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CHAPTER 18
Role of Natural Products in the Pharmacotherapy of Osteoporosis
RAJA CHAKRAVERTY1, SOMOSHREE SENGUPTA
1
2
2,*
, and TATINI DEBNATH
3
3
*Corresponding author
ABSTRACT
Osteoporosis has been operationally defined as metabolic bone disease caused by reduction of bone mass due to lowering of bone mineral density , which causes microarchitectural
deterioration. This is mainly as a result of an imbalance of osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The prime causes of osteoporosis mainly
belong to aging, low levels of physical activity, limb disuse, hormonal imbalances such as
endocrine disorder, as well as immune and genetic factors.
18.1 INTRODUCTION
According to WHO, bone mineral density (BMD) when of less than 2.5 standard deviation
leads to osteoporosis (Salari et al., 2021). The disease has type I and type II classifications
where type I mainly is caused in women over 70 years due to postmenopause, and type
II is caused by several systemic and endocrine diseases as well as malignant neoplasm
(Dobbs et al., 1999). Established treatments available for osteoporosis are bisphosphonate,
calcitonin supplement-oriented drug therapy (Khosla and Hofbauer, 2017), along with
hormone replacement therapy (HRT) with modulation of estrogenic receptor (ER).
In earlier 1940s, estrogen-mediated treatment was administered for both men and
women for the treatment of osteoporosis (Stevenson and Whitehead, 1982). FDA-approved
ultralow dose of estrogen (0.014 mg/day) for the treatment of women causing uterine
hyperplasia, but it would not be the solution for long-term treatment for osteoporosis
(Ettinger et al., 2004). HRT application promisingly recovers hip and spine fractures,
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but prolonged period of hormonal treatment led to adverse side effects such as thromboembolism and the development of breast, ovarian, and endometrial cancer (Bowring and
Francis, 2011).
To overcome the adverse effects of the already established therapeutical concepts for
osteoporosis, plant-based natural products have recently being started in use. Here are
some treatment aspects based on natural products, and their possible mechanism of action
discussed are as follows.
18.1.1 EFFECT OF TRADITIONAL CHINESE MEDICINE (TCM)
TCM is 2500 year old concept of therapy where different approaches such as herbal
medication, acupuncture, change in food habits, massage, and exercise are used as the
remedy for osteoporosis (Sheng et al., 2012). As per the fundamental rule of zàng-fu
theory, there are five components, that is, liver, heart, lung, kidney, and spleen involve
in any physiological medication. Out of which kidney is related to the skeletal structure
of human beings. It is mainly related to development of bone and the generation of bone
marrow in the body; therefore, several kidney-caring medicines could act as effective
therapeutics for bone-related disorders by increasing osteoblast genesis.
There are few plants available in China used for the treatment of bone pain, osteoporosis, osteoarthritis, and rheumatoid arthritis as well. Plants containing compounds such as
Liuwei Dihuang pills commonly called as Liuwei Dihuang tea pills and Zuo-Gui-W an play
an important role in the treatment of osteoporosis (Rufus et al., 2013). Likewise, several
medicinal plants are described below for their medicinal properties for the treatment of
osteoporosis.
S. acutum contains an alkaloid Sinomenine (SN), that is, 8-didehydro-4-hydroxy 3,
7-dimethoxy-17-methyl-α,13α,14α-morphinan-6-one, which was first identified by Ishiwari
in the 1920s (Yamasaki, 1976). After detailed studies about this plant, it was concluded the
alkaloid derivatives of this plant retain great anti-inflammatory , immunoregulatory as well
as analgesic properties such as morphine. These properties help in the prevention of bone
destruction and anabolic effects in bone dysregulation-based clinical trials.
SN improved the clinical condition of arthritis-induced rats through broblast proliferation, and simultaneously increased the level of collagen type II by inducing Th1/Th2 ratio
with matrix metalloproteinases (MMPs) endogenous inhibitor, that is, tissue inhibitors of
metalloproteinase regulation at the site of disease (Zhou et al., 2017). Researchers revealed
that SN works via the RANKL (receptor activator of NF-Kb) signaling pathway (Li et al.,
2013) and induced osteoprotegerin (OPG)/RANKL ratio, which suppress the formation of
osteoclast in osteoporosis (Zhao et al., 2018) (Figure 18.1).
Apart from SN, there are several other derivatives of SN applicable for several inammatory conditions and treatment of osteoporosis as described in Table 18.1.
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FIGURE 18.1 RANKL/OPG signaling in the bone where RANKL binds RANK, and activates the osteoclast
differentiation in diseased condition (a), but when osteoblast secretes OPG via induction of SN, it destroys the
receptor RANKL and stops osteoclast formation (b) by stopping the attachment of RANKL/RANK.
⏎
TABLE 18.1
Derivatives of SN Clinical Trial Model Mechanism of Action Reference
1032 (derivative)
SN Lipopolysaccharide-
Icaritin Ovariectomy (OVX)
Eucommia
ulmoides
Quercetin
Derivatives of SN and Their Mechanism of Action for the Treatment of Osteoporosis
In vitro encephalomyelitis/
dendritic cells
induced osteoclastogenesis
and osteolysis
rat/RAW 264.7 mouse
monocyte cell line/human
PBMC
Osteoarthritis rats/
lipopolysaccharide (LPS)stimulated bone volume
(BV)-2 microglial cells
In vitro RAW 264.7 cells
Downregulation of IL-17, IL-6, and
TNF-α and upregulation of IκBα with
mutation of Th17 receptor
Downregulation of TNF-α, TLR4,
TRAF6, Fra-1, MMP-9, NF-κB, AP-1,
NFAT, and MAPKp38
Downregulation of nuclear factor of
activated T-cells, cytoplasmic 1 (NFATc1)
and TRAF6
Downregulation of IL-1β, IL-6, MMP-3,
phosphorylated mitogen-activated protein
kinases (MAPKs), PI3K/Akt, GSK-3β, and
NF-κB and upregulation of Nrf2 and HO-1
Downregulation of IL-6 and IL-1α and
upregulation of IL-3 and IL-4
Cheng
(2009)
He
et al. (2016)
Tan et al. (2017)
Kwon et al.
(2016)
Oliveira
(2015)
⏎
et al.
et al.
18.1.2 EFFECT OF MALAY TRADITIONAL MEDICINE
The principle of Malay traditional medicine is based on Arabic Unani and Galenic
philosophy, which consist of chants, massage and use of various natural plant sources,
460
microorganisms, and minerals from various sources for health promotion. The medication
is mainly based on a single compound from natural sources in the form of powder, capsule,
pills, makjun-medicated oil, infusion paste, etc. Some of the plants utilized for osteoporosis
are described as follows.
It is commonly known as Tongkat Ali in Malaysia. It is the source of haseurycomanone,
eurycomanol, and eurycomalactone group of alkaloids which increase testosterone level in
the blood resulting in increased bone mass in patients undergoing osteoporosis treatment.
The direct infusion of testosterone may lead to painful effects in some patients especially
those suffering from prostate cancer. Therefore, application of E. longifolia can be a good
alternative for the treatment of osteoporosis.
E. longifolia-induced testosterone in the presence of 5α-reductase is converted into
dihydro testosterone, which actively acts as an androgenic receptor (AR) as well as an ER.
ER-α and ER-β
subtypes are associated with bone metabolism (Almeida et al., 2017). AR
are abundantly present in chondrocytes and osteoblasts; therefore, testosterone-induced
AR promote bone formation. These mainly help in the differentiation of osteoblast and
chondrocyte in patients suffering from osteoporosis (Kawano et al., 2003).
Testosterone deciency inuences the NK-kB pathway via RANKL production leading
to osteoclast production. Therefore, EL-induced testosterone leads to high expression of
insulin growth factor-1 (IGF-1) and IGF-binding protein, nally resulting in osteoblast
differentiation (Li et al., 2009) (Figure 18.2).
It belongs to the family Myrsinaceae (Abd Jalil et al., 2012) locally called as Kacip
Fatimah, Selusuh Fatimah, Rumput Siti Fatimah, Akar Fatimah, Pokok Pinggang, and
Belangkas Hutan (Abd Jalil et al., 2012). It is traditionally used by women for the treatment of abdominal cramps during the menstruation cycle. During postmenopause, it was
found that women lack estrogen, which is the main cause of osteoporosis by apoptosis of
osteoblast. Estrogen mainly regulates the regulation of proinflammatory cytokines, that is,
IL-6 and IL-1, leading to the prevention of osteoclast differentiation. L. pumila is rich in
various bioactive compounds such as flavonoids, ascorbic acid, beta-carotene, anthocyanin, and phenolic compounds (Fathilah et al., 2012), acting as an anti-inflammatory agent
for osteoporosis (Cassidy et al., 2000).
P. sarmentosum commonly known as Keduk is responsible for inducing morphological
changes in osteoporotic bones of rats. Mohammad Asri et al. showed that Sprague-Dawley
461
rats were induced by glucocorticoid, where it inhibits osteoblast function by reducing
cell proliferation and differentiation in the experimental setup. Then, aqueous Piper
sarmentosum leaf extract was induced orally for 125 mg/kg/day. Results showed that the
osteoblast surface and osteoid surface increase but the significant reduction of osteoclast
surface observed while rats receiving PS leaf extract.
FIGURE 18.2 Effects of estrogen and testosterone in the regulation of osteoblast and osteoclast activity
followed by bone formation (Shigehara et al., 2021).
⏎
Osteoblast and osteoclast have been clearly observed where a single nucleus with
predominant cytoplasm indicates osteoblast, which creates osteoid surface formation. But
other than that, in other samples, multinucleated large cells with eosinophilic cytoplasm
were found in Howship’s lacunae.
18.1.3 ANTIOSTEOPOROTIC AGENTS EXTRACTED FROM PLANT SOURCES
Plant species belonging to the following families are being used to extract various antiosteoporotic agents.
The Berberidaceae contain 18 genera in its family commonly called the barberry and are
used traditionally for treating osteoporosis and menopause-related diseases (Liu et al., 2017).
462
Several other species such as Epimedium brevicornum Maxim, Epimedium sagittatum
Maxim, Epimedium pubescens Maxim, and Epimedium koreanum Nakai are also used for
the treatment. The extracted alkaloid from these species helps in bone resorption, trigger bone
formation, as well as block urinary excretion in patients. In the ovariectomized rat model,
it was observed that alkaloids prevent osteoporosis without causing uterine hyperplasia
(Ma et al., 2011). The high expression of alkaline phosphatase (ALP), bone morphogenic
protein-2, and core binding factor-α-1, the alkaloid, influence estrogenic activity, resulting
in maturation of osteoblast, therefore highly useful for differentiation of osteoblast (Tantry
et al., 2012).
An experiment was performed where avonoids isolated from Epimedium were
administered in an osteoporotic rat along with control and observed; the diseased rat
altered the enzymatic activity of the intestine in the presence of ora, which further
enhanced the bioavailability of the drug results osteoblast formation (Zhou et al., 2015)
(Figure 18.3).
FIGURE 18.3 Epimedium flavonoid hydrolyzed by an interstitial enzyme in the osteoporotic rat model into
the form of secondary glycosides or aglycon thereby enhancing their absorption, which shows antiosteoporosis
activity (Zhou et al., 2015).
⏎
In another experiment, avonoid glucoside called Icariin was isolated from the Epimedium
plant. In the ovariectomized rat model, these avonoid-rich extracts reduced bone loss in the
distal femur and tibia by activating ER-based bone regulation and deactivating the tartrateresistant acid phosphate (TRAP) activity resulting in osteoclast reduction (Ma et al., 2011).
Bone marrow stroma multipotent stem cell is a key source of osteoblast, chondrocytes,
adipocytes, cardiomyocytes, and endothelial cells (Zakrzewski et al., 2019). Icariin treatment
to preosteoblastic MC3T3-E1 cell line promotes the overexpression of RunX2, ID-1 along
with enhancement of self-renewal activity, as well as gives osteogenic differentiation in
6-month-old mice. Out of all signaling pathways, that is, MAPK, canonical Wnt/β-catenin,
and BMP, icariin treatment induced BMP-4 and activate BMP signaling pathway in in vitr o
as well as in vivo
model (Zhao et al., 2008) (Figure 18.4).