Alfacalcidol prevents aromatase inhibitor (Letrozole)-induced bone mineral loss in young growing female rats

Long-term aromatase inhibitor use causes bone loss and increases fracture risk secondary to induced estrogen deficiency. We postulated that alfacalcidol (A; vitamin D3 analog) could help prevent the Letrozole (L)-induced mineral bone loss. Fifty intact 1-month-old female rats were randomly divided into basal group; age-matched control group (AMC); L group: oral administration of 2 mg/kg per day; A group: oral administration of 0.1 μg/kg per day; and group L+A for a period of 8 weeks. Eight-week administration of L resulted in a significant increase in body weight, bone length, bone area, bone formation, and bone resorption activities when compared with the AMC group. However, the bone mass and bone mineral density (BMD) were significantly lower than the AMC group. Serum levels of testosterone, LH, FSH, and IGF-1 were significantly higher and serum estrone and estradiol were lower along with a decrease in ovary+uterus horn weight, when compared with the AMC groups. None of those parameters were affected by A treatment, except suppression of bone resorption activities and increased trabecular bone mass and femoral BMD, when compared with the AMC group. Results of L+A combined intervention showed that bone length, bone area, and bone formation activities were higher than the AMC group, and the bone resorption activities were lower and BMD was significantly higher than that of the L group. This study demonstrates that the combined intervention of L and A not only enhances bone growth, but also increases bone density, and the effects of L and A are independent and additive.

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Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

Journal of Endocrinology ◽

10.1530/joe-18-0153 ◽

2018 ◽

Vol 238 (1) ◽

pp. 13-23 ◽

Cited By ~ 12

Author(s):

Thomas Funck-Brentano ◽

Karin H Nilsson ◽

Robert Brommage ◽

Petra Henning ◽

Ulf H Lerner ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Bone Strength ◽

Bending Test ◽

Bone Homeostasis ◽

Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

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Influence of alendronate therapy on the results of densitometric examination after implantation of total hip endoprosthesis

Archives of Public Health ◽

10.3889/aph.2021.5994 ◽

2021 ◽

Vol 13 (1) ◽

pp. 32-38

Author(s):

Ilir Shabani ◽

Antonio Gavrilovski ◽

Vilijam Velkovski ◽

Nenad Atanasov ◽

Shaban Memeti ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Mass ◽

Bone Mineral ◽

Mineral Content ◽

Mineral Density ◽

Periprosthetic Bone ◽

Hip Endoprosthesis ◽

Periprosthetic Bone Loss ◽

Post Implantation

The development of aloarthroplasty of the hip is continuously rising. After implantation of a total cement-free hip endoprosthesis, often there is a periprosthetic femoral bone loss. Alendronate has been shown to be a potent inhibitor of bone resorption activity; it inhibits osteoclastic bone resorption, increases bone mass, and plays a significant role in post-implantation stabilization of the femur. The aim of this study was to determine the effect of alendronate on osteointegration of hip endoprosthesis.Material and methods: The study analyzed 10 patients operated on with implantation of a total cement-free hip endoprosthesis (THP). The included patients were examined by a radiographic method at 6 and 12 months and DXA method at 6 and 12 months. Results: The study showed differences in the values of bone mineral density and bone mineral content in the interval between 6 and 12 months in patients undergoing THP, and hence we can conclude that alendronate therapy after THP implantation reduced periprosthetic loss of bone mass and implant stiffening. Alendronate is a proven inhibitor of periprosthetic bone loss that occurs after prirmary impantation of a total cement-free hip endoprosthesis.

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Probiotics (Bifidobacterium longum) Increase Bone Mass Density and UpregulateSparcandBmp-2Genes in Rats with Bone Loss Resulting from Ovariectomy

BioMed Research International ◽

10.1155/2015/897639 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 62

Author(s):

Kolsoom Parvaneh ◽

Mahdi Ebrahimi ◽

Mohd Redzwan Sabran ◽

Golgis Karimi ◽

Angela Ng Min Hwei ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Bone Mass ◽

Bone Structure ◽

Mass Density ◽

Bifidobacterium Longum ◽

Bone Mass Density ◽

Beneficial Effects ◽

Ovx Rats

Probiotics are live microorganisms that exert beneficial effects on the host, when administered in adequate amounts. Mostly, probiotics affect the gastrointestinal (GI) tract of the host and alter the composition of gut microbiota. Nowadays, the incidence of hip fractures due to osteoporosis is increasing worldwide. Ovariectomized (OVX) rats have fragile bone due to estrogen deficiency and mimic the menopausal conditions in women. Therefore, this study aimed to examine the effects ofBifidobacterium longum(B. longum) on bone mass density (BMD), bone mineral content (BMC), bone remodeling, bone structure, and gene expression in OVX rats. The rats were randomly assigned into 3 groups (sham, OVX, and the OVX group supplemented with 1 mL ofB. longum108–109colony forming units (CFU)/mL).B. longumwas given once daily for 16 weeks, starting from 2 weeks after the surgery. TheB. longumsupplementation increased (p<0.05) serum osteocalcin (OC) and osteoblasts, bone formation parameters, and decreased serum C-terminal telopeptide (CTX) and osteoclasts, bone resorption parameters. It also altered the microstructure of the femur. Consequently, it increased BMD by increasing (p<0.05) the expression ofSparcandBmp-2genes.B. longumalleviated bone loss in OVX rats and enhanced BMD by decreasing bone resorption and increasing bone formation.

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Effect of gender on bone turnover in adult rats during simulated weightlessness

Journal of Applied Physiology ◽

10.1152/japplphysiol.00455.2002 ◽

2003 ◽

Vol 95 (5) ◽

pp. 1775-1780 ◽

Cited By ~ 49

Author(s):

T. E. Hefferan ◽

G. L. Evans ◽

S. Lotinun ◽

M. Zhang ◽

E. Morey-Holton ◽

...

Keyword(s):

Bone Loss ◽

Bone Formation ◽

Cancellous Bone ◽

Female Rats ◽

Male Rats ◽

Mrna Levels ◽

Bone Area ◽

Simulated Weightlessness ◽

Trabecular Separation ◽

Trabecular Number

Prologned spaceflight results in bone loss in astronauts, but there is considerable individual variation. The goal of this rat study was to determine whether gender influences bone loss during simulated weightlessness. Six-month-old Fisher 344 rats were hindlimb unweighted for 2 wk, after which the proximal tibiae were evaluated by histomorphometry. There were gender differences in tibia length, bone area, cancellous bone architecture, and bone formation. Compared with female rats, male rats had an 11.6% longer tibiae, a 27.8% greater cortical bone area, and a 37.6% greater trabecular separation. Conversely, female rats had greater cortical (316%) and cancellous (145%) bone formation rates, 28.6% more cancellous bone, and 30% greater trabecular number. Hindlimb unweighting resulted in large reductions in periosteal bone formation and mineral apposition rate in both genders. Unweighting also caused cancellous bone loss in both genders; trabecular number was decreased, and trabecular separation was increased. There was, however, no change in trabecular thickness in either gender. These architectural changes in cancellous bone were associated with decreases in bone formation and steady-state mRNA levels for bone matrix proteins and cancellous bone resorption. In conclusion, there are major gender-related differences in bone mass and turnover; however, the bone loss in hindlimb unweighted adult male and female rats appears to be due to similar mechanisms.

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Different Molecular Mechanisms Underlie Ethanol-Induced Bone Loss in Cycling and Pregnant Rats

Endocrinology ◽

10.1210/en.2005-0529 ◽

2006 ◽

Vol 147 (1) ◽

pp. 166-178 ◽

Cited By ~ 28

Author(s):

Kartik Shankar ◽

Mats Hidestrand ◽

Rani Haley ◽

Robert A. Skinner ◽

William Hogue ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Bone Mineral ◽

Molecular Mechanisms ◽

Nuclear Factor Κb ◽

Tartrate Resistant Acid Phosphatase ◽

Mineral Density ◽

Pregnant Rats ◽

Estradiol Levels

Chronic ethanol (EtOH) consumption can result in osteopenia. In the current study, we examined the modulation of EtOH-induced bone loss during pregnancy. Nonpregnant and pregnant dams were intragastrically infused either control or EtOH-containing diets throughout gestation (gestation d 5 through 20 or an equivalent period of 15 d) by total enteral nutrition. The effects of EtOH (8.5 to 14 g/kg/d) on tibial bone mineral density (BMD), mineral content (BMC), and bone mineral area were assessed at gestation d 20 via peripheral quantitative computerized tomography. EtOH caused a dose-dependent decrease in BMD and BMC without affecting bone mineral area. Trabecular BMD and BMC were significantly lower in EtOH-treated, nonpregnant dams, compared with pregnant cohorts at the same infused dose of EtOH and urinary ethanol concentrations. Static histomorphometric analysis of tibiae from pregnant rats after EtOH treatment showed decreased osteoblast and osteoid surface, indicating inhibited bone formation, whereas EtOH-treated cycling rats showed higher osteoclast and eroded surface, indicative of increased bone resorption. Circulating osteocalcin and 1,25-dihydroxyvitamin D3 were lower in both EtOH-fed nonpregnant and pregnant rats. Gene expression of osteoclast markers, 70 kDa v-ATPase, and tartrate-resistant acid phosphatase were increased selectively in nonpregnant EtOH-treated rats but not pregnant rats. Moreover, only nonpregnant EtOH-fed rats showed induction in bone marrow receptor activator of nuclear factor-κB ligand mRNA and decreased circulating 17β-estradiol levels. Our data suggest that EtOH-induced bone loss in pregnant rats is mainly due to inhibited bone formation, whereas in nonpregnant rats, the data are consistent with increased osteoclast activation and bone resorption concomitant with decreased estradiol levels.

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Impaired Estrogen Sensitivity in Bone by Inhibiting Both Estrogen Receptor a and b Pathways*

10.31234/osf.io/592mt ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Bone Mineral Density ◽

Estrogen Receptor ◽

Bone Loss ◽

Bone Turnover ◽

Bone Mineral ◽

Female Rats ◽

Wild Type ◽

Mineral Density ◽

Transgenic Rats ◽

Estrogen Sensitivity

Although it is well established that estrogen deficiencycauses osteoporosis among the postmenopausalwomen, the involvement of estrogen receptor (ER) in itspathogenesis still remains uncertain. In the presentstudy, we have generated rats harboring a dominantnegative ERa, which inhibits the actions of not only ERabut also recently identified ERb. Contrary to our expectation,the bone mineral density (BMD) of the resultingtransgenic female rats was maintained at the same levelwith that of the wild-type littermates when sham-operated.In addition, ovariectomy-induced bone loss wasobserved almost equally in both groups. Strikingly, however,the BMD of the transgenic female rats, after ovariectomized,remained decreased even if 17b-estradiol(E2) was administrated, whereas, in contrast, the decreaseof littermate BMD was completely prevented byE2. Moreover, bone histomorphometrical analysis ofovariectomized transgenic rats revealed that the higherrates of bone turnover still remained after treatmentwith E2. These results demonstrate that the preventionfrom the ovariectomy-induced bone loss by estrogen ismediated by ER pathways and that the maintenanceof BMD before ovariectomy might be compensatedby other mechanisms distinct from ERa and ERbpathways.

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The Development of Molecular Biology of Osteoporosis

International Journal of Molecular Sciences ◽

10.3390/ijms22158182 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8182

Author(s):

Yongguang Gao ◽

Suryaji Patil ◽

Jingxian Jia

Keyword(s):

Bone Resorption ◽

Molecular Biology ◽

Bone Formation ◽

Bone Mass ◽

Bone Remodeling ◽

Bone Cells ◽

Cell Activity ◽

Bone Cell ◽

Bone Disorders ◽

Molecular Aspects

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.

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Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

Journal of Endocrinology ◽

10.1530/joe-11-0356 ◽

2011 ◽

Vol 212 (2) ◽

pp. 179-186 ◽

Cited By ~ 11

Author(s):

Rana Samadfam ◽

Malaika Awori ◽

Agnes Bénardeau ◽

Frieder Bauss ◽

Elena Sebokova ◽

...

Keyword(s):

Bone Loss ◽

Bone Mass ◽

Trabecular Bone ◽

Bone Mineral ◽

Combination Treatment ◽

Mass Gain ◽

Ovariectomized Rats ◽

Concomitant Treatment ◽

Mineral Density ◽

Ovx Rats

Peroxisome proliferator-activated receptor (PPAR) γ agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARα agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)+Feno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with Pio+Feno resulted in ∼50% lower fat mass gain compared with Pio treatment alone. Combination treatment with Pio+Feno partially prevented Pio-induced loss of bone mineral content (∼45%) and bone mineral density (BMD; ∼60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with Pio+Feno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the Pio+Feno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the Pio+Feno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARγ and PPARα may reduce the negative effects of PPARγ agonism on bone mass.

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Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss

Journal of Endocrinology ◽

10.1530/joe-15-0280 ◽

2015 ◽

Vol 227 (3) ◽

pp. 129-141 ◽

Cited By ~ 6

Author(s):

Russell T Turner ◽

Michael Dube ◽

Adam J Branscum ◽

Carmen P Wong ◽

Dawn A Olson ◽

...

Keyword(s):

Gene Therapy ◽

Body Weight ◽

Bone Loss ◽

Bone Mass ◽

Bone Turnover ◽

Cancellous Bone ◽

Mass Density ◽

Female Rats ◽

Bone Mass Density ◽

Age Related

Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin,n=7) or a control vector encoding green fluorescent protein (rAAV-GFP,n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (−4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (−80%), serum leptin (−77%), and serum IGF1 (−34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.

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