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Pomegranate Stimulates Mouse Osteoblast Cells

Abstract

Stimulation of osteoblastic differentiation and inhibition of interleukin-6 and nitric oxide in MC3T3-E1 cells by pomegranate ethanol extract.

In this experiment, we studied the effects of pomegranate fruit extract (PE) on the function of osteoblastic MC3T3-E1 cells and the production of local factors in osteoblasts. PE (16 approximately 250 microg/ml) significantly increased the growth of MC3T3-E1 cells (P < 0.05). Moreover, PE (50 microg/ml) caused a significant elevation of alkaline phosphatase (ALP) activity and collagen content in the cells. We then examined the effect of PE on the TNF-alpha-induced production of interleukin-6 (IL-6) and nitric oxide (NO) in osteoblasts. Treatment with PE (10 approximately 50 microg/ml) decreased the TNF-alpha (10(-10) M)-induced production of IL-6 and NO in osteoblasts.

Kim YH, Choi EM
Phytother Res May 2009
PMID: 19107859

Pomegranate Improves Bone Formation and Resorption in Mice

Abstract

Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice.

Pomegranate is known to contain estrogens (estradiol, estrone, and estriol) and show estrogenic activities in mice. In this study, we investigated whether pomegranate extract is effective on experimental menopausal syndrome in ovariectomized mice. Prolongation of the immobility time in forced swimming test, an index of depression, was measured 14 days after ovariectomy. The bone mineral density (BMD) of the tibia was measured by X-ray absorptiometry and the structure and metabolism of bone were also analyzed by bone histomorphometry. Administration of pomegranate extract (juice and seed extract) for 2 weeks to ovariectomized mice prevented the loss of uterus weight and shortened the immobility time compared with 5% glucose-dosed mice (control). In addition, ovariectomy-induced decrease of BMD was normalized by administration of the pomegranate extract. The bone volume and the trabecular number were significantly increased and the trabecular separation was decreased in the pomegranate-dosed group compared with the control group. Some histological bone formation/resorption parameters were significantly increased by ovariectomy but were normalized by administration of the pomegranate extract. These changes suggest that the pomegranate extract inhibits ovariectomy-stimulated bone turnover. It is thus conceivable that pomegranate is clinically effective on a depressive state and bone loss in menopausal syndrome in women.

Mori-Okamoto J, Otawara-Hamamoto Y, Yamato H, Yoshimura H
J Ethnopharmacol May 2004
PMID: 15099854

Cissus Inhibits Bone Loss in Mice

Abstract

Inhibition of Bone Loss by Cissus quadrangularis in Mice: A Preliminary Report.

Women drastically loose bone during and after menopause leading to osteoporosis, a disease characterized by low bone mass increasing the risk of fractures with minor trauma. Existing therapies mainly reduce bone resorption, however, all existing drugs have severe side effects. Recently, the focus is to identify alternative medicines that can prevent and treat osteoporosis with minimal or no side effects. We used Cissus quadrangularis (CQ), a medicinal herb, to determine its effects on bone loss after ovariectomy in C57BL/6 mice. Two-month old mice were either sham operated or ovariectomized and fed CQ diet. After eleven weeks, mice were sacrificed and the long bones scanned using pQCT and μCT. In the distal femoral metaphysis, femoral diaphysis, and proximal tibia, control mice had decreased cancellous and cortical bone, while CQ-fed mice showed no significant differences in the trabecular number, thickness, and connectivity density, between Sham and OVX mice, except for cortical bone mineral content in the proximal tibia. There were no changes in the bone at the tibio-fibular junction between groups. We conclude that CQ effectively inhibited bone loss in the cancellous and cortical bones of femur and proximal tibia in these mice.

Banu J, Varela E, Bahadur AN, Soomro R…
J Osteoporos 2012
PMID: 22779034 | Free Full Text

The full study is available using the link above.

CQ may primarily attenuate bone resorption in OVX mice through the downregulation of proinflammatory cytokines but it does not rule out the possibility that it may also act through other pathways. There are reports that CQ also enhances bone mineralization by accumulating mucopolysaccharides at the site of bone formation [The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control14]. Moreover, CQ is reported to increase calcium uptake and mechanical properties of bone in rats [The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control15]. Phytochemical analyses of CQ show the presence of high levels of calcium, vitamin C, β-carotene [The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control38, The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control39], and flavanoids [The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control25] some of these substances have established beneficial properties on bone. In vitro studies have shown that ethanolic extracts of CQ increased mRNA and proteins related to the bone formation pathway and IGF-I, IGF-II, and IGF binding protein [The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control40, The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control41]. More investigations are necessary to elucidate the mechanism(s) by which CQ influences bone metabolism. However, it is very encouraging to note that in studies done with CQ using very high doses (5000mg/kgbodyweight) [The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control9] have not reported any toxic side effects. In the present study, we have used only 500mg/kgbodyweight of CQ and observed that the liver, spleen, and kidney weights were not altered significantly, suggesting that CQ may not have any severe side-effects….

We conclude that CQ can reduce OVX induced bone loss and it does this in the long bones in a site-specific manner with more effects on the cancellous bone of femur followed by tibia. CQ probably reduces bone resorption primarily by downregulating proinflammatory cytokines that are often increased after ovariectomy. The beneficial effects of CQ are probably due to the flavanoids present.

 

Cissus as a Phytoestrogen-Rich Fraction Compared to Estrogen in Rats

Abstract

Antiosteoporotic activity of phytoestrogen-rich fraction separated from ethanol extract of aerial parts of Cissus quadrangularis in ovariectomized rats.

Cissus quadrangularis L. (C. quadrangularis L.) (Vitaceae) has been reported in Ayurveda for its antiosteoporotic activity. The study separated the phytoestrogen-rich fraction (IND-HE) from aerial parts of C. quadrangularis L. and evaluated its effect on osteoporosis caused by ovariectomy in rats.
IND-HE was separated from the ethanol extract of C. quadrangularis. Ovariectomized female Wistar rats were divided into four groups (n = 6). Group 1: Control (distilled water), Group II: IND-HE (75 mg/kg p.o.), Group III: IND-HE (100 mg/kg p.o.) were treated once daily for 8 weeks and Group IV: standard estradiol group, received estrogen (1 mg/kg, s.c. bi-weekly). The effects on body weight were determined. DEXA (Dual energy-emission X-ray absorptimatory analysis) of whole body bone and femur was carried out. Blood was removed and analyzed for biochemical parameters. After sacrificing the animals, biomechanical study of right tibia and histopathology of pelvic bone was carried out.
IND-HE showed presence of phytoestrogen-rich fraction. IND-HE (75 and 100 mg/ kg) and estrogen treatment showed statistically significant increase in bone thickness, bone density and bone hardness. IND-HE (75 and 100 mg/kg) and estrogen treatment significantly increased serum estradiol. IND-HE (100 mg/kg) (P<0.05) and estrogen treatment increased serum vitamin D3 and serum calcium compared to control. Alkaline phosphatase was significantly reduced by IND-HE (100 mg/kg p.o.) and estrogen treatment. Histopathology and DEXA results indicated that IND-HE (75 and 100 mg/kg) prevented bone loss.
These findings confirm that phytoestrogen-rich fraction (IND- HE) possess good antiosteoporotic activity.

Aswar UM, Mohan V, Bodhankar SL
Indian J Pharmacol May 2012
PMID: 22701244 | Free Full Text

Cissus Reduces Bone Loss in Rats

Abstract

Evidence-based assessment of antiosteoporotic activity of petroleum-ether extract of Cissus quadrangularis Linn. on ovariectomy-induced osteoporosis.

The increasing incidence of postmenopausal osteoporosis and its related fractures have become global health issues in the recent days. Postmenopausal osteoporosis is the most frequent metabolic bone disease; it is characterized by a rapid loss of mineralized bone tissue. Hormone replacement therapy has proven efficacious in preventing bone loss but not desirable to many women due to its side-effects. Therefore we are in need to search the natural compounds for a treatment of postmenopausal symptoms in women with no toxic effects. In the present study, we have evaluated the effect of petroleum-ether extract of Cissus quadrangularis Linn. (CQ), a plant used in folk medicine, on an osteoporotic rat model developed by ovariectomy. In this experiment, healthy female Wistar rats were divided into four groups of six animals each. Group 1 was sham operated. All the remaining groups were ovariectomized. Group 2 was fed with an equivolume of saline and served as ovariectomized control (OVX). Groups 3 and 4 were orally treated with raloxifene (5.4 mg/kg) and petroleum-ether extract of CQ (500 mg/kg), respectively, for 3 months. The findings were assessed on the basis of animal weight, morphology of femur, and histochemical localization of alkaline phosphatase (ALP) (an osteoblastic marker) and tartrate-resistant acid phosphatase (TRAP) (an osteoclastic marker) in upper end of femur. The study revealed for the first time that the petroleum-ether extract of CQ reduced bone loss, as evidenced by the weight gain in femur, and also reduced the osteoclastic activity there by facilitating bone formation when compared to the OVX group. The osteoclastic activity was confirmed by TRAP staining, and the bone formation was assessed by ALP staining in the femur sections. The color intensity of TRAP and ALP enzymes from the images were evaluated by image analysis software developed locally. The effect of CQ was found to be effective on both enzymes, and it might be a potential candidate for prevention and treatment of postmenopausal osteoporosis. The biological activity of CQ on bone may be attributed to the phytogenic steroids present in it.

Potu BK, Rao MS, Nampurath GK, Chamallamudi MR…
Ups. J. Med. Sci. 2009
PMID: 19736603 | Free Full Text

Cissus Stimulates Fetal Bone in Rats

Abstract

Petroleum ether extract of Cissus quadrangularis (LINN) stimulates the growth of fetal bone during intra uterine developmental period: a morphometric analysis.

The aim of the present study was to analyze the effect Cissus quadrangularis plant petroleum ether extract on the development of long bones during the intra-uterine developmental stage in rats.
Pregnant rats (n=12) were randomly assigned into either a control group (n=6) or a Cissus quadrangularis treatment (n=6) group. Pregnant rats in the Cissus quadrangularis group were treated with Cissus quadrangularis petroleum ether extract at a dose of 500 mg/kg body weight from gestation day 9 until delivery. The animals in the control group received an equal volume of saline. Newborn pups were collected from both groups for alizarin red S – alcian blue staining to differentiate ossified and unossified cartilage. The ossified cartilage (bone) was morphometrically analyzed using Scion image software.
Morphometric analysis revealed that the percentage of the total length of ossified cartilage (bone) in pups born to treated dams was significantly higher (P<0.001- -0.0001) than that of the control group.
The results of the present study suggest that maternal administration of Cissus quadrangularis petroleum ether extract during pregnancy can stimulate the development of fetal bone growth during the intra-uterine developmental period.

Potu BK, Rao MS, Kutty NG, Bhat KM…
Clinics (Sao Paulo) Dec 2008
PMID: 19061006 | Free Full Text

Cissus May Increase Osteoblasts via MAPK

Abstract

Cissus quadrangularis extract enhances biomineralization through up-regulation of MAPK-dependent alkaline phosphatase activity in osteoblasts.

Cissus quadrangularis Linn. has been implicated as therapeutic agent for enhancing bone healing. Though its osteogenic activity has been suggested, the underlying mechanism still remains unclear. In the present study, the effects of ethanol extract of C. quadrangularis (CQ-E) on osteoblast differentiation and function were analyzed using murine osteoblastic cells. The results indicated that mRNA expressions of osteoblast-related genes were not affected by the CQ-E treatment. However, alkaline phosphatase (ALP) activity and the extent of mineralized nodules were significantly increased in treated cells compared with controls. The addition of an extracellular regulated kinase 1/2 inhibitor, a Jun N-terminal kinase 1/2/3 inhibitor and a p38 mitogen-activated protein kinase (MAPK) inhibitor resulted in significantly decreased ALP activity, preferentially by p38 MAPK inhibitor. These results suggested that CQ-E may regulate osteoblastic activity by enhancing ALP activity and mineralization process, and the increased ALP activity effect of CQ-E is likely mediated by MAPK-dependent pathway.

Parisuthiman D, Singhatanadgit W, Dechatiwongse T, Koontongkaew S
In Vitro Cell. Dev. Biol. Anim.
PMID: 19057968

Alendronate + Exercise Prevents All Bone Loss During Spaceflight

Abstract

Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight.

We report the results of alendronate ingestion plus exercise in preventing the declines in bone mass and strength and elevated levels of urinary calcium and bone resorption in astronauts during 5.5 months of spaceflight.
This investigation was an international collaboration between NASA and the JAXA space agencies to investigate the potential value of antiresorptive agents to mitigate the well-established bone changes associated with long-duration spaceflight.
We report the results from seven International Space Station (ISS) astronauts who spent a mean of 5.5 months on the ISS and who took an oral dose of 70 mg of alendronate weekly starting 3 weeks before flight and continuing throughout the mission. All crewmembers had available for exercise a treadmill, cycle ergometer, and a resistance exercise device. Our assessment included densitometry of multiple bone regions using X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and assays of biomarkers of bone metabolism.
In addition to pre- and post-flight measurements, we compared our results to 18 astronauts who flew ISS missions and who exercised using an early model resistance exercise device, called the interim resistance exercise device, and to 11 ISS astronauts who exercised using the newer advanced resistance exercise device (ARED). Our findings indicate that the ARED provided significant attenuation of bone loss compared with the older device although post-flight decreases in the femur neck and hip remained. The combination of the ARED and bisphosphonate attenuated the expected decline in essentially all indices of altered bone physiology during spaceflight including: DXA-determined losses in bone mineral density of the spine, hip, and pelvis, QCT-determined compartmental losses in trabecular and cortical bone mass in the hip, calculated measures of fall and stance computed bone strength of the hip, elevated levels of bone resorption markers, and urinary excretion of calcium.
The combination of exercise plus an antiresoptive drug may be useful for protecting bone health during long-duration spaceflight.

Leblanc A, Matsumoto T, Jones J, Shapiro J…
Osteoporos Int Jul 2013
PMID: 23334732

Biking May Help Bones Affected by High Cortisol

Abstract

Effect of physiological exercise on osteocalcin levels in subjects with adrenal incidentaloma.

In the present study, we have evaluated whether physical exercise affect low osteocalcin concentrations observed in patients with subclinical hypercortisolism.
Sixteen patients (10 men and 6 women, age 38-55 yr) with adrenal incidentaloma were studied. Fifteen healthy volunteers matched for age (range 35-47 yr) were used as controls. Subjects were submitted to a 8-week exercise-training program with cycle-ergometer for 1 h/day 3-4 days/week at 60% of their individual VO2 max. Before and after this period, resting venous serum osteocalcin and GH concentrations were measured in the same batch. The blood sampling after 8 weeks of the training program were performed after resting for one day. All patients and controls underwent also the following endocrine evaluation: serum cortisol, plasma ACTH.
Our results demonstrate a significant increase of osteocalcin after physical exercise and a positive correlation between osteocalcin and GH. This later might suggest a role of GH in the increased osteocalcin secretion.
The data of the present study suggest a positive effect of physical exercise on bone metabolism in patients with adrenal incidentaloma.

Coiro V, Volpi R, Cataldo S, Magotti MG…
J. Endocrinol. Invest. Apr 2012
PMID: 22652825

It is surprising the exercise helped considering the form of exercise was cycling – a non-weight bearing exercise.

Resistance Exercise Prevents Bone Loss During Spaceflights

Abstract

Benefits for bone from resistance exercise and nutrition in long-duration spaceflight: Evidence from biochemistry and densitometry.

Exercise has shown little success in mitigating bone loss from long-duration spaceflight. The first crews of the International Space Station (ISS) used the “interim resistive exercise device” (iRED), which allowed loads of up to 297 lb(f) (or 1337 N) but provided little protection of bone or no greater protection than aerobic exercise. In 2008, the Advanced Resistive Exercise Device (ARED), which allowed absolute loads of up to 600 lb(f) (1675 N), was launched to the ISS. We report dietary intake, bone densitometry, and biochemical markers in 13 crewmembers on ISS missions from 2006 to 2009. Of these 13, 8 had access to the iRED and 5 had access to the ARED. In both groups, bone-specific alkaline phosphatase tended to increase during flight toward the end of the mission (p = 0.06) and increased 30 days after landing (p < 0.001). Most markers of bone resorption were also increased in both groups during flight and 30 days after landing (p < 0.05). Bone densitometry revealed significant interactions (time and exercise device) for pelvis bone mineral density (BMD) and bone mineral content (p < 0.01), hip femoral neck BMD (p < 0.05), trochanter BMD (p < 0.05), and total hip BMD (p < 0.05). These variables were unchanged from preflight only for ARED crewmembers, who also returned from flight with higher percent lean mass and lower percent fat mass. Body mass was unchanged after flight in both groups. All crewmembers had nominal vitamin D status (75 ± 17 nmol/L) before and during flight. These data document that resistance exercise, coupled with adequate energy intake (shown by maintenance of body mass determined by dual-energy X-ray absorptiometry [DXA]) and vitamin D, can maintain bone in most regions during 4- to 6-month missions in microgravity. This is the first evidence that improving nutrition and resistance exercise during spaceflight can attenuate the expected BMD deficits previously observed after prolonged missions.

Smith SM, Heer MA, Shackelford LC, Sibonga JD…
J. Bone Miner. Res. Sep 2012
PMID: 22549960