The effects of resveratrol in animal models of primary osteoporosis: a systematic review and meta-analysis

Osteoporosis (OP) is a systemic bone disease characterized by damage to the bone microstructure and decreased bone mass, resulting in bone fragility and easy fracture [1, 2]. Primary osteoporosis, as a major part of OP, is currently a major public health problem facing patients and medical practitioners globally. A decreasing BMD not only increases the incidence of fractures but also has an incalculable impact on patients' financial status and personal and even whole-family quality of life, given that most patients with primary OP are elderly patients (postmenopausal OP and senile OP) [3, 4]. Clinically, anti-OP drugs are categorized into anti-absorptive and pro-synthetic drugs. Widely used options include bisphosphonates (BP), selective estrogen receptor modulators (SERM), and RANK-ligand inhibitors. Despite their popularity, these drugs are associated with various adverse effects. For example, Denosumab, a type of BP, significantly increases BMD in the spine and hip of postmenopausal women with OP. However, due to severe gastrointestinal reactions such as acid reflux, nausea, and vomiting, many patients opt for intravenous administration over oral, potentially impacting treatment compliance of patients [5‐8]. For another example, although oestrogen replacement treatment has a significant effect on treating postmenopausal OP [9], studies have shown that this therapy may increase the risk of breast and uterine cancer. Thus, there is a critical need to identify drugs that are more effective, convenient, and safer for primary OP.

Resveratrol (Res) is a polyphenolic phytoestrogen that is present in the skin of red grapes, peanuts and various other fruits [10, 11] and has potent antioxidant, anti-inflammatory, antiageing, neuroprotective, anticarcinogenic and cardioprotective effects [12, 13]. In vitro evidence has shown that Res can improve the activity of osteoblasts and inhibit the differentiation of osteoclasts [14, 15]. For example, in vitro, Res increases ALP in a dose-dependent manner by promoting the differentiation of osteoblasts [16]. In vivo studies have shown that Res can improve BMD and prevent bone loss in young rats subjected to tail suspension, in ovariectomized (OVX) rats and in old rats subjected to hind limb suspension [17‐19]. However, a large number of existing studies have not yet systematically summarized and analyzed the topic. Therefore, this review aims to comprehensively explore the role of Res in an animal model of primary OP through the use of a meta-analysis of animal experiments for the first time.

The meta-analysis was performed in accordance with PRISMA guidelines (Additional file 1 ) and registered on the PROSPERO platform of the International Register of Systematic Evaluations (No. CRD42023478041).

A total of 714 studies were selected. After removing duplicates, 351 studies remained. Sixty studies were left for full-text screening after screening the titles and abstracts. Finally, 24 studies were analyzed. The basic characteristics of the final 24 studies [15, 17, 19, 21‐41] are shown in Table 1. The search process is shown in Fig. 1.

Several studies (Fig. 2) were thought to have an “unclear risk of bias”, for example, random sequence generation, random housing and random outcome assessment. A low risk of bias was observed for incomplete outcome data, baseline characteristics and selective reporting in all studies except one [19]. Moreover, the funnel plot (n > ten papers) showed that the stability of the results was not affected by publication bias (Additional file 1 ).

This review assessed the protective effects of Res in animal models of primary osteoporosis. Twenty-four articles were analyzed, and eleven results were obtained. This review showed that Res can markedly increase BMD, improve morphometric indices of the trabecular microstructure and serum BTMs concentration, and exert a protective effect on animal models of primary OP.

BMD, a gold standard for diagnosing OP, can be detected via dual-energy X-ray (DXA) or micro-CT. Mizutani K et al. reported that Res can alleviate the decrease in femoral BMD induced by ovariectomy in rats [18, 42], while Li YT et al. suggested that inhibiting bone resorption may be related to the ability of Res to increase BMD because Res can inhibit the production of prostaglandin e2 and interleukin-6 [43]. Kenny reported that the serum testosterone concentration is positively correlated with the BMD, and Res may ameliorate bone loss caused by male hypogonadism by maintaining the balance between RANK and OPG [31]. Therefore, our study evaluated the ability of Res to improve BMD in primary OP patients. This study showed that the BMD in the Res group increased significantly. In addition, the subgroup analysis according to the modeling methods, detection methods or detection positions also yielded significant results. In addition, due to the high heritability of BMD, one study had explored the reason why individual differences exist in the effectiveness of bisphosphonates (a first-line anti-OP drug at present) from the genetics. The findings revealed that, in contrast to rs1544410 A/G, another variant, rs2228570 C/T associated with the vitamin D receptor, exhibited a correlation with a favorable response to antiresorptive therapy. This study prompts us to explore whether the genetic characteristics of diverse primary OP conditions influence the efficacy of resveratrol in improving BMD, given its promising results [44].

It is well-known that the morphometric indices of the trabecular microstructure play a vital role in the diagnosis of osteoporosis [45]. The BV/TV is one of the key indices of trabecular microstructure, and an increase in this parameter indicates that bone anabolism is more common than catabolism and that the bone mass is greater, and vice versa. Ozturk S et al. reported that Res (80 mg/kg/day) can reduce the BV/TV, Tb.N and Tb.Th and prevent a sharp decrease in bone mass caused by ovariectomy by improving the microstructure and biophysical and chemical properties of bone [27]. Therefore, our study evaluated the BV/TV in an animal model of primary OP and revealed that Res can improve bone mass and bone metabolism by increasing the BV/TV. In addition, Tb.Th, Tb.N, and Tb.Sp are the primary parameters used to evaluate the spatial morphological structure of trabecular bone. Once osteoporosis occurs, the Tb.Sp increases, while the Tb.N and Tb.Th decrease. Therefore, by evaluating the above three indices, this study revealed that Res can increase the Tb.Th and Tb.N while reducing the Tb.Sp, thus improving bone loss in an animal model of OP.

Intermediate metabolites or enzymes produced during bone turnover are called serum BTMs. BTMs can be classified as bone formation or bone resorption markers. The former indicates osteoblast activity and bone formation, such as ALP, bALP and OC, while the latter reflects osteoclast activity and bone resorption, such as CTX-1 and TRAP5b. BTMs play a role in diagnosing various bone diseases, determining bone turnover types, predicting the risk of fracture, monitoring treatment compliance and evaluating drug efficacy [22, 36, 40]. The level of BTMs in primary OP is usually normal or slightly elevated. Feng J et al. reported that Res inhibits the generation of osteoclasts in OVX rats by decreasing RANKL and TRAP5b and increasing OPG. This difference may be related to the antiapoptotic, antioxidative and anti-inflammatory effects of Res [26]. Elesawy reported that chronic administration of Res can significantly improve the BMD of the tibia, and the protective mechanism may involve increasing the levels of OC, OPG and ALP [22]. Therefore, the present study showed that ALP, CTX-1 and TRAP5b in the Res group were significantly decreased, and OC tended to decrease. In addition, bALP showed an opposite trend to that of the other indicators, which may be due to the small amount of data. OPG is a metabolite secreted by osteoblasts and can inhibit the formation of osteoclasts by competitively binding with RANK [22, 36, 40]. Our results showed that the OPG in the Res group increased significantly, which improved the state of primary OP. In addition to the above markers, there are other bone metabolic intermediates, including p1np, p1cp, LCa/Cr, dpyr, and ntx [45, 46]. Unfortunately, this review did not pursue further investigation due to challenges in acquiring adequate data.

The study limitations were as follows: (1) Language bias; (2) the reliability of the risk of bias assessment was limited to low-quality included studies; and (3) most of the results were highly heterogeneous; however, we performed a subgroup analysis. The results of the sensitivity analysis were robust (Additional file 1).

Res can markedly increase BMD, improve morphometric indices of the trabecular microstructure and serum BTM concentration, and exert a protective effect on animal models of primary osteoporosis. This study can provide an experimental reference for Res in primary OP. In the future, additional studies are needed to evaluate the effects of Res as an anti-primary OP drug.