Ovarian status influences the skeletal effects of tamoxifen in adult rats

Sibonga, Jean D.; Evans, Glenda L.; Hauck, Eric R.; Bell, Norman H.; Turner, Russell T.

doi:10.1007/bf01807038

Cited by 23 publications

(13 citation statements)

References 36 publications

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“…Dietary nitrate concentrations of ∼0.1 mmol/kg/d in rats have been demonstrated to lower blood pressure 16, and intakes of ∼372 mg total nitrate per day reverse vascular dysfunction in older adult humans 42. Three weeks of dietary nitrate supplementation, a period adequate to observe rapid OVX‐associated bone loss and treatment‐associated effects 43, had no effect on tibial cancellous or cortical bone mass and architecture or histomorphometric indices of bone formation or resorption in OVX rats. Furthermore, increased dietary nitrate had no significant effect on serum biochemical markers of bone turnover.…”

Section: Discussionmentioning

confidence: 99%

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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ScopeStudies suggest diets rich in fruit and vegetables reduce bone loss, although the specific compounds responsible are unknown. Substrates for endogenous nitric oxide (NO) production, including organic nitrates and dietary nitrate, may support NO production in age‐related conditions, including osteoporosis. We investigated the capability of dietary nitrate to improve NO bioavailability, reduce bone turnover and loss.Methods and resultsSix‐month‐old Sprague Dawley rats [30 ovariectomized (OVX) and 10 sham‐operated (sham)] were randomized into three groups: (i) vehicle (water) control, (ii) low‐dose nitrate (LDN, 0.1 mmol nitrate/kg bw/day), or (iii) high‐dose nitrate (HDN, 1.0 mmol nitrate/kg bw/day) for three weeks. The sham received vehicle. Serum bone turnover markers; bone mass, mineral density, and quality; histomorphometric parameters; and fecal microbiome were examined. Three weeks of LDN or HDN improved NO bioavailability in a dose‐dependent manner. OVX resulted in cancellous bone loss, increased bone turnover, and fecal microbiome changes. OVX increased relative abundances of Firmicutes and decreased Bacteroideceae and Alcaligenaceae. Nitrate did not affect the skeleton or fecal microbiome.ConclusionThese data indicate that OVX affects the fecal microbiome and that the gut microbiome is associated with bone mass. Three weeks of nitrate supplementation does not slow bone loss or alter the fecal microbiome in OVX.

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Section: Discussionmentioning

confidence: 99%

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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“…1991). These and more recent studies (Frolik et al 1996;Li et al 1996;Sibonga et al 1996;Ke et al 1997) have shown that tamoxifen prevents ovariectomy-induced bone loss. In intact female rats the results are somewhat conflicting, some studies show no effect (Jordan et al 1987;Moon et al 1991) whereas others show a slight tamoxifen-related decrease of bone tissue (Feldmann et al 1989;Hard et al 1993;Sibonga et al 1996).…”

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confidence: 87%

“…These and more recent studies (Frolik et al 1996;Li et al 1996;Sibonga et al 1996;Ke et al 1997) have shown that tamoxifen prevents ovariectomy-induced bone loss. In intact female rats the results are somewhat conflicting, some studies show no effect (Jordan et al 1987;Moon et al 1991) whereas others show a slight tamoxifen-related decrease of bone tissue (Feldmann et al 1989;Hard et al 1993;Sibonga et al 1996). In postmenopausal women, tamoxifen has been shown to lack negative effects on bone metabolism (Nakanishi et al 1995;Barni et al 1996;Kalef-Ezra et al 1996;Powles et al 1996) and some studies even indicate a weak antiosteoporotic effect (Nakanishi et al 1995;Barni et al 1996).…”

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confidence: 87%

The Effect of Toremifene on Bone and Uterine Histology and on Bone Resorption in Ovariectomised Rats

Karlsson¹,

Mäntylä²,

Hirsimäki³

et al. 1999

Pharmacology & Toxicology

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The effect of the selective oestrogen receptor modulator, toremifene, to inhibit ovariectomy-induced bone loss was studied in rats. The oral doses were 0.3, 3.0 or 30 mg/kg/day for 2 months. 17P-oestradiol ( 5 pgikgiday, subcutaneously) was used as positive control. One group was also treated with a combination of 17P-oestradiol (5 pgikg) and toremifene (3.0 mgikg). Biochemical markers were urinary hydroxyproline and calcium (adjusted with urinary creatinine levels) and the serum level of pyridinoline cross-linked carboxy terminal telopeptide, a bone specific collagen breakdown product. The femoral and sternal trabecular bone thickness served as histological parameters. Ovarectomy increased the levels of hydroxyproline and pyrodinoline and decreased the trabecular bone thickness compared to the sham-operated control group. This was inhibited by both test compounds but 17P-oestradiol was more efficient. Toremifene did not reverse the ovariectomy-induced reduction of urinary calcium but inhibited the 17P-oestradiol-related increase. When administered together with oestradiol, toremifene did not reverse the positive effect of 17P-oestradiol on bone, however toremifene reversed the oestradiol-related uterothrophic effects. These findings indicate that the antagonistic features of toremifene dominate in the rat uterus the agonistic properties do in the bone.

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“…These observations suggest similar skeletal mechanisms of action of estrogen in rats and humans. Furthermore, the skeletal changes in rats in response to partial estrogen agonists have accurately predicted the differential responses of pre-and postmenopausal women to tamoxifen treatment (10,11).…”

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confidence: 99%

Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain

Westerlind

Wronski

Ritman

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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141

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Estrogen deficiency induced bone loss is associated with increased bone turnover in rats and humans. The respective roles of increased bone turnover and altered balance between bone formation and bone resorption in mediating estrogen deficiency-induced cancellous bone loss was investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in the distal femur. However, cancellous bone was preferentially lost in the metaphysis, a site that normally experiences low strain energy. No bone loss was observed in the epiphysis, a site experiencing higher strain energy. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased and decreased in long bones of ovariectomized rats by treadmill exercise and functional unloading, respectively. Functional unloading was achieved during orbital spacef light and following unilateral sciatic neurotomy. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing loading accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in the unloaded and prevented loss in the loaded limb following unilateral sciatic neurotomy in part by reducing indices of bone turnover. These results suggest that estrogen regulates the rate of bone turnover, but the overall balance between bone formation and bone resorption is inf luenced by prevailing levels of mechanical strain.Ovarian hormone deficiency is the most important risk factor for postmenopausal osteoporosis (1, 2). Bone loss also occurs in premenopausal women following ovariectomy (OVX) (3) or treatment with gonadotrophin-releasing hormone agonists (4). Estrogen replacement therapy prevents bone loss in postmenopausal and ovariectomized women, suggesting that 17␤-estradiol is the gonadal hormone that is essential for normal bone balance.The mechanism for the skeletal effects of estrogen are incompletely understood but have been the subject of intense study in laboratory animal models (5). The rat has proven to be especially useful. OVX and gonadotrophin-releasing hormone agonists result in bone loss in rats, and these changes are prevented by estrogen treatment (6-9). These observations suggest similar skeletal mechanisms of action of estrogen in rats and humans. Furthermore, the skeletal changes in rats in response to partial estrogen agonists have accurately predicted the differential responses of pre-and postmenopausal women to tamoxifen treatment (10, 11).The bone loss in postmenopausal women and ovariectomized women and rats is associated with elevated bone turnover (6,(12)(13)(14). However, the bone loss is not uniform; cancellous bone is at a greater risk than cortical bone (7,14,15). In addition, there is site specificity in the loss of cancellous bone. For example, cancellous bone is lost more rapidly from the proximal tibial metaphysis than from vertebral bodies (16). Also, bone is preferenti...

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Ovarian status influences the skeletal effects of tamoxifen in adult rats

Cited by 23 publications

References 36 publications

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

The Effect of Toremifene on Bone and Uterine Histology and on Bone Resorption in Ovariectomised Rats

Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain

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