Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

Abstract

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.

Retracted: Icariin attenuates methotrexate chemotherapy‐induced bone marrow microvascular damage and bone loss in rats

“…The nonsignificant changes in trabecular spacing and trabecular thickness observed in this study are also consistent with findings of previous investigations (T. J. King et al, 2012;T. King et al, 2015;Xian et al, 2007), and MTX-induced reduction in BV/TV (%) corresponded with the decrease in trabecular number as described previously .…”

Sinusoidal Electromagnetic Fields Increase Peak Bone Mass in Rats by Activating Wnt10b/β-Catenin in Primary Cilia of Osteoblasts

“…The stained sections were then observed and photographed under a light microscope. The cell densities of osteoblasts or TRAP‐positive multinuclear osteoclasts lining the surface of trabecular bone were measured in the secondary spongiosa of proximal tibias and expressed as cells/mm 2 trabecular area …”

“…The cell densities of osteoblasts or TRAP-positive multinuclear osteoclasts lining the surface of trabecular bone were measured in the secondary spongiosa of proximal tibias and expressed as cells/ mm 2 trabecular area. (29) For bone histomorphometric analyses, the rats were subcutaneously injected with calcein green (10 mg/kg) and tetracycline hydrochloride (20 mg/kg; Sigma), respectively, at 13 and 3 days prior to their sacrifice. The left tibia was fixed in 80% ethanol, processed without decalcification, and embedded in modified methylmethacrylate.…”

Childhood cancer chemotherapy–induced bone damage: pathobiology and protective effects of resveratrol and other nutraceuticals

“…No side effects were observed in humans or animals with its regular consumption . Recent studies have shown that genistein supplementation in rats with acute MTX treatment preserved osteogenesis and prevented bone loss and marrow adiposity …”