Foot Deformity and Bone Strength in Charcot Neuropathic Osteoarthropathy

Charcot neuropathic osteoarthropathy: CN) is characterized by progressive degradation of bones and joints in a denervated, inflamed foot and ankle. Diabetes mellitus: DM) and peripheral neuropathy: PN) are the most common precursors of CN, which can lead to pedal fracture, subluxation, and dislocation. Bone injury and subtle articular damage characteristic of incipient CN are difficult to visualize with planar radiographs. As a result, CN often progresses until more serious, clinically obvious events occur, contributing to increased risk of ulceration, infection, amputation, and death. The overall purpose of this research was to develop methods using volumetric quantitative computed tomography: vQCT) to assess foot bone strength and foot deformity, in order to provide improved indices of CN onset and progression. Aim 1 describes the development of methods to assess bone mineral density: BMD) and geometric bone strength indices in human metatarsals, as well as an ex vivo validation of ultimate loading strength using cadaver samples. Results in Aim 1 showed that BMD and indices of compressive, bending, and buckling strength were strong correlates of metatarsal ultimate strength. Aim 2 provides group comparisons of vQCT-derived bone strength indices between CN and non-CN individuals, with results showing large decrements in BMD in individuals with CN, though no group differences were found for geometric strength indices. Aim 3 presents method development and reliability assessment of novel 3D techniques to assess foot deformities using bone surface atlases of the tarsal and metatarsal bones, with results suggesting that an automated, template-based method can provide equivalent measurement precision to expert testers. In Aim 4, vQCT-derived, 3D foot deformity measures were compared between CN and non-CN individuals; results showed significant alterations in bone-to-bone orientations that corroborate sagittal plane measurements from X-rays and also provide novel deformity measures that cannot be made using uni-planar X-rays. This dissertation research, completed under the direction of an interdisciplinary team of physical therapists, biomedical engineers, radiologists, and orthopedic surgeons, provides new information regarding bone strength and foot deformities in Charcot neuropathic osteoarthropathy. Most importantly, the tools developed in the course of this research have potential utility for future research to understand the pathophysiological pathways linking diabetes, peripheral neuropathy, foot deformities, and the development and progression of Charcot neuropathic osteoarthropathy

Computed tomography derived bone density measurement in the diabetic foot

Background: The accurate and reliable measurement of foot bone density is challenging and there is currently no gold standard technique. Such measurement is particularly valuable in populations at risk of foot bone pathology such as in those with long term diabetes. With research and development, computed tomography may prove to be a useful tool for this assessment. The aim of this study was to establish the reliability of a novel method of foot bone density measurement in people with diabetes using computed tomography. Methods: Ten feet in people with diabetes were scanned with computed tomography twice with repositioning. Bone density (in Hounsfield units) was assessed in the trabecular and cortical bone in all tarsals and metatarsals. Reliability was assessed with intra-class correlation coefficients (95% confidence intervals), limits of agreement and standard error of measurement. Results: The reliability of the trabecular density of most bones was excellent with intra-class correlation coefficients ranging from 0.68 to 0.91. Additionally, cortical bone density showed fair to good reliability at the talus (0.52), calcaneus (0.59), navicular (0.70), cuboid (0.69), intermediate cuneiform (0.46) and first metatarsal (0.61). Conclusions: The study established the reliability of a practical method of assessing the trabecular and cortical foot bone density using computed tomography scanning. This methodology may be useful in the investigation of foot bone disease occurring in diabetes and its early diagnosis, intervention and assessment of treatment efficacy. Further development of this method is warranted

Multi-system factors associated with metatarsophalangeal joint deformity in individuals with type 2 diabetes

The underlying factors contributing to metatarsophalangeal joint deformity, a known precursor to skin breakdown in individuals with diabetes mellitus (DM), is likely to involve multiple body systems. The purpose of this cross-sectional study was to identify multi-system factors associated with metatarsophalangeal joint deformity in individuals with type 2 DM and peripheral neuropathy

Reproducibility of a peripheral quantitative computed tomography scan protocol to measure the material properties of the second metatarsal

Background: Peripheral quantitative computed tomography (pQCT) is an established technology that allows for the measurement of the material properties of bone. Alterations to bone architecture are associated with an increased risk of fracture. Further pQCT research is necessary to identify regions of interest that are prone to fracture risk in people with chronic diseases. The second metatarsal is a common site for the development of insufficiency fractures, and as such the aim of this study was to assess the reproducibility of a novel scanning protocol of the second metatarsal using pQCT. Methods. Eleven embalmed cadaveric leg specimens were scanned six times; three times with and without repositioning. Each foot was positioned on a custom-designed acrylic foot plate to permit unimpeded scans of the region of interest. Sixty-six scans were obtained at 15% (distal) and 50% (mid shaft) of the second metatarsal. Voxel size and scan speed were reduced to 0.40 mm and 25 mm.sec-1. The reference line was positioned at the most distal portion of the 2nd metatarsal. Repeated measurements of six key variables related to bone properties were subject to reproducibility testing. Data were log transformed and reproducibility of scans were assessed using intraclass correlation coefficients (ICC) and coefficients of variation (CV%). Results: Reproducibility of the measurements without repositioning were estimated as: trabecular area (ICC 0.95; CV% 2.4), trabecular density (ICC 0.98; CV% 3.0), Strength Strain Index (SSI) - distal (ICC 0.99; CV% 5.6), cortical area (ICC 1.0; CV% 1.5), cortical density (ICC 0.99; CV% 0.1), SSI - mid shaft (ICC 1.0; CV% 2.4). Reproducibility of the measurements after repositioning were estimated as: trabecular area (ICC 0.96; CV% 2.4), trabecular density (ICC 0.98; CV% 2.8), SSI - distal (ICC 1.0; CV% 3.5), cortical area (ICC 0.99; CV%2.4), cortical density (ICC 0.98; CV% 0.8), SSI - mid shaft (ICC 0.99; CV% 3.2). Conclusions: The scanning protocol generated excellent reproducibility for key bone properties measured at the distal and mid-shaft regions of the 2 nd metatarsal. This protocol extends the capabilities of pQCT to evaluate bone quality in people who may be at an increased risk of metatarsal insufficiency fractures

Rate of tarsal and metatarsal bone mineral density change in adults with diabetes mellitus and peripheral neuropathy: A longitudinal study

BACKGROUND: In people with diabetes (DM) and peripheral neuropathy (PN), loss of bone mineral density (BMD) in the tarsals and metatarsals contribute to foot complications; however, changes in BMD of the calcaneal bone is most commonly reported. This study reports rate of change in BMD of all the individual bones in the foot, in participants with DM and PN. Our aim was to investigate whether the rate of BMD change is similar across all the bones of the foot. METHODS: Participants with DM and PN (n = 60) were included in this longitudinal cohort study. Rate of BMD change of individual bones was monitored using computed tomography at baseline and 6 months, 18 months, and 3-4 years from baseline. Personal factors (age, sex, medication use, step count, sedentary time, and PN severity) were assessed. A random coefficient model estimated rate of change of BMD in all bones and Pearson correlation tested relationships between personal factor variables and rate of BMD change. RESULTS: Mean and calcaneal BMD decreased over the study period (p \u3c 0.05). Individual tarsal and metatarsal bones present a range of rate of BMD change (-0.3 to -0.9%/year) but were not significantly different than calcaneal BMD change. Only age showed significant correlation with BMD and rate of BMD change. CONCLUSION: The rate of BMD change did not significantly differ across different foot bones at the group level in people with DM and PN without foot deformity. Asymmetric BMD loss between individual bones of the foot and aging may be indicators of pathologic changes and require further investigation. TRIAL REGISTRATION: Metatarsal Phalangeal Joint Deformity Progression-R01. Registered 25 November 2015, https://clinicaltrials.gov/ct2/show/NCT02616263

Osteochondral lesions in distal tarsal joints of Icelandic horses reveal strong associations between hyaline and calcified cartilage abnormalities

Osteochondral lesions in the joints of the distal tarsal region of young Icelandic horses provide a natural model for the early stages of osteoarthritis (OA) in low-motion joints. We describe and characterise mineralised and non-mineralised osteochondral lesions in left distal tarsal region joint specimens from twenty-two 30 ±1 month-old Icelandic horses. Combinations of confocal scanning light microscopy, backscattered electron scanning electron microscopy (including, importantly, iodine staining) and three-dimensional microcomputed tomography were used on specimens obtained with guidance from clinical imaging. Lesion-types were described and classified into groups according to morphological features. Their locations in the hyaline articular cartilage (HAC), articular calcified cartilage (ACC), subchondral bone (SCB) and the joint margin tissues were identified and their frequency in the joints recorded. Associations and correlations between lesion-types were investigated for centrodistal joints only. In centrodistal joints the lesion-types HAC chondrocyte loss, HAC fibrillation, HAC central chondrocyte clusters, ACC arrest and ACC advance had significant associations and strong correlations. These lesion-types had moderate to high frequency in centrodistal joints but low frequencies in tarsometatarsal and talocalcaneal-centroquartal joints. Joint margin lesion-types had no significant associations with other lesion-types in the centrodistal joints but high frequency in both the centrodistal and tarsometatarsal joints. The frequency of SCB lesion-types in all joints was low. Hypermineralised infill phase lesion-types were detected. Our results emphasise close associations between HAC and ACC lesions in equine centrodistal joints and the importance of ACC lesions in the development of OA in low-motion compression-loaded equine joints

Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis.

DNAX adaptor protein 12 (DAP12) is a trans-membrane adaptor molecule that transduces activating signals in NK and myeloid cells. Absence of functional Dap12 results in osteoclast defects and bone abnormalities. Because DAP12 has no extracelluar binding domains, it must pair with cell surface receptors for signal transduction. There are at least 15 known DAP12-associating cell surface receptors with distinct temporal and cell type-specific expression patterns. Our aim was to determine which receptors may be important in DAP12-associated bone pathologies. Here, we identify myeloid DAP12-associating lectin (MDL)-1 receptor (also known as CLEC5A) as a key regulator of synovial injury and bone erosion during autoimmune joint inflammation. Activation of MDL-1 leads to enhanced recruitment of inflammatory macrophages and neutrophils to the joint and promotes bone erosion. Functional blockade of MDL-1 receptor via Mdl1 deletion or treatment with MDL-1-Ig fusion protein reduces the clinical signs of autoimmune joint inflammation. These findings suggest that MDL-1 receptor may be a therapeutic target for treatment of immune-mediated skeletal disorders

Pharmacological Modulation of Inflammation, Bone Loss and Pain in a Murine Model of Inflammatory Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune condition, affecting approximately 1% of the population. RA is characterised by a chronic inflammatory response resulting in destruction of soft and hard tissues within the synovial joints. Disease progression in RA is complex, with multiple signalling pathways identified as crucial to T-cell mediated inflammation and increased osteoclastogenesis in the progression of joint destruction. Cell-adhesion molecules and alterations in apoptotic and autophagic pathways in cells located in the synovial joints have recently emerged as key components of the progression of inflammation and bone destruction in RA. Despite the growing knowledge of these mechanisms, control of bone destruction is still challenging and the prognosis of joint pain is often poor despite optimal control of inflammation. For this reason, it is imperative to utilise appropriate cell culture and in vivo models to identify key signalling pathways and develop targeted therapeutics that may inhibit inflammation, bone destruction and pain concomitantly upon diagnosis or prior to the onset of visible symptoms. The aim of this research was to use in vitro human osteoclast assays in conjunction with a modified collagen-antibody induced arthritis (CAIA) murine model of inflammatory arthritis to determine the effects of emerging novel compounds on inflammation, bone loss and pain-like behaviour. These studies also explored the pathology and progression of pain in a mild and moderate form of the CAIA model whilst extending micro-computed tomography analysis to include assessment of local inflammation and bone volume in the hind paws. The results of these studies support that novel compounds targeting cell adhesion molecules and NF-kB intracellular signalling have the potential to treat inflammatory induced bone loss. The findings presented also highlight the complex mechanisms associated with progression of joint destruction and pain-like behaviour in inflammatory arthritis. Further studies are necessary to elucidate the specific roles of each novel compound and further test the effectiveness of these compounds as potential therapies for RA.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

Imaging of early distal tarsal osteoarthritis in Icelandic horses

The early stages of osteoarthritis (OA) are characterised by focal morphological changes that may slowly progress if joint repair fails. Validated, non-invasive and affordable methods to diagnose the early stage of OA in horses are lacking. The objectives of this thesis were to investigate and validate OA detection methods, and describe the morphological OA changes in the distal tarsal region of a group of young Icelandic horses. Radiography, computed tomography (CT) and magnetic resonance imaging (MRI), light microscopy histology, backscattered electron scanning electron microscopy, and confocal scanning light microscopy were used to investigate osteochondral changes in the joints of the distal tarsal region in 38 two-and-a-half year old Icelandic horses. Radiographs were taken of live horses standing, all other examinations were performed 2-3 months later on non-weight bearing cadaver specimens from the same horses. The results showed that a novel CT and MRI guidance method for osteochondral tissue sample collection improved detection of early OA changes in centrodistal (distal intertarsal) joints compared to standardised sample collection from predetermined locations. Diagnostic imaging and microscopy showed that early OA morphological changes primarily occur in the articular hyaline and calcified cartilage rather than the subchondral bone. The lesions articular mineralisation front defect, central osteophytes and hyperdense mineralisation front protrusions were described in detail in the joints of the distal tarsal region using combined microscopic imaging of embedded block specimens. A comparison of clinical diagnostic imaging methods found that radiography was equal or better than low-field MRI for the detection of early OA in centrodistal joints. Articular mineralisation front defects were identified as a highly specific imaging feature in radiographs for early OA. This thesis provides a detailed morphological description of the osteochondral changes occurring in the early stages of OA in the centrodistal joint of Icelandic horses and proposes a validated, non-invasive, cost-effective radiography method for proceeding with future longitudinal studies of early OA in Icelandic horses