Bone mesenchymal stem cell therapy for ovariectomized osteoporotic rats: a systematic review and meta-analysis

Osteoporosis is a systemic skeletal disease characterized by low bone mass and degradation of the bone microstructure, with consequent increases in the fragility of bone and risk of fracture [1]. A large number of complications have been discovered, which seriously threaten people’s lives and health. Osteoporotic fracture is a serious complication of osteoporosis. Osteoporotic fractures occur following minimal violence or, in some cases, without trauma [2]. In the United States, about 9.9 million people suffer from osteoporosis and 43.1 million have a low bone mineral density (BMD) with an increased likelihood of fractures [1]. Moreover, in China, about 112 million people suffer from osteoporosis, and the prevalence of fractures in people aged more than 50 years of age is 26.6%, with nearly one third of them due to osteoporosis [3].

Tissue engineering technology has been rapidly developed in the fields of bone and cartilage tissue construction, blood vessels, nerves, skin, and so on. As an important part of tissue engineering technology, stem cells have received extensive attention owing to their unique advantages. Bone marrow mesenchymal stem cells (BMSCs) represent a stem cell population that can be harvested from the bone marrow [4] and can differentiate into osteoblasts, fat, cartilage, neuron, and so on. Moreover, BMSCs have attracted much attention because of their advantages, such as easy material extraction and self-renewal [5]. Furthermore, the advantages of autologous transplantation with BMSCs include small trauma, no rejection, and few post-transplant complications [6]. It can effectively avoid bone defects and healing delay in traditional autologous bone transplants. Hence, BMSCs are widely used in cell-level clinical studies on bone and cartilage tissue. But at present, most of the treatment methods of osteoporotic fracture include mainly surgery and conservative intervention, and the severity of osteoporosis affects the occurrence, development, and prognosis of osteoporotic fractures [2]. Additionally, the perioperative treatment of osteoporotic fractures requires attention to prevent the occurrence of re-fracture [7]. Therefore, with the increase of age, the decline of physical health or other factors, new progress in innovative therapy is needed, so cell-based repair therapy has become a promising therapeutic strategy [8].

However, only a small number of the reports have been reported on the clinical application of BMSCs [9], and it is the treatment of osteoporosis, rather than osteoporotic fractures. Most of the stem cell therapy for osteoporotic fractures remains in basic research. For this we focus our attention on animal models. Ovariectomy (OVX) results in the decrease level of estrogen and is well established in investigations of osteoporotic therapies [10]. OVX induces bone loss in animals, and postmenopausal bone loss has many similar features [11], including a rapid decrease in the trabecular bone mass and an increase in bone resorption, and similar skeletal response to therapy with estrogen, bisphosphonates, tamoxifen, calcitonin. These wide-ranging similarities make ovariectomized animal models have been widely used as clinically relevant models of postmenopausal bone loss in women [12]. The ovariectomized (OVX) rat model was approved by the US Food and Drug Administration (FDA) as a preclinical model [13].

Mesenchymal stem cells have been reported beneficial to animal models of OVX [14‐19]. However, in most cases, functional improvement occurs despite minimal engraftment at the site of injury, suggesting that BMSCs may have paracrine effects by secreting factors that promote regeneration without attachment [20, 21]. Although BMSC has been reported to be studied on animals, such as rats, mice, and horses. But BMSC has less research articles on animals other than rats. Therefore, the present study aimed to conduct a systematic review and meta-analysis of the efficacy of BMSCs for OVX rats. The findings can contribute to the clinical trials and treatments in the future.

The analyses showed that BMD values remarkably increased, indicating that BMSCs accelerated callus maturity and ossification. Moreover, the addition of other therapeutic elements to the BMSCs more dramatically increased healing. Indeed, MSC conditioned media can induce a similar or stronger osteogenic effect than transplanted cells [23]. In the BMSC monotherapy group, the BV/TV (%) value was significantly different, while the Tb/Sp value was not. However, in the BMSCs plus other treatment groups, the results were exactly the opposite: the BV/TV (%) values were not significantly different, whereas the Tb/Sp values were. Overall, the possibility of treating the fracture site in the treatment group was significantly higher than that in the control groups, and the MSC conditioned media for bone regeneration could represent an alternative to cell-based therapies in the future.

BMSCs have the ability to differentiate into osteoblasts, fat, cartilage, neuron, and so on, and have low immunogenicity, and multi-potential differentiation. BMSCs have attracted much attention because of their advantages, such as self-renewal and multidirectional differentiation [24]. Moreover, the advantages of autologous bone marrow mesenchymal stem cell transplantation include no rejection and few post-transplant complications, it can effectively avoid bone defect and healing delay of traditional autologous bone transplantation [25]. Although the classical Ex vivo expanded stem cells has been validated, this requiring a lot of cultivate time before implantation [26, 27]. Several researchers have confirmed that recruitment of endogenous MSC is a viable alternative to MSC transplantation [27‐29]. In some studies, BMCS has limited differentiation ability, such as Balakumaran [30] studies have shown that Telomere Biology Disorders (TBD)-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. Additionally, it has been reported that unmodified MSCs showed oncogenic transformation when injected into immune-compromised mice [31]. But recent studies indicates that reports of oncogenic transformation or malignant of MSCs may reflect the role of cell culture cross-contamination rather than true oncogenic transformation [32].

It is possible that the BMSCs can directly differentiate into osteoblasts in a physiological environment. However, the cytokines from transplanted cells are more likely to play an important role in bone metabolism [33]. Given that BMSC number from marrow decline with age [34]. Whereas, in the treatment of bone diseases, not only BMSCs but also ADSCs [35], muscle-derived stem cells [36], and so on, all can be induced to be divided into osteoblasts. In addition, in clinical aspects, some studies have shown that intracoronary injection of autologous BMSC can improvement in left ventricular function in patients with anterior ST-segment elevation myocardial infarction [37]. Carlos [38] et al., also reported that BMSC were transplanted into the perilesional area in five patients bearing sequels of stroke, with excellent tolerance and without complications. It has also been reported that autologous BMSCs transplantation for the treatment of breast cancer related lymphedema is effective and feasible [39]. Gunter [40] et al., found that in patients with malignant liver lesions, the combination of CD133 BMSC with portal vein embolization administration significantly increased hepatic regeneration. Women have been using stem cell technology for cosmetic indications for the past few years, and there seems to be a reason to believe that stem cells can now be used to solve more serious clinical symptoms [41].

Modern medical treatment of osteoporotic fracture is based on inhibiting bone resorption, promoting bone formation, and regulating blood calcium and blood phosphorus levels to improve pain symptoms [42]. Commonly used drugs are calcium, bisphosphonate, calcitonin, parathyroid hormone, and so on. Moreover, the drugs are combined with nonsteroidal painkillers and physical therapy [43]. Antiresorptive agents fail to adequately restore bone mass and bone quality, and daily injections of parathyroid hormone (PTH) can increase bone mass to stimulate bone formation. However, chronically elevated PTH levels cause bone resorption exceeding bone formation, ultimately resulting in osteoporosis [44] and the risk of developing osteosarcoma. Therefore, treatment options for promoting bone regeneration and reversing bone loss are currently limited. Unfortunately, researchers do not always get the results of clinical trials, and most of the results have not been published in peer-reviewed journals [45]. In short, due to the unsatisfied treatment effect, we investigate the feasibility of BMSCs to provide more clinical treatment in future.

This meta-analysis included various fracture sites (femur, tibia, and mandibles), different initiation times of treatment (1–12 weeks), different BMSC doses and sources, and various measurement standards and calculation methods. Animal information was not comprehensive, such as intervention methods, and outcome indicators, which could cause a high heterogeneity [46]. Thus, random-effects models were used for the analysis and more models of different types of fracture, unified measurement, and same treatment time are needed to verify the efficiency of BMSCs.

In summary, as stem cell therapy may develop into a new treatment for osteoporotic fractures, more systematic studies are needed to investigate the regime, safety, and efficacy for fracture healing. Nowadays, the application of BMSCs in the field of orthopedics is developing rapidly. Cell-based strategies have appeared as hopeful treatment strategies when the intrinsic regenerative potential is reduced by health, age, or other factors [8]. The BMSCs could remarkably increased BMD values of osteoporotic fractures Rats. This indicating that BMSCs accelerated callus maturity, promoted ossification of the fracture site and restore the mechanical properties of the bone. Therefore, the role of BMSCs in the treatment of orthopedic diseases has become more important. Although all the research is still in the basic stage, in view of the increasing research in this field, it is believed that BMSC transplantation has a very good clinical application prospect in treating areas of bone and cartilage in the future.