Glucosamine for osteoarthritis: controversy and new research

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Pauline McCoy
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1 Glucosamine for osteoarthritis: controversy and new research Tassos Anastassiades MD, PhD, FRCP Professor of Medicine & Biochemistry, Director Arthritis Center, Queen s University, Kingston, ON

2 Two parts to the talk 1. Glucosamines: Usage in osteoarthritis and ageing (Controversy in clinical trials) 2. My Research: Translational - basic science and animal models (for arthritis and osteoporosis)

3 What Is Glucosamine (GlcN)? A hexosamine sugar Acts as a building block for proteoglycans of cartilage in joints and for hyaluronic acid. These are key components of articular cartilage In proteoglycans and all glycoproteins GlcN is always N-acetylated

4 GlcN: Abundant Naturally Occurring Source Chitin Most abundant polymer in animal kingdom Chitin Chitosan Glucosamine (GlcN) (N-actyl GlcN)

5 Why Is GlcN Use Important?

6 Why Is GlcN Use Important?

7 Why Is OA An Important Problem?

Why Is OA An Important Problem? Source: www.

8 Why Is OA An Important Problem? Source: art0010.html

10 Market Size The global nutriceutical industry sales are forecast to touch $187 billion by 2010, owing to increasing sales in the U.S. and the European Union (EU), as also within the emerging markets like China and India. The value of the global market for GlcN supplements is estimated at $2bn, with an annual growth rate of 7% (Euromonitor International) Glucosamine industry consists of at least 239 companies engaged in marketing, R&D, processing, production, and distribution GlcN sales for domestic animal joint health estimated to be over $500M per year in US sales to veterinarians and pet owners (Estimates from a US veterinary Co).

11 Are Classical GlcNs Effective in Treating Human OA? - Metanalysis of RCTs

12 Metanalysis of RCTs (cont d)

13 Metanalysis of RCTs (cont d)

14 1. Large NIH Trial (GAIT): Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med Feb 23;354(8): Clegg DO et al. Compared with placebo (60.1%),the rate of response to glucosamine was not significantly different (P=0.30). Response to chondroitin sulfate was also NS (+5.3%, P=0.17). Response to GlcN + CS treatment was also NS (+6.5%, P=0.09). Response in the celecoxib control group was 10.0% higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with GlcN + CS therapy than with placebo (79.2 percent vs percent, P=0.002). Subgroup After the fact analysis. Conclude: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee.

15 Controversy over efficacy of GlcN in OA continues: The issue of sponsor bias. BMJ. Conclusions Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged. (Institute of Social and Preventive Medicine, Univ of Bern, Switzerland Apparently independent of Industry) Int J Clin Practice. Conclusion: The results of the present cost-effectiveness analysis suggested that GS is a highly cost-effective therapy alternative compared with paracetamol and PBO to treat patients diagnosed with primary knee OA. (Funded by a ESCEO-Amgen grant received from the European Society for Clinical and Economical Aspect of Osteoarthritis and Osteoporosis and by Rottapharm, Italy.)

16 Safety of GlcN Compounds (Chem Selection Working Grp*) Generally considered safe in man at doses 1,500 mg p.o./day Mouse: oral LD50 (mg/kg) = 15,000, iv = 1,100, SC = 6,200* 0.1% solution of GlcN.HCl 1 ml/100 g induced chromosomal aberrations (CA) in mouse bone marrow cells* Cell growth inhibition in many systems dose dependent* (+ our studies) Liver toxicity with parenteral use* Blood glucose levels increased significantly during glucosamine hydrochloride infusion and returned to normal after 24 hours* Routinely used in animals to mimic the insulin resistance caused by high glucose and insulin *

17 Our Synthetic N-AcylGlcNs (higher N-Acyls than NAc in GlcNAc): OH O OH O HO N H R OH 1. Are not known to be part of mammalian GPs or GAGs. 2. can not be detected in baseline sera.

18 Chemistry: Synthesis of GlcNBu: We can isolate & re-crystallize pure compound in good yield.

19 Chemistry: N-Acyl GlcN Analogues Side Chain MW (Da) MP ( C) Yield (%) Formula Propionyl C 9 H 17 O 6 N Butyryl (cgmp mnfg) C 10 H 19 O 6 N (GlcNBu) Pentanyl C 11 H 21 O 6 N Hexanyl C 12 H 23 O 6 N Heptanyl C 13 H 25 O 6 N Lauryl C 18 H 35 O 6 N 4-Pentenyl C 11 H 19 O 6 N Benzyl C 13 H 17 O 6 N 2Methylbutyryl C 11 H 21 O 6 N

20 Summary for and against biological experimental evidence that GlcN works in OA For: large number of studies show vqrious effects that are interpreted as being positve, at very low concentrations of GlcN. Against: the more convincing studies were done at higher GlcN concentrations, where GlcN is inhibitory. So inhibitory effects on breakdown of cartilage proteins (like Collagen) are interpreted as being positive (i.e. inhibition of inhibition), but are not specific. All pharmokinetic studies of GlcN concentrations in sera of patients have shown extremely tiny amounts, after taking grams of GlcN orally. These very small concentrations are unlikely to be biologicall important and are against the original nutritional hypopthesis for GlcN action (providing building blocks for cartilage proteoglycans)

21 Biological Effects: Chondrocytes from various mammals: GlcNBu but not GlcN was chondroprotective, especially at highre concentratiions. Human OA Chondrocytes: Micro-Arrays. # Up Regulated # Down Regulated GlcN GlcNBu

22 Pharmacokinetic Summary Oral biioavailability : 17%; IP: 100%. Rapidly absorbed after oral doses. Efficiently cleared. No significant effect of food on pharmacokinetics. No breakdown in gut detected. No breakdown in circulation detected. (gut rather than liver mainly responsible for relatively low bioavailability).

23 Safety of GlcNBu No toxicity in culture (up to 10 mm) Negative mutagenicity by Ames test ( µg/ml) No adverse effects in rats (up to 12,000 mg/kg) or other animals (primarily p.o.) Formal large animal safety studies not done

24 Animal Models inflammatory polyarthritis: rat, streptococcal cell wall antigen -chronic phase with severe cartilage loss Osteoporosis: Ovariectomised rat 6 months Osteoarthritis: Aged beagle dog (documented OA).

25 Streptococcal Cell Wall (SCW) Inflammatory Arthritis Model (RA) - single IP injenction

26 SCW (RA) Model: Effect of oral GlcNBu on joint destruction (preliminary by Faxitron) Glc & GlcN-treated rats GlcNBu-treated rats

27 Micro CT analysis of bone isosurfaces (Articular Cartilage) (a) Arthritis, no Rx (b) Arthritis, low dose Rx (c) Arthritis, high dose Rx (d) No Arthritis, no Rx

28 SCW (RA) model: Effect of GlcNBu on BMD (DXA) Summary of methods: 140 long bones were scanned by micro-dexa. BMD and BMC assessed. Utilized a pre-defined region of interest (ROI) distal femur, proximal tibia. Femur ROI Tibia ROI

29 Bone morphometry for the SCW model BONE MORPHOMETRY PARAMETERS Dosage group compared Region of proximal tibia Trabecular Bone Volume (%) Structure Model Index Trabecular Separation Trabecular Number Trabecular Thickness (mm) Subchondral Plate Thickness (mm) GlcNBu High Dose vs SCW GlcNBu Low Dose vs SCW lateral epiphysis medial epiphysis metaphy sis lateral epiphysis medial epiphysis metaphy sis

30 The Osteoporotic Ovariectomized (Ovx) Rat Model Rationale: In the inflammatory arthritis model, GlcNBu treatment resulted in a relatively small effect on inflammation, but a prominent effect on: (i) preservation of cartilage and (ii)on subchondral bone microarchitecture. Question: Could the effect of GlcNBu on bone occur in the absence of inflammation (i.e. a primary effect on bone)? Method: Preventive protocol. DEXA scans of the lumbar spine and femur were performed for the live, anesthetized animals, at baseline time points indicated. At sacrifice (6 months), femurs and spines were dissected and DEXAs and Biomechanical measurements were performed.

31 The effect on bone mineral properties of feeding N-butyryl glucosamine (GlcNBu) or glucose (Glc) to sham ovariectomized (OVX) and OVX rats (A) BMC was preserved in the OVX, GlcNBu treated group (B) BMD was preserved in the OVX, GlcNBu treated group

32 The effect on the energy to failure of femora during 3-point bending (non-normalized data) after feeding or glucose (Glc) to sham ovariectomized (OVX) and OVX rats. Femoral energy to failure was preserved in the OVX, GlcNBu treated group and exceeds values in the other groups.

33 First Dog Study (Weight-dependent dosing: mg GlcNBu BID, orally with gelatin) Veterinary Scores

34 First Dog Study Owner Scores

35 Second dog study Comparison of Therapeutic Benefits of GlcNBu and Carprofen in Treatment of Osteoarthritis in Beagle dogs (Double blind crossover design)

36 Conclusions Running through maze and Quality of Life questionnaire. GlcNBu increased running speed; Carprofen did not affect running speed. Both GlcNBu and Carprofen produced statistically significant improvement in ratings on QOL questionnaire. Both GlcNBu and Carprofent produced statistically significant improvement on the pain score associated with QOL questionnaire.

37 Conclusions (Force plate analysis) GlcNBu produced statistically significant benefits in maximum force, maximum peak pressure, and stance time as assessed by the forcemat protocol. With respect to benefits in OA, GlcNBu and Carprofen appear to be at least equally effective.

N-acyl Glucosamines : A Different Paradigm

38 N-acyl Glucosamines : A Different Paradigm for Industry? A metabolism-based approach for positioning product development between pharmaceuticals and/or nutriceuticals ANACOTI Ltd. Analogues for Connective Tissues After meeting questions: anastass@queensu.ca

39 Demographics of GlcN Use

Clinical Evidence Report

Clinical Evidence Report A multi-center study of the effect of a therapeutic food supplemented with fish oil omega-3 fatty acids on the carprofen dosage in dogs with osteoarthritis. Fritsch DA, Allen TA, Dodd CE, et al. J Am Vet