ABSTRACT
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-month 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 vBMD from baseline at Month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro finite element-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12 months, 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 > 0.05). 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.
Osteogenesis imperfecta, or OI, is a rare disorder affecting patients' bones causing pain and an increased chance of the bone breaking. Setrusumab is a possible treatment for OI being studied in a clinical trial called Asteroid. The goal of Asteroid was to determine which dose of setrusumab helped adults with OI the most: 2, 8, or 20 mg/kg. Researchers looked at the density of patients' bones and estimated how strong their bones were before setrusumab and again after 12 months of treatment to see how they improved with treatment. Researchers could compare these improvements to see which dose of setrusumab helped patients the most. Patients on the highest dose of setrusumab (20 mg/kg) experienced improvements in the density of their arm bones (radius) and leg bones (tibia) after 12 months. The strength of these bones also improved. The density of other bones including the spine, hip, and the overall skeleton (total body) also improved with treatment. Of patients who had side effects after receiving setrusumab, most were mild or moderate intensity. Overall, setrusumab improved the bones of patients with OI with no serious safety concerns. More studies will include even more patients to see how setrusumab can improve their bones.
ABSTRACT
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.
Subject(s)
Deep Learning , Gaucher Disease , Magnetic Resonance Imaging , Osteonecrosis , Gaucher Disease/diagnostic imaging , Gaucher Disease/pathology , Humans , Osteonecrosis/diagnostic imaging , Magnetic Resonance Imaging/methods , Male , Female , Adult , Femur/diagnostic imaging , Femur/pathology , Middle Aged , Image Processing, Computer-Assisted/methods , Adolescent , Young Adult , Bone Marrow/diagnostic imaging , Bone Marrow/pathologyABSTRACT
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).
Subject(s)
Hip Fractures , Osteocytes , Humans , Bone Density , Femur Head , Hip Fractures/diagnostic imaging , OsteogenesisABSTRACT
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL RELEVANCE STATEMENT: 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. KEY POINTS: ⢠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.
Subject(s)
Ankle Joint , Ankle , Humans , Ankle/diagnostic imaging , Ankle Joint/diagnostic imaging , Reproducibility of Results , Tomography, X-Ray Computed/methods , Weight-BearingABSTRACT
INTRODUCTION: Two million out of the UK's 5 million routine diagnostic CT scans performed each year incorporate the thoracolumbar spine or pelvic region. Up to one-third reveal undiagnosed osteoporosis or vertebral fractures. We developed an intervention, Picking up Hidden Osteoporosis Effectively during Normal CT Imaging without additional X-rays ('PHOENIX'), to facilitate early detection and management of osteoporosis in people attending hospitals for CT scans. METHODS AND ANALYSIS: A multicentre, randomised, pragmatic feasibility study. From the general CT-attending population, women aged ≥65 years and men aged ≥75 years attending for CT scans are invited to participate, via a novel consent form incorporating Fracture Risk Assessment (FRAX) questions. Those at increased 10-year risk (within the amber or red zones of the UK FRAX graphical outputs for further action) are block randomised (1:1:1) to (1) PHOENIX intervention, (2) active control or (3) usual care. The PHOENIX intervention comprises (i) retrieving the CT scans using the NHS Image Exchange Portal, (ii) Mindways QCT Pro software analysis of CT hip and spine none density with CT vertebral fracture assessment, (iii) sending the participants' general practitioner (GP) a clinical report including diagnosis, necessary investigations and recommended treatment. Baseline CT scans from groups 2 and 3 are assessed with the PHOENIX intervention only at study end. Assuming 25% attrition, the study is powered to find a predicted superior osteoporosis treatment rate with PHOENIX (20%) vs 16% among patients whose GPs were sent the FRAX questionnaire only (active control) and 5% in the usual care group. Five hospitals are participating to determine feasibility. The co-primary feasibility outcome measures are (a) ability to randomise 375 patients within 10 months and (b) retention of 75% of survivors, completing their 1-year bone health outcome questionnaire. Secondary 1-year outcomes include osteoporosis/vertebral fracture identification rates and osteoporosis treatment rates. Stakeholder acceptability and economic aspects are evaluated. ETHICS AND DISSEMINATION: Approved by committee (National Research Ethics Service) East of England (EE) as REF/19/EE/0176. Dissemination will be through the Royal Osteoporosis Society (to patients and public) as well as to clinician peers via national and international bone/rheumatology scientific and clinical meetings. TRIAL REGISTRATION NUMBER: ISRCTN14722819.
Subject(s)
Osteoporosis , Osteoporotic Fractures , Spinal Fractures , Aged , Feasibility Studies , Female , Humans , Male , Multicenter Studies as Topic , Osteoporosis/diagnostic imaging , Osteoporotic Fractures/diagnostic imaging , Osteoporotic Fractures/prevention & control , Randomized Controlled Trials as Topic , Tomography, X-Ray Computed , X-RaysABSTRACT
The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.
ABSTRACT
The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF-family receptor-α2 (GFRα2) and its ligand, neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.
Subject(s)
Interleukin-6 , Osteogenesis , Cholinergic Agents , Cholinergic Fibers , Glial Cell Line-Derived Neurotrophic Factor Receptors/physiologyABSTRACT
We report the case of a phosphaturic mesenchymal tumor of the ankle; an extremely rare lesion that causes osteomalacia via paraneoplastic renal phosphate wasting. A 41-year-old man was referred to plastic surgery with a swelling over the anterior ankle, which had been increasing in size for 1 year. Focused ultrasound assessment was inconclusive, but excision biopsy demonstrated features in keeping with a phosphaturic mesenchymal tumor. Evidence of tumor-induced osteomalacia was subsequently identified on review of historical biochemistry. The patient was followed-up for 1 year with normalization of serum phosphate. In this case report, we present a discussion of the differential diagnosis for foot and ankle soft tissue lesions, and a review of the literature regarding the diagnosis and management of these tumors. Accurate identification of any soft tissue lesion on clinical examination alone is extremely challenging and excision biopsy should be considered in cases of diagnostic uncertainty.
Subject(s)
Hypophosphatemia , Mesenchymoma , Neoplasms, Connective Tissue , Osteomalacia , Paraneoplastic Syndromes , Adult , Ankle/diagnostic imaging , Humans , Male , Mesenchymoma/diagnosis , Mesenchymoma/diagnostic imaging , Neoplasms, Connective Tissue/diagnostic imaging , Neoplasms, Connective Tissue/surgeryABSTRACT
Osteoporosis causes bones to become weak, porous and fracture more easily. While a vertebral fracture is the archetypal fracture of osteoporosis, it is also the most difficult to diagnose clinically. Patients often suffer further spine or other fractures, deformity, height loss and pain before diagnosis. There were an estimated 520,000 fragility fractures in the United Kingdom (UK) in 2017 (costing £4.5 billion), a figure set to increase 30% by 2030. One way to improve both vertebral fracture identification and the diagnosis of osteoporosis is to assess a patient's spine or hips during routine computed tomography (CT) scans. Patients attend routine CT for diagnosis and monitoring of various medical conditions, but the skeleton can be overlooked as radiologists concentrate on the primary reason for scanning. More than half a million CT scans done each year in the National Health Service (NHS) could potentially be screened for osteoporosis (increasing 5% annually). If CT-based screening became embedded in practice, then the technique could have a positive clinical impact in the identification of fragility fracture and/or low bone density. Several companies have developed software methods to diagnose osteoporosis/fragile bone strength and/or identify vertebral fractures in CT datasets, using various methods that include image processing, computational modelling, artificial intelligence and biomechanical engineering concepts. Technology to evaluate Hounsfield units is used to calculate bone density, but not necessarily bone strength. In this rapid evidence review, we summarise the current literature underpinning approved technologies for opportunistic screening of routine CT images to identify fractures, bone density or strength information. We highlight how other new software technologies have become embedded in NHS clinical practice (having overcome barriers to implementation) and highlight how the novel osteoporosis technologies could follow suit. We define the key unanswered questions where further research is needed to enable the adoption of these technologies for maximal patient benefit.
ABSTRACT
Background Imaging of structural disease in osteoarthritis has traditionally relied on MRI and radiography. Joint space mapping (JSM) can be used to quantitatively map joint space width (JSW) in three dimensions from CT images. Purpose To demonstrate the reproducibility, repeatability, and feasibility of JSM of the knee using weight-bearing CT images. Materials and Methods Two convenience samples of weight-bearing CT images of left and right knees with radiographic Kellgren-Lawrence grades (KLGs) less than or equal to 2 were acquired from 2014 to 2018 and were analyzed retrospectively with JSM to deliver three-dimensional JSW maps. For reproducibility, images of three sets of knees were used for novice training, and then the JSM output was compared against an expert's assessment. JSM was also performed on 2-week follow-up images in the second cohort, yielding three-dimensional JSW difference maps for repeatability. Statistical parametric mapping was performed on all knee imaging data (KLG, 0-4) to show the feasibility of a surface-based analysis in three dimensions. Results Reproducibility (in 20 individuals; mean age, 58 years ± 7 [standard deviation]; mean body mass index, 28 kg/m2 ± 6; 14 women) and repeatability (in nine individuals; mean age, 53 years ± 6; mean body mass index, 26 kg/m2 ± 4; seven women) reached their lowest performance at a smallest detectable difference less than ±0.1 mm in the central medial tibiofemoral joint space for individuals without radiographically demonstrated disease. The average root mean square coefficient of variation was less than 5% across all groups. Statistical parametric mapping (33 individuals; mean age, 57 years ± 7; mean body mass index, 27 kg/m2 ± 6; 23 women) showed that the central-to-posterior medial joint space was significantly narrower by 0.5 mm for each incremental increase in the KLG (threshold P < .05). One knee (KLG, 2) demonstrated a baseline versus 24-month change in its three-dimensional JSW distribution that was beyond the smallest detectable difference across the lateral joint space. Conclusion Joint space mapping of the knee using weight-bearing CT images is feasible, demonstrating a relationship between the three-dimensional joint space width distribution and structural joint disease. It is reliably learned by novice users, can be personalized for disease phenotypes, and can be used to achieve a smallest detectable difference that is at least 50% smaller than that reported to be achieved at the highest performance level in radiography. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Roemer in this issue.
Subject(s)
Imaging, Three-Dimensional/methods , Osteoarthritis, Knee/diagnostic imaging , Tomography, X-Ray Computed/methods , Weight-Bearing , Feasibility Studies , Female , Humans , Male , Middle Aged , Reproducibility of Results , Retrospective StudiesABSTRACT
BACKGROUND: Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes. METHODS: We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering. RESULTS: Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM ßosteophyte = 0.30 [0.01, 0.58], p = 0.019 and ßJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (ß = 8.3 [0.7, 15.98], p = 0.032). CONCLUSIONS: HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.
Subject(s)
Osteoarthritis, Hip , Osteoarthritis, Knee , Osteophyte , Bone Density , Cohort Studies , Female , Humans , Male , Middle Aged , Osteoarthritis, Hip/diagnostic imaging , Osteophyte/diagnostic imaging , Prospective StudiesABSTRACT
Albright hereditary osteodystrophy (AHO) is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. AHO and pseudohypoparathyroidism (PHP) have been used interchangeably in the past. The term PHP describes end-organ resistance to parathyroid hormone (PTH), occurring with or without the physical features of AHO. Conversely, pseudopseudohypoparathyroidism (PPHP) describes individuals with AHO features in the absence of PTH resistance. PHP and PPHP are etiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gs α) locus (GNAS) in chromosome 20q13. Another less-recognized group of skeletal dysplasias, termed acrodysostosis, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gs α-cyclic adenosine monophosphate-protein kinase A signaling pathway. We describe the clinical course and genotype of two adult patients with overlapping AHO features who harbored novel pathogenic variants in GNAS (c.2273C > G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C > T, p.Ala268Val, NM_002734.4), respectively. We highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses and discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide signaling disorder classification system.
Subject(s)
Dysostoses/genetics , Intellectual Disability/genetics , Osteochondrodysplasias/genetics , Parathyroid Hormone-Related Protein/metabolism , Parathyroid Hormone/metabolism , Pseudohypoparathyroidism/genetics , Signal Transduction , Dysostoses/metabolism , Humans , Intellectual Disability/metabolism , Male , Middle Aged , Osteochondrodysplasias/metabolism , Pseudohypoparathyroidism/metabolismABSTRACT
Bone modeling is a biological process of bone formation that adapts bone size and shape to mechanical loads, especially during childhood and adolescence. Bone modeling in cortical bone can be easily detected using sequential radiographic images, while its assessment in trabecular bone is challenging. Here, we performed histomorphometric analysis in 21 bone specimens from biopsies collected during hip arthroplasty, and we proposed the criteria for histologically identifying an active modeling-based bone formation, which we call a "forming minimodeling structure" (FMiS). Evidence of FMiSs was found in 9 of 20 specimens (45%). In histomorphometric analysis, bone volume was significant higher in specimens displaying FMiSs compared with the specimens without these structures (BV/TV, 31.7 ± 10.2 vs. 23.1 ± 3.9%; p < 0.05). Osteoid parameters were raised in FMiS-containing bone specimens (OV/BV, 2.1 ± 1.6 vs. 0.6 ± 0.3%; p < 0.001, OS/BS, 23.6 ± 15.5 vs. 7.6 ± 4.2%; p < 0.001, and O.Th, 7.4 µm ± 2.0 vs. 5.2 ± 1.0; p < 0.05). Our results showed that the modeling-based bone formation on trabecular bone surfaces occurs even during adulthood. As FMiSs can represent histological evidence of modeling-based bone formation, understanding of this physiology in relation to bone homeostasis is crucial.
ABSTRACT
PURPOSE: The aim of this study was to develop and evaluate a method for measuring the cortical bone thickness from computed tomography (CT) scans with metallic implants and to assess the benefits of metal artefact removal software. METHODS: A previously validated technique based on the fitting of a cortical model was modified to also model metal structures when required. Cortical thickness measurements were taken over intact bone segments and compared with the corresponding contralateral bone segment. The evaluation dataset includes post-operative CT scans of a unipolar hemi-arthroplasty, a dynamic hip screw fixation, a bipolar hemi-arthroplasty, a fixation with cannulated screws and a total hip arthroplasty. All CT scans were analysed before and after processing with metal artefact removal software. RESULTS: Cortical thickness validity and accuracy were improved through the use of a modified metalwork-optimised model and metal artefact removal software. For the proximal femoral segments of the aforementioned cases, the cortical thickness was measured with a mean absolute error of 0.55, 0.39, 0.46, 0.53 and 0.69 mm. The hemi-pelvis produced thickness errors of 0.51, 0.52, 0.52, 0.47 and 0.67 mm, respectively. CONCLUSIONS: The proposed method was shown to measure cortical bone thickness in the presence of metalwork at a sub-millimetre accuracy. This new technique might be helpful in assessing fracture healing near implants or fixation devices, and improve the evaluation of periprosthetic bone after hip replacement surgery.
Subject(s)
Arthroplasty, Replacement, Hip , Bone Screws , Cortical Bone/diagnostic imaging , Multidetector Computed Tomography/methods , Aged , Aged, 80 and over , Artifacts , Female , Femur , Humans , MaleABSTRACT
BACKGROUND: Hip fractures are mainly caused by accidental falls and trips, which magnify forces in well-defined areas of the proximal femur. Unfortunately, the same areas are at risk of rapid bone loss with ageing, since they are relatively stress-shielded during walking and sitting. Focal osteoporosis in those areas may contribute to fracture, and targeted 3D measurements might enhance hip fracture prediction. In the FEMCO case-control clinical study, Cortical Bone Mapping (CBM) was applied to clinical computed tomography (CT) scans to define 3D cortical and trabecular bone defects in patients with acute hip fracture compared to controls. Direct measurements of trabecular bone volume were then made in biopsies of target regions removed at operation. METHODS: The sample consisted of CT scans from 313 female and 40 male volunteers (158 with proximal femoral fracture, 145 age-matched controls and 50 fallers without hip fracture). Detailed Cortical Bone Maps (c.5580 measurement points on the unfractured hip) were created before registering each hip to an average femur shape to facilitate statistical parametric mapping (SPM). Areas where cortical and trabecular bone differed from controls were visualised in 3D for location, magnitude and statistical significance. Measures from the novel regions created by the SPM process were then tested for their ability to classify fracture versus control by comparison with traditional CT measures of areal Bone Mineral Density (aBMD). In women we used the surgical classification of fracture location ('femoral neck' or 'trochanteric') to discover whether focal osteoporosis was specific to fracture type. To explore whether the focal areas were osteoporotic by histological criteria, we used micro CT to measure trabecular bone parameters in targeted biopsies taken from the femoral heads of 14 cases. RESULTS: Hip fracture patients had distinct patterns of focal osteoporosis that determined fracture type, and CBM measures classified fracture type better than aBMD parameters. CBM measures however improved only minimally on aBMD for predicting any hip fracture and depended on the inclusion of trabecular bone measures alongside cortical regions. Focal osteoporosis was confirmed on biopsy as reduced sub-cortical trabecular bone volume. CONCLUSION: Using 3D imaging methods and targeted bone biopsy, we discovered focal osteoporosis affecting trabecular and cortical bone of the proximal femur, among men and women with hip fracture.
Subject(s)
Hip Fractures/etiology , Osteoporosis/complications , Aged , Area Under Curve , Biopsy , Cortical Bone/pathology , Female , Femur Neck/pathology , Hip Fractures/pathology , Humans , Male , Odds Ratio , Osteoporosis/pathology , ROC CurveABSTRACT
BACKGROUND: Teriparatide (TPTD) is an anabolic agent indicated for the treatment of severely osteoporotic patients who are at high risk of fragility fractures. The originally approved duration of TPTD treatment in several regions, including Europe, was 18 months. However, studies of areal bone mineral density (aBMD) showed additional benefit when treatment is continued beyond 18 months, and the drug is currently licenced for 24 months. Improvements in cortical structure at the proximal femur have already been shown in patients given TPTD for 24 months using quantitative computed tomography (QCT). Here, we investigate whether cortical and endocortical trabecular changes differ between an 18- and 24-month treatment. METHODS: Since an 18- versus 24-month TPTD study using QCT has not been conducted, we studied combined QCT data from four previous clinical trials. Combined femoral QCT data from three 18-month TPTD studies ('18-month group') were compared with data from a fourth 24-month trial ('24-month group'). Cortical parameters were measured over the entire proximal femur which allowed for a comparison of the mean changes as well as a visual comparison of the colour maps of changes after 18 and 24 months TPTD. RESULTS: For both the combined 18-month group and the 24-month group, overall cortical thickness and endocortical trabecular density increased, while overall cortical bone mineral density decreased. While the changes in the 24-month group were of greater magnitude compared to the 18-month group, the differences were only significant for the endocortical trabecular density (ECTD), corrected for age, weight, femoral neck T-score, total hip T-score and the baseline mean ECTD. CONCLUSION: Although the combination of data from different clinical trials is not optimal, these data support the concept that the duration of TPTD in the 18-24 month phase is of clinical relevance when considering improvement in hip structure.
Subject(s)
Femur/drug effects , Teriparatide/pharmacology , Aged , Bone Density/drug effects , Female , Femur/pathology , Femur/physiopathology , Humans , Middle Aged , Osteoporosis/drug therapy , Osteoporosis/pathology , Osteoporosis/physiopathology , Teriparatide/therapeutic use , Time FactorsABSTRACT
High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (â¼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (â¼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.
Subject(s)
Bone and Bones/pathology , Genetic Loci , Mutation/genetics , Adult , Aged , Case-Control Studies , Estrogen Replacement Therapy , Exons/genetics , Female , Humans , Male , Menopause , Middle Aged , Models, Molecular , Organ Size , Phenotype , Young AdultABSTRACT
OBJECTIVE: To assess the relationship between proximal femoral cortical bone thickness and radiological hip osteoarthritis using quantitative 3D analysis of clinical computed tomography (CT) data. METHODS: Image analysis was performed on clinical CT imaging data from 203 female volunteers with a technique called cortical bone mapping (CBM). Colour thickness maps were created for each proximal femur. Statistical parametric mapping was performed to identify statistically significant differences in cortical bone thickness that corresponded with the severity of radiological hip osteoarthritis. Kellgren and Lawrence (K&L) grade, minimum joint space width (JSW) and a novel CT-based osteophyte score were also blindly assessed from the CT data. RESULTS: For each increase in K&L grade, cortical thickness increased by up to 25 % in distinct areas of the superolateral femoral head-neck junction and superior subchondral bone plate. For increasing severity of CT osteophytes, the increase in cortical thickness was more circumferential, involving a wider portion of the head-neck junction, with up to a 7 % increase in cortical thickness per increment in score. Results were not significant for minimum JSW. CONCLUSIONS: These findings indicate that quantitative 3D analysis of the proximal femur can identify changes in cortical bone thickness relevant to structural hip osteoarthritis. KEY POINTS: ⢠CT is being increasingly used to assess bony involvement in osteoarthritis ⢠CBM provides accurate and reliable quantitative analysis of cortical bone thickness ⢠Cortical bone is thicker at the superior femoral head-neck with worse osteoarthritis ⢠Regions of increased thickness co-locate with impingement and osteophyte formation ⢠Quantitative 3D bone analysis could enable clinical disease prediction and therapy development.
Subject(s)
Femur Head/pathology , Femur Neck/pathology , Imaging, Three-Dimensional/methods , Osteoarthritis, Hip/pathology , Tomography, X-Ray Computed/methods , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Osteoarthritis, Hip/diagnostic imaging , Osteophyte/diagnostic imaging , Osteophyte/pathology , Risk Factors , Severity of Illness IndexABSTRACT
Hip fracture risk is known to be related to material properties of the proximal femur, but fracture prediction studies adding richer quantitative computed tomography (QCT) measures to dual-energy X-ray (DXA)-based methods have shown limited improvement. Fracture types have distinct relationships to predictors, but few studies have subdivided fracture into types, because this necessitates regional measurements and more fracture cases. This work makes use of cortical bone mapping (CBM) to accurately assess, with no prior anatomical presumptions, the distribution of properties related to fracture type. CBM uses QCT data to measure the cortical and trabecular properties, accurate even for thin cortices below the imaging resolution. The Osteoporotic Fractures in Men (MrOS) study is a predictive case-cohort study of men over 65 years old: we analyze 99 fracture cases (44 trochanteric and 55 femoral neck) compared to a cohort of 308, randomly selected from 5994. To our knowledge, this is the largest QCT-based predictive hip fracture study to date, and the first to incorporate CBM analysis into fracture prediction. We show that both cortical mass surface density and endocortical trabecular BMD are significantly different in fracture cases versus cohort, in regions appropriate to fracture type. We incorporate these regions into predictive models using Cox proportional hazards regression to estimate hazard ratios, and logistic regression to estimate area under the receiver operating characteristic curve (AUC). Adding CBM to DXA-based BMD leads to a small but significant (p < 0.005) improvement in model prediction for any fracture, with AUC increasing from 0.78 to 0.79, assessed using leave-one-out cross-validation. For specific fracture types, the improvement is more significant (p < 0.0001), with AUC increasing from 0.71 to 0.77 for trochanteric fractures and 0.76 to 0.82 for femoral neck fractures. In contrast, adding DXA-based BMD to a CBM-based predictive model does not result in any significant improvement.
Subject(s)
Bone and Bones/pathology , Hip Fractures/complications , Hip Fractures/diagnosis , Osteoporotic Fractures/complications , Osteoporotic Fractures/diagnosis , Aged , Area Under Curve , Humans , Male , Models, Biological , Odds Ratio , ROC Curve , Reproducibility of ResultsABSTRACT
Regular exercisers have lower fracture risk, despite modest effects of exercise on bone mineral content (BMC). Exercise may produce localized cortical and trabecular bone changes that affect bone strength independently of BMC. We previously demonstrated that brief, daily unilateral hopping exercises increased femoral neck BMC in the exercise leg versus the control leg of older men. This study evaluated the effects of these exercises on cortical and trabecular bone and its 3D distribution across the proximal femur, using clinical CT. Fifty healthy men had pelvic CT scans before and after the exercise intervention. We used hip QCT analysis to quantify BMC in traditional regions of interest and estimate biomechanical variables. Cortical bone mapping localized cortical mass surface density and endocortical trabecular density changes across each proximal femur, which involved registration to a canonical proximal femur model. Following statistical parametric mapping, we visualized and quantified statistically significant changes of variables over time in both legs, and significant differences between legs. Thirty-four men aged mean (SD) 70 (4) years exercised for 12-months, attending 92% of prescribed sessions. In traditional regions of interest, cortical and trabecular BMC increased over time in both legs. Cortical BMC at the trochanter increased more in the exercise than control leg, whereas femoral neck buckling ratio declined more in the exercise than control leg. Across the entire proximal femur, cortical mass surface density increased significantly with exercise (2.7%; p < 0.001), with larger changes (> 6%) at anterior and posterior aspects of the femoral neck and anterior shaft. Endocortical trabecular density also increased (6.4%; p < 0.001), with localized changes of > 12% at the anterior femoral neck, trochanter, and inferior femoral head. Odd impact exercise increased cortical mass surface density and endocortical trabecular density, at regions that may be important to structural integrity. These exercise-induced changes were localized rather than being evenly distributed across the proximal femur.