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International Journal of
Environmental Research
and Public Health
Review
Protective Effects of Selected Botanical Agents
on Bone
James Jam Jolly 1, Kok-Yong Chin 1ID , Ekram Alias 2, Kien Hui Chua 3and
Ima Nirwana Soelaiman 1, *
1Department of Pharmacology, Faculty of Medicine, Pusat Perubatan Universiti Kebangsaan Malaysia,
Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Wilayah Persekutuan Kuala Lumpur, Malaysia;
jamesjamjolly@yahoo.com.my (J.J.J.); chinkokyong@ppukm.ukm.edu.my (K.-Y.C.)
2Department of Biochemistry, Faculty of Medicine, Pusat Perubatan Universiti Kebangsaan Malaysia,
Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Wilayah Persekutuan Kuala Lumpur, Malaysia;
ekram.alias@ppukm.ukm.edu.my
3Department of Physiology, Faculty of Medicine, Pusat Perubatan Universiti Kebangsaan Malaysia,
Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Wilayah Persekutuan Kuala Lumpur, Malaysia;
ckienhui@gmail.com
*Correspondence: imasoel@ppukm.ukm.edu.my; Tel.: +603-4040-5514
Received: 12 April 2018; Accepted: 8 May 2018; Published: 11 May 2018
Abstract:
Osteoporosis is a serious health problem affecting more than 200 million elderly people
worldwide. The early symptoms of this disease are hardly detectable. It causes progressive bone
loss, which ultimately renders the patients susceptible to fractures. Osteoporosis must be prevented
because the associated fragility fractures result in high morbidity, mortality, and healthcare costs.
Many plants used in herbal medicine contain bioactive compounds possessing skeletal protective
effects. This paper explores the anti-osteoporotic properties of selected herbal plants, including their
actions on osteoblasts (bone forming cells), osteoclasts (bone resorbing cells), and bone remodelling.
Some of the herbal plant families included in this review are Berberidaceae, Fabaceae, Arecaceae,
Labiatae, Simaroubaceaea, and Myrsinaceae. Their active constituents, mechanisms of action, and
pharmaceutical applications were discussed. The literature shows that very few herbal plants have
undergone human clinical trials to evaluate their pharmacological effects on bone to date. Therefore,
more intensive research should be performed on these plants to validate their anti-osteoporotic
properties so that they can complement the currently available conventional drugs in the battle
against osteoporosis.
Keywords: bone remodelling; complementary therapies; herbal medicine; osteoblast; osteoclast
1. Introduction
Osteoporosis is a metabolic bone disorder resulting from an imbalance of bone remodelling,
in which the rate of bone resorption is higher than the rate of bone formation [
1
,
2
]. In turn, this
gives rise to low bone mass, microarchitectural deterioration, and eventually an increased risk for
fragility fractures [
1
–
3
]. Osteoporosis can be classified into primary (Type I and II) and secondary
osteoporosis. Primary type I osteoporosis occurs in women soon after menopause (postmenopausal
osteoporosis) and in men during and after middle-age [
4
]. On the other hand, primary type II or senile
osteoporosis is due to old age. Both sexes may develop primary type II osteoporosis over the age of
70, whereby both trabecular and cortical bones degenerate, thus causing proximal femora, vertebrae,
and radii fractures. Women have a two-fold higher risk than men to suffer from primary type II
osteoporosis due to their low peak bone mass [
2
,
4
–
6
]. Secondary osteoporosis is due to medications or
certain medical conditions, such as hypogonadism, hyperparathyroidism, or leukemia [
7
]. Prolonged
Int. J. Environ. Res. Public Health 2018,15, 963; doi:10.3390/ijerph15050963 www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2018,15, 963 2 of 16
use of some medications can lead to bone loss, such as oral or high-dose inhaled corticosteroids,
thyroid hormone replacement, and aromatase inhibitors [
7
–
9
]. Osteoporosis is closely associated with
increased mortality due to complications of osteoporotic fractures, particularly at the vertebrae and
hips [2,10,11].
Most current therapies for osteoporosis focus on inhibiting bone resorption and reducing
bone remodelling [
12
,
13
]. Parathyroid hormone, and its analogue teriparatide, are the only
anabolic therapies available to treat severe osteoporosis [
14
]. The current drug therapies have
been proven to improve bone mineral density and reduce fracture risk, but prolonged use has been
associated with various side effects [
15
,
16
]. Therefore, the search for new drugs is ongoing [
17
,
18
].
In addition, the prophylactic agents for osteoporosis are limited to calcium and vitamin D. Recent
advancement in phytomedicine has stimulated interests to transform herbal plants into treatment
for chronic diseases, like osteoporosis [
2
,
12
,
19
]. Some vigorously studied herbal plants have
demonstrated antiosteoporotic effects in cellular and animal studies [
13
,
19
,
20
]. These include
Rhizoma alismatis [
21
], Curculiginis rhizoma [
22
], Hemidesmus indicus (L). R. Br [
23
], Passiflora foetida [
24
],
Cissus quadrangularis [25], and Dalbergia sissoo [26].
In this paper, selected herbal plants which have demonstrated skeletal protecting effects in
scientific studies were reviewed. Their geographical origin, active chemical components, and
mechanism of action were discussed. The herbal plants included in this review were tested at least
in animal or cellular (cultured osteoblasts and osteoclasts) studies, and their bioactive constituents
had been identified. Six plant families originating from the Asian continent were discussed, namely
Berberidaceae (East Asia), Fabaceae (East Asia), Arecaceae (Southeast Asia), Labiatae (Southeast Asia),
Simaroubaceaea (Southeast Asia), and Myrsinaceae (Southeast Asia).
2. Antiosteoporotic Constituents Extracted from Natural Plants
2.1. The Berberidaceae Family
Epimedium plants (a genus of flowering plants from the Berberidaceae family) are low-growing
and deciduous perennial plants [
27
–
29
]. They are also known as barrenwort, fairy wings, and bishop’s
hat. The leaves of other species such as Epimedium brevicornum Maxim, Epimedium sagittatum Maxim,
Epimedium pubescens Maxim, and Epimedium koreanum Nakai have been used traditionally to combat
osteoporosis and menopause-related diseases in China [
27
,
30
–
32
]. These herbal medicinal plants are
used throughout the ages as an antiosteoporotic agent in Chinese traditional medicine [
27
,
30
–
32
]. The
crude extract of Epimedium flavonoids contain icariin, epimedin B, and epimedin C. These compounds
have been identified as the main antiosteoporotic constituents of Epimedium plants by inhibiting bone
resorption, triggering bone formation, and blocking urinary calcium excretion [
27
,
30
–
32
]. They have
also been shown to prevent osteoporosis without causing uterine hyperplasia in the ovariectomized
rat model [20,27,30,31].
The Epimedium flavonoids possess estrogenic activity and improve the maturation of osteoblasts
by inducing the expression of alkaline phosphatase (ALP), bone morphogenetic protein-2 (BMP-2) and
core binding factor
α
1 (Cbf
α
1). They also increase expression of osteoprotegerin (OPG) but reduce the
expression of receptor activator of nuclear factor-
κ
B ligand (RANKL), thereby inhibiting the formation
of osteoclasts [
27
,
30
–
33
]. Several studies also showed that Epimedium flavonoids upregulated
expressions of BMP or Wingless-type signalling (Wnt-signaling) pathway related regulators, like
cyclin D [20,27,30,31].
Icariin has been identified as the most active flavonoid glucoside extract of Epimedium
plant
[27,31]
. Icariin inhibits bone loss in the distal femur and tibia in ovariectomized rat
models [
20
,
27
,
30
,
31
]. It is suggested that icariin activates estrogen receptor (ER) and induces
ER-dependent bone activity [
20
,
27
,
30
,
31
]. Icariin also decreases the tartrate-resistant acid phosphate
activity (TRAP) activity of osteoclasts, their size and bone resorption activity. This is achieved by
lowering IL-6 and TNF-
α
expression [
20
,
27
,
30
,
31
]. Icariin can inhibit cyclooxygenase type-2 (COX-2)
Int. J. Environ. Res. Public Health 2018,15, 963 3 of 16
activity, expression of LPS-induced hypoxia inducible factor-1
α
(HIF-1
α
), and activation of the p38 and
c-Jun N-terminal kinase (JNK) in osteoclasts [
20
,
27
,
30
,
31
]. It also inhibits osteoclasts differentiation by
reducing ERK1/2 and Iκ-BαLPS-induced activation [20,27,30,31].
Ikarisoside A is a natural flavonoid extracted from Epimedium species of E. koreanum. It possesses
antioxidant and anti-inflammatory properties in LPS-stimulated bone marrow-derived macrophage
precursor cells and in RAW264.7 cells [
20
,
30
,
31
]. It also inhibits the formation of osteoclasts and
bone resorption activity from these precursor cells [
20
,
31
]. Moreover, Ikarisoside A reduces the
expression of osteoclastic genes, such as TRAP, matrix metalloproteinase 9 (MMP-9), cathepsin K,
and receptor activator of NF-
κ
B (RANK) [
20
,
30
,
31
]. This is achieved by suppressing the activation of
the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
κ
B), JNK, and protein kinase B
(Akt)-RANKL [
20
,
30
,
31
]. Thus, it can be concluded that Ikarisoside A has the potential to be used as a
remedy to treat diseases involving rheumatoid arthritis and osteoporosis [20,30,34]
2.2. The Fabaceae Family
The soybean, scientifically known as Glycine max L. (Fabaceae), is mainly grown in Southwest
Asia [
27
]. It is a rich source of proteins and flavonoids, such as daidzein, biochanin A, and genistein [
27
].
Supplementing soybean protein in the diet is effective in reducing the loss of bone mineral density
in ovariectomized rats [
27
,
35
,
36
]. In animal models of bone loss, isoflavones can preserve trabecular
microstructure [
27
,
37
]. They act by modulating gene expression of collagen type I (COL I), osteocalcin,
calciotropic receptor, ALP, cytokines, and growth factors [
27
,
38
]. The phytoestrogens in soybean have
been shown to exert significant effects on bone metabolism in postmenopausal women. It could be used
as a dietary supplement to prevent postmenopausal osteoporosis since isoflavones can improve bone
turnover markers, bone mineral density, and bone strength among postmenopausal women [
27
,
36
–
38
].
However, the skeletal effects of soy isoflavones supplementation in humans remain debatable because
several meta-analyses reported that the effects were minimal [
39
,
40
]. Nevertheless, further studies are
necessary to verify the magnitude of the skeletal effects of soy isoflavones in humans.
Genistein is an isoflavone exhibiting estrogenic effect on bone. It modulates B-lymphopoiesis in
bone marrow and inhibits bone degradation without any estrogenic effect in the uterus [
27
,
41
]. The
antiosteoporotic effects of flavonoids depend on the mixture of their estrogenic agonist–antagonist
properties [
27
,
41
]. Other studies suggest that the antiosteoporotic effects may be derived from other
biochemical properties of flavonoids, including enzymatic inhibition of certain protein kinases or
activation of estrogen type I receptors [
27
]. The clinical effectiveness of the flavonoids may be
dependent on their ability to produce equol, an isoflavandiol metabolized by gut microflora from
daidzein [27,42]. It shows a higher estrogenic activity than the predominant flavonoids [27,42].
Herbal plants of the species Psoralea corylifolia L. (commonly known as Malay Tea, Cot Chu, or Ku
Tzu locally) belongs to the family Fabaceae [
27
]. The fruit of this plant is used traditionally to treat
bone fractures, osteomalacia, osteoporosis, and joint disorders [
13
,
43
]. The fruit extract of P. corylifolia
significantly increases the serum concentration of inorganic phosphorus and induces bone calcification
in rats [
27
,
43
]. The crude extracts of its fruit and seed, as well as two of its dominant isoflavones (corylin
and bavachin), have been found to stimulate bone formation [
27
,
43
]. Extracts of P. corylifolia from
different parts of the plants also contain bakuchalcone, psoralen, bakuchiol, psoralidin, bavachinin,
isopsoralen, and flavones [44].
Some bioactive compounds isolated from P. corylifolia have been found to exert bone-protective
effects. Bavachalcone can inhibit osteoclastogenesis by hindering the ERK and Akt signaling, as well
as Chromosome-Fos (c-Fos) and nuclear factor of activated T cells c1 (NFATc1) induction during
differentiation [
27
,
43
]. Psoralidin, bakuchiol, isobavachin, and corylin have been found to have
strong antioxidant activities, whereas other compounds, such as bavachin and corylin, have been
shown to stimulate osteoblastic proliferation [
13
,
27
]. Bakuchiol has a three-fold higher binding
affinity for estrogen receptor alpha (ER
α
) than for estrogen receptor beta (ER
β
) [
13
,
27
]. It does not
have significant uterotrophic activity, although demonstrating
in vitro
estrogenic activity [
27
,
45
]. It
Int. J. Environ. Res. Public Health 2018,15, 963 4 of 16
can reduce postmenopausal bone loss by increasing ALP, calcium concentrations, serum estrogen
concentration, and bone mineral density [
27
,
45
]. Psoralen, a coumarin-like derivative extracted from
the fruit of P. corylifolia L., has stimulatory effects on new bone formation [
27
,
46
,
47
]. It also modulates
differentiation of osteoblasts in a dose-dependent manner in primary mouse calvariae by upregulating
osteoblast-specific genes expression of osteocalcin, type I collagen, and sialoprotein [
46
,
47
]. Psoralen
affects BMP signalling activation in order to promote differentiation of osteoblasts [
46
–
48
]. It stimulates
BMP-2 and BMP-4 gene expression, as well as increases phospho-Smad1/5/8protein level [
46
–
48
].
This evidence suggests that psoralen is a potent anabolic agent in treating osteoporosis [46–48].
2.3. The Arecaceae Family
Oil palm in the palm family (Arecaceae) is mostly cultivated as a source of oil [
49
]. Oil palm
is grown extensively in the equator region of native West and Central Africa, as well as in Asian
countries including Malaysia and Indonesia [
50
]. The most planted species of Arecaceae Family is
Elaeis guineensis (African oil palm) and other species such as Elaeis oleifera (American oil palm) and
Attalea maripa (Maripa palm) are lesser known [
51
]. Palm oil is an edible vegetable oil derived from
the mesocarp (orange-red pulp) of the oil palm fruits [
49
]. It is naturally reddish in colour due to the
presence of high beta-carotene content [52,53].
Palm oil of Elaeis guineensis is well known to have high content of vitamin E [
49
]. Vitamin E is a
conjoint term for tocopherol and tocotrienol isoforms which are well-known for their antioxidant and
anti-inflammatory properties as well as other beneficial effects on the body [
54
,
55
]. Both isoforms of
tocopherols and tocotrienols exist in four different forms in nature: namely;
α
-,
β
-,
γ
-, and
δ
- [
55
,
56
].
In nature, these isomers are normally present as a mixture of varying composition [
57
]. For example,
vitamin E extracted from crude palm oil consists of around 36%
α
-tocopherol, and the rest are made
up by the four tocotrienol isomers [58]. On the other hand, vitamin E from annatto extract comprises
of approximately 90% δ-tocotrienol and the rest is γ-tocotrienol [59].
The anti-oxidative and anti-inflammatory properties of tocotrienol make it a suitable
anti-osteoporotic agent [
60
,
61
]. Both oxidative stress and inflammation are known to be involved in the
pathogenesis of osteoporosis [
62
,
63
]. Oxidative stress has been shown to harm osteoblasts by affecting
their differentiation and survival rate [
64
]. Additionally, oxidative stress also enhances the signalling of
osteoclasts and simultaneously promotes their differentiation [
65
]. Proinflammatory cytokines—such
as interleukin-1, interleukin-6, and tumour necrosis factor
α
—are also increased by oxidative stress,
and they are also harmful to the bone [66].
A study by Hermizi et al. (2009) has shown that, both tocotrienol-rich fraction and
gamma-tocotrienol supplementations were effective in retaining trabecular bone structure in
nicotine-induced bone loss model [
67
]. Also, Aktifanus et al. (2012) and Soelaiman et al.
(2012) have reported that, supplementation with tocotrienol reduced single-labelled surface and
increased double-labelled surface in the ovariectomized rats [
68
,
69
]. In addition, ovariectomized rats
supplemented with 30 and 60 mg/kg body weight of palm vitamin E had shown significantly higher
bone mineral density at the femur and vertebrae as compared to the control untreated group [
70
].
Similar findings were reported in the testosterone deficiency, buserelin, and glucocorticoid-induced
bone loss model [
71
–
76
]. Studies also have shown that palm vitamin E was able to restore bone calcium
levels in the femur and vertebra of orchidectomized and ovariectomized rats [70,71].
The skeletal effects of vitamin E have been tested in many human studies but in most cases
synthetic alpha-tocopherol was used (reviewed in [
77
,
78
]). The efficacy of palm vitamin E mixture rich
in tocotrienol in preventing osteoporosis has not been studied so far. A similar vitamin E mixture, also
rich in tocotrienol, from annatto beans has been tested by Shen et al. (2018) [
79
]. The results showed
that tocotrienol decreased bone resorption markers and oxidative stress in post-menopausal osteopenic
women after 12 weeks [79].
Int. J. Environ. Res. Public Health 2018,15, 963 5 of 16
2.4. The Labiatae Family
A Chinese herb known as Salvia miltiorrhiza Bunge (commonly known as ‘dan shen’ or ‘red sage
root’) from the family of Labiatae is traditionally used to treat diseases related to cardio-cerebral
disorders [
48
,
80
,
81
]. S. miltiorrhiza has been shown pharmacologically to possess anticoagulation,
blood flow improvement, anti-inflammatory, free radical scavenging, and mitochondrial protective
properties [
48
,
81
,
82
]. Phytochemical studies of S. miltiorrhiza Bunge have revealed multiple
groups of compounds, including tanshinones (tanshinone I, tanshinone IIA, 16-dihydrotanshinone I,
cryptotanshinone) and phenolics (salvianolic acid A, protocatechuicaldehyde, and salvianolic acid
B) [
27
,
83
,
84
]. Treatment with S. miltiorrhiza significantly prevents the decrease in trabecular bone
mass and bone mineral density, reduces TRAP activity and parameters of oxidative stress, which
includes malondialdehyde (MDA) and nitric oxide (NO) induced by sex hormones deficiency in
rodents [
20
,
27
,
82
]. Tanshinones are reported to reduce the TRAP-positive multinucleated osteoclast
formation [
85
]. Tanshinone IIA is proven to partially inhibit ovariectomy-induced bone loss by
reducing bone turnover
in vivo
[
27
,
85
,
86
]. It inhibits osteoclast formation by suppressing the c-fos and
NFATc1 expression induced by RANKL [27,85,86].
Salvianolic acid A from S. miltiorrhiza Bunge can inhibit bone loss in rats given long-term
prednisone [
20
,
87
]. This is achieved by regulating osteogenesis and suppressing adipogenesis
in bone marrow stromal cells [
20
,
87
]. Similarly, Salvianolic acid B has been used to inhibit
glucocorticoid-induced cancellous bone loss and suppress adipogenesis [
20
]. It modulates the
differentiation of bone marrow stromal cell (MSC) to osteoblasts and upregulates osteoblastic activities.
It decreases the differentiation of glucocorticoid-associated adipogenesis through modulating the
expression of Dickkopf-1, RUNX2, peroxisome proliferator-activated receptor-gamma (PPAR-
γ
), and
β-catenin in MSC [20,88].
2.5. The Simaroubaceae Family
Tongkat Ali, also known as Eurycoma longifolia, from the family Simaroubaceae, is a traditional
herbal plant found in Malaysia [
89
,
90
]. The root extract of Tongkat Ali is a well-known folk remedy
among the Malaysians used to enhance fertility and sexuality, and delay ageing [
89
]. The bioactive
compounds of these plants contain quassinoid alkaloids which are believed to cure allergies, relieve
fevers, reduce tumours, and treat malaria [
89
,
91
]. Other bioactive compounds found in this plant are
tannins and high-molecular-weight glycoproteins, polysaccharides and mucopolysaccharides [89].
Eurycomalactone, eurycomanone, and eurycomanol of E. longifolia have been shown to increase
testosterone level in the blood and are capable of inhibiting the sex hormone-binding globulin [
89
,
92
,
93
].
Testosterone is known to enhance bone formation and prevent osteoporosis [
89
,
94
,
95
]. Testosterone
and 5-
α
-dihydrotestosterone suppress RANKL and the number of colony-forming unit-macrophages,
thereby reducing osteoclast numbers [
96
]. Consequently, the bone degradation process will be
halted and bone density will be maintained [
92
,
93
]. Testosterone replacement increases bone density
and mass and is an effective treatment for male osteoporosis due to hypogonadism [
89
,
93
–
95
,
97
].
However, it comes with some side effects, such as increased risk for prostate cancer, polycythemia,
and cardiovascular events [
98
]. E. longifolia, as an androgenic compound, may act as an alternative to
prevent osteoporosis associated with low testosterone level [
89
,
92
,
93
]. It has a good safety profile and
convenient oral administration [89,92,93].
2.6. The Myrsinaceae Family
The herbal plant traditionally known as Kacip Fatimah (Labisia pumila) belongs to the family
Myrsinaceae [
99
,
100
]. Labisia pumila water extract is traditionally used by Malay women to treat
menstrual irregularities and dysmenorrhoea [
99
,
100
]. It is also used to improve uterine contraction
post-delivery and to promote sexual function [
99
,
100
]. Its water extract is also being consumed
to treat diseases such as gonorrhoea, rheumatism, dysentery, and bone disorders [
101
]. The plant
Int. J. Environ. Res. Public Health 2018,15, 963 6 of 16
L. pumila is capable of inducing the production of estrogen. Post-menopausal women are prone to have
osteoporosis due to decreased circulating estrogen [
100
,
102
]. Estrogen induces osteoclast apoptosis
and inhibits osteoblast apoptosis [
99
,
100
]. This reduces bone degradation and increases bone formation
activity [99,100].
Pro-inflammatory cytokines, such as IL-1 and IL-6, are capable of influencing osteoclastogenesis
by self-renewal stimulation [
101
]. These pro-inflammatory cytokines are inhibited by the presence
of estrogen [
99
,
101
,
102
]. According to recent studies, L. pumila is capable of inducing the production
of estrogen. Therefore, L. pumila can be regarded as an alternative to estrogen replacement therapy
(ERT) [99,101,102].
Also, L. pumila exerts anti-oxidant properties due to the presence of active compounds, such
as ascorbic acid, anthocyanin, beta-carotene, flavonoids, and phenolic compounds [
101
,
102
]. Other
active constituents of L. pumila, such as anthocyanin and phenolics, also play a role as anti-oxidant
and anti-inflammatory agents [
101
,
102
]. These effective free radical scavengers can help to improve
chronic diseases related to oxidative stress [102].
3. Perspectives
Several important issues should be considered when using natural herbal plants to treat
osteoporosis. These issues are (i) selectivity: the mechanism of action, selective binding to
sites of action and any possible resistance of the compound towards bioactive site action; (ii)
therapeutic/pharmaceutical index: the benefit-to-risk ratio of the applied bioactive compound
and clinical trials before being used as a standard therapy or along with standard therapy; (iii)
controllability: the rate of targeted bioactive compound must be clear, reproducible and controllable;
and lastly, (iv) convenience: preferably, the drug should be orally administered; therefore the liquid or
tablet dosage form must be initially formulated and stabilized, making it easier to be taken orally [
22
].
The safety of herbal remedies should also be studied intensively. There is a widespread belief
that herbals are natural and harmless. However, studies have shown that hepatotoxicity is the most
frequently reported toxic effect of herbal remedies [
22
,
100
]. Therefore, precise investigation of the
bioactive compounds and scientific data regarding the safety and toxicity are needed before definite
clinical trials are conducted.
In addition, standardization of medical herbal plants should also be emphasized. The lack of
standardization has contributed to difficulties in validating the efficacy of the plants, which is important
for further study of targeted bioactive compounds. Plants that are commonly used in laboratory
experiments should be investigated thoroughly in terms of their pharmacology and therapeutic effect
before being tested in patients suffering from osteoporosis and other bone-related diseases.
Many natural herbal plants have the potential to be developed as anti-osteoporotic agents.
However, only a fraction of these plants has been thoroughly investigated by researchers. More
reliable, efficient, and rapid bioassays should be developed to examine the antiosteoporotic efficacy
of these botanical extracts, as well as to identify the compounds responsible for the bone-protective
effects and mechanism involved. Most anti-osteoporotic agents derived from herbal medicinal plants
can be used as prophylactic rather than therapeutic agents. If no clinical trials are done, the application
and development of these herbal plants will remain restricted and undiscovered. It is important to
translate laboratory findings to clinical outcomes to enable drugs from natural plants to be used for
human therapy.
There are some limitations pertaining to the discussion of this review. Quality assessment was not
performed on the studies included in this review. Therefore, some studies quoted might be subjected to
biases and errors. The readers should interpret the studies with caution. Most botanical agents cited do
not have a complete safety profile, either in animal or in humans. In most animal studies, the efficacy
data of these botanical agents are not complemented with safety data. Therefore, the therapeutic index
of these agents remains elusive to the readers.
Int. J. Environ. Res. Public Health 2018,15, 963 7 of 16
4. Conclusions
Herbal plants are a rich source of medicinal compounds that can be used to prevent osteoporosis.
Many animal and cellular studies have been conducted to demonstrate the antiosteoporotic effects of
these botanical extracts and their bioactive compounds (Table 1). They modulate bone remodelling by
acting directly on the bone cells or through lowering oxidative stress and inflammation or increasing
sex hormone levels (Figure 1). Through enhancing bone formation and suppressing bone reabsorption,
these agents can improve bone mass and reduce the risk of fragility fracture. Fracture prevention also
relies on improvements in muscle strength, coordination, and cognitive function. Botanical agents may
affect these bodily functions, but they are outside the scope of this review. A proper human clinical
trial to validate their bone-protective effects needs to be conducted. The use of botanical compounds
as an intervention for osteoporosis also faces issues of standardization, selectivity, and safety. These
issues should be overcome to promote their use in preventing osteoporosis.
Int. J. Environ. Res. Public Health 2018, 15, x 7 of 17
reabsorption, these agents can improve bone mass and reduce the risk of fragility fracture. Fracture
prevention also relies on improvements in muscle strength, coordination, and cognitive function.
Botanical agents may affect these bodily functions, but they are outside the scope of this review. A
proper human clinical trial to validate their bone-protective effects needs to be conducted. The use of
botanical compounds as an intervention for osteoporosis also faces issues of standardization,
selectivity, and safety. These issues should be overcome to promote their use in preventing
osteoporosis.
Figure 1. The role of botanical bioactive compounds in regulating bone metabolism. They may act
directly on the bone cells, or through reducing inflammation and oxidative stress, or indirectly via
increasing the level of sex hormones and interacting with sex hormone receptors on bone cells.
Figure 1.
The role of botanical bioactive compounds in regulating bone metabolism. They may act
directly on the bone cells, or through reducing inflammation and oxidative stress, or indirectly via
increasing the level of sex hormones and interacting with sex hormone receptors on bone cells.
Int. J. Environ. Res. Public Health 2018,15, 963 8 of 16
Table 1. Summary of anti-osteoporotic properties of medicinal plants.
Family Scientific Name Compound Pharmacological study
Berberidaceae
E. brevicornum Maxim
E. sagittatum Maxim
E. pubescens Maxim
E. koreanum Nakai
E. koreanum
âPrevents osteoporosis without causing uterine
hyperplasia in ovariectomized rats.
âInhibits bone resorption, triggers bone formation,
and blocks urinary calcium excretion.
â
Increases the messenger ribonucleic acid expressions
of bone morphogenetic protein and wingless-type
signaling pathway related regulators such as bone
morphogenetic protein-2 and cyclin D.
âStimulates osteoblast proliferation via estrogen
receptor-dependent mechanism.
âPossesses estrogenic activity and is able to regulate
bone metabolism and improve the maturation of
osteoblasts by inducing alkaline phosphatase, bone
morphogenetic protein-2, macrophage colony
stimulating factor, osteoprotegerin, receptor
activator of nuclear factor-κB ligand, core binding
factor α1, and interliukin-6 and signaling effectors
against decapentaplegic protein 4.
Iicarin
â
Inhibits bone loss in the distal femur and tibia of the
rat model and postmenopausal women.
â
Decreases tartrate-resistant acid phosphatase activity
of osteoclasts, decreases the size of
lipopolysaccharide-induced osteoclasts formation,
prevents lipopolysaccharide-induced bone
resorption and interleukin-6 and tumor necrosis
factor-αexpression.
âInhibits cyclooxygenasetype-2 synthesis, expression
of lipopolysaccharide-induced hypoxia inducible
factor-1α, and lipopolysaccharide-mediated
activation of the p38 and Jun N-terminal kinase
involved in osteoclasts differentiation.
âReduces extracellular regulated-kinases 1/2 and
lipopolysaccharide-induced activation.
âReduces specific genes of osteoclasts:
tartrate-resistant acid phosphatase, matrix
metalloproteinase-9, cathepsin K and receptor
activator of nuclear factor-kappa-B ligand.
Ikarisoside A
â
Shows antioxidant and anti-inflammatory properties
in lipopolysaccharide-stimulated bone
marrow-derived macrophage precursor cells and in
RAW264.7 cells.
âInhibits activation of nuclear factor
kappa-light-chain-enhancer of activated B cells, Jun
N-terminal kinase, protein kinase B-receptor
activator of nuclear factor-κB ligand pathway in
osteoclasts and their resorbing activity.
Fabaceae Glycine max L.
Psoralea corylifolia L.
â
Dietary soybean protein supplementation is effective
in reducing loss of bone mineral density in
ovariectomized rats.
âImproves bone turnover markers, bone mineral
density, and bone strength among
postmenopausal women.
â
Modulates bone metabolism-related gene expression
of collagen type I, osteocalcin, calciotropic receptor,
alkaline phosphatase, cytokines, and growth factors.
âInduces bone calcification in rats.
â
Increases the concentration of inorganic phosphorus
in serum.
â
Regulates the trabecular microstructure and prevent
bone loss in postmenopausal women and
animal models.
Genistein
âShows estrogenic effects in the bone but not in
the uterus.
âModulates B-lymphopoiesis.
âInhibits bone degradation.
Int. J. Environ. Res. Public Health 2018,15, 963 9 of 16
Table 1. Cont.
Family Scientific Name Compound Pharmacological Study
Fabaceae Glycine max L.
Psoralea corylifolia L.
Bavachalcone
âInhibits osteoclastogenesis.
âInhibits the extracellular regulated-kinases and
protein kinase B signalling and chromosome-Fos and
nuclear factor of activated T cells c1 induction
during differentiation.
Psoralidin, Isobavachin âStrong antioxidant.
Bavachin Corylin âStimulates osteoblastic proliferation.
Bakuchiol
âHas high binding affinity for ERα.
âShows no significant uterotrophic activity.
âStimulates estrogenic activity in vitro.
âReduces postmenopausal bone loss by increasing
alkaline phosphatase, calcium concentrations, serum
estrogen concentration, and bone mineral density.
Psoralen
âStimulates new bone formation.
âStimulates differentiation of osteoblasts in a
dose-dependent manner in primary mouse calvariae.
âUpregulates osteoblast-specific genes expression of
osteocalcin, type I collagen and sialoprotein.
âStimulates bone morphogenetic protein-2 and bone
morphogenetic protein-4 gene expression.
Arecaceae Elaeis guineensis Tocotrienol
âWell-known for their antioxidant, anti-oxidative
stress, anti-inflammatory properties and
anti-osteoporotic agent.
âSuppresses the proinflammatory
cytokines expression.
â
Effective in retaining trabecular bone structure in the
nicotine-induced bone loss model.
âReduces of single-labelled surface and increased in
double-labelled surface in the ovariectomized rats.
âIncreases bone mineral density at the femur and
vertebrae of the rats in the testosterone deficiency
and the glucocorticoid bone loss model.
âRestores bone calcium level at the femur and
vertebra of orchidectomized and
ovariectomized rats.
âImproves biomechanical strength of the femur in
normal male rats.
Labiatae Salvia miltiorrhiza Bunge
In ovariectomized rats:
âPrevents the decrease in trabecular bone mass and
bone mineral density.
âReduces the tartrate-resistant acid
phosphatase activity.
âDecreases oxidative stress.
Tanshinones
âReduces the tartrate-resistant acid
phosphatase-positive multinucleated
osteoclast formation
Tanshinones IIA
âPartially inhibits ovariectomy-induced bone loss by
reducing bone turnover.
Salvianolic acid A
âInhibits bone loss in rats given
long-term prednisone.
âStimulates osteogenesis.
âSuppresses adipogenesis in bone marrow
stromal cells.
Int. J. Environ. Res. Public Health 2018,15, 963 10 of 16
Table 1. Cont.
Family Scientific Name Compound Pharmacological Study
Labiatae Salvia miltiorrhiza Bunge Salvianolic acid B
â
Inhibits glucocorticoid-induced cancellous bone loss.
âSuppresses adipogenesis.
âStimulates bone marrow stromal cell differentiation
to osteoblasts.
âUpregulates osteoblastic activities.
âModulates the expression of messenger of
ribonucleic acid of dickkopf-1, runt-related
transcription factor 2, peroxisome
proliferator-activated receptor gamma, and
β-catenin in mesenchymal stem cell.
Simaroubaceaea Eurycoma longifolia
âAndrogenic substance with a good safety profile.
Eurycomalactone
Eurycomanol
âIncreases testosterone level in the blood.
âInhibits sex hormone-binding globulin.
Eurycomanone âIncreases testosterone level in the blood.
Myrsinaceae Labisia pumila
âUsed traditionally to treat female sexual problems.
âStimulates the production of estrogen.
âStimulates the production of estrogen.
Ascorbic acid
Anthocyanin
Beta-carotene,
Flavonoids phenolic
compounds
âAnti-oxidant and free radical scavengers-effective
free radical scavengers in conditions, such as
osteoporosis and rheumatism, which are related to
ageing and oxidative stress.
âAnti-inflammatory agents.
Author Contributions: All authors contributed equally to the writing of this manuscript.
Acknowledgments:
We thank Universiti Kebangsaan Malaysia for supporting the study via grant GUP-2017-060
and GUP-2017-012.
Conflicts of Interest: The authors report no conflicts of interest in this work.
Abbreviations
ALP Alkaline phosphatase
BMP-2/4 Bone morphogenetic protein-2/4
M-CSF Macrophage colony stimulating factor
OPG Osteoprotegerin
RANKL Receptor activator of nuclear factor-κB ligand
Cbfα1 Core binding factorα1
SMAD4 Signaling effectors mothers against decapentaplegic protein 4
Wnt-signaling Wingless-type signaling
cyclinD Cyclin dependent
OVX Ovariectomized
ER Estrogen receptor
TRAP Tartrate-resistant acid phosphatase
LPS Lipopolysaccharides
IL-6/1 Interleukin-6/1
TNF-αTumor necrosis factor
COX-2 Cyclooxygenasetype-2
HIF-1αHypoxia inducible factor-1α
p38 Protein 38
JNK Jun N-terminal kinase
Int. J. Environ. Res. Public Health 2018,15, 963 11 of 16
ERK1/2 Extracellular regulated-kinases 1/2
Iκ-BαLPS ikappa-Balpha lipopolysaccharide
MMP-9 Matrix metalloproteinase-9
Akt Protein Kinase B
NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells
RANK receptor activator of NF-κB
COL I collagen type I
NFATc1 nuclear factor of activated T cells c1
c-Fos Chromosome-Fos
B-lymphopoiesis Bone marrow-lymphopoiesis
ERα/ERβEstrogen receptor alpha/beta
BMD Bone mineral density
Osx Osteoblast-specific transcription factor osterix
MDA malondialdehyde
NO nitric oxide
mRNA Messenger ribonucleic acid
Dickkopf-1 DKK-1
Runx2 Runt-related transcription factor 2
PPAR-γPeroxisome proliferator-activated receptor gamma
β-catenin Beta-cateni
MSC Mesenchymal stem cell
EL Eurycoma longifolia
ERT estrogen replacement therapy
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