Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis

Miyanishi, Keita; Yamamoto, Takuaki; Irisa, T.; Yamashita, Akihisa; Jingushi, Seiya; Noguchi, Yasuo; Iwamoto, Yukihide

doi:10.1016/s8756-3282(01)00663-9

Cited by 153 publications

(148 citation statements)

References 30 publications

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“…Consistent with previous studies, we also found compression of blood vessels by enlarged bone marrow fat cells (Fig. 5A) in the control group, which could decrease blood perfusion and lead to ischemia [22,30]. The decreased size of fat cells in LIPUS-treated limbs could decrease the intramedullary pressure and improve blood perfusion.…”

Section: Discussionsupporting

confidence: 92%

“…The decreased activity of MSCs results in inadequate bone repair, which may be a triggering step leading to the onset and pathogenesis of steroid-associated osteonecrosis [13,14]. The reduced trabecular bone volume, enlarged fat cells, and poor mechanical properties observed in steroid-associated osteonecrosis femoral heads are the result of reduced osteogenic differentiation and osteoblast activity [22,36]. The current study revealed substantially lower percentages of empty lacunae, thicker trabecular bones, and smaller fat cells in the femoral heads in the LIPUS group, suggesting better bone repair in LIPUS-treated steroid-associated osteonecrosis.…”

Section: Discussionmentioning

confidence: 99%

“…VEGF protein expression also was not different (p = 0.0124, Fig. 6) between the LIPUS group (23 ± 6; 95% CI, [19][20][21][22][23][24][25][26][27] and the control group (22 ± 6; 95% CI, 18-26).…”

Section: Bmp-2 and Vegf Expressionmentioning

confidence: 90%

“…This is partially because the exact pathophysiology of steroid-associated osteonecrosis is unclear. It is thought that steroids interrupt blood flow by damaging the endothelial cells and altering lipid metabolism, leading to the production of fat emboli [4,17,18,22]. Studies have shown that bone repair during the early stages of steroid-associated osteonecrosis is inadequate owing to the decreased activity of osteoblasts and bone marrow-derived stem cells after lengthy periods of steroid treatment [5,35].…”

Section: Introductionmentioning

confidence: 99%

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Low-intensity Pulsed Ultrasound Enhances Bone Repair in a Rabbit Model of Steroid-associated Osteonecrosis

Zhu

Cai

Lin

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Steroids are a leading cause of femoral head osteonecrosis. Currently there are no medications available to prevent and/or treat steroid-associated osteonecrosis. Low-intensity pulsed ultrasound (LIPUS) was approved by the FDA for treating delayed union of bone fractures. Some studies have reported that LIPUS can enhance bone formation and local blood flow in an animal model of fracture healing. However, whether the effect of osteogenesis and neovascularization by LIPUS can enhance the repair progress in steroid-associated osteonecrosis is unknown.Questions/purposes We hypothesized that LIPUS may facilitate osteogenesis and neovascularization in the reparative processes of steroid-associated osteonecrosis. Using a rabbit animal model, we asked whether LIPUS affects (1) bone strength and trabecular architecture; (2) blood vessel number and diameter; and (3) BMP-2 and VEGF expression. Methods Bilateral femoral head necrosis was induced by lipopolysaccharide and methylprednisolone in 24 rabbits. The left femoral heads of rabbits received LIPUS therapy (200 mW/cm 2 ) for 20 minutes daily and were classified as the LIPUS group. The right femoral heads of the same rabbits did not receive therapy and were classified as the control group. All rabbits were euthanized 12 weeks after LIPUS therapy. Micro-CT, biomechanical testing, histologic evaluation, immunohistochemistry, quantitative realtime PCR, and Western blot were used for examination of the effects of LIPUS. Results Twelve weeks after LIPUS treatment, the loading strength in the control group was 355 ± 38 N (95% CI, 315-394 N), which was lower (p = 0.028) than that in the LIPUS group (441 ± 78 N; 95% CI, 359-524 N). The bone tissue volume density (bone volume/total volume) in the LIPUS group (49.29% ± 12.37%; 95 % CI, 36.31%-62.27%) was higher (p = 0.022) than that in the control group (37.93% ± 8.37%; 95 % CI, 29.15%-46.72%). The percentage of empty osteocyte lacunae in the LIPUS group (17% ± 4%; 95% CI, 15%-20%) was lower (p = 0.002) than that in the control group (26% ± 9%; 95% CI, 21%-32%). The mineral apposition rate (lm/day) in the LIPUS group (2.3 ± 0.8 lm/day; 95% CI, 1.8 2.8 lm/day) was higher (p = 0.001) than that in the control group (1.6 ± 0.3 lm/day; 95% CL, 1.4-1.8 lm/day). The number of blood vessels in the LIPUS group (7.8 ± 3.6/mm 2 ; 95% CI, 5.5-10.1 mm 2 ) was greater (p = 0.025) than the number in Hanxiao Zhu and Xunzi Cai contributed equally to this work and should be considered as co-first authors.The institution of the authors has received funding from the National Natural Science Foundation of China (Hangzhou, Zhejiang, China) (81101377, 81101345, 81171687, 81371954, 81201414, 81201416, 81401785, 81472113) 123Clin Orthop Relat Res (2015) 473:1830-1839 DOI 10.1007 Clinical Orthopaedics and Related Research ® A Publication of The Association of Bone and Joint Surgeons® the control group (5.7 ± 2.6/mm 2 ; 95% CI, 4.0-7.3 mm 2 ). Messenger RNA (mRNA) and protein expression of BMP-2 in the LIPUS group (75 ± 7, 95% CI, 70-7...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Bmp-2 and Vegf Expressionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Low-intensity Pulsed Ultrasound Enhances Bone Repair in a Rabbit Model of Steroid-associated Osteonecrosis

Zhu

Cai

Lin

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…1). 14,21 The percentage necrotic area in each respective section was measured using a computerized image analyzing system (Nippon Poladigital Co., Tokyo, Japan; Fig. 2).…”

Section: Preparation Of Histological Sections and Detection Of Osteonmentioning

confidence: 99%

Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid‐induced osteonecrosis in a rabbit model

Masada

Iwakiri

Oda

et al. 2007

Journal Orthopaedic Research

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Low hepatic cytochrome P4503A (CYP3A) activities might play an important role for inducing osteonecrosis of the femoral head (ONFH) by corticosteroids. However, the relationship between hepatic CYP3A activity and steroid-induced ONFH is unknown. We have examined the relationship between hepatic CYP3A activity and the inducibility of ONFH in a rabbit model. Sixty rabbits were divided into three groups. Hepatic CYP3A inducer (phenobarbital, group P; n ¼ 15), inhibitor (itraconazole, group I; n ¼ 15), or saline (group C, n ¼ 30) was administrated for 3 weeks before intramuscular methylprednisolone. In groups P and I, hepatic CYP3A levels were measured by midazolam clearance before treatment (baseline) and before methylprednisolone injection. All animals were sacrificed 3 weeks after methylprednisolone injection and both femurs were harvested and examined histologically for osteonecrosis. Midazolam clearance was significantly increased and decreased, compared with baseline in groups P and I respectively (p < 0.0005, p < 0.002). The incidence of osteonecrosis in group P (33%) was significantly lower than in group I (100%) and group C (83%; p < 0.001 for both). The percentage necrotic area to whole bone marrow area on cross sections in group P (8.2 AE 5.9%) was significantly lower than in group I (69.8 AE 20.8%) and group C (51.5 AE 30.7%; p < 0.005 for both). Hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids, suggesting possible prevention of the steroid-induced osteonecrosis by reducing steroid dose in poor corticosteroid metabolizers. ß

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Combined effects of an anticoagulant and a lipid‐lowering agent on the prevention of steroid‐induced osteonecrosis in rabbits

Motomura¹,

Yamamoto²,

Miyanishi³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate the effects of combination treatment with an anticoagulant (warfarin) plus a lipid-lowering agent (probucol) on the prevention of steroid-induced osteonecrosis (ON) in rabbits.Methods. Adult male Japanese white rabbits were injected once intramuscularly with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were then divided into 4 groups and treated as follows: one group received warfarin plus probucol (WP; n ‫؍‬ 25), one received probucol alone (PA; n ‫؍‬ 30), one received warfarin alone (WA; n ‫؍‬ 26), and one received no treatment (nonprophylactic [NP]; n ‫؍‬ 20). Two weeks after the steroid injection, the femora and humeri were examined histopathologically for the presence of ON. The sizes of the bone marrow fat cells were examined morphologically. Hematologic examinations were performed before and after the steroid injection.Results. The incidence of ON in the WP group (5%) was significantly lower than that observed in the NP group (70%). While the incidence rates of ON in the PA (38%) and WA (33%) groups were also significantly lower than that in the NP group, they were significantly higher than that observed in the WP group. The sizes of the bone marrow fat cells in both the WP (53.5 ؎ 4.1 m) and the PA (52.0 ؎ 5.0 m) groups were significantly smaller than those in the NP group (60.0 ؎ 4.0 m). We also observed a prolongation of the prothrombin time and a reduction in the plasma lipid levels in the WP group during the study.Conclusion. This study experimentally confirmed that the combined use of an anticoagulant and a lipidlowering agent helps prevent steroid-induced ON in rabbits.

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Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis

Cited by 153 publications

References 30 publications

Low-intensity Pulsed Ultrasound Enhances Bone Repair in a Rabbit Model of Steroid-associated Osteonecrosis

Low-intensity Pulsed Ultrasound Enhances Bone Repair in a Rabbit Model of Steroid-associated Osteonecrosis

Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid‐induced osteonecrosis in a rabbit model

Combined effects of an anticoagulant and a lipid‐lowering agent on the prevention of steroid‐induced osteonecrosis in rabbits

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