Z. Q. Ren,1,2 Y. F. Wang,3 G. F. Ao,2 H. X. Chen,3 M. Huang,4 M. X. Lai,3 H. D. Zhao,2 and R. Zhao5

Abstract

Background

Osteoporosis is becoming more prevalent in aging societies worldwide, and the economic burden attributable to osteoporotic fractures is substantial. The medications presently available to treat osteoporosis have side effects. Acupuncture is widely used for treating osteoporotic postmenopausal women because it is non-invasive and has fewer side effects, but the powerful clinical evidence for its efficacy remains insufficient. Our study intends to explore the effect of overall adjustment acupuncture (OA) in the treatment of postmenopausal osteoporosis (PMOP).

Methods/design

This study is a randomized, sham-controlled, patient- and assessor-blinded trial and aims to evaluate the effect of OA in women with PMOP. We will recruit 104 women aged 45–70 years with a diagnosis of PMOP. Participants will be randomly allocated in a 1:1 ratio to the OA group and the sham acupuncture (SA) group. Both groups will receive real herbal medicine treatment as a basic treatment twice a day for 3 months, the OA group receives real acupuncture treatment and the SA group receives placebo acupuncture treatment (non-penetrating, sham skin-needle therapy, sham cupping). All patients will receive acupuncture treatment twice per week for 3 months. The primary outcome is bone mineral density (BMD) and the secondary outcomes include estradiol (E2), follicle-stimulating hormone (FSH), bone gla protein (BGP), bone alkaline phosphatase (BALP), total antioxidant capacity (TAC), advanced oxidation protein products (AOPP), PPARγ, β-catenin, FoxO3a levels, visual analog pain scale score (VAS), Traditional Chinese medicine (TCM) syndrome scores and quality of daily life score (QOL). Outcome measures will be collected at baseline, middle of the treatment (1.5 months), the end of treatment (3 months). The present protocol followed the SPIRIT guidelines and fulfills the SPIRIT Checklist.

Conclusion

This study will be conducted to compare the efficacy of OA versus SA. This trial should help to evaluate whether OA can effectively prevent and treat PMOP by improving the estrogen levels of postmenopausal women. The mechanism is to improve the imbalance of osteogenic differentiation and lipogenesis of bone-marrow cells under oxidative stress.

Trial registration

Chinese Clinical Trial Registry, ID: ChiCTR1800017581. Registered on 5 August 2018. URL:http://www.chictr.org.cn.

Keywords: Osteoporosis, PMOP, Acupuncture, Sham acupuncture, Protocol, Randomised controlled trial

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Introduction

The high incidence and the associated pain and fractures of postmenopausal osteoporosis (PMOP) have seriously threatened many women’s physical and mental health, as well as their life quality. According to statistics, about one quarter of perimenopausal women will develop osteoporosis, and these women will lose bone mass rapidly within 5 years post menopause; the premenopausal loss is two to three times that of younger women [1]..The prevention and treatment of PMOP is directly related to the physical and mental health outcomes of most postmenopausal women, and this has great social and practical significance.

Postmenopausal osteoporosis is caused by a decline of ovarian function, rapid aging of the body, decreased estrogen levels, hyperabsorptive function, and compensatory enhancement of osteoblastic bone formation. All of these factors result in a high degree of bone metabolism. The ensuing state of negative balance eventually leads to a decrease in bone mass, destruction of bone microstructure, reduction of bone strength, and a type of systemic bone metabolic disease that is prone to fractures [2]. In recent years, it has been recognized that PMOP is caused by aging, and estrogen deficiency. As the basic pathogenesis of aging, oxidative stress plays an important role in the occurrence of related diseases. Estrogen is a powerful antioxidant, and increased accumulation of reactive oxygen species (ROS) induces oxidative stress, eventually lead to PMOP [3]. It is generally believed that with the increase of ROS and oxidative damage, the formation and survival of bone osteoblasts decreases, while osteoclastic differentiation and activity increase [4, 5]. Some researches show that acupuncture which is performed on the basis that conventional orally administered calcium improves bone density and serum estradiol levels in PMOP patients. The mechanism may be that acupuncture can increase estrogen levels and promote osseous calcium deposition, can affect the bone turnover in order to increase bone density [6]. Oxidative stress-mediated balance of the FoxO3a-β-catenin-PPARγ signal axis may play an important role in bone-marrow mesenchymal stem cells (BMSCs). β-catenin plays a central role in the regulation of osteogenic differentiation and osteoblast activity in the bone-marrow-fat environment [7].

At present, the prevention and treatment of osteoporosis (POP) mainly depends on pharmaceuticals, but there are certain side effects [8], and their long-term effect is unsatisfactory. Estrogen therapy, as a complementary replacement therapy for PMOP, has a long-term application with definite effects, but may often cause adverse events such as breast cancer or endometrial cancer [9]. The side effects of other medicines which are commonly used in clinical practice have also become increasingly prominent. Adverse reactions, such as atypical femoral fractures and mandibular necrosis, caused by the use of bipionate have also attracted increasing attention [10]. The findings have affected their acceptance by many patients. Therefore, it is significant to find a safe, effective, ecologically green, natural, and non-side-effect-causing treatment. Also, first-line clinical medicine is mostly focused on inhibiting the abnormally active bone resorption dominated by osteoclasts. Simply inhibiting osteolysis is difficult to fundamentally treat osteoporosis. The mature growth of osteoblasts is the basis of bone health, so we should pay more attention to the research on methods of promoting bone formation.

Acupuncture therapy is a important therapy for the prevention and treatment of chronic metabolic diseases in traditional Chinese medicine (TCM). The clinical treatment of acupuncture for this disease is mainly to strengthen the kidney and bones, while regulating the spleen and kidney. The clinical effect of acupuncture on this disease is definite, and it can significantly improve the symptoms of low-back pain, limb weakness and kidney deficiency caused by PMOP. Acupuncture can not only alleviate and improve clinical symptoms, such as pain, in patients with osteoporosis, but also can prevent osteoporosis by regulating the levels of endocrine hormones in the body, increasing bone density, and improving abnormal bone metabolism [11, 12].

The currently recognized principles of TCM treatment of osteoporosis are syndrome differentiation, overall regulation, prevention and treatment [13]. “Overall adjustment acupuncture” (OA) is a kind of acupuncture treatment based on TCM, which is an effective, systematic, comprehensive and multi-pathway treatment of osteoporosis. The OA is based on more than 20 years of clinical experience and experimental verification. It combines the main etiology and pathogenesis of osteoporosis with kidney and spleen deficiency. It involves a systematic process for osteoporosis and it combines acupuncture, moxibustion, and skin-needling organically to stimulate the meridian system such as those of the skin, collaterals, and meridians. According to the full regulation of this therapy, osteoporosis has been treated by improving clinical symptoms and patients’ quality of life through multiple channels [14]. During the early stages of clinical treatment, it was found that the OA method has a good effect on PMOP, but a systematic and comprehensive clinical study has not been conducted and, thus, its mechanism of action is not clear. This trial will study the efficacy, safety and mechanism of acupuncture therapy on PMOP. There are few reports on the treatment of PMOP by sham acupuncture (SA) as a control group. Our trial hypothesis is that overall regulation acupuncture treats PMOP by increasing the estrogen levels of postmenopausal women and improving the imbalance of osteogenic and adipogenic differentiation of BMSCs caused by oxidative stress in the human body.