The effects of strength training and raloxifene on bone health in aging ovariectomized rats

doi:10.1016/j.bone.2015.11.023

Bone

Volume 85, April 2016, Pages 45-54

https://doi.org/10.1016/j.bone.2015.11.023 Get rights and content

Highlights

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Bone loss in the femoral neck is attenuated by strength training and raloxifene
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Strength training and raloxifene improved bone microarchitecture and strength in aging
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Strength training and raloxifene improved immunolabeling pattern for RUNX-2
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Strength training and raloxifene resulted in a reduction of the SMI and DA.
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Strength training is as effective as raloxifene in osteoporosis prevention.

Abstract

The aim of this study was to investigate the effects of strength training (ST) and raloxifene (Ral), alone or in combination, on the prevention of bone loss in an aging estrogen-deficient rat model. Aging Wistar female rats were ovariectomized at 14 months and allocated to four groups: (1) non-trained and treated with vehicle, NT-Veh; (2) strength training and treated with vehicle, ST-Veh; (3) non-trained and treated with raloxifene, NT-Ral; and (4) strength training and treated with raloxifene, ST-Ral. ST was performed on a ladder three times per week and Ral was administered daily by gavage (1 mg/kg/day), both for 120 days. Areal bone mineral density (aBMD), strength, microarchitecture, and biomarkers (osteocalcin, OCN; osteoprotegerin, OPG; and tartrate-resistant acid phosphatase, TRAP) were assessed. Immunohistochemistry was performed for runt-related transcription factor 2 (RUNX2), osterix (OSX), OCN, OPG, TRAP, and receptor activator of nuclear factor kappa-B ligand (RANKL). The rats that performed ST (ST-Veh) or were treated with Ral (NT-Ral) showed significant improvements in aBMD (p = 0.001 and 0.004), bone strength (p = 0.001), and bone microarchitecture, such as BV/TV (%) (p = 0.001), BS/TV (mm²/mm³) (p = 0.023 and 0.002), Conn.Dn (1/mm³) (p = 0.001), Tb.N (1/mm) (p = 0.012 and 0.011), Tb.Th (1/mm) (p = 0.001), SMI (p = 0.001 and 0.002), Tb.Sp (p = 0.001), and DA (p = 0.002 and 0.007); there was also a significant decrease in plasma levels of OCN (p = 0.001 and 0.002) and OPG (p = 0.003 and 0.014), compared with animals in the NT-Veh group. Ral, with or without ST, promoted an increased immunolabeling pattern for RUNX2 (p = 0.0105 and p = 0.0006) and OSX (p = 0.0105), but a reduced immunolabeling pattern for TRAP (p = 0.0056) and RANKL (p = 0.033 and 0.004). ST increased the immunolabeling pattern for RUNX2 (p = 0.0105), and association with Ral resulted in an increased immunolabeling pattern for OPG (p = 0.0034) and OCN (p = 0.0024). In summary, ST and Ral administration in aged, estrogen-deficient Wistar female rats is associated with a decrease in bone turnover marker plasma levels, increased activity of cells that promote osteoblastogenesis, and decreased activity of cells that promote osteoclastogenesis; these are correlated with higher aBMD, bone strength, and bone microarchitecture at the femoral neck. The results indicate that strength training and Ral are potential tools to reduce the risk of fractures at clinically relevant sites.

Introduction

Osteoporosis is a bone disease characterized by increased risk of fracture. Its prevalence is increasing as a result of longer life expectancies and population aging; consequently, it is responsible for a rise in social and public health problems [1], [2]. Osteoporosis arises from changes in bone homeostasis, which result in impairments to the remodeling cycle [3]. Hip fractures are one of the most common types of fracture that affect people with osteoporosis, and are associated with a higher level of disability and health care costs than all other osteoporotic fractures [4], [5]. Fourteen percent of the total number of fractures in the USA are femoral neck fractures, which account for 72% of the total cost of treating osteoporotic fractures [6].

Among local and systemic factors that contribute to an imbalance in the activity of bone cells, estrogen has an important role to play in bone health as a result of both direct and indirect activity [7]. Postmenopausal women have an increased risk of fragility fractures related to changes in hormonal levels [8]; these changes result in a decrease in bone mineral density (BMD), due to an increase in bone resorption relative to bone formation [9]. Preventive and therapeutic interventions for maintaining bone health are therefore extremely important given the impact on functional independence and quality of life in older people. In recent years, several studies have identified pathways involved in the maintenance and formation of bone that can be used for targeting drug therapy, such as the use of anabolic agents (parathyroid hormone) [10], and antiresorptive treatments, such as immunological (RANKL antibody) [11], hormone replacement [12], and bisphosphonate therapy [13].

Raloxifene (Ral), a selective estrogen receptor modulator (SERM), is an example of a class of pharmacological compounds with beneficial effects on bone tissue [14] and that lower the risk of breast cancer [15]. Clinical studies have demonstrated that Ral prevents bone loss and lowers the risk of fracture by modulating bone turnover [16]. Ral has been described as an antiresorptive drug, but the presence of estrogen receptors in osteoblasts and bone marrow stromal cells suggests that Ral can have a direct role in the regulation of osteoblast lineage cells as well as an osteoblast stimulatory role [17], [18]. However, the mechanism by which this SERM exerts its effect on bone cells has yet to be fully elucidated [17], and no in vivo study has documented an effect of Ral on osteoblasts.

Strength training (ST) has been proposed as an alternative to drug therapy in the prevention and treatment of osteoporosis, as a means of preventing deterioration of bone mass. ST exercises are known to increase bone strength and bone mass [19], and improve bone microarchitecture [20], whereas a sedentary lifestyle has been associated with increased bone resorption [21]. Mechanical loading also influences a range of tissues, including muscle, tendons, and ligaments, and represents a means of protecting skeletal integrity in a nonpharmacological fashion [22]. In the postmenopausal period, there is decreased activity of estrogen receptor α in bone cells, with a concurrent decline in the responsiveness of bone to mechanical load, which further exacerbates deterioration of bone quality [23], [24], [25]. This is a possible explanation for bone loss in postmenopausal women in amounts comparable to that associated with disuse [26].

Considering bone fragility in old age, it is essential to propose interventions that can minimize bone loss and validate preventive measures for primary osteoporosis. Thus, the aim of this study was to investigate the effects of ST and Ral, alone or in combination, on the prevention of bone loss in an aged estrogen-deficient rat model.

Section snippets

Animals

All animal procedures were approved (Process number 001,397–2010) by the Institutional Animal Care and Use Committee of the Faculty of Dentistry (Univ. Estadual Paulista – UNESP, Araçatuba, SP, Brazil) and complied with the Guide for Care and Use of Laboratory Animals.

Female Wistar rats aged 13–18 months were obtained from the central animal facility of the Faculty of Dentistry of Araçatuba, and were housed at 22 °C (± 2 °C) under a 12:12 h light:dark cycle. The animals were allowed free access to

Effect of ST and Ral treatment on body weight, uterus weight, and estradiol plasma concentration

After the 120-day intervention, there were no significant main effects for Ral or ST, and no significant interactions between Ral and ST for body weight (p > 0.05, Table 1). Successful OVX was confirmed at sacrifice, using uterus weight and estradiol plasma concentration. There were no significant effects for ST or Ral, and no significant interactions between ST and Ral for uterus weight and estradiol plasma concentration (p > 0.05, Table 1).

Effect of ST and Ral treatment on bone mass, strength, and trabecular microarchitecture in the femoral neck

The representative 3D reconstructed micro-CT images of

Discussion

This study clearly demonstrates that ST and Ral can prevent deterioration of bone mineral density, microarchitecture, and strength in the femoral neck of aged estrogen-deficient Wistar female rats. This shows that the critical role of estrogen deficiency in bone loss is attenuated to the same extent by ST and Ral.

Femoral neck fractures cause the most morbidity and mortality of any osteoporotic fracture. As such, a study investigating potential therapeutic interventions for the prevention of

Conclusion

We conclude that hypoestrogenism-induced osteopenia during the aging process can be reversed using ST and Ral. Therefore, we suggest that physical exercise (ST) and drug treatment (Ral) are effective interventions in the prevention of osteopenia. They induce an improvement in bone quality, along with a lower risk of fractures, and consequently a better quality of life for women in whom hormone replacement therapy or bisphosphonates are contraindicated. Moreover, ST itself, without associated

Grants

CAPES (Coordination of Improvement of Higher Education Personnel/number 2010/03,112–6) and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo/number 2010/09,393–7) supported this work.

Disclosures

There are no conflicts of interest to be disclosed by any author.

Acknowledgments

We thank the Universidade Estadual Paulista “Júlio de Mesquita Filho,” research foundations (Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES), and the Brazilian Society of Physiology for supporting the present study. We would also like to thank Dr. Euclides Braga Malheiros (UNESP, Jaboticabal, SP, Brazil) and Dr. Sílvia Helena Venturoli Perri (Faculty of Veterinary Medicine, UNESP, Araçatuba, SP, Brazil) for

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Milk kefir therapy improves the skeletal response to resistance exercise in rats submitted to glucocorticoid-induced osteoporosis
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Citation Excerpt :
Initially, the animals were subjected to an adaptation, in which they were encouraged to climb a ladder without any kind of painful stimulus. On the first day of week 7, a maximum load test was performed (Stringhetta-Garcia et al., 2016). Then, exercise was performed 3×/wk, with one rest day between the exercise days, during 120 days.
Glucocorticoid-induced osteoporosis (GIO) has emerged as a challenge after long-term glucocorticoids (GCs) administration. Exercise has been an important non-pharmacological option, while medications modulate bone remodeling despite adverse effects. In this way, milk Kefir (MK) therapy stands out as a safe alternative to improve bone metabolism. Our study aimed to investigate the effect of MK associated to resistance exercise on bone loss in rats with GIO. For this, sixty male Wistar rats were divided into 2 groups: normal (N) and subjected to GIO, which was subdivided into 4 groups: control (C), milk kefir therapy (K), Exercise (Ex), and Exercise+K (ExK). GIO was induced by dexamethasone (7 mg/kg – i.m.; 1×/wk, 5 wk). MK was administered daily (1×/day; 0.7 ml/animal) and the climb exercise with load was performed 3×/wk; both for 16 wk. Femur was collected for assessment of bone microarchitecture, quality and metabolism. GIO markedly reduced trabecular bone volume density (BV/TV) (−35 %), trabecular thickness (Tb.Th) (−33 %), mineral content of femur (−26 %) as well as bone collagen content (−56 %). Bone strength and its biomechanical properties given by flexural strength (−81 %), fracture load (−80 %), and the number of osteocytes (−84 %) were lowered after GIO. GCs reduced osteoblast number and function while increased osteoclast number, altering bone remodeling (p < 0.05). On the other hand, ExK significantly improved bone microarchitecture and quality, marked by fractal dimension increase (+38 %), cortical volume (+34 %), BV/TV (+34 %), Tb.Th (+33 %), mineral content and collagen maturity, while reduced the space between trabecula (−34 %). The Ex and ExK increased the number of osteocytes (p < 0.05) and they were able to reverse the lower osteoblast number. Both treatments used alone significantly enhanced bone biomechanical properties, but the ExK showed a more significant improvement. ExK ameliorated bone strength and biomechanics (p < 0.05) and stimulated bone formation and modulated bone remodeling (p < 0.05). MK and exercise administered isolated or in association increased the percentage of collagen bone filling after GIO (p < 0.05), but only ExK improved collagen maturity. Our results showed that MK associated to resistance exercise enhanced bone microarchitecture, quality and metabolism, being therefore an interesting tool to improve skeletal response during GIO.
Analysis of the femoral neck from rats in the periestropause treated with oxytocin and submitted to strength training
2022, Bone
Among the interventions used to prevent osteoporosis in female organisms, strength training (ST) and oxytocin (OT) stand out, as a promising hormone with anabolic action on bone. This study aimed to verify whether the combined action of OT and ST, compared to isolated interventions, potentiates the bone remodeling process of the femoral neck of Wistar rats during periestropause. Forty Wistar rats (18 months) with irregular estrous cycle were randomly distributed into groups: 1-Vehicle (Veh; NaCl 0.15 mol/L ip); 2-Oxytocin (Ot; 134 μg/kg/ip); 3-Strength training (St); 4-Ot + St. The animals of the 1, 2 and 4 groups received two intraperitoneal injections with an interval of 12 h every 30 days, totaling 8 injections at the end of the experimental period (18 to 21 months). The animals in the St and Ot + St groups performed ST on a ladder 3 times a week, maximal voluntary carrying capacity (MVCC) test monthly. After 120 days, the animals were euthanized; the femur was collected for analysis of biomechanical testing, densitometry, bone microtomography, Raman spectroscopy, tissue PCR, and blood for analysis of bone biomarkers, liver damage, and oxidative stress. The main effects in the Ot group were observed in the maximum load and energy in the compression testing (femoral head), and stiffness and energy in the three-points bending testing (femur diaphysis). In addition, the main effects occurred on the bone mineral density (BMD), cortical thickness (Ct.Th), number of pores (Po.N), polar moment of inertia (J), trabecular thickness (Tb.Th), and connectivity density (Conn.Dn), Bone alkaline phosphatase (Alp), Tumor necrosis factor receptor superfamily member 11b (Opg), Tumor necrosis factor ligand superfamily member 11 (Rankl) and Cathepsin K (Ctsk) expression. There was an effect in the tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP). In the St group, the main effect was observed on the energy (compression and the three-points bending), stiffness, aBMD, BMD, cortical bone area (Ct.Ar), Po.N, trabecular bone volume (BV/TV), Tb.Th and in the mineralization ratio (ѵ₁PO₄/proline), Runt-related transcription factor 2 (Runx2), Bone morphogenetic protein 2 (Bmp2), Alp, Osteopontin/secreted phosphoprotein 1 (Opn/Spp1), Opg, Tumor necrosis factor receptor superfamily member 11ª (Rank), Rankl, Ctsk expression. There was an effect in the TRAP and ALP. The interaction in the combination of therapies in the Ot + St group was verified in energy to maximum load (compression and three-points bending testing), stiffness, BMD, Ct.Th, J, Tb.Th and ѵ₁PO₄/proline. In the gene analysis there was interaction in the Runx2, Osterix/Sp7 transcription factor (Osx/Sp7), Bmp2, Alp, Osteocalcin/Bone gamma-carboxyglutamate protein (Ocn/Bglap), Opg, Rankl and Acid phosphatase 5, tartrate resistant (Trap/Acp5) expression. In addition, the combination of OT and ST resulted in a higher maximum load compared to the Veh group, with higher BV/TV than the Ot group, higher Rankl and Ctsk expression than Veh and Ot groups, and lower Po.N and lower activity of TRAP than the other groups. In oxidative stress, total antioxidant capacity (TAC) was lower. These results showed that the combination of interventions is a promising anabolic strategy for the prevention of osteoporosis in the period of periestropause, standing out from the effects of isolated interventions.
Therapeutic potential of annatto tocotrienol with self-emulsifying drug delivery system in a rat model of postmenopausal bone loss
2021, Biomedicine and Pharmacotherapy
Citation Excerpt :
In this study, treatment with raloxifene preserved the bone microarchitecture, calcium content and strength. These findings agree with a study by Stringhetta-Garcia et al., which reported that raloxifene prevents bone microarchitecture and strength deterioration in the femoral neck of aged estrogen-deficient Wistar female rats [53]. We suggest that SEDDS-formulated annatto-tocotrienol share the same efficacy as raloxifene in treating postmenopausal osteoporosis.
Tocotrienol has been shown to prevent bone loss in animal models of postmenopausal osteoporosis, but the low oral bioavailability might limit its use. A self-emulsifying drug delivery system (SEDDS) could increase the bioavailability of tocotrienol. However, evidence of this system in improving the skeletal effects of tocotrienol is scanty. This study aims to evaluate the therapeutic efficacy of annatto tocotrienol with SEDDS in a rat model of postmenopausal bone loss. Ten-month-old female Sprague Dawley rats were randomized into six groups. The baseline group was euthanatized at the onset of the study. Four other groups underwent ovariectomy to induce estrogen deficiency. The sham underwent similar surgery procedure, but their ovaries were retained. Eight weeks after surgery, the ovariectomized rats received one of the four different regimens orally daily: (a) SEDDS, (b) annatto tocotrienol [60 mg/kg body weight (b.w.)] without SEDDS, (c) annatto-tocotrienol (60 mg/kg b.w.) with SEDDS, (d) raloxifene (1 mg/kg b.w.). After eight weeks of treatment, blood was collected for the measurement of delta-tocotrienol level and oxidative stress markers. The rats were euthanized and their bones were harvested for the evaluation of the bone microstructure, calcium content and strength. Circulating delta-tocotrienol level was significantly higher in rats receiving annatto tocotrienol with SEDDS compared to the group receiving unformulated annatto-tocotrienol (p < 0.05). Treatment with unformulated or SEDDS-formulated annatto tocotrienol improved cortical bone thickness, preserved bone calcium content, increased bone biomechanical strength and increased antioxidant enzyme activities compared with the ovariectomized group (p < 0.05). Only SEDDS-formulated annatto tocotrienol improved trabecular microstructure, bone stiffness and lowered malondialdehyde level (p < 0.05 vs the ovariectomized group). The improvement caused by annatto tocotrienol was comparable to raloxifene. In conclusion, SEDDS improves the bioavailability and skeletal therapeutic effects of annatto tocotrienol in a rat model of postmenopausal bone loss. This formulation should be tested in a human clinical trial to validate its efficacy.
Effect of pre-treatment of strength training and raloxifene in periestropause on bone healing
2020, Bone
Citation Excerpt :
After all rats showed estrous cycle irregularity, they were randomly assigned to one of four groups: 1: non-trained plus vehicle (NT/Veh n = 30); 2: non-trained plus Ral (NT/Ral, n = 30); 3: ST plus vehicle (ST/Veh n = 30); or 4: ST plus Ral (ST/Ral, n = 30). At the beginning of the 18th month, animals in the NT/Ral and ST/Ral groups received 2.3 mg/kg of Ral (Sigma Aldrich, Munich, Germany) in 0.3 mL of physiological saline solution administered 3×/week by gavage for 120 days, protocol adapted from Stringhetta-Garcia and collaborators [14,15]. Animals in the other treatment groups received a physiological saline solution (0.3 mL) by gavage for the same time period.
There is evidence that strength training (ST) and raloxifene (Ral) treatment during periestropause promotes better bone quality. We wanted to determine whether the skeletal benefits of ST or Ral treatment, performed during periestropause, would persist after fracture. Therefore, the present study aimed to analyze the influence of pre-treatment with ST and administration of Ral during periestropause on bone healing after total unilateral osteotomy.
Senescent female Wistar rats between 18 and 21 months of age, performed ST on a ladder three times per week, were administered Ral by gavage (2.3 mg/kg/day), or an association of both. After 120 days, the treatments were interrupted, and a total osteotomy was performed on the left tibia in all animals. They were euthanized 1 and 8 weeks post-osteotomy.
The administration of Ral during periestropause worsened the biochemical and oxidative profile, decreased gene expression of markers related to bone resorption and remodeling, which negatively affected the physicochemical properties; this lead to changes in the bone callus microarchitecture and mass, as well as a decrease in callus resistance to torsional deformation, resulting in lower tissue quality during bone healing. In contrast, ST performed prior to the osteotomy resulted in better bone healing, improvement of the biochemical and oxidative profile, alteration of the genetic profile in favor of bone formation and resorption, as well as the physic-ochemical properties of the callus. These changes led to better microarchitecture and bone mass and increased callus resistance to torsional deformation, confirming its beneficial effect on the quality of bone tissue, providing acceleration of bone consolidation. The combination of therapies at this exercise intensity and drug dosage showed a negative interaction, where the negative effect of Ral overcame the positive effect of ST, leading to decreased tissue quality in the bone healing process.
This study indicates that in addition to excellent non-pharmacological therapy and action in the prevention of osteoporosis, ST performed during the aging period may increase bone quality at the onset of healing and provide improved bone consolidation. Furthermore, the anti-osteoclastogenic effect of Ral shown in this model delayed the bone repair process, resulting in considerable clinical concern.
Raloxifene retards cartilage degradation and improves subchondral bone micro-architecture in ovariectomized rats with patella baja-induced - patellofemoral joint osteoarthritis
2020, Osteoarthritis and Cartilage
Abnormal remodeling of subchondral bone (SB) induced by estrogen deficiency has been shown to be involved in osteoarthritis (OA). Raloxifene (RAL) is commonly used to treat postmenopausal osteoporosis (OP). However, little is known about its effects on OA combined with estrogen deficiency. This study was performed to evaluate the efficacy of RAL on patella baja-induced patellofemoral joint OA (PFJOA) in an ovariectomized rat model.
Patellar ligament shortening (PLS) and ovariectomy (OVX) were performed simultaneously in 3-month-old female Sprague–Dawley rats, which were treated with RAL (10 mg/kg/day) or vehicle at 72 h postoperatively for 10 weeks. PFJOA was assessed by immunohistochemistry (IHC), real-time polymerase chain reaction (PCR), tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assay (ELISA), micro-computed tomography (μCT), histomorphology and behavioral analyses.
X-ray examinations showed that patella baja was successfully established by PLS. Histomorphological analysis revealed that PFJOA was significantly exacerbated by OVX and markedly alleviated by RAL. Moreover, RAL improved cartilage metabolism by decreasing MMP-13, ADAMTS-4, and caspase-3 and increasing Col-II and aggrecan at both the protein and mRNA levels. Furthermore, RAL markedly improved bone mass and SB microarchitecture and reduced osteoclast numbers and the serum osteocalcin and CTX-I levels. Although RAL showed a trend toward reducing pain sensitivity based on mechanical allodynia testing, this result was not statistically significant.
These findings demonstrate that RAL treatment retards PFJOA progression in an ovariectomized rat model, suggesting that it may be a potential candidate for amelioration of the progression of PFJOA accompanied by postmenopausal OP.
Strength training reverses ovariectomy-induced bone loss and improve metabolic parameters in female Wistar rats
2018, Life Sciences
Citation Excerpt :
This model is employed in a countless works, making possible the discovery of new drugs and strategies, such as exercise, to improve bone health [6,21–24]. It has been demonstrated that physical exercise attenuates bone mass loss due to mechanical stimulation, improves cardiovascular parameters, has neuroprotective effects, and ensures a good functioning of the metabolic apparatus in intact and ovariectomized rats [7,10,15]. Recently, Chow et al. [25] reported that callus formation in fractured long bones were enhanced by vibration therapy, which improves estrogen receptor alpha (ERα) expression in osteocytes and the regeneration of this injury due to changes in gene expression.
Menopause induces osteoporosis, sarcopenia, insulin resistance, and dyslipidemia. Ovariectomized (OVX) rat is an animal model, which mimetics postmenopausal conditions. The present study aimed to test the effects of strength training protocol on bone mineral density and metabolic parameters in OVX rats. Female Wistar rats were randomly separated in four groups: non-ovariectomized rats (Sham); ovariectomized rats (OVX); OVX treated with 17β-estradiol (HR); and OVX trained group (TR). At 70-days-old OVX groups were submitted to a bilateral ovariectomy. Hormonal replacement and strength training were performed three times per week, for 60 days. 17β-estradiol was administered by intramuscular injection (50 μg/kg of BW) and strength training protocol was composed by four series of 12 repetitions with 65–75% of 1RM. As expected, OVX impaired glucose homeostasis, promoted weight and adiposity gain, dyslipidemia, sarcopenia and osteoporosis, but hormonal replacement and strength training improved most of these parameters. Both HR and TR normalize glucose homeostasis; however, only TR restores blood insulin. OXV also reduced the maximum force in 42%, but TR improved this parameter in 110%, in addition TR prevents sarcopenia and fat mass gain. Interestingly, strength training was able to improve significantly BMD. Taken together, these data suggest that strength training can be effective in the treatment of damage caused by OVX, which in a translational context, becomes an effective non-pharmacological strategy to improve the health of postmenopausal women, reducing costs with secondary symptoms, mainly caused by weight gain, sarcopenia and osteoporosis.

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Original Full Length ArticleThe effects of strength training and raloxifene on bone health in aging ovariectomized rats

Highlights

Abstract

Introduction

Section snippets

Animals

Effect of ST and Ral treatment on body weight, uterus weight, and estradiol plasma concentration

Effect of ST and Ral treatment on bone mass, strength, and trabecular microarchitecture in the femoral neck

Discussion

Conclusion

Grants

Disclosures

Acknowledgments

Lancet

J. Orthop. Sci.

Bone

Gene

J. Biol. Chem.

Arch. Oral Biol.

Bone

Bone

Exp. Gerontol.

Osteoporosis management in post-menopausal women

Minerva Ginecol.

Secular trends in the incidence of hip and other osteoporotic fractures

Osteoporos. Int.

Postmenopausal osteoporosis as a failure of bone's adaptation to functional loading: a hypothesis

J. Bone Miner. Res.

Geographic and ethnic disparities in osteoporotic fractures

Nat. Rev. Endocrinol.

Epidemiology of fracture risk with advancing age

J. Gerontol. A Biol. Sci. Med. Sci.

Raloxifene: mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice

Open Orthop. J.

Identifying postmenopausal women at high risk of fracture in populations: a comparison of three strategies

J. Am. Geriatr. Soc.

Bone fractures after menopause

Hum. Reprod. Update

Estrogen alone or in combination with parathyroid hormone can decrease vertebral MEF2 and sclerostin expression and increase vertebral bone mass in ovariectomized rats

Osteoporos. Int.

A review of denosumab for the treatment of osteoporosis

Patient Prefer. Adherence

Effects of raloxifene and estradiol on bone turnover parameters in intact and ovariectomized rats

J. Physiol. Biochem.

Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. vertebral efficacy with risedronate therapy (VERT) Study Group

Osteoporos. Int.

Molecular mechanism of tissue-specific actions of SERM

Clin. Calcium

Continuing outcomes relevant to evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene

J. Natl. Cancer Inst.

Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. multiple outcomes of raloxifene evaluation (MORE) investigators

JAMA

Effects of resistance exercise training on mass, strength, and turnover of bone in growing rats

Eur. J. Appl. Physiol.

A comparison of resistance and aerobic training for mass, strength and turnover of bone in growing rats

Eur. J. Appl. Physiol.

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Original Full Length Article
The effects of strength training and raloxifene on bone health in aging ovariectomized rats