Let us move on to a very interesting question, especially in relation to tendon pain caused by fluoroquinolones: is mitochondrial dysfunction a cause of tendon disease?

The effect of fluoroquinolone antibiotics on mitochondrial function has been well documented. At this stage, there is no doubt that many of the chronic symptoms experienced by people with FQAD are caused by mitochondrial dysfunction. But does this also apply to tendon damage? Let’s take a look at the current literature.

Recently, secondary mitochondrial dysfunction, independent of fluoroquinolone antibiotics, has been postulated as a cause of tendinopathy. There is an association between oxidative stress and chronic tendinopathy, reduced collagen synthesis, reduced proteoglycan synthesis, and pathological tendon calcification. Electron microscopy has also demonstrated reduced mitochondrial numbers. For example, in a study using a murine supraspinatus tendinopathy model induced by subacromial impingement, mitochondrial alteration was demonstrated. After the cause of impingement was removed, mitochondria gradually recovered with subsequent healing of the tendon. In the same animal model, superoxide dismutase (SOD), an enzyme ubiquitously present in the mitochondrion that converts the superoxide radical to oxygen and hydrogen peroxide, was shown to be significantly reduced. SOD activity also increased after impingement removal. It is therefore speculated that mitochondrial dysfunction or oxidative stress may be the cause of tendinopathies and that their treatment may also be part of the healing process.(3)

Pathophysiology of Fluoroquinolone-associated tendon disorder

Damage to collagen tissue by fluoroquinolones has different mechanisms. The text below discusses the following properties:

• Influence on tenocyte metabolism and influence on matrix metallo-proteinases.
• The influence of oxidative stress on the development of tendon diseases after fluoroquinolone administration
• Chelation of divalent cations and its consequences
• The effect of fluoroquinolone antibiotics on the hydroxylation of proline to hydroxyproline in collagen synthesis

Metabolism of tenocytes and influence on matrix metallo-proteinases.

Fluoroquinolones act primarily via inhibition of bacterial DNA gyrase, as well as topoisomerase IV. Unfortunately, levofloxacin, moxifloxacin & co. have a direct effect on the metabolism of fibroblasts. Tenocytes(3,4) fibroblasts specific to tendons, produce collagen and elastin, with collagen responsible for stability and elastin for elasticity of tendons.(5,1)

Animal studies demonstrated that fibroblasts of the Achilles tendon, paratenon, and shoulder capsule increased matrix degradation, decreased synthesis of new matrix, and reduced cell proliferation after exposure to ciprofloxacin at physiological concentrations.(5)

Matrix metalloproteinases (MMPs) are enzymes with the function of remodeling tendons.5 This remodeling is crucial for the adaptation of the tendon to activity and controls the assembly and disassembly from tissue. There is differential expression of MMPs in healthy compared to degenerative tendons in humans. Therefore, one theory is that MMPs influence the development of tendinopathies.(5)

MMP-3 expression and activity is increased in tendons that must withstand high mechanical loads, such as the Achilles or supraspinatus tendon, because increased remodeling is likely required due to repetitive microtrauma.(5)

Studies have shown that after exposure to ciprofloxacin, the expression of MMP-3 as well as MMP-1 increases in human fibroblasts from tendon cells.(5) If MMPs are upregulated, this leads to thinner and reduced collagen fibrils.

This may account for the reduced amount of type I collagen, elastin, fibronectin, and beta-1 integrin in tendons after exposure to ciprofloxacin.(5)

Because of these changes, tendon rupture may occur acutely after treatment with fluoroquinolones, especially in tendons with reduced regenerative capacity and tendons that were already structurally compromised.(5)

Interestingly, attempts to inhibit matrix metalloproteinases with (natural) substances as a therapy for fluoroquinolone-induced tendon pain have shown little to no success. For more details, see the article on the treatment of fluoroquinolone-associated tendinopathies. 

The role of oxidative stress in the development of tendon disorders

Oxidative stress is significantly increased after exposure to a fluoroquinolone antibiotic. There is a causal relationship between oxidative stress and the induction of MMP-2, therefore oxidative stress is now thought to be partly responsible for tendon toxicity. This hypothesis is also supported by studies showing that the tendon toxicity of fluoroquinolone antibiotics can be reduced by the administration of antioxidants such as vitamin E or coenzyme Q10.(5)

Thus, oxidative damage to mitochondria in tendon cells after exposure to fluoroquinolones has already been reported.(5) In my view, this is a clear indication that secondary mitochondriopathy is also of significance in tendon diseases caused by fluoroquinolones.

Thus, general therapy with antioxidants seems to be useful in fluoroquinolone-induced tendon pain, at least as prophylaxis against further damage.

Chelation of divalent cations and its consequences

In addition to their effect on fibroblasts, fluoroquinolones are known to chelate divalent and trivalent cations such as calcium, magnesium, iron, or zinc.(5) Magnesium and iron, along with vitamin C, are important co-factors in the hydroxylation of proline to hydroxyproline6 and are thus critical for collagen synthesis.

In addition, magnesium and other cations are known to have a direct effect on the regulation of integrins. Integrins are transmembrane proteins that are involved in the structural stability of cells, such as attachment of cells to the extracellular matrix or to other cells. Integrins are now thought to be essential for maintaining the integrity of musculoskeletal tissues.(5)

Interestingly, similar biochemical changes have been shown in animals on an artificial diet deficient in magnesium for 6 weeks compared with animals after treatment with a fluoroquinolone antibiotic.(5) This strengthens the hypothesis that the toxicity of ciprofloxacin and co. is related, among other things, to the chelation of magnesium.(5)

Therefore, the daily high-dose administration of magnesium is recommended in the therapy of fluoroquinolone-induced tendon pain. A substitution of vitamin C also seems to be useful, especially in view of the fact that most of the patients show a low vitamin C level in laboratory tests.

The effect of fluoroquinolone antibiotics on the hydroxylation of proline to hydroxyproline in collagen synthesis

As described, fluoroquinolone antibiotics inhibit prolyl-4-hydroxylase, the enzyme that hydroxylates the amino acid proline to hydroxyproline.(7) The hydroxylation of proline takes place in the rough endoplasmic reticulum and requires, among other things, ascorbic acid (vitamin C).(8) As mentioned above, other cofactors are cations such as magnesium and iron as well as alpha-ketoglutarate.6 Alpha-ketoglutarate is a key product of the Krebs cycle.(9)

There was previously the idea of substituting the missing hydroxyproline with, for example, collagen powder. From our experience, it cannot be clearly shown so far that regular substitution has any effect on tendon pain.

Much more frequently, it helps those affected to take a magnesium supplement. Magnesium acts as a natural NMDA inhibitor in the CNS. Pain in FQAD patients often does not correlate with objectifiable damage to the tendon and it is assumed that a local interaction between tendon tissue and periphery and the central nervous system is the potential cause of the severe pain experienced by those affected. The observation that magnesium or medication for nerve pain more often leads to relief of tendon pain than, for example, the substitution of collagen or vitamin C, supports this theory.

Due to the low toxicity of the co-factors of the hydroxylation of proline (e.g. vitamin C) and of natural MMP inhibitors (e.g. propolis), substitution of these substitutions is often nevertheless justified in view of the severity of the disability caused by fluoroquinolone-associated tendinopathy and the lack of better alternatives. Further information on this can be found in our article on the treatment of fluoroquinolone-associated tendinopathy.

Source:

1. Pathogenesis of tendinopathies: inflammation or degeneration? Michele Abate et al.
2. Biology of tendon injury: healing, modeling and remodeling P. Sharma and N. Maffuli; 2006
3. Mitochondrial Dysfunction and potential mitochondrial protectant treatments in Tendinopathy, Xueying Zhan et al. 2021 DOI: 10.1111/nyas.14599
4. https://www.amboss.com/de/wissen/Tendinopathie
5. Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for usage in the Athletic Population; Mederic M Hall, Jonathan T Finnoff, Jay Smith 
6. Mitochondrien, Symptome, Diagnose und Therapie; Bodo Kuklinski 
7. Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells; Sujan Badal, Yeng F. Her, L. James Maher 
8. Histologie das Lehrbuch, Ulrich Welsch, Wolfgang Kummer, Thomas Deller Elsevier 5. Auflage 2018
9. Alpha-Ketoglutarate: Physiological Functions and Applications; Nan Wu et al.