Table 2 Consensus and research recommendations for each question addressed

Consensus

Research recommendations

Although older age is the greatest risk factor for OA, OA is not an inevitable consequence of growing old.

To investigate GlcN on the following parameters:

• Telomere erosion

1. Chondrocytes have the capacity to biosynthesize GlcN from glucose in health and disease. There is no evidence that chondrocyte GlcN requirement is modified with age or pathological situation.

• Mitochondrial dysfunction

• Reactive oxygen species (ROS) and antioxidants production

2. To study the influence of ageing on the synthesis of GlcN by chondrocytes in in vitro and spontaneous models of OA in animal is recommended.

• Responsiveness to anabolic growth factors

3. Study of the production of GlcN by chondrocytes at different stages of OA development in animal models should be performed.

• Autophagy

4. The senescence-associated secretory phenotype of articular chondrocytes should be better characterized to differentiate ageing and OA affected cartilage.

• Apoptosis

5. At the present time there is no evidence that GlcN modulates this phenotype and no studies have been performed on the effects of GlcN on aged cartilage. New and more focused studies are clearly needed to determine if GlcN can affect oxidative stress, mitochondrial function, autophagy and responsiveness to cytokines and growth factors.

• The expression of transcription factors associated with longevity (i.e. SirT1 and FoxO)

6. There is some in vitro evidence that GlcN modulate glucose metabolism is chondrocytes.

• The accumulation Advanced Glycation End products in ECM.

7. There is some evidence on systemic effect of GlcN through reduction of inflammatory marker and anabolic effects on cartilage.

Question 2. How does the metabolic kinetic look like? What about the Cmax levels?

Consensus

Research recommendations

1. Heterogeneous level of endogenous level of GlcN is comprised between 1μM and 2μM

• To study the influence of various diets enriched in GlcN and ageing on the endogenous level of GlcN

2. Translation of animal models concerning the basal level must been done with caution because there are species differences in GlcN in absorption and bioavailability.

• To better quantify the resting plasma levels of GlcN with future developments in MS-technologies and bioanalytical techniques that should contribute to the standardization of assays used to detect.

3. There is no information on the interference of diet, age and other gastrointestinal comorbidities on the GlcN phamarcokinetic profile.

• To study higher doses of GlcN in human OA to look for beneficial mechanisms of action of GlcN.S in experimental models

• To perform more pharmacokinetic and pharmacodynamic studies in human as well as in animals

• To consider the formulation and complexation of the preparations in future in vitro studies on GlcN

• To take into account the serum and synovium levels from clinical trials (physiological effects found around serum levels of 10μM) to determine the in vitro concentration used in future studies should take into account

• To better investigate the distribution of GlcN in the different joint tissues

Question 3. How can GlcN contribute to cartilage maintenance in healthy subjects, and how can it be demonstrated?

Consensus

Research recommendations

1. GlcN might contribute to the maintenance of joint health in OA patients, but this should be demonstrated in clinical trials designed to investigate its effect on healthy subjects with high risk of OA and evaluating parameters which can establish the link between consumption of GlcN and the maintenance of joints (e.g. biochemical markers and/or MRI). This statement is based on the following observations:

• To investigate the effect of GlcN in the maintenance of healthy subjects. This should be done as recommended in the framework of OARSI, in young subjects with high risk factors of OA

• To investigate the effects of GlcN on a panel of functional imaging and biochemical markers investigating joint tissue metabolism.

- In vitro and ex vivo studies on normal and OA chondrocytes demonstrated stimulating effect of GlcN with supra-pharmacological concentrations on the synthesis of cartilage matrix components and inhibiting potencies on pro-catabolic and pro-inflammatory factors.

- Prophylactic evidence has been shown in some animal models.

- Up-to-date, there is no convincing data demonstrating the potential benefit of GlcN in healthy subjects.

Question 4. Can GlcN reduce the risk of OA development?

Consensus

Research recommendations

1. No data on modulating risk factors of OA.

• To search the influence of GlcN on metabolic (e.g. adipokine secretions, systemic inflammation) and structural risk factors (e.g.; osteophytes, bone marrow lesions)

2. Some animal and cases report in human suggest that chronic use of GLcN in diabetes or “pre-diabetes” individuals might lead to insulin resistance. However the level of proofs is not sufficient and we lack long term studies of GlcN use for individuals with diabetes or pre diabetes. Based on the available evidence, no specific recommendation for controlling glycemia in patients taking GlcN could be addressed

• To identify surrogate marker for risk factors investigation (e.g. multiplex biological test including markers of inflammation, glucose, fat tissue, bone and cartilage metabolism or aggregate score integrating biological, imaging and clinical)

• To design clinical trials on well-defined subgroups with a specific risk profile (metabolic syndrome, etc.) to demonstrate beneficial effects of GlcN on risk factors or risk profile.