Marrow Fat Content Research Articles

Diffusion tensor imaging and magnetic resonance spectroscopy assessment of cancellous bone quality in femoral neck of healthy, osteopenic and osteoporotic subjects at 3T: Preliminary experience

We assessed the potential of diffusion tensor imaging (DTI) in combination with proton magnetic resonance spectroscopy (1H-MRS), in cancellous bone quality evaluation of the femoral neck in postmenopausal women. IntroductionDTI allows for non-invasive microarchitectural characterization of heterogeneous tissue. In this work we hypothesized that DTI parameters mean diffusivity (MD) and fractional anisotropy (FA) of bone marrow water, can provide information about microstructural changes that occur with the development of osteoporosis disease. Because osteoporosis is associated with increased bone marrow fat content, which in principal can alter DTI parameters, the goal of this study was to examine the potential of MD and FA, in combination with bone marrow fat fraction (FF), to discriminate between healthy, osteopenic and osteoporotic subjects, classified according to DXA criteria. Materials and methodsForty postmenopausal women (mean age, 68.7years; range 52–81years), underwent a Dual-energy X-ray absorptiometry (DXA) examination in femoral neck, to be classified as healthy (n=12), osteopenic (n=14) and osteoporotic (n=14) subjects. 1H-MRS and DTI (with b value=2500s/mm2) of femoral neck were obtained in each subject at 3T. The study protocol was approved by local Ethics Committee. MD, FA, FF and MD/FF, FA/FF were obtained and compared among the three bone-density groups.One-way ANOVA with multiple comparisons Bonferroni test and Pearson correlation analysis were applied. Receiver operating characteristic (ROC) curve analysis was also performed. ResultsReproducibility of DTI measures was satisfactory. CV was approximately 2%–3% for MD and 4%–5% for FA measurements. Moreover, no significant difference was found in both MD and FA measurements between two separate sessions (median 34days apart) comprised of six healthy volunteers.FF was able to discriminate between healthy and osteoporotic subjects only. Conversely MD and FA were able to discriminate healthy from osteopenic and healthy from osteoporotic subjects, but they were not able to discriminate between osteopenic and osteoporotic patients. A significant correlation between MD and FF was observed in healthy group only. A moderate correlation was found between MD and T-score when all groups together are considered. No significant correlation was found between MD and T-score within groups. A significant positive correlation between FA and FF was found in both osteopenic and osteoporotic groups. Vice-versa no correlation between FA and FF was observed in healthy group. A high significant positive correlation was found between FA and T-score in all groups together, in healthy and in osteoporotic groups. MD/FF and FA/FF are characterized by a higher sensitivity and specificity compared to MD and FA in the discrimination between healthy, and osteoporotic subjects.MD/FF vs FA/FF graph extracted from femoral neck, identify all healthy individuals according to DXA results. ConclusionDTI-1H-MRS protocol performed in femoral neck seems to be highly sensitive and specific in identifying healthy subjects.A MR exam is more expensive when compared to a DXA investigation. However, even though DXA BMD evaluation has been the accepted standard for osteoporosis diagnosis, DXA result has a low predictive value on patients' risk for future fractures. Thus, new approaches for examining patients at risk for developing osteoporosis would be desirable.Preliminary results showed here suggest that future studies on a larger population based on DTI assessment in the femoral neck, in combination with 1H-MRS investigations, might allow screening of high-risk populations and the establishment of cut-off values of normality, with potential application of the method to single subjects.

Molecular and functional characterization of human bone marrow adipocytes

Adipocytes are a cell population largely located in the human bone marrow cavity. In this specific microenvironment where adipocytes can interact with a variety of different cells, the role of fat is mainly unknown. To our knowledge, this report is the first to characterize mature adipocytes isolated from human bone marrow (BM-A) molecularly and functionally to better understand their roles into the hematopoietic microenvironment. Healthy BM-A were isolated after collagenase digestion and filtration. We studied the morphology of BM-A, their gene expression and immunophenotypic profile and their functional ability in the hematopoietic microenvironment, comparing them with adipocytes derived from adipose tissue (AT-A). BM-A showed a unilocular lipid morphology similar to AT-A and did not lose their morphology in culture; they showed a comparable pattern of stem cell-surface antigens to AT-A. In line with these observations, molecular data showed that BM-A expressed some embryonic stem cells genes, such as Oct4, KLf4, c-myc, Gata4, Tbx1, and Sox17, whereas they did not express the stem cell markers Sox2 and Nanog. Moreover, BM-A had long telomeres that were similar to bone marrow mesenchymal stem cells. Notably, BM-A supported the survival and differentiation of hematopoietic stem cells in long-term cultures. These results showed that BM-A are stromal cells with a gene expression pattern that distinguished them from AT-A. BM-A showed stem cell properties through their hematopoietic supporting function, which was certainly linked to their role in the maintenance of the bone marrow microenvironment. Depending on specific demands, BM-A may acquire different functions based on their local environment.

Computerized quantification of bone tissue and marrow in stained microscopic images

Stained histological images assist physicians to identify different types of tissues or cells and their architectures. They can be applied on the diagnosis of various diseases and the assessment of treatment effects. Osteoporosis is an aging disease that reduces the density of bones and increases the risk of bone fracture. Literatures indicate that osteoporosis is associated with the ratio of trabecular bone tissues and bone marrow cells, and bones in osteoporosis patients consist of a significantly higher marrow fat content. Interactive segmentation of bone tissue and different types of bone marrow cells in high-resolution histological images, however, is a very tedious and labor-intensive process. The aim of this study is to develop an automatic algorithm to quantify the areas of different tissues such as the trabecular bones and yellow and red marrow cells. This image segmentation method consists of a series of mathematical morphological operation steps based on both the color and morphology features of tissues and was implemented in Matlab. The results obtained from the proposed method have been verified by comparing with those obtained interactively from an experienced histotechnician (Pearson correlation coefficient > 0.94, P < 0.001). The result suggests that the proposed algorithm can effectively assist physicians to quantify stained bone histological images.

Bone marrow fat content in the elderly: A reversal of sex difference seen in younger subjects

To investigate vertebral bone marrow fat content in elderly subjects related to sex, age, and bone mineral density (BMD) and relate these findings to published data in younger subjects. A total of 259 healthy subjects (145 females, 114 males; age range, 62-90 years) underwent proton ((1) H) MR spectroscopy of L3 vertebral body and BMD of the lumbar spine with results stratified according to age. Ninety age- and BMD-matched subjects were selected to determine sex differences in marrow fat content and BMD. In females, vertebral marrow fat content rose sharply between 55 and 65 years of age while in males vertebral marrow fat content rose gradually throughout life. Vertebral marrow fat content in females more than 60 years was approximately 10% higher in females than males, i.e., a reversal of sex difference reported in marrow fat content for subjects less than 60 years. Marrow fat content increases sharply in female subjects between 55 and 65 years of age while male subjects continue to increase marrow fat at a more gradual steady rate. Females older than 60 years have a higher marrow fat content than males. This increased deposition in marrow fat concurs with recognized changes in extraosseous fat distribution in postmenopausal females.

Implications of body condition on the unsustainable predation rates of endangered mountain caribou

Both top-down and bottom-up processes influence herbivore populations, and identifying dominant limiting factors is essential for applying effective conservation actions. Mountain caribou are an endangered ecotype of woodland caribou (Rangifer tarandus caribou) that have been declining, and unsustainable predation has been identified as the proximate cause. To investigate the role of poor nutrition, we examined the influence of sex, season, age class, and available suitable habitat (i.e., old-growth forest>140 years) per caribou on bone marrow fat content of caribou that died (n = 79). Sex was the only strong predictor of marrow fat. Males that died during and post rut had lower marrow fat than females or males at other times of year. Old-growth abundance per caribou, season, and age class did not predict marrow fat. Caribou killed by predators did not have less marrow fat than those that died in accidents, suggesting that nutritionally stressed caribou were not foraging in less secure habitats or that predators selected nutritionally stressed individuals. Marrow fat in endangered and declining populations of mountain caribou was similar to caribou in other, more viable populations. Our results support previous research suggesting that observed population declines of mountain caribou are due to excessive predation that is not linked to body condition.

Bone marrow fat quantification of osteoporotic vertebral compression fractures: comparison of multi-voxel proton MR spectroscopy and chemical-shift gradient-echo MR imaging

Only a few studies have used in/opposed phase method for a quantitative evaluation of fat fraction in the spine. To compare multivoxel proton MR spectroscopy and chemical-shift gradient-echo MR imaging for bone marrow fat quantification in vertebral compression fractures (VCF). Vertebral marrow fat quantification in fifteen patients was measured at 3.0-T. Multi-voxel proton spectroscopy (MRS) and in/opposed-phase MR imaging using a fat map build with a triple-echo gradient-echo sequence was used. All the patients had benign vertebral collapse. Bone marrow fat content was evaluated by both techniques in compressed (acute or chronic) and in non-compressed vertebrae. The percentage of fat fraction measured by the triple-echo sequence was well correlated with those calculated by MRS (r(2) = 0.85; P < 10(-4)). There was a significant decrease of fat fraction in acute VCF versus both chronic VCF (P < 10(-9)) and non-fractured vertebrae (P < 10(-7)). There was no significant difference in fat fraction evaluated by both techniques between non-fractured vertebrae and chronic VCF. We have validated the in/opposed phase method compared with MRS for vertebral bone marrow fat quantification. The fat mapping using a triple-echo gradient-echo sequence allows distinguishing acute and chronic benign VCF.

Dynamic evaluation of an osteoporosis rabbit model induced by ovariectomy and glucocorticoid with MR spectroscopy and micro-CT

Objective To dynamically assess the regular pattern of both bone quantity and bone quality by means of MR spectroscopey and Micro-CT scanning in an osteoporosis rabbit model induced by ovariectomy and glucocorticoid, so as to explore the advantage of combining MRS with Micro-CT. Methods Sixty 8-month-old,mature female New Zealand white rabbits were allocated into three groups. Group B ( n =20 ) underwent bilateral ovariectomy (OVX) and Group C (n =20 ) underwent OVX combining with daily i. m. injections of methylprednisolone sodium succinate (MPS). Group A ( n =20 ) were used as sham controls. Bone marrow fat fraction (FF) and bone microstructure parameters were detected by MR spectroscopy and Micro-CT scanning at 2,4,8, and 10 weeks ( 5 rabbits at each time point every group) after operation in three groups. Results Lumber spine bone marrow FF in Group C was significantly increased over the time course of osteoporosis development with significant difference between Group C and Group A at 4,8,and 10 weeks after operation( all P＜0. 01 ). Bone mineral density(BMD) in Group C at 8 and 10 weeks after OVX was significantly decreased compared with Group A ( P＜0. 0l ). A moderately significant negative correlation between marrow fat content and bone microstructure parameters such as BMD, bone volume fraction, trabecular thickness, connectivity density, and trabecular plate number was found, while FF was positively correlated with structure model index and trabecular spacing( all P＜0. 01 ). Conclusions MRS and MicroCT scanning noninvasively evaluate the bone marrow changes of osteoporosis in the field of pathophysiology and microstructure. Combination of both modalities seems to be valuable in the early, comprehensive assessment of bone quality and bone mass in osteoporosis. Key words: Osteoporosis; Model, rabbit; Magnetic resonance spectroscope ; Micro-CT

Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging

Hematological deficiencies increase with aging, including anemias, reduced responses to hematopoietic stress and myelodysplasias. This investigation tested the hypothesis that increased bone marrow (BM) fat content in humans with age was associated with decreased numbers of side population (SP) hematopoietic stem cells, and this decrease correlated with changes in cytokine levels. BM was obtained from the femoral head and trochanteric region of the femur removed at surgery for total hip replacement (N = 100 subjects). In addition, BM from cadavers (N = 36), with no evidence of hip disease, was evaluated for fat content. Whole trabecular marrow samples were ground in a sterile mortar and pestle, and cellularity and lipid content determined. Marrow cells were stained with Hoechst dye and SP profiles were acquired. Plasma levels of insulin-like growth factor (IGF)-1, stromal-derived factor (SDF)-1 and interleukin (IL)-6 were measured using ELISA. Fat content in the BM of human subjects and cadavers increased with age. The numbers of SP stem cells in BM as well as plasma IGF-1 and SDF-1 levels decreased in correlation with increased BM fat. IL-6 had no relationship to changes in marrow fat. These data suggest that increased BM fat may be associated with a decreased number of SP stem cells and IGF-1 and SDF-1 levels with aging. These data further raise a more general question as to the role of adipose cells in the regulation of tissue stem cells.

Aspectos óseos de la enfermedad de Gaucher

The exposition aims, is to review the pathophysiological mechanisms of bone marrow involvement and the patterns of marrow infiltration by Gaucher cells. We have reviewed the different methods of assessment of bone marrow infiltration and its temporal development. Qualitative methods include simple radiography, magnetic resonance imaging (MRI), computed tomography (CT) and radioisotope. The simple radiography is the basic element, but its sensitivity is limited and only allows for assessing changes and trabecular bone remodeling MRI allows us to appreciate the bone marrow infiltration, detection of complications and response to therapy. Radioisotopes can contribute to the differential diagnosis of osteomyelitis and bone crises. Among the quantitative methods are the QCSI (quantitative chemical shift imaging) and the dual-energy X-ray absorptiometry (DEXA), as well as new quantitative techniques of CT, MRI and ultrasound densitometry. The QCSI performed an assessment of fat content of bone marrow in the spine. DEXA quantifies bone density by measuring the attenuation coefficient. The semiquantitative methods have various “scores” to establish criteria for generalized bone disease endpoints of disease progression and response to therapy.

Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus?

To compare vertebral bone marrow fat content quantified with proton MR spectroscopy ((1)H-MRS) with the volume of abdominal adipose tissue, lumbar spine volumetric bone mineral density (vBMD), and blood biomarkers in postmenopausal women with and without type 2 diabetes mellitus (T2DM). Thirteen postmenopausal women with T2DM and 13 age- and body mass index-matched healthy controls were included in this study. All subjects underwent (1)H-MRS of L1-L3 to quantify vertebral bone marrow fat content (FC) and unsaturated lipid fraction (ULF). Quantitative computed tomography (QCT) was performed to assess vBMD of L1-L3. The volumes of abdominal subcutaneous/visceral/total adipose tissue were determined from the QCT images and adjusted for abdominal body volume (SAT(adj)/VAT(adj)/TAT(adj)). Fasting blood tests included plasma glucose and HbA1c. Mean FC showed an inverse correlation with vBMD (r = -0.452; P < 0.05) in the whole study population. While mean FC was similar in the diabetic women and healthy controls (69.3 ± 7.5% versus 67.5 ± 6.1%; P > 0.05), mean ULF was significantly lower in the diabetic group (6.7 ± 1.0% versus 7.9 ± 1.6%; P < 0.05). SAT(adj) and TAT(adj) correlated significantly with mean FC in the whole study population (r = 0.538 and r = 0.466; P < 0.05). In contrast to the control group, significant correlations of mean FC with VAT(adj) and HbA1c were observed in the diabetic group (r = 0.642 and r = 0.825; P < 0.05). This study demonstrated that vertebral bone marrow fat content correlates significantly with SAT(adj), TAT(adj), and lumbar spine vBMD in postmenopausal women with and without T2DM, but with VAT(adj) and HbA1c only in women with T2DM.

Low bone accrual is associated with osteocyte apoptosis in alcohol-induced osteopenia

Alcohol is known to decrease bone mineral density (BMD) and to induce trabecular microarchitecture deterioration. However, little is known about the effects of chronic alcohol consumption on osteocytes in situ. The aim of this study was to assess the effects of a high alcohol dose on osteocytes in an alcohol-induced osteopenia model. 24 male Wistar rats, 2-months old were separated in 2 groups: Control (C) or Alcohol (A35). The rats in the A35 group drank a beverage composed of 35% ethanol v/v mixed to water for 17 weeks. BMD was assessed by DXA, while the microarchitecture was analyzed using μCT. Bone remodeling was studied measuring serum concentration of osteocalcin, NTx and TRAP. Bone marrow adiposity, osteoblastic lineage differentiation, osteocyte morphology and apoptosis were assessed using bright field, epifluorescence, transmission electron and confocal microscopy. BMD, trabecular thickness, TRAP and NTx concentration were significantly decreased in A35, while cortical thickness was thinner. There were 10 fold more cells stained with cleaved caspase-3, and 35% more empty lacunae in A35, these data indicating a large increase in osteocyte apoptosis in the A35 group. The number of lipid droplets in the marrow was increased in A35 (7 fold). Both the osteocyte apoptosis and the fat bone marrow content strongly correlated with femur BMD (p=0.0017, r = -0.72 and p=0.002, r = -0.70) and whole body BMD. These data suggest that low BMD is associated with osteocyte apoptosis and bone marrow fat content in alcohol-induced osteopenia.

Quantification of vertebral bone marrow fat content using 3 tesla MR spectroscopy: Reproducibility, vertebral variation, and applications in osteoporosis

To determine the reproducibility of proton MR spectroscopy ((1) H-MRS) for assessing vertebral bone marrow adiposity at 3 Tesla (T); to evaluate variation of marrow adiposity at different vertebral levels; and to demonstrate the feasibility of using (1) H-MRS at 3T for evaluating marrow adiposity in subjects with low bone density. Single voxel MRS was acquired at vertebral body L1 to L4 at 3T in 51 postmenopausal females including healthy controls (n = 13) and patients with osteoporosis/osteopenia (n = 38). Marrow fat contents were compared between vertebral levels and between groups using analysis of variance (ANOVA). Six subjects were scanned twice to evaluate technique reproducibility. The average coefficient of variation of vertebral marrow fat content quantification was 1.7%. Marrow fat content significantly increased from L1 to L4. The average fat content was significantly elevated in patients with osteoporosis/osteopenia compared with controls, adjusted for age and body mass index (P < 0.05). In vivo MRS at high field strength provides reliable measurement of marrow adiposity with excellent reproducibility and can be a valuable tool for providing complementary information on bone quality and potentially also fracture risk.

Inverse Correlation Between BMI and Time-to-Engraftment After Pediatric HSCT: Implications for the Role of Adipocytes in Hematopoietic Stem and Progenitor Cell (HSPC) Function

Recent studies have shown that adipocytes directly negatively regulate hematopoietic stem cell (HSC) function. It has also been shown that visceral adiposity correlates with bone marrow fat content and therefore increased adipocyte-HSC interaction, which may link high body mass index (BMI) with increased negative regulation of HSC function. Clinically, this has significant implications for stem cell transplant patients, particularly as Americans in general and the pediatric population in particular becomes more obese.

Prediction of bone loss in elderly female subjects by MR perfusion imaging and spectroscopy

To determine whether MR perfusion indices or marrow fat content at baseline can predict areal bone mineral density (BMDa) loss. Repeat dual x-ray absorptiometry (DXA) of the hip was performed in female subjects at 2 years (n = 52) and 4 years (n = 45) following baseline MR perfusion imaging and spectroscopy of the hip. Percentage reduction in femoral neck BMDa at 4 years post-baseline was greater in subjects with below median acetabulum enhancement slope (E(slope)) (-5.6 ± 1.2 Vs -1.1 ± 1.2 (mean ± standard error) p = 0.014) or muscle maximum enhancement (E(max)) (-5.7 ± 1.2 Vs -0.23 ± 1.2, p = 0.009) after adjusting for baseline co-variables. Baseline MR parameters correlated with reduction in BMDa at 4 years (acetabulum E(slope) r = 0.517, p = 0.0003; muscle E(max) r = 0.306, p = 0.043) as well as traditionally applied clinical risk factors. Acetabulum E(slope), femoral neck E(max) and marrow fat content at baseline had sensitivities of 89%, 81% and 72% respectively at distinguishing between fast (>1%/annum) (n = 18) and slow (<1%/annum) (n = 27) BMD losers. Elderly female subjects with reduced perfusion indices at baseline had increased femoral neck bone loss at 4 years. Selected perfusion indices and marrow fat content have a moderate to high sensitivity in discriminating between fast and slow bone losers.

Evaluation of vertebral bone marrow fat content by chemical-shift MRI in osteoporosis

To quantitatively evaluate vertebral bone marrow fat content and investigate its association with osteoporosis with chemical-shift magnetic resonance imaging (CS-MRI). Fifty-six female patients (age range 50-65 years) with varying bone mineral densities as documented with dual x-ray absorptiometry (DXA) were prospectively included in the study. According to the DXA results, the patients were grouped as normal bone density, osteopenic, or osteoporotic. In order to calculate fat content, the lumbar region was visualized in the sagittal plane by CS-MRI sequence. "Region of interest" (ROI)s were placed within L3 vertebral bodies and air (our reference point) at different time points by different radiologists. Fat content was calculated through "signal intensity (SI) suppression rate" and "SI Index". The quantitative values were compared statistically with those obtained from DXA examinations. Kruskal-Wallis, and Mann-Whitney U tests were used for comparisons between groups. The reliability of the measurements performed by two radiologists was evaluated with the "intraclass correlation coefficient". This study was approved by an institutional review board and all participants provided informed consent to participate in the study. Eighteen subjects with normal bone density (mean T score, 0.39 ± 1.3 [standard deviation]), 20 subjects with osteopenia (mean T score, -1.79 ± 0.38), and 18 subjects with osteoporosis (mean T score, -3 ± 0.5) were determined according to DXA results. The median age was 55.9 (age range 50-64 years) in the normal group, 55.5 (age range 50-64 years) in the osteopenic group, and 55.1 (age range 50-65 years) in the osteoporotic group (p = 0.872). In the CS-MRI examination, the values of "SI suppression ratio" and "SI Index" (median [min:max]) were calculated by the first and second reader, independently. There was no statistically significant difference between the groups with regard to vertebral bone marrow fat content (p > 0.05). According to the "intraclass correlation coefficient", the measurements were reliable (0.55 and 0.60). Vertebral bone marrow fat content calculated with CS-MRI is not a reliable parameter for predicting bone mineral density in female patients aged between 50 and 65 years.

Damage and Recovery of the Bone Marrow Microenvironment Induced by Cancer Chemotherapy – Potential Regulatory Role of Chemokine CXCL12/Receptor CXCR4 Signalling

The bone marrow microenvironment houses haematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and their progeny, supports haematopoiesis, osteogenesis, osteoclastogenesis, and adipogenesis. It plays a key role in maintaining homeostatic production of erythroid, myeloid or lymphoid cells, appropriate bone mass and bone health throughout life. Through cell-cell adhesion and chemotactic axes, a reciprocal inter-dependent relationship exists between these two cell lineages. Following chemotherapy-induced myelosuppression observed in cancer patients, HSCs are induced to enter into the cell cycle in order to re-establish the damaged microenvironment. These cells not only have the capacity to mobilize to the peripheral blood, but the ability to repopulate the marrow cavity as required. However, depending on the dosage and length of chemotherapy treatment, complications in bone and bone marrow recovery occur. This may manifest as marrow haematopoietic depletion, high marrow fat content, reduced bone formation and aggravated osteoclastic bone resorption. Although the molecular and cellular mechanisms governing injured states of the marrow microenvironment are yet to be fully elucidated, many reports have demonstrated the CXCL12/CXCR4 axis plays an important role in regulating the two cell lineages. Their interaction maintains bone marrow homeostasis and orchestrates its regeneration following chemotherapy. This review explores movement of MSC and HSC, haematopoiesis, commitment of osteoblasts, osteoclasts, and adipocytes, as well as the major signalling pathways that regulate these cellular processes under chemotherapy-treated conditions. This review also discusses molecular targets that are being used clinically or are currently under investigation for preserving the bone marrow microenvironment during or enhancing recovery after chemotherapy.

Relationship between serum vitamin D levels, adipocytes, and bone density in pre-adolescents and teenagers with newly diagnosed acute lymphoblastic leukemia.

e20009 Background: Vitamin D regulates several metabolic and hormonal pathways, which may be important in both the biology of acute lymphoblastic leukemia (ALL) and the pathogenesis of therapy-related complications. In normal individuals, there is a linkage between Vitamin D and adipose tissue. In persons with ALL older than 10 years, obesity is associated with increased risk of relapse and therapy-related bone abnormalities, but its relationship with Vitamin D is unknown. Methods: We are conducting a clinical study to assess the relationship between obesity, vitamin D and bone and bone marrow changes in pre-adolescents and teenagers with ALL. At diagnosis, at end of Induction and before starting Maintenance therapy patients are studied for serum levels of vitamin 25[OH]D, PTH, alkaline phosphatase and calcium, and for total body fat and calcium content by DEXA scans. The size and the cortical bone density is assessed by CT; the bone marrow fat content is studied by MRI using a 1.5 T GE MR unit to obtain coronal images of the femur with the Dixon sequence, which allows for the differentiation between fat and water based on different resonant frequency differences. Bone marrow biopsies are performed at diagnosis and at the end of induction to assess the spatial relationship between osteoblasts, adipocytes and hematopoietic cells. We planned to enroll 70 patients divided in two cohorts: in the first cohort patients with low vitamin D are only observed, while those in the second cohort will receive Vitamin D and calcium therapy starting after completing Induction. Our preliminary results of the first cohort indicate that vitamin D deficit is almost universal at diagnosis of ALL: vitamin D levels correlate with the amount of body fat and the initial bone density. By the end of Induction, vitamin D levels and bone density decreased in all the patients, accompanied by an increase in body fat and in serum PTH. Studies correlating these findings with bone marrow changes by histology and radiology are in progress. No significant financial relationships to disclose.

Human osteoblasts derived from mesenchymal stem cells express adipogenic markers upon coculture with bone marrow adipocytes

In osteoporosis, bone loss is accompanied by greater adiposity in the marrow. Given the cellular proximity within the bone marrow, we wondered whether adipocytes might have a paracrine impact on osteoblast differentiation. To test this hypothesis, we cocultured adipocytes with osteoblasts derived from mesenchymal stem cells (MSCs) in the absence of direct cell contact and then analyzed gene expression changes in the osteoblastic population by using real-time reverse transcription polymerase chain reaction. We found that, upon coculture, MSC-derived osteoblasts showed appearance of adipogenic (lipoprotein lipase, leptin) and decrease of osteogenic (osteocalcin) mRNA markers. Our results indicate that in vitro, MSC-derived adipocytes are capable of inducing MSC-derived osteoblasts to differentiate to an adipocyte phenotype. These new data suggest that (i) transdifferentiation of committed osteoblasts into adipocytes may contribute to the increase in marrow fat content at the expense of bone-forming cells and (ii) this switch might be initiated by the adipocytes themselves.

Modified brix model analysis of bone perfusion in subjects of varying bone mineral density

To apply pharmacokinetic modeling to the investigation of bone perfusion in subjects of varying bone mineral density. This study re-analyzed previous experimental data. A modified pharmacokinetic model was applied to data obtained from two prior studies of dynamic contrast-enhanced MR imaging of L3 vertebral body in 165 subjects (65 males, 100 females), classified into three groups (normal, osteopenia, and osteoporosis) according to bone mineral density. Three parameters, amplitude A, exchange rate (k(ep)), and elimination rate (k(el)), were obtained by fitting the signal intensity to the pharmacokinetic model. These parameters were compared across the three groups for males and females, respectively. Perfusion parameters, amplitude A was found to be reduced in osteoporotic subjects with additional, though less pronounced, reductions found in the permeability constant (A*k(ep)) and the elimination rate (k(el)). Increased marrow fat content was found in osteoporotic bone, which helped to partially explain the observed reduction in interstitial space. By pharmacokinetic model, bone perfusion can be quantitatively analyzed with alteration in functional parameters related to microcirculation in subjects of varying bone mineral density. Developing bone marrow specific pharmacokinetic models should help to deepen knowledge of physiological and pathological perfusion changes occurring in bone.

Growth hormone regulates the balance between bone formation and bone marrow adiposity

Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age-related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin-like growth factor 1 (IGF-1) levels, and mRNA levels for IGF-1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17β -estradiol, IGF-1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF-1 but not in mice deficient in serum IGF-1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling-deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation. © 2010 American Society for Bone and Mineral Research