Pueraria mirifica is amazingly beneficial in so many ways. In October 2016, we discussed the clinical studies with Dr. Christian Northrup showing that P. mirifica is not only better than the leading pharmaceutical for treating menopausal symptoms, but it is also safer. In November 2016, we discussed with Dr. Margaret Ritchie how P. mirifica reduces the risk of cancer and examined the epidemiological and mechanistic evidence. Now, let’s discuss with Professor Suchinda Malaivijitnond, Ph.D., an additional health benefit: P. mirifica helps build stronger, healthier bones, too. More people can be helped by this herb if only they know more about it. This is why I wrote the book “Pueraria mirifica: Chemistry and Biology” in 2017 (Nutritional Research Press ISBN: 978-0-692-11135-2).
Estrogens and Bone
Bone is at its strongest when a person is around age 30, and thereafter begins to decline. One reason so many women dread menopause is that this decline begins to accelerate at menopause, increasing their risk of bone loss (osteoporosis) and possibly even death due to complications resulting from a broken hip.
Osteoporosis is a progressive disease characterized by low bone mass and deterioration of bone tissue structure. In 2001, the National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy defined osteoporosis as a “skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.” Osteoporosis is an asymptomatic disease that occurs gradually and with no pain, so many, if not most, people do not realize that they are suffering from it until after they fracture a bone.
Although low bone mineral density increases the risk for fracture, most fractures occur in postmenopausal women and elderly men who are at moderate risk. Worldwide, one in three women over age 50 will experience osteoporotic fractures, as will one in five men over age 50. In women, 80% of fractures occur in the forearm; 75% in the humerus; 70% in the hip, and 58% in the spine. Overall, 61% of osteoporotic fractures occur in women. A 10% loss of bone mass in the vertebrae can double the risk of vertebral fractures, and similarly, a 10% loss of bone mass in the hip can result in a 2.5 times greater risk of hip fracture.
Though bones appear to be inorganic calcium rocks, they are dynamic, living tissue that is continually being replaced. Cells called osteoblasts are responsible for making new bone and other cells, called osteoclasts, are needed to remove old bone and reabsorb bone components. The action of osteoclasts is critical in the maintenance and repair of bones. This ongoing process is called bone remodeling: Bone-resorbing osteoclasts disassemble and digest bone proteins and minerals at a molecular level by secreting acid and enzymes called collagenases. If osteoblasts break down the bone more quickly than it is replaced, then bone tends to become less dense and is therefore likely to break more easily. Bone loss occurs universally with aging, but a clear acceleration of bone loss is seen during and after menopause or following a failure or removal of the ovaries due to estrogen deficiency.
The health of a woman’s bones is associated with her estrogen levels. Estrogens are major endocrine regulators involved in the growth and maintenance of bone in both women and men. Estrogen receptors alpha (ER-α) and beta (ER-β) are found on osteoblasts and osteoclasts cells throughout the body. The bone-sparing effect of estrogens is mediated mainly by ER-α, but the effect of ER-α can be slightly modulated by ER-β. Some selective estrogen receptor modulators (SERMS) exert agonistic (supportive) effects in bone and antagonistic effects in breast (1).
Builds Bone and Protects Against Bone Loss
As Professor Margaret Ritchie discussed, various estrogens can activate estrogen receptors in such a way as to activate the genes that produce the proteins needed to form healthy bones. The good news is that the two most active phytoestrogens in P. mirifica, miroestrol and its sister compound deoxymiroestrol, can have the same bone-building effects on estrogen receptors as estrogens.
Animal studies support a dose-dependent benefit of P. mirifica on bone mass. P. miriﬁca prevented bone loss in male rats that had been castrated (2) and female rats that had their ovaries removed (3). It improved lowered bone mineral content and density caused by sex steroid hormone deﬁciencies, functioning through both osteoblast and osteoclast cells (4). P. miriﬁca extract significantly increased the mRNA expression of alkaline phosphatase and osteoprotegerin, biomarkers for bone growth. (mRNA is a molecule involved in protein synthesis and the transmission of genetic information.) It also decreased the mRNA expression of receptor activator of nuclear factor-κB ligand, an osteoclastogenic factor, suggesting that it could induce bone mass by enhancing osteoblast differentiation and suppressing osteoclast function. The researchers concluded that “the findings, therefore, corroborated the potential benefit of P. mirifica extract and puerarin in the prevention and treatment of postmenopausal osteoporosis.”
In 2008, researchers at a university hospital in Thailand conducted a randomized, double-blinded, placebo-controlled study of P. miriﬁca in healthy postmenopausal women, ages 45 to 60, to determine how P. miriﬁca effects bone loss in humans. Fifty-one of 71 women randomly received a dose of 20, 30, and 50 mg of P. miriﬁca per day. The other 20 women in the study were given a placebo. After 24 weeks of treatment, the group taking the herb showed a 41% decrease in bone-specific alkaline phosphatase levels compared with the control group (5). The researchers concluded that “Pueraria mirifica at a dose of 20, 30, and 50 mg/day for a 24-week period demonstrated an estrogen-like effect on bone turnover rate. Pueraria mirifica did not demonstrate an estrogen-like effect on endometrial thickness and endometrial histology.”
A leading scientist who researches the benefits of P. mirifica on bone is Suchinda Malaivijitnond, Ph.D., in the department of biology at Chulalongkorn University in Bangkok. Let’s ask Professor Suchinda about the meaning of her years of research on P. miriﬁca and bone health. By the way, it’s the accepted custom in Thailand to refer to her when speaking as Professor Suchinda, rather than Professor Malaivijitnond.
Dr. Suchinda Malaivijitnond is a Professor at the Department of Biology, Faculty of Science at Chulalongkorn University in Bangkok, Thailand. Her research focus is about the effects of phytoestrogens from endemic Thai plant Pueraria mirifica on reproductive organs, bone (osteoporosis) and brain (Alzheimer’s disease) tested in vitro and in laboratory animals (rodents and monkeys). Based on the vast knowledge on non-human primates gained both from the laboratory and field studies, she has established the National Primate Research Center of Thailand.
Passwater: Professor Suchinda, how long have you been researching the health benefits of P. mirifica?
Suchinda: I started my P. miriﬁca research in 1999. I could see the potential for P. miriﬁca helping many people, but there were many scientific questions that still needed to be studied. At first, some of the areas that I wanted to study were how the phytoestrogens in P. miriﬁca affect the health of humans, what the optimal dose to take was, were there undesirable side effects, and so on. After studying these basic parameters, I went on to study the effect of P. miriﬁca on the reproductive system, and especially on the hypothalamic-pituitary-ovarian axis, a group of hormone glands that play a critical part in the development and regulation of a number of the body’s systems, such as the reproductive and immune systems. We have gained considerable knowledge about this. Our focus is now turning to research on aging diseases in association with the increasing proportion of aging population in Thailand, and of course in the world. We now have changed our research direction from reproduction to aging diseases related to estrogen deficiency in postmenopausal women. We are especially focusing on bone and brain research. We are actively researching the effects of P. miriﬁca on osteoporosis and neurodegenerative diseases, particularly Alzheimer’s disease.
Passwater: Let’s start at the beginning. Why do postmenopausal women lose bone density and increase their risk of fractures? How is healthy bone density maintained?
Suchinda: Estrogen plays an important role in keeping the homeostasis of bone remodeling, by suppressing bone resorbing cells (osteoclasts) and stimulating bone forming cells (osteoblasts). Both osteoclasts and osteoblasts have estrogen receptors and therefore can respond to P. miriﬁca. Interestingly, estrogen receptors are expressed in the same degree in the bone cells of both males and females. Thus, P. miriﬁca phytoestrogens can be used to combat osteoporosis in both human sexes.
Postmenopausal women lose their ovarian function and there is little or no production of the estrogens. Before perimenopause, the estrogen balance favors the homeostasis of bone by balancing bone formation and bone resorption. During and after perimenopause, a woman’s body has fluctuating estrogen levels and becomes what is called estrogen deprived. The osteoclasts and osteoblasts are no longer in balance. By then, bone mass (density and content) is decreased, which leads to a decrease in bone strength, and if faced with strong mechanical stress such as falling down, bone fractures can then more readily occur.
To maintain a healthy bone mass, a high level of peak bone mass (high bone quantity) and good bone structure (bone quality) is needed. Bone loss occurs naturally as one ages. That’s why we say that osteoporosis is a silent and asymptomatic disease. It is best to supplement with estrogen or estrogen-like substances before the bone loss occurs to acquire the peak bone mass. Also, based on our findings in rats and monkeys that P. miriﬁca can retain bone mass at the level where the treatment is initiated, this implies that the earlier you use P. miriﬁca, the higher and healthier bone mass you can have. We also found that to acquire the anti-osteoporotic effect of P. miriﬁca on bone, at least four years are suggested for humans.
Passwater: What are the mechanisms of action of these compounds on estrogen receptors? How do these compounds act on estrogen receptors to modify gene expression in osteoblasts and/or osteoclasts so as to improve bone health?
Suchinda: P. miriﬁca phytoestrogens, after binding with estrogen receptors, can pass through both genomic and non-genomic pathways. Through the genomic pathway, the phytoestrogen miroestrol stimulates gene expression and through non-genomic pathway, other phytoestrogens stimulate activation of the related enzymes. We found that, for osteoblasts, P. miriﬁca stimulates proliferation, differentiation, and mineralization (or calcium deposition), resulting in increased bone formation. For osteoclasts, P. miriﬁca induces cell death (or apoptosis), and suppresses cell proliferation, differentiation, fusion, and function, resulting in suppressed bone resorption. Taken together, bone mass will be maintained.
Passwater: In 2007 and 2008, your research group at Chulalongkorn University published results showing that P. mirifica improved the compounds in the body that are associated with improved bone health. Have other research groups confirmed these findings?
Suchinda: Oh yes. The findings from those studies showing that P. miriﬁca could prevent bone loss in both male and female animals (2,3) were followed up with a randomized, double-blinded, placebo-controlled study shortly thereafter. A research team at Ramathibodi Hospital and Mahidol University in Bangkok also published in 2008 that P. miriﬁca has health benefits for menopausal health (5). The researchers measured the serum surrogate parameter of bone turnover (markers of bone turnover) and found that P. miriﬁca has a positive effect on bones. They also examined safety indicators and concluded that the absence of an effect on breast ultrasonography indicated no increased risk of breast pathology. Additionally, the absence of effects on blood, liver, and kidney function may indicate that there are no safety concerns with this herb.
Passwater: What indicators and markers of gene expressions did you research in your 2014 Phytomedicine study (6)?
Suchinda: As just mentioned, we had published our earlier studies showing that P. miriﬁca could prevent bone loss in both male and female animals (2,3). The mechanisms identified in research with rat bone cells in vitro were clearly shown to be induction of bone formation and suppression of bone resorption by upregulation (stimulation) of mRNA expression of alkaline phosphatase (ALP) and osteoprotegerin (OPG), respectively. (Note: ALP is an enzyme that can remove phosphate groups from many types of molecules; OPG is a protein also known as an osteoclastogenesis inhibitory factor that can reduce the production of osteoclasts. OPG production is stimulated in vivo by the female sex hormone estrogen.)
For the 2014 Phytomedicine paper, we tested the effect of P. miriﬁca extract on primary monkey osteoblasts in cell cultures and found that P. miriﬁca extract stimulated expression of genes associated with osteoblast differentiation (such as the ALP gene). At the same time, it indirectly suppressed osteoclast differentiation via the reduction of expression of RANKL/OPG ratio. (Note: RANKL stands for receptor activator of nuclear factor kappa-B ligand, which is involved in bone regeneration and remodeling.)
We published another paper in 2016 based on research conducted in postmenopausal monkeys. It indicates that P. miriﬁca improves both the bone quantity and bone quality at the cortical diaphysis (the main or midsection shaft of a long bone). Generally, most bone fractures occur in the long bones that mainly consist of cortical bone tissue. Thus, this study confirms that P. miriﬁca could be a candidate for therapeutic intervention to reduce bone fractures in osteoporotic menopausal women (7).
It is important to keep in mind when attempting to understand the remodeling process that bone is a very dynamic organ that remakes itself all the time.
Passwater: What can be concluded from this study?
Suchinda: That study provided support for P. miriﬁca as a therapeutic agent against bone fragility. Now our studies on P. miriﬁca and bone have gone beyond that and we can now conclude that P. miriﬁca has a high potential to be developed as anti-osteoporotic agent for human use. It is a natural-based product whose safety has already been already confirmed. Moreover, we recently found that P. miriﬁca can accelerate bone healing in postmenopausal osteoporotic monkeys. This is another benefit of this herb which you should keep in mind, because some anti-osteoporotic pharmaceuticals, although they can slow bone loss somewhat, at the same time, they slow the bone healing process.
Passwater: You have also published in September 2016, an article examining the effects of P. mirifica on bone health, while also checking on the actions of P. mirifica on other body systems (8). What were your findings?
Suchinda: That study indicated that P. miriﬁca could be used as an anti-osteoporotic agent for postmenopausal women but that its administration should be initiated as early as possible, such as at the perimenopausal period. The dose needed for effective bone health, between 50 and 100 mg per day, is safe and does not demonstrate any undesirable estrogen-like effect on reproductive organs.
Passwater: More importantly, you also published the results of your study with naturally menopausal monkeys that year (9). Please tell us something about this important study.
Suchinda: In this study, postmenopausal osteoporotic monkeys were divided into two groups (five per group), and fed daily with standard diet alone (PMP0 group) or diet mixed with 1000 mg/kg body weight (BW) of PM powder (PMP1000 group) for 16 months. Every two months, the bone mineral density (BMD), bone mineral content (BMC) and bone geometry parameters (cortical area and thickness and periosteal and endosteal circumference) at the distal radius and proximal tibia were determined using peripheral quantitative computed tomography together with plasma and urinary bone markers.
Compared with the baseline (month 0) values, the cortical, but not trabecular, BMDs and BMCs and the cortical area and thickness at the metaphysis and diaphysis of the radius and tibia of the PMP0 group continuously decreased during the 16-month study period. In contrast, PMP1000 treatment ameliorated the bone loss mainly at the cortical diaphysis by decreasing bone turnover, as indicated by the lowered plasma bone-specific alkaline phosphatase and osteocalcin levels.
Generally, changes in the cortical bone geometry were in the opposite direction to the cortical bone mass after PMP1000 treatment. This study indicated that postmenopausal monkeys continuously lose their cortical bone compartment, and they have a higher possibility for long bone fractures. Oral PMP treatment could improve both the bone quantity (BMC and BMD) and quality (bone geometry).
Passwater: Osteoporosis is a health risk that is directly linked to menopause. Low levels of estrogen cause the bone-building osteoblast cells to be less active than the bone-removal osteoclasts cells. The miroestrol and deoxymiroestrol in P. mirifica act as a substitute for the body’s estrogen. These potent phytoestrogens activate the ER-β receptors in the osteoblast cells in bones to improve their bone health by making them flexible, stronger, and resistant to fractures. In essence, the action of P. mirifica is similar to estrogen substitutes but without their adverse side effects.
Thank you Professor Suchinda for explaining how P. mirifica improves bone health, especially during and after menopause. Your research on how P. mirifica also improves memory and brain health is also important. Let’s discuss that next month.
1. Börjesson, AE, Farman HF, Movérare-Skrtic S, et al. “SERMs have substance-speciﬁc effects on bone, and these effects are mediated via ER-αAF-1 in female mice.” Am J Physiol Endocrinol Metab 310: E912–E918 (2016). doi: 10.1152/ajpendo.00488.2015.
2. Urasopon N, Hamada Y, Asaoka K, and Malaivijitnond S. “Pueraria mirifica: a phytoestrogen-rich herb, prevents bone loss in orchidectomized rats.” Maturitas 56; 3: 322–331 (2007).
3. Urasopon N, Hamada Y, Cherdshewasart W, and Malaivijitnond S. “Preventive effects of Pueraria mirifica on bone loss in ovariectomized rats. Maturitas 59: 137–148 (2008).
4. Tiyasatkulkovit W, Malaivijitnond S, Charoenphandhu N, et al. “Pueraria mirifica extract and puerarin enhance proliferation and expression of alkaline phosphatase and type I collagen in primary baboon osteoblasts.” Phytomedicine 21: 1498–1503 (2014).
5. Manonai J, Chittacharoen A, Udomsubpayakul U, et al. “Effects and safety of Pueraria mirifica on lipid profiles and biochemical markers of bone turnover rates in healthy postmenopausal women.” Menopause 15; 3: 530–535 (2008). doi: 10.1097/gme.0b013e31815c5fd8.
6. Tiyasatkulkovit W, Charoenphandhu N, Wongdee K, and Malaivijitnond S. “Upregulation of osteoblastic differentiation marker mRNA expression in osteoblast-like UMR106 cells by puerarin and phytoestrogens from Pueraria mirifica.” Phytomedicine 19: 1147–55 (2012).
7. Kittivanichhkul D, Charoenphandhu N, Khemawoot P, et al. “Pueraria mirifica alleviates cortical bone loss in naturally menopausal monkeys.” J Endocrinol 231; 2: 121-133 (2016).
8. Suthon S, Jaroenporn S, Charoenphandhu N, Malaivijitnond S, et al. “Anti-osteoporotic effects of Pueraria candollei var. miriﬁca on bone mineral density and histomorphometry in estrogen-deﬁcient rats. J Nat Meds 70: 225–233 (2016).
9. Kittivanichkul, D., Charoenphandhu, N., Khemawoot, P. and
Malaivijitnond, S. Pueraria mirifica alleviates cortical bone loss in naturally menopausal monkeys. J Endocrinol. 2016 Nov;231(2):121-133. Epub 2016 Sep 6.
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