Review

Cannabinoid receptors in osteoporosis and osteoporotic

pain: a narrative update of review
Jing Wanga , Hong-xia Lub and Jing Wangc
a
Department of Osteoporosis, The Second Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China , bDepartment of
Ultrasound, The Second Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China and cDepartment of Nephrology, The
Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China

Keywords Abstract
cannabinoid receptors; glial cells;
osteoporosis; pain; TRPV1 Objective Osteoporosis is a skeletal disease with decreased bone mass and alter-
ation in microarchitecture of bone tissue, and these changes put patients in risk
Correspondence of bone fracture. As a common symptom of osteoporosis and complication of
Jing Wang, Department of Osteoporosis,
osteoporotic fracture, chronic pain is a headache for clinicians. Nonsteroidal
The Second Affiliated Hospital of Shenzhen
University, No. 118 LongJing Second Road,
anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors and opioid drugs
Baoan District, Shenzhen, Guangdong can temporarily reduce osteoporotic pain but have relevant side effects, such as
Province, China. addiction, tolerability and safety. The review summarized the recent advance-
E-mail: wangjing1mail@163.com ments in the study of CB receptors in osteoporosis and osteoporotic pain and
related mechanisms.
Received February 27, 2019 Key findings Recent studies indicated the two nociceptive receptors, cannabi-
Accepted June 15, 2019
noid receptor (CB) and transient receptor potential vanilloid type 1 (TRPV1)
doi: 10.1111/jphp.13135
channel, are co-expressed in bone cells and play important role in the metabo-
lism of bone cells, suggesting that dualtargeting these 2 receptors/channel may
provide a novel approach for osteoporotic pain. In addition, both CB receptor
and TRPV1 channel are found to be expressed in the glial cells which play vital
role in mediating inflammation, chronic pain and metabolism of bone cells, sug-
gesting a role of glial cells inosteoporotic pain.
Summary Multiple-targeting against glial cells, CB receptors and TRPV1 channel
may be one effective therapeutic strategy for osteoporotic pain in the future, fol-
lowing the elucidation of the complicated mechanism.

treatment can effectively prevent the further development

Introduction
As one common disorder in the ageing era, particularly for
menopausal women, osteoporosis is a worldwide disease
caused by the reduction of bone mineral density (BMD)
and alteration of bone architecture which results in the
increase of bone fragility and fracture risk. Because of the
complicated causes of osteoporosis such as age, sex, post-
menopausal status, rheumatoid arthritis, vitamin D defi-
ciency, low calcium intake, hyperkyphosis, alcohol abuse
and long-term of certain therapies, etc, the management of
osteoporosis is still a headache problem, and controversial
effects are encountered although there are a variety of
advancements.[1,2]
Because osteoporosis is a systemic disorder affecting all
bones of the body, it has different demonstrations in clinic.
Amongst, osteoporotic pain is the most prevalent morbid-
ity and greatly affects the life quality of patients.[3] As
osteoporotic pain is an early sign of osteoporosis, correct
of osteoporosis and occurrence of osteoporotic fracture
which is an important cause of morbidity and mortal-
ity.[3,4] However, due to the complex of pathologies of
osteoporosis, it is still not very clear of its mechanism.
Recent studies have shown that the central nervous sys-
tem (CNS), including neurons and glial cells, plays an
important role in regulating bone metabolism and there-
fore in the pathology of osteoporosis through cannabinoid
receptors (CB1 and CB2)[5,6] which are involved in pain
modulation.[7,8] In addition, the transient receptor poten-
tial vanilloid type 1 (TRPV1) which is increased in dorsal
root ganglia innervating femur of rats with osteoporosis[9]
also modulates the activities of osteoblasts[10–12] and
pain[13,14] through the interaction with glial cells and CB
receptors.[13] These results imply that the CB and TRPV1
receptors may play important role in the pathology of
osteoporosis and osteoporotic pain, following more and
more studies are performed in this field (Table 1).

© 2019 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2019), pp. **–** 1
Cannabinoid receptor and osteoporotic pain Jing Wang et al.

Table 1 The key references and findings about the cannabinoid sys-
Cannabinoid and osteoporosis tem in osteoporotic pain
Cannabis is widely used for recreation with a long history, Reference
and cannabinoids are proposed to play a role in bone number First author (year) Key findings
homoeostasis. Although a national survey of people at age [34]
Bellini G (2017) TPRV1 channel and CB2
of 20–59 years failed to find association between self-re- receptor show opposite effect
ported cannabis use and bone mineral density (BMD) of in modulating osteoclasts
hip or spine,[15] more and more data support the idea that [46]
Franks LN (2018) Inhibition of CB2 receptor with
the endocannabinoid (EC) system which is composed of inverse agonist prevented
cannabinoids (tetrahydrocannabinol, cannabidiol, arachi- inflammation and
donoylethanolamine, 2-arachidonoylglycerol and cannabi- osteoclastogenesis
[13]
Giordano C (2012) TRPV1 channel antagonist and
nol), receptors (CB1 and CB2) and related synthetic and
CB1 receptor agonist inhibit
catalytic enzymes (Figure 1), plays an important roles in neuropathic pain
osteoporosis. For example, endocannabinoids anandamide [10]
He LH (2017) TRPV1 channel facilitates
(AEA) and 2-arachidonoylglycerol (2-AG) are detected in fracture via promotion of
the skeleton while CB1 and CB2 receptors are expressed in osteoblast activity.
[40]
bone cells, suggesting that the EC system is involved in the Huo W (2018) Microglia is involved in bone
pathogenesis of osteoporosis. Consistently, pharmacologi- cancer pain
[14,31]
Kanaya K (2016) TRPV1 channel is involved in
cal and genetic inactivation of EC system could inhibit
osteoporotic pain via osteoclast
bone absorption/loss and increase bone mass in adult mice. activity.
In addition, the CB1 and CB2 receptors have a protective [16,28,38]
Lozano-Ondoua AN Activation of CB2 receptor
effect against age-dependent bone loss in the ageing mice (2010, 2013), Lu C attenuates breast cancer-
regardless of gender.[16] One study indicated that activation (2017) induced bone pain and bone
of CB1 receptor also promotes osteoporosis induced by loss
[37]
corticosteroid in young rats but prevents osteoporosis in Miost J (2018) Activation of CB1and blockade
of TRPV1 receptor attenuate
aged rats.[17] The expression of CB2 receptor is down-regu-
osteoarthritis
lated in osteoporotic patients while over-expression of CB2 [30]
Naito Y (2017) Osteoporotic pain involves
receptors in osteoporotic bone marrow stem cells (BMSCs) TRPV1 activation and CGRP
increases the activity of alkaline phosphatase (ALP), phos- expression to affect bone
phorylation of p38 mitogen-activated protein kinase resorption
[11]
(MAPK), expression of osteogenic genes and deposition of Reni C (2016) TRPV1 channel is involved in
mineralized extracellular matrix.[18] Activation of CB2 diabetes-induced osteoporotic
pathology
receptor is found to increase the activity of ALP, expression [17]
Samir SM (2014) CB1 receptor is involved in
of osteogenic genes and calcium deposition in extracellular osteoporosis
matrix. On the contrary, knockdown of CB2 receptor by [9]
Yoshino K (2014) Osteoporosis increases TRPV1
siRNA shows opposite effects and reduces the phosphoryla- activities in DRG neurons
tion of p38 MAPK. In addition, the CB2 receptor in the innervating femur
bone marrow of samples is lower in osteoporotic patients
when compared with that of healthy people.[19] Knockout
of CB1 and CB2 receptor gene can enhance the bone mass CB2 receptor produces high-turnover osteoporosis in aged
of mice at birth and adulthood, and prevent bone loss mice which show relative uncoupling of bone resorption
induced by ovariectomy through inhibiting the activities of from bone formation and reduced capacity to form bone
osteoclast. The age-related increase of bone mass in CB1 nodules in vitro, and impairs PTH-induced ALP activity.
and CB2 receptors double knockout mice is due to the On the contrary, activation of CB2 receptor promotes bone
overweighting of osteoclast inhibition against reduction of formation of nodule in wild-type osteoblasts but not in
bone formation, which is in contrast with reports showing CB2 knockout osteoblasts, cell migration and ERK phos-
higher bone loss in single inactivation of CB1 or CB2 recep- phorylation in MC3T3-E1 osteoblast-like cells. Action of
tor, suggesting an overlapping but non-redundant roles in CB2 receptor also prevents bone loss induced by ovariec-
regulating osteoclast and osteoblast activities by CB1 and tomy in wild-type mice by stimulating bone formation but
CB2 receptors, and also indicating that combined inhibi- not in ovariectomized CB2 knockout mice.[21] These results
tion of CB1 and CB2 receptors should be considered in further indicated that CB receptors are involved in
treating age-related bone loss, whereas blockade of individ- osteopathogenesis but may have different roles which
ual receptors may be detrimental.[20] Similarly, knockout of remain to be further studied.

2 © 2019 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2019), pp. **–**
Jing Wang et al.
(a)
THC
(c)
Extracellular
CB1 Intracellular
CB2
Figure 1 The EC system. Structure of natural cannabinoid THC (a), endocannabinoid AEA, AA, 2-AG and related enzymes (FAAH, MGL) (b), and
structures of cannabinoid receptors CB1 and CB2 (c).
Cannabinoids and osteoporotic pain
Chronic pain is one of the most important complications of
osteoporosis and is a challenging management for clini-
cians.[22,23] In addition to the direct effects of resulting frac-
ture which can cause acute and chronic nociceptive and
neuropathic pain,[24] pain is also a common feature in osteo-
porosis without fracture.[3] It has been reported that post-
menopausal women have significant higher prevalence of low
back pain[25] and there is an association of repetitive pain with
regional migratory osteoporosis (RMO).[26] Central sensitiza-
tion has been suggested to play an important role in the devel-
opment and maintenance of chronic pain related with
osteoporotic fracture which is difficult for treatment and usu-
ally requires a comprehensive strategy including a large spec-
trum of drugs and non-pharmacological treatments.[23,27]
The EC system has been implicated in pain modula-
tion[7,8] and may be involved in the osteoporotic pain as
the EC system is involved in the pathology of osteoporosis
as mentioned above. In fact, it is found that activation of
CB2 receptor by agonists JWH015 could via cytokine/che-
mokine suppression reduce breast cancer-induced bone
loss and severe bone pain induced by implanting the spon-
taneously occurring murine mammary cell line (66.1) into
the femur intramedullary space.[28]
Mechanism of CB in osteoporotic
pain
Interaction of CB receptors with TRPV1
channel
As a Ca2+ permeable cation channel and pro-nociceptive
channel,[29] TRPV1 is found to be expressed in bone tissue
© 2019 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2019), pp. **–**
Cannabinoid receptor and osteoporotic pain
(b)
HO H
N
O
AEA
Fatty acid amide
OH
hydrolase
H 2N
O
AA
OH
OH OH OH
Monoacylglycerol
ygy
lipase
O
OH
2-AG
2 AG O
OH
O
and bone marrow cells, while blockade of TRPV1 signifi-
cantly inhibits the bone metabolism in ovariectomized
mice,[14] suggesting TRPV1 channel plays important role in
osteoporosis by promoting bone loss induced by ovariec-
tomy (OVX). TRPV1 knockout reduces the number of
osteoclasts, impairs the osteoclast formation and resorption
activity, decreases the oscillation frequency and peak con-
centration of cytoplasmic calcium in osteoclast precur-
sors.[10] Consistently, ovariectomy of mice produces
osteoporosis and mechanical hyperalgesia, and up-regulates
the expression of TRPV1 channel and calcitonin gene-re-
lated peptide (CGRP) in dorsal root ganglion DRG) neu-
rons.[30] It is found that the TRPV1-positive neurons are
increased in DRG innervating osteoporotic femur of
mice[9] while the DRG neurons are sensory neurons playing
critical role in pain transmission. Inhibition of TRPV1
channel can attenuate pain behaviours in mice with osteo-
porosis induced by OVX.[31] These results suggest TPRV1
channel may play a vital role in menopausal osteoporosis
and related pain.
As TRPV1 channel and CB1/CB2 receptors are found to
be co-expressed in human osteoclast and mesenchymal
stem cells, selective TRPV1 channel agonist resiniferatoxin
increased the activity of osteoclast, suggesting that TRPV1
channel and CB1/2 receptors might crosstalk in modulating
the homoeostasis of bone mineralization and resorption by
different actions of anandamide.[32,33] Recently, it is found
that the TRPV1 channel and CB1/2 receptors oppositely
modulate the activity of human osteoblast in culture, that
is, CB2 receptor promoting osteogenesis whereas TRPV1
channel inhibiting osteogenesis in glucocorticoid- or OVX-
induced bone mass loss.[34,35] Consistently, osteoclasts from
patients with osteosarcoma shows significant increase of
pro-osteoporotic tartrate-resistant acid phosphatase
3
Cannabinoid receptor and osteoporotic pain
(TRAP) and decrease of CB2 receptor when compared to
osteoclasts from healthy donors. The immunomodulator
mifamurtide reduces the expression of TRAP, PKCbeta2
and TRPV1, and increases CB2 receptor in osteoclasts from
healthy donors,[36] implying there is an interaction between
CB receptors and TRPV1 channel in modulating bone
metabolism. In a study of osteoarthritis of which the main
symptom is chronic pain, dual-acting component targeting
CB receptors and TRPV1 channel demonstrated strong jus-
tification,[37] further implying an interaction in modulating
osteoporotic pain between CB receptors and TRPV1 chan-
nel of which remains to be further studied.
Other mechanisms
In a variety of studies of pain induced by bone cancer
which is one common cause of osteoporosis by itself or
chemotherapy,[16,28,36] the expression of G-protein-coupled
receptor kinase 2 (GRK2) in spinal cord is down-regulated
and the down-regulation of GRK2 is inhibited by CB2
receptor agonist but potentiated by CB2 receptor antago-
nist.[38] This study implies that CB2 receptor may affect the
activities of GRK2. Activation of CB2 receptor also
increases the activities of PI3K/Akt, which is enhanced by
receptor activator of NFjB ligand and parathyroid hor-
mone.[39] In the development of bone cancer pain, it is
found that the microglial cells in spinal cord display
increase of classically activated state and decrease of alter-
natively activated state; and these changes are accompanied
with over-production of IL-1b and inhibition of IL-10.[40]
On the other feature, bone fracture could activate glial cells
in spinal cord.[41] These results imply that glial cells which
play important in cannabinoid-mediated pain[7,8] may also
play role in osteoporotic pain through inflammation which
is also a common reason for osteoporosis and osteoporotic
pain.[42] In addition, it is reported that bone cells also
express leptin and leptin receptor which is modulated by
glucocorticord and dexamethasone.[43] All these studies
suggest that the involvement of the nervous system includ-
ing glial cells may be another mechanism for cannabinoid
to modulate osteoporosis and osteoporotic pain, which
remains to be further studied.
Rubus coreanus Miquel (RCM) is found to inhibit the
osteolysis of osteoclasts and the dysplastic progress in
prostate gland, and to increase the expressions of CB
receptors and osteoprotegerin.[44] These results suggest
that cannabinoid receptor-related up-regulation of
osteoblastogenesis contributes to the anti-osteoporotic
effect of RCM in prostatic hyperplasia by simultaneously
altering the activation of osteoblasts and osteoclasts.
They also imply that treatment with RCM may benefit
these patients with osteoporosis due to prostatic disease.
It is found that rats treated with the non-psycoactive
4 © 2019 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2019), pp. **–**
Jing Wang et al.
Glia
Nerve injury
Inflammaon
Cancer
TRPV1
1 channel
CB R t rs
Receptor
Osteoblast Osteoclast
Osteoporosis
n
Pain
Figure 2 The mechanism of CB receptors in osteoporotic pain.
cannabidiol display increases of serum osteocalcin and
bone mineral density of tibiae and femurs, and decreases
of serum collagen type I cross-linked C-telopeptide.[22]
The usage of cannabinoid to treat rats suffering spinal
cord injury which commonly induces chronic pain but
effective treatment is not identified also increases bone
volume, trabecular thickness and trabecular number, and
decreases trabecular separation in proximal tibiae. These
effects may be related with the up-regulation of mRNAs
of alkaline phosphatise, osteoprotegerin, wnt3a, Lrp5 and
ctnnb1, and down-regulation of mRNAs of receptor acti-
vator of NF-kappaB ligand and tartrate-resistant acid
phosphatase in femurs.[45]
In addition, the first-generation ridaifen compound
RID-B can bind to and/or inactivate CB1 and/or CB2
receptors, demonstrating anti-inflammatory and anti-os-
teoclastogenic properties.[46] These results imply that
cannabinoids play a complicated role in cancer-related
osteoporosis and pain through complicated mechanisms.
Conclusion
There are more and more studies[32,37] verified that both
CB receptors and TRPV1 channel are involved in the meta-
bolism of bone cells and the pathology of osteoporosis
which is an common complication of many pathological
conditions (such as chemotherapy, cancer and menopause)
and cause of osteoporotic pain (Table 1). The interaction
Jing Wang et al. Cannabinoid receptor and osteoporotic pain

between these two pain-related receptors raises more and

more attentions for the elucidation of their mechanism in Declarations
modulating osteoporosis and osteoporotic pain,[33]
through complicated mechanisms including inflammation, Conflict of interest
cancer and nerve injury to affect osteoblasts and osteoclasts The Authors declare that they have no conflicts of interest
(Figure 2). Targeting again CB receptors and TRPV1 chan- to disclose.
nel has been a novel therapeutic approach against chronic
pain,[37,47] and may be a strategy for osteoporosis and
osteoporotic pain in the future. In addition, following the Acknowledgements
elucidation of glial cells in osteoporosis and osteoporotic The study was supported by the National Natural Science
pain through inflammation,[40–42] it is possible to design Foundation of China (NSFC#81371230) and Committee of
multi-target drugs against glia, CB receptors and TRPV1 Science and Technology Innovation of Shenzhen
channel for osteoporosis and osteoporotic pain.[48] (JCYJ201504021520056).

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