Osteoporosis, Osteoarthritis, and Subchondral Insufficiency Fracture: Recent Insights.

The increased incidence of osteoarthritis (OA), particularly knee and hip OA, and osteoporosis (OP), owing to population aging, have escalated the medical expense burden. Osteoarthritis is more prevalent in older women, and the involvement of subchondral bone fragility spotlights its association with OP. Notably, subchondral insufficiency fracture (SIF) may represent a more pronounced condition of OA pathophysiology. This review summarizes the relationship between OA and OP, incorporating recent insights into SIF. Progressive SIF leads to joint collapse and secondary OA and is associated with OP. Furthermore, the thinning and fragility of subchondral bone in early-stage OA suggest that SIF may be a subtype of OA (osteoporosis-related OA, OPOA) characterized by significant subchondral bone damage. The high bone mineral density observed in OA may be overestimated due to osteophytes and sclerosis and can potentially contribute to OPOA. The incidence of OPOA is expected to increase along with population aging. Therefore, prioritizing OP screening, early interventions for patients with early-stage OA, and fracture prevention measures such as rehabilitation, fracture liaison services, nutritional management, and medication guidance are essential.

Effect of longer femoral head on leg length, offset, and range of motion in total hip arthroplasty: a simulation study.

In this study, we investigated the relationship between head length, leg length, offset, and dislocation resistance using range of motion (ROM) simulations based on computed tomography data to examine if a longer femoral head reduces the risk of dislocation. The femoral components were set to eliminate leg length differences with a + 0 mm head, and variations for + 4-, + 7-, and + 8-mm heads were analyzed. Offset and ROM were assessed when longer heads were used, with the leg length adjusted to be similar to that of the contralateral side. While internal rotation at flexion and external rotation at extension increased with + 4-mm longer heads, the + 7- and + 8-mm heads did not increase dislocation resistance. When adjusting for leg length, the longer heads showed no significant differences in offset and ROM. Enhancing dislocation resistance by solely increasing the offset with a longer head, while simultaneously adjusting the depth of stem insertion, may be a beneficial intraoperative technique. Although a + 4-mm longer head possibly increases ROM without impingement, heads extended by + 7 or + 8 mm may not exhibit the same advantage. Therefore, surgeons should consider this technique based on the implant design.

Methylprednisolone pulse-enhanced neutrophil extracellular trap formation in mice with imiquimod-induced lupus-like disease, resulting in ischaemia of the femoral head cartilage.

OBJECTIVES: Methylprednisolone (mPSL) pulse therapy is an essential option for patients with active systemic lupus erythematosus, but there is a risk of adverse events related to microcirculation disorders, including idiopathic osteonecrosis of the femoral head (ONFH). Recent studies have revealed that excessive neutrophil extracellular traps (NETs) are involved in microcirculation disorders. This study aimed to demonstrate that mPSL pulse could induce NETs in lupus mice and identify the factors contributing to this induction. METHODS: Six mice with imiquimod (IMQ)-induced lupus-like disease and six normal mice were intraperitoneally injected with mPSL on days 39 to 41, and five mice with IMQ-induced lupus-like disease and six normal mice were injected with phosphate-buffered saline. Pathological examinations were conducted to evaluate the ischaemic state of the femoral head and tissue infiltration of NET-forming neutrophils. Proteome analysis was performed to extract plasma proteins specifically elevated in mPSL-administered mice with IMQ-induced lupus-like disease, and their effects on NET formation were assessed in vitro. RESULTS: Mice with IMQ-induced lupus-like disease that received mPSL pulse demonstrated ischaemia of the femoral head cartilage with tissue infiltration of NET-forming neutrophils. Proteome analysis suggested that prenylcysteine oxidase 1 (PCYOX1) played a role in this phenomenon. The reaction of PCYOX1-containing very low-density lipoproteins (VLDL) with its substrate farnesylcysteine (FC) induced NETs in vitro. The combined addition of IMQ and mPSL synergistically enhanced VLDL-plus-FC-induced NET formation. CONCLUSION: PCYOX1 and related factors are worthy of attention to understand the underlying mechanisms and create novel therapeutic strategies for mPSL-mediated microcirculation disorders, including ONFH.

Validation of parameters recommended for secondary screening for developmental dysplasia of the hip in Japan.

BACKGROUND: Based on the Japanese Pediatric Orthopaedic Association's guidelines, secondary screening and imaging including ultrasonography and radiography, are recommended in infants with limited hip abduction (<70°) or in those with multiple risk factors including the following: asymmetrical skin creases, a family history of developmental dysplasia of the hip, female sex, and pelvic position at delivery. However, there is still little information regarding the usefulness of this guideline. The objective of this study was to investigate the association between the risk factors and developmental dysplasia of the hip diagnosed using ultrasound and radiography. METHODS: A total of 356 infants (67 boys and 289 girls) underwent secondary ultrasonographic and radiological screening for developmental dysplasia of the hip in our hospital. Risk factors were documented from their medical records. The recommended item score, which we defined as an integrated value of the recommended item, was calculated for each patient. The limitation of hip abduction alone was a criterion for secondary screening; therefore, we defined the scores as follows: the limitation of hip abduction scored 2 points and other recommended scores were assigned 1 point. If the recommended item score was 2 points or more, we classified the infants as high-risk. RESULTS: A total of 280 of 356 infants were included in the high-risk group, which showed a higher ratio of cases with abnormal imaging findings than the low-risk group. According to the multivariate logistic regression analyses among the recommended items, being female, skin asymmetry, and limb limitation were identified as independent risk factors for imaging abnormality and the need for Pavlik harness treatment. CONCLUSIONS: The recommended items for secondary screening based on the Japanese Pediatric Orthopaedic Association's guidelines could be useful for screening infants in need of treatment.

Anatomical and Simulation Studies Based on Three-Dimensional-Computed Tomography Image Reconstruction of Femoral Offset.

Although the hip joint morphology varies by race, few studies have investigated the associations between two-dimensional (2D) and three-dimensional (3D) morphologies. This study aimed to use computed tomography simulation data and radiographic (2D) data to clarify the 3D length of offset, 3D changes in the hip center of rotation, and femoral offset as well as investigate the anatomical parameters associated with the 3D length and changes. Sixty-six Japanese patients with a normal femoral head shape on the contralateral side were selected. In addition to radiographic femoral, acetabular, and global offsets, 3D femoral and cup offsets were investigated using commercial software. Our findings revealed that the mean 3D femoral and cup offsets were 40.0 mm and 45.5 mm, respectively; both were distributed around the mean values. The difference between the 3D femoral and cup offsets (i.e., 5 mm) was associated with the 2D acetabular offset. The 3D femoral offset was associated with the body length. In conclusion, these findings can be applied to the design of better ethnic-specific stem designs and can help physicians achieve more accurate preoperative diagnoses.

Noncanonical Pyroptosis Triggered by Macrophage-Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis.

OBJECTIVE: The severity of osteoarthritis (OA) and cartilage degeneration is highly correlated with the development of synovitis, which is mediated by the activity of inflammatory macrophages. A better understanding of intercellular communication between inflammatory macrophages and chondrocytes should aid in the discovery of novel therapeutic targets. We undertook this study to explore the pathologic role of inflammatory macrophage extracellular vesicles (EVs) in cartilage degeneration. METHODS: Macrophages were stimulated by treatment with bacterial lipopolysaccharides to mimic the state of inflammatory macrophages, and the resulting EVs were harvested for chondrocyte stimulation in vitro and for intraarticular injection in a mouse model. The stimulated chondrocytes were further subjected to RNA-sequencing analysis and other functional assays. The action of caspase 11 was disrupted in vitro using a specific small interfering RNA or wedelolactone, and in experimental murine OA models by intraarticular injection of wedelolactone. RESULTS: Stimulated chondrocytes exhibited a significant elevation in the expression of chondrocyte catabolic factors. Consistent with these results, RNA-sequencing analyses of stimulated chondrocytes indicated that up-regulated genes were mainly categorized into apoptotic process and tumor necrosis factor signaling pathways, which suggests the induction of apoptotic process. Moreover, these chondrocytes exhibited a significant elevation in the expression of pyroptosis-related molecules that were correlated with the expression of chondrocyte catabolic factors. The disruption of caspase 11 significantly alleviated pyroptotic and catabolic processes in stimulated chondrocytes and pathologic changes in collagenase-induced and joint instability-induced OA models. CONCLUSION: Our results provide new insight into the pathologic mechanisms of OA and suggest that noncanonical pyroptosis in chondrocytes represents an attractive therapeutic target for treatment.

Inhibitory role of Annexin A1 in pathological bone resorption and therapeutic implications in periprosthetic osteolysis.

There is currently no therapy available for periprosthetic osteolysis, the most common cause of arthroplasty failure. Here, the role of AnxA1 in periprosthetic osteolysis and potential therapeutics were investigated. Reducing the expression of AnxA1 in calvarial tissue was found to be associated with increased osteolytic lesions and the osteolytic lesions induced by debris implantation were more severe in AnxA1-defecient mice than in wild-type mice. AnxA1 inhibits the differentiation of osteoclasts through suppressing NFκB signaling and promoting the PPAR-γ pathway. Administration of N-terminal-AnxA1 (Ac2-26 peptide) onto calvariae significantly reduced osteolytic lesions triggered by wear debris. These therapeutic effects were abrogated in mice that had received the PPAR-γ antagonist, suggesting that the AnxA1/PPAR-γ axis has an inhibitory role in osteolysis. The administration of Ac2-26 suppressed osteolysis induced by TNF-α and RANKL injections in mice. These findings indicate that AnxA1 is a potential therapeutic agent for the treatment of periprosthetic osteolysis.

Low-Grade Inflammation in the Pathogenesis of Osteoarthritis: Cellular and Molecular Mechanisms and Strategies for Future Therapeutic Intervention.

Osteoarthritis (OA) is a musculoskeletal disease characterized by cartilage degeneration and stiffness, with chronic pain in the affected joint. It has been proposed that OA progression is associated with the development of low-grade inflammation (LGI) in the joint. In support of this principle, LGI is now recognized as the major contributor to the pathogenesis of obesity, aging, and metabolic syndromes, which have been documented as among the most significant risk factors for developing OA. These discoveries have led to a new definition of the disease, and OA has recently been recognized as a low-grade inflammatory disease of the joint. Damage-associated molecular patterns (DAMPs)/alarmin molecules, the major cellular components that facilitate the interplay between cells in the cartilage and synovium, activate various molecular pathways involved in the initiation and maintenance of LGI in the joint, which, in turn, drives OA progression. A better understanding of the pathological mechanisms initiated by LGI in the joint represents a decisive step toward discovering therapeutic strategies for the treatment of OA. Recent findings and discoveries regarding the involvement of LGI mediated by DAMPs in OA pathogenesis are discussed. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach for the treatment of OA.

Inflammasome Activation in the Hip Synovium of Rapidly Destructive Coxopathy Patients and Its Relationship with the Development of Synovitis and Bone Loss.

Rapidly destructive coxopathy (RDC), a rare disease of unknown etiology, is characterized by the rapid destruction of the hip joint. In the current study, the potential involvement of inflammasome signaling in the progression of RDC was investigated. Histopathologic changes and the gene expression of inflammasome activation markers in hip synovial tissues collected from patients with RDC were evaluated and compared with those of osteoarthritis and osteonecrosis of the femoral head patients. The synovial tissues of patients with RDC exhibited remarkable increases in the number of infiltrated macrophages and osteoclasts, and the expression of inflammasome activation markers was also increased compared with those of osteoarthritis and osteonecrosis of the femoral head patients. To further understand the histopathologic changes in the joint, a co-culture model of macrophages and synoviocytes that mimicked the joint environment was developed. Remarkably, the gene expression levels of NLRP3, GSDMD, IL1B, TNFA, ADMTS4, ADMTS5, MMP3, MMP9, and RANKL were significantly elevated in the synoviocytes that were co-cultured with activated THP-1 macrophages, suggesting the association between synovitis and inflammasome activation. Consistent with these findings, osteoclast precursor cells that were co-cultured with stimulated synoviocytes exhibited an increased number of tartrate-resistant acid phosphatase-positive cells, compared with cells that were co-cultured with non-stimulated synoviocytes. These findings suggest that the activation of inflammasome signaling in the synovium results in an increase in local inflammation and osteoclastogenesis, thus leading to the rapid bone destruction in RDC.

Determination of optimal concentration of vitamin E in polyethylene liners for producing minimal biological response to prosthetic wear debris.

The introduction of vitamin E-blended ultra-high molecular weight polyethylene (VE-UHMWPE) for use in prosthetic components of hip implants has resulted in the production of implants that have excellent mechanical properties and substantially less adverse cellular responses. Given the importance of a biological response to wear in the survival of a prosthesis, we generated wear debris from UHMWPE that had been prepared with different concentrations of vitamin E of 0.1, 0.3, 0.5, and 1% and evaluated their biological reaction in vitro and in vivo. All types of VE-UHMWPE debris promoted a significantly lower expression of Tnf-α in murine peritoneal macrophages than that induced by conventional UHMWPE debris. However, levels of Tnf-α were not significantly different among the macrophages that were stimulated with VE-UHMWPE wear at the concentrations tested. The ability of wear debris to induce inflammatory osteolysis was assessed in a mouse calvarial osteolysis model. The expressions of Tnf-α, Il-6, and Rankl in granulomatous tissue formed around the wear debris were significantly reduced in mice that had been implanted with 0.3%VE-UHMWPE debris as compared to the corresponding values for mice that had been implanted with UHMWPE debris. Consistent with this finding, 0.3%VE-UHMWPE debris showed the lowest osteolytic activity, as evidenced by the reduced bone resorption area, the degree of infiltration of inflammatory cells and the TRAP staining area. Our results suggested that a 0.3% vitamin E concentration is the most appropriate concentration for use in prosthetic components with a reduced adverse cellular response for prolonging the life-span of the implant.

Effect of periacetabular osteotomy on the distribution pattern of subchondral bone mineral density in patients with hip dysplasia.

Despite the availability of long-term follow-up data, the effect of pelvic osteotomy on the natural history of osteoarthritis is not yet fully understood, partly because there is untapped potential for radiographs to better describe osteoarthritis. Therefore, this study aimed to assess the distribution of subchondral bone mineral density (BMD) across the acetabulum in patients with hip dysplasia immediately (2 weeks) and 1 year after undergoing periacetabular osteotomy (PAO). To that end, we reviewed 40 hips from 33 patients with developmental dysplasia of the hip who underwent PAO between January 2016 and July 2019 at our institution. We measured subchondral BMD through the articular surface of the acetabulum using computed tomography osteoabsorptiometry, dividing the distribution map into nine segments. We then compared the subchondral BMD between 2 weeks and 1 year after PAO in each area. At 2 weeks after PAO, the high-density area tended to be localized particularly in the lateral part of the acetabulum, whereas 1 year after PAO, the high-density area moved to the central and lateral parts. The percentage ratios of the subchondral BMD for the central-posterior, lateral-central, and lateral-posterior areas relative to the central-central area were significantly decreased at 1 year after PAO, as compared to those at 2 weeks after PAO. These findings suggest that loading was altered by PAO to be more similar to physiological loading. A long follow-up observational study is warranted to confirm the association between early changes in subchondral BMD by PAO and joint degeneration.

Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis.

Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway.

A growing body of evidence suggests that immune factors that regulate osteoclast differentiation and bone resorption might be promising therapeutic agents for the treatment of osteoporosis. The expression of CLCF1, an immune cell-derived molecule, has been reported to be reduced in patients with postmenopausal osteoporosis. This suggests that it may be involved in bone remodeling. Thus, we explored the functional role of CLCF1 in osteoclastogenesis and bone loss associated with osteoporosis. Surprisingly, the administration of recombinant CLCF1 repressed excessive bone loss in ovariectomized mice and prevented RANKL-induced bone loss in calvarial mouse model. Likewise, the addition of recombinant CLCF1 to RANKL-stimulated monocytes resulted in a significant suppression in the number of differentiated osteoclasts with small resorption areas being observed on dentine slices in vitro. At the same dosage, CLCF1 did not exhibit any detectable negative effects on the differentiation of osteoblasts. Mechanistically, the inhibition of osteoclast differentiation by the CLCF1 treatment appears to be related to the activation of interferon signaling (IFN) and the suppression of the NF-κB signaling pathway. Interestingly, the expression of the main components of IFN-signaling namely, STAT1 and IRF1, was detected in macrophages as early as 1 h after stimulation with CLCF1. Consistent with these results, the blockade of STAT1 in macrophages abolished the inhibitory effect of CLCF1 on osteoclast differentiation in vitro. These collective findings point to a novel immunoregulatory function of CLCF1 in bone remodeling and highlight it as a potentially useful therapeutic agent for the treatment of osteoporosis.

Flightless I is a catabolic factor of chondrocytes that promotes hypertrophy and cartilage degeneration in osteoarthritis.

Synovial macrophages that are activated by cartilage fragments initiate synovitis, a condition that promotes hypertrophic changes in chondrocytes leading to cartilage degeneration in OA. In this study, we analyzed the molecular response of chondrocytes under condition of this type of stimulation to identify a molecular therapeutic target. Stimulated macrophages promoted hypertrophic changes in chondrocytes resulting in production of matrix-degrading enzymes of cartilage. Among the top-upregulated genes, FliI was found to be released from activated chondrocytes and exerted autocrine/paracrine effects on chondrocytes leading to an increase in expression of catabolic and hypertrophic factors. Silencing FliI in stimulated cells significantly reduced expression of catabolic and hypertrophic factors in cocultured chondrocytes. Our further results demonstrated that the FliI-TLR4-ERK1/2 axis is involved in the hypertrophic signaling of chondrocytes and catabolism of cartilage. Our findings provide a new insight into the pathogenesis of OA and identify a potentially new molecular target for diagnostics and therapeutics.

Evaluation of whole-body modalities for diagnosis of multifocal osteonecrosis-a pilot study.

BACKGROUND: This study aimed to investigate the ability of whole-body bone scintigraphy (WB-BS) in the detection of multifocal osteonecrosis (ON) compared to whole-body magnetic resonance imaging (WB-MRI) and to clarify the characteristics of patients with multifocal ON among those with ON of the femoral head (ONFH) using WB-MRI. METHODS: Forty-six patients who had symptomatic ONFH and underwent surgery in our hospital from April 2019 to October 2020 were included in the study. Data on patient demographics, including age, sex, body mass index (BMI), history of corticosteroid intake, alcohol abuse, smoking, and symptomatic joints, were collected from their medical records. All patients underwent WB-MRI and WB-BS before surgery. RESULTS: The agreement in the detection of ON by WB-MRI vs the uptake lesions by WB-BS in the hip joints was moderate (κ = 0.584), while that in other joints was low (κ < 0.40). Among the 152 joints with ON detected by WB-MRI, 92 joints (60.5%) were symptomatic, and 60 joints (39.5%) were asymptomatic. Twelve out of the 46 (26.0%) patients had multifocal (three or more distinct anatomical sites) ON. Nonetheless, while WB-BS detected symptomatic ON detected by WB-MRI as uptake lesions in 82.6% (76/92) of the joints, asymptomatic ON detected by WB-MRI was detected as uptake lesions in 21.7% (13/60) of the joints. All patients with multifocal ON had a history of steroid therapy, which was significantly higher than that in patients with oligofocal ON (P = 0.035). The patients with a hematologic disease had multifocal ON at a higher rate (P = 0.015). CONCLUSIONS: It might be difficult for WB-BS to detect the asymptomatic ON detected by WB-MRI compared to symptomatic ON. Considering the cost, examination time, and radiation exposure, WB-MRI might be useful for evaluating multifocal ON. Larger longitudinal studies evaluating the benefits of WB-MRI for detecting the risk factors for multifocal ON are required.

Predictors of cartilage degeneration in patients with subchondral insufficiency fracture of the femoral head: a retrospective study.

BACKGROUND: There is evidence that the cause of primary osteoarthritis (OA) is related to the changes in subchondral bone; however, the influence of subchondral insufficiency fracture (SIF) of the femoral head on the degeneration of the hip joint and the prognostic factors related to joint degeneration remain unclear. The objectives of this study were (1) to investigate the natural history of joint space width after the occurrence of SIF and (2) to investigate the associations between joint space narrowing and bone metabolic markers as well as magnetic resonance imaging (MRI) among the patients with SIF. METHODS: Between January 2010 and December 2019, 238 patients in whom band pattern of the femoral head were observed on MRI visited Hokkaido University Hospital. Among these patients, 44 hips in 41 patients were diagnosed with SIF and eligible for this retrospective study. We evaluated the joint space width (JSW) of the hip on the radiograph obtained at the first and last visits, length of the band lesion on MRI, bone mineral density by dual-energy X-ray absorptiometry, and bone metabolism markers. Similarly, the factors associated with the necessity of surgery and the progression of the narrowing of the joint space were evaluated. RESULTS: Fifteen of the 44 hips required total hip arthroplasty (THA). A significant decrease was observed in the JSW from the first visit to the final follow-up. Changes in the JSW were associated with the length of band patterns, serum type 1 procollagen-N-propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRACP-5b) during diagnosis. Additionally, bone metabolic markers tended to be associated with the length of the band pattern. CONCLUSIONS: SIF could cause joint space narrowing and hip OA. In addition to MRI findings as prognostic predictors of SIF, as previously described, bone metabolic markers were equally associated with changes in JSW, suggesting that these parameters could be useful in predicting the prognosis of SIF. Considering that bone metabolic markers trended to be associated with the length of band pattern, they might reflect the local severity.