Bone marrow Fat - A Novel Quantification Method and Potential Clinical Applications

Ageing bone is characterised by increased marrow fat infiltration altering its composition and microstructure, thus predisposing the person to osteoporosis. Yet to date, non-invasive quantifications of marrow fat are limited to special MRI techniques, and clinical studies examining marrow fat in the ageing skeleton are scarce. Thus, the key aims of this thesis are to: · Validate a new non-invasive technique of marrow fat quantification using CT technology · Determine the effects of dietary fatty acids on marrow fat · Measure marrow fat content in different skeletal regions in healthy older men · Determine the effect of exercise and calcium on marrow fat. The imaging techniques employed in our animal and human studies were micro CT (µCT) and quantitative CT (QCT) respectively. All images were analysed with the imaging software Slice O Matic version 4.1 (Tomovision). Regions of interest [ROIs] were Volumes of interests (VOIs) of bone, fat and blood measured in µm3 or mm3. Individual tissue volumes, expressed as percentages of the total marrow volume, and ratios of tissue volumes were also used in the analysis. Global and local thresholds for individual tissue volumes were determined separately for µCT and QCT. Thresholds for µCT were those derived from the initial validation study, whereas those for QCT were based on previous published data. To account for partial volume averaging effects, further manual refinement of threshold ranges were undertaken by inspection of individual pixels and their neighbours. This manual process was carried out for both µCT and QCT to derive local thresholds for use in manual segmentation and computation of volumes. Our validation study showed that quantification of marrow fat using µCT was reliable and accurate compared to the gold standard technique- histology- when reliably defined thresholds were used. Good agreement between tissue volumes measured by histology and those computed by the imaging software was demonstrated. We applied this technique to quantify marrow fat in an animal model of senile osteoporosis, and showed that fatty acids (ω- 3 and ω-6) had dual effects on bone. With QCT studies, we confirmed the age related increase in marrow adiposity, and more significantly, different ratios between fat and bone in common fracture regions. Similarly, exercise affects marrow fat differently in different regions, and there was a trend to statistically significant changes to marrow fat with exercise. In conclusion, this body of work showed that quantification of marrow fat using CT is promising, and has future clinical implications. However, significantly more clinical studies are needed to confirm these findings and refine shortfalls in quantification capabilities

Once-yearly zoledronic acid in hip fracture prevention

Osteoporosis is an escalating global problem. Hip fractures, the most catastrophic complication of osteoporosis, continue to cause significant mortality and morbidity despite increasing availability of effective preventative agents. Among these agents, oral bisphosphonates have been the first choice for the treatment and prevention of osteoporotic fractures. However, the use of oral bisphosphonates, especially in the older population, has been limited by their side effects and method of administration thus compromising their persistent use. The resultant low adherence by patients has undermined their full potential and has been associated with an increase in the incidence of fragility fractures. Recently, annual intravenous zoledronic acid (ZOL) has been approved for osteoporosis. Randomized controlled trials have demonstrated ZOL to be safe, have good tolerability and produce significant effect on bone mass and microarchitecture. Adherence has also been shown to be better with ZOL. Furthermore two large trials firmly demonstrated significant anti-osteoporotic effect (∼59% relative risk reduction of hip fractures) and mortality benefit (28% reduction in mortality) of ZOL in older persons with recent hip fractures. In this review, we report the current evidence on the use of ZOL for the prevention of hip fractures in the elderly. We also report the pharmacological characteristics and the advantages and disadvantages of ZOL in this particular group

Clinical outcomes of impaired muscle and bone interactions

Muscle and bone are in constant interaction. With aging, there is a progressive decline in muscle mass, known as sarcopenia, as well as in bone mass, which is known as osteopenia/osteoporosis. Sarcopenia and osteoporosis increase the risk of suffering falls and fractures, respectively. In fact, the simultaneous occurrence of osteoporosis and sarcopenia has been observed in a subset of frailer individuals at higher risk of disability, falls and fractures. However, the particular clinical outcomes that are unique to the sarco-osteoporotic patients remain unknown. In this review, we propose a common mechanism of sarco-osteoporosis and summarize those clinical and biochemical features that are prevalent in sarco-osteoporotic subjects. We expect that by describing a set of biological, clinical and functional characteristics that are associated with sarco-osteoporosis, this information could be used to inform the design of future trials and to develop interventions for this particular syndrome

The effect of dietary fatty acids on bone marrow fat in a murine model of senile osteoporosis

Sponsor(s):Amer Geriatr Soc ; Supplement: 1INTRODUCTION: Aging induces high levels of marrow fat infiltration, which have a deleterious effect on bone mass. In contrast, fatty acids may exert protective effects on bone. Nevertheless, mechanisms and potential regulation of these phenomena remain poorly understood. AIM: To analyse the changes in bone parameters and fat distribution induced by different dietary fatty acids in a murine model of senile osteoporosis. METHODS: Two-month-old senescence accelerated P8 (SAMP8) mice and their SAMR1 normal controls were divided in different groups (n=20/group) and subjected to the following diets: (1) standard "growth"; (2) "sunflower" (high 6/ 3 ratio); (3) borage (high linoleic acid); (4) "fish" (high in long 3). Mice were fed ad-libitum for 10 months and then euthanized for bone and fat investigation using microCT technologies. CT scan images were analysed by SliceOmatic (Tomovision™, Montreal, Canada). Images were blind-assessed by two evaluators. Hundred slices of the region of interest were selected for each mouse. Total marrow fat volume was determined and compared to changes in bone mass and total body and visceral adipose weights. RESULTS: Whereas sunflower diet exacerbated bone loss, fish and borage diets countered bone alteration in SAMP8 osteoporotic mice (p<0.05). This protection of bone parameters was associated with a significant raise in total body weight and visceral fat volumes for the group fed the fish diet and with a non-significant change in marrow fat volume in all of the SAMP8 groups. CONCLUSION: Dietary regulation of bone mass by borage and fish oils is independent of an effect on marrow fat volume being most likely associated with their direct effect on other bone cells or by regulating fat-secreted factors. Due to their bone-protective effect, borage and fish diet could constitute a new nutritional strategy to prevent age-related bone loss in the near future

Yield and cost-effectiveness of laboratory testing to identify metabolic contributors to falls and fractures in older persons

Summary: Falls and fractures constitute a major cause of morbidity and mortality among older adults. Although falls and fractures share similar risk factors, there is no integrated approach to identifying secondary causes of both entities. We report a cost-effective approach to identify metabolic causes of falls and fractures in the clinical setting. Purpose: Falls and fractures are a major cause of morbidity and mortality among older adults. Metabolic disorders contributing to the combined risk of falls and fractures are frequent but often go undetected. The most efficient and cost-effective laboratory screening strategy to unmask these disorders remains unknown. The purpose of this study was to identify the most cost-effective laboratory tests to detect undiagnosed metabolic contributors and to decide treatment of these disorders in older persons. Methods: This is a cross-sectional study design, which included all participants attending the Falls & Fractures Clinic, Nepean Hospital (Penrith, Australia) between 2008 and 2013. Chemistry profile included 25(OH) vitamin D, parathyroid hormone (PTH), albumin, creatinine, calcium, phosphate, vitamin B-12, folate, and thyroid-stimulating hormone (TSH) for all patients, and serum testosterone in men. The number of new diagnoses identified and their cost-effectiveness (cost in US$per patient screened and cost per new diagnosis) were calculated. Results: A total of 739 participants (mean age 79, 71$190.19 per patient screened and $257.64 per diagnosis. Conclusions: The minimum cost-effective battery for occult metabolic disorders in older adults at risk of falls and fractures should include serum vitamin D, PTH, TSH, creatinine/eGFR, testosterone (in men), and calcium

Comprehensive nutritional status in sarco-osteoporotic older fallers

Objectives: In older persons, the combination of osteoporosis and sarcopenia has been proposed as a subset of frailer individuals at higher risk of falls and fractures. However, the particular nutritional status of the sarco-osteoporotic (SOP) patients remains unknown. The goal of this study was to obtain a comprehensive picture of nutritional status in SOP patients. Design: Cross-sectional study. Setting: Falls & Fractures Clinic, Nepean Hospital (Penrith, Australia). Participants: 680 subjects (mean age=79, 65% female) assessed between 2008–2013. Measurements: Assessment included medical history, mini-nutritional assessment, physical examination, bone densitometry and body composition by DXA, and blood tests for nutritional status (albumin, creatinine, hemoglobin, vitamin D, vitamin B-12, calcium, phosphate and folate). Patients were divided in 4 groups: 1) osteopenia/osteoporosis (BMD6 remained independently associated with SOP after adjustment for all variables including inflammatory conditions. Hypoalbuminemia (<35 g/L) was associated with just osteopenia/osteoporosis (OR: 2.03, 95%CI 1.08–3.81, p<0.01) and just sarcopenia (OR: 1.77, 95%CI 1.0–3.0, p<0.01) compared to normal. No differences in vitamin D, glomerular filtration rate, albumin, corrected calcium, phosphate, red blood cells folate or vitamin B12 levels were found between the subgroups. Conclusions: In approaching SOP patients, early prevention protocols directed to optimize their nutritional status would be a key strategy to prevent poor outcomes such as falls and fractures in this high risk population. Therefore, nutritional assessment and early nutritional supplementation should be essential domains in this strategy

Phenotype of sarcopenic obesity in older individuals with a history of falling

Background: Although sarcopenic obesity is associated with disability in middle-aged community-dwelling individuals, the phenotype of sarcopenic obesity in people 65 and older, especially those with a history of falls, remain unknown. To fill this knowledge gap, the goal of this study was to obtain a comprehensive phenotype of sarcopenic obesity in this high-risk population. Methods: Cross-sectional study of 680 subjects (mean age = 79 +/- 9, 65% female) assessed between 2009 and 2013 at the Falls and Fractures Clinic, Nepean Hospital (Penrith, Australia). The assessment included a comprehensive examination, posturography, gait velocity, grip strength, bone densitometry and body composition by DXA, and blood tests for biochemical status. Patients were divided into four groups based on DXA and clinical criteria: 1) sarcopenic obese; 2) non-sarcopenic obese; 3) sarcopenic and; 4) non-sarcopenic/non-obese. The difference between groups was assessed by one-way ANOVA, chi-square analysis, and multivariable linear regression. Results: Sarcopenic obese subjects were older (81.1 +/- 7.3), mostly female and more likely to have lower bone mineral density, lower grip strength, slower gait velocity, and poor balance. Sarcopenic obese individuals also showed significantly higher parathyroid hormone and lower vitamin D. Conclusions: We identified a particular set of clinical and biochemical characteristics in our subgroup of sarcopenic obese older fallers. Identification of these particular characteristics in the clinical setting is essential in order to prevent poor outcomes in this high-risk population

Vitamin D status in relation to postural stability in the elderly

Objectives: Postural instability (PI) is an important risk factor for falls, especially in the frail older population. In this study, we investigated the impact of vitamin D deficiency on PI in a sample of community dwelling older subjects. Our objective was to determine the potential association between vitamin D deficiency and PI in older fallers. Design: Cross-sectional study. Setting: Falls and Fractures Clinic, Department of Geriatric Medicine, Nepean Hospital, Penrith, Australia. Participants: One hundred and forty-five adults aged 65 years and older who have had at least one episode of a fall within the six months prior to assessment at the Falls and Fractures Clinic. Measurements: Serum 25(OH) vitamin D3 [25(OH)D3] and parathyroid hormone concentrations were determined at baseline. Subjects were separated into 3 groups based on serum 25(OH)D3 levels with the following cut-off values: 50 nmol/L (normal). Other baseline measurements included body mass index, mini-nutritional assessment, grip strength, serum calcium concentration and creatinine clearance, which were used as covariables. PI was assessed using a computerized virtual reality system (Medicaa, Uruguay). Measured parameters included limits of stability (LOS) and centre of pressure (COP) under eyes closed on foam (ECF) and visio-vestibular stimulation. The estimated swaying area, computed from the ellipse of confidence under eyes closed standing on foam (ECF), was also used as a PI parameter. Gait velocity (GV) was measured using a GaitRITE walkway system. Results: Posture was impaired in vitamin D deficiency (<30 nmol/L) as indicated by lower LOS (90 +/- 18), higher ECF (25 +/- 10) and slower GV (55 +/- 7) as compared with the insufficient and normal groups. After adjustment for demographic, biochemical and anthropometric variables, vitamin D deficiency significantly correlated with low LOS and high COP under ECF. Conclusion: Low levels of vitamin D were associated with PI. This association could also have an effect on slow GV and increased risk of falls. In conclusion, using an objective method to measure balance in older fallers we have identified a novel role of vitamin D in balance control. Prospective studies are required to confirm the effect of vitamin D on PI and elucidate the mechanisms of this association

Effects of balance training using a virtual-reality system in older fallers

Poor balance is considered a challenging risk factor for falls in older adults. Therefore, innovative interventions for balance improvement in this population are greatly needed. The aim of this study was to evaluate the effect of a new virtual-reality system (the Balance Rehabilitation Unit [BRU]) on balance, falls, and fear of falling in a population of community-dwelling older subjects with a known history of falls. In this study, 60 community-dwelling older subjects were recruited after being diagnosed with poor balance at the Falls and Fractures Clinic, Nepean Hospital (Penrith, NSW, Australia). Subjects were randomly assigned to either the BRU-training or control groups. Both groups received the usual falls prevention care. The BRU-training group attended balance training (two sessions/week for 6 weeks) using an established protocol. Change in balance parameters was assessed in the BRU-training group at the end of their 6-week training program. Both groups were assessed 9 months after their initial assessment (month 0). Adherence to the BRU-training program was 97%. Balance parameters were significantly improved in the BRU-training group (P < 0.01). This effect was also associated with a significant reduction in falls and lower levels of fear of falling (P < 0.01). Some components of balance that were improved by BRU training showed a decline after 9 months post-training. In conclusion, BRU training is an effective and well-accepted intervention to improve balance, increase confidence, and prevent falls in the elderly