Effects of medicinal herbs on osteoporosis: a systematic review based on clinical trials

Osteoporosis is rapidly turning into a global epidemic, leading to high rates of morbidity and mortality due to the resulting complications such as osteoporotic fractures in older people. Therefore, this review investigated the findings of clinical trials regarding the effects of medicinal herbs on osteoporosis. To this end, several keywords were used to search for relevant articles indexed in the Institute for Scientific Information and PubMed, including “Osteoporosis” or “Bone loss” AND “medicinal plant” or “phyto*” or “herb*”. Finally, 43 articles were included in the review. There are several mechanisms for anti-osteoporosis effects. Estrogen-like effects, especially soy phytoestrogenic compounds and other herbal compounds and formulations, can enhance bone formation markers, as well as antioxidant and anti-inflammatory capacity, while decreasing bone resorption biomarkers. Therefore, they can be used as complementary medicine for osteoporosis, especially in postmenopausal older women. However, for more reliable evidence, further studies are still needed because most studies have addressed soy, and the number of randomized controlled trials conducted on other herbal drugs is small. The plants possess the androgen-like properties that play an important role in the promotion of bone health. In addition, herbal treatments are supportive and slow-acting and thus such treatments are suggested for prevention and maintenance purposes rather than fast-acting treatments.


Introduction
Osteoporosis is considered a serious growing health issue that causes many osteoporotic fractures globally each year due to impaired bone quality (1). In addition, osteoporosis is responsible for impaired stem cell differentiation and impaired bone microarchitecture/mineralization, especially in older women (2). Although this disease can be clinically silent and the people do not usually undergo screening and prevention measures for it, the cost of osteoporotic fractures imposes a heavy burden on the healthcare system (3,4). The disease also substantially decreases the quality of life in patients and elder women (5). Further, osteoporosis is a multifactorial disorder and its risk factors include age over 65 years, postmenopausal estrogen loss or age associated with the deterioration of the microarchitecture, along with the family history of fracture, smoking, obesity, and low body mass index. The disease has also secondary risk factors that encompass underlying disorders and the use of certain drugs (2). Therefore, several therapeutic strategies are available to fight the disease. Although there are several anti-osteoporotic drugs and treatments of choice for improving bone mineral density (BMD), numerous needs remain unmet and several side effects and treatment failures are also reported due to therapeutic methods (6,7). Nowadays, the use of medicinal plants is growing for the treatment of various diseases. Fewer side effects, cost-effectiveness, and convenient access have positively contributed to the popularity of medicinal plantbased treatments (8). Although medicinal plants and their derivatives can effectively maintain the bone metabolism in a balanced state and increase lumbar spine BMD, herbal treatments have not come up with convincing outcomes regarding the treatment or prevention of osteoporosis (9,10).
Many articles have acknowledged the therapeutic value of medicinal plants although these theories do not rely on reliable data from clinical trials. Therefore, the present review article evaluated the effects of medicinal plants on osteoporosis according to the results of clinical trials.

Materials and Methods
To conduct this review article, keywords such as "Osteoporosis" or "Bone loss" AND "medicinal plant" or "phyto*" or "herb*" were utilized to search for relevant articles indexed in the Institute for Scientific Information and PubMed using the EndNote software. A standard form was also prepared, including items such as the author, the title or purpose of the study, medicinal plant or formulation(s) or constitute(s) names, the type of intervention, the dosage, the duration, outcome, publishing journal, and the number of co-authors. Then, the full texts of the articles that fulfilled the purpose of the review were included in the analysis after achieving the agreement of the co-authors, followed by recording the above-mentioned information in the form. Next, clinical trials conducted on osteoporosis were considered as the inclusion criteria. Moreover, the articles that had a positive effect on osteoporosis were included in the review. However, those articles reporting studies with non-positive effects, review articles, articles with inaccessible full texts, non-English language articles, and studies irrelevant to the main aim of the review were excluded after obtaining the agreement of all authors. Overall, 43 studies were included in the final analysis (Figure 1).

Results
The use of medicinal plant-based products and derivatives is considered as a convenient and cost-effective method for improving bone health. They even can be used as a food or dietary supplement to prevent postmenopausal osteoporosis. The interventions were reported to exert inflammatory and metabolic impacts, to decrease turnover markers and increase calcium conservation (11,12). A  total of 52 articles were included in the final analysis after studying the articles by two of the co-authors and according to the inclusion and exclusion criteria.
Medicinal plants and their compounds can be effective against osteoporosis via various mechanisms of action (Table 1).

Discussion
In this study, medicinal plants were found to prevent or reduce the symptoms of osteoporosis through several mechanisms. Conversely, however, some studies showed that these natural medicines may not have an impact on this disease. For example, in the study of Brink et al., supplementation with 110 mg/d of soy isoflavone aglycone for one year in postmenopausal women failed to prevent postmenopausal bone loss or affect bone turnover (54). Similarly, another study indicated that 200 mg of soy isoflavones daily for 2 years did not prevent bone loss in menopausal women (55). Consistently, some studies have reported that treatment with isoflavones (aglycone equivalents), Trifolium pratense extract, and semelil (Angipars W) could not prevent a decline in BMD and had no significant effect on bone biomarkers and thus bone health (56)(57)(58)(59). According to previous studies and the present one, it seems that differences in the study populations and the lack of controlling for confounding factors such as soy or phytoestrogens consumption in the control group may have led to these inconsistencies. The concomitant treatments, the duration of the studies, and the administration route of the herbal compounds may have also contributed to these differences.
Based on the findings of this review study, there are several mechanisms for the effect of medicinal plants on osteoporosis. Osteoporosis is characterized by skeletal degeneration with a reduction in BMD and the deterioration of the microarchitecture of the bone tissue, which leads to a fracture (60). This disease is more prevalent in postmenopausal women than older men because these women are more likely to develop osteoporosis compared to men due to massive declines in estrogen levels during menopause, which can lead to an increase in the bone-resorption activity and a decline in bone formation (61,62). Estrogenic compounds like phytoestrogens affect bone via promoting the production of calcitonin, lowering the sensitivity of bone mass to parathyroid hormone, reducing the calcium excretion from the kidney, and accelerating intestinal calcium resorption. Further, estrogen can directly influence the bone, which, in turn, can inhibit bone resorption and increase bone density (63). Another mechanism is the anti-inflammatory and antioxidant effects of medicinal plants. Furthermore, inflammation cytokines exert substantial impacts on bone loss and osteoporosis (2). Phytoestrogens are able to suppress the production of proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), IL-1, IL-6, and IL-7 as well. This is why these proinflammatory cytokines are elevated in postmenopausal women (64). In addition, the antioxidant capacity of herbal drugs can serve to scavenge free radicals, leading to the inhibition of cyclooxygenase-2 (COX-2) and TNF-α production and expression. This results in a decrease in the receptor activator of NF-κβ ligand (RANKL) expression (RANKL-stimulated RAW 264.7 cells also in bone marrow-derived macrophages), leading to a decline in the osteoclast activity, which, finally, reduces bone loss (64)(65)(66).
Moreover, herbal drugs can promote bone formation markers such as AKP, serum 25-hydroxyvitamin D, bone Gla protein, and osteocalcin but decrease bone resorption markers like serum collagen type 1and β-CTX. Figure 2 summarizes the most important mechanisms of medicinal plants and their derivatives reported in clinical trials.
Although plant compounds are considered natural, Combination therapy decreased bone turnover markers and the risk of osteoporosis Granado et al (53) they can lead to certain complications under certain circumstances such as the type of plant, dosage, and the duration of use. A meta-analysis demonstrated that the long-term consumption of phytoestrogens did not significantly increase the side effects such as endometrial hyperplasia, vaginal bleeding, endometrial cancer, and breast cancer, but elevated the rates of gastrointestinal side effects (67). In this review, the side effects had also been included and reported in some studies. Such side effects were reported following the consumption of higher doses of plant compounds, and certain side effects were widely developed after the consumption of phytochemicals. For example, some studies reported that high doses of genistein can cause gastrointestinal complications (42,43,49). The main limitation in most clinical trials was the lack of making any comparisons between different doses of herbal derivatives and different populations as well as the lack of control for the confounding factors. According to our review, previous randomized controlled trials addressed very few herbal plants in order to evaluate their pharmacological effects on humans' bone health, most of which were conducted on soy phytochemicals. Therefore, more rigorous research should be done on these plants to evaluate their anti-osteoporotic properties.

Conclusion
Medicinal plants and their derivatives can be used to enhance bone formation markers, along with antioxidant and anti-inflammatory capacity, but decrease bone resorption biomarkers. Thus, they can be utilized as complementary medicine for osteoporosis, especially in postmenopausal older women. However, further studies are needed in this regard. The plants possess the androgen-like properties that are important for the promotion of bone health. On the other hand, modern pharmaceuticals are also employed to quickly promote none mineral density for people at high risk. In addition, herbal treatments are supportive and slow-acting, and therefore they are suggested to be used for prevention and maintenance purposes rather than fastacting treatments.

Conflict of Interests
The authors have no conflict of interests.