The following information is provided as a summary page outlining a relationship between oxidized low-density lipoproteins (oxLDL), osteoarthritis (OA), aseptic loosening after total knee arthroplasty, atypical avascular necrosis, and avascular necrosis (AVN) for interested parties. A very detailed review of the pathophysiology of osteoarthritis and or other related conditions is not provided in this reading. Thus, nothing herein shall be considered definitive or all-inclusive. Further, the relationships described require a thorough understanding of the orthopaedic basic sciences in view of published data on cardiovascular disease. Simple terms are used where possible for the general public.
Importantly, orthopaedic surgery as a specialty is fragmented among many subspecialties, e.g., Adult Reconstruction, Sports, Hand and Upper Extremity, Tumor, Foot and Ankle, Sports, Trauma, Spine, and General Orthopaedics. While sub-specializations may facilitate a good outcome for specific orthopaedic conditions, joint preservation requires the skills of a Sports orthopaedist and an Adult Reconstruction orthopaedist in combination. Indeed, a 55-year-old with OA or AVN does not usually visit a Sports orthopedist for treatment. That said, the subspecialty of an orthopaedist may influence how a given disease is perceived, making the review of any cardiovascular literature to broaden one’s understanding of OA or AVN highly unlikely. This so-called influenced perception can be considered a confirmational bias independent of the standard of care, and it indirectly limits one’s knowledge because a clinically relevant relationship between cardiovascular disease and osteoarthritis, and AVN is not broadly known.
In 2002, Brannon endoscopically (intraosseous endoscopy) observed calcified marrow spaces within femoral heads having AVN. This observation was noted before and after debridement of the femoral head. The purpose of intraosseous endoscopy (placing an arthroscope inside of the femoral head) was to document the presence of actively bleeding blood vessels that would supply a bone graft packed therein after core decompression and thorough debridement. This simple technique allowed for more precise debridement beyond a simple core decompression and is as thorough as a free vascularized fibula graft procedure, the lightbulb procedure, and the trapdoor procedure. Further, this visual observation provided the rationale for avoiding an invasive revascularization procedure and demonstrated the presence of calcified marrow spaces in hips that were read as positive and negative for AVN on preoperative MRIs. Importantly, bone biopsies confirmed the presence of AVN in hips that were considered negative for AVN on MRI. Calcified marrow spaces, deep within a typical AVN lesion, were also found and noted to be identical to the calcified marrow spaces within the hips considered to be negative for AVN on MRI. Steinberg uses the size of the typical AVN lesion on MRI to predict outcome after core decompression and promotes the concept of the extent of involvement. This staging is based on a sclerotic margin surrounding the necrotic bone (bone with calcified marrow spaces1). This understanding established a standard of care for AVN by implying circumscription of a lesion within the femoral head, but such understanding is irreconcilable in view of Brannon.1 In other words, surgical and histopathologic findings support diffuse disease, while the staging system of Steinberg supports localized disease. That said, one becomes less likely to advance improved treatment options for AVN when the wisdom of Steinberg is not questioned nor decoded beyond its basic premise. For example, in 1936 Ernst Freund identified calcified marrow spaces in collected bone specimens from the first reported case of bilateral avascular necrosis.2 Steinberg recognized Freund for describing bilateral disease but went no further. Thus, no efforts have ever been made to understand the etiology of the calcified marrow spaces of Freund in view of Brannon. In contradistinction to Steinberg, Brannon teaches endoscopic visualization of the necrotic burden within the femoral head. The necrotic burden is the avascular bone (bone with calcified marrow spaces) throughout the femoral head. AVN is a disease wherein more diffuse portions of the bone are avascular and such avascular bone may not always be surrounded by the sclerotic margin of Steinberg. Learmonth noted a success rate of only 14% following core decompression,3 whereas Ficat noted a success rate of 89% following core decompression.4 This significant variation in outcome implies that when treatment is decided based on the concept of a localized lesion (extent of involvement), substantial amounts of avascular bone (bone with calcified marrow spaces) that do NOT appear on MRI in the manner described by Steinberg may remain within the femoral head after core decompression. In 2002, Brannon contemplated this shortcoming and developed a system to visually examine the inside of the femoral head after core decompression. Lowry et al.5 in 2006, and then Zaidi et al.6 in 2010, attempted to characterize the observations of Brannon by noting significant levels of hypoxia-inducible factor 1-alpha (HIF-1α) associated with MRI negative and histology positive AVN. The presence of HIF-1α could explain micro hypoxia within the femoral head, but the calcified marrow spaces of Freund in view of Brannon remained unexplained. Nonetheless, near-identical hip pain in those hips with MRI findings consistent with classic AVN is observed in hips with MRI findings inconsistent with classic AVN. These so-called MRI negative and histology positive hips (Atypical AVN) reveal calcified marrow spaces on intraosseous endoscopy. We strongly contemplate that these MRI negative and pathology positive hips are the hips that go on to develop classic osteoarthritis. Worse yet, some patients may suffer from hip pain for many years until their x-rays begin to show degenerative disease. Therefore, how and why do marrow spaces calcify? What are the consequences of calcified marrow spaces relative to the longevity of the femoral head?
In 1947, Fremont Chandler described AVN as a coronary of the hip, and for a short time, AVN was known as Chandler’s Disease. In his paper, Chandler described the femoral head as being an end-organ similar to the heart with the view that the foveal artery (the artery that supplies the very top of the femoral head) made little to no contribution to the blood supply of the femoral head in the adult.7 Then in 1985, Brown and Goldstein won the Nobel Prize for characterizing cholesterol metabolism having identified low-density lipoprotein (LDL) receptors on liver cells. Low-density lipoproteins transport cholesterol, cholesterol esters, and triglycerides through the bloodstream. Subsequently, numerous investigators described the role of LDL (bad cholesterol) and high-density lipoproteins, HDL (good cholesterol) as biomarkers for atherosclerosis and ischemic cardiac events. Triglycerides, the main source of fat in the foods we eat, and cholesterol cross the small intestine to enter the vascular system via the lymphatic system. When LDL levels in the blood stream are high, the liver downregulates its receptors for LDL. This excess LDL continues to circulate in the bloodstream and may then enter the tissue surrounding the inside lining cells of the arteries of the heart. The LDL passes through small gaps between the cells that line the insides of the arteries. The inside lining of the artery is called the endothelium and this endothelial lining, comprised of endothelial cells, is found throughout the entire venous and arterial vascular systems. While there are no receptors for LDL on endothelial cells, there are receptors on endothelial cells for oxidized low-density lipoproteins, oxLDL. The oxidation of LDL occurs when LDL cholesterol particles in the body react with free radicals. Free radicals are unstable molecules that are produced as a result of normal metabolism. One can expect more oxLDL in the bloodstream when LDL levels are high. That said, the recently identified receptor for oxLDL is a 52k Da transmembrane protein called the lectin-like oxidized low-density lipoprotein receptor (LOX-1) encoded on chromosome 12p. LOX-1 has properties of single nucleotide polymorphisms (SNPs) that give rise to the splicing variant LOXIN. LOXIN has been shown to dimerize with native LOX-1 and protects endothelial cells from damage by oxLDL by reducing the number of LOX-1 receptors on endothelial cell membranes for binding of oxLDL.8,9
Figure 1: Intraosseous endoscopy. Core decompression of the femoral head (FH) has been completed and an arthroscope has been placed inside of the FH. Intraosseous endoscopy reveals the occluded marrow spaces of Freund.2 Note the difference in color between the calcified marrow spaces and the spongy (cancellous) bone. The calcium deposited is a pathologic process, thus it displays a different color. The calcium deposits obstruct the blow flow through the marrow spaces. This pattern of calcification is identical to the calcified marrow spaces within the avascular bone described by Steinberg. Additionally, this type of calcification is observed after debridement when residual necrotic bone remains inside of the FH. This is not an artifact. If treatment is provided based on an MRI that does NOT describe the necrotic burden of Brannon, less favorable outcomes are likely to occur. The osteocytes within the spongy bone are unable to receive oxygen and nutrients from the blood supply when the marrow spaces are occluded, and as a result, the cells die due to a lack of oxygen, i.e., avascular necrosis. Not recognizing this fundamental concept early in the course of treatment may result in a hip progressing to osteoarthritis. The MRI of Steinberg and the sclerotic margin restrictively imply circumscription of a localized area of bone with occluded marrow spaces, when in fact occluded marrow spaces are more diffuse within the femoral head. It is important to note that any treatment for AVN to the femoral head should include restoration of porosity and transosseous blood flow. Introducing a bone graft substitute of any kind into the FH to promote increased density within the femoral is not advised. Increasing the density of the bone within the FH will invariably decrease the diameter of the marrow spaces. Further, synthetic grafts require a diseased FH with AVN to act on the bone graft substitute packed therein when the bone graft should be acting (providing needed cells and proteins) on the diseased FH. These kinds of considerations by the development team at OSI over many years led to more efficient ways to obtain large volumes of autologous bone because autologous bone can act on the diseased FH. Autologous cancellous bone is osteogenic, osteoconduction, and osteoinductive. At OSI, we consider the removal of dead bone during a core decompression and its replacement with something that was never alive, a synthetic graft, the least favorable of several grafting options and should be avoided.
Nonetheless, once LDL is sequestered in the outside tissue lining of a blood vessel, the intima, it is not easily cleared and is subsequently oxidized by free radicals. Free radicals are generated under normal metabolic conditions or conditions wherein tissue cells experience decreased oxygen, e.g., hypoxia. This scenario is common within the bone where excess fat imparts pressure on the small blood vessels (capillaries) that travel throughout the marrow spaces resulting in decreased blood flow. These areas of decreased blood flow experience micro hypoxia resulting in increased levels of HIF-1α, as noted by Zaidi et. al.5 We note that this obstruction of blood flow may be intravascular (fat globules, LDL, traveling within the bloodstream) as well. The level of free radicals increases as a given cell experiences increasingly hypoxic conditions. Once the oxLDL is formed, it binds to the endothelial cell via LOX-1, which in turn stimulates the endothelial cell to release cytokines IL-1β, IL-6, and TNFα, and chemokines, such as CCL2 and CCL5. The released cytokines are proinflammatory and likely give rise to the well-recognized bone marrow edema, BME, and lesions seen on MRI in some patients with OA. The released chemokines recruit monocytes to the area as scavenger cells. Once monocytes enter the area, they differentiate into macrophages that engulf the oxLDL and then become foam cells in the case of cardiovascular disease, CVD. Foam cells increase in size as larger amounts of oxLDL are engulfed. These foam cells die through a process of apoptosis, thus providing a necrotic nidus for extracellular matrix calcification by trans-differentiated smooth muscle cells (osteoblast-like cells). This process leads to plaque formation, e.g., calcification of the blood vessels around the heart, and comprises CVD. In regards to bone, bone lining cells (osteoblast NOT osteocytes) may initiate calcification (a pathologic process–note the difference in the color of the deposited calcium within the marrow spaces in Figure 1 above), not ossification (a physiologic process–the process of mineralization of type I collagen), of the marrow spaces through extracellular matrix vesicle deposition onto the native spongy bone. As the calcification process within the marrow spaces continues, the blood supply to the spongy bone is lost and the bone cells die. The calcified spongy bone (cancellous bone) may now appear dense and be considered subchondral sclerosis x-ray or mixed-signal heterogeneity on MRI. This pattern of mixed-signal heterogeneity may well present as a starburst within the center of the femoral head (densely sclerotic bone surrounded by osteopenic bone) on axial CT images.1 This process of calcification may augment the mechanically induced “thickening” of the cancellous bone postulated by Pugh, Radin, and Rose.10 Further, the calcified marrow spaces obstruct the transosseous blood flow within the femoral head causing the blood flow to become stagnant where the superior retinacular, the inferior vincular, and the foveal arteries enter the bone.11 Within the joint, at the foveal artery, the ligamentum teres becomes congested along with the pulvinar. This intraarticular congestion decreases the space available for the ligamentum teres, SALT, within the cotyloid fossa and leads to lateral subluxation of the femoral head during midstance, rim loading, and articular sided labral tears as the femoral head progresses towards OA.12,13 Once the cotyloid fossa pulvinar calcifies it is called a central acetabular osteophyte. A pincer lesion at the rim of the acetabulum is a common finding as well. Relative to the superior reticular and inferior vincular arteries, the stagnant blood flow in these areas of the femoral head along with intraosseous fat lead to the development of alpha and beta CAM lesions, and bone spurs (osteophytes) in some cases.
Figure 2: Debridement of the femoral head in Figure 1 has been completed after core decompression in a case of AVN and the arthroscope has been returned to the femoral head. OSI’s unique patented system allows for complete fluid control of the visual field so that the surgeon can localize the blood flow and map out further debridement as needed. This mitigates observing “blood everywhere.” The left panel reveals active bleeding from the intraosseous blood vessels described by Boraiah et al.,11 but initially, the blood flow is somewhat sluggish. The right panel demonstrates how the intraosseous blood flow improves as the intraosseous fat escapes. These kinds of findings over the past 20 years have contributed to the success of the Hip Tool Bone Graft Stabilization procedure, allowing many patients with AVN to avoid a revascularization procedure, as OSI’s approach debrides necrotic bone to a bleeding host bed, and then stabilizes autologous bone graft placed inside of the residual cavity with the Hip Tool. As described in the above reading, the blood vessels that supply the femoral head are obstructed and secondarily create changes within the joint. That said, OSI provides its patented specialized hip arthroscopy system to address the articular-sided changes of AVN, namely, congestion of the cotyloid fossa, CAM and pincer lesions, and articular-sided labral tears, during a single procedure.1,12,13,17
In the case of a knee, the cancellous bone in the patellofemoral sulcus becomes increasingly occluded and sclerotic and the space available for the excess intraosseous fat continuously decreases. As a result, the excess fat is forced to exit at the osteochondral junction, the bone’s weakest point, wherein a bone spur will develop and oxLDL are released into the joint. OxLDL has been shown to be destructive to articular cartilage and simultaneously cause inflammation within the joint.14 The menisci become increasingly trapped as the bone spurs enlarge. The knee is staged as having mild, moderate, or severe osteoarthritis according to the Kellgren-Lawrence system.
Figure 3: Artist rendition of OA of the knee. Calcified marrow spaces resulting from cytokine-mediated matrix vesicle deposition of calcium by bone lining cells (osteoblast). Increased intraosseous pressure forces the fat within the marrow spaces to exit the bone at the bone’s weakest point, the osteochondral junction. As the fat exits, bone spurs develop at the osteochondral junction. The exiting fat comprises LDL, oxLDL, cholesterol, and cholesterol esters. Importantly, intraosseous oxLDL is engulfed via the LOX-1 scavenger receptors on macrophages. Once engulfed, the macrophages are polarized to the M1 phenotype resulting in a profound increase in proinflammatory cytokines, IL-1β, IL-6, TNF-α, and M1-surface marker CD86. These proinflammatory cytokines likely give rise to the bone marrow edema lesions seen on MRI, resulting in osteopenia and intraosseous insufficiency fractures. OxLDL has been shown to be destructive to articular cartilage as well. Additionally, increasing intake of saturated fats and trans fats contributes to the intraosseous fat load within the bone.
The relationship between CVD, OA, AVN, and Atypical AVN is apparent through the shared unfavorable metabolic product, oxLDL. While cardiology has extensively studied oxLDL and the use of statins to lower the incidence of ischemic cardiac events, orthopaedics appears to have missed this correlation relative oxLDL induced calcification of marrow spaces. This appears largely due to the subspecialization of orthopaedics and the recognized success of arthroplasty. However, increasing volumes of joint replacements and revisions are not sustainable, aside from an analysis of the lifetime costs of OA in the United States.15 That said, this broader view of OA allows one to reconsider certain orthopaedic conditions in view of perceived putative physiologic differences amongst them. When performing a total knee replacement, is there a large amount of oxLDL released into the circulation upon deflation of the tourniquet, comprising an oxLDL storm? Could an oxLDL storm explain fat embolism syndrome in the case of a long bone fracture? Do these oxLDLs bind to the endothelial lining of the deep veins and cause inflammation leading to clot formation and a DVT? OxLDL binding to endothelial cells can lead to platelet aggregation. Cardiac data has shown that plaque formation, which requires binding of oxLDL to endothelial cells and macrophages, is more likely in areas where laminar flow is absent.16 This summary postulates that the binding of oxLDL to endothelial cells is more likely in areas where blood flow is sluggish. In the case of aseptic loosening, does oxLDL contribute to the chronic inflammation observed through the release of proinflammatory cytokines and M1 polarization of macrophages via their phenotypic plasticity? While autophagy is considered the primary mechanism of aseptic loosening, the role oxLDL may play has not been considered.16 Basic physiology teaches beta fatty acid oxidation and that the intestinal absorption of triglycerides into the vascular system is via the lymphatics. This knowledge allows one to consider triglycerides, cholesterol, and cholesterol ester molecules, unaffected by the first-pass effect of the liver, as biomarkers of one’s diet, save for the inborn error of metabolism of familial hypercholesterolemia described by Brown and Goldstein. Further, the SNPs on chromosome 12p for LOX-1 oxLDL receptors may help explain why OA is NOT solely a disease of obese patients with diabetes and hypertension. Is the SNP heterozygous or homozygous? Nonetheless, the orthopaedist should counsel his or her patients about fat intake after an arthroplasty, irrespective of the benefits of a normal BMI, recognizing that oxLDL is still produced even in the replaced knee and such unfavorable metabolic byproduct may accumulate at the bone prosthesis interface and contribute to loosening of the prosthesis. Could oxLDL levels serve as a biomarker of potential aseptic loosening in early continued chronic knee pain after an arthroplasty? Would preoperative levels be beneficial in this regard? Indeed, arthroscopy for osteoarthritis with a meniscus tear or mechanical symptoms can potentially be beneficial when the basic science of the disease being treated is broadly understood. However, performing arthroscopy or even an arthroplasty under the influence of a confirmational bias that excludes new data and a broader understanding of disease, “total knees work well, everybody knows arthroscopy is NOT effective, there are no peer-reviewed articles in the Journal on oxLDL, I have never heard of this oxLDL concept, robots eliminate concerns about malalignment, wear debris through autophagy is the sole cause of aseptic loosening and that is what is on the Boards, I am not concerned about my cases, they always go well,” will not advance the standard of care.
Clearly, the above can be viewed from countless perspectives, with a plethora of commentary about its source and the intent thereof; none of which is relevant. What is relevant is that a summary has been provided of the data published in the peer-reviewed literature, as information only, on OA, AVN, Atypical AVN, and CVD, to include their references, and at a minimum, one should be motivated to read through these references and ask the questions we asked to seek answers for those that need the expertise of the orthopaedist the most, the patient. The answers we obtained have been critical to our success over the past 20 years. We are confident that this data, comprising a broader view of OA and AVN, cannot be ignored. The use of the joint preservation products we developed in your practice is independent of any duty of care owed to a patient. The orthopedist must act as a responsible steward of data and resources, counseling the patient so that they are aware of the options they might have for joint preservation based on the orthopaedist’s best recommendations.
