Changes in Local Bone Density in Early Thumb Carpometacarpal Joint Osteoarthritis.

PURPOSE: Thumb carpometacarpal (CMC) osteoarthritis (OA) represents a major source of functional morbidity. The effects of early CMC OA on loading and use patterns potentially lead to changes in local bone density and microarchitecture. Hounsfield units (HU), a quantitative attenuation coefficient obtained from computed tomography (CT) scans, have been shown to be a reliable marker of bone density. We hypothesized that early CMC OA is associated with lower local bone density about the CMC joint as assessed by HU. METHODS: We examined HU units from CT scans in 23 asymptomatic subjects and 91 patients with early CMC OA. The HU measurements were obtained within cancellous portions of the trapezium, capitate, first and third metacarpal bases, and distal radius. Linear regression models, with age and sex included as covariates, were used to assess the relationship between CMC OA and HU values at each anatomical site. RESULTS: Early OA patients had significantly lower HU than asymptomatic subjects within the trapezium (mean, 377 HU vs 436 HU) and first metacarpal bases (265 HU vs 324 HU). No significant group differences were noted at the capitate, third metacarpal, or distal radius. Male sex and younger age were associated with significantly higher HU at all the anatomical sites, except the first metacarpal base, where age had no significant effect. CONCLUSIONS: Subjects presenting with early CMC OA had significantly lower bone density as assessed with HU at the thumb CMC joint (trapezium and first metacarpal base). Early thumb CMC OA and discomfort may lead to diminished loading across the basal joint, producing focal disuse osteopenia. These findings in symptomatic early arthritis suggest a relationship between symptoms, functional use of the CMC joint, and local bone density. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

The Envelope of Physiological Motion of the First Carpometacarpal Joint.

Much of the hand's functional capacity is due to the versatility of the motions at the thumb carpometacarpal (CMC) joint, which are presently incompletely defined. The aim of this study was to develop a mathematical model to completely describe the envelope of physiological motion of the thumb CMC joint and then to examine if there were differences in the kinematic envelope between women and men. In vivo kinematics of the first metacarpal with respect to the trapezium were computed from computed tomography (CT) volume images of 44 subjects (20M, 24F, 40.3 ± 17.7 yr) with no signs of CMC joint pathology. Kinematics of the first metacarpal were described with respect to the trapezium using helical axis of motion (HAM) variables and then modeled with discrete Fourier analysis. Each HAM variable was fit in a cyclic domain as a function of screw axis orientation in the trapezial articular plane; the RMSE of the fits was 14.5 deg, 1.4 mm, and 0.8 mm for the elevation, location, and translation, respectively. After normalizing for the larger bone size in men, no differences in the kinematic variables between sexes could be identified. Analysis of the kinematic data also revealed notable coupling of the primary rotations of the thumb with translation and internal and external rotations. This study advances our basic understanding of thumb CMC joint function and provides a complete description of the CMC joint for incorporation into future models of hand function. From a clinical perspective, our findings provide a basis for evaluating CMC pathology, especially the mechanically mediated aspects of osteoarthritis (OA), and should be used to inform artificial joint design, where accurate replication of kinematics is essential for long-term success.

In Vivo kinematics of the trapeziometacarpal joint during thumb extension-flexion and abduction-adduction.

PURPOSE: The primary aim of this study was to determine whether the in vivo kinematics of the trapeziometacarpal (TMC) joint differ as a function of age and sex during thumb extension-flexion (Ex-Fl) and abduction-adduction (Ab-Ad) motions. METHODS: The hands and wrists of 44 subjects (10 men and 11 women with ages 18-35 y and 10 men and 13 women with ages 40-75 y) with no symptoms or signs of TMC joint pathology were imaged with computed tomography during thumb extension, flexion, abduction, and adduction. The kinematics of the TMC joint were computed and compared across direction, age, and sex. RESULTS: We found no significant effects of age or sex, after normalizing for size, in any of the kinematic parameters. The Ex-Fl and Ab-Ad rotation axes did not intersect, and both were oriented obliquely to the saddle-shaped anatomy of the TMC articulation. The Ex-Fl axis was located in the trapezium and the Ab-Ad axis was located in the metacarpal. Metacarpal translation and internal rotation occurred primarily during Ex-Fl. CONCLUSIONS: Our findings indicate that normal TMC joint kinematics are similar in males and females, regardless of age, and that the primary rotation axes are nonorthogonal and nonintersecting. In contrast to previous studies, we found Ex-Fl and Ab-Ad to be coupled with internal-external rotation and translation. Specifically, internal rotation and ulnar translation were coupled with flexion, indicating a potential stabilizing screw-home mechanism. CLINICAL RELEVANCE: The treatment of TMC pathology and arthroplasty design require a detailed and accurate understanding of TMC function. This study confirms the complexity of TMC kinematics and describes metacarpal translation coupled with internal rotation during Ex-Fl, which may explain some of the limitations of current treatment strategies and should help improve implant designs.

Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice.

Clubfoot affects 1 in 1000 live births, although little is known about its genetic or developmental basis. We recently identified a missense mutation in the PITX1 bicoid homeodomain transcription factor in a family with a spectrum of lower extremity abnormalities, including clubfoot. Because the E130K mutation reduced PITX1 activity, we hypothesized that PITX1 haploinsufficiency could also cause clubfoot. Using copy number analysis, we identified a 241 kb chromosome 5q31 microdeletion involving PITX1 in a patient with isolated familial clubfoot. The PITX1 deletion segregated with autosomal dominant clubfoot over three generations. To study the role of PITX1 haploinsufficiency in clubfoot pathogenesis, we began to breed Pitx1 knockout mice. Although Pitx1(+/-) mice were previously reported to be normal, clubfoot was observed in 20 of 225 Pitx1(+/-) mice, resulting in an 8.9% penetrance. Clubfoot was unilateral in 16 of the 20 affected Pitx1(+/-) mice, with the right and left limbs equally affected, in contrast to right-sided predominant hindlimb abnormalities previously noted with complete loss of Pitx1. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1(-/-) E12.5 hindlimb buds compared with the wild-type, suggesting that muscle hypoplasia was due to abnormal early muscle development and not disuse atrophy. Our morphological data suggest that PITX1 haploinsufficiency may cause a developmental field defect preferentially affecting the lateral lower leg, a theory that accounts for similar findings in human clubfoot.

Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice.

Obesity is generally protective against osteoporosis and bone fracture. However, recent studies indicate that the influence of obesity on the skeleton is complex and can be detrimental. We evaluated the effects of a high-fat, obesogenic diet on the femur and radius of 1100 mice (males and females) from the Large-by-Small advanced intercross line (F34 generation). At age 5 months, bone morphology was assessed by microCT and mechanical properties by three-point bending. Mice raised on a high-fat diet had modestly greater cortical area, bending stiffness, and strength. Size-independent material properties were unaffected by a high-fat diet, indicating that diet influenced bone quantity but not quality. Bone size and mechanical properties were strongly correlated with body mass. However, the increases in many bone traits per unit increase in body mass were less in high-fat diet mice than low-fat diet mice. Thus, although mice raised on a high-fat diet have, on average, bigger and stronger bones than low-fat-fed mice, a high-fat diet diminished the positive relationship between body mass and bone size and whole-bone strength. The findings support the concept that there are diminishing benefits to skeletal health with increasing obesity. © 2019 American Society for Bone and Mineral Research.

Comparison of transhumeral socket designs utilizing patient assessment and in vivo skeletal and socket motion tracking: a case study.

PURPOSE: This case study compares the impact of two prosthetic socket designs, a "traditional" transhumeral (TH) socket design and a Compression Released Stabilized (CRS) socket. METHODS: A CRS socket was compared to the existing socket of two persons with transhumeral amputation. Comparisons included assessments of patient comfort and satisfaction with fit, as well as dynamic kinematic assessment using a novel high-speed, high-resolution, bi-plane video radiography system (XROMM, for X-ray Reconstruction of Moving Morphology). RESULTS: Subjects were more satisfied with the comfort of the traditional sockets, although they had positive impressions about aspects of the fit and style of the CRS socket, and thought that it provided better control. Dynamic kinematic assessment revealed that the CRS socket provided better control of the residual limb within the socket, and had less slippage as compared to a traditional TH socket design. CONCLUSIONS: The TH CRS socket provided better control of the residual limb within the socket, and had less slippage. However, participants were less satisfied with the comfort and overall utility of the CRS socket, and stated that additional fitting visits/modifications to the CRS socket were needed. It is possible that satisfaction with the CRS socket may have improved with prosthetic adjustment and more acclimation time. Implications for Rehabilitation A comfortable, good fitting prosthetic socket is the key factor in determining how long (or if) an upper limb amputee can tolerate wearing a prosthesis. This case series was a comparison of two socket designs, a 'traditional' socket design and a Compression Released Stabilized (CRS) socket design in persons with transhumeral amputation. The CRS socket provided better control of the residual limb within the socket, and had less slippage. However, its tightness made it more difficult to don. Both subjects were less satisfied with the comfort and overall utility of the CRS socket. However, satisfaction might have been improved with additional fitting visits and more acclimation time.

Superficial zone cellularity is deficient in mice lacking lubricin: a stereoscopic analysis.

BACKGROUND: Lubricin, a mucinous glycoprotein secreted by synoviocytes and chondrocytes plays an important role in reducing the coefficient of friction in mammalian joints. Elevated cartilage surface friction is thought to cause chondrocyte loss; however, its quantification and methodological approaches have not been reported. We adapted a stereological method and incorporated vital cell staining to assess cellular loss in superficial and upper intermediate zones in lubricin deficient mouse cartilage. METHODS: The femoral condyle cartilage of the intact knees from lubricin wild type (Prg4 (+/+)), heterozygote (Prg4 (+/-)), and knockout (Prg4 (-/-)) mice was imaged using fluorescein diacetate (FDA), propidium iodide (PI), and Hoechst staining, and confocal microscopy. Three dimensional reconstructions of confocal images to a depth of 14 µm were analyzed using Matlab to determine the volume fraction occupied by chondrocytes in cartilage of both medial and lateral femoral condyles. Living chondrocyte volume fraction was defined as FDA stained chondrocyte volume/total volume of superficial + upper intermediate zone. Living and dead (total) chondrocyte volume fraction was defined as FDA + PI stained chondrocyte volume/total volume of superficial + upper intermediate zone. MicroCT provided an orthogonal measure of cartilage thickness. Immunohistology for activated caspase-3 and TUNEL staining were performed to evaluate the presence of apoptotic chondrocytes in Prg4 mutant mice. RESULTS: Living chondrocyte volume fraction of the medial femoral condyle was significantly lower in Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.002) and Prg4 (+/-) (p = 0.002) littermates. There was no significant difference in medial condyle chondrocyte volume fraction between Prg4 (+/+) and Prg4 (+/-) mice (p = 0.82). No significant differences were observed for the chondrocyte volume fraction for the lateral condyle (p > 0.26). Cartilage thickness increased in the medial condyle for Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.02) and Prg4 (+/-) (p = 0.03) littermates, and the lateral condyle for Prg4 (-/-) mice compared to Prg4 (+/+) (p < 0.0001) and Prg4 (+/-) (p < 0.0001) littermates, indicating that a multi-dimensional increase in cartilage volume did not artifactually lower the chondrocyte volume fraction in the medial condyle. Significantly higher number of caspase-3 positive cells were observed in the superficial and upper intermediate zone cartilage of the medial femoral condyle of Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.01) and Prg4 (+/-) (p = 0.04) littermates, and the lateral femoral condyle of Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.02) and Prg4 (+/-) (p = 0.02) littermates. There were no significant differences in TUNEL staining among different Prg4 genotypes in both condyles (p > 0.05 for all comparisons). CONCLUSIONS: Increased Caspase-3 activation is observed in Prg4 deficient mice compared to Prg4 sufficient littermates. Absence of Prg4 induces loss of chondrocytes in the superficial and upper intermediate zone of mouse cartilage that is quantifiable by a novel image processing technique.

Extracellular matrix-blood composite injection reduces post-traumatic osteoarthritis after anterior cruciate ligament injury in the rat.

The objective of this study was to determine if an injection of a novel extracellular matrix scaffold and blood composite (EMBC) after anterior cruciate ligament (ACL) injury would have a mitigating effect on post-traumatic osteoarthritis (PTOA) development in rat knees. Lewis rats underwent unilateral ACL transection and were divided into three groups as follows: (1) no further treatment (ACLT; n = 10); (2) an intra-articular injection of EMBC on day 0 (INJ0; n = 11); and (3) an intra-articular injection of EMBC on day 14 (INJ14; n = 11). Ten additional animals received capsulotomy only (n = 10, SHAM group). The OARSI histology scoring of the tibial cartilage and micro-CT of the tibial epiphysis were performed after 35 days. The ratio of intact/treated hind limb forces during gait was determined using a variable resistor walkway. The OARSI cartilage degradation sum score and total degeneration width were significantly greater in the ACLT group when compared to the INJ0 (p = 0.031, and p = 0.005) and INJ14 (p = 0.022 and p = 0.04) group. Weight bearing on the operated limb only decreased significantly in the ACLT group (p = 0.048). In the rat ACL transection model, early or delayed injection of EMBC ameliorated the significant decrease in weight bearing and cartilage degradation seen in knees subjected to ACL transection without injection. The results indicate that the injection of EMBC may slow the process of PTOA following ACL injury and may provide a promising treatment for PTOA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:995-1003, 2016.

Older asymptomatic women exhibit patterns of thumb carpometacarpal joint space narrowing that precede changes associated with early osteoarthritis.

In small joints, where cartilage is difficult to image and quantify directly, three-dimensional joint space measures can be used to gain insight into potential joint pathomechanics. Since the female sex and older age are risk factors for carpometacarpal (CMC) joint osteoarthritis (OA), the purpose of this in vivo computed tomography (CT) study was to determine if there are any differences with sex, age, and early OA in the CMC joint space. The thumbs of 66 healthy subjects and 81 patients with early stage CMC OA were scanned in four range-of-motion, three functional-task, and one neutral positions. Subchondral bone-to-bone distances across the trapezial and metacarpal articular surfaces were computed for all the positions. The joint space area, defined as the articular surface that is less than 1.5mm from the mating bone, was used to assess joint space. A larger joint space area typically corresponds to closer articular surfaces, and therefore a narrower joint space. We found that the joint space areas are not significantly different between healthy young men and women. Trends indicated that patients with early stage OA have larger CMC joint space areas than healthy subjects of the same age group and that older healthy women have larger joint space areas than younger healthy women. This study suggests that aging in women may lead to joint space narrowing patterns that precede early OA, which is a compelling new insight into the pathological processes that make CMC OA endemic to women.

Early osteoarthritis of the trapeziometacarpal joint is not associated with joint instability during typical isometric loading.

The saddle-shaped trapeziometacarpal (TMC) joint contributes importantly to the function of the human thumb. A balance between mobility and stability is essential in this joint, which experiences high loads and is prone to osteoarthritis (OA). Since instability is considered a risk factor for TMC OA, we assessed TMC joint instability during the execution of three isometric functional tasks (key pinch, jar grasp, and jar twist) in 76 patients with early TMC OA and 44 asymptomatic controls. Computed tomography images were acquired while subjects held their hands relaxed and while they applied 80% of their maximum effort for each task. Six degree-of-freedom rigid body kinematics of the metacarpal with respect to the trapezium from the unloaded to the loaded task positions were computed in terms of a TMC joint coordinate system. Joint instability was expressed as a function of the metacarpal translation and the applied force. We found that the TMC joint was more unstable during a key pinch task than during a jar grasp or a jar twist task. Sex, age, and early OA did not have an effect on TMC joint instability, suggesting that instability during these three tasks is not a predisposing factor in TMC OA.

Experimental and finite element analysis of strains induced by axial tibial compression in young-adult and old female C57Bl/6 mice.

Axial compression of the mouse tibia is used to study strain-adaptive bone (re)modeling. In some studies, comparisons between mice of different ages are of interest. We characterized the tibial deformation and force-strain relationships in female C57Bl/6 mice at 5-, 12- and 22-months age. A three-gauge experimental method was used to determine the strain distribution at the mid-diaphysis, while specimen-specific finite element analysis was used to examine strain distribution along the tibial length. The peak strains in the tibial mid-diaphyseal cross-section are compressive and occur at the postero-lateral apex. The magnitudes of these peak compressive strains are 1.5 to 2 times those on the opposite, antero-medial face (a site often used for strain gauge placement). For example, -10 N force applied to a 5-months old mouse engenders a peak compressive strain of -2800 µÎµ and a tensile strain on the antero-medial face of +1450 µÎµ. The orientation of the neutral axis at the mid-diaphysis did not differ with age (p=0.46), indicating a similar deformation mode in young and old tibiae. On the other hand, from 5- to 22-months there is a 25% reduction in cortical thickness and moment of inertia (p<0.05), resulting in significantly greater tibial strain magnitudes in older mice for equivalent applied force (p<0.05). We conclude that comparisons of tibial loading responses in young-adult and old C57Bl/6 tibiae are facilitated by similar deformation pattern across ages, but that modest adjustment of force levels is required to engender matching peak strains.

Thumb carpometacarpal joint congruence during functional tasks and thumb range-of-motion activities.

Joint incongruity is often cited as a possible etiological factor for the high incidence of thumb carpometacarpal (CMC) joint osteoarthritis (OA) in older women. There is evidence suggesting that biomechanics plays a role in CMC OA progression, but little is known about how CMC joint congruence, specifically, differs among different cohorts. The purpose of this in vivo study was to determine if CMC joint congruence differs with sex, age, and early stage OA for different thumb positions. Using CT data from 155 subjects and a congruence metric that is based on both articular morphology and joint posture, we did not find any differences in CMC joint congruence with sex or age group, but found that patients in the early stages of OA exhibit lower congruence than healthy subjects of the same age group.

Predicting ex vivo failure loads in human metatarsals using bone strength indices derived from volumetric quantitative computed tomography.

We investigated the capacity of bone quantity and bone geometric strength indices to predict ultimate force in the human second metatarsal (Met2) and third metatarsal (Met3). Intact lower extremity cadaver samples were measured using clinical, volumetric quantitative computed tomography (vQCT) with positioning and parameters applicable to in vivo scanning. During processing, raw voxel data (0.4mm isotropic voxels) were converted from Hounsfield units to apparent bone mineral density (BMD) using hydroxyapatite calibration phantoms to allow direct volumetric assessment of whole-bone and subregional metatarsal BMD. Voxel data were realigned to produce cross-sectional slices perpendicular to the longitudinal axes of the metatarsals. Average mid-diaphyseal BMD, bone thickness, and buckling ratio were measured using an optimized threshold to distinguish bone from non-bone material. Minimum and maximum moments of inertia and section moduli were measured in the mid-diaphysis region using both a binary threshold for areal, unit-density measures and a novel technique for density-weighted measures. BMD and geometric strength indices were strongly correlated to ultimate force measured by ex vivo 3-point bending. Geometric indices were more highly correlated to ultimate force than was BMD; bone thickness and density-weighted minimum section modulus had the highest individual correlations to ultimate force. Density-weighted geometric indices explained more variance than their binary analogs. Multiple regression analyses defined models that predicted 85-89% of variance in ultimate force in Met2 and Met3 using bone thickness and minimum section modulus in the mid-diaphysis. These results have implications for future in vivo imaging to non-invasively assess bone strength and metatarsal fracture risk.