Altered Subchondral Bone Mineral Density in Painful Knee Osteoarthritis Without Cysts: A Comparative Analysis of Lateral and Medial Regions

doi:10.21203/rs.3.rs-4975009/v1

Objectives

This study aims to elucidate the mechanisms underlying pain generation and progression in knee osteoarthritis (KOA) by investigating alterations in proximal tibial subchondral bone mineral density (BMD) among individuals experiencing painful KOA without subchondral cysts, utilizing three-dimensional (3D) bone densitometry.

Methods

A prospective, single-center data collection was conducted at the 960th Hospital of the Joint Logistics Support Force of the PLA. We employed a 3D bone densitometry technique to assess BMD in specific regions. Knee pain was evaluated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Based on WOMAC scores, the knees of each patient were categorized into a moderate-severe pain group and a mild pain group. We explored the correlation between BMD and pain and analyzed differences among various pain subgroups.

Results

Computed tomography (CT) imaging of 84 knees from 42 patients revealed a significant association between BMD and pain. The moderate-to-severe pain group exhibited higher BMD in the lateral compartment compared to the mild pain group. Statistically significant differences were observed in 0-2.5 mm lateral-posterior, 2.5-5.0 mm lateral-anterior, 5.0-7.5 mm medial-posterior, and 7.5-10.0 mm lateral-posterior.

Conclusions

The altered subchondral bone density of the proximal tibia may play a pivotal role in the pathogenesis of KOA-related pain in patients.

Knee osteoarthritis (KOA) is a painful joint disease that leads to both cartilage damage and alterations in the subchondral bone. While pain stands as the primary symptom, understanding the underlying mechanisms of this pain is hindered by specific structural factors [1].

Several factors, including bone marrow lesions (BMLs), bone cysts, subchondral bone mineral density (BMD), and articular cartilage defects, are frequently associated with subchondral bone deterioration [2–4]. Previous research employing two-dimensional (2D) dual-energy X-ray absorptiometry (DXA) has shown connections between proximal tibial bone mineral density (BMD) and KOA-related pain. However, these studies yielded conflicting results, possibly due to inherent limitations in the 2D imaging tools. These limitations arise from measuring BMD in conjunction with selected analysis regions containing cortical and/or trabecular bone, which may respond differently to the effects of KOA [5–7].

Computed tomography osteoabsorptiometry (CT-OAM), employing quantitative computed tomography (QCT) imaging methods and maximum intensity projection image processing, holds the potential to comprehensively assess subchondral bone and 3D BMD, providing the added advantage of distinguishing between cortical and trabecular bone [8, 9]. While the CT technique has been applied in some studies to evaluate subchondral BMD within the osteoarthritic human proximal tibia [3, 10–12]), there remains controversy regarding which specific BMD parameters, such as those in the medial and lateral compartments, are directly associated with knee osteoarthritis (KOA)-related pain[7, 13, 14]. Burnett et al. reported a focal increase in BMD within the subchondral trabecular area in patients experiencing severe nocturnal pain, without excluding cysts [11]. Additionally, Burnett et al. proposed that low BMD of tibial epiphyseal trabecular bone between the epiphyseal line and 7.5 mm from the subchondral surface, along with the tibial metaphyseal trabecular low BMD 10.0 mm distal from the epiphyseal line, may influence the pathogenesis of pain associated with KOA[13].

The primary objective of this study was to investigate and compare BMD parameters for each specific compartment, utilizing image processing-based CT technology. The focus was on exploring the relationship between pain and BMD within the 0–10.0 mm subchondral level in all subjects experiencing unilateral pain. This densitometry technique enables the evaluation of 3D BMD, accurately excluding cortical bone during measurement. Through a within-person matched knee analysis of discordant pain, non-structural pain determinants, such as pain susceptibility, were controlled for. The study specifically concentrated on BMD changes in KOA patients without subchondral cysts and delved into the pathogenesis of KOA-related pain.

Study participants

Patients were prospectively enrolled from the general and orthopedic outpatient clinics of the 960th Hospital of the Joint Logistics Support Force of the PLA between January 2023 and July 2023.

Approval for the study was granted by the Institutional Research Board of the 960th Hospital of the Joint Logistics Support Force of the PLA under Grant No. (2023) Research Ethics Review No. (020). Written informed consent was obtained from all study participants, and the experiments adhered to relevant guidelines and regulations.

The inclusion criteria comprised patients with discordant knee pain lasting ≥ 3 months in the past 12 months or pain for most days in the past month, along with definite radiographic evidence of osteoarthritis in at least one compartment of at least one knee, and an age exceeding 40 years. Exclusion criteria included individuals with a prior history of other forms of joint disease, such as bone implants, osteonecrosis, or CT scans revealing bone cysts. Patients taking medications affecting bone metabolism (e.g., bisphosphonates) were also excluded.

Participant assessment

Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters squared. To assess pain intensity at the affected knee joint, the pain section of the Western Ontario McMasters Osteoarthritis Index (WOMAC) was utilized [15]. This involved measuring pain on a 10-point scale (ranging from 0 for no pain to 9 for severe pain) across five categories: walking on a flat surface, climbing or descending stairs, pain at night, sitting or lying, and standing upright (representing the most severe pain). The individual element pain scores were then summed to derive a WOMAC pain score within the range of 0 to 45. During knee X-ray scans, the knee joint was observed in a non-flexed position for standing images, while a flexed position of 135 degrees was applied for lateral images. The severity of knee osteoarthritis (KOA) was determined using Kellgren-Lawrence (KL) grading [16], with grading ranging from 0 to 4. Knee alignment was categorized as varus, valgus, or neutral based on the angle between the femoral and tibial axes. Varus alignment was defined as an angle less than 176 degrees, valgus alignment as an angle greater than 180 degrees, and neutral alignment as 176–180 degrees[7]. The diagnosis of cysts relies on CT image reconstructions using bone and soft tissue windows, where cysts are identified as well-defined, round or oval, low-density lesions with a diameter exceeding two voxels. KL grading and cyst diagnosis were conducted using a double-blind method by two diagnostic physicians, each possessing over ten years of work experience.

Participant classification

A total of 53 patients diagnosed with knee osteoarthritis (KOA) participated in the study, with 11 patients excluded due to the presence of subchondral cysts revealed in CT scans. The final cohort comprised 42 patients, consisting of 14 men and 28 women, with a mean age of 55.7 ± 9.0 years and a BMI of 25.9 ± 3.0. This group contributed data for a comprehensive analysis of 84 knees. Relevant participant characteristics, including Kellgren-Lawrence (KL) grading and knee alignment in weight-bearing situations, are presented in Table 1.

Patients received separate WOMAC scores for their right and left knee joints based on their perception of knee pain. Subsequently, patients' right and left knee joints were divided into two groups based on their respective WOMAC scores. The "moderate-severe pain" group was characterized by a relatively high WOMAC score, while the "mild pain" group had a relatively low WOMAC score. A control group was established, comprising participants with no pain according to WOMAC and a Kellgren-Lawrence (KL) grade of 0.

CT scan parameters

CT scanning parameters included a tube voltage of 120 kVp, automatic tube current modulation, axial scanning plane, a slice thickness of 0.625 mm, and an in-plane pixel size of 0.625 mm × 0.625 mm. The effective radiation dose per scan was estimated to be less than 0.16 mSv using software (CT-DOSE, Neusoft Medical System, Shenyang, China), corresponding to a natural background radiation exposure of fewer than 16 days in a comparable time frame [17].

Quantitative CT (QCT) acquisition

A 256-slice spiral CT instrument (NeuViz Glory, Neusoft Medical, Shenyang, China) was employed for bone imaging. Each participant underwent CT scans with a solid QCT reference phantom (FT/HK-2000, Huake Testing New Technology Development Institute, Chengdu, China) beneath them. Phantoms facilitated the conversion of grayscale CT Hounsfield Units (HU) to apparent BMD (mg/cm³ K₂HPO₄). Previous human studies validated that QCT density measurements accurately reflect true BMD. Simultaneous CT scans of both legs were performed with the participant in a supine position, focusing on the distal femur, patella, and proximal tibia. However, only the proximal tibia was analyzed in this study.

Equivalent volume BMD values are determined by converting grayscale Hounsfield units (HU) to BMD, a linearly proportional measure to the CT value of bone tissue and its BMD on the same CT image frame. This relationship is expressed as:

$$\:\text{B}\text{M}\text{D}=\frac{{\text{H}\bullet\:({\mu\:}_{x}/{\mu\:}_{w})\bullet\:(\text{k}\text{V}\text{p}/\text{V})}^{\text{n}}}{\text{C}\text{T}\:\text{v}\text{a}\text{l}\text{u}\text{e}\:\text{i}\text{n}\text{d}\text{e}\text{x}\text{i}\text{n}\text{g}\:\text{f}\text{a}\text{c}\text{t}\text{o}\text{r}\bullet\:{\rho\:}_{w}\bullet\:{\mu\:}_{x}\bullet\:{\rho\:}_{x}}$$

Here, H is the CT value in Hu, $\:{\mu\:}_{x}$ and $\:{\mu\:}_{w}$ are the linear attenuation coefficients of the measured tissue and water, respectively in $\:{cm}^{-1}$; $\:\text{k}\text{V}\text{p}/\text{V}$ is the ratio of the mass attenuation coefficient associated with the CT tube's voltage value (a constant for the same device), n is the specified CT value indexing factor (usually 1000) in HU. $\:{\rho\:}_{w}$ is the density of water and $\:{\rho\:}_{x}$ is the mass attenuation coefficient and mass density of the measured tissue, in $\:{cm}^{2}/g$ and $\:{g/cm}^{3}$.

To mitigate the impact of uncontrollable fluctuations in CT equipment's kV values on CT values, the body model is synchronized with bone tissue during scanning. The 3D imaging and precise indexing of CT values enable the Quantitative CT (QCT) technique to detect changes as subtle as several milligrams of BMD. This technique demonstrates a repeatability of 0.8% over 10 scans at any interface and maintains an accuracy error within ± 1.5%.

Image normalization

Image normalization procedures were conducted for each case before measurement. Utilizing AVW 2.0 software (Neusoft Medical, Shenyang, China) for postprocessing, a bone window was selected for Multi-Planar Reconstruction (MPR). CT image postprocessing at the workstation involved 3D BMD measurement. In the sagittal position, the localization line's longitudinal axis aligned parallel to the knee joint's long axis. For coronal positioning, the line connecting the lowest points of the inner and outer condyles of the tibial plateau was identified, and the line was placed in proximity to the upper edge of the tibial cortex. In the transverse position, this layer was defined as the subchondral level.

Regional analysis

Delineation of the medial and lateral tibial compartments: To delineate the medial and lateral tibial compartments, a continuous line is drawn at the widest point of the tibial plateau. The length of this line is measured, and it is then divided into three segments in proportions of 40%, 20%, and 40%. Subsequently, a plumb line is drawn at the two nodes representing 40%, creating a clear demarcation. The areas on either side of the plumb line, extending to the edge of the tibia, are defined as the medial and lateral tibial compartments.

Delineation of the anterior and posterior compartments: The anterior and posterior compartments of the tibia are delineated by dividing the anterior and posterior dimensions of each plateau into two subregions with equal spacing. These subregions are labeled as L1, L2, L3 and L4, as illustrated in Fig. 1.

Region of Interest (ROI) Definition: The ROI is manually drawn by modifying the ROI boundary of the medial and lateral platforms while ensuring the exclusion of cortical bone. This meticulous delineation process, conducted by operators who have received proper training to identify and distinguish different types of bone tissue, allows for accurate assessment and analysis within the designated compartments. Following the definition of the ROI, a second check by an experienced expert is performed to ensure that no cortical bone has been mistakenly included.

All assessments were performed at four subchondral surface depths, each corresponding to specific anatomical structures: (1) 0-2.5 mm: This depth aligns closely with the density of the subchondral endplate and cortical bone [18]; (2) 2. 5–5.0 mm: Proximity to the density of the subchondral trabeculae characterizes this depth [10]; (3) 5.0-7.5 mm: This range corresponds to the density of the area between the subchondral trabecular and the proximal epiphyseal line trabeculae.. (4) 7.5–10.0 mm: This depth mirrors the density of the proximal epiphyseal plate trabeculae.

Statistical analysis

BMD was determined by calculating the mean from three CT scans. Quantitative variables were summarized using descriptive statistics (mean ± SD). To affirm the correlation between body mass index (BMI) and Western Ontario McMasters Osteoarthritis Index (WOMAC), the Spearman correlation coefficient was utilized. Additionally, a chi-square test was conducted to verify the correlation between Kellgren-Lawrence (KL) grading and WOMAC. Exploring the variability in BMD between the "moderate-severe pain" group and the "mild pain" group involved the application of a paired t-test. Statistical analysis was carried out using SPSS 25 software (SPSS Inc.), and statistical significance was defined at p < 0.05.

Upon statistical analysis, the chi-square test indicated no significant association between KL-grading and the WOMAC scores (x² = 0.566, p = 0.452). Similarly, the Spearman correlation coefficient demonstrated no significant correlation between body mass index (BMI) and WOMAC scores (correlation coefficient = 0.071, p = 0.656).

The results of the paired t-test are presented in Table 2 and Fig. 2. Specifically, a significant difference in L2 bone mineral density (BMD) at 0–2.5 mm from the subchondral surface was identified (t = 2.158, p = 0.043). Participants with "moderate-severe pain" exhibited higher lateral BMD in the L2 region compared to those with "mild pain" (mean difference 63.80 mg/cm3; Cohen's d value 0.471). Further distinctions emerged at 2.5-5.0 mm from the subchondral surface, with L1 and L3 demonstrating statistically significant differences in BMD (L1: t = 3.242, p = 0.004; L3: t = -3.668, p = 0.001). Notably, participants with "moderate-severe pain" displayed higher L1 BMD (mean difference 44.32 mg/cm3; Cohen's d value 0.691) and lower L3 BMD (mean difference − 32.55 mg/cm3; Cohen's d value of 0.782) than their "mild pain" counterparts. Additionally, statistical significance was observed for L4 at 5.0–7.5 mm below the subchondral surface(t = -3.875, p = 0.001). In this instance, participants with "moderate-severe pain" exhibited lower L4 BMD than those with "mild pain" (mean difference − 30.32 mg/cm3; Cohen's d-value 0.846; p < 0.01). The investigation extended to L2 at 7.5–10.0 mm from the subchondral surface(t = 2.325, p = 0.030), revealing higher lateral BMD in "moderate-severe pain" patients compared to their "mild pain" counterparts (mean difference 25.65 mg/cm3; Cohen's d value 0.496). No statistical significance was found in other regions.

Data for the control group, characterized by a WOMAC score of 0 and a Kellgren-Lawrence (KL) grade of 0, are presented in Table 3. This group consisted of 28 participants, evenly distributed between genders (14 men and 14 women), with an average age of 52.50 ± 6.68 years and a BMI of 24.45 ± 3.09.

The findings establish a notable correlation between tibial subchondral bone mineral density (BMD) and pain severity in patients with knee osteoarthritis (KOA). Figure 3 visually represents the outcomes of the within-person matched knee analysis, specifically illustrating the discordant pain levels. It is evident from the analysis that within the "moderate-severe pain" group, the lateral compartment exhibited elevated BMD, whereas the medial compartment displayed diminished BMD in comparison to the "mild pain" group. The findings of Burnett et al. are consistent with our results[7]. Specifically, they observed that patients with knee OA pain exhibited higher BMD on the lateral side, while the medial BMD tended to decrease. In a subsequent study, Burnett et al. further discovered that trabecular BMD was lower in patients with knee pain[13].

Figure 4 presents the topographic color map of BMD for both left and right legs in normal subjects, revealing no significant differences. Contrary to some studies associating body mass index (BMI) with pain [19], our results indicate no such correlation. This inconsistency may stem from the predominance of early to middle stages of arthritis in our study participants and a concentrated BMI range (25.9 ± 3.0), potentially influencing the impact of BMI on pain.

The results strongly indicate that altered subchondral bone mineral density (BMD) in the tibia is a distinctive feature associated with knee osteoarthritis (KOA)-related pain. Focal increases in BMD were observed at specific depths (0-2.5 mm in LP, 2.5-5 mm in L1, and 7.5–10.0 mm in LP), and several factors contribute to this phenomenon. Research demonstrates that, under normal weight-bearing conditions, the inner knee compartment bears around 60% of the load, concentrating stress along the lower limb force line, while the lateral compartment bears approximately 40% of the load [20, 21]. According to Wolf's law, bone density and strength change in response to stress, with higher-stress areas exhibiting increased BMD. Under normal conditions, this implies that medial BMD should surpass lateral BMD. Notably, patients with KOA often exhibit varus deformity, altering the load distribution between the medial and lateral tibial compartments. Due to the parallel functions of these compartments, increased load is naturally transferred to the lateral compartments, prompting self-adjustments in movement and posture by patients to alleviate stress on the medial compartment and joint pain. This adaptation leads to higher lateral BMD near the subchondral surface to fulfill the mechanical requirements of increased load transfer [22].

Moreover, in the early stages of KOA progression, various pathogenic factors induce abnormalities in the osteoarticular surface, subjecting the subchondral bone to repeated overload pressure and resulting in structural damage. During this process, the subchondral bone trabeculae undergo thinning, reducing the bone volume fraction and BMD. Patients with KOA experience greater load and susceptibility to abnormal stress in the medial compartment, leading to increased osteoclast reactivity, enhanced bone resorption, and accelerated bone remodeling. Consequently, BMD decreases in the early stages of KOA progression [12, 23–25]. Our study involving 66 cases in the early stages of KOA progression revealed reduced BMD in the medial region, aligning with bone loss and decreased bone mineral content in the cancellous bone beneath the cartilage during the initial phases of KOA [26, 27].

Although alterations in subchondral tibial bone mineral density (BMD) contribute to the onset and progression of pain in knee osteoarthritis (KOA), detecting BMD changes in KOA patients proves challenging through X-ray images. This difficulty may elucidate the absence of a correlation between pain and Kellgren-Lawrence (KL) grade in our study findings. For instance, a 54-year-old female participant exhibited KL-2 and WOMAC score 10 in her left leg, while her right leg had KL-0 and WOMAC score 30. Remarkably, the right leg demonstrated significantly lower BMD on the medial side and higher BMD on the lateral side compared to the left leg. This disparity could be attributed to BMD-related knee pain, impacting local innervation not captured by X-ray images. The extensive innervation of subchondral trabeculae implies that BMD alterations affect both local innervation and the mechanical properties of bone [28–30]. The deep layers of calcified cartilage receive nourishment through blood vessels and nerves traversing countless tiny channels in the subchondral bone [31]. The distribution of these channels varies with stress levels [32]. Increased local stress in KOA patients leads to more channels, neovascularization promoting inflammatory cell invasion, growth of new unmyelinated sensory nerves, and enhanced local nociceptive receptors, culminating in joint pain [33, 34].

To our knowledge, this study is the first to investigate the correlation between depth-specific proximal tibial subchondral bone mineral density (BMD) and symptomatic knee osteoarthritis (KOA) in patients without subchondral cysts, encompassing those with early-middle-stage OA (KL 0–2) and late-stage OA (KL 3–4). Rigorous selection criteria were employed to avoid inaccuracies in BMD measurements arising from the presence of cysts. The subchondral bone typically includes the subchondral bone plate and 6 mm of cancellous bone beneath, serving to safeguard joint cartilage and prevent injury. The cancellous bone in this region, situated farther away, exerts minimal influence on the onset and progression of KOA[13]. Earlier studies proposed that necrotic bone surrounding cysts contributes to pain[33]. However, the association between cysts and pain might diminish in the advanced stages of KOA, wherein bone remodeling levels may decrease or reach equilibrium. As a result, the cyst structure surrounding the cysts could exhibit higher BMD, rendering it resilient to the impact of elevated stress [34]. Regardless of the KOA stage, our findings emphasize that local BMD, rather than cysts, at depths of 2.5–10.0 mm from the subchondral surface plays a pivotal role in the pathogenesis of KOA-related pain. Furthermore, the within-person matched knee analysis of discordant pain in this study offers a significant advantage by controlling for individual variations in non-structural pain determinants, such as pain susceptibility factors, which might obscure structure-pain relationships [1].

This study is subject to several limitations. Firstly, the exclusion of cases with subchondral cysts was solely based on CT scans. Given the resolution limitations of CT imaging, smaller cysts may have been overlooked. Secondly, the sample size in our study was relatively modest. Despite observing lower medial BMD values in the moderate-severe pain group compared to the mild or no pain group, statistical significance was not attained. To validate our observations, a more extensive study with a larger sample size is warranted. Thirdly, the study design was cross-sectional in nature. To validate our findings and provide a more comprehensive understanding, larger and longitudinal studies are essential.

Funding

The authors state that this work has not received any funding.

Author Contribution

GS proposed the concept of a study on bone density in patients with osteoarthritis of the knee, and then worked with CX to design the study protocol, including the required research methods and experimental design. PX collected and collated the data and worked with CX to complete the first draft of the paper. YZ, SZ and YF also participated in data collection and collation and performed statistical analysis of the data. The interpretation and discussion of the experimental results were done jointly. GS and KL supervised and guided the entire research process, suggested revisions and ideas for the manuscript, and managed and coordinated the research project. All authors read and approved the final version of the manuscript.

Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Javaid MK, Kiran A, Guermazi A, et al (2012) Individual MRI and radiographic features of knee OA in subjects with unilateral knee pain: Health ABC study. In: Arthritis Rheum. 201264103246-3255. https://www.escholar.manchester.ac.uk/uk-ac-man-scw:164166. Accessed 4 Jan 2023
Madry H, van Dijk CN, Mueller-Gerbl M (2010) The basic science of the subchondral bone. Knee Surg Sports Traumatol Arthrosc Off J ESSKA 18:419–433. https://doi.org/10.1007/s00167-010-1054-z
Johnston JD, Masri BA, Wilson DR (2009) Computed tomography topographic mapping of subchondral density (CT-TOMASD) in osteoarthritic and normal knees: methodological development and preliminary findings. Osteoarthritis Cartilage 17:1319–1326. https://doi.org/10.1016/j.joca.2009.04.013
Crema MD, Roemer FW, Marra MD, et al (2010) Contrast-enhanced MRI of subchondral cysts in patients with or at risk for knee osteoarthritis: the MOST study. Eur J Radiol 75:e92-96. https://doi.org/10.1016/j.ejrad.2009.08.009
Lo GH, Hunter DJ, Zhang Y, et al (2005) Bone marrow lesions in the knee are associated with increased local bone density. Arthritis Rheum 52:2814–2821. https://doi.org/10.1002/art.21290
Dore D, Ding C, Jones G (2008) A pilot study of the reproducibility and validity of measuring knee subchondral bone density in the tibia. Osteoarthritis Cartilage 16:1539–1544. https://doi.org/10.1016/j.joca.2008.04.012
Burnett WD, Kontulainen SA, McLennan CE, et al (2015) Knee osteoarthritis patients with severe nocturnal pain have altered proximal tibial subchondral bone mineral density. Osteoarthritis Cartilage 23:1483–1490. https://doi.org/10.1016/j.joca.2015.04.012
Hirsch AC, Hotz G, Rosendahl W, et al (2017) CT-Osteoabsorptiometry (CT-OAM) - a new investigation technique in the field of mummy research. Anthropol Anz Ber Uber Biol-Anthropol Lit 74:1–7. https://doi.org/10.1127/anthranz/2017/0694
Müller-Gerbl M, Putz R, Kenn R (1992) Demonstration of subchondral bone density patterns by three-dimensional CT osteoabsorptiometry as a noninvasive method for in vivo assessment of individual long-term stresses in joints. J Bone Miner Res Off J Am Soc Bone Miner Res 7 Suppl 2:S411-418. https://doi.org/10.1002/jbmr.5650071409
Johnston JD, Kontulainen SA, Masri BA, Wilson DR (2010) A comparison of conventional maximum intensity projection with a new depth-specific topographic mapping technique in the CT analysis of proximal tibial subchondral bone density. Skeletal Radiol 39:867–876. https://doi.org/10.1007/s00256-009-0835-2
Burnett WD, Kontulainen SA, McLennan CE, et al (2019) Knee osteoarthritis patients with more subchondral cysts have altered tibial subchondral bone mineral density. BMC Musculoskelet Disord 20:14. https://doi.org/10.1186/s12891-018-2388-9
Bennell KL, Creaby MW, Wrigley TV, Hunter DJ (2008) Tibial subchondral trabecular volumetric bone density in medial knee joint osteoarthritis using peripheral quantitative computed tomography technology. Arthritis Rheum 58:2776–2785. https://doi.org/10.1002/art.23795
Burnett WD, Kontulainen SA, McLennan CE, et al (2017) Proximal tibial trabecular bone mineral density is related to pain in patients with osteoarthritis. Arthritis Res Ther 19:200. https://doi.org/10.1186/s13075-017-1415-9
Burnett WD, Kontulainen SA, McLennan CE, et al (2015) Response to Letter to the Editor: “Is subchondral bone mineral density associated with nocturnal pain in knee osteoarthritis patients?” Osteoarthritis Cartilage 23:2299–2301. https://doi.org/10.1016/j.joca.2015.06.015
Bellamy N, Buchanan WW, Goldsmith CH, et al (1988) Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15:1833–1840
Kellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16:494–502. https://doi.org/10.1136/ard.16.4.494
Radiology (ACR) RS of NA (RSNA) and AC of Radiation Dose. In: Radiologyinfo.org. https://www.radiologyinfo.org/en/info/safety-xray. Accessed 4 Jan 2023
Yamada K, Healey R, Amiel D, et al (2002) Subchondral bone of the human knee joint in aging and osteoarthritis. Osteoarthritis Cartilage 10:360–369. https://doi.org/10.1053/joca.2002.0525
Alghadir AH, Khan M (2022) Factors affecting pain and physical functions in patients with knee osteoarthritis: An observational study. Medicine (Baltimore) 101:e31748. https://doi.org/10.1097/MD.0000000000031748
Lee S-S, Celik H, Lee D-H (2018) Predictive Factors for and Detection of Lateral Hinge Fractures Following Open Wedge High Tibial Osteotomy: Plain Radiography Versus Computed Tomography. Arthrosc J Arthrosc Relat Surg Off Publ Arthrosc Assoc N Am Int Arthrosc Assoc 34:3073–3079. https://doi.org/10.1016/j.arthro.2018.06.041
Jo H-S, Park J-S, Byun J-H, et al (2018) The effects of different hinge positions on posterior tibial slope in medial open-wedge high tibial osteotomy. Knee Surg Sports Traumatol Arthrosc Off J ESSKA 26:1851–1858. https://doi.org/10.1007/s00167-017-4526-6
Wada M, Maezawa Y, Baba H, et al (2001) Relationships among bone mineral densities, static alignment and dynamic load in patients with medial compartment knee osteoarthritis. Rheumatol Oxf Engl 40:499–505. https://doi.org/10.1093/rheumatology/40.5.499
Ding M, Danielsen CC, Hvid I (2001) Bone density does not reflect mechanical properties in early-stage arthrosis. Acta Orthop Scand 72:181–185. https://doi.org/10.1080/000164701317323444
Day JS, Ding M, van der Linden JC, et al (2001) A decreased subchondral trabecular bone tissue elastic modulus is associated with pre-arthritic cartilage damage. J Orthop Res Off Publ Orthop Res Soc 19:914–918. https://doi.org/10.1016/S0736-0266(01)00012-2
Ding M, Odgaard A, Hvid I (2003) Changes in the three-dimensional microstructure of human tibial cancellous bone in early osteoarthritis. J Bone Joint Surg Br 85:906–912
Adebayo OO, Ko FC, Wan PT, et al (2017) Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice. Osteoarthritis Cartilage 25:2108–2118. https://doi.org/10.1016/j.joca.2017.08.016
Muraoka T, Hagino H, Okano T, et al (2007) Role of subchondral bone in osteoarthritis development: a comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis. Arthritis Rheum 56:3366–3374. https://doi.org/10.1002/art.22921
CHEN B, PEI G, JIN D, et al (2007) Distribution and property of nerve fibers in human long bone tissue. Chin J Traumatol 10:3–9. https://doi.org/10.5555/cjt.1008-1275.10.01.p3.01
Mach DB, Rogers SD, Sabino MC, et al (2002) Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 113:155–166. https://doi.org/10.1016/s0306-4522(02)00165-3
Radin E, Paul I, Rose R (1972) ROLE OF MECHANICAL FACTORS IN PATHOGENESIS OF PRIMARY OSTEOARTHRITIS. The Lancet 299:519–522. https://doi.org/10.1016/S0140-6736(72)90179-1
Green WT, Martin GN, Eanes ED, Sokoloff L (1970) Microradiographic study of the calcified layer of articular cartilage. Arch Pathol 90:151–158
Ahmed AM, Burke DL, Yu A (1983) In-vitro measurement of static pressure distribution in synovial joints--Part II: Retropatellar surface. J Biomech Eng 105:226–236. https://doi.org/10.1115/1.3138410
MacDonald I, Liu S-C, Su C-M, et al (2018) Implications of Angiogenesis Involvement in Arthritis. Int J Mol Sci 19:2012. https://doi.org/10.3390/ijms19072012
Ashraf S, Wibberley H, Mapp PI, et al (2011) Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis. Ann Rheum Dis 70:523–529. https://doi.org/10.1136/ard.2010.137844

Table 1. Characteristics for all participants

Characteristic

Participants

n

KL-grading

KL-0

KL-1

KL-2

KL-3

KL-4

42 (50%)

14 (16.7%)

10 (11.9%)

14 (16.7%)

4 (4.8%)

Knee alignment

Neutral

Internally turned

Externally turned

58 (69.0%)

11 (13.1%)

15 (17.9%)

Table 1 demonstrates the number and percentage of KL-grading and alignments for 84 knees in 42 patients.

Table 2. Results of paired t-test for participant bone mineral density

Region	Region	Depth(mm)	Bone Mineral Density (mg/cm³)		Mean difference	Cohen's d value	P-value
			mild Pain	moderate-severe pain	(mm)
LA	L1	0-2.5	350.47±197.24	408.65±160.11	58.19	0.342	0.133
		2.5-5.0	207.27±132.35	251.59±118.65	44.32	0.691	0.004
		5.0-7.5	197.77±102.48	223.74±81.00	25.97	0.333	0.142
		7.5-10.0	169.20±112.09	210.86±109.76	41.66	0.442	0.050
L2	L2	0-2.5	483.34±273.30	547.14±278.28	63.80	0.471	0.043
		2.5-5.0	205.88±92.99	221.00±117.31	15.11	0.283	0.199
		5.0-7.5	186.78±85.89	204.88±94.03	18.10	0.264	0.241
		7.5-10.0	167.58±72.36	193.23±65.26	25.65	0.496	0.030
MA	L3	0-2.5	223.36±115.83	210.60±114.08	-12.76	0.196	0.379
		2.5-5.0	134.41±98.05	101.86±74.52	-32.55	0.782	0.001
		5.0-7.5	117.23±93.06	96.04±95.23	-21.20	0.419	0.069
		7.5-10.0	78.76±67.52	69.37±58.65	-9.39	0.193	0.377
MP	L4	0-2.5	455.77±275.54	416.67±211.94	-39.11	0.196	0.100
		2.5-5.0	300.91±257.37	224.49±126.24	-76.41	0.323	0.145
		5.0-7.5	248.27±115.55	217.95±119.09	-30.32	0.419	0.001
		7.5-10.0	227.61±150.14	198.20±129.03	-29.42	0.435	0.054

Table 2 shows the bone mineral density (BMD) difference in the L1-L4 region, 0-10.0 mm below the tibial cartilage for all patients. BMD is presented as mean ± standard deviation, with Cohen's d used to measure effect size (approximately 0.2 for small, 0.5 for medium, and 0.8 for large effects). Statistical significance (p < 0.05) is indicated in bold.

Table 3. Bone mineral density in participants with WOMAC of 0 and KL score of 0

Region	Depth(mm)	Bone Mineral Density (mg/cm³)
L1	0-2.5	470.83±251.02
	2.5-5.0	265.70±167.02
	5.0-7.5	243.28±118.67
	7.5-10.0	235.33±145.55
L2	0-2.5	560.84±269.93
	2.5-5.0	276.32±93.44
	5.0-7.5	241.20±78.57
	7.5-10.0	215.51±80.85
L3	0-2.5	297.44±123.78
	2.5-5.0	172.73±100.52
	5.0-7.5	134.39±100.51
	7.5-10.0	114.20±84.25
L4	0-2.5	575.01±346.32
	2.5-5.0	307.91±136.15
	5.0-7.5	288.61±186.89
	7.5-10.0	272.49±198.10

Table 3 shows the bone mineral density (BMD) difference in the L1-L4 region, 0-10.0 mm below the tibial cartilage for all patients. BMD is presented as mean ± standard deviation.

No competing interests reported.

Altered Subchondral Bone Mineral Density in Painful Knee Osteoarthritis Without Cysts: A Comparative Analysis of Lateral and Medial Regions

Status:

Version 1

Abstract

Figures

Introduction

Methods

Statistical analysis

Results

Discussion

Declarations

Funding

Author Contribution

Data Availability

References

Tables

Additional Declarations

Status:

Version 1