Bone Protective Effects of Danggui Buxue Tang Alone and in Combination With Tamoxifen or Raloxifene in vivo and in vitro

Abstract

Danggui Buxue Tang (DBT), a traditional Chinese Medicine decoction containing Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), is commonly prescribed for women in China as a remedy for menopausal symptoms. Previous study indicated that DBT stimulated cell growth and differentiation of human osteosarcoma MG-63 cells and exhibited estrogenic properties via estrogen receptors (ERs). The present study aimed to study the bone protective effects of DBT and its potential interactions with selective estrogen receptor modulators (SERMs, tamoxifen and raloxifene) in both in vivo and in vitro models as they act via similar ERs. Six-month-old Sprague-Dawley rats were randomly assigned to the following treatments for 12 weeks: (1) sham-operated control group with vehicle (sham), (2) ovariectomized group with vehicle (OVX), (3) OVX with 17β-estradiol (E2, 2.0 mg/kg day), (4) OVX with tamoxifen (Tamo, 1.0 mg/kg day), (5) OVX with raloxifene (Ralo, 3.0 mg/kg day), (6) OVX with DBT (DBT, 3.0 g/kg day), (7) OVX with DBT+Tamoxifen (DBT+Tamo), and (8) OVX with DBT+Raloxifene (DBT+Ralo). Effects of DBT and potential interactions between DBT and SERMs were also evaluated in MG-63 cells. DBT, tamoxifen, raloxifene, and their combinations significantly increased bone mineral density (BMD) and improved trabecular bone properties, including bone surface (BS), trabecular bone number (Tb.N), and trabecular bone separation (Tb.Sp), as well as restored changes in bone turnover biomarkers and mRNA expression of genes involved in bone metabolism in OVX rats. Furthermore, DBT, SERMs, and their combinations significantly increased serum estradiol and suppressed follicle stimulating hormone and luteinizing hormone in OVX rats, suggesting the possible involvement of the hypothalamus–pituitary–gonadal axis in mediating their bone protective effects. However, SERMs, but not DBT, significantly increased uterus index in OVX rats. DBT significantly induced ALP activity and estrogen response element-dependent transcription in MG-63 cells. Our study demonstrated that DBT alone and in combinations with SERMs could exert bone protective effects in vitro and in vivo.

Drug-Herb Interaction Between Selective Estrogen Receptor Modulators and Estrogenic Herbal Medicine Er-Xian Decoction in Bone in Vivo and in Vitro

“…As expected, EXD and SERMs was effective in attenuating bone loss at three bone sites regarding BMD and bone microarchitecture in mature ovariectomized rats. EXD and SERMs could restore the serum OCN level, a speci c osteoblast product, and is considered a biomarker for bone formation [15] while only SERMs could restore urinary DPD level, a breakdown product of collagen during bone resorption and is a biomarker for bone resorption in OVX rats [13]. Afterward, we demonstrated that EXD could interact with SERMs to exert bone protection.…”

“…The dose of EXD, tamoxifen and raloxifene used in the present was selected based on our previous study and converted from its clinical dosages [11], while dosages of tamoxifen and raloxifene used in the present study were chosen based on our previous study in OVX rats [13], which are equivalent to 11 mg/kg.day and 33.3 mg/kg.day in human, respectively. These dosages are close to the clinical dosages of them (10-40 mg/kg.day of tamoxifen for breast cancer treatment, 60mg/kg.day of raloxifene for treatment and prevention of osteoporosis as well as prevention for breast cancer).…”

“…Sham-operated rats treated with vehicle were used as control. Dosages of E2, tamoxifen, raloxifene, and EXD were chosen based on equivalent human dosages and/or previous preclinical studies [11,13]. During the whole treatment, the animals were pair-fed with phytoestrogen-free diet (AIN-93M, Research diet, New Jersey, USA) to remove the in uence of phytoestrogens in the diet.…”

Selective Estrogen Receptor Modulator-Like Activities of Herba epimedii Extract and its Interactions With Tamoxifen and Raloxifene in Bone Cells and Tissues

“…Bone properties of the trabecular bone at the proximal tibia and distal femur as well as lumbar vertebra were determined by micro-CT (μCT40, Scanco Medical, Switzerland) as previously described ( Zhou et al, 2018 ). The source energy selected for this study was 70 KVp and 114 μA with a resolution of 21 μm.…”

Deciphering the Underlying Mechanism of Eucommiae Cortex against Osteoporotic Fracture by Network Pharmacology

“…TCM has been used in China for thousands of years, and it exerts a beneficial therapeutic effect and reduces side effects through multiple herb combinations to prevent and treat various diseases [ 12 ]. Meanwhile, TCM has increasingly been found to be effective in the treatment of osteoporosis [ 13 , 14 ].…”