28 years) with bilateral knee OA secondary to osteonecrosis with BMAC injections on one side, and with TKA on the other side [21]. In this study, subchondral BMAC injections provided similar clinical results compared with TKA, with a lower complication rate and a quicker recovery. ...
Article
PurposeSubchondral bone is becoming a treatment target for knee OA patients, with promising early findings on the use of bone marrow aspirate concentrate (BMAC). The aim of this prospective, multi-centric pilot study was to evaluate safety as well as clinical and MRI outcomes of a combined approach of intra-articular and subchondral BMAC injections.Methods Thirty patients (19 men, 11 women, 56.4 ± 8.1 years) with symptomatic knee OA were treated with a combination of an intra-articular and two subchondral BMAC injections (femoral condyle and tibial plateau). Patients were evaluated at baseline and at 1–3–6–12 months of follow-up with the IKDC subjective, VAS, KOOS, and EQ-VAS scores. The MRI evaluation was performed with the WORMS score.ResultsNo major complications were reported and only two patients were considered treatment failures, requiring a new injective or surgical treatment. The IKDC subjective score improved significantly from 40.5 ± 12.5 to 59.9 ± 16.1 at 3 months, 59.1 ± 12.2 at 6 months, and 62.6 ± 19.4 at 12 months (p < 0.0005). A similar improvement was reported for VAS pain and all KOOS subscales at all follow-ups, while EQ-VAS did not show any significant improvement. The MRI analysis showed a significant bone marrow edema reduction (p = 0.003), while the remaining WORMS parameters did not show any significant changes.Conclusion The pilot evaluation of this combined BMAC injective treatment showed safety and positive outcome up to 12 months of follow-up in patients with symptomatic knee OA associated with subchondral bone alterations. These findings suggest that targeting both subchondral bone and joint environment can provide promising results, and that BMAC can be a valid option for this combined approach to treat knee OA.
... Answers to these ardent questions are in work with different types of studies coming from leading schools all over the globe. A current debate and high-volume research will be outlined in a special issue dedicated to osteonecrosis and different modern methods of treatment including stem cell therapies and edited by Philippe Hernigou from France [20,21]. Powerful data is in work in Italy in preparation for the special issue dedicated to this strong orthopaedic school represented by Francesco Falez and his service from Rome. ...
... Indeed, in knee joints previously treated with concentrated adipose tissue infusion, we detected the presence of new tissue formation starting from the bone side of the osteochondral lesion, with the presence of a strong bone remodeling, whereas in joint of untreated cases, this neo-tissue formation was not evident. The effective subchondral bone formation has also been shown in knee condyle osteonecrosis, where treatment with bone marrowderived MSCs showed improvement on cartilage and bone marrow lesions observed at the site of bone marrow subchondral injection [30]. The reported data suggest an initial subchondral healing process, which could be followed by reconstruction of the chondroid matrix. ...
Article
Full-text available
Purpose Osteoarthritis (OA) is characterized by articular cartilage degeneration and subchondral bone sclerosis. OA can benefit of non-surgical treatments with collagenase-isolated stromal vascular fraction (SVF) or cultured-expanded mesenchymal stem cells (ASCs). To avoid high manipulation of the lipoaspirate needed to obtain ASCs and SVF, we investigated whether articular infusions of autologous concentrated adipose tissue are an effective treatment for knee OA patients. Methods The knee of 20 OA patients was intra-articularly injected with autologous concentrated adipose tissue, obtained after centrifugation of lipoaspirate. Patients’ articular functionality and pain were evaluated by VAS and WOMAC scores at three, six and 18 months from infusion. The osteogenic and chondrogenic ability of ASCs contained in the injected adipose tissue was studied in in vitro primary osteoblast and chondrocyte cell cultures, also plated on 3D-bone scaffold. Knee articular biopsies of patients previously treated with adipose tissue were analyzed. Immunohistochemistry (IHC) and scanning electron microscopy (SEM) were performed to detect cell differentiation and tissue regeneration. Results The treatment resulted safe, and all patients reported an improvement in terms of pain reduction and increase of function. According to the osteogenic or chondrogenic stimulation, ASCs expressed alkaline phosphatase or aggrecan, respectively. The presence of a layer of newly formed tissue was visualized by IHC staining and SEM. The biopsy of previously treated knee joints showed new tissue formation, starting from the bone side of the osteochondral lesion. Conclusions Overall our data indicate that adipose tissue infusion stimulates tissue regeneration and might be considered a safe treatment for knee OA.
... Nevertheless, this study was criticized for its small number and for methodological shortcomings [29]. Hernigou et al. used autologous subchondral stem injections in corticosteroid-induced bilateral osteonecrosis of the knee in 30 young patients in one knee and total knee arthroplasty in the other knee and reported at an average follow-up of 12 years results favouring the use of subchondral bone marrow injections [30]. ...
Article
Full-text available
Purpose Based on the irreversible destruction of hyaline cartilage, post-traumatic osteoarthritis (PTOA) is a notorious sequalae after interarticular knee fractures. This study evaluates the clinical efficacy and applicability of immediate post-operative intra-articular injection of hyaluronic acid (IA HA) into the knee joint with an intra-articular fracture. Methods Prospective randomized case-control study involving 40 patients (20 in each group) with intra-articular knee fracture with an average follow up of 23 months (range 18m -24m). 20 patients with intraarticular distal femoral or intraarticular proximal tibial fractures who met our inclusion criteria received three intra-articular hyaluronic acid injections weekly starting immediately after ORIF. Another 20 patients serving as control group received no injection after ORIF. Patients were assessed functionally with Knee injury and Osteoarthritis Outcome Score (KOOS) and IKDC International Knee Documentation Committee (IKDC) score. Plain Xrays and when indicated CT scans were used to assess radiological union. Results The results showed patients treated with intra-articular Hyaluronic acid injection after fixation had significantly less pain (KOOS) (P = 0.01). No significant difference was found between both groups in other KOOS related outcome measures, complications, functional outcome or quality of life. Conclusions These preliminary results support a direct role for hyaluronic acid in the acute phase of the inflammatory process that follows articular injury and provides initial evidence for the efficacy for IA HA. Level of Evidence: Level 2
... Darüber hinaus sollte eine Level-III-Studie der Arbeitsgruppe von Garay-Mendoza [10], in der nach einer Nachbeobachtungszeit von 6 Monaten eine U¨berlegenheit der BMAC-Therapie gegenüber Acetaminophen p.o. (per os) festgestellt wurde, und eine randomisierte, einfach-verblindete und Placebo-kontrollierte Studie von Shapiro, in der der Vorteil einer Kombination von BMAC und PRP gegenüber einer Placebo-Injektion (NaCl) an 50 Kniegelenken mit bilateraler Arthrose im 1-Jahres-Followup hervorgehoben werden [34]. Ebenfalls interessant ist die Studie von Hernigou et al., die 30 Patienten mit bilateraler Osteonekrose unilateral mit einer KTEP (Knietotalendoprothese) versorgten und kontralateralen Knie BMAC injizierten[12]. Interessanterweise war der der PROM (Patient-Reported Outcome Measure) in beiden Gruppen gleich hoch, bei jedoch einer höheren Komplikationsrate in der KTEP-Gruppe. ...
Zusammenfassung Die „Stammzelltherapie“ ist in aller Munde; nicht nur im wissenschaftlichen Kontext, sondern auch im populärwissenschaftlichen, sodass das Interesse und auch die Hoffnungen auf Arzt- und Patientenseite groß sind. Potentiell besitzen Stammzellen ein großes Indikationsspektrum, das neben der Knorpel- auch die Meniskus- und Bandregeneration miteinschließt. Für letztere Indikationen liegen zwar präklinische und vereinzelte klinische Studien vor, jedoch werden hier einerseits sehr unterschiedliche Konzepte verfolgt und andererseits liegt eine große Heterogenität der applizierten Zellen und eine Unschärfe der Terminologie der Stammzelle vor, sodass die ersten Ergebnisse als vielversprechend eingestuft werden können, es aber noch kontrollierter Studien bedarf, bevor diese Therapien für die Meniskus- und Bandregeneration in den klinischen Alltag Einzug erhalten. Im Vergleich zu Anwendungen an den Menisken und dem Bandapparat ist die Anwendung von „Stammzellen“ zur Behandlung von fokalen Knorpelschäden – wo im Vergleich zur etablierten ACT (Autologen Chondrozyten Transplantation) vergleichbare Ergebnisse gezeigt werden konnten – und der Arthrose besser untersucht und weiterverbreitet, weshalb im Folgenden auf die Injektionstherapie bei Arthrose im Detail eingegangen werden soll.
... Accessed May 20, 2020) with their efficacy reported against a wide variety of injuries and diseases, coupled with an established safety record in human patients [17]. In bone regeneration, several clinical studies have demonstrated MSCs to be safe and efficacious for the treatment of bone defects and diseases such as osteonecrosis [18][19][20][21][22]. Despite their therapeutic effects, cellular MSC therapies incur significant costs and challenges as they require stringently monitored manufacturing, handling, and storage to ensure optimal viability and potency of cells needed for transplantation [23]. ...
Article
Full-text available
The ability of bone for regeneration has long been recognized. However, once beyond a critical size, spontaneous regeneration of bone is limited. Several studies have focused on enhancing bone regeneration by applying mesenchymal stromal/stem cells (MSCs) in the treatment strategies. Despite the therapeutic efficacy of MSCs in bone regeneration, cell-based therapies are impeded by several challenges in maintaining the optimal cell potency and viability during expansion, storage and final delivery to patients. Recently, there has been a paradigm shift in therapeutic mechanism of MSCs in tissue repair from one based on cellular differentiation and replacement to one based on secretion and paracrine signalling. Among the broad spectrum of trophic factors, extracellular vesicles (EVs) particularly the exosomes have been reported to be therapeutically efficacious in several injury/disease indications, including bone defects and diseases. The current systematic review aims to summarize the results of the existing animal studies which were conducted to evaluate the therapeutic efficacy of MSC exosomes for bone regeneration. Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, the PubMed and The Cochrane Library database were searched for relevant controlled preclinical animal studies. A total of 23 studies were identified, with the total sample size being 690 rats or mice and 38 rabbits. Generally, MSC exosomes were found to be efficacious for bone regeneration in animal models of bone defects and diseases such as osteonecrosis and osteoporosis. In these studies, MSC exosomes promoted new bone formation with supporting vasculature, and displayed improved morphological, biomechanical and histological outcomes, coupled with positive effects on cell survival, proliferation and migration, osteogenesis and angiogenesis. Unclear-to-low risk in bias and incomplete reporting in the primary studies highlighted the need for standardization in outcome measurements and reporting. Further studies in large animal models to establish the safety and efficacy would provide useful information on guiding the design of clinical trials.
... The ADSC regenerative and anti-inflammatory effects in OA are well documented in both preclinical and clinical studies [6,7]. With respect to culture expansion, a one-step approach based on bone marrow concentrate (BMC) or stromal vascular fraction (SVF) shows numerous advantages: the reduction of surgical times and cell manipulation and the transplantation of the cell niche in toto [8][9][10][11][12]. ...
Article
PurposeAiming to prevent cartilage damage during early osteoarthritis (OA), the therapeutic challenge is to restore and maintain the physiological and functional properties of such a tissue with minimally invasive therapeutic strategies.Methods Accordingly, an in vivo model of early OA in sheep was here treated through three different cell therapies (culture expanded ADSCs, SVF, and culture expanded AECs) thus to preserve the joint surface from the progression of the pathology. Three months after the treatment injections, their performance was assessed through mechanical automated mapping (Young’s modulus and cartilage thickness), gross evaluation of articular surfaces, and biochemical analysis of the synovial fluid.ResultsNo severe degeneration was observed after three months from OA induction. Cartilage mechanical properties were crucial to identify early degeneration. All the treatments improved the macroscopic cartilage surface aspect and reduced pro-inflammatory cytokines in the synovial fluid. Among the three treatments, SVF highlighted the best performance while ADSCs the worst.Conclusion Despite that the evaluated experimental time is an early follow-up and, thus, longer trial is mandatory to properly assess treatments effectiveness, the proposed multidisciplinary approach allowed to obtain preliminary, but also crucial, results concerning the reduction in OA signs on cartilage properties, in osteophyte development and in all the inflammatory markers.
... Cell therapy has been of growing interest in tissue engineering as it can have a wide variety of application supplementation and/or replacement of existing cells, recruitment of surrounding cells, and providing a therapeutic microenvironment for dying cells. In the case of osteoarthritis, cell therapy aims to help repair degenerating cartilage by regenerating articular chondrocytes and sometimes even the subchondral bone [20][21][22]. This can be done by providing a few types of cells along the chondrocyte lineage, such as injection of stem cells [23,24], chondroprogenitor cells [15,16], or even autologous chondrocytes [25,26]. ...
Article
Osteoarthritis (OA) is a chronic degenerative disease characterized by multiple pathological conditions such as synovitis, degeneration of the articular cartilage, subchondral bone remodeling, and osteophyte formation. Local chronic inflammation response induces degradation of cartilage and the poor regenerative ability of articular cartilage due to its avascular nature and limited regeneration of chondrocytes affecting the microenvironment of the joint. Current clinical treatments provide temporal pain relief but have failed to treat OA pathogenesis. In addition, surgical invasive methods have the risk of adverse complications such as long-term pain and increased morbidity. Therefore, there is a need to develop novel therapeutic strategies to prevent adverse effects seen in current surgical approaches. Minimally invasive therapies have been explored to overcome the limitations of conventional OA therapies. In recent years, cellular-based therapies have been employed to suppress inflammation and promote cartilage regeneration by using progenitor cells and stem cells including induced pluripotent stem cells (iPSCs) and genetically modified cells. The present review summarizes the status of cellular-based therapy for OA treatment. We suggest that minimally invasive intervention in the microenvironment of the joint may overcome the current limitation for OA treatment. Osteoarthritis is a chronic degenerative disease for which many therapies are insufficient in treating disease pathogenesis and instead provide transient symptomatic relieves such as pain and inflammation. Those treatments that do target the progression of the disease include surgical intervention and, depending on the age of the patient, these procedures may not even be an option. Minimally invasive cellular-based therapies help to lower the financial burden and attenuate disease progression rather than providing temporary relief of the symptoms. These cellular therapies are reviewed in this manuscript.
... Previous independent studies have documented an agerelated decline in BM-MSC numbers, measured either as CFU-F or CD271 + CD45counts, in healthy individuals [16,19,34]. Based on these results, some studies have suggested that the amount of harvested bone marrow should be adjusted according to the age of the patient, in order to 9 Stem Cells International achieve a target BM-MSC number for bone repair [34,48]. In our study, we have observed a slightly inverse correlation between donor age and the BM-MSC numbers in fresh samples. ...
Article
Full-text available
The potential use of bone marrow mesenchymal stromal cells (BM-MSCs) for the treatment of osteonecrosis in sickle cell disease (SCD) patients is increasing. However, convenient BM-MSC quantification and functional property assays are critical factors for cell-based therapies yet to be optimized. This study was designed to quantify the MSC population in bone marrow (BM) samples from SCD patients with osteonecrosis (SCD group) and patients with osteoarticular complications not related to SCD (NS group), using flow cytometry for CD271+CD45-/low cell phenotype and CFU-F assay. We also compared expanded BM-MSC osteogenic differentiation, migration, and cytokine secretion potential between these groups. The mean total cell number, CFU-F count, and CD271+CD45-/low cells in BM mononuclear concentrate were significantly higher in SCD than in NS patients. A significant correlation between CD271+CD45-/low cell number and CFU-F counts was found in SCD (r = 0.7483; p = 0.0070) and NS (r = 0.7167; p = 0.0370) BM concentrates. An age-related quantitative reduction of CFU-F counts and CD271+CD45-/low cell number was noted. Furthermore, no significant differences in the morphology, replicative capacity, expression of surface markers, multidifferentiation potential, and secretion of cytokines were found in expanded BM-MSCs from SCD and NS groups after in vitro culturing. Collectively, this work provides important data for the suitable measurement and expansion of BM-MSC in support to advanced cell-based therapies for SCD patients with osteonecrosis.
... Концентрацию тромбоцитов в получаемой ОТП рассчитывали с помощью гематологического анализатора "Erba Elite 3", (Чехия), а ОТП кодировали согласно международной согласительной классификации PRP (platelet-rich plasma), принятой в 2020 г. [15]. ...
Article
Full-text available
The aim of the study was to determine the effectiveness of autologous bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP) intraosseous injection in the treatment of patients with knee OA stages II-III. Materials and Methods. The multicenter randomized study involved 40 patients (27 women, 13 men, average age 67.07.8 years, BMI 32.74.8, duration of disease 17.33.7 months) with knee OA of stages II-III according to the Kellgren-Lawrence (K-L) classification. Patients of the main (BMAC group) group (n = 19) underwent a single intraosseous injection of BMAC, in the comparison group (n = 21) a PRP injection (PRP group). The results were evaluated after 1, 3, 6, 12 months with the verbal rating scale (VRS), VAS, Leken and WOMAC scales. Results. Comparison of the results in the groups on the VRS showed that at an earlier time (3 and 6 months), the preferences of patients were in favor of the treatment of BMAC (65% and 55% positive reviews) before PRP (55% and 45% positive reviews), whereas after 12 months the differences were insignificant. Analysis of VAS indicators in patients of both groups indicated a more pronounced decrease in the severity of pain syndrome after BMAC intraosseous injection. The analysis of the Leken scale indicators showed in favor of BMAC throughout the entire observation period, the differences were most pronounced in the first 3 months of observation. The ratio of the values of the WOMAC index in both patients groups indicated statistically significant differences that persisted in all periods of follow-up, the increase in indicators occurred to a lesser extent after the introduction of BMAC compared with PRP. Conclusion. A single intraosseous BMAC injection has an advantage over a similar PRP injection in terms of pain, knee function and physical activity of patients at all follow-up periods. Both methods of treatment are equally safe.
... BMAC demonstrated an overall improvement in pain and function but did not demonstrate superiority over the other intra-articular options, and its effects did not outperform saline controls after 12 months of followup [138]. When combined with platelet products, BMAC injections demonstrated better results than exercise therapy in knee OA patients at 24 months of follow-up [139] and had similar results compared with total knee arthroplasty in younger patients with knee OA secondary to corticosteroid-related osteonecrosis at an average of 12 years of follow-up [140]. Further studies are needed to support routine clinical use. ...
Article
Full-text available
Purpose of Review To present a synthesis of recent literature regarding the treatment of patellofemoral arthritis Recent Findings Risk factors of PFJ OA include patella malalignment or maltracking, injury to supportive structures including the MPFL, dysfunction of hamstring and quadriceps coordination, lower limb alignment, trochlear dysplasia, patellar trauma, or ACL surgery. Special physical exam maneuvers include patellar grind test, apprehension test, and lateral patellar tilt angle. Radiographs that should be obtained first-line include weight bearing bilateral AP, lateral, and Merchant views. CT and MRI are used to assess trochlear dysplasia, excessive patellar height, and TT-TG distance. Non-operative management options discussed include non-pharmacologic treatment (patient education, self-management, physical therapy, weight loss), ESWT, cold therapy, taping, bracing, and orthotics. Pharmacologic management options discussed include NSAIDs, acetaminophen, oral narcotics, and duloxetine. Injection therapies include glucocorticoids, hyaluronic acid, PRP, and other regenerative therapies (BMAC, adipose, or mesenchymal stem cells). Other treatment options include radiofrequency ablation and botulinum toxin. The algorithm for the surgical treatment of PFJ OA can begin with arthroscopic assessment of the PF articular cartilage to address mechanical symptoms and to evaluate/treat lateral soft tissue with or without overhanging lateral osteophytes. If patients fail to have symptomatic improvement, a TTO can be considered in those patients less than 50 years of age or active patients >50 years old. In patients with severe PFJ OA, refractory to the above treatments, PFA should be considered. While early PFA design and technique were less than encouraging, more recent implant design and surgical technique have demonstrated robust results in the literature. Summary Patellofemoral osteoarthritis is a challenging orthopedic problem to treat, in that it can often affect younger patients, with otherwise well-functioning knees. It is a unique entity compared to TF OA with distinct epidemiology, biomechanics and risk factors and treatment options.
... For example, Darrow and Shaw et al. documented excellent clinical outcomes following a series of four BMC intra-articular knee and hip injections [43,44]. Alternatively, an intraosseous/subchondral approach, as described by Hernigou et al. [46][47][48] may be an even more effective and durable approach that is homologous and retains the desirable point-of-care characteristics of being minimally invasive, more accessible and less expensive than surgery. Thus, to improve the translation of the BMC approach and enhancement of the success of the procedure will require better characterization of the patients in real-life scenarios and improvements to the BMC acquisition, processing and delivery protocols. ...
Article
Aim: Describe the safety and effectiveness of intra-articular bone marrow concentrate (BMC) injection to treat knee and/or hip osteoarthritis (OA) in a Canadian cohort. Materials & methods: A total of 112 patients with refractory OA received a single intra-articular injection of BMC into their knee(s) and/or hip(s). Pain, disability and quality of life were prospectively assessed prior to and 3, 6 and 12 months post-injection. Results: Outcome scores were significantly improved at all time points post-BMC injection with maximal improvement observed at 3–6 months. Improvements were unrelated to patient age, sex or radiographic OA severity. The complication rate was <2%. Interpretation: In this Canadian cohort, knee/hip OA treated with a single BMC injection resulted in significant improvements in pain, disability and quality of life and a low complication rate.
... Recent research has shown the promising potential for stem cells to regenerate ECM proteins and functions [ 14,15 ]. At the same time, orthobiologics approaches have the potential to facilitate tissue regeneration and repair [ 16,17,18 ], and controlling the initiation of the inflammatory response to induce inflammatory cytokines is known to promote angiogenesis [ 19,20 ]. ...
Article
PurposeThis review aims to summarize the evidence for the role of mechanotherapies and rehabilitation in supporting the synergy between regeneration and repair after an orthobiologic intervention.MethodsA selective literature search was performed using Web of Science, OVID, and PubMed to review research articles that discuss the effects of combining mechanotherapy with various forms of regenerative medicine.ResultsVarious mechanotherapies can encourage the healing process for patients at different stages. Taping, bracing, cold water immersion, and extracorporeal shockwave therapy can be used throughout the duration of acute inflammatory response. The regulation of angiogenesis can be sustained with blood flow restriction and resistance training, whereas heat therapy and tissue loading during exercise are recommended in the remodeling phase.Conclusion Combining mechanotherapy with various forms of regenerative medicine has shown promise for improving treatment outcomes. However, further studies that reveal a greater volume of evidence are needed to support clinical decisions.
... The mechanism of action of BMC is not yet fully understood but is theorized to include paracrine signaling (13,14), tissue differentiation (15), exosome release (16), mitochondrial transfer (17), and alteration of macrophage function to promote anabolism rather than catabolism (18). BMC has shown promise in treating knee OA (19)(20)(21), anterior cruciate ligament (ACL) tears (22,23), rotator cuff pathology (24), osteonecrosis (25)(26)(27), and nonunion fractures (28). Though there is much promising early clinical evidence, the rapid rise of regenerative medicine has led to some concerning practices (29). ...
Article
Background: Acute and degenerative musculoskeletal disorders are among the most common etiologies of disability worldwide. Recently, there has been interest in the field of regenerative medicine to bridge the gap between conservative and surgical management of these conditions. Autologous bone marrow concentrate is one type of injectate that has increased in popularity over the last few decades. Though there is promising evidence supporting its efficacy, standard of care practice guidelines to govern the appropriate use and implementation of such technology are currently lacking. Objectives: The aim of this article is to report findings from a survey administered using the Delphi technique to a group of physicians using bone marrow concentrate in practice to determine best practice consensus regarding optimization of patient safety and education. Study design: Delphi panel technique. Setting: The study was first announced at a national meeting and continued remotely across the United States via 4 rounds of online surveys. Methods: An initial panel of 30 expert members was convened and a 5-member steering committee was established. Four rounds of consensus questionnaires totaling 11 unique questions were distributed. Ten questions included a 5-point Likert scale from "Strongly Agree" to "Strongly Disagree," and one question had a selection of 5 options regarding minimum level of evidence required. The anonymized aggregate results of each round were shared with the group prior to voting in the subsequent round in accordance with the Delphi process. Consensus was defined as 80% agreement of the statements indicating either "Strongly Agree" or "Agree" for the 10 questions with the Likert Scale and 80% agreement among 2 of 5 choices in the question regarding levels of evidence. Results: Three invited participants were excluded by the second round of questions due to lack of response in a timely manner, leaving 27 physicians queried. Nine of the 11 questions met criteria for > 80% consensus. Areas of agreement included importance of a treatment registry, candidacy grading, expanded informed consent, scientific accuracy in advertising, institutional review board approval for novel uses, performance of procedures by only licensed physicians or mid-level providers with direct physician oversight, use of image guidance for injections, data submission for publication in peer reviewed literature, and a minimum requirement of case-series level of evidence for use of bone marrow concentrate in musculoskeletal medicine. The 2 areas that did not meet criteria for consensus included online publishing of individual clinic data and standards around cell counting for dosing. Limitations: The Delphi panel of experts was convened on a voluntary basis rather than a nomination process. Our panel of experts were all physicians who use bone marrow concentrate in practice, therefore it is possible that a different panel of experts within other disciplines would reach different conclusions. Conclusions: There is significant consensus among a panel of physicians performing bone marrow concentrate injections regarding best practice guidelines for musculoskeletal conditions.
Article
Full-text available
Background: Bone marrow lesions are a radiographic indication of bony pathology closely associated with advanced osteoarthritis of the adjacent joint. Injection of autologous orthobiologic products, including bone marrow concentrate and platelet-rich plasma, have demonstrated safety and efficacy in treating both advanced osteoarthritis (via intraarticular injection) and associated bone marrow lesions (via intraosseous injection). The relative efficacy of intraarticular versus intraosseous injection of orthobiologics has not been evaluated at the present time. Objectives: The objective was to evaluate differences in orthobiologic bone marrow lesions treatment, either as a collateral result of intraarticular injection with bone marrow concentrate and platelet products alone, or intraosseous plus intraarticular injection as measured by patient reported outcomes. Study design: This study employed a prospective case-matched cohort design. Setting: This study took place at a single outpatient interventional orthopedic pain clinic. Methods: Using data from a prospective orthobiologic treatment registry of knee patients, a population of knee osteoarthritis with bone marrow lesions patients who had undergone only intraarticular knee injections of bone marrow concentrate and platelets (for symptomatic advanced osteoarthritis) were age, gender, and disease severity case-matched to a series of advanced osteoarthritis and bone marrow lesions patients who underwent intraosseous plus intraarticular injections. Self-reported patient outcomes for Numeric Pain Scale, International Knee Documentation Committee, lower extremity functional scale, and a modified single assessment numeric evaluation were compared between the 2 treatment groups. Results: Eighty patients were included, 40 in each group. Although pain and functional outcome scores were significantly improved in both treatment groups, there was no statistically significant differences in patient reported outcomes based on the type of treatment. Limitations: There are several limitations to this study, including multiple providers performing the injections, varying onset of symptoms to treatment, and additional injections after their initial treatment, that were not controlled. In addition, increasing the sample size may be beneficial as well, particularly with the large bone marrow lesions group, which did suggest possible improvement with intraosseous plus intraarticular over the intraarticular, although was not statistically significant in our sample. Limited data availability for this cohort as well as some missing data are other limitations to consider. Conclusion: Treating knee bone marrow lesions with intraosseous bone marrow concentrate and platelet products did not affect patient reported outcomes.
Article
Full-text available
(1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. (2) Methods: PubMed, Web of Science, and the Cochrane Library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. (3) Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. (4) Conclusions: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.
Article
Purpose The nutritional basis for rickets was described between 1880 and 1915, at the same period of discovery of other “vital substances” or vitamins. In contrast, rickets could also be prevented or cured by sunshine. But as the capacity to produce vitamin D depends on exposure to ultraviolet B rays (UVB) from sunlight or artificial sources, vitamin D became one of the most frequently used “drugs” in the twentieth century to compensate for insufficient exposure to UVB of humans. Furthermore, as the understanding of vitamin D metabolism grew during the twentieth century, other concerns than rickets occurred for the orthopaedic surgeon: In recent history, deficiency is explored as being an associated factor of different bone pathologies as fracture or prosthetic infection. The aim of this review is to analyze these new data on vitamin D. Materials and methods During the twentieth century, there were many concerns for the orthopaedic surgeon: sources and synthesis of vitamin D, regulation of the calcium deposition process for both children and adults, when vitamin D deficiency is observed, and what the best method of vitamin D supplementation is. As target genes regulated by vitamin D are not limited to those involved in mineral homeostasis, orthopedists recently discovered that vitamin D might prevent periprosthetic infection. Results The primary source (80%) of vitamin D is dermal synthesis related to the sun. Dietary sources (20%) of vitamin D are fat fishe, beef, liver, and eggs. Vitamin D is produced industrially to be used in fortified foods and supplements. Maintenance of skeletal calcium balance is mediated through vitamin D receptors. Progenitor cells, chondrocytes, osteoblasts, and osteoclasts contain these receptors which explains the role of vitamin D in cell therapy, in the prevention of rickets and osteomalacia. Despite fortified foods, the prevalence of deficiency remains endemic in north latitudes. However, the definition of vitamin D insufficiency or deficiency remains controversial. Vitamin D has been evaluated in patients undergoing fractures and elective orthopaedic procedures Although supplementation may not be able to prevent or cure all the orthopaedic pathologies, oral supplementation is able to improve the vitamin D levels of deficient patients. These vitamin D level improvements might be associated with better functional and clinical outcomes after some surgical procedures and improvement of immunity to decrease the risk of infection in arthroplasties. Conclusion Vitamin D deficiency is frequent and concerns millions of people in the world. It is therefore normal to find hypovitaminosis in various orthopaedic populations including trauma and arthroplasties. However, we do not know exactly if this phenomenon only reflects the general prevalence of vitamin D deficiency or has an influence on the outcome of some pathologies on specific populations at risk. After the success of treatment of rickets, it is disappointing that we are still wondering in the twenty-first century whether supplementation of a substance synthetized millions of years ago by plankton and necessary for growth of all the animals may improve (or not) clinical and functional outcomes of a simple fracture in humans.
Chapter
Symptomatic cartilage lesions and early osteoarthritis (OA) are musculoskeletal issues with both significant clinical and large economic burdens. Despite regenerative techniques, such as the use of autologous chondrocytes, the complete healing of damaged cartilage with consistent reproduction of normal hyaline cartilage has not yet been achieved. Alternatively, mesenchymal stromal cells (MSC) have received considerable research attention as a cellular therapy injective option. MSC populations are the product of competitive expansion and clone selection starting from a mixed population of heterogeneous tissue-specific colony connective progenitors (CTPs). While MSC populations vary significantly from batch to batch and patient to patient, culture-expanded MSCs are relatively easy to generate and are capable of chondrogenic differentiation potential. Intra-articular (IA) injection of MSCs can be an efficient and minimally invasive delivery system. The results of preclinical studies have provided preliminary evidence of safety and efficacy of MSCs for the treatment of OA. Several clinical trials have demonstrated that IA injection of MSCs has beneficial outcomes for patients with OA. The use of concentrates, mainly from bone marrow and adipose tissue, is recently growing to take advantage of MSC potential while avoiding the complexity related to cell expansion. In this chapter, we discuss the feasibility of IA injection of MSCs and concentrates, and the current evidence on the clinical efficacy as a potential therapy for patients with cartilage lesions and OA.
Article
AbstractA systematic review of clinical applications of MSCs in the treatment of knee osteoarthritis (OA). Twenty-three papers were included in the final analysis (10 on BMAC and 13 on SVF). Of these, only 4 were randomised controlled trials (RCTs). The Coleman Score, used for bias risk evaluation, revealed an overall poor quality of the studies. In terms of clinical application, despite the apparent safety and the short-term positive clinical outcomes, clinicians reported different preparation and administration methods. The available literature is not sufficient to make any recommendation on the use of either product in clinical practice, even though they have both shown to be safe and have some short-term beneficial effects.
Article
Full-text available
Background: The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. Objectives: The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. Methods: The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature.RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions.• The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III.• Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique.Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities.Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use.Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. Conclusions: Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. Key words: Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.
Article
PurposeRecently, mesenchymal stem cells (MSCs) have been proposed as potential treatment modalities for knee osteoarthritis. However, indications and long-term results have not been frequently reported. The purpose of this study was to determine whether bone marrow lesion on MRI are predictive of risk progression to total knee arthroplasty during the first ten years after subchondral cell therapy.Methods This study included 140 adults aged 65 to 90 years. These 140 patients (mean age 75.4 ± 14.2 years) planned to undergo staged-bilateral total knee arthroplasty (TKA) for medial osteoarthritis, had “comparable” pain in both knees, and accepted randomization of the knees for surgery. They received TKA on one side and a subchondral injection of MSCs (from iliac bone marrow concentrate) on the contralateral knee during the same anaesthetic. The bone marrow graft of 20 cm3 volume (10 cc in the tibia and 10 cc in the femur) contained average 7800 MSCs/mL (range 3120 to 11,560). The baseline volume of bone marrow lesions (BMLs) on the tibia and on the femoral condyle determined on MRI was average 3.4 cm3 (range 0.4 to 6.4 cm3). The risk of subsequent knee arthroplasty due to absence of bone marrow lesions regression as well as osteoarthritis (OA) grade was evaluated with Cox proportional-hazards ratio after control of baseline variables (number of cells injected, age, knee alignment).ResultsAfter treatment with MSCs injection in bone marrow lesions of the subchondral bone, medial femorotibial compartment BML volume experienced regression over 24 months (mean regression 1.5 cm3, range 0.8 to 3.2 cm3). At the most recent follow up (average of 15 years, range 10 to 20 years), a total of 25 (18%) of the 140 patients underwent total knee arthroplasty performed at a mean of ten years (range, 5 to 15 years) after the date of the cell therapy. The overall incidence of knee arthroplasty after cell therapy was 1.19% per person-year which was equivalent to the risk of a revision for a primary TKA in the contralateral knees of the same patient population (21 revisions, corresponding to 1.00% revision per person-year; p = 0.34). After adjusting for confounders, persistent BMLs larger than 3 cm3 after cell therapy was a strong independent risk factor for total knee arthroplasty (hazard ratio HR = 4.42 [95% CI = 2.34 to 7.21]; p < 0.001), regardless of OA grade, with higher risks demonstrated for larger BMLs. Incidence rates of arthroplasty were also higher for young patients and for knees presenting severe malalignment.Conclusions This study showed that subchondral bone marrow concentrate (as compared with TKA) had a sufficient effect on pain to postpone or avoid the TKA in the contra lateral joint of patients with bilateral osteoarthritis. Bone marrow lesions were predictive factors for future knee arthroplasty in the knee with subchondral cell therapy at ten years follow-up.
Chapter
Spontaneous osteonecrosis of the knee (SONK) presents a challenging treatment scenario as the etiology of these lesions has been poorly defined, and therefore appropriate treatment remains uncertain. More recently, it has been proposed that these lesions are better characterized as the culmination of subchondral insufficiency fractures of the knee (SIFK). As a result, treatment options better aimed at reversing or halting this pathophysiologic process have been considered. The use of injectable orthobiologics, such as platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and calcium phosphate, has become of interest for treating such lesions. However, the efficacy of these treatment modalities remains poorly understood. The purpose of the current chapter is to provide a comprehensive and evidence-based review of the pathophysiology of and risk factors for SIFK. Additionally, this chapter discusses the most recent evidence surrounding the use of orthobiologics to treat SIFK and future directions for research pertaining to this pathology.
Article
Background Early detection and intervention are critical to maintaining the native articular cartilage prior to collapse in secondary osteonecrosis of the knee (SOK). We conducted a retrospective study documenting the initial stage of presentation and the progression of SOK. Methods Our database was reviewed for patients younger than 65 years-of-age diagnosed with atraumatic SOK between 2002-2018. Demographic data, plain radiographs as well as MRI at initial evaluation, and initial treatment were classified and analyzed. Results One-hundred and four patients with 164 knees were identified. Mean age was 39 ± 16 years. Females (64%) with bilateral disease (58%) predominated. Seventy-five percent of patients had a history of corticosteroid use, of which 41% were diagnosed with hematologic malignancy and lupus. Fifteen percent of patients had a history of ethanol abuse. At initial presentation, 55% of patients were diagnosed with Ficat-Arlet stage I/II, while 45% were diagnosed with Ficat-Arlet stage III/IV. We found a significant difference in the mean age of patients at early-stage of SOK with corticosteroid use (31 ± 12 years-of-age) when compared to ethanol use (43 ± 13 years-of-age, p=0.02). Treatments included observation (57%), joint preservation surgery (20%), and total knee arthroplasty (23%). Conclusion Nearly half of patients presented at late-stage compromising the potential for joint preservation. The difference in age of referral by over a decade, based on etiology of SOK, suggests a strong provider-based referral or screening bias may be present. Hence, a multidisciplinary approach to earlier detection and referral may be a more effective strategy for preventing the progression of SOK.
Article
Purpose: There is an increasing number of reports on the treatment of knee osteoarthritis (OA) using mesenchymal stem cells (MSCs). However, it is not known what would better drive osteoarthritis stabilization to postpone total knee arthroplasty (TKA): targeting the synovial fluid by injection or targeting on the subchondral bone with MSCs implantation. Methods: A prospective randomized controlled clinical trial was carried out between 2000 and 2005 in 120 knees of 60 patients with painful bilateral knee osteoarthritis with a similar osteoarthritis grade. During the same anaesthesia, a bone marrow concentrate of 40 mL containing an average 5727 MSCs/mL (range 2740 to 7540) was divided in two equal parts: after randomization, one part (20 mL) was delivered to the subchondral bone of femur and tibia of one knee (subchondral group) and the other part was injected in the joint for the contralateral knee (intra-articular group). MSCs were counted as CFU-F (colony fibroblastic unit forming). Clinical outcomes of the patient (Knee Society score) were obtained along with radiological imaging outcomes (including MRIs) at two year follow-up. Subsequent revision surgeries were identified until the most recent follow-up (average of 15 years, range 13 to 18 years). Results: At two year follow-up, clinical and imaging (MRI) improvement was higher on the side that received cells in the subchondral bone. At the most recent follow-up (15 years), among the 60 knees treated with subchondral cell therapy, the yearly arthroplasty incidence was 1.3% per knee-year; for the 60 knees with intra-articular cell therapy, the yearly arthroplasty incidence was higher (p = 0.01) with an incidence of 4.6% per knee-year. For the side with subchondral cell therapy, 12 (20%) of 60 knees underwent TKA, while 42 (70%) of 60 knees underwent TKA on the side with intra-articular cell therapy. Among the 18 patients who had no subsequent surgery on both sides, all preferred the knee with subchondral cell therapy. Conclusions: Implantation of MSCs in the subchondral bone of an osteoarthritic knee is more effective to postpone TKA than injection of the same intra-articular dose in the contralateral knee with the same grade of osteoarthritis.
Article
Introduction: Chronic musculoskeletal pain is very prevalent, and accounts for major health-care expenses. Many of the present therapeutic modalities are only partially effective, and great interest is now posed on regenerative medicine. Areas covered: The authors discuss the role of a variety of regenerative medicine options to induce and favor regeneration and healing of tendon tissue, focusing on the role of mesenchymal stem cell therapy and their derivatives. Expert opinion: Stem cells, tissue engineering, and growth factors are new strategies for tendon repair and regeneration. MSCs not only can differentiate in tendon cells, but also secrete several cytokines that modulate inflammation and tissue healing. Future studies should be undertaken to overcome current obstacles to clinical translation. Further investigation of cell source, isolation, expansion, and differentiation methods, characterization of the tenogenic differentiation pathways, and clarifications of tendon-specific molecular markers are required. The role of donor variability, tendon type, and anatomic location also requires further understanding and research.
Article
This study aimed to evaluate the effect of bone marrow aspirate concentrate (BMAC) in the treatment of osteoarthritis of the thumb first carpometacarpal joint. Injections were carried out in 27 thumbs. According to the Dell classification, there were 2 stage I, 11 stage II, 13 stage III and 1 stage IV cases. The bone marrow was aspirated from the iliac crest, concentrated by centrifugation, and injected under fluoroscopic control into the pathological thumb. Results were assessed at a mean 16 months’ follow-up (range, 8–26). Clinical evaluation comprised QuickDASH and PRWE scores, pain at rest on a numerical analog scale (NAS), and thumb column abduction on goniometry. QuickDASH and PRWE scores were 59 (range, 27–82) and 88 range, 37–125) preoperatively and 29 (range, 0–64) and 50 (range, 1–99) postoperatively, respectively. Mean pain at rest on NAS improved from 7 (range, 1–10) to 4 (range, 0–9). Thumb abduction improved by a mean 18 ° over preoperative data. No postoperative complications were found. Two patients had to be operated on for inefficacy of injection. This is the first article presenting the effect of an intra-articular injection of BMAC in the thumb first carpometacarpal joint and the results were encouraging. Many patients showed improved quality of life and pain relief. These injections appear to be an effective means of postponing surgery.
Article
Objective: To systematically review the available clinical evidence regarding the safety and efficacy of knee intraosseous injections for the treatment of bone marrow lesions in patients affected by knee osteoarthritis. Design: A literature search was carried out on PubMed, Embase, and Google Scholar databases in January 2020. The following inclusion criteria were adopted: (1) studies of any level of evidence, dealing with subchondral injection of bone substitute materials and/or biologic agents; (2) studies with minimum 5 patients treated; and (3) studies with at least 6 months' follow-up evaluation. All relevant data concerning clinical outcomes, adverse events, and rate of conversion to arthroplasty were extracted. Results: A total of 12 studies were identified: 7 dealt with calcium phosphate administration, 3 with platelet-rich plasma, and 2 with bone marrow concentrate injection. Only 2 studies were randomized controlled trials, whereas 6 studies were prospective and the remaining 4 were retrospective. Studies included a total of 459 patients treated with intraosseous injections. Overall, only a few patients experienced adverse events and clinical improvement was documented in the majority of trial. The lack of any comparative evaluation versus subchondral drilling alone is the main limitation of the available evidence. Conclusions: Knee intraosseous injections are a minimally invasive and safe procedure to address subchondral bone damage in osteoarthritic patients. They are able to provide beneficial effects at short-term evaluation. More high-quality evidence is needed to confirm their potential and to identify the best product to adopt in clinical practice.
Article
Background: Secondary osteonecrosis of the knee (SOK) generally occurs in relatively young patients; at advanced stages of SOK, the only viable surgical option is total knee arthroplasty (TKA). We conducted a retrospective study to investigate implant survivorship, clinical and radiographic outcomes, and complications of contemporary cemented bicompartmental TKA with/without patellar resurfacing for SOK. Methods: Thirty-eight cemented TKAs in 27 patients with atraumatic SOK, mean age 43 years (17 to 65), were retrospectively reviewed. Seventy-four percent had a history of corticosteroid use, and 18% had a history of alcohol abuse. Patellar osteonecrosis was coincidentally found in six knees (16%), and all were asymptomatic without joint collapse. The mean follow-up was 7 years (2 to 12). Knee Society Score (KSS) and radiographic outcomes were evaluated at 6 weeks, 1 year, then every 2-3 years. Results: Ninety-two percent had implant survivorship free from revision with significant improvement in KSS. Causes of revision included aseptic tibial loosening (one), deep infection (one), and instability with patellofemoral issues (one). Four of six cases also with patellar osteonecrosis received resurfacing, including one with periprosthetic patellar fracture after minor trauma, with satisfactory clinical results after conservative treatment. None of unrevised knees had progressive radiolucent lines or evidence of loosening. An unresurfaced patella, use of a stem extension or a varus-valgus constrained prosthesis constituted 18%, 8% and, 3%, respectively. Conclusion: Cemented TKAs with selective stem extension in patients with SOK had satisfactory implant survivorship and reliable outcomes. Secondary osteonecrosis of the patella should be carefully evaluated prior to operation.
Article
Knee pathology including osteoarthritis and chondral defects continue to account for a large burden of health care visits and significant dysfunction among patients. Injectable biologics have become a focus of greater interest as treatment to mitigate symptoms and potentially restore function or structure. In particular, bone marrow derived treatments, such as aspirated bone marrow aspirate concentrate (commonly referred to as BMAC) have attracted attention as one of the few options that may contain viable autologous stem and progenitor cells that are compliant with Federal Drug Administration regulations. However, recent literature has reported significant shortcomings including variability in the preparation methods, quality reporting, and outcome measures used to assess BMAC efficacy. This manuscript provides a comprehensive review of the most recent recommendations for processing and reporting BMAC in clinical trials with special focus on knee pathology, and presents an evidence-based discussion of the most recent studies reporting on patient outcomes.
Article
Recent perspectives suggest that osteoarthritis (OA) is a disease involving not only the articular cartilage but also the osteochondral unit, including the synovium, supportive cartilage and subchondral bone. Current conservative treatments for OA are symptomatic and do not prevent progression or reverse the disease process. Compelling data show that intra-articular orthobiologic injections, such as platelet-rich plasma and mesenchymal stromal cells, are effective in providing relief of OA symptoms. However, recent data suggest that injections of orthobiologics into the subchondral bone may be superior to intra-articular injections for the management of OA. This review highlights the rationale and current evidence for intra-articular and subchondral bone injections of orthobiologics for the treatment of OA.
Article
Full-text available
Introduction: Osteoarthritis causes a progressive deterioration to the protective cartilage between the joints leading to chronic pain and disability. This review focuses on the intrinsic potential of MSCs to stabilize and repair the cartilage tissue of the knee joint in knee osteoarthritis (KOA) patients. Methods: An online search through the PubMed database was conducted, limiting the search to the English language and human clinical trials within the past 5 years. Twenty-one clinical trials passed the inclusion criteria. Combined, those trials involved the participation of 589 patients where the progress of the treatments was monitored between a 4-month to 7-years period. The cartilage volume and defects were observed through an MRI to provide an objective assessment. While the pain and knee function were monitored using KOOS, VAS, and WOMAC scoring scales providing a subjective assessment. Results: MRI scans obtained from clinical trials demonstrate a slowed progression of cartilage degeneration and early signs of cartilage regeneration in KOA patients at the 12-month follow-up period. No major adverse effects were observed post-intervention. The overall KOOS, WOMAC, and VAS scores in patients receiving MSC treatment were reduced, suggesting subjective improvements in knee function and pain reduction when compared to patients in the placebo group. Conclusion: The use of MSC therapy is a valid form of treatment for KOA as it targets the disease itself rather than the symptoms. We found MSC therapy in KOA patients to be safe, effective, and feasible in its execution.
Article
Full-text available
Osteoarthritis (OA) is a degenerative disorder of the cartilage and is one of the leading causes of disability, particularly amongst the elderly, wherein patients with advanced-stage OA experience chronic pain and functional impairment of the limbs, thus resulting in a significantly reduced quality of life. The currently available treatments primarily revolve around symptom management, and is thus palliative rather than curative. The aim of the present review is to briefly discuss the limitations of some of the currently available treatments for patients with OA, and highlight the value of the potential use of stem cells in cellular therapy, which is widely regarded as the breakthrough that can address the present unmet medical needs for treatment of degenerative diseases, such as OA. The advantages of stem cell therapy, particularly mesenchymal stem cells, and the challenges involved are also discussed in this review.
Article
Biologically augmented surgical treatments of orthopaedic conditions are increasingly popular. Bone marrow aspirate concentrate is a key orthobiologic tissue source, and the field is moving from the standard iliac crest marrow aspiration toward local aspirations of marrow depots that are accessible during the standard-of-care procedures in an attempt to reduce morbidity, surgery time, and cost. Here, we present the aspiration of the standard iliac marrow depot, but through a novel acetabular approach during total hip arthroplasty. This procedure markedly simplifies biologic augmentation with bone marrow aspirate concentrate in this large patient cohort.
Article
Full-text available
Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease (SCD). To delay hip arthroplasty, core decompression combined with concentrated total bone marrow (BM) treatment is currently performed in the early stages of the osteonecrosis. Cell therapy efficacy depends on the quantity of implanted BM stromal cells. For this reason, expanded bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) can be used to improve osteonecrosis treatment in SCD patients. In this study, we quantitatively and qualitatively evaluated the function of BMSCs isolated from a large number of SCD patients with osteonecrosis (SCD-ON) compared with control groups (patients with osteonecrosis not related to SCD (ON) and normal donors (N)). BM total nuclear cells and colony-forming efficiency values (CFE) were significantly higher in SCD-ON patients than in age and sex-matched controls. The BMSCs from SCD-ON patients were similar to BMSCs from the control groups in terms of their phenotypic and functional properties. SCD-ON patients have a higher frequency of BMSCs that retain their bone regeneration potential. Our findings suggest that BMSCs isolated from SCD-ON patients can be used clinically in cell therapy approaches. This work provides important preclinical data that is necessary for the clinical application of expanded BMSCs in advanced therapies and medical products.
Article
Full-text available
Aspirating bone marrow from the iliac crest using small volumes of 1-4 ml with a 10-ml syringe has been historically proposed for harvesting adult mesenchymal stem cells and described as a standard technique to avoid blood dilution. The disadvantage of repeated small aspirations is that there is a significantly increased time to harvest the bone marrow. However, it is not known if a large volume syringe can improve the rate of bone marrow aspiration without increasing blood dilution, thus reducing the quality of the aspirate. We compared the concentrations of mesenchymal stem cells obtained under normal conditions with two different size syringes. Thirty adults (16 men and 14 women with a mean age of 49 ± 14 years) underwent surgery with aspiration of bone marrow from their iliac crest. Bilateral aspirates were obtained from the iliac crest of the same patients with a 10-ml syringe and a 50-ml syringe. Cell analysis determined the frequencies of mesenchymal stem cells (as determined by the number of colonies) from each size of syringe. The cell count, progenitor cell concentration (colonies/ml marrow) and progenitor cell frequency (per million nucleated cells) were calculated. All bone marrow aspirates were harvested by the same surgeon. Aspirates of bone marrow demonstrated greater concentrations of mesenchymal stem cells with a 10-ml syringe compared with matched controls using a 50-ml syringe. Progenitor cell concentrations were on average 300 % higher using a 10-ml syringe than matched controls using a 50-ml syringe (p < 0.01). In normal human donors, bone marrow aspiration from 30 patients demonstrated a reduced mesenchymal stem cell number in aspirates obtained using a larger volume syringe (50 ml) as compared with a smaller volume syringe (10 ml).
Article
Full-text available
Osteonecrosis is a major treatment complication of pediatric leukemias owing to its potential to cause joint deterioration. Because of potential long-term effects of osteonecrosis on joints, information regarding its progression and collapse in different patients can be used to identify high-risk groups, advise the patients and parents of this complication, and potentially consider the risk for development of osteonecrosis in planning primary treatment. We therefore determined: (1) the incidence of joint collapse and/or pain in young patients with hematologic malignancies diagnosed with ON of the knee; (2) risk factors associated with collapse; and (3) the relationship between size and location of osteonecrotic knee lesions and the likelihood of joint collapse. We retrospectively reviewed 109 patients with hematologic malignancies and MRI-confirmed knee osteonecrosis. The median age was 11.5 years (range, 2.3-18.8 years) at primary diagnosis of hematologic malignancy and a median age of 13.4 years (range, 2.7-23.3 years) at diagnosis of osteonecrosis of the knee. For analyses, we used the first and last MR images. Minimum clinical followup was 2.3 years after diagnosis of knee osteonecrosis (median, 6 years; range, 2.3-7.17 years). Joint collapse occurred in 22% (24 of 109). Older age, pain at osteonecrosis presentation, and lesions extending to the articular surface of distal femoral epiphyses were associated with joint collapse. Younger patients and those without extensive femoral epiphyseal involvement have a better prognosis for osteonecrosis of the knee. Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
Article
Full-text available
Microfracture and drilling elicit a cartilage repair whose quality depends on subchondral bone repair. Alternatively activated (AA) macrophages express arginase-1, release angiogenic factors, and could be potential mediators of trabecular bone repair. Chitosan-glycerol phosphate (GP)/blood implants elicit arginase-1+ macrophages in vivo through neutrophil-dependent mechanisms and improve trabecular bone repair of drilled defects compared with drilling alone. Controlled laboratory study. Bilateral trochlear cartilage defects were created in 15 rabbits, microdrilled, and treated or not with chitosan-GP/blood implant to analyze AA macrophages, CD-31+ blood vessels, bone, and cartilage repair after 1, 2, or 8 weeks. Neutrophil and macrophage chemotaxis to rabbit subcutaneous implants of autologous blood and chitosan-GP (+/-blood) was quantified at 1 or 7 days. In vitro, sera from human chitosan-GP/blood and whole blood clots cultured at 37 degrees C were analyzed by proteomics and neutrophil chemotaxis assays. Chitosan-GP/blood clots and whole blood clots released a similar profile of chemotactic factors (PDGF-BB, IL-8/CXCL8, MCP-1/CCL2, and no IL-1beta or IL-6), although chitosan clot sera attracted more neutrophils in vitro. Subcutaneous chitosan-GP (+/-blood) implants attracted more neutrophils (P < .001) and AA macrophages than whole blood clots in vivo. In repairing subchondral drill holes, chitosan-GP/blood implant attracted more AA macrophages at 1 and 2 weeks and more blood vessels at 2 weeks compared with drilled controls. Treatment elicited a more complete woven bone repair at 8 weeks than controls (P = .0011) with a more uniform, integrated collagen type II+ cartilage repair tissue. Conclusion and AA macrophages may play a role in the regeneration of subchondral bone, and chitosan-GP can attract and transiently accumulate these cells in the repair tissue. The resulting improved subchondral repair could be advantageous toward enhancing integration of a restored chondral surface to the subchondral bone.
Article
Full-text available
Osteonecrosis is a complication of corticosteroid therapy with limited treatment options in young, active patients. These options include debridement, core decompression, osteotomy, allografting, and partial or total knee replacement. Few studies exist regarding the use of osteochondral allografts for treatment of steroid-associated osteonecrosis. We asked if fresh osteochondral allografts would (1) heal to host bone in the presence of osteonecrosis, (2) provide a clinically meaningful decrease in pain and improvement in function, and (3) prevent or postpone the need for prosthetic arthroplasty. Twenty-two patients (28 knees) who underwent osteochondral allografting for high-grade, corticosteroid-associated osteonecrosis were evaluated. Their average age was 24.3 years (range, 16-44 years). The mean graft surface area was 10.8 cm(2) (range, 5.0-19.0 cm(2)). Evaluation included a modified (for the knee) D'Aubigné and Postel (18-point) score, International Knee Documentation Committee (IKDC), and Knee Society function scores. The minimum followup was 25 months (mean, 67 months; range, 25-235 months). Five knees failed. The graft survival rate was 89% (25 of 28). The mean D'Aubigné and Postel score improved from 11.3 to 15.8; 19 of 25 (76%) had a score greater than 15. The mean IKDC pain score improved from 7.1 to 2.0, mean IKDC function score from 3.5 to 8.3, and mean Knee Society function score from 60.0 to 85.7. Our data suggest osteochondral allografting is a reasonable salvage option for osteonecrosis of the femoral condyles. TKA was avoided in 27 of the 28 of knees at last followup. Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.
Article
Full-text available
To describe the natural history of subchondral bone marrow lesions (BMLs) in a sample of subjects with knee osteoarthritis (OA) or at risk of developing it. Additionally, to examine the association of change in BMLs from baseline to 30-month follow-up with the risk of cartilage loss in the same subregion at follow-up. 1.0 T MRI was performed using proton density-weighted, fat-suppressed sequences. BML size and cartilage status were scored in the same subregions according to the WORMS system. Subregions were categorised based on comparison of baseline and follow-up BML status. A logistic regression model was used to assess the association of change in BML status with cartilage loss over 30 months using stable BMLs as the reference group. 395 knees were included. 66% of prevalent BMLs changed in size; 50% showed either regression or resolution at follow-up. The adjusted odds ratios (95% confidence intervals) of cartilage loss in the same subregion at follow-up for the different groups were 1.2 (0.5 to 1.6) for regressing BMLs, 0.9 (0.5 to 1.6) for resolving BMLs, 2.8 (1.5 to 5.2) for progressing BMLs, 0.2 (0.1 to 0.3) for subregions with no BMLs at baseline and follow-up and 3.5 (2.1 to 5.9) for newly developing BMLs. BML size at baseline was associated with risk of subsequent cartilage loss. The majority of pre-existing BMLs decreased in size at follow-up. Absence of BMLs was associated with a decreased risk of cartilage loss, while progressing and new BMLs showed a high risk of cartilage loss in the same subregion.
Article
Full-text available
Osteonecrosis of the knee comprises two separate disorders, primary spontaneous osteonecrosis which is often a self-limiting condition and secondary osteonecrosis which is associated with risk factors and a poor prognosis. In a series of 61 knees (38 patients) we analysed secondary osteonecrosis of the knee treated by a new technique using multiple small percutaneous 3 mm drillings. Total knee replacement was avoided in 59 knees (97%) at a mean follow-up of 3 years (2 to 4). Of the 61 knees, 56 (92%) had a successful clinical outcome, defined as a Knee Society score greater than 80 points. The procedure was successful in all 24 knees with small lesions compared with 32 of 37 knees (86%) with large lesions. All the procedures were performed as day cases and there were no complications. This technique appears to have a low morbidity, relieves symptoms and delays more invasive surgery.
Article
Background: Lack of consensus exists on the use of cementless total knee arthroplasty (TKA) in patients with knee osteonecrosis. Therefore, this study was conducted to evaluate (1) implant survivorship; (2) clinical outcomes and complications; and (3) radiographic outcomes of primary cementless TKA in knee osteonecrosis. Methods: This study included 46 patients (49 knees) who had knee osteonecrosis and underwent primary cementless TKA and had a mean follow-up of 44 months (range 36-96). Kaplan-Meier analysis was used to evaluate implant survivorship. Follow-up was performed post-operatively at 6 weeks, 3 months, and annually thereafter. Clinical outcomes including the Knee Society Scores (KSS) for pain and function, changes in range-of-motion, complications, and radiographic outcomes were analyzed. Results: Aseptic implant survivorship was 97.9% (95% confidence interval 1.01-0.93) and all-cause implant survivorship was 95.9% (95% confidence interval 1.01-0.9), with 1 septic and 1 aseptic failures. The mean KSS for pain was 93 points (range 85-100) and the mean KSS for function was 84 points (range 70-90). Additionally, 1 patient had superficial wound necrosis and was treated with local wound care with no further sequela. Otherwise, no evidence of loosening, subsidence, or progressive radiolucencies were noted on radiological evaluation. Conclusion: Excellent implant survivorship, clinical, and radiographic outcomes of primary cementless TKA in the setting of knee osteonecrosis was demonstrated. Although further long-term study is needed to validate survivorship, new generation cementless TKA implants provide promising results in this subset of patients.
Article
Purpose: No study has reported the risk of other site osteonecroses after the diagnosis of multifocal osteonecrosis related to corticosteroids in patients who continue this corticosteroid treatment. An analysis of the time-course to other sites of osteonecrosis, as well as the effects of underlying corticosteroid risk factor on the evolution of asymptomatic lesions at the time of diagnosis, is presented. Methods: Two hundred patients were followed prospectively every year during a minimum ten years with a radiograph if a joint became symptomatic. In absence of evidence of osteonecrosis on radiographs of a symptomatic or non-symptomatic joint (hips, shoulders, knees, ankles), patients had an MRI performed at the most recent follow up. The average duration of follow-up after inclusion of the patient in the study was 15 years (range 10-20). Results: Of the 200 patients followed for an average of 15 years (minimum 10 years, maximum 20 years), 35 patients developed new osteonecrosis lesions during the period of study. Asymptomatic lesions became symptomatic and a high number of collapse was observed resulting in 258 arthroplasties (187 hips, 51 shoulders, 20 knees) at the most recent follow up. Conclusion: The continuation of peak doses (>200 mg) of corticosteroids predicted (p = 0.04) occurrence of new lesions and the continuation of corticosteroids without peak dose was a risk for quicker progression to collapse.
Article
Purpose: Should the trocar suddenly lose contact with bone during bone marrow aspiration, it may result in visceral injury. The anatomy of the ilium and the structures adjacent to the iliac bone were studied to determine the danger of breach by a trocar introduced into the iliac crest. Methods: The authors followed two series of patients, one series to do measurements of distance and angles of the structures at risk to the iliac bone and the other to evaluate the risk of a trocar being directed outside the iliac wing during bone marrow aspiration. The authors also examined 24 pelvices by computed tomography (CT) scans of mature adults (48 iliac crests). Lines dividing the iliac wing into six equal sectors were used to form sectors (e.g. sector 1 anterior, sector 6 posterior). Vascular or neurological structures were considered at risk if they were accessible to the tip of a 10-cm trocar introduced into the iliac crest with a possible deviation of 20° from the plane of the iliac wing on the three-dimensional reconstruction. The authors tracked bone marrow aspiration of six different surgeons and calculated among 120 patients (480 entry points) the number of times the needle lost contact with bone in each sector of aspiration. Results: The sector system reliably predicted safe and unsafe areas for trocar placement. Among the 480 entry points in the 120 patients, 94 breaches were observed and higher risks were observed in the thinner sectors. The risk was also higher in obese patients and the risk decreased with more experienced surgeons. The trocar could reach the external iliac artery on pelvic CT scans in the four most anterior sectors with a higher frequency in women. Posterior sectors were at risk for sciatic nerve and gluteal vessel damage when the trocar was pushed deeper than 6 cm into the posterior iliac crest. In cadavers, the dissection demonstrated nine vascular or neurological lesions. Conclusions: Using the sector system, trocars can be directed away from neural and vascular structures and toward zones that are likely to contain larger bone marrow stock.
Article
Purpose The bony anatomy of the human ilium has been well described from a qualitative perspective; however, there are little quantitative data to help the surgeon to perform bone marrow aspiration from the iliac crest in the thickest part of the ilium. The minimum thickness of the spongiousus bone in an iliac wing (transverse thickness between the two tables) is an important factor in ensuring the safe placement of a trocar between the two tables of the iliac wing. For example, with an 8-gauge (3.26 mm) trocar, one can consider that if the transverse thickness of the spongiousus bone of the iliac wing is
Article
To evaluate population-based systemic lupus erythematosus (SLE) arthroplasty rates and compare them with rates in patients with no inflammatory or autoimmune conditions. Administrative hospital discharge databases from 10 American states were used to compare knee, hip, and shoulder arthroplasty rates from 1991 to 2005 in patients with SLE and in patients with no inflammatory or autoimmune conditions. Arthroplasties were performed on patients with SLE (n = 4253) and patients with noninflammatory conditions (n = 2,762,660). Arthroplasty rates for patients with noninflammatory conditions almost doubled from 1991 to 2005 (124.5 cases/100,000 persons vs 247.5/100,000; p < 0.001). A similar trend was observed for SLE (0.17/100,000 vs 0.38/100,000; p < 0.001). The mean age at arthroplasty in patients with noninflammatory conditions decreased (71.5 ± 11.8 vs 69.0 ± 12.0; p < 0.001), whereas the mean age in patients with SLE increased (47.3 ± 17.0 vs 56.8 ± 16.0; p < 0.001). When stratified by age and sex, arthroplasty in cases of SLE increased in all groups except for women < 44 years old. In 1991, osteonecrosis accounted for 53% and osteoarthritis (OA) 23% of cases of SLE; by 2005 this relationship had reversed, with osteonecrosis accounting for 24% and OA 61% of cases of SLE. From 1991 to 2005, arthroplasty rates increased in patients with SLE in similar proportions to overall joint replacement rates. The age of patients with SLE arthroplasty increased and fewer cases were due to osteonecrosis. These data suggest significant changes are occurring patients with SLE are now living long enough to develop OA and are healthy enough to undergo elective surgery.
Article
We describe a novel treatment of secondary osteonecrosis (ON) of the femoral condyles that is relatively simple, has low morbidity, and does not preclude the patient from other more extensive treatments in the event of failure. Three patients with extensive secondary ON of the femoral condyles were treated with decompression and debridement of the area of ON and grafting with the Cellect DBM System (Depuy Spine, Inc., Raynham, Mass), which provided a graft matrix enriched with a 3-fold to 4-fold increase in osteoprogenitor cells. At 2 years, all 3 patients had no complications and had excellent results with near-normal function and activity levels. Our preliminary results demonstrate that this technique is a viable option, at least in the short term, especially in patients with extensive, multifocal lesions.
Article
There is no consensus with respect to the best procedures to preserve the knee joint in patients with osteonecrosis of the knee. We performed a systematic review of the literature between 1999 and 2012. Only 10 of 1057 studies met our inclusion criteria. Core decompression prevented additional surgical treatment in pre-collapse knees with a failure rate of 10.4% (7 of 67 knees). Autogenous and osteochondral grafts decreased the need for additional surgery in both pre-collapse (0%, 20 of 20) and post-collapse knees (10.5%, 8 of 76 knees). Although these results are quite promising multi-center randomized trials are needed to identify the optimal procedures to treat this disease.
Article
- Cartilaginous defects in the knee occur frequently and can cause the patient considerable limitations.- They are diagnosed and classified by means of MRI and arthroscopy.- The surgical options available to treat deep chondral laesions include bone marrow stimulation techniques (microfracture treatment), chondrocyte therapies (autologous chondrocyte implantation) and tissue replacement therapies (osteochondral autologous transplantation).- Microfracture treatment and osteochondral autologous transplantation are suitable for treating chondral laesions that extend to the subchondral bone and are smaller than 2 and 4 cm2, respectively.- Autologous chondrocyte implantation is a suitable method for treating single symptomatic chondral laesions larger than 2 cm2 in adults up to 50 years of age.- There are no significant differences regarding the effectiveness of microfracture treatment, autologous chondrocyte implantation and osteochondral autologous transplantation for small defects: all show good clinical and functional short- and medium-term results.- New second- and third-generation autologous chondrocyte implantation techniques seem to yield more sustainable tissue repair and better clinical long-term results for laesions larger than 4 cm2 in comparison to microfracture treatment.
Article
Osteonecrosis is a disabling complication in children and young adults with acute lymphoblastic leukaemia. It can affect any or multiple joints but the hip and knee are most frequently involved and a cause of long-term disability. The problem is almost exclusively that of older children and young adults of whom over 70% have asymptomatic changes on screening magnetic resonance imaging and 15-20% have resulting symptoms. Dexamethasone is associated with a higher risk than prednisolone in US but not European or UK trials and alternate week scheduling of dexamethasone in the intensification course is associated with a lower risk than a continuous 3-week schedule in US trials. Genetic factors and obesity contribute to the risk, as do metabolic abnormalities caused by drugs, such as asparaginase, which increase tissue exposure to steroids. Management is primarily supportive but a minority of patients require surgical intervention including replacement of the affected joint. A variety of surgical techniques and, latterly, bisphophonates, have been tried to prevent progression but their efficacy remains uncertain. Whether patients should continue to receive steroids after diagnosis of osteonecrosis is uncertain but most trial investigators recommend stopping them after completion of the intensification phase of treatment.
Article
The purpose of this study was to clarify the incidence of (CS)-associated osteonecrosis among different underlying diseases and to evaluate the risk factors for steroid-associated osteonecrosis in a prospective MRI study. We prospectively used MRI to study 337 eligible underlying disease patients requiring CS therapy and succeeded in examining 1199 joints (hips and knees) in 302 patients with MRI for at least 1 year starting immediately after the onset of CS therapy (1-year follow-up rate of 90%). The underlying diseases included SLE in 687 joints (173 patients) and a variety of other rheumatological disorders in 512 joints (129 patients). The incidence of osteonecrosis was significantly higher in SLE patients than in non-SLE patients (37 vs 21%, P = 0.001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk of osteonecrosis compared with paediatric patients [odds ratio (OR) = 13.2], that high daily CS dosage (>40 mg/day) entailed a significantly higher risk of osteonecrosis compared with the dosage of <40 mg/day (OR = 4.2), that SLE patients had a significantly higher risk of osteonecrosis compared with non-SLE patients (OR = 2.6) and that male patients had a significantly higher risk of osteonecrosis compared with female patients (OR = 1.6). These findings suggest that the incidence of CS-associated osteonecrosis varies among different underlying diseases.
Article
Osteonecrosis (ON) of the knee is a progressive disease that often leads to subchondral collapse and disabling arthritis. Recent studies have identified three distinct pathologic entities, all of which were previously described as knee ON: secondary ON, spontaneous ON of the knee, and postarthroscopic ON. Radiographic and clinical assessment is useful for differentiating these conditions, predicting disease progression, and distinguishing these conditions from other knee pathologies. The etiology, pathology, and pathogenesis of secondary ON of the knee are similar to those found at other sites (eg, hip, shoulder). Spontaneous ON is a disorder of unknown etiology. Postarthroscopic ON has been described as an infrequent but potentially destructive complication. Various treatment modalities (eg, core decompression, bone grafting, high tibial osteotomy, arthroplasty), have been used with varying degrees of success for each type of ON. Secondary ON frequently progresses to end-stage disease, and early surgical intervention is recommended. Initial management of spontaneous ON of the knee and postarthroscopic ON is typically nonsurgical, with observation for clinical or radiographic progression.
Article
Over the past few decades, significant progress has been made with respect to new concepts about the pathogenesis of osteoarthritis (OA). This article summarises some of the knowledge we have today on the involvement of the subchondral bone in OA. It provides substantial evidence that changes in the metabolism of the subchondral bone are an integral part of the OA disease process and that these alterations are not merely secondary manifestations, but are part of a more active component of the disease. Thus, a strong rationale exists for therapeutic approaches that target subchondral bone resorption and/or formation, and data evaluating the drugs targeting bone remodelling raise the hope that new treatment options for OA may become available.
Article
Synovitis in knee osteoarthritis (OA) patients is a significant risk factor for disease progression. This study aimed at developing a magnetic resonance imaging (MRI) scoring system allowing reliable and sensitive assessment of synovitis severity in knee OA patients without the use of a contrast agent. Imaging was performed without contrast agent, using a 1.5T and a knee coil. For the synovial membrane, the MRI exam included two axial sequences: a T2-weighted (synovial fluid) and a gradient echo (GRE) (synovial membrane). Synovial membrane thickness was measured on four regions of interest (ROI): medial and lateral recesses, and medial and lateral suprapatellar bursa, with each graded/scored from 0 to 3, for a maximum of 12. A validation study was performed on a cohort of 27 knee OA patients having MRI at baseline. A subset of 14 patients had an additional MRI acquisition and symptom assessment at Day 60. Evaluation of disease symptoms was done with Western Ontario and McMaster Universities OA Index and visual analog scale, and of cartilage volume, menisci and subchondral bone, with MR images from a 3D spoiled gradient recalled (SPGR) sequence. The synovial membrane thickness grade was 1.9+/-0.5 (mean+/-SD) with a score of 7.1+/-2.3. The intra-reader (r=0.91) and inter-reader (r=0.82) correlation coefficients were excellent (P<0.0001). The medial compartment grade was 1.9+/-0.6 and score was 3.4+/-1.4, and of the lateral compartment were 2.0+/-0.7 and 3.7+/-1.5, respectively. The grade and score for the suprapatellar bursa and recess were 1.8+/-0.7 and 3.5+/-1.5, and 2.1+/-0.5 and 3.9+/-0.9, respectively. No statistically significant differences in the ROI score and grade were observed between medial and lateral compartments or between recess and suprapatellar bursa. A positive correlation was found between the global severity of synovitis at baseline and the presence of a medial meniscal extrusion (P<0.04), and the loss of cartilage volume at 60 days (P<0.03). This newly developed MRI technology for the assessment of synovial membrane thickness in knee OA patients was shown to be accurate and reproducible.
Article
A new total knee rating system has been developed by The Knee Society to provide an up-to-date more stringent evaluation form. The system is subdivided into a knee score that rates only the knee joint itself and a functional score that rates the patient's ability to walk and climb stairs. The dual rating system eliminates the problem of declining knee scores associated with patient infirmity.
Article
In the Swedish Multicenter Study of Knee Arthroplasty, 115 knees in 110 patients with knee osteonecrosis represented all reported cases treated with knee arthroplasty in the period from 1975 to 1986. Primary medial femoral condyle osteonecrosis was the most common osteonecrosis reported (89%). Preoperative roentgenograms were staged according to the type of osteonecrosis and classified according to the grade of arthrosis. Detailed measurements of the size of the lesion were also performed. For primary medial femoral osteonecrosis, the width of the lesion averaged 45% of the condyle. The mean width of the lesion (anteroposterior size) was 21 mm and the mean length (lateral size) was 34 mm. The mean depth on lateral roentgenograms was 6 mm. There was a high correlation of results among the various methods of measurement. Using regression analysis, it was possible to approximate the volume of the lesion even from a single measurement of the width on anteroposterior view. The size of osteonecrosis of the knee can be used to plan resection and select the implant design.
Article
Despite their age, patients younger than 50 years who have collapse of their femoral condyles caused by steroid associated avascular necrosis have few options except total knee arthroplasty. There have been no specific reports of the results of total knee replacements for this disease. Between 1980 and 1993, 31 porous coated anatomic total knee replacements were performed in 21 patients younger than 50 years of age with avascular necrosis of the femoral condyles and tibial plateaus. There were 17 women and 4 men, with an average age of 36 years (range, 22-48 years). Seventeen of 21 patients had systemic lupus erythematosus, and all patients had a history of corticosteroid use. Patients underwent a complete clinical and radiographic evaluation at final followup that averaged 8.2 years (range, 2-16 years). Overall, there were 17 good and excellent results (55%). Eleven knees were revised for aseptic loosening (37%), and 3 additional knees (10%) ultimately were revised for deep sepsis. All 6 knees in patients with no diagnosis of systemic lupus erythematosus had excellent clinical results. There were only 11 of 25 successful outcomes (44%) in the patients with systemic lupus erythematosus. There were no differences in results when patients were stratified by degree of steroid use, cemented versus cementless fixation, or activity level.
Article
We have evaluated bone-marrow activity in the proximal femur of patients with corticosteroid-induced osteonecrosis and compared it with that of patients with osteonecrosis related to sickle-cell disease and with a control group without osteonecrosis. Bone marrow was obtained by puncture of the femoral head outside the area of necrosis and in the intertrochanteric region. The activity of stromal cells was assessed by culturing fibroblast colony-forming units (FCFUs). We found a decrease in the number of FCFUs outside the area of osteonecrosis in the upper end of the femur of patients with corticosteroid-induced osteonecrosis compared with the other groups. We suggest that glucocorticosteroids may also have an adverse effect on bone by decreasing the number of progenitors. The possible relevance of this finding to osteonecrosis is discussed.
Article
There have been only a few reports that evaluate the outcome of total knee arthroplasty in patients with steroid-induced osteonecrosis of the knee. We retrospectively reviewed 31 total knee arthroplasties in 24 patients with confirmed steroid-induced osteonecrosis of the knee. The average follow-up was 64 months. Of surviving knees, 92% had significant improvement in knee scores. Five knees (16%) required a revision procedure. Reasons for revision were aseptic loosening in 3 knees and sepsis in 2 knees. Complications not requiring revision occurred in 6 of 31 knees (19%). Survivorship of total knee arthroplasty to revision in patients with steroid-induced avascular necrosis of the knee was 84% at 5 years. Although there was a slightly higher complication rate, this may, in part, be due to the severity of the patients' underlying disease processes. Total knee arthroplasty can be a successful procedure for chronically ill patients with steroid-induced osteonecrosis.
Article
The purposes of this study were to define the clinical, demographic, and radiographic patterns of atraumatic osteonecrosis of the distal part of the femur and the proximal part of the tibia at presentation and to report the outcome of treatment of this condition. Two hundred and forty-eight knees in 136 patients who were younger than the age of fifty-five years were treated at our institution between July 1, 1974, and September 15, 1998, for atraumatic osteonecrosis of the distal part of the femur or the proximal part of the tibia, or both. Demographic and radiographic features were characterized. The results of nonoperative treatment, core decompression, arthroscopic debridement, and total knee arthroplasty were evaluated. There were 106 female patients and thirty male patients, and their mean age was thirty-six years (range, fifteen to fifty-four years) at the time of diagnosis. One hundred and one patients (74 percent) had involvement of other large joints, with eighteen (13 percent) presenting initially with knee symptoms. One hundred and one patients (74 percent) had a disease that affected the immune system; sixty-seven of them had systemic lupus erythematosus. One hundred and twenty-three patients (90 percent) had a history of corticosteroid use. Technetium-99m bone-scanning missed lesions in sixteen (29 percent) of fifty-six knees. Eight (20 percent) of forty-one initially symptomatic knees treated nonoperatively had a successful clinical outcome (a Knee Society score of at least 80 points and no additional surgery) at a mean of eight years. The knees that remained severely symptomatic for three months were treated with either core decompression (ninety-one knees) or total knee arthroplasty (seven knees). Seventy-two (79 percent) of the ninety-one knees treated with core decompression had a good or excellent clinical outcome at a mean of seven years. Efforts to avoid total knee arthroplasty with repeat core decompression or arthroscopic debridement led to a successful outcome in fifteen (60 percent) of twenty-five knees. Thirty-four (71 percent) of forty-eight knees treated with total knee arthroplasty had a successful clinical outcome at a mean of nine years. Atraumatic osteonecrosis of the knee predominantly affects women, and in our study it was associated with corticosteroid use in 90 percent of the patients. Evaluation should include standard radiographic and magnetic resonance imaging of all symptomatic joints. Prognosis was negatively related to large juxta-articular lesions. Nonoperative treatment should be reserved for asymptomatic knees only. Core decompression was successful (a Knee Society score of at least 80 points and no additional surgery) in 79 percent of the knees in which the disease was in an early stage. Total knee arthroplasty was successful in only 71 percent of the knees.
Article
Core decompression with bone graft is used frequently in the treatment of osteonecrosis of the femoral head. Many different techniques have been described. In the current series, grafting was done with autologous bone marrow obtained from the iliac crest of patients operated on for osteonecrosis of the hip. The results of a prospective study of 189 hips in 116 patients treated with core decompression and autologous bone marrow grafting are reported. Patients were followed up from 5 to 10 years. The outcome was determined by the changes in the Harris hip score, by progression in radiographic stages, and by the need for hip replacement. The bone marrow was harvested with the patient under general anesthesia. The usual sites were the anterior iliac crests. The aspirated marrow was reduced in volume by concentration and injected into the femoral head after core decompression with a small trocar. When patients were operated on before collapse (Stage I and Stage II), hip replacement was done in nine of the 145 hips. Total hip replacement was necessary in 25 hips among the 44 hips operated on after collapse (Stage III and Stage IV). To measure the number of progenitor cells transplanted, the fibroblast colony forming unit was used as an indicator of the stroma cell activity. Patients who had the greater number of progenitor cells transplanted in their hips had better outcomes.
Article
Bone marrow aspirated from the iliac crest contains progenitor cells that can be used to obtain bone-healing of nonunions. However, there is little available information regarding the number and concentration of these cells that are necessary to obtain bone repair. The purpose of this study was to evaluate the number and concentration of progenitor cells that were transplanted for the treatment of nonunion, the callus volume obtained after the transplantation, and the clinical healing rate. Marrow was aspirated from both anterior iliac crests, concentrated on a cell separator, and then injected into sixty noninfected atrophic nonunions of the tibia. Each nonunion received a relatively constant volume of 20 cm(3) of concentrated bone marrow. The number of progenitor cells that was transplanted was estimated by counting the fibroblast colony-forming units. The volume of mineralized bone formation was determined by comparing preoperative computerized tomography scans with scans performed four months following the injection. The aspirates contained an average (and standard deviation) of 612 +/- 134 progenitors/cm(3) (range, 12 to 1224 progenitors/cm(3)) before concentration and an average of 2579 +/- 1121 progenitors/cm(3) (range, 60 to 6120 progenitors/cm(3)) after concentration. An average total of 51 x 10(3) fibroblast colony-forming units was injected into each nonunion. Bone union was obtained in fifty-three patients, and the bone marrow that had been injected into the nonunions of those patients contained >1500 progenitors/cm(3) and an average total of 54,962 +/- 17,431 progenitors. The concentration (634 +/- 187 progenitors/cm(3)) and the total number (19,324 +/- 6843) of progenitors injected into the nonunion sites of the seven patients in whom bone union was not obtained were both significantly lower (p = 0.001 and p < 0.01, respectively) than those in the patients who obtained bone union. The volume of the mineralized callus measured at four months on the computerized tomography scans of the patients who had union ranged from 0.8 to 5.3 cm(3) (mean, 3.1 cm(3)). There was a positive correlation between the volume of mineralized callus at four months and the number (p = 0.04) and concentration (p = 0.01) of fibroblast colony-forming units in the graft. There was a negative correlation between the time needed to obtain union and the concentration of fibroblast colony-forming units in the graft (p = 0.04). Percutaneous autologous bone-marrow grafting is an effective and safe method for the treatment of an atrophic tibial diaphyseal nonunion. However, its efficacy appears to be related to the number of progenitors in the graft, and the number of progenitors available in bone marrow aspirated from the iliac crest appears to be less than optimal in the absence of concentration.
Article
The reported outcomes of patients who underwent total or unicompartmental knee arthroplasty for secondary and spontaneous osteonecrosis of the knee are often from studies that lack the number of subjects necessary to generate meaningful conclusions. We systematically reviewed the available literature in order to define the outcomes of patients after total knee arthroplasty for secondary osteonecrosis and after total or unicompartmental knee arthroplasty for spontaneous osteonecrosis of the knee. A literature review yielded twenty cohorts with demographic patient information and outcome scores (global knee scores, radiographic outcomes, and revision rates) for patients who had knee arthroplasty as treatment for either secondary or spontaneous osteonecrosis of the knee. The mean preoperative and postoperative global knee scores, the mean revision rate, and the categorization of the mean "poor" and mean "good" outcomes for the knees with each underlying disease were tabulated and reported. The demographic data and the reported mean global knee scores were weighted by the number of knees in each study. Total knee arthroplasty was performed in 150 knees with secondary osteonecrosis and 148 knees with spontaneous osteonecrosis, and unicompartmental knee arthroplasty was performed in sixty-four knees with spontaneous osteonecrosis. Total knee arthroplasty for spontaneous osteonecrosis of the knee was associated with the best outcomes (higher "good" and postoperative global knee scores and lower revision [3%] and "poor" outcome [6%] rates compared with the other two groups). The outcomes after total knee arthroplasty in knees with secondary osteonecrosis as well as in knees with spontaneous osteonecrosis were better in the cohorts operated on during or after 1985 than in those operated on before 1985. Similarly, the outcomes after unicompartmental knee arthroplasty in knees with spontaneous osteonecrosis of the knee were also better in the cohorts operated on during or after 1985 than in those operated on before 1985. Total knee arthroplasty performed as treatment for either secondary osteonecrosis or spontaneous osteonecrosis and unicompartmental knee arthroplasty performed as treatment for spontaneous osteonecrosis were associated with improved outcomes in cohorts with more recent operative dates. The evidence suggests that the use of contemporary cemented implants in total knee arthroplasty and the selective use of stems and augments in patients who have development of secondary osteonecrosis after total knee arthroplasty are producing outcomes that are comparable to those seen after total knee arthroplasty for osteoarthritis. Although the outcomes of patients who have total knee arthroplasty for the treatment of spontaneous osteonecrosis of the knee have historically been favorable, such outcomes have also shown particular improvement in the studies from more recent operative periods. Although poor outcomes were seen after unicompartmental knee arthroplasty in earlier studies of patients with spontaneous osteonecrosis of the knee, it is possible that those results were secondary to inappropriate patient selection, as the authors of the most recent and, to our knowledge, the only study to follow established operative indications regarding the use of unicompartmental knee arthroplasty reported excellent results. Therapeutic Level IV. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.
Article
Background: Osteonecrosis of the distal portion of the femur produces a segment of dead bone in the weight-bearing portion of the femoral condyle, frequently associated with subchondral fracture and collapse and eventually resulting in secondary osteoarthritis. Treatment of these late stages of osteonecrosis in the knee can be problematic. The purpose of the present study was to evaluate a new surgical technique in which the subchondral osteonecrotic lesion is removed. The bone defect is then reconstructed with impacted bone grafts to prevent collapse and/or to regain distal femoral sphericity. Methods: In this prospective, one-surgeon study, nine consecutive knees in six patients were studied, all of which had extensive corticosteroid-associated osteonecrotic lesions of the femoral condyles. Six knees had collapsed lesions when they were initially treated. The mean age of the patients was thirty-one years. Both the clinical and radiographic outcomes were assessed at a minimal follow-up time of two years. Results: At a mean follow-up time of fifty-one months, none of the reconstructed knees had been converted to a total knee prosthesis. The objective Knee Society score improved from a mean of 63 to 89 points. The functional Knee Society score improved from a mean of 19 to 81 points. During the follow-up period, there was no progression of collapse observed; however, three knees showed early signs of osteoarthritis. Clinical success was achieved in six of eight knees, and radiographic success was achieved in seven of nine knees. Conclusions: At the time of writing (at the time of midterm follow-up), this method appears attractive as a joint-preserving procedure. It is a relatively simple procedure that is not likely to interfere with future knee procedures. It appears that this technique can be effective in knees with collapse of the femoral condyle, and it may delay the need for a total knee arthroplasty. Level of evidence: Therapeutic Level IV. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.
Article
Clinical presentation of osteoarthritis (OA) is dominated by pain during joint use and at rest. OA pain is caused by aberrant functioning of a pathologically altered nervous system with key mechanistic drivers from peripheral nerves and central pain pathways. This review focuses on symptomatic pain therapy exemplified by molecular targets that alter sensitization and hyperexcitability of the nervous system, for example, opioids and cannabinoids. We highlight opportunities for targeting inflammatory mediators and their key receptors (for example, prostanoids, kinins, cytokines and chemokines), ion channels (for example, NaV1.8, NaV1.7 and CaV2.2) and neurotrophins (for example, nerve growth factor), noting evidence that relates to their participation in OA etiology and treatment. Future neurological treatments of pain appear optimistic but will require the systematic evaluation of emerging opportunities.
Article
Results of cross-sectional studies have suggested that bone marrow lesions (BMLs) visualized on magnetic resonance imaging (MRI) are related to knee pain, but no longitudinal studies have been done. This study was undertaken to determine whether enlarging BMLs are associated with new knee pain. Subjects ages 50-79 years with knee osteoarthritis (OA) or at high risk of knee OA were asked twice at baseline about the presence of knee pain, aching, or stiffness (classified as frequent knee pain) on most days; absence of knee pain was the baseline eligibility criterion. At 15 months' followup, subjects were again queried twice about frequent knee pain. A case knee was defined as absence of knee pain at baseline but presence of knee pain both times at followup. Controls were selected randomly from among knees with absence of pain at baseline. All MR images were scored for volume of BMLs in the medial, lateral, and patellofemoral compartments. We focused on the maximal change in BML score among the knee compartments from baseline to 15 months. Multiple logistic regression, with adjustments for demographic and clinical variables, was used to assess whether an increased BML score is predictive of the development of knee pain. Among case knees, 54 of 110 (49.1%) showed an increase in BML score within a compartment, whereas only 59 of 220 control knees (26.8%) showed an increase (P < 0.001 by chi-square test). A BML score increase of at least 2 units was much more common in case knees than in control knees (27.5% versus 8.6%; adjusted odds ratio 3.2, 95% confidence interval 1.5-6.8). Among case knees with increased BMLs, most already had BMLs at baseline, with enlarging BMLs at followup, but among the subset of knees with no BMLs at baseline, new BMLs were more common in case knees (11 [32.4%] of 34) than in control knees (9 [10.8%] of 83). Development of knee pain is associated with an increase in BMLs as revealed on MRI.
Article
Bone marrow lesions (BML) are important in established knee osteoarthritis, predicting pain and progression of disease. Whether BML are also associated with longitudinal changes in knee structure in an asymptomatic population is unknown. 148 healthy pain-free women in middle age with no history of knee injury or clinical knee osteoarthritis who had a magnetic resonance imaging (MRI) scan performed on their dominant knee at baseline, had another MRI 2 years later to assess whether having a BML present at baseline affected change in tibiofemoral cartilage defects and tibial cartilage volume. BML were present in 14.9% of women at baseline. The risk of progression of total tibiofemoral cartilage defects was significantly higher when a very large BML was present (odds ratio 5.55, 95% CI 1.04 to 29.6) compared with when no BML was present, after adjusting for potential confounders. In the lateral compartment, the rate of cartilage volume loss was significantly greater when a BML was present after adjusting for confounders (regression coefficient 39.2 mm(3), 95% CI 11.1 to 67.2, p = 0.007). In healthy women without pain at baseline, large BML were associated with both progression of cartilage defects in the whole tibiofemoral joint and more rapid lateral tibial cartilage loss. These data suggest that the relationship between BML and knee cartilage in healthy women is similar to that described in established osteoarthritis. It is possible that BML may predict an increased risk of knee osteoarthritis and facilitate the identification of novel interventions to prevent disease.
Bone impaction grafting for corticosteroid-associated osteonecrosis of the knee
  • W H Rijnen
  • J S Luttjeboer
  • B W Schreurs
  • WH Rijnen