Regionally specific compensation for bone loss in the tibial trabeculae of estrogen-deficient rats

Background: Bone mineral density (BMD) and microstructural variations have been extensively investigated in recent years; however, the compensation for bone loss between different regions is still unclear. Purpose: To fully characterize regional variations in bone mineral density (BMD) as well as the microstructure and dynamic changes of rat tibial trabeculae that occur with bone loss associated with estrogen deficiency. Material and Methods: Female Sprague-Dawley rats were ovariectomized (OVX), sham-operated (sham), or left unoperated (baseline control). The left tibiae were harvested at baseline, and at postoperative weeks 3 and 15. High-resolution micro-computed tomography (µCT) was used to identify the densitometric and microstructural properties of trabeculae in the proximal ends of the rat tibia, specifically the epiphysis and metaphysis. Results: Volumetric BMDs at the organ (organ BMD) and tissue (tissue BMD) levels were significantly higher for trabeculae at the epiphysis than metaphysis. Moreover, trabeculae at the epiphysis were thicker, and fewer in number and connectivity than those at the metaphysis, which were more rod like. Trabeculae at the metaphysis were more susceptible to bone loss induced by estrogen deprivation than at the epiphysis, and the regions varied greatly in their adaptation to this loss. At the metaphysis, trabecular tissue BMD and thickness were unexpectedly higher at postoperative week 15 than week 3 or baseline. In contrast, at the epiphysis, tissue BMD did not change with time, but trabecular thickness significantly increased at week 15 compared to baseline and was also greater in OVX compared to sham rats. Conclusion: Metaphyseal and epiphyseal trabeculae show regionally specific variations in BMD and microstructure. The former are more susceptible to bone loss induced by estrogen deficiency and would be strengthened by either hypertrophy or hypermineralization, while epiphyseal trabeculae are mainly strengthened by thickening.

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Effects of ginsenoside Rg3 on bone loss, bone mineral density and osteoclast number in glucocorticoid-induced osteoporosis rats, and the likely michanism of action

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i4.19 ◽

2020 ◽

Vol 19 (4) ◽

pp. 811-815

Author(s):

Maoxiu Peng ◽

Gangyl Jiang ◽

Shaoqi He ◽

Chengxuan Tang

Keyword(s):

Bone Mineral Density ◽

Bone Loss ◽

Bone Mineral ◽

Lumbar Vertebrae ◽

Ginsenoside Rg3 ◽

Model Group ◽

Mineral Density ◽

Alendronate Sodium ◽

Trabecular Thickness ◽

Osteoclast Number

Purpose: To investigate the effect of ginsenoside Rg3 on bone loss, bone mineral density (BMD) and osteoclast number in glucocorticoid-induced osteoporosis (GIOP) rats, and the mechanism of action involved.Methods: Sixty female Wistar rats were assigned to control, model group, ginsenoside Rg3, and alendronate sodium groups, comprised of 15 rats per group. The osteoporosis rat model was established via intramuscular injection of dexamethasone. Changes in bone mineral content (BMC), BMD trabecular thickness and area, osteoblasts and osteoclasts in femurs and lumbar vertebrae were measured after 3 months of treatment.Results: There were significantly higher BMC and BMD levels in ginsenoside Rg3 group than in alendronate rats (p < 0.05). The thickness and trabecular area in femur and lumbar vertebrae in the ginsenoside Rg3 group were significantly higher than those in the model group (p < 0.05), but were comparable with those in the alendronate sodium group (p > 0.05). There were marked increases in osteoblasts, and marked decreases in osteoclasts in the ginsenoside Rg3 group, alendronate sodium and control rats, relative to model rats (p < 0.05).Conclusion: Ginsenoside Rg3 arrests bone loss, and enhances bone density, trabecular thickness and area, bone microstructure, osteoblast activity and population of osteoclasts number in glucocorticoidinduced osteoporotic rats. This provides a new research direction for the clinical treatment ofosteoporosis. Keywords: Ginseng soap, Rg3, Glucocorticoid, Osteoporosis, Bone loss, Bone mineral density, Osteoclast population

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A Novel Peptide, CK2.3, Improved Bone Formation in Ovariectomized Sprague Dawley Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21144874 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4874 ◽

Cited By ~ 1

Author(s):

Linda Sequeira ◽

John Nguyen ◽

Liyun Wang ◽

Anja Nohe

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mineral ◽

Single Photon ◽

Femoral Shaft ◽

Ovariectomized Rats ◽

Sprague Dawley ◽

Micro Computed Tomography ◽

Mineral Density

Osteoporosis is a bone disease that has no definite cure. Current treatments for osteoporosis are divided into two categories: anti-resorptive and anabolic. However, these treatments are not perfect and have considerable risks. In addition, bone quality often declines over time with these treatments. We designed a peptide, CK2.3, that has both anabolic and anti-resorptive effects on bone. We reported that CK2.3 induced osteoblastic mineralization, promoted bone formation, and suppressed osteoclastogenesis in vivo. The effect of CK2.3 to rescue an osteoporosis phenotype model has never been shown. In this study, we demonstrated the effect of CK2.3 in ovariectomized rats, a standard model of osteoporosis. We systemically injected CK2.3 at 2.3 µg/kg each day for five consecutive days. Micro-computed tomography indicated that CK2.3 increased bone mineral density, (bone volume/tissue volume) BV/TV and (trabecular number) TbN, and decreased (trabecular space) TbSp in the femoral head. Similarly, single photon absorptiometry showed that treatment with CK2.3 increased bone mineral density in the lumbar spine and the pelvis. Additionally, we observed increased femoral shaft stiffness with ovariectomized rats treated with CK2.3. We also detected no significant changes in the weight of organs such as the heart, lung, liver, kidney, and spleen. An advantage of CK2.3 over current treatments was that it not only promoted bone formation but also improved fracture resistance. In conclusion, we demonstrated CK2.3 as a new anabolic treatment for osteoporosis.

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Creatine Monohydrate Increases Bone Mineral Density in Young Sprague-Dawley Rats

Medicine & Science in Sports & Exercise ◽

10.1249/mss.0b013e318031fac4 ◽

2007 ◽

Vol 39 (5) ◽

pp. 816-820 ◽

Cited By ~ 26

Author(s):

ANAMARIA ANTOLIC ◽

BRIAN D. ROY ◽

MARK A. TARNOPOLSKY ◽

RONALD F. ZERNICKE ◽

GREGORY R. WOHL ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Creatine Monohydrate ◽

Sprague Dawley ◽

Mineral Density ◽

Sprague Dawley Rats

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Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton

Endocrinology ◽

10.1210/en.2010-0566 ◽

2010 ◽

Vol 151 (12) ◽

pp. 5591-5601 ◽

Cited By ~ 38

Author(s):

Laleh Ardeshirpour ◽

Susan Brian ◽

Pamela Dann ◽

Joshua VanHouten ◽

John Wysolmerski

Keyword(s):

Bone Mineral Density ◽

Bone Resorption ◽

Bone Loss ◽

Bone Turnover ◽

Bone Mineral ◽

Gnrh Agonist ◽

Estrogen Deficiency ◽

Trabecular Architecture ◽

Mineral Density ◽

Long Acting

During lactation, calcium is mobilized from the maternal skeleton to supply the breast for milk production. This results in rapid but fully reversible bone loss. Prior studies have suggested that PTHrP, secreted from the breast, and estrogen deficiency, due to suckling-induced central hypogonadism, combine to trigger bone resorption. To determine whether this combination was sufficient to explain bone loss during lactation, we raised PTHrP levels and decreased levels of estrogens in nulliparous mice. PTHrP was infused via osmotic minipumps and estrogens were decreased either by using leuprolide, a long-acting GnRH agonist, or by surgical ovariectomy (OVX). Bone mineral density declined by 23.2 ± 1.3% in the spine and 16.8 ± 1.9% in the femur over 10 d of lactation. This was accompanied by changes in trabecular architecture and an increase in both osteoblast and osteoclast numbers. OVX and PTHrP infusion both induced a modest decline in bone mineral density over 10 d, but leuprolide treatment did not. The combination of OVX and PTHrP was more effective than either treatment alone, but there was no interaction between PTHrP and leuprolide. None of the treatments reproduced the same degree of bone loss caused by lactation. However, both forms of estrogen deficiency led to an increase in osteoclasts, whereas infusion of PTHrP increased both osteoblasts and osteoclasts. Therefore, although the combination of PTHrP and estrogen deficiency contributes to bone loss, it is insufficient to reproduce the full response of the skeleton to lactation, suggesting that other factors also regulate bone metabolism during this period.

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Lugol’s solution but not formaldehyde affects bone microstructure and bone mineral density parameters at the insertion site of the rotator cuff in rats

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02394-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Xaver Feichtinger ◽

Patrick Heimel ◽

Claudia Keibl ◽

David Hercher ◽

Jakob Emanuel Schanda ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Insertion Site ◽

Bone Microstructure ◽

Bone Architecture ◽

Control Group ◽

Sprague Dawley ◽

Micro Computed Tomography ◽

Mineral Density ◽

Microstructure Parameters

Abstract Background This study aimed to investigate whether rodent shoulder specimens fixed in formaldehyde for histological and histomorphometric investigations and specimens stained using Lugol’s solution for soft tissue visualization by micro-computed tomography (microCT) are still eligible to be used for bone architecture analysis by microCT. Methods In this controlled laboratory study, 11 male Sprague-Dawley rats were used. After sacrifice and exarticulation both shoulders of healthy rats were assigned into three groups: (A) control group (n = 2); (B) formaldehyde group (n = 4); (C) Lugol group (n = 5). Half of the specimens of groups B and C were placed in a 4% buffered formaldehyde or Lugol’s solution for 24 h, whereas the contralateral sides and all specimens of group A were stored without any additives. MicroCT of both sides performed in all specimens focused on bone mineral density (BMD) and bone microstructure parameters. Results BMD measurements revealed higher values in specimens after placement in Lugol’s solution (p < 0.05). Bone microstructure analyses showed increased BV/TV and Tb.Th values in group C (p < 0.05). Specimens of group C resulted in clearly decreased Tb.Sp values (p < 0.05) in comparison to the control group. Formaldehyde fixation showed minimally altered BMD and bone microstructure measurements without reaching any significance. Conclusions MicroCT scans of bone structures are recommended to be conducted natively and immediately after euthanizing rats. MicroCT scans of formaldehyde-fixed specimens must be performed with caution due to a possible slight shift of absolute values of BMD and bone microstructure. Bone analysis of specimens stained by Lugol’s solution cannot be recommended.

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Impaired Estrogen Sensitivity in Bone by Inhibiting Both Estrogen Receptor a and b Pathways*

10.31234/osf.io/592mt ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Bone Mineral Density ◽

Estrogen Receptor ◽

Bone Loss ◽

Bone Turnover ◽

Bone Mineral ◽

Female Rats ◽

Wild Type ◽

Mineral Density ◽

Transgenic Rats ◽

Estrogen Sensitivity

Although it is well established that estrogen deficiencycauses osteoporosis among the postmenopausalwomen, the involvement of estrogen receptor (ER) in itspathogenesis still remains uncertain. In the presentstudy, we have generated rats harboring a dominantnegative ERa, which inhibits the actions of not only ERabut also recently identified ERb. Contrary to our expectation,the bone mineral density (BMD) of the resultingtransgenic female rats was maintained at the same levelwith that of the wild-type littermates when sham-operated.In addition, ovariectomy-induced bone loss wasobserved almost equally in both groups. Strikingly, however,the BMD of the transgenic female rats, after ovariectomized,remained decreased even if 17b-estradiol(E2) was administrated, whereas, in contrast, the decreaseof littermate BMD was completely prevented byE2. Moreover, bone histomorphometrical analysis ofovariectomized transgenic rats revealed that the higherrates of bone turnover still remained after treatmentwith E2. These results demonstrate that the preventionfrom the ovariectomy-induced bone loss by estrogen ismediated by ER pathways and that the maintenanceof BMD before ovariectomy might be compensatedby other mechanisms distinct from ERa and ERbpathways.

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P129 Predictors of low bone mineral density in rheumatoid arthritis

Rheumatology ◽

10.1093/rheumatology/keab247.124 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Malika A Swar ◽

Marwan Bukhari

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Bone Mineral Density ◽

Family History ◽

Bone Loss ◽

Femoral Neck ◽

Bone Mineral ◽

Fragility Fracture ◽

Mineral Density ◽

History Of

Abstract Background/Aims Osteoporosis (OP) is an extra-articular manifestation of rheumatoid arthritis (RA) that leads to increased fracture susceptibility due to a variety of reasons including immobility and cytokine driven bone loss. Bone loss in other populations has well documented risk factors. It is unknown whether bone loss in RA predominantly affects the femoral neck or the spine. This study aimed to identify independent predictors of low bone mineral density (BMD) in patients RA at the lumbar spine and the femoral neck. Methods This was a retrospective observational cohort study using patients with Rheumatoid arthritis attending for a regional dual X-ray absorptiometry (DEXA) scan at the Royal Lancaster Infirmary between 2004 and 2014. BMD in L1-L4 in the spine and in the femoral neck were recorded. The risk factors investigated were steroid use, family history of osteoporosis, smoking, alcohol abuse, BMI, gender, previous fragility fracture, number of FRAX(tm) risk factors and age. Univariate and Multivariate regression analysis models were fitted to explore bone loss at these sites using BMD in g/cm2 as a dependant variable. . Results 1,527 patients were included in the analysis, 1,207 (79%) were female. Mean age was 64.34 years (SD11.6). mean BMI was 27.32kg/cm2 (SD 5.570) 858 (56.2%) had some steroid exposure . 169(11.1%) had family history of osteoporosis. fragility fracture history found in 406 (26.6%). 621 (40.7%) were current or ex smokers . There was a median of 3 OP risk factors (IQR 1,3) The performance of the models is shown in table one below. Different risk factors appeared to influence the BMD at different sites and the cumulative risk factors influenced BMD in the spine. None of the traditional risk factors predicted poor bone loss well in this cohort. P129 Table 1:result of the regression modelsCharacteristicB femoral neck95% CIpB spine95%CIpAge at scan-0.004-0.005,-0.003<0.01-0.0005-0.002,0.00050.292Sex-0.094-0.113,-0.075<0.01-0.101-0.129,-0.072<0.01BMI (mg/m2)0.0080.008,0.0101<0.010.01130.019,0.013<0.01Fragility fracture-0.024-0.055,0.0060.12-0.0138-0.060,0.0320.559Smoking0.007-0.022,0.0350.650.0286-0.015,0.0720.20Alcohol0.011-0.033,0.0 5560.620.0544-0.013,0.1120.11Family history of OP0.012-0.021,0.0450.470.0158-0.034,0.0650.53Number of risk factors-0.015-0.039,0.0080.21-0.039-0.075,-0.0030.03steroids0.004-0.023,0.0320.030.027-0.015,0.0690.21 Conclusion This study has shown that predictors of low BMD in the spine and hip are different and less influential than expected in this cohort with RA . As the FRAX(tm) tool only uses the femoral neck, this might underestimate the fracture risk in this population. Further work looking at individual areas is ongoing. Disclosure M.A. Swar: None. M. Bukhari: None.

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SAT0477 A TWO-YEAR LONGITUDINAL STUDY COMPLETION, LONGITUNEAL STUDY, THE DIFFERENCE IN BONE LOSS IN PATIENTS WITH EROSIVE AND NON-EROSIVE HAND OSTEOARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4790 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1195.2-1195

Author(s):

K. Pavelka ◽

L. Šenolt ◽

O. Sleglova ◽

J. Baloun ◽

O. Růžičková

Keyword(s):

Bone Mineral Density ◽

Longitudinal Study ◽

Lumbar Spine ◽

Bone Loss ◽

Bone Mineral ◽

Hand Osteoarthritis ◽

Mineral Density ◽

Erosive Disease ◽

Femur Neck ◽

American College Of Rheumatology

Background:Hand osteoarthritis (OA) and its more severe subset erosive hand OA are common causes of pain and morbidity. Some metabolic factors were suggested to be implicated in erosive disease. Few studies investigated differences in systemic bone loss between erosive and non-erosive hand OA.Objectives:To compare the change of bone mineral density (BMD) between patients with erosive and non-erosive hand OA in a two-year longitudinal study.Methods:Consecutive patients with symptomatic HOA fulfilling the American College of Rheumatology (ACR) criteria were included in this study. Erosive hand OA was defined by at least one erosive interphalangeal joint. All patients underwent clinical assessments of joint swelling and radiographs of both hands. DEXA examination of lumbar spine, total femur and femur neck was performed at the baseline and after two years.Results:Altogether, 141patients (15 male) with symptomatic nodal HOA were included in this study and followed between April 2012 and January 2019. Out of these patients, 80 had erosive disease after two years. The disease duration (p<0.01) was significantly higher in patients with erosive compared with non-erosive disease at baseline.Osteoporosis (T-score <-2.5 SD) was diagnosed in 12.5% (9/72) of patients with erosive hand OA and in 8.06% (5/57) of patients with non-erosive hand OA at baseline. BMD was significantly lowered in patients with erosive compared with non-erosive disease at baseline (lumbar spine: 1.05g/cm2 vs. 1.13 g/cm2, p<0.05, total femur: 0.90 g/cm2 vs. 0.97 g/cm2, p<0.01 and femur neck: 0.86 g/cm2 vs. 0.91, p<0.05). T-scores of lumbar spine (-0.96 vs. -0.41 SD, p<0.05), total femur (-0.69 vs. -0.33 SD, p<0.05) and femur neck (-1.14 vs. -0.88 SD, p<0.05) were also significantly lowered in patients with erosive compared with non-erosive disease.Two years, the BMD remained also significantly lowered in patients with erosive compared with non-erosive disease (lumbar spine: 1.05g/cm2 vs. 1.14 g/cm2, p<0.05, total femur: 0.92 g/cm2 vs. 0.97 g/cm2, p<0.05 and femur neck: 0.86 g/cm2 vs. 0.91, p<0.05), which was in agreement with the finding for T-scores of lumbar spine (-1.05 vs. -0.39 SD, p<0.05), total femur (-0.74 vs. -0.34 SD, p<0.01) and femur neck (-1.07 vs. -0.72 SD, p<0.01).Conclusion:These results suggest that patients with erosive hand OA are at higher risk for the development of general bone loss. Over two years patients with erosive disease had significant lower bone mineral density at all measured sites.References:[1]This work was supported by the project AZV no. 18-00542 and MHCR No. 023728.Acknowledgments:Project AZV no. 18-00542 and MHCR No. 023728Disclosure of Interests:Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Ladislav Šenolt: None declared, Olga Sleglova: None declared, Jiří Baloun: None declared, Olga Růžičková: None declared

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Conditional disruption of IGF-I gene in type 1α collagen-expressing cells shows an essential role of IGF-I in skeletal anabolic response to loading

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00440.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. E1191-E1197 ◽

Cited By ~ 41

Author(s):

Chandrasekhar Kesavan ◽

Jon E. Wergedal ◽

K.-H. William Lau ◽

Subburaman Mohan

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Mechanical Strain ◽

Bone Size ◽

Size Difference ◽

Mineral Density ◽

Trabecular Thickness ◽

Bone Response ◽

Igf I ◽

I Gene

To establish a causal role for locally produced IGF-I in the mechanical strain response in the bone, we have generated mice with conditional disruption of the insulin-like growth factor (IGF) I gene in type 1α2 collagen-expressing cells using the Cre-loxP approach. At 10 wk of age, loads adjusted to account for bone size difference were applied via four-point bending or axial loading (AL) in mice. Two wk of bending and AL produced significant increases in bone mineral density and bone size at the middiaphysis of wild-type (WT), but not knockout (KO), mice. In addition, AL produced an 8–25% increase in trabecular parameters (bone volume-tissue volume ratio, trabecular thickness, and trabecular bone mineral density) at the secondary spongiosa of WT, but not KO, mice. Histomorphometric analysis at the trabecular site revealed that AL increased osteoid width by 60% and decreased tartrate-resistance acidic phosphatase-labeled surface by 50% in the WT, but not KO, mice. Consistent with the in vivo data, blockade of IGF-I action with inhibitory IGF-binding protein (IGFBP4) in vitro completely abolished the fluid flow stress-induced MC3T3-E1 cell proliferation. One-way ANOVA revealed that expression levels of EFNB1, EFNB2, EFNA2, EphB2, and NR4a3 were different in the loaded bones of WT vs. KO mice and may, in part, be responsible for the increase in bone response to loading in the WT mice. In conclusion, IGF-I expressed in type 1 collagen-producing bone cells is critical for converting mechanical signal to anabolic signal in bone, and other growth factors cannot compensate for the loss of local IGF-I.

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