Musculoskeletal System

Arachidonic acid is metabolised down two branches, cyclooxygenase to prostaglandins and 5-lipoxygenase to leukotrienes.

Conventional NSAIDs block only the first, which is why they work and why blocking COX-1 damages the stomach lining. The boswellic acids inhibit 5-lipoxygenase, a target no common analgesic hits, and several herbs act on both branches at once ^{16Reference 16Brien et al. · 2006ReviewDevil’s claw (Harpagophytum procumbens) for osteoarthritis — review of efficacy and safetyView study →}.

Curcumin, ginger and willow bark all show mixed COX and LOX profiles.

This is the most credible pharmacological reason a herb might relieve joint pain with a different side-effect profile rather than simply being a weaker aspirin.

Osteoarthritis is not purely mechanical. IL-1β and TNF-α drive matrix metalloproteinase release from chondrocytes, and those enzymes degrade cartilage.

Devil’s claw’s harpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes ^{17Reference 17Haseeb et al. · 2017In vitroHarpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes — in vitroView study →}, a nettle leaf extract reduces matrix metalloproteinase expression in human chondrocytes ^{55Reference 55Schulze-Tanzil et al. · 2002In vitroEffects of the antirheumatic remedy Hox alpha, a stinging nettle leaf extract, on matrix metalloproteinases in human chondrocytes — in vitroView study →}, comfrey root extract inhibits NF-κB signalling at two distinct steps ^{34Reference 34Seigner et al. · 2019In vitroA Symphytum officinale root extract exerts anti-inflammatory properties by affecting two distinct steps of NF-κB signaling — in vitroView study →}, and arnica’s helenalin inhibits NF-κB by directly alkylating the p65 subunit ^{40Reference 40Lyss et al. · 1998In vitroThe anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-κB by directly targeting p65 — in vitroView study →}.

If any of this translated into structural protection it would be significant. So far it has not been shown to.

Willow bark is the origin story of the most-used drug in the world. Salicin was isolated from Salix, gave its name to salicylic acid, and led to acetylsalicylic acid.

The pharmacology has a twist that matters clinically. Salicin is a prodrug converted by gut flora and the liver to salicylic acid, and a standardised willow extract delivers far less salicylate than an aspirin tablet, yet trials find analgesia comparable to meaningful NSAID doses ^{27Reference 27Vlachojannis et al. · 2009Systematic reviewA systematic review on the effectiveness of willow bark for musculoskeletal painView study →}.

The polyphenol fraction appears to contribute independently.

Willow bark is not aspirin. It does not have a useful antiplatelet effect, and it still carries the salicylate cautions.

The most interesting mechanism here, because it is destructive rather than inhibitory.

Capsaicin binds TRPV1 on nociceptive C-fibres, opening a calcium channel, and sustained or high-concentration exposure floods the nerve terminal with calcium and causes reversible degeneration of the fibre itself. The nerve ending is not blocked, it is temporarily retracted, which is why a single high-concentration patch application gives weeks of relief and why the first application burns.

It is also why capsaicin is one of the few well evidenced options for neuropathic pain ^{35Reference 35Derry et al. · 2013Meta-analysisTopical capsaicin (high concentration) for chronic neuropathic pain in adults — Cochrane systematic review and meta-analysisView study →}, a notoriously drug-resistant category.

The oldest topical rationale, and a partly real one.

Rubefacients cause local vasodilation and a sensation of warmth, which increases blood flow and, on gate-control reasoning, floods the dorsal horn with competing sensory input that reduces perception of the deeper pain. Cayenne, mustard, ginger and essential-oil liniments all work here.

The vasodilation is real, the gate-control explanation is plausible, and a good part of the effect of any rubbed-on preparation is the rubbing.

The antispasmodic mechanism, best characterised in cramp bark.

Its coumarin scopoletin is a documented antispasmodic ^{42Reference 42Nicholson et al. · 1967In vitroScopoletin, an antispasmodic component of Viburnum opulus and V. prunifolium — in vitroView study →} that acts by interfering with intracellular calcium mobilisation ^{43Reference 43Oliveira et al. · 2001In vitroIntracellular calcium mobilisation as a target for the spasmolytic action of scopoletin — in vitroView study →}, and a second constituent, viopudial, has separate smooth-muscle relaxant activity ^{41Reference 41Nicholson et al. · 1972Viopudial, a hypotensive and smooth-muscle antispasmodic from Viburnum opulus — animal and isolated tissueView study →}.

All of that concerns smooth muscle, the involuntary kind in the gut, uterus and vessel walls. Skeletal muscle cramp is a different tissue with different physiology, and the traditional use of cramp bark for leg cramps rests on an extrapolation the pharmacology does not support.

The bone mechanism has two arms.

Bone is continuously demolished by osteoclasts and rebuilt by osteoblasts, with RANKL signalling driving osteoclast formation. Devil’s claw’s harpagoside inhibits RANKL-induced osteoclastogenesis and prevents inflammation-mediated bone loss in mice ^{64,65Reference 64Kim et al. · 2015AnimalHarpagoside inhibits RANKL-induced osteoclastogenesis via the Syk-Btk-PLCγ2-Ca²⁺ pathway and prevents inflammation-mediated bone loss — mouse modelView study →Reference 65Kim et al. · 2022AnimalHarpagoside attenuates local bone erosion and systemic osteoporosis in collagen-induced arthritis in miceView study →}.

The other arm is hormonal. The loss of estrogen at menopause accelerates bone resorption, and the red clover isoflavones formononetin and biochanin A bind estrogen receptors, preferentially ERβ, which is the rationale for the bone-density trials below.

Neither arm has produced a fracture-outcome result, which is the endpoint that matters.