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Efficacy and Tolerability of an Undenatured Type II Collagen Supplement in Modulating Knee Osteoarthritis Symptoms: A Multicenter Randomized, Double-Blind, Placebo-Controlled Study

James P. Lugo, Zainulabedin M. Saiyed, Nancy E. Lane
Nutrition Journal 2016 15:14

Bibliography

PubMed
PMID 26822714
PubMed Central
PMC4731911
DOI
10.1186/s12937-016-0130-8
Funding
InterHealth Nutraceuticals, Inc. (Benicia, CA) sponsored and managed the trial; data collection was carried out independently by Laila Pharmaceuticals Pvt. Ltd., India, and data analyses were performed by an independent statistician. Biohack Blueprint assessment: two of the three authors (JPL, ZMS) are employees of InterHealth Nutraceuticals, the manufacturer and sponsor of the UC-II product tested. The third author (NEL) provided consulting services to InterHealth. This is disclosed in the article's Competing Interests section.
Competing interests
JPL and ZMS are employees of InterHealth Nutraceuticals. NEL provided consulting services to InterHealth. This study was sponsored by InterHealth Nutraceuticals, Inc. Benicia, CA. The study was run and managed independently by Laila Pharmaceuticals Pvt. Ltd., India. Data collection was done by the clinical study staff at each respective site. Data analyses was performed by an independent statistician.

Study snapshot

DesignMulticenter, randomised, double-blind, placebo-controlled and active-comparator-controlled clinical trial
ModelAdults aged 40–75 years with moderate-to-severe knee osteoarthritis (Kellgren-Lawrence radiographic grade 2 or 3)
Samplen=191 randomised (UC-II n=63; glucosamine hydrochloride + chondroitin sulfate [GC] n=66; placebo n=62); n=186 eligible for efficacy/safety analysis; n=164 completers
InterventionUndenatured type II collagen (UC-II), 40 mg/day (delivering 1.2 mg of undenatured type II collagen as determined by validated ELISA) vs glucosamine hydrochloride 1500 mg/day plus chondroitin sulfate 1200 mg/day (GC) vs placebo, for 180 days. This is a microgram-to-low-milligram oral-tolerance-type dose of undenatured collagen — mechanistically and quantitatively distinct from gram-scale hydrolysed collagen peptide supplementation reviewed elsewhere on this site.
Duration180 days, with interim assessments at days 1, 7, 30, 60, 90, 120, 150 and 180
EndpointsTotal WOMAC score (pain, stiffness, physical function) — primary; Lequesne Functional Index (LFI); Visual Analog Scale (VAS) for pain; WOMAC subscales; Knee flexion range of motion; Serum biomarker COMP; serum CRP; synovial IL-6 and MMP-3 (protocol 003348 only)

What the study showed, in plain terms

This is another trial worth reading carefully for what it is not testing: it uses undenatured type II collagen (UC-II), a chicken-sternum-derived ingredient given at a 40 mg daily capsule dose (delivering just 1.2 mg of actual undenatured collagen), not the gram-scale hydrolysed collagen peptides covered elsewhere on this site.

In this 180-day, three-arm trial of 191 adults with moderate-to-severe knee osteoarthritis, the UC-II group showed a significantly greater reduction in overall WOMAC score than both placebo and a glucosamine-plus-chondroitin (GC) comparator group. All three WOMAC subscales — pain, stiffness and physical function — improved significantly more with UC-II than placebo.

Two of the three authors are employees of InterHealth Nutraceuticals, the company that manufactures and sponsors UC-II, which is disclosed in the paper. This paper is included in the Data Center as a differentiation reference: readers researching "collagen for joints" may encounter UC-II-type products marketed on trials like this one, and should understand it is not the same ingredient, dose or evidence base as the hydrolysed collagen peptides reviewed elsewhere on this site.

Key findings

  • At day 180, UC-II produced a significantly greater reduction in total WOMAC score than placebo (−551 vs −414; 95% CI −232 to −42; p=0.002) and than GC (−551 vs −454; 95% CI −190 to −3; p=0.04).
  • All three WOMAC subscales improved significantly more with UC-II than placebo: pain (p=0.0003), stiffness (p=0.004), physical function (p=0.007); pain and stiffness also improved significantly more than GC (p=0.016 and p=0.044 respectively).
  • Mean VAS pain score decreased significantly more with UC-II than placebo (22.6 vs 17.0; p=0.002) and than GC (22.6 vs 18.4; p=0.025).
  • Lequesne Functional Index improved significantly more with UC-II than placebo (2.9 vs 2.1; p=0.009) and than GC (2.9 vs 2.2; p=0.008).
  • Subjects with higher baseline serum COMP levels (≥285 ng/mL, a cartilage-turnover biomarker) showed a larger UC-II treatment effect than those with lower baseline COMP.
  • Rescue medication use was significantly lower in the UC-II group (11/63, entire study period) than in GC (21/65) or placebo (28/58); p=0.001.
  • No significant between-group differences were observed in knee flexion range of motion, or in serum/synovial biomarkers (COMP, CRP, IL-6, MMP-3) after adjustment.
  • Safety outcomes did not differ between groups; no subject withdrew due to an adverse event attributable to any study product.

What this study can and cannot tell us

  • Tests undenatured type II collagen at microgram-to-low-milligram doses via a proposed oral-tolerance immune mechanism — a fundamentally different ingredient, dose scale and mechanism from the hydrolysed collagen peptides reviewed elsewhere in this Data Center; results cannot be extrapolated to hydrolysed collagen peptide products.
  • Two of three authors are employees of the sponsoring manufacturer (InterHealth Nutraceuticals), a direct financial conflict of interest.
  • 27 of 191 randomised subjects (14%) dropped out before completion, concentrated more heavily in the GC arm (8 dropouts) than UC-II (9, but from a similar base).
  • No significant change in knee flexion range of motion or in most serum/synovial inflammatory biomarkers was detected, so the improvements are primarily symptomatic (pain/function) rather than confirmed structural or biomarker-level effects.
  • As the authors note, additional studies elucidating the precise mechanism of UC-II's action are warranted.

Related papers in the corpus

Tier 2
Effects of Oral Administration of Type II Collagen on Rheumatoid Arthritis
David E. Trentham et al. · Science · 1993
Tier 4
Therapeutic Efficacy and Safety of Undenatured Type II Collagen Singly or in Combination with Glucosamine and Chondroitin in Arthritic Dogs
M. D'Altilio et al. · Toxicology Mechanisms and Methods · 2007

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology