Abstract
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This review summarizes the sclerotic zone's pathophysiology, characterization, formation process, and impact on femoral head necrosis.
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The sclerotic zone is a reaction interface formed during the repair of femoral head necrosis.
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Compared with normal bone tissue, the mechanical properties of the sclerotic zone are significantly enhanced.
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Many factors influence the formation of the sclerotic zone, including mechanics, bone metabolism, angiogenesis, and other biological processes.
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The sclerotic zone plays an essential role in preventing the collapse of the femoral head and can predict the risk of the collapse of the femoral head.
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Regulating the formation of the sclerotic zone of the femoral head has become a direction worthy of study in treating femoral head necrosis.
Introduction
Osteonecrosis of the femoral head (ONFH) is a joint and difficult-to-treat disease, often leading to claudication and pain in the hip joint, limited mobility (1), and eventually leading to the collapse of the femoral head and hip osteoarthritis within 1–4 years of onset (2). The disease is common in young adults, and its prevalence is rising, bringing a heavy burden to families and society (3). Major risk factors for non-traumatic femoral head osteonecrosis include the application of glucocorticoids (4, 5) and alcohol consumption (6). The mechanism of femoral head necrosis may be due to the interruption of blood circulation in the femoral head due to various causes, such as damage to the vascular endothelium and the formation of microvessels leading to reduced perfusion in the femoral head, as well as intramedullary hypertension in the femoral head, which leads to arteriovenous stagnation and occlusion (7, 8, 9, 10). At the same time, osteocyte apoptosis, osteoblast reduction, osteoclast increase, and bone remodeling imbalance (11) lead to the accumulation of a large number of microfractures in the femoral head, involving the subchondral bone, which eventually manifests as the collapse of the subchondral bone (12). In addition, the concentration of local shear stresses between the femoral head's necrotic area and common bone tissue areas may cause the femoral head to collapse (13). A sclerotic zone exists in the transition area between the necrotic and common bone tissue in the femoral head (14), also known as a sclerotic rim, which is a dense bone band of higher strength than the normal cancellous bone of the femoral head produced during the repair process of femoral head necrosis (15). This article provides a review of the pathophysiology of the sclerotic zone in femoral head necrosis, the formation process, and the impact on femoral head necrosis.
Pathology of femoral head necrosis and sclerotic zone formation
The death of bone marrow hematopoietic cells occurs within 6–12 h in the pathological process of bone necrosis (16), while osteoblasts (osteocytes, osteoblasts, and osteoclasts) can survive for 12–48 h (16, 17) and adipocytes for 2–5 days (16). Then, within the tissue adjacent to the necrotic area, there is angiogenesis and bone marrow reactivity changes with increased inflammatory fibrovascular infiltration. A reactive interface of continuous repair ensues to isolate and repair the necrotic area that appears as a border on the femoral head sample (18). Over time, this reactive interface matures and progresses, and its essence is vascularized granulation tissue to repair the necrotic area, known as the creeping substitution zone (19). Because this area is richly vascularized, osteoblasts and osteoclasts are supported, allowing osteoblasts to deposit on necrotic bone trabeculae and osteoclasts to resorb the necrotic bone so that the bone weakening caused by the reactive interface at the edge of the creeping substitution zone is compensated, bone strengthening occurs, and eventually a sclerotic zone is formed (19). However, in the vast majority of cases, the repair interface cannot replace or repair areas of osteonecrosis (20). Besides, increased bone resorption at the junction of the reaction zone and the subchondral bone, as well as the synergistic effect of the weight on the femoral head, leads to subchondral bone fracture, and eventually to femoral head collapse and hip osteoarthritis (21).
Characterization of the sclerotic zone
Irregular dense bone tissue is seen between the area of femoral head necrosis and normal tissue, called sclerotic zone (13); it is the repair interface between the two during the repair of femoral head necrosis (Fig. 1).
The femoral head section (black arrow: the sclerotic zone).
Citation: EFORT Open Reviews 8, 6; 10.1530/EOR-22-0092
In the x-ray and the CT images (Fig. 2A, B and C) (19, 22, 23), the sclerotic zone appears as an irregular patchy or striated hyperdense shadow at the junction of necrotic tissue and normal tissue, while CT shows necrotic bone fractures and granulation tissue on the side of the sclerotic zone near the necrotic area (24). Furthermore, in the MRI images (19, 25), the sclerotic zone is not evident and exhibits a band-like, ring-like low signal rim on the T1 and T2 signal (Fig. 2D), suggesting a change in the structure and bone mineral salt content of the sclerotic zone reparative granulation tissue at the reaction interface. When micro-CT was applied to the necrotic femoral head (12, 26, 27), it was observed that the bone trabeculae in the sclerotic zone were disorganized and anisotropically arranged, and the trabeculae were thickened and fused. In contrast, the bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) values in the sclerotic zone of the femoral head increased compared with the normal femoral head, while the trabecular separation (Tb.Sp) values decreased. It indicates that in the osteosclerotic zone, as the BMD increases, the trabecular structure become dense, the trabecular hypertrophy, the number of trabeculae increase, and the trabecular separation become narrow. Also, the quantitative parameters of bone marrow perfusion on dynamic contrast-enhanced MRI and Raman spectroscopy suggest the presence of active bone repair in the bone tissue of the sclerotic zone (28).
The radiology of sclerotic zone in femoral head necrosis. (A) X-ray image (white arrow: sclerotic zone); (B–C) CT images (white arrow: sclerotic zone); (D) T1 signal in MRI (white arrow: sclerotic zone).
Citation: EFORT Open Reviews 8, 6; 10.1530/EOR-22-0092
The histology showed that the bone trabeculae in the sclerotic zone were thickened and increased in number (12), the arrangement was disorganized, and microfractures were observed (26). There were more bone lacunas in the trabeculae (29) and a large number of blood vessels in the sclerotic zone (30), woven bone, cartilage-like bone, and disordered new bone formation near the sclerotic zone (31). There was a significant increase in the number of alkaline phosphatase (ALP)-stained positive osteoblasts in the sclerotic zone, whereas there was no significant difference in the number of tartrate-resistant acid phosphatase (TRAP)-stained positive osteoclasts (12, 27). Increased apoptosis of osteoblasts was seen (31). However, the composition of the sclerotic zone did not differ significantly from the normal zone (31).
As a result of the earlier changes within the sclerotic zone of the femoral head, the mechanical parameters of the sclerotic zone also changed. Compared with the normal femoral head, the elastic modulus of the sclerotic zone increased by 58%, the yield strength by 42%, and the ultimate strength by 45%, indicating that the biomechanical strength of the sclerotic zone of the femoral head was significantly increased (32).
In addition, a study compared the sclerotic zone formed by femoral head necrosis with the osteoarthritic sclerotic zone of the hip and suggests that the thickness of bone trabeculae in the sclerotic zone formed by femoral head necrosis was higher than that in the osteoarthritic sclerotic zone of the hip. The bone marrow perfusion and bone repair in the sclerotic zone were more substantial than those in the osteoarthritic sclerotic zone of the hip (28), revealing the difference between the sclerotic zone of the femoral head necrosis and the osteoarthritic sclerotic zone of the hip.
Factors affecting the formation of the sclerotic zone
Mechanics
According to Wolff's law (33), the human or animal skeleton remodels itself to adapt to changes in load. Some researchers applied finite element analysis to study the stress changes in the femoral head during early femoral head necrosis, and found that stresses in the femoral head, such as shear stress and equivalent stresses, were redistributed (34), and the stresses focus on the repair interface between the necrotic area and normal tissue (35, 36). In order to accommodate the redistributed stress, bone tissue below the interface undergoes reconstruction: cancellous bone is realigned, bone trabeculae are thickened, and biomechanical properties are enhanced (26). Furthermore, later in order to accommodate the stress concentration at the junction of the thinner bone trabeculae in the necrotic area and the thicker bone trabeculae in the repaired area, eventually leading to the formation of a sclerotic zone (18), and later to accommodate the stress concentration at the junction of the thinner bone trabeculae in the necrotic area and the thicker bone trabeculae in the repaired area, eventually leading to the formation of a sclerotic zone (18). With the progression of the disease, the trabecular bone thickened, the degree of hardening of the sclerosing zone changed (13), and the stresses changed (22). Remodel of bone tissue is influenced by various mechanical factors (37); among the relevant stresses, compressive stress can enhance osteoblast activity and promote bone regeneration (38), and shear stress can stimulate osteoblast proliferation (39).
Bone metabolism
Cytokines and their pathways play an essential role in sclerotic zone formation by regulating cell differentiation, proliferation, apoptosis, and promoting angiogenesis. Immunohistochemistry showed (27) that bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 7 (BMP7), Runt-associated transcription factor 2 (Runx2), and osteoprotegerin (OPG) were expressed in the trabecular matrix of the sclerotic zone of the femoral head. Furthermore, RT-PCR results show that (27) the expression of Runx2 and BMP2 in the sclerotic zone was higher than in other parts of the necrotic femoral head, as well as the expression of nuclear factor receptor activator kB (RANK) was higher than that in normal tissue and lower than that in necrotic tissue and subchondral bone area. The nuclear factor receptor activator ligand (RANKL) expression and the ratio of RANKL/OPG were significantly lower than in other areas (12). Besides this, transforming growth factor beta 1 (TGFβ-1) expression was increased in the femoral head necrosis area (40). While western blot showed that (27) the expression of BMP2, BMP7, Runx2, and OPG was higher than in other sites, the expression of RANK and RANKL was higher than the normal tissue and subchondral bone area but lower than the necrotic tissue. The earlier results illustrate the increased activity of osteoblasts and osteoclasts in the sclerotic zone and active bone reconstruction. The skeletal system maintains homeostasis and function by regulating osteoblasts and osteoclasts. Among them, the OPG/RANKL/RANK signaling pathway is an important pathway that regulates bone metabolism (41). Bone remodel depends on the balance of OPG and RANKL (42); when the ratio of RANKL/OPG increases, the number and activity of osteoclasts increase. TGFβ-1, BMP2, and BMP7 belong to the TGF-β superfamily and play an essential role in bone formation through the TGF-β/BMP signaling pathway (43, 44). BMP2 and BMP7 have intense osteoinductive activity (45, 46), inducing differentiation of undifferentiated mesenchymal cells into osteoblasts, thereby inducing bone formation. TGFβ-1 is an important osteogenic regulator that promotes osteoblast proliferation and apoptosis of osteoclasts (47) and bone reconstruction (48). RUNX2 is a specific osteogenic differentiation transcription factor that promotes the transcription of genes related to osteoblast and chondrocyte mineralization and their differentiation into osteoblasts. RUNX2 also plays a vital role in bone growth and regulates cell differentiation and osteoblasts, osteoclasts, and various cytokines related to bone metabolism (49, 50).
Angiogenesis
Some studies have shown that vascular damage precedes changes in bone microstructure during femoral head necrosis (32). Femoral head microcirculation disorders may be a cause of osteonecrosis (51). Many microvessels provide blood supply for the formation of the sclerotic zone. Various cytokines and pathways are involved in vascular formation, including the hypoxia-inducible factor-1 (HIF-1α) signaling pathway and its downstream target, vascular endothelial growth factor (VEGF). HIF-1α is a critical transcription factor that mediates cellular adaptation to hypoxia (52) and plays an essential role in the coupled regulation of angiogenesis–osteogenesis during bone repair and regeneration (53). Angiogenesis and osteogenesis genes are coupled at specific vascular subtypes in the skeleton (54). Thus, blood vessels are essential for bone reconstruction, and this process is dependent on the HIF-1α pathway (55). Sustained activation of the HIF-1α pathway in osteoblasts upregulates VEGF and stimulates bone reconstruction (56). It has been shown that activation of the HIF-1α signaling pathway by HIF-1α molecules and modulation of its downstream target VEGF can intervene in femoral head necrosis (57). The sclerotic zone is a repair area located between the necrotic area and normal tissue of the femoral head, which is active in angiogenesis and other repair activities, but its specific mechanisms have been poorly studied.
Apoptosis and autophagy
Apoptosis and autophagy affect the formation of the femoral sclerotic area. Apoptosis is a programmed cell death to protect the overall homeostasis of the muscle by a complex mechanism (58). During femoral head necrosis, glucocorticosteroid and other factors can directly cause apoptosis of osteoblasts (59) and osteoclasts (60) and inhibit apoptosis of osteoclasts (61), thus affecting bone transformation and bone formation, as well as leading to apoptosis of vascular endothelial cells and affecting the blood supply within the femoral head (62). It has been reported that regulation of various cytokines and pathways, including AMPK pathway (63), mTOR pathway (64), PI3K/Akt pathway50, Wnt/β-catenin pathway (65), endoplasmic reticulum stress, and mitochondrial pathway-related pathways (66, 67), miRNA (68), exosomes (69, 70), and their interactions can interfere with apoptosis and prevent the development and progression of femoral necrosis. Autophagy is a protective mechanism for cells under conditions of external stimulation or starvation, providing nutrients to cells through the degradation of intracellular proteins and damaged organelles to maintain intracellular homeostasis and internal environmental homeostasis (71) and to save cells from apoptosis. It has been shown that hormone-induced autophagy can reduce the apoptosis rate of osteoblasts and osteocytes (72, 73). Therefore, apoptosis and autophagy interact with each other to jointly condition the pathological process of femoral head necrosis and are closely related to the formation of the sclerotic zone.
The role of the sclerotic zone in ONFH
It has been reported that sclerotic bands can slow down the collapse process of the femoral head during ONFH repair (74, 75). However, this is related to the location, morphology, and integrity of the sclerotic zone formation, and the mechanism may be that the high-density bone trabeculae within the sclerotic zone maintain the mechanical strength and, under certain conditions, form a closed sclerotic rim to reduce the original high stress in the subchondral bone (75). Some studies have shown that patients with a continuous sclerotic zone would not experience femoral head collapse, while patients with a discontinuous sclerotic zone had a 63% femoral head collapse rate. In contrast, all patients without a sclerotic zone eventually experienced femoral head collapse (76). Moreover, ARCO stage II ONFH with a ring-shaped sclerotic zone usually has an ideal prognosis (77). When the ring-shaped sclerotic zone is located in the weight-bearing area, femoral head collapse progresses slowly, and hip symptoms are not obvious, which has no significant impact on the patient's daily life. When the sclerotic zone is located in the non-weight-bearing area, the patient's symptoms disappear spontaneously gradually (77). Besides this, Zhang et al. (78) found that the sclerotic band followed specific shapes that determined the mechanical conduction's stability after examining plenty of images of the femoral head with sclerotic bands and proposed a ‘sclerotic band’ type of classification system. The classification system divided the sclerotic band into ‘U’, ‘inverted U’, ‘X’, and ‘S’ types according to the sclerotic band morphology as well as the stability of mechanical conduction. Based on this, the classification system expends more subtypes to assess the femoral head's stability. By scoring the stability of the femoral head, the classification system can provide additional information for clinical determination of the risk of femoral head collapse.
However, some research suggests that the formation of the sclerotic area hinders the growth of new vessels and bone tissue into the necrotic zone, which is detrimental to bone repair (79), but there is currently insufficient evidence to support this view. Besides this, finite element analysis of different types of the sclerotic zone indicates that the concentrated shear stress and strain at the junction between the sclerotic and necrotic area will lead to an intra-femoral microfracture (13) and eventually extends to the subchondral bone, resulting in a subchondral bone fracture and the femoral head collapse (18, 36). Therefore, using CT images, Huang et al. (22) studied the dynamic evolution of bone structure and the risk of dynamic collapse in femoral head necrosis and showed that soft tissue volume in the sclerotic zone decreased while the volume and bone density of sclerotic bone increased as the disease progressed, suggesting that sclerotic bone volume and bone density could be used as indicators to assess the risk of femoral head collapse.
Many studies on ONFH are currently hoping to find a valid method to accurately predict the prognosis and risk of collapse of ONFH (80, 81, 82). Most studies concluded that the femoral head is prone to collapse when the extent of necrosis is large and the necrotic area overlaps with the weight-bearing area. In contrast, Yu et al. (83) proposed the proportion of sclerotic bands to predict the risk of femoral head collapse. The final results showed that the percentage of the sclerotic zone was significant in predicting a femoral head collapse in ONFH, and the risk of collapse was low when the percentage of sclerosis was more significant than 30% and higher when it was less than 30%, and adequate mechanical support should be provided. However, as the article mentioned, the method has some limitations: the method could not be applied to predict the prognosis of ONFH at ARCO stages 0 and I because CT images do not reveal the sclerotic rim. Besides this, measurement of the proportion of the proximal sclerotic rim would be difficult to perform if the boundary of the focus was not clearly displayed for various reasons. We considered that combining the approach and the ‘sclerotic band’ type of classification system mentioned above can improve the performance of predicting collapse based on the sclerotic band.
Discussion
The specific role and influence of the sclerotic zone in the process of femoral head necrosis have not been thoroughly studied yet, and the specific molecular mechanism of its formation needs to be further investigated. However, the formation of the sclerotic zone and the formation site and morphology play a crucial role in the collapse of the femoral head and its prognosis in ONFH pathology. Compared with normal tissue, the mechanical parameters of the sclerotic zone appear to be enhanced with the thickening of bone trabeculae. When the sclerotic zone provides sufficient mechanical support to the subchondral bone, it can prevent the femoral head from collapsing. Based on this theory, the clinical prediction model was proposed to predict the risk of femoral head collapse by applying the ratio of the sclerotic zone with high accuracy.
On the other hand, the sclerotic zone also obstructs or interrupts the repair of the necrotic area, making treating femoral head necrosis difficult. Therefore, how to regulate the formation of the femoral head sclerosis band becomes the direction of further research. The formation of sclerotized bands is influenced by a variety of cytokines and mechanical factors. By intervening in related pathways such as bone metabolism, bone differentiation, angiogenesis, apoptosis, and autophagy, we can intervene in cell differentiation and bone trabecular formation at different stages of necrotic repair, so as to regulate the form and location of sclerotic zone formation. In need of mechanical support, part of the subchondral bone is formed through the strength of sclerotic zone in order to prevent the collapse of the femoral head. To prevent the crawling replacement of of a thick sclerotic zone that would hinder the repair of femoral head necrosis area, or for patients with high-risk factors such as application of glucocorticoid, early control of the formation of the sclerotic zone is required. In addition, the necrotic area is limited in order to treat the femoral head necrosis. The possibility of drug therapy for femoral head necrosis should also be discussed.
Conclusion
The sclerotic zone is a reaction interface formed during the repair of femoral head necrosis. Compared with normal bone tissue, the mechanical properties of the sclerotic zone are significantly enhanced. Many factors influence the formation of the sclerotic zone, including mechanics, bone metabolism, angiogenesis, and other biological processes. The sclerotic zone plays an essential role in preventing the collapse of the femoral head and can predict the risk of the collapse of the femoral head. Regulating the formation of the sclerotic zone of the femoral head has become a direction worthy of study in treating femoral head necrosis.
ICMJE conflict of interest statement
The authors declare that they have no competing interests
Funding
This study is financially supported by Shenyang Science and Technology Bureau Technology Talent Application Technology Research Project (grant no. 21-174-9-03); Department of Science and Technology of Liaoning Province (grant No.2017020223-201).
Ethical review statement
This research did not require approval by the local ethics board.
Consent to participate
The participants approved the x-ray, CT, MRI, and the femoral head section images used in this study and signed an informed consent form.
Author contribution statement
P-qL, G-zZ, and D-cH conceived and designed the study. P-qL, G-zZ, BW, and X-LD performed literature search. P-qL, G-Zz, BW, and X-LD organized related papers. P-qL and G-zZ wrote the manuscript. All authors contributed to the article and approved the submitted version.
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