PURPOSE: Genetic factor is an important predisposing element influencing the susceptibility to osteoporosis and related complications. The purpose of the present study is to investigate whether genetic polymorphisms of farnesyl diphosphate synthase (FDPS) or geranylgeranyl diphosphate synthase (GGPS) genes were associated with the response to bisphosphonate therapy. MATERIALS AND METHODS: In the present study, 144 Korean women with osteoporosis were included. Among 13 genetic polymorphisms found within the FDPS and GGPS1 gene, 4 genetic polymorphisms with frequencies > 5% were selected for further study. Bone mineral density (BMD) response after 1 year treatment of bisphosphonate therapy was analyzed according to the genotypes. RESULTS: Women with 2 deletion allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher femoral neck BMD at baseline compared with those with one or no deletion allele (0.768 +/- 0.127 vs. 0.695 +/- 0.090 respectively; p = 0.041). The response rate of women with 2 deletion allele of GGPS1 -8188A ins/del (28.6%) was significantly lower than the rate of women with one (81.4%) or no deletion allele (75.0%) (p = 0.011). Women with 2 deletion allele of GGPS1 -8188A ins/del had 7-fold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188 after adjusting for baseline BMD (OR = 7.48; 95% CI = 1.32-42.30; p = 0.023). Other polymorphisms in FDPS or GGPS1 were not associated with lumbar spine BMD or femoral neck BMD. CONCLUSION: Our study suggested that GGPS1 - 8188A ins/del polymorphism may confer susceptibility to femoral neck BMD response to bisphosphonate therapy in Korean women. However, further study should be done to confirm the results in a larger population.
Aged ; Asian Continental Ancestry Group ; Bone Density/*drug effects/*genetics ; Bone Density Conservation Agents/*pharmacology ; Dimethylallyltranstransferase/*genetics ; Diphosphonates/*pharmacology ; Farnesyltranstransferase/*genetics ; Female ; Geranyltranstransferase/*genetics ; Humans ; Middle Aged ; Polymorphism, Genetic/*genetics

Objective: To investigate the effect of resveratrol on peak bone mineral density and bone mass in growing rats. Methods: Thirty-six female healthy Wistar rats were randomly divided into control group, icariin group and resveratrol group with 12 rats in each group. Icariin (25 mg·kg^-1·d^-1), resveratrol (8.4 mg·kg^-1·d^-1) or equal volume of distilled water were given by gavage to icariin group, resveratrol group and control group, respectively. The rats were sacrificed after 12 weeks. The organ indexes were calculated and pathology sections were observed; the bone mineral density (BMD), bone biomechanics, serum bone metabolism index, and results of micro-CT scan were analyzed. Results: During the experiment, the body weight of rats showed an increasing trend and there was no significant difference among three groups (P0.05). There were no significant differences in organ index of vital organs and pathological changes among the groups (all P0.05). Compared with the control group, the whole body BMD, and the BMDs of femur and vertebrae in icariin and resveratrol groups were significantly increased after 12 weeks (all P<0.05). The maximum load values of femur and vertebrae, as well as elastic modulus of vertebrae in icariin and resveratrol groups were significantly higher than those in control group (P<0.05 or P<0.01). Micro-CT scan showed that the volumetric BMD, number of trabecular, trabecular thickness and bone volume/tissue volume of the cancellous bone in icariin and resveratrol groups were significantly higher and the trabecular separation was significantly lower than those in the control group (P<0.05 or P<0.01); while there was no significant difference in volumetric BMD of cortical bone for femur. The contents of osteocalcin in icariin and resveratrol groups were significantly higher than those in control group (all P<0.05), while the contents of tartarte-resistant acid phosphatase 5b (TRACP5b) were significantly lower than those in control group (all P<0.05).Conclusion: Resveratrol can inhibit bone resorption and enhance bone formation, so as to improve the peak bone mass and bone density, enhance bone strength and improve the microstructure of bone tissue in young rats.
Animals ; Bone Density ; drug effects ; Bone and Bones ; diagnostic imaging ; drug effects ; Female ; Femur ; drug effects ; Osteocalcin ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Resveratrol ; pharmacology ; Tartrate-Resistant Acid Phosphatase ; genetics ; metabolism

OBJECTIVETo investigate the association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride(RLX) on bone mineral density (BMD) and bone turnover markers in postmenopausal women with osteoporosis.

METHODSA total of 68 unrelated postmenopausal women with osteoporosis of Han ethnicity aged 47-74 years were randomly divided into 2 groups of 34 women: RLX group (60 mg were given daily for 12 months) and placebo group. BMD and bone turnover markers were measured at baseline, 6 and 12 months after treatment. The polymorphisms of Xba I and Pvu II sites in estrogen receptor 1 gene(ESR1), Ras I site in ESR2 gene, and start codon (Fok I) and CDX2 binding sites in vitamin D receptor gene (VDR) were analyzed.

RESULTSA total of 58 patients completed 12 months of study period. By the end of study, the increased percentage of BMD in lumbar spine 2-4 (L2-4), total hip, and trochanter were found significantly different between RLX group and placebo group(P<0.05), and the decreased percentage of C-telopeptide and osteocalcin were significantly different between the two groups (P<0.01). The BMD of total hip and trochanter of women with FF genotypes of VDR Fok I site were decreased by 1.98%+/-4.86% and 2.26%+/-4.73% respectively in the RLX group, but those of women with Ff/ff genotypes were increased by 2.52%+/-2.75% and 2.74 %+/-2.97%, respectively(P<0.05). Moreover, the total hip BMD of women with PP/Pp genotypes of ESR1 Pvu II site was increased by 2.12%+/-2.78%, and of women with pp genotype it was decreased by 1.34%+/-3.73%(P<0.05). However, no significant association was observed of the polymorphisms of five sites with the changes of BMD and bone turnover markers in the placebo group.

CONCLUSIONThe effect of RLX on BMD in postmenopausal women with osteoporosis is regulated by the polymorphisms of Fok I of VDR gene and Pvu II of ESR1 gene. The study is valuable to select this drug according to genotype of patients in clinical.

Aged ; Biomarkers ; metabolism ; Bone Density ; drug effects ; genetics ; Bone Diseases, Metabolic ; genetics ; metabolism ; Bone Remodeling ; drug effects ; genetics ; Bone and Bones ; drug effects ; Double-Blind Method ; Female ; Humans ; Middle Aged ; Osteoporosis ; drug therapy ; Osteoporosis, Postmenopausal ; drug therapy ; Polymorphism, Genetic ; Postmenopause ; drug effects ; Raloxifene Hydrochloride ; pharmacology ; therapeutic use ; Selective Estrogen Receptor Modulators ; pharmacology ; Women

OBJECTIVETo investigate the molecular mechanism of TFE (total flavone of epimedium) in the treatment of osteoporosis, and then provide experimental evidence for modernization and further development of TFE as an traditional Chinese medicine.

METHODSSixty healthy female SD rats with aged 4 months were randomly divided into three groups (including control group in which rats received sham surgery, OVX group in which ovariectomized rats didn't give any medicine after the removal of ovaries and TFE group in which ovariectomized rats administrated TFE), 20 rats in each group. Compared bone mineral density (BMD) between before operation and at 4th week after operation in order to verify the establishment of osteoporotic model (criteria: BMD decreased more than 20% at 4th week after operation). The rats in TEF group were administrated total flavone of epimedium(concentration 30 mg/ml, 10 ml/kg, qd) orally for 4 weeks. After this, killed rats to harvest the lower part of the femur and detected BMD again. Applying the reverse transcriptase-polymerase chain reaction technique (RT-PCR) to detect expression of OPG, OPGL mRNA in bone tissue.

RESULTS(1) At 4th week after ovariectomy, the mean BMD of lumbar vertebra in TFE group fell to (0.084 +/- 0.020) g/cm2. Administrated with TFE for 4 weeks,the BMD increased to (0.112 +/- 0.009) g/cm2. There was significant improvement compare with the OVX group (P < 0.05). (2) Compared between OVX group and TFE group, The OPG mRNA expression of TFE group obviously enhanced. There was significant difference in statistics (P < 0.05). However,the promotion for OPGL mRNA expression were detected between OVX group and TFE group,there was no significant difference in statistics (P > 0.05).

CONCLUSIONThis study showed that TFE could inhibit differentiation and maturation of osteoclast through enhancing OPG mRNA expression, accordingly,to treat osteoporosis.

Animals ; Bone Density ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Epimedium ; chemistry ; Female ; Flavones ; Flavonoids ; pharmacology ; Gene Expression Regulation ; drug effects ; Osteoblasts ; drug effects ; metabolism ; physiology ; Osteoprotegerin ; genetics ; Ovariectomy ; RANK Ligand ; genetics ; RNA, Messenger ; genetics ; metabolism ; Rats

OBJECTIVETo explore the role of bone morphogenetic protein-7 (BMP-7) in strontium ranelate (Sr)-induced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).

METHODSBMSCs were isolated from 4-week-old rats and cultured in vitro. The third or fourth passages of BMSCs were examined using alkaline phosphatase kit for changes in ALP activity in response to treatment with different concentrations of Sr. Calcium nodules in the induced cells were detected using alizarin red staining, and the cellular BMP-7 expression was detected by Western blotting.

RESULTSWithin the concentration range of 0.1-3.0 mmol/L, Sr dose-dependently increased ALP activity in rat BMSCs. ALP activity reached the highest level after treatment with 3 mmol/L Sr, which also significantly promoted the formation of calcium nodules. Within the range of 0.1-3.0 mmol/L, Sr dose-dependently enhanced the expression of BMP-7, and its peak expression occurred following 3 mmol/L Sr treatment. Noggin (100 ng/ml), an inhibitor of BMP-7, obviously suppressed Sr-induced over-expression of BMP-7 and reduced ALP activity and calcium nodule formation in the BMSCs.

CONCLUSIONSr promotes osteogenic differentiation of rat BMSCs by increasing the expression of BMP-7.

Animals ; Bone Density Conservation Agents ; pharmacology ; Bone Marrow Cells ; cytology ; Bone Morphogenetic Protein 7 ; genetics ; metabolism ; Cell Differentiation ; drug effects ; Cells, Cultured ; Female ; Male ; Mesenchymal Stromal Cells ; cytology ; metabolism ; Organometallic Compounds ; pharmacology ; Osteoblasts ; cytology ; Osteogenesis ; drug effects ; Rats ; Thiophenes ; pharmacology

OBJECTIVETo investigate the treatment effects and mechanisms of pyrroloquinoline quinine(PQQ) on defective teeth and mandible in Bmi-1 knockout mice.

METHODSMale and female Bmi1(+/-) mice were paired with each other from the same nest. At the age of 7 weeks, the mice were divided into three groups, the wild type mice received normal diet(10 mice, WT group), Bmi1(-/-) mice received normal diet (10 mice, BKO group), and the Bmi1(-/-) mice received normal diet and PQQ diet(10 mice, BKO+PQQ group). X-ray and micro- CT were used to detect mandible and dental size and bone mineral density. HE staining, histochemical and immunohistochemical methods were respectively used to detect alveolar bone thickness of cortical bone, predentin thickness of mandibular first molar, mandibular osteoblast number and osteoclast number. Flow cytometry was used to detect reactive oxygen species(ROS) levels of various organs(femur, thymus and liver). The data were statistically analyzed with one-way ANOVA and t test.

RESULTSCompared with BKO mice, BKO+PQQ mice partially rescued total body phenotype, increased body weight and prolonged survival time. X- ray and micro- CT showed the size of the mandible and teeth and bone mineral density of PQQ+BKO mice increased compared with BKO mice. In PQQ+BKO mice, mandibular alveolar bone cortical thickness [(68.65 ± 0.25) µm] was significantly different from that in BKO mice [(42.45 ± 0.35) µm] (P<0.01). There was significant difference in predentin thickness of mandibular first molar between PQQ+BKO mice [(4.25 ± 0.15) µm] and BKO mice [(31.55 ± 0.35) µm] (P<0.001). The number of osteoblasts in the mandible of BKO+PQQ mice [(38.45 ± 0.25) cell/mm³] was significantly higher than that in the BKO mice [(18.15 ± 0.55) cell/mm³] (P<0.01). However, the number of osteoclasts in the BKO+PQQ mice [(9.45 ± 0.25) cell/mm³] was significantly lower than that in the BKO group [(14.25 ± 0.35) cell/mm³] (P<0.01). Compared with the BKO group, ROS levels of the femur, thymus and liver in the BKO+PQQ mice were significantly decreased (P<0.01).

CONCLUSIONSThe results indicate that PQQ may have treatment effects on defective teeth and mandible through promoting osteoblast bone formation and reducing osteoclast bone resorption, scavenging ROS and reducing DNA damage.

Animals ; Bone Density ; drug effects ; Bone Resorption ; prevention & control ; Female ; Male ; Mandible ; drug effects ; pathology ; physiopathology ; Mice ; Mice, Knockout ; Organ Size ; Osteoblasts ; cytology ; drug effects ; Osteoclasts ; cytology ; drug effects ; Osteogenesis ; drug effects ; physiology ; PQQ Cofactor ; pharmacology ; Polycomb Repressive Complex 1 ; genetics ; Proto-Oncogene Proteins ; genetics ; Reactive Oxygen Species ; analysis ; Tooth ; drug effects ; pathology ; physiopathology ; X-Ray Microtomography

OBJECTIVETo investigate the preventive and therapeutic effect of Bushen Ningxin decoction (BSNX) on postmenopausal osteoporosis.

METHODSThe BALB/c female mice postmenopausal osteoporosis model was established. The model mice were treated by BSNX, with 17beta-estradiol (E2) and normal saline as positive and negative control, respectively. All mice were sacrificed after 12 weeks' treatment, the serum cytokines Th1/Th2, bone mineral density (BMD) of vertebrae (L3 - 4) and left femur were determined, and morphological quantitative analysis of bone tissue of right femurs was performed and osteoprotegerin (OPG) mRNA expression in tibia was detected by semi-quantitative RT-PCR. The ratio in weight of uterus to body was calculated, and uterine slice was gotten for histological observation.

RESULTSAs compared with the negative control group, the level of interferon-gamma (IFN-gamma) was significantly increased (P < 0.01) and interleukin-4 (IL-4) decreased (P < 0.05) in the BSNX treated group. The BMD of mice were improved, area of bone trabecula and OPG mRNA expression were increased in the BSNX treated and E2 treated group (P < 0.01). But the uterus in the former was significantly smaller than that in the latter (P < 0.01), while it was not significantly different to that in the negative control group.

CONCLUSIONBSNX can selectively prevent and cure the postmenopausal osteoporosis, it has no or slight stimulation on uterus. The mechanism may relate with its effects in regulating the deviation of Th1/Th2, enhancing the OPG expression and inhibiting the activity of osteoclasts.

Animals ; Bone Density ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Mice ; Mice, Inbred BALB C ; Osteoporosis ; drug therapy ; etiology ; Osteoprotegerin ; biosynthesis ; genetics ; Ovariectomy ; Phytotherapy ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Th1 Cells ; drug effects ; Th2 Cells ; drug effects

It is well known that estrogen can inhibit bone absorption, decrease bone turnover and preserve bone mass. Some studies indicated that the effect of estrogen on calcium and bone is relative to vitamin D system, while others also reported that this effect of estrogen is independent of vitamin D. The genomic effect of 1alpha, 25(OH)(2)D(3)is mediated by the nuclear vitamin D receptor (VDR) in a ligand-dependent manner. Hypocalcemia, hyperparathyroidism and osteomalacia are developed in VDR gene knockout mice. To determine whether the effect of estrogen on calcium and bone is dependent on VDR, this study examined the effect of exogenous estrogen on calcium and bone homeostasis in VDR gene knockout mice. Male and female wild type (WT) and VDR gene knockout heterozygous mice were mated each other and the genotyping of their offsprings were determined by PCR. At age of 21-day, WT and knockout mice were weaned and treated by one of three different regimens: (1) WT-vehicle group: the WT mice were injected with normal saline; (2) VDR KO-vehicle group: the VDR gene knockout mice were injected with normal saline; (3) VDR KO-E group: the VDR gene knockout mice were subcutaneously injected with estradiol, 0.2 mug per mouse, once daily for 1 month. The bone mineral density (BMD) of mice was measured using dual-energy X-ray absorptiometry. All mice were sacrificed at age of 50-day. Blood was taken by heart puncture under anesthesia and serum calcium was measured by autoanalyser.Tibiae were removed, fixed and embedded with the methylmethacrylate (MMA), and undecalcified sections were cut. These sections were stained for mineral with the von Kossa staining procedure and counterstained with toluidine blue. Static histomorphometric analyses were performed on those stained sections. The results showed that the serum calcium level was (2.10+/-0.37) mmol/L in the VDR KO-vehicle mice and rose to (2.80+/-0.41) mmol/L in the VDR KO-E mice although it was still lower than WT-vehicle mice [(3.10+/-0.48) mmol/L]. BMD and mineralized trabeculer volume were increased significantly in VDR KO-E group compared with that in VDR KO-vehicle group. These results suggest that exogenous estrogen can improve calcium absorption and skeletal mineralization in a VDR-independent manner.
Animals ; Bone Density ; Calcification, Physiologic ; drug effects ; Calcium ; metabolism ; Estrogens ; pharmacology ; Female ; Gene Knockout Techniques ; Homeostasis ; Mice ; Mice, Knockout ; Receptors, Calcitriol ; genetics

OBJECTIVETo investigate the association of estrogen receptor alpha (ER-alpha) PvuII polymorphisms with the effect of calcium supplementation on bone development in Chinese pubertal girls, and to study the importance of calcium supplementation by maximizing the peak bone mass at their pubertal stage for bone development and osteoporosis prevention and the role of estrogen in regulating bone mass.

METHODSNinety-four pubertal girls were recruited in the study and divided into two groups and three sub-groups according to the ER-alpha PvuII polymorphisms. One year before and after calcium supplementation, bone mineral density (BMD) was measured by DEXA, while BGP, BAP, TRACP5b, and 25-OH-VitD(3), as well as estrogen were detected by ELISA. Analysis of covariance was used to examine the effect of ER-alpha polymorphisms on bone development.

RESULTSThe absolute increase and percentage change of BGP were significantly higher in the supplemented group than in the control group (P<0.05). In the intervened group, The increase and percentage change of the total body and radio distal 1/3 BMD were higher in PP than in PP genotype (P<0.05), and the increase of BAP in Pp was also higher than PP in the same group (P<0.05).

CONCLUSIONPP genotype shows a better response to calcium supplementation than the other PvuII polymorphisms.

Adolescent ; Asian Continental Ancestry Group ; Biomarkers ; Bone Density ; drug effects ; Calcium ; administration & dosage ; pharmacology ; Dietary Supplements ; Estrogen Receptor alpha ; genetics ; Female ; Humans ; Polymorphism, Genetic ; Puberty ; physiology

OBJECTIVETo study the effect of eight specifications of Cervi Cornu Pantotrichum on the osteoporosis of ovariectomized rats and grade the eight different specifications of Cervi Cornu Pantotrichum.

METHODTotally 100 SD female rats were divided randomly into 10 groups, namely the normal group, the model group and eight Cervi Cornu Pantotrichum groups of different specifications. Their bilateral ovaries were excised to reproduce the osteoporosis model. Meanwhile, the rats were given the eight different specifications of Cervi Cornu Pantotrichum for consecutively 12 weeks. Subsequently, the effects of the different specifications of Cervi Cornu Pantotrichum on bone mineral density and serum biochemical indicators of rats were observed. A clustering analysis was made for the eight specifications of Cervi Cornu Pantotrichum, with the serum content of ALP, BMP-2 and BGP as influencing factors.

RESULTAfter 12 weeks, the eight different specifications of Cervi Cornu Pantotrichum could significantly improve ALP, BMP-2, BGP in serum and bone mineral density of ovariectomized rats. And the cluster analysis showed similar results to the quality classification of traditional commercial herbs Cervi Cornu Pantotrichum.

CONCLUSIONDifferent specifications of Cervi Cornu Pantotrichum can antagonize the osteoporosis of ovariectomized rats, and their effects are related to the quality of commercial herbs.

Animals ; Bone Density ; drug effects ; Bone Morphogenetic Protein 2 ; genetics ; metabolism ; Deer ; Disease Models, Animal ; Female ; Horns ; chemistry ; Humans ; Osteoporosis, Postmenopausal ; drug therapy ; genetics ; metabolism ; physiopathology ; Ovariectomy ; Rats ; Rats, Sprague-Dawley