The effects of PPARγ inhibitor on bones and bone marrow fat in aged glucocorticoid-treated female rats.

Progressive bone marrow (BM) fat accumulation is a common bone loss characteristic in older populations and glucocorticoid (GC)-induced skeletal destruction that is inversely associated with bone synthesis and directly associated with increased peroxisomal proliferator-activated receptor gamma (PPARγ) expression. PPARγ inhibition is an efficient therapeutic strategy for aged- and GC-related skeletal disorders. This study aimed to evaluate the effect of PPARγ inhibition on aged GC-treated female rats. It was hypothesised that bisphenol A diglycidyl ether (BADGE) could inhibit marrow adiposity and improve osteogenesis by inhibiting PPARγ, thereby preventing GC-induced osteoporosis (GIO). Female Sprague-Dawley rats (n = 32, age = 18 months) were randomly allocated to one of the following groups: (1) control, (2) BADGE (30 mg/kg/day, intraperitoneal), (3) methylprednisolone (MP; 30 mg/kg/day, subcutaneous), and (4) MP + BADGE. After eight weeks of treatment, bone density (BD) and trabecular bone microarchitectures were quantified by micro-computed tomography (CT), and BM adipocytes were quantified by histopathology. Additionally, mRNA and protein expression of adipogenic and osteogenic markers were quantified by reverse transcription-quantitative polymerase chain reaction. Furthermore, serum bone turnover biomarker levels were quantified by enzyme-linked immunosorbent assay. MP treatment led to marrow adipogenesis and bone deterioration. However, rats treated with MP + BADGE showed lower marrow adipogenesis, as indicated by smaller marrow adipocyte diameter, decreased density and area percentages, reduced expression of marrow adipogenic genes and proteins, improved BD and trabecular microarchitectures, increased expression of osteogenic genes and proteins, and higher levels of serum bone formation markers. These results were consistent with the differences observed between control and BADGE mono-treated rats. In conclusion, BADGE treatment attenuates BM adiposity and improves bone formation in aged GC-treated female rats by inhibiting PPARγ. Therefore, PPARγ might be a potential target for treating GIO in older populations.

Associations of Fat Mass and Fat Distribution With Bone Mineral Density in Non-Obese Postmenopausal Chinese Women Over 60 Years Old.

Background: Bone mineral density (BMD) loss is a major complication of menopause, and this loss is closely associated with Fat mass (FM). The relationship between FM, fat distribution (FD), and BMD in postmenopausal women, however, remains incompletely understood. The present study was thus developed to explore these associations between body fat accumulation, FD, and BMD among non-obese postmenopausal women over the age of 60. Methods: This was a cross-sectional analysis of 357 healthy postmenopausal women between the ages of 60.2 and 86.7 years. Dual-energy X-ray absorptiometry (DXA) was utilized to measure total and regional BMD as well as fat-related parameters including total FM, android and gynoid fat, body fat percentage (BF%), and total lean mass (LM) for all subjects. The android-to-gynoid fat ratio (AOI) was used to assess FD. Pearson's correlation testing and multiple regression analyses were used to explore relationships among AOI, LM, FM, and BMD. Results: Both LM and FM were positively correlated with total and regional BMD in univariate analysis (all P < 0.01), whereas BMD was not significantly associated with AOI in any analyzed site other than the head. Multivariate linear regression models corrected for age, height, and years post-menopause, revealed a sustained independent positive relationship between FM and BMD (standard ß range: 0.141 - 0.343, P < 0.01). The relationship between FM and BMD was unaffected by adjustment for LM (standard ß range: 0.132 - 0.258, P < 0.01), whereas AOI had an adverse impact on BMD at most analyzed skeletal sites (total body, hip, femoral neck, arm, leg, and head) (standard ß range: -0.093 to -0.232, P < 0.05). These findings were unaffected by using BF% in place of FM (standard ß range: -0.100 to -0.232, P < 0.05). Conclusions: In this cohort of non-obese postmenopausal women over the age of 60 from China, total FM was positively associated with BMD, while AOI was negatively correlated with BMD. As such, a combination of proper weight gain and the control of central obesity may benefit the overall bone health of women after menopause.

Urinary iodine concentration and radioactive iodine therapeutic response in patients with differentiated thyroid cancer.

Aim: Urinary iodine concentration (UIC) may assess radioactive iodine ablation. Materials & methods: According the 2015 American Thyroid Association guidelines, patients were categorized into low- to intermediate-risk or high-risk groups. The iodine concentration in the morning urine specimens was measured by the ceric ion-arsenious acid method. Results: In the low- to intermediate-risk group (113 cases), nonexcellent response (non-ER) was associated with higher UIC, higher UIC subgroups (p < 0.05), higher pre-ablative stimulated thyroglobulin levels (p < 0.01). In the high-risk group (68 cases), the non-ER rate was higher in the higher pre-ablative stimulated thyroglobulin group (p < 0.01), but not significantly different between the UIC and UIC subgroups (p > 0.05). Conclusion: The non-ER rate was related to UIC in the low- to intermediate-risk group; however, UIC did not affect the non-ER rate in the high-risk group.

Recombinant Human Growth Hormone Ameliorates Cognitive Impairment in Stroke Patients.

OBJECTIVE: We aimed to determine the effects of recombinant human growth hormone (rhGH) replacement on cognitive function in subjects with poststroke cognitive impairment using resting-state functional magnetic resonance imaging. METHODS: We included 60 patients with a first-ever stroke for 3 months and a diagnosis of cognitive impairment who were randomized 1:1 to receive either rhGH subcutaneously or placebo injection for 6 months. All subjects were required to receive the same rehabilitative therapy program. Both groups were subjected to pretreatment and posttreatment neuropsychological assessment using the Montreal Cognitive Assessment, serum neurotrophic factors, biomarkers of glucose and lipid metabolism, and functional magnetic resonance imaging during 6 months of the study period. The pattern of brain activity was determined by examining the functional connectivity and amplitude of low-frequency fluctuations (ALFF) of blood oxygen level dependent signal. RESULTS: Forty-three (82.7%) completed the study. Treatment with rhGH reduced levels of triglycerides and low-density lipoprotein cholesterol but did not significantly altered plasma concentrations of glucose and glycated hemoglobin. We found a significant increase in serum insulin-like growth factor 1 levels (32.6%; P < 0.001) in the rhGH-treated group compared with that in the controls. After 6 months of rhGH treatment, mean Montreal Cognitive Assessment score improved from 16.31 (5.32) to 21.19 (6.54) (P < 0.001). The rhGH group showed significant increased area of activation with increased ALFF values in the regions of the frontal lobe, putamen, temporal lobe, and thalamus (P < 0.05), relative to the baseline conditions. The correlation analysis revealed that the ALFF and functional connectivity of default mode network was positively correlated with the ΔMoCA score and ΔIGF-1 levels; that is, the more the scale score increased, the higher the functional connection strength. No undesirable adverse effects were observed. CONCLUSIONS: The rhGH replacement has a significant impact on global and domain cognitive functions in poststroke cognitive impairment.

To assess differential features of marrow adiposity between postmenopausal women with osteoarthritis and osteoporosis using water/fat MRI.

OBJECTIVE: To assess the differential features of marrow adiposity between osteoarthritis (OA) and osteoporosis (OP) in postmenopausal women using water/fat MRI. METHODS: This cross-sectional study included 97 postmenopausal women (OA [n = 25], OA + osteopenia [n = 27], OA + OP [n = 23], and OP groups [n = 22]). Water/fat MRI, dual-energy x-ray absorptiometry and biochemical analysis were performed to assess vertebral marrow fat fraction, bone mineral density, and bone biomarkers, respectively. Harris Hip Score was recorded to evaluate hip function. RESULTS: There were significant differences in marrow fat content among the OA, OA + osteopenia, and OA + OP groups, between OP and OA participants with normal bone mass or osteopenia (all P < 0.05); no significant difference was observed between OA + OP and OP groups. Serum levels of leptin and ß-Crosslaps in OA with normal bone mass and osteopenic OA groups were higher than in OP group. Marrow fat fraction was inversely correlated with Harris Hip Score (r = -0.371, P = 0.013), bone mineral density (r = -0.554, P = 0.009) and leptin levels (r = -0.610, P < 0.001). In multivariate regression analysis, marrow fat fraction was found to have a consistent and unchanged inverse association with leptin levels (Sß = -0.311, P = 0.002) and bone mineral density (Sß =  -0.265, P = 0.006) after adjusting for age, years since menopause, and body mass index. CONCLUSIONS: Postmenopausal OA with OP have a phenotype with higher marrow adiposity. OA and OP could coexist, for the presence of a specific subgroup of OA with increased marrow fat accumulation and high risk of developing OP.

Comparison of chemical shift-encoded water-fat MRI and MR spectroscopy in quantification of marrow fat in postmenopausal females.

PURPOSE: To validate a chemical shift-encoded (CSE) water-fat imaging for quantifying marrow fat fraction (FF), using proton magnetic resonance spectroscopy (MRS) as reference. MATERIALS AND METHODS: Multiecho T2 -corrected MRS and CSE imaging with eight-echo gradient-echo acquisitions at 3T were performed to calculate marrow FF in 83 subjects, including 41 with normal bone mineral density (BMD), 26 with osteopenia, and 16 with osteoporosis (based on DXA). Eight participants were scanned three times with repositioning to assess the repeatability of CSE FF map measurements. Pearson correlation coefficient, Bland-Altman 95% limit of agreement, and Lin's concordance correlation coefficient were calculated. RESULTS: The Pearson correlation coefficient was 0.979 and Lin's concordance correlation coefficient was 0.962 between CSE-based FF and MRS-based FF. All data points, calculated using the Bland-Altman method, were within the limits of agreement. The intra- and interrater agreement for average CSE-based FF was excellent (intrarater, intraclass correlation coefficient [ICC] = 0.993; interrater, ICC = 0.976-0.982 for different BMD groups). In the subgroups of varying BMD, inverse correlations were observed to be very similar between BMD (r = -0.560 to -0.710), T-score (r = -0.526 to -0.747), and CSE-based FF, and between BMD (r = -0.539 to -0.706), T-score (r = -0.501 to -0.742), and MRS-based FF even controlling for age, years since menopause, and body mass index. The repeatability for CSE FF map measurements expressed as absolute precision error was 1.45%. CONCLUSION: CSE imaging is equally accurate in characterizing marrow fat content as MRS. Given its excellent correlation and concordance with MRS, the CSE sequence could be used as a potential replacement technique for marrow fat quantification. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:66-73.

Panax notoginseng saponins mitigate ovariectomy-induced bone loss and inhibit marrow adiposity in rats.

OBJECTIVE: Previous data have suggested that Panax notoginseng saponins (PNS) can prevent estrogen deficiency-induced bone loss by dual action: stimulation of new bone formation and inhibition of bone resorption. Marrow adipogenesis has been identified as a negative indicator of skeletal strength and integrity. This study assessed the effects of early PNS supplementation on bone microarchitecture preservation and marrow fat content in an ovariectomized rat model. METHODS: Forty adult female Sprague-Dawley rats were randomly assigned to four equal groups for 12 weeks of treatment: (1) sham operation (SHAM) + vehicle; (2) ovariectomy (OVX) + vehicle; (3) OVX + 17ß-estradiol (25 µg/kg); (4) OVX + PNS (300 mg/kg/d, PO). Marrow fat content of the femur was determined, using fat/water magnetic resonance imaging (MRI), at baseline and 6 and 12 weeks after operation. At the end of the experiment, bone turnover, trabecular microarchitecture, and marrow adipocytes were assessed by serum biomarkers, micro-computed tomography (micro-CT), and histopathology, respectively. The effects of PNS on adipocytic differentiation were reflected by expression levels of the adipogenic genes PPARγ2 and C/EBPα, as determined by reverse transcription-polymerase chain reaction. RESULTS: Ovariectomized rats experienced remarkable increases in marrow fat content across time points, which were accompanied by elevated rate of bone turnover, global volumetric bone density, and trabecular microarchitecture deterioration. These OVX-induced pathological changes are reversible in that most of them could be mostly corrected upon 17ß-estradiol treatment. PNS treatment significantly reduced marrow adipogenesis (adipocyte density, -27.2%; size, -22.7%; adipocyte volume-to-tissue volume ratio, -53.3%; all P < 0.01) and adipocyte marker gene expression, and prevented bone mass loss and microarchitecture deterioration. Moreover, PNS enhanced osteoblast activity but suppressed osteoclast turnover, as evidenced by decreased levels of serum C-terminal telopeptides of type I collagen and elevated levels of alkaline phosphatase. CONCLUSIONS: PNS mitigates estrogen deficiency-induced deterioration of trabecular microarchitecture and suppresses marrow adipogenesis.

The temporal characterization of marrow lipids and adipocytes in a rabbit model of glucocorticoid-induced osteoporosis.

OBJECTIVE: To characterize the temporal changes in marrow lipids content and adipocytes in the development of glucocorticoid-induced osteoporosis (GIOP) in rabbits using MR spectroscopy. SUBJECTS AND METHODS: Twenty 20-week-old female rabbits were randomized to a control group and a GIOP group equally. Marrow lipids fraction and bone mineral density at the left proximal femur and L3-L4 vertebrae were measured by MR spectroscopy and dual-energy X-ray absorptiometry at week 0, 4, 8, and 12. Marrow adipocytes were quantitatively evaluated by histopathology. RESULTS: Marrow adiposity in the GIOP group showed a significant increase over time, with a variation of marrow lipids fraction (+35.9 %) at week 4 from baseline and it was maintained until week 12 (+75.2 %, p < 0.001 for all). The GIOP group demonstrated continuous deterioration of bone with significant difference between the two groups at week 8, followed by increased marrow fat with significant difference at week 4 (p < 0.05 for all). In comparison with the controls, marrow adipocyte density in the GIOP group increased by 57.1 % at week 8 and 35.4 % at week 12, respectively. A reduction (-13.3 %) in adipocyte mean diameter at week 8 (but an increase (+22.7 %) at week 12) were observed in the GIOP group compared with the control group (p < 0.05 for all). There was significant difference between two periods (p = 0.023) in adipocyte mean diameter in the GIOP group. The percentage area of marrow adipocytes in the GIOP group was 62.8 ± 8.7 % at week 8 and 79.2 ± 7.7 % at week 12, both of which were significantly higher than those of the controls (p < 0.05 for all). CONCLUSIONS: Marrow adipogenesis is synchronized with bone loss in the development of GIOP, which was characterized by a significant increase in the number of small-sized marrow adipocytes in the relatively early stage and concomitant volume increase later on. MR spectroscopy appears to be the most powerful tool for detecting the sequential changes in marrow lipid content.

Marrow adiposity recovery after early zoledronic acid treatment of glucocorticoid-induced bone loss in rabbits assessed by magnetic resonance spectroscopy.

BACKGROUND: Although there is an inverse relationship between bone mass and marrow adiposity, the reversal function of zoledronic acid (ZOL) on increased marrow fat has not been studied. The aim of our study is to use the 3T magnetic resonance spectroscopy (MRS) to characterize the dynamical change process of the marrow fat responding to early ZOL treatment in the rabbit model with glucocorticoid-induced bone loss. METHODS: Fifteen 20-week-old female New Zealand White rabbits were randomized to control group, methylprednisolone (MPS) group, and MPS+ZOL group equally. Bone mineral density (BMD) and marrow fat fraction (FF) at L3-L4 vertebrae and left proximal femur were measured by Dual-energy X-ray absorptiometry and MRS at week 0, 4, 8, and 12. The animals were euthanized at the end of our experiment and their left femurs were dissected out for the histopathological examination. RESULTS: The MPS group demonstrated a remarkable increase in FF but a reduction in BMD compared with the controls at week 4 and 8, respectively (P<0.05 for all). Early treatment of ZOL can inhibit bone degeneration, although the bone mass would not recover to its original level. FF in MPS group exhibited a dramatic increase over time, with an increased FF variation (+31.6%, P=0.009) at week 4 from baseline and it was maintained until week 12 (+75.2%, P<0.001). In MPS+ZOL group, the FF returned to baseline value after the ZOL treatment. Comparing with the controls, larger marrow adipocyte density, the mean of the adipocyte diameter, and the percentage area of the adipocyte were observed in the MPS group (P<0.05 for all), whereas there were no significant differences in quantitative parameters of marrow adipocytes between the ZOL-treated group and the normal rabbits. CONCLUSION: An increase of the marrow adiposity is synchronized with the deterioration of the MPS-induced bone mass. A single dose of early ZOL can reverse the marrow adiposity to its original level completely.