Supplement evidence and counter-evidence

Three 2022 papers, starting with a rabbit study of dietary supplements:

“Adding native type II collagen (NC) to the combination of chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), and hyaluronic acid (HA) showed improvements on osteoarthritis progression. Disease progression was monitored at different time points using magnetic resonance imaging biomarkers, measurement of hyaluronic acid in synovial fluid, and macroscopic and microscopic evaluations of cartilage, synovial membrane and subchondral bone.

CTR (control group–no treatment), CGH (60.38 mg/kg CS + 75.47 mg/kg GlHCl + 3.35 mg/kg HA) and CGH-NC (60.38 mg/kg CS + 75.47 mg/kg GlHCl + 3.35 mg/kg HA + 0.67 mg/kg NC). Clearer colors result in an increase of the frequency of each stage of the disease. Significant differences can be appreciated in the CGH-NC group, compared to the other groups over time.


Oral administration of CS with GlHCl and HA, with or without NC, is safe, and provides significant improvements in OA progression. Adding NC leads to better outcomes seen on macroscopic and microscopic evaluation and MRI biomarkers.” “Improved Joint Health Following Oral Administration of Glycosaminoglycans with Native Type II Collagen in a Rabbit Model of Osteoarthritis”

A rodent study of bone growth and similar dietary supplements taken separately found pretty much the opposite:

“Female C57BL/6 mice bred in house were used. Starting at 11 weeks of age, animals were given dietary supplements of either hydrolyzed type I collagen at 1 g/kg, glucosamine sulfate potassium chloride at 300 mg/kg, chondroitin sulfate sodium salt at 250 mg/kg, or fish oil at 1 g/kg. These values were calculated using a body surface area (BSA) calculation from human dosage values of 81.1 mg/kg for collagen, 24.3 mg/kg for glucosamine, 20.3 mg/kg for chondroitin sulfate and 81.1 mg/kg for fish oil.


Our findings indicate that dietary supplements had little impact on bone morphology or mechanics in young female mice and cannot be used to improve bone’s fracture resistance. Bone quality, inferred from material-level mechanical properties and fracture toughness, did not improve with treatment. The only alteration in bone quality was a decrease in elastic modulus with glucosamine or fish oil, which is considered negative and would not be advantageous in preventing fracture.

These data suggest that adding more basic components of the bone matrix into the diet of growing mice does not improve quality of bone tissue. Dietary supplements may be more beneficial in individuals without a balanced diet or in those with an increased risk of fracture, such as those experiencing estrogen loss.” “Dietary supplements do not improve bone morphology or mechanical properties in young female C57BL/6 mice”

This second study cited a 2015 article Translating dosages from animal models to human clinical trials—revisiting body surface area scaling in this context:

“Dosage in this study was determined by using the BSA formula. This technique does have its drawbacks as it does not take into differences in murine metabolism as discussed more in depth elsewhere, but the lack of pharmacokinetic data for dietary supplements in mice prevented a more complex conversion.”

That article has been cited many times, including in a 2022 review:

“Dose-based methodologies for predicting human clinical doses from preclinical data were assessed for oncology drugs. BSA-based approaches were predictive for small molecule oncology drugs, in particular for kinase inhibitors and cytotoxic agents, but prediction was poor for drugs with immune and endocrine components to their mechanisms.

BSA conversion of doses was clearly inappropriate for large molecules. Direct mg/kg-based prediction was more relevant to large molecules with molecular weight > 100 kDa and in particular antibody-drug conjugates.

This approach is theoretically applicable to other therapeutic areas, and if validated in other therapeutic areas, may provide an easy estimate of clinical doses early in the drug discovery and development process to facilitate compound selection and risk management. Later in the drug development process, dose-based methods should be superseded by exposure- and mechanism-based methodologies whenever possible.” “Predicting Approximate Clinically Effective Doses in Oncology Using Preclinical Efficacy and Body Surface Area Conversion: A Retrospective Analysis”

I’ve used body surface area calculations for human equivalent doses, for example, the small molecule sulforaphane at 177.3 g / mol or 177 Da.

Three of the first study’s human equivalent doses can be calculated by the body surface area factor 0.324 for rabbits since molecular weight of chondroitin sulfate is 463.37 g / mol, glucosamine hydrochloride is 215.63 g / mol, and hyaluronic acid is 403.31 g / mol. Human equivalent doses are:

  • Chondroitin sulfate (.324 x 60.38 mg) x 70 kg = 1,369 mg;
  • Glucosamine hydrochloride (.324 x 75.47 mg) x 70 kg = 1,712 mg; and
  • Hyaluronic acid (.324 x 3.35 mg) x 70 kg = 76 mg.

These three weights are all close to supplement weights advertised to be effective.

Undenatured type II collagen in the first study is 300 kDa, and hydrolyzed type I collagen in the second study varies from 0.3 to 8 kDa. Per the third paper’s recommendation of using mg/kg calculations for large molecules, human equivalent doses would be (0.67 mg x 70 kg) = 47 mg for type II and (81.1 mg x 70 kg) = 5,677 mg for type I, respectively. These two weights are also close to supplement weights advertised to be effective.


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