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Objective: Osteoarthritis (OA) is a highly prevalent chronic condition. The subchondral bone plays an important role in onset and progression of OA making it a potential treatment target for disease-modifying therapeutic approaches. However, little is known about changes of periarticular bone mineral density (BMD) in OA and its relation to meniscal coverage and meniscal extrusion at the knee. Thus, the aim of this study was to describe periarticular BMD in the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort at the knee and to analyze the association with structural disease severity, meniscal coverage and meniscal extrusion., Design: Quantitative CT (QCT), MRI and radiographic examinations were acquired in 275 patients with knee osteoarthritis (OA). QCT was used to assess BMD at the femur and tibia, at the cortical bone plate (Cort) and at the epiphysis at three locations: subchondral (Sub), mid-epiphysis (Mid) and adjacent to the physis (Juxta). BMD was evaluated for the medial and lateral compartment separately and for subregions covered and not covered by the meniscus. Radiographs were used to determine the femorotibial angle and were evaluated according to the Kellgren and Lawrence (KL) system. Meniscal extrusion was assessed from 0 to 3., Results: Mean BMD differed significantly between each anatomic location at both the femur and tibia (p < 0.001) in patients with KL0. Tibial regions assumed to be covered with meniscus in patients with KL0 showed lower BMD at Sub (p < 0.001), equivalent BMD at Mid (p = 0.07) and higher BMD at Juxta (p < 0.001) subregions compared to regions not covered with meniscus. Knees with KL2-4 showed lower Sub (p = 0.03), Mid (p = 0.01) and Juxta (p < 0.05) BMD at the medial femur compared to KL0/1. Meniscal extrusion grade 2 and 3 was associated with greater BMD at the tibial Cort (p < 0.001, p = 0.007). Varus malalignment is associated with significant greater BMD at the medial femur and at the medial tibia at all anatomic locations., Conclusion: BMD within the epiphyses of the tibia and femur decreases with increasing distance from the articular surface. Knees with structural OA (KL2-4) exhibit greater cortical BMD values at the tibia and lower BMD at the femur at the subchondral level and levels beneath compared to KL0/1. BMD at the tibial cortical bone plate is greater in patients with meniscal extrusion grade 2/3., Competing Interests: Declaration of competing interest FWR is shareholder of Boston Imaging Core Lab. (BICL), LLC. He is consultant to Calibr and Grünenthal; RH is a member of the speakers bureau and a consultant of Siemens Healthineers, outside the submitted work. MK reports grants from IMI-APPROACH, during the conduct of the study; consulting fees from GlaxoSmithKline, Pfizer, Merck-Serono, Kiniksa, Abbvie, Flexion, Galapagos, Jansen, CHDR, UCB, Novartis outside the submitted work and all paid to institution; FJB funding from Gedeon Richter Plc., Bristol-Myers Squibb International Corporation (BMSIC), Sun Pharma Global FZE, Celgene Corporation, Janssen Cilag International N·V, Janssen Research & Development, Viela Bio, Inc., Astrazeneca AB, UCB BIOSCIENCES GMBH, UCB BIOPHARMA SPRL, AbbVie Deutschland GmbH & Co.KG, Merck KGaA, Amgen, Inc., Novartis Farmacéutica, S.A., Boehringer Ingelheim España, S.A, CSL Behring, LLC, Glaxosmithkline Research & Development Limited, Pfizer Inc., Lilly S.A., Corbus Pharmaceuticals Inc., Biohope Scientific Solutions for Human Health S.L., Centrexion Therapeutics Corp., Sanofi, MEIJI FARMA S.A., Kiniksa Pharmaceuticals, Ltd. Grunenthal, Asofarma Mexico, Gebro Pharma, Roche, Galapagos, Regeneron; FB is shareholder of 4Moving Biotech and 4P,Pharma, reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Novartis, Pfizer, Roche, Sanofi, Servier, Peptinov, TRB Chemedica, Viatris. WW is employee and shareholder of Chondrometrics GmbH. AL is employee of Servier. The other authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To verify earlier data in cadavers that in female subjects with OA meniscal coverage is associated with lowered bone mineral density of the underlying subchondral bone in the proximal tibia by investigating the local bone mineral density (BMD) distribution within the epiphysis., Methods: BMD of the subchondral bone of the tibia was measured by QCT in 67 elderly females diagnosed with OA (Kellgren-Lawrence grades 2-3). The epiphysis was subdivided along the axis of the tibia into a subchondral-epiphyseal VOI covering the first 5-6 mm below the subchondral bone plate, a mid-epiphyseal VOI covering the adjacent 7-8 and a juxtaphyseal VOI of another 7-8 mm that bordered the growth plate. These VIOs were further divided into lateral and medial and then into anterior, mid and posterior sub-VOIs. Finally, all subVOIs were divided in one subVOI covered by the menisci (CM) and another not covered by the menisci (nCM). BMD ratios of these two subVOIs were compared., Results: In the subchondral epiphysis BMD was significantly lower (Medial: mean BMD diff  = 125 mg/cm 3 , p<0.001; Lateral: mean BMD diff  = 56 mg/cm 3 p < 0.001) in subVOIs covered by the meniscus compared to subVOIs not covered by the meniscus. The BMD difference was no longer significant in the mid epiphysis (Medial: mean BMD diff  = 10 mg/cm 3 , p>0.82; Lateral: mean BMD diff  = 7 mg/cm 3 , p=0.99) and was reversed in the juxtaphysis. With a few exceptions these BMD differences were independent of the lateral-medial and the anterior-mid-posterior position. BMD significantly (p<0.05) decreased with age independent on whether the location was covered or uncovered by the meniscus, however the BMD ratio of the corresponding nCM and CM subVOIs did not significantly (p>0.1) change with age., Conclusion: In-vivo QCT measurements of the BMD distribution in the proximal tibia indicate a protective effect of the menisci in the subchondral bone close to the joint. This protective effect is age independent despite the overall age-related decrease of BMD., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Osteoarthritis (OA) is a disease of the whole joint characterized by cartilage loss and subchondral bone remodeling. The role of microcracks in cartilage integrity and subchondral bone homeostasis is not fully understood. The main goal of this work was to evaluate microcrack density in both calcified cartilage and subchondral bone plate in relation to cartilage damage in humans and to better define the association of microcracks and osteocyte density in subchondral bone., Methods: We investigated 18 bone cores from cadaveric human knees that were stained with En-Bloc Basic Fuchsin. We quantified microcrack density, osteocyte density, cartilage surfaces and cartilage damage. The presence of microcracks was confirmed for each bone core by scanning electron microscopy. Finally, trabecular subchondral bone parameters were measured by micro-CT., Results: Microcracks were detected in both calcified cartilage and subchondral bone plate. The density of microcracks in both calcified cartilage (CC) and subchondral bone plate (SBP) was negatively correlated with cartilage damage (r = -0.45, p < 0.05). The presence of microcracks in SBP was associated with a lower histological OA score. Osteocytes formed a dendrite network that abruptly stopped at the border of calcified cartilage. Osteocyte density in subchondral bone plate was increased in the presence of microcracks in calcified cartilage., Conclusions: Subchondral bone plate microcracks might be required for maintaining cartilage homeostasis. Microcracks in calcified cartilage may trigger osteocyte density in subchondral bone plate with subsequent regulation of subchondral bone remodeling to prevent cartilage damage., (Copyright © 2019 Elsevier Inc. All rights reserved.)

High resolution-peripheral quantitative computed tomography (HR-pQCT) measurements are carried out in clinical research protocols to analyze cortical bone. Micro-computed tomography (micro-CT) is a standard tool for ex vivo examination of bone in 3D. The aim of this work was to evaluate cortical measurements derived from HR-pQCT images compared to those from synchrotron radiation (SR) micro-CT in a distal position (4.2 cm from the distal pilon). Twenty-nine tibia specimens were scanned with HR-pQCT using protocols provided by the manufacturer. The standard measured outcomes included volumetric bone density (gHA/cm(3)) of the cortical region (Dcomp), and the cortical thickness (Ct.Th, mm). New features, such as cortical porosity (Ct.Po) and mean pore diameter (Ct.Po.Dm), were measured by an auto-contouring process. All tibias were harvested from the posterior region and imaged with SR micro-CT (voxel size=7.5 μm). The cortical thickness, (Ct.Thmicro-CT), porosity (PoV/TV), pore diameter, pore spacing, pore number, and degree of mineralization of bone (DMB) were obtained for SR micro-CT images. For standard measurements on HR-pQCT images, site matched analyses with micro-CT were completed to obtain Dcomplocal and Ct.Thlocal. Dcomp was highly correlated to PoV/TV (r=-0.84, p<10(-4)) but not to DMB. Dcomplocal was correlated to PoV/TV (r=-0.72, p<10(-4)) and to DMB (r=0.40, p>0.05). Ct.Thlocal and Ct.Thmicro-CT were moderately correlated (r=0.53, p<0.01). Ct.Th and Ct.Po results from the autocontouring process are influenced by the level of trabecularization of the cortical bone and need manual correction of the endosteal contour. Distal tibia is a reliable region to study cortical bone with Dcomp as the best parameter because it reflects both the micro-porosity (Havers canals) and macro-porosity (resorption lacunae) of the cortical bone., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Osteoporotic hip fractures represent a major public health problem associated with high human and economic costs. The anatomical variation of the tissue mineral density (TMD) and of the elastic constants in femoral neck cortical bone specimens is an important determinant of bone fragility. The purpose of this study was to show that a Synchrotron radiation microcomputed tomography system coupled with a multiscale biomechanical model allows the determination of the 3-D anatomical dependence of TMD and of the elastic constants (i.e. the mechanical properties of an anisotropic material) in human femoral neck. Bone specimens from the inferior femoral neck were obtained from 18 patients undergoing standard hemiarthroplasty. The specimens were imaged using 3-D synchrotron micro-computed tomography with a voxel size of 10.13 μm, leading to the determination of the anatomical distributions of porosity and TMD. The elastic properties of bone tissue were computed using a multiscale model. The model uses the experimental data obtained at the scale of several micrometers to estimate the components of the elastic tensor of bone at the scale of the organ. Statistical analysis (ANOVA) revealed a significant effect of the radial position on porosity and TMD and a significant effect of axial position on TMD only. Porosity was found to increase in the radial direction moving from the periosteum inwards (p<10(-5)). At any given distance from the periosteum, porosity does not vary noticeably along the bone axis. TMD was found to be significantly higher (p<10(-5)) in the periosteal region than in other bone locations and decreases from the periosteal to the endosteal region with an average slope of 10.05 g.cm(-3).m(-1), the decrease being faster in the porous part of the samples (average slope equal of 30.04 g.cm(-3).m(-1)) than in dense cortical bone. TMD was found to decrease from the distal to the proximal part of the femur neck (average slope of 6.5 g.cm(-3).m(-1)). Considering TMD variations in the radial direction induces weak changes of bone properties compared to constant TMD. TMD variations in the axial direction are responsible for a significant variation of elastic constants. These results demonstrate that the anatomical variations of TMD affect the bone elastic properties, which could be explained by the complex stress field in bone affecting bone remodeling. TMD spatial variations should be taken into account to properly describe the spatial heterogeneity of elastic coefficients of bone tissue at the organ scale., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In addition to bone quantity, bone quality affects bone strength. Bone quality depends in part on the degree of mineralization of bone tissue (DMB). The relationship between the DMB distribution and the risk of osteoporotic hip fractures remains incompletely investigated. Here, our aim was to compare DMB distribution in femoral neck cortex specimens from 23 women with hip fractures (age, 65-96 years) and 14 control women (age, 75-103 years). Mineralization was determined using quantitative microradiography. We evaluated the following parameters of DMB frequency histograms, for both osteons and interstitial tissue: mode (oDMB(Al)mode and intDMB(Al)mode, respectively); 25th (oDMB(Al)q25, intDMB(Al)q25), 50th (oDMB(Al)q50, intDMB(Al)q50), and 75th (oDMB(Al)q75, intDMB(Al)q75) percentiles; and interquartile range (oDMB(Al)iqr, intDMB(Al)iqr). For each specimen, we also calculated the variance of pixel mineral content for osteons and interstitial tissue (oDMB(Al)var and intDMB(Al)var). We used nonparametric tests to compare frequency histogram parameters between hip-fractured women and controls and Fisher's test to compare variances between groups. All frequency histogram parameters for osteons and interstitial tissue except the 25th percentile, and the variances of pixel mineral content in osteons and interstitial tissue, were significantly different between hip-fractured women and controls, indicating greater heterogeneity of mineralization in the hip-fracture patients than in the controls. These cross-sectional data suggest that bone fragility may be related to greater DMB heterogeneity in osteons and interstitial tissue., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The incidence of osteoporotic hip fractures increases with age, more sharply in women than in men, as a result of qualitative and quantitative bone alterations. Mineralization (a qualitative parameter) showed no differences with age or sex in cancellous bone in earlier studies. Few studies assessed such differences in cortical bone, a major contributor to femoral bone strength. The aim of this in vitro cross-sectional study of a large group of human femoral midshafts was to look for age- and sex-related differences in the degree and distribution of cortical mineralization that might be implicated in bone fragility., Methods: Cortical bone specimens from 193 femurs were studied using quantitative microradiography, with an aluminum step-wedge reference. The femurs were from 99 females and 94 males in a Caucasian anthropological collection covering a broad age spectrum. We determined the mean degree of mineralization of osteons (On.DMB-Al), interstitial tissue (Int.DMB-Al), and total bone (Tt.DMB-Al), and representative parameters of density histograms. Results were expressed as relative values. Age- and sex-related differences in DMB-Al values were evaluated using non-parametric tests., Results: Degree of tissue mineralization (Tt.DMB-Al) decreased significantly with age in females (r=-0.257; P=0.010) but did not change in males. Tt.DMB-Al was higher in females than males until 50 years of age (P=0.001) but was lower in elderly females than elderly males (P=0.016). DMB-Al distribution varied significantly with sex and age. The first DMB-Al quartiles in osteons and interstitial tissue were not different between males and females, but the third quartile and interquartile range differed significantly (P=0.032 and P=0.000, respectively). The mineralization difference between the two tissues indicated greater bone heterogeneity in females than males (P=0.000)., Conclusions: In this in vitro cross-sectional study of anterior midfemoral cortical specimens, the degree and distribution of mineralization varied with age and sex. In females, mineralization started at a higher level than in males but was lower in the sixth decade, falling below the level in males. Mineralization was far more stable throughout life in males. In elderly females, the lower degree and greater heterogeneity of mineralization may have consequences on bone strength and the risk of fracture.

The strength of bone depends on both bone quantity and bone quality. One determinant of bone quality is the degree of mineralization of bone tissue (DMB). To assess the role for DMB in osteoporotic hip fractures, we compared the degree of mineralization in femoral neck cortex from 23 women with hip fractures (age, 65-96 years) and 14 female controls (age, 75-103 years) using quantitative microradiography calibrated with an aluminum step wedge. Variables were DMB in osteons (oDMB(Al)mean) and interstitial tissue (exDMB(Al)mean). Wilcoxon signed-rank tests were used to compare oDMB(Al)mean to exDMB(Al)mean in each group, and Mann-Whitney tests to compare oDMB(Al)mean and exDMB(Al)mean between hip-fracture patients and controls. DMB was significantly lower in the osteons than in the interstitial tissue in both groups (hip-fracture group, P=0.000; control group, P=0.001). DMB values in osteons and interstitial tissue were significantly greater in the hip-fracture patients than in the controls (P=0.007 and P=0.005, respectively). These cross-sectional data suggest that bone fragility may be related to a higher degree of tissue mineralization.

Purpose: To evaluate the precision of 3D QCT of the spine., Methods: Interoperator analysis reproducibility of two different 3D QCT analysis systems (QCTPro from Mindways Software Inc and MIAF-Spine from the Institute of Medical Physics, University of Erlangen) was evaluated in 29 postmenopausal women. For each analysis system four different trained operators analyzed all scans independently. Results of the vertebrae L1 and L2 were averaged. With QCTPro BMD of the central trabecular elliptical VOI was analyzed. With MIAF-Spine integral, trabecular and cortical BMD, BMC and volume were analyzed in the total vertebral body, the elliptical cylinder and the Osteo VOIs that were further subdivided into superior, mid and inferior subVOIs, each., Results: Precision errors (%CVrms) for the central trabecular VOI that is also used in the traditional single slice QCT techniques were 1.7+/-2.2% and 0.6+/-0.6% for QCTPro and MIAF-Spine, respectively. For MIAF-Spine integral BMD precision errors were lowest in the total and mid Osteo subVOIs (0.5+/-0.5%). Trabecular BMD precision errors were lowest in the mid subVOIs (0.6+/-0.6%). For trabecular BMD there were no differences among the total vertebral body, elliptical cylinder and Osteo VOIs. Cortical BMD precision errors were lowest in the mid total vertebral body subVOI (2.1+/-1.9%) and slightly higher in the mid of the Osteo subVOI. Precision errors in the superior and inferior subVOIs were typically 50% to 100% higher compared to the mid subVOIs., Discussion: Compared to QCTPro MIAF-Spine uses an automated 3D segmentation and an anatomic vertebral coordinate system to position a variety of analysis VOIs. This results in better precision than the more manually assisted analysis used by QCTPro. In-vivo precision errors will be approximately 0.5% higher compared to the analysis precision errors reported here (13). The results demonstrate that with 3D QCT in-vivo precision errors of about 1%-1.5% for trabecular and 2.5% to 3% for cortical bone can be obtained in postmenopausal women.

Type II autosomal dominant osteopetrosis (ADO II, Albers-Schonberg disease) is a genetic condition characterized by generalized osteosclerosis predominating in some skeletal sites such as the spine and pelvis. ADO II is rare, and most available clinical descriptions are based on small numbers of patients. We report the clinical and radiological manifestations in 42 ADO II patients. To our knowledge, this is the largest series reported so far. Our inclusion criterion was presence on radiographs of the spine of vertebral endplate thickening, producing the classic sandwich vertebra appearance. We found various patterns of sandwich vertebra, of which we provide a description to assist physicians in diagnosing ADO II. The classic bone-within-bone appearance was present in most but not all skeletal sites. The radiological penetrance of the disease was high (90%) and increased after 20 years of age. As many as 81% of our patients experienced clinical manifestations. Fractures were common (78% of patients) and healed slowly. Hip osteoarthritis developed in 27% of patients and required arthroplasty in 9 of the 16 affected hips. Nonmandibular osteomyelitis occurred in 4 cases (11%). Twenty-four percent of patients had thoracic or lumbar scoliosis. Orthopedic surgery was performed in 52.8% of patients, of whom half had at least three surgical procedures for internal fracture fixation, arthroplasty, limb deformity correction, or treatment of surgical complications. There was a high rate of surgical complications including nonunion, infection, prosthesis loosening, and intraoperative fractures. Nearly two-thirds of patients (64%) had stomatologic manifestations, including mandibular osteomyelitis in 4 patients (11%). Cranial nerve involvement responsible for hearing loss, bilateral optic atrophy, and/or facial palsy was present in 14 patients but was clearly attributable to ADO II in only 6 cases (16%). This large series sheds new light on several aspects of ADO II, most notably the possibility of severe clinical complications. Although other forms of osteopetrosis are considerably more severe, the name "benign osteopetrosis" previously used for ADO II is probably a misnomer.