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