Bone Disorders

The homeostasis of the skeletal structure is determined by a continuous process of bone remodelling. Among the different pathophysiological changes that can affect it, osteoporosis represents the main one, with its consequent impact on bone mass loss.

Osteoporosis is characterised as a disease resulting from changes in the skeletal architecture and reduced bone mineral density, what leads to greater bone fragility and, consequently, a greater risk of skeletal fractures.¹ Its incidence increases with advancing age, due to the natural imbalance of bone remodeling process, besides being significantly higher in females, due to hormonal changes resulting mainly from the post-menopausal period. It is known that more than 50% of menopausal women are subject to an osteoporosis-related fracture; while this same percentage contrasts with 20% for the male population.² Other possible causes for the development of osteoporosis includes drug therapies, endocrine disorders, eating disorders, immobilization of limbs, among others.³

The role of the Endocannabinoid System (ECS) in the context of this pathology is mainly represented by its CB2 receptors, which are present in greater concentration in peripheral tissues, being highly available in the skeletal system. Relevant here is the expression of CB2 in osteoblastic and osteoclastic cells, involved in the bone remodelling process. In these cells, CB2 receptors are involved in the stimulation of bone formation and inhibition of bone resorption, respectively.4

The mechanism behind this stimulation of osteoblastic function can be explained by two pathways, related to the stages of maturation of such cells. In partially differentiated osteoblast progenitor cells, the activation of CB2 receptors triggers a mitogenic stimulus, with consequent expansion of the colony of osteoblast precursors. As for mature osteoblasts, the activation of CB2 leads to the stimulation of its cellular functions, such as the synthesis of the alkaline phosphatase enzyme and the matrix mineralization process.4 Thus, the CB2 receptor stimulation in osteoblastic cells represents a pro osteogenic factor.5

Considering the role of CB2 receptors over osteoclast cell’s functions, it gets to be oppositional, since its activation leads to an inhibition of such cells’ mitogenic process. Also due to the activation of CB2, the formation of the osteoclastic lineage is limited by the consequent inhibition of its RANKL expression, a receptor involved in signalling the formation, activation and survival of osteoclastic cells.4

It has been shown that the CNR2 gene polymorphism, responsible for decoding the CB2 receptor, is associated with changes in bone density, as well as the development of more severe cases of osteoporosis. Thus, the literature relates the lower expression and/or lower efficacy of CB2 as one of the etiological causes of this bone disorder.6

It is understood that a decreased level of estradiol leads to a delay in the apoptotic process of osteoclastic cells, a factor that favors the reduction of bone density.7 Still considering the CB2 receptor, studies indicate a relationship of its expression with estradiol; an expression that gets to be increased by hormone-induced mechanisms.8 Those findings are consistent with the fact that the menopausal period, accompanied by a reduction in estrogen levels, is the period related to greater bone fragility and higher incidence of osteoporosis.

Regarding the role of the CB1 receptor in bone regulation, evidence is still uncertain, but points to a dual, age-dependent role of this receptor. Preclinical studies showed that young animals treated with CB1 antagonists had increased bone mass, while elderly animals, under the same antagonist therapy, suffered from bone loss. In such a way, the indications seem to bring to light an antagonistic role of the CB1 receptor in the face of bone accumulation at an early age, in contrast to a bone protective role played by CB1 in old age.9 Such findings may also be related to the fact that CB1 receptors are present in very low amounts in bone cells, but their expression in osteoblastic cells increases with advancing age, which seems to be related to the supposed protective role of this receptor against age-related bone loss.10 More evidence is needed to clarify this dual role of CB1, though.

It is also interesting to point out the role of ECS in bone homeostasis through endocannabinoids activity. One study showed the absence of Anandamide and 2-AG in synovial fluids of healthy patients, but detected the presence of those two compounds in fluids of patients with osteoporosis and rheumatoid arthritis. It is known that endocannabinoids are compounds synthesised on demand by the body, in situations of need, so such findings contribute to strengthen evidence of the natural compensatory role of ECS in these pathologies.11

Taking into account the mechanisms here described, evidence points as a potential therapeutic strategy for intervention in bone comorbidities, drugs that target the modulation of CB2 receptors6 In this context, cannabinoid compounds gain relevance.

Several studies bring to light the role of CBD and THC compounds in bone homeostasis. Considering the process of bone regeneration after a fracture, one of the main mechanisms involved is that of endochondral ossification, in which a cartilaginous structure initially forms at the site of the injury/fracture, being mineralized and reabsorbed over time, to give place to a bone matrix. The latter is then modelled, forming a mature bone structure. In this process, a preclinical study showed that both CBD and THC showed activity to reduce the size of the cartilaginous structure, 4 weeks after fracture, which can be explained by the ability of these compounds to stimulate cartilage resorption.12 Furthermore, the study found that both compounds were able to render forming bones stronger and stiffer within 6 weeks post fracture. However, in 8 weeks time, this characteristic was sustained only by CBD, while THC seemed to partially attenuate this obtained bone rigidity. The study then concludes that CBD is more relevant for biomechanical gains in the bone regeneration process.

Seeking to understand what determined the best mechanical outcomes obtained with cannabinoids, the previous study considered that one of the possible determining factors is the better quality of the crosslinking of the collagen structure that accompanies the bone regeneration process. This structure seems to have its formation optimised by CBD, since it stimulates the expression of the PLOD1 enzyme, which acts in the collagen cross-linking process, related to the quality of the bone structure. Conversely, THC shown to reduce the expression of this same enzyme, which is consistent with the findings of this study.6

Also consistent with the stimulation of PLOD1 expression by CBD, are the scientific findings that this cannabinoid plays a significant role in the regeneration process of fractured or fragile bones, but does not affect the homeostasis of healthy bones.13

Other skeletal imbalances pertinent here are cancer-induced bone disorders, common in patients with bone tumours, such as osteosarcoma. Manifestations of these conditions include bone pain, reduced mobility, increased tendency for fracture, neural compression, and hypercalcemia.14

Osteoclastic cells of patients with osteosarcoma have reduced expression of CB2 receptors, compared to healthy individuals and, during the chemotherapy process, this expression tends to drop even further. As a result, the loss of bone density in these patients is frequently seen, which is compatible with the findings raised so far. The modulation of CB2 receptors is therefore a valid therapeutic strategy to be considered, having shown potential both in the reduction and possible reversal of cancer-induced bone disorders, as well as in bone cancer therapy itself.15 To be highlighted here that CB2 receptors activation has already shown to have an effect on apoptosis and on induced tumour necrosis, on the reduction of osteoclast formation and differentiation, and on tumour angiogenic reduction.14 Furthermore, it is valid to mention the known analgesic activity provided by the modulation of the endocannabinoid system, relevant here as a therapeutic benefit for pain derived from bone cancer.14 With these considerations, therapy with CB2 agonists was studied and suggested as a promising treatment for cancer-induced bone pain, bone loss and bone fractures, without implying significant central nervous system effects, since CB2 receptors are much less expressed at this level.16

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