3-D joint space mapping at the ankle from weight-bearing CT: reproducibility, repeatability, and challenges for standardisation.

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.

Phosphaturic Mesenchymal Tumor of the Ankle: A Case Report and Review of the Literature.

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.

Quantitative Three-dimensional Assessment of Knee Joint Space Width from Weight-bearing CT.

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.

Identification of novel pathogenic variants and features in patients with pseudohypoparathyroidism and acrodysostosis, subtypes of the newly classified inactivating PTH/PTHrP signaling disorders.

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.

Quantitative 3D analysis of bone in hip osteoarthritis using clinical computed tomography.

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.

Deep learning-based quantification of osteonecrosis using magnetic resonance images in Gaucher disease.

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.

Buds of new bone formation within the Femoral Head of Hip Fracture Patients Coincide with Zones of Low Osteocyte Sclerostin.

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).

PHOENIX (Picking up Hidden Osteoporosis Effectively during Normal CT Imaging without additional X-rays): protocol for a randomised, multicentre feasibility study.

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.

Digital health interventions for osteoporosis and post-fragility fracture care.

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.

A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.

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.

Increased development of radiographic hip osteoarthritis in individuals with high bone mass: a prospective cohort study.

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.

Opportunistic diagnosis of osteoporosis, fragile bone strength and vertebral fractures from routine CT scans; a review of approved technology systems and pathways to implementation.

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.

Evidence for Ongoing Modeling-Based Bone Formation in Human Femoral Head Trabeculae via Forming Minimodeling Structures: A Study in Patients with Fractures and Arthritis.

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.

A single infusion of zoledronate prevents bone loss after stroke.

BACKGROUND AND PURPOSE: Stroke is a major risk factor for hip fracture. Patients with intermediate rather than severe or mild stroke deficits at the time of hospital discharge have the most fractures. This proof-of-concept study evaluated the efficacy of a single infusion of zoledronate, an intravenous bisphosphonate, in preserving hip bone density after stroke. METHODS: In a 1-year randomized, double-blind, placebo-controlled, clinical trial, 27 newly hemiplegic patients (6 females, 21 males) with acute stroke were assigned to receive 4 mg of the intravenous zoledronate (n=14) or placebo (n=13) within 35 days. Strict inclusion criteria were followed-up to ensure recruited patients were likely to have residual functional impairment. Both groups received calcium and vitamin D supplementation. The primary outcome measure was the change in bone mineral density (BMD; Lunar Prodigy) at the hemiplegic hip during the year of investigation. RESULTS: The treatment was generally well tolerated. Mean total hip BMD was unchanged in the hemiplegic hip of the zoledronate group (mean 0.0% change), whereas in the placebo group the total hip BMD changed by -5.5%, with the greatest bone loss observed in the trochanteric subregion (mean, -8.1%). On the unaffected side the mean change in total hip BMD was +1.0% with zoledronate versus a mean change of -2.7% without. Repeated measures ANOVA confirmed the significance of the differences between groups at both hips (hemiplegic, P<0.001; unaffected, P=0.002). CONCLUSIONS: Stroke patients were protected from the deleterious effects of hemiplegia on hip bone density for at least 1 year after a single infusion of zoledronate.

An exploratory study into measuring the cortical bone thickness from CT in the presence of metal implants.

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.

Focal osteoporosis defects play a key role in hip fracture.

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.

Reduced vitamin D in acute stroke.

BACKGROUND AND PURPOSE: Stroke leads to a reduction in bone mineral density, altered calcium homeostasis, and an increase in hip fractures. Vitamin D deficiency is well documented in long-term stroke survivors and is associated with post-stroke hip fractures. Less is known regarding levels in acute stroke. METHODS: We compared the serum 25-dihydroxyvitamin D levels of 44 patients admitted to an acute stroke unit with first-ever stroke with results obtained by measuring 96 healthy ambulant elderly subjects every 2 months for 1 year. Statistical Z scores of serum vitamin D were then calculated after seasonal adjustment for the month of sampling. RESULTS: The mean Z score of vitamin D in acute stroke was -1.4 SD units (95% CI, -1.7, -1.1), with 77% of patients falling in the insufficient range. CONCLUSIONS: Reduced vitamin D was identified in the majority of patients with acute stroke throughout the year and may have preceded stroke. Vitamin D is a potential risk marker for stroke, and the role of vitamin D repletion in enhancing musculoskeletal health after stroke needs to be explored.

Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation.

Osteocytes are the most abundant cells in bone and are ideally located to influence bone turnover through their syncytial relationship with surface bone cells. Osteocyte-derived signals have remained largely enigmatic, but it was recently reported that human osteocytes secrete sclerostin, an inhibitor of bone formation. Absent sclerostin protein results in the high bone mass clinical disorder sclerosteosis. Here we report that within adult iliac bone, newly embedded osteocytes were negative for sclerostin staining but became positive at or after primary mineralization. The majority of mature osteocytes in mineralized cortical and cancellous bone was positive for sclerostin with diffuse staining along dendrites in the osteocyte canaliculi. These findings provide for the first time in vivo evidence to support the concept that osteocytes secrete sclerostin after they become embedded in a mineralized matrix to limit further bone formation by osteoblasts. Sclerostin did not appear to influence the formation of osteocytes. We propose that sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces. In doing so, sclerostin may act as a key inhibitory signal governing skeletal microarchitecture.

Parathyroid hormone - a bone anabolic and catabolic agent.

A key factor in the control of bone remodelling is parathyroid hormone (PTH), the principal regulator of calcium homeostasis. Elevated levels of PTH increase bone turnover, leading to either anabolic or catabolic effects on the skeleton depending upon the pattern and duration of elevation. New evidence indicating that downregulation of an osteocyte signal (sclerostin, the SOST gene product) occurs in response to intermittent PTH has rekindled interest in the key role played by osteocytes and bone-lining cells in co-ordinating surface anabolic activity. Microarray analysis has also delineated many genes and pathways regulated by intermittent and continuous PTH in osteoblasts and whole bones.

The Effects on the Femoral Cortex of a 24 Month Treatment Compared to an 18 Month Treatment with Teriparatide: A Multi-Trial Retrospective Analysis.

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.