Cannabis and Bone Health

The increased social acceptance and growing interest in cannabis and cannabis-based preparations has expanded the availability and use of these products for both recreational use and for a wide range of medicinal purposes, including the treatment of nausea and vomiting due to chemotherapy, loss of appetite in HIV/AIDS-associated cachexia, spasms in multiple sclerosis, chronic pain conditions, and seizures, among many others, including osteoporosis. While research on cannabis for osteoporosis is in its infancy, a growing number of cell and animal studies provide insight into cannabis’ potential in bone health. Following is a review of the role the endocannabinoid system (ECS) plays in bone metabolism and the manner by which cannabinoids affect bone health.

Osteoporosis
Healthy bones are essential, as they provide support as well as a place for the muscles to attach, and they allow us to move freely. They also protect the brain, heart, and other vital organs from injury. The bones also store essential minerals such as calcium and phosphorous to keep bones strong and release them to meet the body’s needs. However, osteoporosis, which is characterized by low bone mineral density (BMD) and increased risk of fractures, is common.

In the United States, an estimated 10.2 million people aged 50 and older have osteoporosis, and about 43.3 million more people have low bone mass (osteopenia).1 Causes of osteoporosis include glucocorticoid steroid treatments (eg, prednisone, methylprednisolone), lack of estrogen (eg, early menopause, hysterectomy, ovariectomy), lack of weight-bearing exercise, poor diet, heavy smoking, heavy drinking, and low body weight. Osteoporosis risk increases dramatically with age, and women are about four times more likely than men to develop osteoporosis and two times more likely than men to have osteopenia.2 Furthermore, one in two women and up to one in four men will break a bone in their lifetime due to osteoporosis.3 The high economic burden and increased morbidity and mortality costs associated with osteoporosis necessitate new prevention and treatment options, including the use of cannabis-related products.

ECS Review
The ECS regulates a number of biological processes, including immune response regulation, pain perception, appetite regulation, emotion processing, learning and memory, sleep, temperature control, motor function development, and bone metabolism. The ECS consists of the body’s own endogenous cannabinoids, referred to as endocannabinoids, cannabinoid receptors, and the enzymes involved in their synthesis and degradation.

Endocannabinoids
Endocannabinoids are neurotransmitters made in the body that interact with cannabinoids and other receptors. The two primary endocannabinoids are anandamide and 2-archidonoyl glycerol.

Receptors
Endocannabinoids interact with the two primary cannabinoid receptors: cannabinoid-1 (CB1) receptors which are found in the central nervous system, and cannabinoid-2 (CB2) receptors which are typically present in the peripheral nervous system and in immune cells. They also interact with other receptors, including G-protein coupled receptors (GPR55 and GPR119), transient receptor potential vanilloid (TRPV1 and TRPV4), peroxisome proliferator-activated receptors (PPARα and PPARγ), and various ion channels.4 Endocannabinoid interaction with these receptors results in various physiological responses depending on the type of receptor and its location in the body. For example, cannabinoids may target CB1 receptors in a spinal nerve to relieve pain or bind to a CB2 receptor in an immune cell, which signals that the body is experiencing inflammation.

Cannabinoids
The term cannabinoids refers to endocannabinoids (made in the body), phytocannabinoids (found in the cannabis plant), or synthetic cannabinoids (made in a lab). Phytocannabinoids and synthetic cannabinoids mimic the effects of endocannabinoids on receptors.

The cannabis sativa plant is made up of hundreds of different cannabinoids, terpenes, flavonoids, and other compounds. The most studied and best-known phytocannabinoids are THC and CBD. THC acts as a partial agonist of CB1 and CB2 receptors but has higher affinity for the CB1 receptor. 5 CBD is a weak CB1 and CB2 antagonist with effects on TRPV1 and TRPV2, and GPR55.6

Bone Metabolism
Bone metabolism is a continual cycle of bone growth and bone resorption that is regulated by an array of hormonal and regulatory influences and specialized cells known as osteoblasts and osteoclasts.

Osteoblasts and Osteoclasts
Osteoblasts are responsible for generating new bone and maintaining bone integrity and shape. They function in groups to form “osteoid” bone, which is made up of collagen and other proteins. Osteoclasts are large cells that cause bone resorption—the breakdown of bone and release of minerals into the body. Imbalances between osteoblasts and osteoclasts can lead to bone diseases, including osteoporosis.

ECS Expression in Bone
The ECS is also expressed in bone and synovial tissues and is known to play an important role in bone metabolism by regulating bone mass, bone loss, and bone cell function. Anandamide and 2-archidonoyl glycerol are produced locally in bone, and CB1 and CB2 receptors, TRPV1 channels, and GPR55 are all found in bone osteoclasts and osteoblasts.6 Disruptions in the balancing act between osteoclasts and osteoblasts can trigger bone loss, and accelerated osteoclast activity plays an important role in the pathogenesis of osteoporosis. Thus, cannabis-based therapies that can attenuate osteoclast activity or increase osteoblast activity could be beneficial as a potential treatment option for osteoporosis.

Mouse Models
Much of our knowledge about the ECS and its role in bone metabolism comes from mouse models. These are valuable as the bones of rats are similar to those of humans, representing a dynamic tissue that is constructed and reconstructed throughout life by bone modeling and remodeling.7

CB1 Receptors
To study the clinical manifestations of postmenopausal osteoporosis, animal models using mice with ovariectomy have been used to mimic estrogen deficiency-induced bone loss. Accelerated bone loss in females occurs after menopause, when the ovaries stop producing the female sex hormone estrogen and contribute significantly to declining bone health in females. In a study using mice with ovariectomy, researchers demonstrated that CB1 receptors regulate osteoclastic bone resorption in adult mice and that CB1 receptor activation stimulates osteoclast activity, which results in increased bone turnover and bone loss.8 The inactivation of CB1 receptors resulted in increased bone mass and protected the mice from ovariectomy-induced bone loss. The researchers raised the possibility that recreational or therapeutic use of cannabis derivatives that act as agonists at cannabinoid receptors may enhance bone loss and predispose individuals to osteoporosis. They also suggested that cannabinoid receptor antagonists may represent a promising new class of antiresorptive drugs for the treatment of osteoporosis and other bone diseases associated with increased osteoclast activity.

CB2 Receptors
While both CB1 and CB2 receptors have important effects on the skeleton, CB2 receptors are more highly expressed than CB1 receptors in bone cells, including osteoblasts, osteocytes, and osteoclasts. CB2 receptor stimulation has been reported to have antiosteoporosis function and increases bone mass by enhancing the number and activity of osteoblasts, inhibiting the proliferation of osteoclasts, and stimulating fibroblastic formation by myeloid cells.9 These effects support CB2 receptors as possible molecular targets in the diagnosis and treatment of osteoporosis.

TRPV1 Channels
Human osteoblasts and osteoclasts express TRPV1 channels.10 Anandamide has been found to activate TRPV1 in human osteoclasts in vitro, stimulating osteoclasts activity and bone turnover and increasing CB2 expression in osteoclasts 10-fold.11

TRPV1 is also involved in glucocorticoid-associated bone loss. Extended glucocorticoid use (eg, prednisone, methylprednisolone) can dramatically decrease bone formation rate and increase osteoporosis risk, and significantly increases the risk of fractures. This appears to be due to the prolonged lifespan of osteoclasts (increased resorption) and decreased lifespan of osteoblasts (reduced bone formation).12 While this increased resorption has been demonstrated, much of the glucocorticoid-related bone loss is caused by reduced bone formation, which persists throughout glucocorticoid administration.

GPR55
GPR55 is also expressed in human and mouse osteoclasts and osteoblasts. Studies provide evidence that while GPR55 agonists can inhibit osteoclast formation, they also stimulate osteoclast resorption, therefore promoting bone loss.13 Conversely, CBD, which is a GPR55 antagonist, has positive effects against bone loss through enhanced osteoclast formation and impaired osteoclast resorptive activity. This effect has been seen in male mice with targeted inactivation of GPR55 resulting in increased numbers of osteoclast, but these osteoclasts were unable to effectively resorb bone effectively since trabecular bone mass was increased and cartilage remnants at the growth plate were not resorbed efficiently.

Effects of THC on Bone
THC is a partial agonist of the CB1 and CB2 receptors but has higher affinity for the CB1 receptor. THC’s effects are largely due to the activation of CB1 receptors, which give rise to the euphoric effects of cannabis, along with memory impairments and increased risk of psychosis. Despite THC’s activation of CB1, it may have a detrimental effect on bone healing due to a dual toxicity profile that prevents osteogenesis and induces cell death in a number of cell types, including neurons and mesenchymal stem cells.5

Cannabis smoke inhalation has been shown to reduce bone healing around titanium implants in a rat fracture model.14 This suggests a potential negative effect of THC on bone healing. Furthermore, heavy cannabis use has been linked to low BMD, low BMI, high bone turnover, and increased risk of fracture, although it is unclear to what extent this is caused solely by the ingestion of THC.15

CBD Effects on Bone
CBD lacks the ability to produce the psychoactivity seen with THC and is primarily an anti-inflammatory agent. CBD also has demonstrated tremendous potential in improving bone health. CBD antagonizes cannabinoid receptor GPR55 and is, thus, an inverse agonist of the CB2 receptor. Compared with THC, CBD has lower affinity to the CB1 and CB2 receptors. In vivo studies have demonstrated that CBD can inhibit bone resorption via modulation of GPR55 signaling and activation of CB2 receptors.13

Caryophyllene Benefits
While CBD holds tremendous promise in bone health, there’s additional interest in beta-caryophyllene, which is one of the most abundant terpenes in cannabis and also possesses cannabinoid activity. Sometimes referred to simply as caryophyllene, this naturally occurring terpene is found not only in cannabis but also in a number of fruits, vegetables, herbs, and spices. Caryophyllene has been found to bind directly to the CB2 receptor without activating CB1 and TRPV1.16 This could be a benefit in osteoporosis as CB2 activation promotes osteoblast activity and the formation of new bone while avoiding the stimulation of osteoclasts that results from CB1 and TRPV1 activation. A recent study found that mice receiving a diet including beta-caryophyllene experienced higher bone volume and BMD.17

CBD Benefits Bone Healing
Collagen is a type of protein that imparts structure and strength to bone and tissues. The ends of bones are cushioned and protected by cartilage, which is also composed of collagen. It also improves BMD and metabolism in people with chronic bone conditions such as osteoporosis and osteoarthritis.

Researchers have found that CBD can significantly enhance bone healing. A study conducted on rats found that CBD, even when isolated from THC, can significantly enhance bone healing.18 For the study, rats with midfemoral fractures, were used to evaluate the effects of CBD alone and CBD in combination with THC. One group of rats was injected with CBD, and another with a combination of CBD and THC. The researchers found that CBD alone was associated with a “markedly enhanced” healing process in the femora after eight weeks. They noted that CBD alone makes bones stronger during healing, enhancing the collagenous matrix, which provides the basis for new mineralization of bone tissue. Furthermore, after being treated with CBD, the healed bone is harder to break in the future.

Spinal Cord Injury Bone Loss
Researchers investigating the therapeutic effects of CBD on sublesional bone loss in a rat model with spinal cord injury found that CBD enhanced bone volume, trabecular thickness, and trabecular number and reduced trabecular separation in proximal tibiae.19 CBD also appeared to increase ultimate compressive load, stiffness, and energy to max force of femoral diaphysis. With these results, the author concludes that CBD administration reduces the severity of spinal cord injury–induced sublesional cancellous bone loss. If these findings translate to humans, it would be promising as patients with spinal cord injury undergo severe loss of bone minerals below the level of the lesion and have limited treatment options.

Heavy Cannabis Use
While there’s promising data that cannabinoids may be good for bones, according to a Scottish study, heavy cannabis use appears to have detrimental effects on bone health and is linked to low BMD, low BMI, high bone turnover, and increased risk of fracture. The study found that heavy users of cannabis had twice the risk of suffering a broken bone compared with people who smoke only tobacco cigarettes.15

The study included 170 regular cannabis users and a control group of 114 tobacco cigarette smokers. Heavy cannabis use was defined as having smoked cannabis on at least 5,000 occasions, while moderate use was defined as having smoked cannabis more than five times but less than 5,000 times during a lifetime. The average heavy cannabis user was 40 years old, and the average cigarette smoker was about 49 years old. Bone density of participants was evaluated along with reviews of their medical histories for past fractures.

It should be noted that the average heavy cannabis users in the study reported using the drug more than 47,000 times, which equates to having smoked cannabis five times a day for 25 years. And while heavy users appear to have much lower bone density and greater risk of suffering a broken bone compared with nonusers, moderate cannabis use in the study had no negative effect on bone health.

Due to the study’s design, according to the researchers, they could not prove a cause-and-effect relationship between cannabis smoking and bone density. However, the study’s results should prompt health care providers to educate cannabis users about the potential increase in osteoporosis risk and increase screening accordingly.

Final Thoughts
While more evidence is needed, there appears to be tremendous promise for cannabinoids, especially CBD and caryophyllene, to help improve bone health. However, the moderation of cannabis use may be warranted to avoid many of the potential risks associated with the heavy use of cannabis, including possible bone loss.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References