scholarly journals Androstenedione treatment reduces loss of cancellous bone volume in ovariectomised rats in a dose-responsive manner and the effect is not mediated by oestrogen

1998 ◽  
Vol 156 (2) ◽  
pp. 331-339 ◽  
Author(s):  
CK Lea ◽  
V Moxham ◽  
MJ Reed ◽  
AM Flanagan
Keyword(s):  
Bone Turnover ◽  
Cancellous Bone ◽  
Plasma Concentrations ◽  
Significant Degree ◽  
Bone Volume ◽  
Simultaneous Treatment ◽  
Ovx Rats ◽  
Dose Dependent Fashion ◽  
A Minor ◽  
Dose Dependent

We have tested the hypothesis that androstenedione (administered as 21-day, slow-release pellets) is converted to active sex steroids and reduces bone turnover in the ovariectomised rat model. We found that ovariectomy resulted in a minor but significant reduction in plasma concentrations of androstenedione and testosterone and a more significant reduction in oestrone (E1) and oestradiol (E2). This was associated with the expected substantial loss of metaphyseal cancellous bone volume. Androstenedione (1.5-100 mg) pellets increased the plasma concentrations of androstenedione and testosterone above those in the ovariectomised (ovx) rats in a dose-responsive manner, whereas E2 plasma concentrations were increased to a minor but significant degree above those in the ovx animals. Androstenedione reduced loss of cancellous bone volume in a dose-dependent fashion by reducing bone turnover. The 1.5, 5 and 100 mg androstenedione-induced effect on bone turnover was not abrogated by simultaneous treatment with Arimidex, an aromatase inhibitor. This implies that the skeletal-protective effect of androstenedione was not oestrogen-mediated.

Physiological plasma levels of androgens reduce bone loss in the ovariectomized rat

1998 ◽  
Vol 274 (2) ◽  
pp. E328-E335 ◽  
Author(s):  
C. K. Lea ◽  
A. M. Flanagan
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Protective Effect ◽  
Cancellous Bone ◽  
Plasma Levels ◽  
Slow Release ◽  
Bone Volume ◽  
Ovariectomized Rat ◽  
Ovx Rats ◽  
Reduce Bone Loss

The effect of androstenedione (ADIONE) slow-release pellets on cancellous bone volume (BV/TV) at the tibial metaphysis was investigated in ovariectomized (OVX) rats at various times from 21 to 180 days. Plasma levels of ADIONE and testosterone (T) in OVX rats were significantly reduced at 21 days and were restored close to levels in the sham rats with the 1.5-mg ADIONE pellet. OVX animals with and without ADIONE pellets resulted in close to a 50% reduction in BV/TV by day 21. By day 180, OVX rats had only ∼5% BV/TV, whereas that in ADIONE-treated OVX rats was significantly greater at ∼12%. The reduced BV/TV was associated with increased bone resorption and formation. In a separate 90-day experiment, we found that the antiandrogen, Casodex, abrogated the ADIONE-induced skeletal-protective effect in OVX rats, whereas the antiaromatase, Arimidex, had no effect. This provides evidence that ADIONE protects against the development of osteopenia in the estrogen-deficient rat and mediates its effect through androgens and not estrogens.

scholarly journals Concentration of Insulin-Like Growth Factor (IGF)-I and -II in Iliac Crest Bone Matrix from Pre- and Postmenopausal Women: Relationship to Age, Menopause, Bone Turnover, Bone Volume, and Circulating IGFs1

1998 ◽  
Vol 83 (7) ◽  
pp. 2331-2337 ◽  
Author(s):  
Thomas Seck ◽  
Beate Scheppach ◽  
Stefan Scharla ◽  
Ingo Diel ◽  
Werner F. Blum ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Turnover ◽  
Cancellous Bone ◽  
Iliac Crest ◽  
Bone Matrix ◽  
Bone Volume ◽  
Human Bone ◽  
Age Related ◽  
Igf I ◽  
The Mean

Insulin-like growth factor-I (IGF-I) and -II are important local regulators of bone metabolism, but their role as determinants of human bone mass is still unclear. In the present study, we analyzed the concentration of IGF-I and -II in the bone matrix of 533 human biopsies from the iliac crest that were obtained during surgery for early breast cancer. There was an inverse association of bone matrix IGF-I concentration with age that was unaffected by menopause. Bone matrix IGF-I was positively associated with histomorphometric and biochemical parameters of bone formation and bone resorption and with cancellous bone volume. Based on the estimates of the linear regression analysis, women with a bone matrix IGF-I concentration 2 sd above the mean had a 20% higher bone volume than women with a bone matrix IGF-I concentration 2 sd below the mean. In contrast, serum IGF-I was neither correlated with bone turnover nor with bone volume and was only weakly associated with bone matrix IGF-I when adjusted for the serum concentration of IGF binding protein-3. Bone matrix IGF-II was positively associated with the osteoblast surface, but in contrast to IGF-I, tended to be positively associated with age and was unrelated to cancellous bone volume. In summary, our study suggests the following. 1) The concentration of IGF-I in cancellous bone undergoes age-related decreases that are similar to those of circulating IGF-I. 2) Menopause has no effect on this age-related decline. 3) Physiological differences in bone matrix IGF-I are associated with differences in iliac crest cancellous bone volume. 4) Bone matrix IGF-I is a better predictor of cancellous bone volume than circulating IGF-I. 5) The role of IGF-II in human bone tissue is clearly distinct from that of IGF-I.

The regulation by thyroid hormones and androgen of epidermal growth factor synthesis in the submandibular gland and its plasma concentrations in mice

1989 ◽  
Vol 121 (2) ◽  
pp. 269-275 ◽  
Author(s):  
S. Kasayama ◽  
M. Yoshimura ◽  
T. Oka
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Thyroid Hormones ◽  
Submandibular Gland ◽  
Testosterone Propionate ◽  
Plasma Concentrations ◽  
Maximal Increase ◽  
Dose Dependent Fashion ◽  
Epidermal Growth ◽  
Dose Dependent

ABSTRACT The effects of androgen and thyroid hormones on epidermal growth factor (EGF) synthesis in the submandibular gland and on plasma EGF concentrations in mice were examined. Testosterone propionate was administered alone or in combination with l-thyroxine (T4) to female mice for 2 weeks. The submandibular EGF concentrations were increased by the administration of testosterone propionate in a dose-dependent fashion; the maximal increase, 20-fold, being produced by a dose of 2 mg every other day. The EGF levels were increased sevenfold by T4, which also enhanced the stimulatory effect of suboptimal doses of testosterone propionate. Cyproterone acetate, an anti-androgen, inhibited the testosterone propionate-induced increase, but not the T4-induced increase. Plasma EGF concentrations were raised by testosterone propionate but not by T4. Both hormones stimulated the accumulation of 4·7 kb preproEGF mRNA in the submandibular gland, which occurred almost in a parallel manner with the increase in submandibular EGF concentrations. These results suggest that EGF synthesis in the submandibular gland is regulated by alterations in the level of its mRNA by thyroid hormones and androgen, and that the rise in plasma EGF concentrations is under the influence of androgen but not of thyroid hormones. Journal of Endocrinology (1989) 121, 269–275

Distinct effects of ovarian transplantation and exogenous 17 β-oestradiol on cancellous bone of osteopenic ovariectomized rats

1995 ◽  
Vol 133 (4) ◽  
pp. 483-488 ◽  
Author(s):  
Andrea C Gallagher ◽  
Timothy J Chambers ◽  
Jonathan H Tobias
Keyword(s):  
Bone Loss ◽  
Bone Metabolism ◽  
Cancellous Bone ◽  
Ovarian Function ◽  
Bone Volume ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Serum Progesterone ◽  
Ovarian Transplantation ◽  
Ovx Rats

Gallagher AC, Chambers TJ, Tobias JH. Distinct effects of ovarian transplantation and exogenous 17 β-oestradiol on cancellous bone of osteopenic ovariectomized rats. Eur J Endocrinol 1995;133:483–8. ISSN 0804–4643 Although 17 β-oestradiol (E2) is known to prevent bone loss, prolonged administration of E2 is unable to reverse this in female rats rendered osteopenic by ovariectomy. To determine whether this reflects a failure to replace other components of ovarian function involved in bone metabolism, we compared the effects of administering E2 to osteopenic ovariectomized (ovx) rats with those of ovarian transplantation. Ovariectomy was performed in female rats. After 13 weeks, by which time marked bone loss had occurred, one group of ovx animals received ovaries from donor rats, and, after a delay of 2 weeks to allow oestrus cycles to return, a further group received E2 5 μg · kg−1 · day−1 for 9 weeks. The dose of E2 was chosen as that which in preliminary studies restored mean serum E2 levels to that of intact female rats. The study was terminated 24 weeks after ovariectomy. Both E2 and ovarian transplantation largely restored indices of oestrogenic exposure in ovx rats to those of sham-ovx animals. Animals receiving ovarian transplants also showed a small increase in serum progesterone and full restoration of serum testosterone. However, while ovarian transplantation also returned indices of cancellous bone metabolism to those of sham-ovx animals, there was little increase in bone volume. Interestingly, exogenous E2 caused a greater increase in cancellous bone volume than ovarian transplantation but also caused more marked suppression of bone formation, as assessed at the end of the study. In conclusion, exogenous E2 and ovarian transplantation exerted distinct effects on skeletal metabolism in osteopenic ovx rats, although the basis for this difference is currently unclear. JH Tobias, Department of Histopathology, St George's Hospital Medical School, London SW17 ORE, UK

Time-course of vertebral and femoral bone loss in rats administered gonadotrophin-releasing hormone agonist

1993 ◽  
Vol 138 (1) ◽  
pp. 115-125 ◽  
Author(s):  
T. Kurabayashi ◽  
T. Fujimaki ◽  
M. Yasuda ◽  
Y. Yamamoto ◽  
K. Tanaka
Keyword(s):  
Bone Turnover ◽  
Bone Metabolism ◽  
Time Course ◽  
Bone Volume ◽  
Femoral Bone ◽  
Mineral Density ◽  
Releasing Hormone ◽  
Ovx Rats ◽  
Group 3 ◽  
Gonadotrophin Releasing Hormone

ABSTRACT This study was carried out (1) to compare the time-course of the change in bone metabolism in rats administered gonadotrophin-releasing hormone agonist (GnRHa) and bilaterally ovariectomized (OVX) rats and (2) to investigate the changes in bone metabolism after discontinuance of GnRHa. Seventy female Sprague–Dawley rats, aged 90 days, were divided into four groups. Group 1 underwent a sham operation, group 2 was surgically ovariectomized and group 3 was given a GnRHa (leuprorelin acetate for depot suspension) s.c. injection every 30 days. Group 3 was further divided into three subgroups: rats were administered GnRHa for 12 months (GnRHa 12M), 6 months (GnRHa 6M) or 3 months (GnRHa 3M). Group 4 served as a basal control. The bone mineral density (BMD) of lumbar vertebrae and femoral bone, measured by dual-energy X-ray absorptiometry, and the serum bone metabolic parameters were determined every 45–90 days. The bone histomorphometry of lumbar vertebra was measured on days 180 and 360 after surgery. GnRHa 12M rats showed significantly lower BMD of vertebrae and femoral bone, lower bone volume and higher bone turnover compared with sham-operated rats and those with secondary hyperparathyroidism on days 180 and 360. Their time-course for changes in bone metabolism was almost the same as that of OVX rats. GnRHa-discontinued rats showed a recovery of bone turnover. The recovery of BMD in GnRHa 6M rats was smaller than that of GnRHa 3M rats after GnRHa discontinuance. The bone volume for GnRHa 6M rats was significantly lower than that for GnRHa 3M on day 360. Journal of Endocrinology (1993) 138, 115–125

Effects of leucine, isoleucine, or threonine infusion on leucine metabolism in humans

1987 ◽  
Vol 253 (4) ◽  
pp. E428-E434 ◽  
Author(s):  
W. F. Schwenk ◽  
M. W. Haymond
Keyword(s):  
Protein Metabolism ◽  
Plasma Concentrations ◽  
Normal Subjects ◽  
Whole Body ◽  
Body Protein ◽  
Specific Amino Acid ◽  
Leucine Metabolism ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Stimulation Of

Leucine and/or its alpha-keto acid, alpha-ketoisocaproate (KIC), have been reported to spare protein in humans. To determine whether specific amino acid infusions affect whole-body protein metabolism as estimated by changes in leucine flux and oxidation, five groups of normal subjects were infused with saline, leucine (0.47 and 0.94 mumol . kg-1 . min-1), isoleucine (0.47 mumol . kg-1 . min-1), or threonine (0.47 mumol . kg-1 . min-1). Independent estimates of leucine metabolism were obtained using simultaneous infusions of [3H]-leucine and alpha-[14C]ketoisocaproate. Nearly identical results were obtained using either tracer compared with the saline controls. Compared with the saline controls, leucine infusion 1) had no effect on estimated rates of appearance of endogenous leucine, 2) stimulated leucine oxidation, 3) decreased plasma concentrations of other amino acids, and 4) stimulated non-oxidized leucine disappearance in a dose-dependent fashion. In contrast, isoleucine and threonine infusions had no effect on leucine metabolism. Assuming the validity of the isotope model employed, these data suggest that the purported anabolic effect of leucine infusion on whole-body protein metabolism is mediated via stimulation of protein synthesis rather than decreased proteolysis.

scholarly journals Differential Responses of Estrogen Target Tissues in Rats Including Bone to Clomiphene, Enclomiphene, and Zuclomiphene*

Endocrinology ◽  
1998 ◽  
Vol 139 (9) ◽  
pp. 3712-3720 ◽  
Author(s):  
Russell T. Turner ◽  
Glenda L. Evans ◽  
James P. Sluka ◽  
M. D. Adrian ◽  
Henry U. Bryant ◽  
...  
Keyword(s):  
Body Weight ◽  
Cancellous Bone ◽  
Serum Cholesterol ◽  
Bone Volume ◽  
Female Rats ◽  
Uterine Weight ◽  
Mineral Density ◽  
Trabecular Thickness ◽  
Uterine Epithelial Cell ◽  
Dose Dependent

Abstract The substituted triphenylethylene antiestrogen clomiphene (CLO) prevents cancellous bone loss in ovariectomized (OVX’d) rats. However, CLO is a mixture of two stereoisomers, enclomiphene (ENC) and zuclomiphene (ZUC), which have distinctly different activities on reproductive tissues and tumor cells. The purpose of the present dose response study was to determine the effects of ENC and ZUC on nonreproductive estrogen target tissues. These studies were performed in 7-month-old female rats with moderate cancellous osteopenia that was established by ovariectomizing rats 1 month before initiating treatment. OVX resulted in increases in body weight, serum cholesterol, endocortical resorption, and indices of cancellous bone turnover, as well as decreases in uterine weight, uterine epithelial cell height, bone mineral density, bone strength, and cancellous bone area. Estrogen treatment for 3 months restored body weight, uterine histology, dynamic bone measurements, and osteoblast and osteoclast surfaces in OVX’d rats to the levels found in the age-matched sham-operated rats. In contrast, estrogen only partially restored cancellous bone volume and uterine weight, and it reduced serum cholesterol to subnormal values. CLO was a weak estrogen agonist on uterine measurements and a much more potent agonist on body weight, serum cholesterol, and dynamic bone measurements. CLO increased trabecular thickness in osteopenic rats and was the most effective treatment in improving cancellous bone volume and architecture. ZUC was a potent estrogen agonist on all tissues investigated and had dose-dependent effects. In contrast, ENC had dose-dependent effects on most measurements similar to CLO and decreased the uterotrophic effects of ZUC. It is concluded that ENC antagonizes the estrogenic effects of ZUC on the uterus but that the beneficial effects of CLO on nonreproductive tissues in OVX’d rats is conferred by both isomers. Furthermore, the combined actions of the two isomers on bone volume and architecture were more beneficial than either isomer given alone.

PRECLINICAL STUDIES OF ALENDRONATE

1999 ◽  
Vol 03 (03) ◽  
pp. 209-216
Author(s):  
Jenny Zhao ◽  
Yebin Jiang ◽  
Harry K. Genant
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Turnover ◽  
Trabecular Bone ◽  
Bending Strength ◽  
Bone Volume ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Dose Dependent

Alendronate has been developed for the treatment of diseases characterized by increased bone resorption, such as osteoporosis. It increases metaphyseal bone density, bone volume, femoral bending strength and vertebral compressive strength, in a dose-dependent manner, in growing, intact rats. In ovariectomized (OVX) rats, alendronate increases femoral bone mass and tibial trabecular bone volume in a dose-dependent manner, and increases femoral midshaft bending strength. In rats immobilized by unilateral sciatic neurectomy, it inhibits bone loss and is dose-dependent. In rats, alendronate prevents high-turnover osteopenia induced by hyperthyroidism or by administration of immunosuppressant agent cyclosporin-A. Also in rats, treatment with prostaglandin E 2 and alendronate does not inhibit prostaglandin E 2-induced stimulation of bone formation on endocortical and periosteal surfaces. It does, however, prevent prostaglandin E 2-induced cortical bone porosity as a result of increased bone resorption, leading to an increase in cortical thickness and an increase in three-point bending strength of the femoral midshaft. At up to five times the dose used for treatment of osteoporosis in clinical trials, alendronate causes no abnormalities in bone remodeling, bone structure, or structural mechanical properties of the femur or vertebrae in intact beagles. Treatment with alendronate before or during fracture healing, or both, has no adverse effects on the union, strength, bone formation or mineralization of bone in mature beagle dogs. In intact minipigs, sodium fluoride increases and alendronate decreases bone turnover, while sodium fluoride, but not alendronate, decreases L4 strength and femoral stiffness. Small-angle X-ray scattering and backscattered electron imaging show that the trabecular bone matrix is more uniformly mineralized after alendronate treatment. In OVX baboons, which show bone changes similar to those seen in postmenopausal women, alendronate prevents an increase in bone turnover, and increases both bone volume and strength in vertebrae, in a dose-dependent manner. Alendronate also reduces the bone loss of alveolar support associated with periodontitis in monkeys. Thus, alendronate inhibits bone resorption and bone turnover, increases bone quantity accompanied by improved bone quality in some of the intact animals and in the animal models.

scholarly journals Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Corinne E. Metzger ◽  
S. Anand Narayanan ◽  
Peter H. Phan ◽  
Susan A. Bloomfield
Keyword(s):  
Bone Loss ◽  
Bone Turnover ◽  
Inflammatory Cytokines ◽  
Cancellous Bone ◽  
Proximal Humerus ◽  
Bone Volume ◽  
Hindlimb Unloading ◽  
Tnf Α ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Abstract Disuse-induced bone loss is characterized by alterations in bone turnover. Accruing evidence suggests that osteocytes respond to inflammation and express and/or release pro-inflammatory cytokines; however, it remains largely unknown whether osteocyte inflammatory proteins are influenced by disuse. The goals of this project were (1) to assess osteocyte pro-inflammatory cytokines in the unloaded hindlimb and loaded forelimb of hindlimb unloaded rats, (2) to examine the impact of exogenous irisin during hindlimb unloading (HU). Male Sprague Dawley rats (8 weeks old, n = 6/group) were divided into ambulatory control, HU, and HU with irisin (HU + Ir, 3×/week). Lower cancellous bone volume, higher osteoclast surfaces (OcS), and lower bone formation rate (BFR) were present at the hindlimb and 4th lumbar vertebrae in the HU group while the proximal humerus of HU rats exhibited no differences in bone volume, but higher BFR and lower OcS vs. Con. Osteocyte tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), RANKL, and sclerostin were elevated in the cancellous bone of the distal femur of HU rats vs. Con, but lower at the proximal humerus in HU rats vs. Con. Exogenous irisin treatment increased BFR, and lowered OcS and osteocyte TNF-α, IL-17, RANKL, and sclerostin in the unloaded hindlimb of HU + Ir rats while having minimal changes in the humerus. In conclusion, there are site-specific and loading-specific alterations in osteocyte pro-inflammatory cytokines and bone turnover with the HU model of disuse bone loss, indicating a potential mechanosensory impact of osteocyte TNF-α and IL-17. Additionally, exogenous irisin significantly reduced the pro-inflammatory status of the unloaded hindlimb.

scholarly journals A Histomorphometric Comparison of the Effects of Heparin and Low-Molecular-Weight Heparin on Cancellous Bone in Rats

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3236-3242 ◽  
Author(s):  
Jeffrey M. Muir ◽  
Jack Hirsh ◽  
Jeffrey I. Weitz ◽  
Maureen Andrew ◽  
Edward Young ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Alkaline Phosphatase ◽  
Bone Resorption ◽  
Bone Formation ◽  
Cancellous Bone ◽  
Low Molecular Weight Heparin ◽  
Serum Alkaline Phosphatase ◽  
Bone Volume ◽  
Low Molecular Weight ◽  
Dose Dependent

Abstract Long-term heparin treatment causes osteoporosis through, an as yet, undefined mechanism. To investigate this phenomenon and to determine the relative benefits of low-molecular-weight heparin (LMWH) use, we treated rats with once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.5 U/g), the LMWH, Tinzaparin (1.0 U/g or 0.5 U/g), or placebo (saline) for a period of 32 days. The effects on bone were then compared both histomorphometrically and biochemically by measuring urinary type I collagen cross-linked pyridinoline (PYD) and serum alkaline phosphatase, markers of bone resorption and formation, respectively. Histomorphometric analysis of the distal third of the right femur, in the region proximal to the epiphyseal growth plate, demonstrated that both heparin and LMWH decrease cancellous bone volume in a dose-dependent fashion, but that heparin causes significantly more cancellous bone loss than does LMWH. Although both heparin and LMWH decrease osteoblast and osteoid surface to a similar extent, only heparin increases osteoclast surface. In support of these histomorphometric findings, biochemical markers of bone turnover demonstrated that both heparin and LMWH treatment produce a dose-dependent decrease in serum alkaline phosphatase, consistent with reduced bone formation, whereas only heparin causes a transient increase in urinary PYD, consistent with an increase in bone resorption. Based on these observations, we conclude that heparin decreases cancellous bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption. In contrast, LMWH, causes less osteopenia than heparin because it only decreases the rate of bone formation.

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