Why Accutane Can Cause Joint Pain and Stunted Growth

Introduction

Having clear skin could be a great boost to your confidence, but is it worth sacrificing potential height for? The evidence for Accutane’s effects on the musculoskeletal system is extensive. In fact, as many half of patients treated with Accutane report experiencing back pain. Whilst prescribers might be inclined to dismiss skeletal pain as just another pesky side effect, it’s happening for legitimate reasons.

Studies have found that retinoic acid (the primary metabolite of Accutane) causes an increase in the cells that break down bone tissue called Osteoclasts. This is perhaps why Accutane can cause a significant increase in the risk of bone fracturing and even osteoporosis. The disruptive effect of Accutane also extends to cartilage structures, which is of particular concern for those still in the key growth period of teenagehood.

Cartilage is needed to develop new bone through a process called Endochondral ossification. The destructive effect of Isotretinoin on cartilage might prevent patients from reaching their full potential height, with one case study showing a patient missing their predicted height by 5cm! [21]

B12 and folate for back pain

One of the most commonly experienced adverse reactions to Accutane is joint pain or stiffness throughout the body but particularly in the lower back. One study found that after an average treatment length of 6-8months resulted in 49.3% of patients reporting back pain (at doses less than 1mg/kg per day). [1]

The reports of skeletal pain aren’t unjustified, as Accutane has been found to increase the risk of bone fracture and osteoporosis.[2] Studies on rats have demonstrated that the primary metabolite of Accutane increases the activity of cells that down bone called osteoclasts. [3]

The cause of this troublesome side effect is still largely unknown, however a probable mechanism involving Homocysteine has been proposed. This amino acid is metabolic product which can have a number of nasty consequences if allowed to build up in the blood, such as contributing to cardiovascular disease. One of the more notable adverse effects of Accutane is in inducing a state of Hyperhomocysteinemia.

This doesn’t just pose a cardiovascular risk, but can also have a direct impact of bone metabolism. It’s been found that elevated Homocysteine can accumulate in skeletal structures by collagen binding. This stimulates the activity of the type of cell that breaks down bone called Osteoclasts, whilst also repressing the cells that form new bone called Osteoblasts. [2]

Under healthy conditions the elevated Homocysteine is converted into Methionine using B12 or Folate, or broken down by B6. In fact treating Hyperhomocysteinemia in Accutane patients with high dose B12 and folate has been found to resolve any associated musculoskeletal discomfort. [4] To read how B12 can also be useful in treating Accutane induced hairloss (read more here).

Cartilage and skeletal growth

Cartilage is mostly composed of cells called Chondrocytes, they function by maintaining the extracellular matrix of various elastin and collagen fibres, making cartilage strong and flexible. They are found in all joints as well as in the intervertebral discs and provide the cushioning in joint movements.

Micrograph of hyaline cartilage, showing chondrocytes in an extracellular matrix, Robert M. Hunt, Public domain, via Wikimedia Commons

Cartilage begins to grow in early development in a process called chondrification, which is also pivotal in skeletal development since skeletal structures rely upon cartilage for new bone growth. Endochondral ossification is process of skeletal development that using the cartilage as a template. The Chondrocytes transform during this process first by enlarging, before then dying and calcifying. Osteoblasts (bone generating cells) then migrate into this area and lay down a bone matrix. [6]

One of the most fundamental signaling pathways in regulating new bone growth is the Wnt/β-catenin signaling pathway. This pathway plays a crucial role in mediating the effects of retinoids on the body, particularly in how retinoids like Accutane influence stem cell behavior through differentiation and proliferation. For a deeper understanding of this process, I highly recommend reading this article. In short, β-catenin is a protein that signals for growth in tissues throughout the body, but is particularly important in bone health by determining both osteogenesis (formation of bone) and chondrogenesis. [5]

β-catenin is typically bound within a structure called the ‘destruction complex’, constantly breaking it down. It can be released from the destruction complex in response to PI3K/AKT signalling, which is regulated by growth factors such as IGF-1 (the metabolite of Human Growth Hormone). [For more details, read here]

The role of β-catenin

Retinoic acid has been shown to significantly alter the differentiation pattern of chondrocytes. Differentiation is the process by which stem cells become specialised into specific tissue cells. This process is vital in maintaining the health of organs that require continual renewal and growth, including the brain, skin and more. The impact of Retinoids on skeletal development is most strikingly observed in babies overexposed to Vitamin A in utero. These babies often display severe craniofacial and limb malformation, if they survive gestation at all. In vitro evidence shows that Retinoic acid inhibits the formation of chondroblasts (the cells that form chondrocytes), resulting in the cessation of cartilage formation and ultimately the loss of pre-existing cartilage structures. [7] [8]

Retinoic acid has been shown to exert many of its effects by decreasing β-catenin, by enhancing its destruction complex action through suppressing the PI3K-Akt pathway.[9][10]Many of the observed effects of retinoic acid on chondrocytes match the known effects of suppressing β-catenin signalling on chondrocytes, suggesting that this may be the relevant mechanism of action. Inhibition of β-catenin in chondrocytes resulted in increased cell apoptosis (cell death) and “articular cartilage destruction”. [11]

The role of β-catenin in development of bone and cartilage is complex, and the direction of effect depends on the state of maturation of the tissue. Early in development, β-catenin inhibits the differentiation of mesenchymal stem cells into cartilage, and conversely the effect is enhanced by Retinoic acid. [12] The nature of the spatiotemporal patterning is guided by HOX genes and the different RAR isoforms.[13]

The potentially destructive effects of Accutane on cartilage structures could be of particular concern for patients treated during their key growing years. By inhibiting new cartilage growth Accutane could prematurely seal the epiphyseal growth plates at the end of long bones. It’s hard to say exactly how profound this effect could be, however one case study posits that an individual missed their projected growth target by 5cm! [14][21]

What is the effect of Lithium?

Whilst cartilage is evidently important during key growth years, it’s also important throughout adult life for joint health. The superficial zone (SFZ) of articular cartilage is the top layer that contributes to the smooth joint motion through the production of lubricin. This layer also can undergo self renewal. β-catenin is continually active in the SFZ. Enhancing β-catenin has been shown to increase the thickness of the SFZ layer, pointing to its crucial role. [15]

Lithium is a metal present in low quantities in certain food sources. It’s also prescribed at very high doses in treating a number of psychiatric conditions. Surprisingly it acts in an opposing manner to Accutane in a variety of tissue (read more here). Lithium potently increases β-catenin signalling by inhibiting GSK3β. It has been shown that Lithium can greatly reduce catabolic markers in human articular chondrocytes – even preserving cartilage following a surgical intervention. [16]

Other studies have found that in an inflammatory model of cartilage destruction, lithium helped to prevent matrix catabolism and preserve mechanical integrity of the joints. [17] The cartilage-preserving effects were attributed to GSK3β inhibition, rather than simply β-catenin accumulation.

This action of Lithium on GSK3β can even strengthen skeletal structures by opposing the action of nuclear factor-kappa B (NF-κB) – another key target of Accutane treatment. [18] Further studies demonstrate the beneficial effects of lithium in preserving cartilage in the context of cytokine degradation, by inhibiting the p38 MAPK pathway. [19]

The most intriguing demonstration of the beneficial role of Lithium in skeletal structures comes from a study of fowls. Adolescent fowls supplemented with lithium experienced increased height development, further contrasting its effects against those of Accutane.[20]

Article Summary

Accutane’s effects on musculoskeletal system: Accutane (Isotretinoin) has significant effects on bones and cartilage, potentially causing side effects like back pain, joint pain, and an increased risk of bone fractures and osteoporosis.
Impact on bone tissue: Accutane increases osteoclast activity (cells that break down bone), which leads to bone degradation. This can hinder bone formation, contributing to skeletal pain and weakened bone structures.
Effect on growth: Retinoic acid, Accutane’s primary metabolite, disrupts cartilage formation necessary for bone growth, potentially stunting height development in teenagers by preventing full bone growth (e.g., one case study showed a height deficit of 5cm).
Joint pain and stiffness: A common side effect of Accutane is joint stiffness, especially in the lower back, with nearly half of the patients in one study reporting back pain after treatment.
Hyperhomocysteinemia risk: Accutane can induce hyperhomocysteinemia (high homocysteine levels), which negatively affects bone metabolism by increasing osteoclast activity and reducing osteoblasts (cells that form new bone).
Cartilage development and bone growth: Cartilage is essential for bone growth, with chondrocytes (cartilage cells) playing a critical role. Accutane disrupts this process, inhibiting cartilage formation and potentially leading to premature closure of growth plates.
β-catenin’s role: β-catenin is crucial for bone and cartilage development. Accutane suppresses beta-catenin activity, contributing to cartilage destruction, reduced bone growth, and joint health issues.
Lithium’s opposite effect: Lithium, in contrast to Accutane, enhances β-catenin activity and promotes cartilage and bone preservation, with studies showing its potential to protect joints and even boost height development in adolescent animals.