Osteoporosis, a condition marked by increased fracture risk, remains under-diagnosed and under-treated worldwide, resulting in a substantial "treatment gap"-the difference between those eligible for osteoporosis treatment and those who actually receive it. While the concept of closing the treatment gap is commendable, and has galvanized clinical and policy efforts, this position statement argues that the prevailing narrative is in danger of becoming disease-focused and parentalistic, neglecting person-centered care. An international consensus group, including public contributors with lived experience were convened to define and characterize the "osteoporosis care gap" as a broader framework, encompassing deficits not only in pharmacological treatment but also in diagnosis, assessment, and multi-disciplinary management. The care gap is thus defined as "the discrepancy between the care provided to those at risk of osteoporotic fractures and best practice, person-centered care." Multi-level determinants of the care gap are identified including: societal-low public awareness underpinned by unhelpful stereotypes, and prevalent health inequalities; health policy-insufficient prioritization, diagnostic confusion, and lack of incentivization; healthcare service-fragmented care pathways with unclear roles and poor communication, inadequate follow-up, and insufficient support for shared decision making; and individual-unmet needs for care which is person-centered, participatory, understandable, equitable, holistic and multidisciplinary, and respects autonomy. The statement calls for a person-centered, equitable, and multidisciplinary approach to osteoporosis care, integrating the perspectives and needs of patients, families, and caregiver. Actions needed at societal and policy level are described, including increasing public awareness, increasing health policy prioritization, with clear professional leadership. The components of osteoporosis care are described in terms of case finding, assessment, treatment, and review. Addressing this, care gap requires coordinated efforts from policymakers, healthcare services, and professionals, with a renewed focus on equity and patient values and preferences.

In this review, we will examine the pathophysiology, anatomy, biochemistry, and genotype-phenotype correlation of femoral fractures in adult hypophosphatasia. Hypophosphatasia (HPP) is a rare genetic disease characterized by low activity of tissue-nonspecific alkaline phosphatase (TNAP). The disease presents a broad spectrum of clinical manifestations primarily determined by the degree of residual TNAP activity. Adults with HPP of moderate clinical severity may present with spontaneous femoral fractures that are like the atypical femoral fractures (AFF) of long-term bisphosphonates users. In this review, we will focus on the paradox that while HPP can cause biopsy-proven osteomalacia (pathologically impaired bone mineralisation), the spontaneous femoral fractures that characterise adult HPP do not exhibit typical osteomalacia features. Instead, they resemble the femoral fractures that occur in other diseases such as osteopetrosis where bone becomes excessively dense, brittle and highly mineralised due to osteoclast dysfunction. This review examines the key aspects of the pathophysiology of femoral fractures in adults with HPP, offering new insights into the role of anatomical, molecular and biochemical bone abnormalities that characterise the disease. Further investigations of HPP patients with femoral fracture are needed to examine the nanoscale crystal structure of the bone and to study abnormalities in fracture healing and bone resorption.

OBJECTIVES:Bone remodelling plays a role in osteoarthritis. Shape analysis using Computed Tomography (CT) enables 3-D evaluation of periarticular bone by combining statistical shape modelling (SSM) and cortical bone mapping (CBM). In a cross-sectional analysis, we explored the relationship between 3-D bone shape, cortical thickness (CTh) and trabecular attenuation (TA) in individuals with knee osteoarthritis. METHODS:The distal femur and proximal tibia were segmented from 133 CT-scans with knee osteoarthritis. Canonical objects were registered to each individual object for SSM. Generalized estimating equations looked for associations of shape modes with Kellgren-Lawrence-Grade (KLG). Statistical parametric mapping (SPM) then established any dependence of CTh and TA on bone shape. RESULTS:Shape mode 2 (SM2) was significantly associated with KLG (OR 1.43 per SD, 95%CI: 1.28-1.59, p<0.05). Marginal articular bone showed significant CTh dependence on SM2 (increase of up to 0.2 mm per SD, p<0.05). TA was significantly dependent on SM2 across nearly all the femoral articular surface (decrease of 40 HU per SD, p<0.05) and in the posterolateral tibial plateau (decrease of 20 HU per SD, p<0.05). CONCLUSION:We uncovered a 3-D shape mode recognisable as osteoarthritic that was associated with radiographic disease status in patients with pre- to moderate knee OA and overweight. Increase in this shape mode was associated with greater cortical thickening at the joint margins, likely related to osteophytosis, and reduced subchondral trabecular attenuation, the implications of which are not yet understood. Further work on combining 3-D shape and bone parameter distributions could improve identification of structural disease progression.

Objective Extrusion of the meniscus is known to be a key factor in the development of knee osteoarthritis. Here, we investigate the precise relationship between meniscal extrusion and weight bearing 3-D joint space width (JSW) distribution. Design Weight-bearing computed tomography (WBCT) images were acquired at the 144-month visit in the Multicenter Osteoarthritis Study. For each knee, 3-D JSW maps were created. MRI data from the same visit were assessed for both medial and lateral meniscal extrusion grade determined by the MRI Osteoarthritis Knee Score. Statistical parametric mapping (SPM) was used to test for any significant dependence of 3-D JSW distribution on meniscal extrusion grade by location. Results 568 knees were included in the analysis. SPM demonstrated significant differences in 3-D JSW distribution according to the extent of both medial and anterior extrusion of the medial meniscus in a pattern that suggested a posteromedial shift of the femur on the tibia. Medial extrusion of the medial meniscus was also associated with significantly lower JSW across the central-to-posterior medial joint space. The low prevalence of lateral meniscus extrusion meant that results for this may be underpowered or unrepresentative. Conclusion Establishing links between 3-D JSW and meniscal extrusion is an important step in developing the clinical utility of WBCT for the evaluation of osteoarthritis. Further study is required to establish whether 3-D JSW is sensitive enough to detect meniscal extrusion before articular cartilage damage has occurred, to develop this as a biomarker for early disease.

Osteogenesis imperfecta (OI) is a rare genetic disorder commonly caused by variants of the type I collagen genes COL1A1 and COL1A2. OI is associated with increased bone fragility, bone deformities, bone pain, and reduced growth. Setrusumab, a neutralizing antibody to sclerostin, increased areal bone mineral density (aBMD) in a 21-week phase 2a dose escalation study. The phase 2b Asteroid (NCT03118570) study evaluated the efficacy and safety of setrusumab in adults. Adults with a clinical diagnosis of OI type I, III, or IV, a pathogenic variant in COL1A1/A2, and a recent fragility fracture were randomized 1:1:1:1 to receive 2, 8, or 20 mg/kg setrusumab doses or placebo by monthly intravenous infusion during a 12-mo treatment period. Participants initially randomized to the placebo group were subsequently reassigned to receive setrusumab 20 mg/kg open label. Therefore, only results from the 2, 8, and 20 mg/kg double-blind groups are presented herein. The primary endpoint of Asteroid was change in distal radial trabecular volumetric bone mineral density (vBMD) from baseline at month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro-finite element (microFE)-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12 mo, there was a significant increase in mean (SE) failure load in the 20 mg/kg group (3.17% [1.26%]) and stiffness in the 8 (3.06% [1.70%]) and 20 mg/kg (3.19% [1.29%]) groups from baseline. There were no changes in radial trabecula vBMD (p>05). Gains in failure load and stiffness were similar across OI types. There were no significant differences in annualized fracture rates between doses. Two adults in the 20 mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation.

INTRODUCTION Change in shape of the distal femur demonstrated with MRI is an established biomarker for structural OA progression in clinical trials. This “B-score” has been ported across to CT with minimal bias, which brings the opportunity to include 3-D evaluation of periarticular bone distribution in shape analysis by combining statistical shape modelling (SSM) and cortical bone mapping (CBM). OBJECTIVE To look for significant relationships between 3-D knee shape and bone distribution with CT. METHODS This exploratory analysis was performed ancillary to the LOSEIT trial evaluating the efficacy of liraglutide in inducing and maintaining weight loss and pain relief in overweight patients with knee OA. After exclusions, 133 participants were included, 65 from the placebo group, 68 from the liraglutide group. All had baseline CT (140kV) and weight-bearing radiographs of both knees. Both knees were segmented from the CT data for CBM using Stradview followed by registration of canonical objects to femurs and tibias using wxRegSurf. SSM was performed on combined femur and tibia registrations using MATLAB 2024a. Index knee data were taken from each participant. Generalized estimating equation (GEE) analysis looked for associations of the first 10 shape modes with KLG controlling for age, sex and mass using Bonferroni correction. 3-D cortical thickness (CTh) and subcortical trabecular attenuation (TA) maps were transferred to the canonical objects. SPM analysis was performed using the MATLAB Surfstat toolbox to establish dependence of CTh and TA distribution on shape controlling for age, sex, mass and KLG. RESULTS Study participants were 89 females and 44 males with mean +/- SD age of 59.6 +/- 9.2 yrs, mass 93.3 +/- 16.7 kg and an index knee breakdown of KLG1 = 19, KLG2 = 57, KLG3 = 57. GEE showed shape mode 2 (SM2) was the only mode significantly associated with KLG with an odds ratio of 1.43 (1.28-1.59 95% CI, P<<0.05) for each SD of the mode (Fig. 1, * = P<0.05). Subjective visualization showed substantial similarities of SM2 to the B-score, namely increased femoral articular surface area with marginal articular prominence and narrowing of the intercondylar distance (Fig. 2, +/- 3xSD of the mode). SPM showed subchondral TA was significantly dependent on SM2 across nearly all the femoral articular surface (P<0.05), showing up to 40 HU drop for each increase in SD (Fig 2). Small zones of marginal articular bone at the lateral tibiofemoral compartment showed significant CTh dependence on the shape mode (P<0.05) with an increase of up to 0.2 mm for each SD increase (Fig. 2), but the association was limited to this compartment. In the tibia, this combined shape mode represented peaked widening of the tibial plateau rim, with significant dependence of TA in the posterior lateral tibial plateau (-20 HU per SD increase) and CTh around the medial plateau margin (+0.1 mm per SD increase). CONCLUSION Our shape mode 2 was a visual correlate of the B-score and significantly associated with KLG. 3-D analysis demonstrated significantly lower trabecular attenuation in femoral subchondral bone with increasing shape mode along with greater cortical thickness at the joint margins. This distribution suggests that bony remodeling of the articular surface with more advanced structural disease not only involves changes in bone shape, but also widespread subchondral trabecular density loss (as opposed to focal sclerosis) and increased bone thickness at joint margins consistent with osteophytosis. Combining these 3-D bone parameters with shape may therefore be of value in developing future predictive models.

Gaucher disease is one of the most common lysosomal storage disorders. Osteonecrosis is a principal clinical manifestation of Gaucher disease and often leads to joint collapse and fractures. T1-weighted (T1w) modality in MRI is widely used to monitor bone involvement in Gaucher disease and to diagnose osteonecrosis. However, objective and quantitative methods for characterizing osteonecrosis are still limited. In this work, we present a deep learning-based quantification approach for the segmentation of osteonecrosis and the extraction of characteristic parameters. We first constructed two independent U-net models to segment the osteonecrosis and bone marrow unaffected by osteonecrosis (UBM) in spine and femur respectively, based on T1w images from patients in the UK national Gaucherite study database. We manually delineated parcellation maps including osteonecrosis and UBM from 364 T1w images (176 for spine, 188 for femur) as the training datasets, and the trained models were subsequently applied to all the 917 T1w images in the database. To quantify the segmentation, we calculated morphological parameters including the volume of osteonecrosis, the volume of UBM, and the fraction of total marrow occupied by osteonecrosis. Then, we examined the correlation between calculated features and the bone marrow burden score for marrow infiltration of the corresponding image, and no strong correlation was found. In addition, we analyzed the influence of splenectomy and the interval between the age at first symptom and the age of onset of treatment on the quantitative measurements of osteonecrosis. The results are consistent with previous studies, showing that prior splenectomy is closely associated with the fractional volume of osteonecrosis, and there is a positive relationship between the duration of untreated disease and the quantifications of osteonecrosis. We propose this technique as an efficient and reliable tool for assessing the extent of osteonecrosis in MR images of patients and improving prediction of clinically important adverse events.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) contributes substantially to the burden of cardiovascular disease and fractures in patients with CKD. An increasing arsenal of diagnostic tools, including bone turnover markers and bone imaging, is available to support clinicians in the management of CKD-associated osteoporosis. Although not mandatory, a bone biopsy remains useful in the diagnostic workup of complex cases. In this special report, the European Renal Osteodystrophy (EUROD) initiative introduces the concept of a kidney-bone multidisciplinary team (MDT) for the diagnosis and clinical management of challenging cases of CKD-associated osteoporosis. In 2021, the EUROD initiative launched virtual clinical-pathological case conferences to discuss challenging cases of patients with CKD-associated osteoporosis, in whom a bone biopsy was useful in the diagnostic workup. Out of these, we selected four representative cases and asked a kidney-bone MDT consisting of a nephrologist, an endocrinologist and a rheumatologist to provide comments on the diagnostic and therapeutic choices. These cases covered a broad spectrum of CKD-associated osteoporosis, including bone fracture in CKD G5D, post-transplant bone disease, disturbed bone mineralization, severely suppressed bone turnover and severe hyperparathyroidism. Comments from the MDT were, in most cases, complementary to each other and additive to the presented approach in the cases. The MDT approach may thus set the stage for improved diagnostics and tailored therapies in the field of CKD-associated osteoporosis. We demonstrate the clinical utility of a kidney-bone MDT for the management of patients with CKD-MBD and recommend their establishment at local, national, and international levels.

ABSTRACT Romosozumab treatment reduces the rate of hip fractures and increases hip bone density, increasing bone formation by inhibiting sclerostin protein. We studied the normal pattern of bone formation and osteocyte expression in the human proximal femur because it is relevant to both antisclerostin treatment effects and fracture. Having visualized and quantified buds of new bone formation in trabeculae, we hypothesized that they would coincide with areas of (a) higher mechanical stress and (b) low sclerostin expression by osteocytes. In patients with hip fracture, we visualized each bud of active modeling-based formation (forming minimodeling structure [FMiS]) in trabecular cores taken from different parts of the femoral head. Trabecular bone structure was also measured with high-resolution imaging. More buds of new bone formation (by volume) were present in the higher stress superomedial zone (FMiS density, N.FMiS/T.Ar) than lower stress superolateral (p < 0.05), and inferomedial (p < 0.001) regions. There were fewer sclerostin expressing osteocytes close to or within FMiS. FMiS density correlated with greater amount, thickness, number, and connectivity of trabeculae (bone volume BV/TV, r = 0.65, p < 0.0001; bone surface BS/TV, r = 0.47, p < 0.01; trabecular thickness Tb.Th, r = 0.55, p < 0.001; trabecular number Tb.N, r = 0.47, p < 0.01; and connectivity density Conn.D, r = 0.40, p < 0.05) and lower trabecular separation (Tb.Sp, r = −0.56, p < 0.001). These results demonstrate modeling-based bone formation in femoral trabeculae from patients with hip fracture as a potential therapeutic target to enhance bone structure. © 2023 American Society for Bone and Mineral Research (ASBMR).

Joint alignment is an important factor in OA affecting how forces pass through the knee. The increasing use of weight bearing computed tomography (WBCT) in OA research has made the weight bearing stance an important consideration in 3-D imaging analysis, but its influence through biomechanics on the joint and subchondral bone is not fully understood. To investigate the relationship between knee joint alignment and 3-D joint parameters derived from joint space mapping of WBCT imaging in individuals with radiographic OA. WBCT of both knees was acquired at the 144-month visit of the Multicenter Osteoarthritis Study (MOST). Knees with a KLG ≥2 were included in the analysis, taking the side with higher KLG or averaging subsequent results from both sides if equal. Joint space mapping was performed to obtain the 3-D JSW distribution along with femoral (f) and tibial (t) subchondral bone thickness (ST) and trabecular attenuation (TA). Everyone's knee parameter maps were then transferred to a canonical joint surface. Alignment of the knee joint was measured as the angle between the central axis of the distal femur and proximal tibia in a coronal multiplanar reformat slab of the WBCT data: neutral alignment was set as zero with varus signed positive (figure part (a)). Statistical parametric mapping (SPM) was performed using a general linear model to test the dependence of each 3-D parameter distribution on alignment controlling for age, sex, mass, height, and joint space shape modes. SPM results were plotted on the canonical joint surface with unmasked regions representing a significance level of P<0.05. 136 knees were included in the analysis, 84 of which were females. Mean ± SD age was 66.4 ± 9.8 yrs; mass 85.3 ± 17.8 kg; height 1.69 ± 0.1 m. The distribution of radiographic grading was KL2 = 103; KL3 = 32; KL4 = 1. Mean alignment was 0.38 ± 3.80°. For each degree from valgus to varus, JSW was significantly narrower in the medial compartment and wider in the lateral compartment by up to 0.1 mm (figure part (d)). While TA was significantly greater by up to 10 AU in the medial femur (figure part (b)) and medial tibia (figure part (f)), there was up to 0.05 mm significantly thinner ST in the lateral femur (figure part (c)) and lateral tibia (figure part (e)). The opposite effects can be inferred for each degree towards valgus. The same analysis on KLG 0 and 1 knees in the same cohort (mean ± SD alignment 0.66 ± 2.94°) revealed no significant relationships. Subchondral bone plate and trabecular bone appear to behave differently in the medial and lateral compartments when considering knee joint alignment in individuals with OA. Greater subchondral trabecular bone attenuation was seen in the medial compartment with varus alignment, while greater subchondral bone plate thickness was seen in the lateral compartment with valgus alignment. Whether alignment is the cause or effect of OA and any altered biomechanics that may influence bone and joint space behaviour requires further investigation, but this study does establish that the forces associated with alignment appear to have different effects on subchondral bone in different compartments. National Institutes of Health, University of Kansas (R01AR071648), University of Iowa (U01AG18832) and University of California-San Francisco (U01AG19069). NS is a consultant for Integra BioLife, Trice Medical and Pacira Biosciences. TT has been a consultant for Curvebeam AI. The authors would like to thank participants and staff of the MOST study. CORRESPONDENCE ADDRESS: [email protected]

We present a 3-D approach to joint space width (JSW) measurement across the ankle from weight-bearing CT (WBCT) to demonstrate inter-operator reproducibility, test-retest repeatability, and how differences in angulation affect ankle JSW distribution. One side from repeat WBCT imaging of both feet and ankles was analysed from 23 individuals as part of their routine clinical care pathway. Joint space mapping was performed at four facets across the talus: talonavicular, talar dome and medial gutter (dome-medial), lateral gutter, and posterior subtalar. Inter-operator reproducibility was calculated for two users, while test-retest repeatability was calculated by comparing the two visits, both presented as Bland-Altman statistics. Statistical parametric mapping determined any significant relationships between talocrural joint space angulation and 3-D JSW distribution. The average ± standard deviation interval between imaging was 74.0 ± 29.6 days. Surface averaged bias ± limits of agreement were similar for reproducibility and repeatability, the latter being: talonavicular 0.01 ± 0.26 mm, dome-medial 0.00 ± 0.28 mm, lateral gutter − 0.02 ± 0.40 mm, and posterior subtalar 0.02 ± 0.34 mm. Results are presented as 3-D distribution maps, with optimum test–retest repeatability reaching a smallest detectable difference of ± 0.15 mm. Joint space mapping is a robust approach to 3-D quantification of JSW measurement, inter-operator reproducibility, and test–retest repeatability at the ankle, with sensitivity reaching a best value of ± 0.15 mm. Standardised imaging protocols and optimised metal artefact reduction will be needed to further understand the clinical value of these 3-D measures derived from WBCT. Weight-bearing computed tomography is an increasingly important tool in the clinical assessment of orthopaedic ankle disorders. This paper establishes the performance of measuring 3-D joint space width using this technology, which is an important surrogate marker for severity of osteoarthritis. • Joint space width values and error metrics from across the ankle measured from weight-bearing CT can be presented as 3-D maps that show topographic variation. • The best sensitivity for detecting meaningful change in 3-D joint space width at the ankle was ± 0.15 mm, a value less than the isotropic imaging voxel dimensions. • Standardised imaging protocols and optimised metal artefact reduction will be needed to understand the clinical value of 3-D measures from weight-bearing CT.

Abnormal shape of the distal femur is the defining characteristic of trochlear dysplasia (TD), leading to abnormal contact forces and early degeneration at the patellofemoral joint, as well as an increased risk of lateral patellar dislocation. In severe clinical cases treatment with various surgical techniques aims to normalise trochlea morphology and medialise patellofemoral knee forces. 1) To evaluate differences in 3-D bone distribution at the distal femur between normal individuals and TD; and 2) to demonstrate how these parameters discriminate between these two groups. 20 healthy volunteers without radiological signs of TD and 20 individuals with Dejour type B or D dysplasia and patellar instability were recruited, both groups aged 18-45 years with no history of arthritis, connective tissue disease, or traumatic knee conditions requiring physical or operative treatment. The TD group were awaiting surgical trochleoplasty after failing conservative treatment. With a 50:50 proportion of left and right knees in the TD group, a random matched 50:50 split of left and right knees were chosen for comparison in the healthy volunteers. Weight bearing computed tomography (WBCT) of the target knee in 20°of flexion using a Carestream Onsight© scanner, with full imaging details. The distal femur was semi-automatically segmented using inhouse software Stradview. A canonical distal femur was registered to each individual to build a 3-D statistical shape model from the registrations using inhouse software wxRegSurf. Cortical bone mapping was also performed on all femurs to measure 3-D distribution of cortical thickness (CTh) and trabecular attenuation (TA), which were then transferred to the canonical femur. Statistical parametric mapping (SPM) tested the dependence of the 3-D distribution of the bony parameters on the presence of TD. Mean values were taken from within the largest SPM significant region of interest (ROI) for CTh and TA, and used along with sex, age and shape mode coefficients in receiver operating characteristic analysis to deliver area under the curve (AUC) in a leave-one-out cross-validation classifier predictive model for TD. Mean (± SD) age of all participants was 30.5 ± 5.2 years, with an even split of sexes in both groups. SPM showed significantly thicker CTh in the TD group along the outer lateral margin of the lateral trochlea by up to 0.6 mm (left figure, unmasked blue patch). TA was significantly lower by up to 100 units in the TD group at the medial trochlea region (right figure, unmasked red patch). Shape mode 3 had already been demonstrated in another study as the only mode to be significantly related to TD (not shown). AUC (95% CI) in prediction of TD with age + sex was 0.75 (0.59-0.88), for shape mode 3 was 0.84 (0.69-0.94), for the TA ROI mean was 0.84 (0.68-0.95), and the CTh ROI mean was 0.97 (0.87-1). Trochlear dysplasia cases selected for surgical treatment have a 3-D distribution of cortical bone thickness and density around the distal femur significantly different to normal individuals in patterns that suggest abnormal shift of contact forces laterally. Cortical bone thickness was an excellent classifier, followed by shape mode 3. These 3-D derived parameters should be further evaluated in separate populations. Since morphological normalisation of the trochlea groove and medialisation of patellofemoral joint forces is the goal of surgical correction to protect the joint for early degeneration, monitoring of these bone and shape parameters seems promising and may be useful to monitor in long term post-surgical follow-up.

Weight bearing CT (WBCT) technology has been increasingly used in imaging of knee osteoarthritis in recent years because of its ability to assess the weight bearing joint space. However, relatively little is known regarding the extent to which this cone beam technology can provide useful information on peri-articular bone beyond the subchondral regions. To explore relationships between WBCT-derived 3-D cortical bone thickness and trabecular bone attenuation at the distal femur with concurrent joint space narrowing phenotypes. WBCT imaging was obtained ancillary to the Multicenter Osteoarthritis Study at the 144-month visit. After semi-automatic segmentation, femoral cortical thickness (fCT) and trabecular attenuation (fTA) maps were created for each of 663 available distal femurs using cortical bone mapping. A template was registered to each individual distal femur and a 3-D statistical shape model created, followed by transfer of fCT and fTA distribution maps onto the template. A statistical parametric mapping (SPM) general linear model adjusted for age, sex, BMI, and the first 5 shape modes (controlling for effects of systematic misregistration) was used to test the dependence of fCT and fTA in turn on the experimental variables of concurrent radiographic medial and lateral OARSI joint space narrowing (JSN) grade. One knee from each participant was selected for inclusion, taking the side with worse compartmental baseline JSN grade or randomly if equal. 16 knees were excluded due to unachievable registration, with a final study set of a single knee from 386 individuals. 219 were female, mean ± SD age was 63.6 ± 9.6 yrs, mass 82.3 ± 17.7 kg, height 169 ± 9 cm, and BMI 28.5 ± 5.0 kg/m2. SPM significance ROIs according to baseline medial (left, figs 1 & 2) and lateral (right, figs 3 & 4) JSN phenotypes are shown for fCT (top row, figs 1 & 3) and fTA (bottom row, figs 2 & 4). SPM revealed significantly greater fCT by up to ∼0.1mm and fTA by up to ∼40 attenuation units (AU) for each increment in baseline JSN grade along the outer margin of the respective compartments (unmasked blue zones in each figure). Significantly greater fCT by up to ∼0.1mm for each increment in medial JSN grade also spread across the anterior aspect of the medial femoral condyle suggesting a wider regional relationship. 3-D distribution of fCT and fTA follow distinct patterns according to OARSI JSN phenotype, relating to recognised distributions of marginal osteophytosis and subchondral sclerosis. These results indicate that cone beam WBCT can quantify cardinal bony structural features of osteoarthritis and that their distribution is related to specific osteoarthritis OARSI JSN phenotypes. National Institutes of Health, University of Kansas (R01AR071648), University of Iowa. (U01AG18832), University of California-San Francisco (U01AG19069), Boston University (U01AG018820). NS is a consultant for Integra BioLife, Trice Medical and Pacira Biosciences. The authors would like to thank participants and staff of the MOST study. CORRESPONDENCE ADDRESS: [email protected]

3-D joint space width (JSW) measured from weight bearing CT (WBCT) has been suggested to be more sensitive than radiographic 2-D measurement in detecting joint space narrowing (JSN), but its diagnostic value in osteoarthritis is yet to be established. To determine the predictive validity of 3-D JSW measurement from baseline WBCT compared to 2-D radiographic measures in identifying structural disease progression at the knee. WBCT knee imaging was acquired at the 144-month visit of the Multicenter Osteoarthritis Study (MOST) with radiographic Kellgren and Lawrence grade (KLG), medial and lateral tibiofemoral radiographic OARSI JSN grades. Progression in medial and lateral JSN grade was recorded 2 years subsequent. After semi-automatic segmentation of 663 available knees, joint space mapping was performed to create 3-D JSW maps. A template was registered to each individual joint surface, a 3-D statistical shape model created, and JSW measurements transferred to the template. A statistical parametric mapping (SPM) general linear model adjusted for age, sex, BMI, and the first 5 shape modes (controlling for effects of systematic misregistration) was used to test the dependence of baseline 3-D JSW on baseline medial and lateral JSN in turn. One knee per participant was included in the SPM model, when required selecting side according to worst baseline compartmental JSN grade or randomly if equal. Mean JSW values from significantly narrower SPM ROIs were taken for all knees and used in receiver operating characteristic analysis to deliver areas under the curve (AUC) in a leave-one-out cross-validation classifier predictive model for future worsening of medial and lateral JSN at 2 years. This prediction model also tested baseline KLG, medial and lateral JSN grade. All predictive models were controlled by inclusion of age, sex, and BMI and compared against each other. 10 knees did not have radiographic grading, so the study set consisted of 653 knees from 394 individuals. 218 participants were female, mean ± SD age was 63.5 ± 9.6 years, mass 82.7 ± 17.7 kg, height 170 ± 9 cm, and BMI 28. 5 ± 5.0 kg/m2. SPM revealed regions of significantly narrower baseline medial JSW up to ∼0.75 mm per increment in medial JSN grade (unmasked medial compartment red zone in fig. 1) and narrower baseline lateral JSW up to ∼1 mm per increment in baseline lateral JSN grade (unmasked lateral compartment red zone in fig. 2). Mean medial and lateral ROI JSW values were taken at all available knees for predictive modelling. AUC values with 95% confidence limits showed that baseline mean medial ROI JSW (0.68, 0.61-0.74) was worse than baseline KLG (0.75, 0.68-0.81) and no better than medial JSN (0.73, 0.65-0.79) or lateral JSN (0.66, 0.6-0.71) in predicting future medial JSN. However, baseline mean lateral ROI JSW (0.84, 0.72-0.91) was better than medial JSN (0.61, 0.49-0.72) and lateral JSN (0.71, 0.54-0.86) in prediction of future lateral JSN. It was also better than baseline KLG (0.77, 0.76-0.86) but not outside the 95% confidence limits, however combining baseline lateral ROI JSW and KLG in the model further improved the AUC (0.87, 0.78-0.92) beyond the limits for just KLG (0.77, 0.76-0.86). Baseline 3-D lateral compartment JSW from WBCT is better than 2-D radiographic measures at predicting progression in lateral compartment JSN, but the same was not seen for medial JSN. This suggests an important role for 3-D weight bearing JSW in assessment of knee osteoarthritis according to disease phenotype. National Institutes of Health, University of Kansas (R01AR071648), University of Iowa (U01AG18832) and University of California-San Francisco (U01AG19069). NS is a consultant for Integra BioLife, Trice Medical and Pacira Biosciences. The authors would like to thank participants and staff of the MOST study. CORRESPONDENCE ADDRESS: [email protected]

An important development in osteoarthritis imaging has been the ability to assess joint space width (JSW) from weight bearing CT (WBCT). The value of combining JSW with subchondral bone parameters in disease assessment is less well understood, particularly with respect to disease phenotype. To investigate associations of worsening medial and lateral tibiofemoral compartment structural disease over 2 years with a multivariate combination of baseline 3-D JSW and bony parameters from WBCT. WBCT knee imaging was acquired at the 144-month visit of the Multicenter Osteoarthritis Study along with same-visit and 2-year follow-up medial and lateral OARSI joint space narrowing (JSN) grade. After semi-automatic segmentation of 663 available knees, joint space mapping delivered 3-D JSW maps. Cortical bone mapping was performed to measure trabecular attenuation (TA), endocortical thickness (ET), and subchondral thickness (ST) at the femoral (f) and tibial (t) surfaces. A template was registered to each individual joint surface, a 3-D statistical shape model created, and all 7 spatially co-located parameters transferred to the template. A statistical parametric mapping (SPM) general linear model adjusted for age, sex, BMI, and the first 5 shape modes (controlling for effects of systematic misregistration) was used to test the dependence of JSW plus each bone parameter in turn on the experimental variables of 2-year medial and lateral OARSI JSN worsening. One knee per participant was used, selecting the side with greater JSN worsening, randomly if equal. 10 knees did not have radiographic grading, so the analysis used single knees from 394 individuals. 218 were female, mean ± SD age was 63.5 ± 9.6 years, mass 82.7 ± 17.7 kg, height 170 ± 9 cm, and BMI 28.5 ± 5.0 kg/m2. SPM results (figs 1-4 below) revealed significant parameter ROIs in the lateral tibiofemoral compartment that were associated with worsening of medial and lateral OARSI JSN grade at 2 years. Baseline lateral compartment JSW was significantly wider by up to ∼1 mm (unmasked lateral compartment blue zone in fig. 1) in combination with lower baseline tTA by up to ∼25 attenuation units (AU) (unmasked lateral compartment red zone in fig. 2) for each increment in future medial JSN over 2 years. The reverse was demonstrated for future lateral JSN with narrower baseline lateral JSW by up to ∼1 mm (unmasked lateral compartment red zone in fig. 3) in combination with higher baseline tTA by up to ∼25 AU (unmasked lateral compartment blue zone in fig. 4) for each grade of future lateral JSN over 2 years. Baseline JSW was significantly narrower at the lateral margin of the lateral compartment by up to ∼1 mm in combination with thicker tST and fST by up to ∼0.2 mm for each grade of future lateral JSN (not shown). Baseline medial 3-D JSW did not relate to any substantial significant future narrowing for any JSW-bone parameter combination for future medial or lateral JSN. ET results (with JSW) were very similar to those for ST at both sides of the joint. 3-D JSW analysed in combination with bone parameters at the lateral (but not medial) tibiofemoral compartment are significantly related to future medial and lateral OARSI JSN grade. Lower lateral compartment tTA (with higher JSW) is related to future medial JSN and may be an effect of trabecular remodelling from reduced lateral loading, while greater thickness of subchondral and endocortical bone in the lateral compartment (alongside lower JSW) can be explained by subchondral sclerosis. These results suggest the lateral compartment warrants closer attention for following both medial and lateral compartmental progression. National Institutes of Health, University of Kansas (R01AR071648), University of Iowa. (U01AG18832), University of California-San Francisco (U01AG19069), Boston University (U01AG018820). NS is a consultant for Integra BioLife, Trice Medical and Pacira Biosciences. The authors would like to thank participants and staff of the MOST study. CORRESPONDENCE ADDRESS: [email protected].

Objective:Computed tomography (CT) can deliver multiple parameters relevant to osteoarthritis. In this study we demonstrate that a 3-D multiparametric approach at the weight bearing knee with cone beam CT is feasible, can include multiple parameters from across the joint space, and can reveal stronger relationships with disease status in combination. Design:33 participants with knee weight bearing CT (WBCT) were analysed with joint space mapping and cortical bone mapping to deliver joint space width (JSW), subchondral bone plate thickness, endocortical thickness, and trabecular attenuation at both sides of the joint. All data were co-localised to the same canonical surface. Statistical parametric mapping (SPM) was applied in uni- and multivariate models to demonstrate significant dependence of parameters on Kellgren & Lawrence grade (KLG). Correlation between JSW and bony parameters and 2-week test-retest repeatability were also calculated. Results:SPM revealed that the central-to-posterior medial tibiofemoral joint space was significantly narrowed by up to 0.5 mm with significantly higher tibial trabecular attenuation up to 50 units for each increment in KLG as single features, and in a wider distribution when combined (p<0.05). These were also more strongly correlated with worsening KLG grade category. Test-retest repeatability was subvoxel (0.37 mm) for nearly all thickness parameters. Conclusions:3-D JSW and tibial trabecular attenuation are repeatable and significantly dependent on radiographic disease severity at the weight bearing knee joint not just alone, but more strongly in combination. A quantitative multiparametric approach with WBCT may have potential for more sensitive investigation of disease progression in osteoarthritis.