Table 2

Epidemiology studies reporting null or negative association between hyperglycaemia or diabetes mellitus and osteoarthritis

Author /year /country (study name)	Study design	N	Site of OA	Definition of OA	Comparison of obesity at baseline	Adjustment of obesity/ age	Quality indicators			Main results
Author /year /country (study name)	Study design	N	Site of OA	Definition of OA	Comparison of obesity at baseline	Adjustment of obesity/ age	Selection	Comparability (BMI and age)*§	Outcome	Main results
Prospectivecohortstudies
Leung 2017, Singapore (Singapore Chinese Health Study)9	CH	63 257	Knee	Arthroplasty	Mean BMI: DM: 24.0±3.3 kg/m² Non-DM: 23.0±3.2 kg/m²	Age, sex, BMI and other variables	****	BMI* Age (^∅)	***	No significant risk of knee OA, comparing DM to non-DM. Men: adj OR=0.64 (95% CI 0.40 to 1.02). Women: adj OR=0.63 (95% CI 0.51 to 0.77).
Monira Hussain 2014, Australia (Melbourne Collaborative Prospective cohort Study)29	CH	13 753	Hip and knee	Arthroplasty	Mean BMI Hip OA: 27.3±4.7 kg/m² Knee OA:29.7±5.3 kg/m² Non-OA: 26.8±4.5 kg/m²	Age, sex, BMI and other variables	***	BMI (^∅) Age (^∅)	**	No significant risk of hip/knee OA, comparing DM to non-DM. Hip: adj HR=1.10 (95% CI 0.88 to 1.37) Knee: adj HR=1.07 (95% CI 0.88 to 1.30)
Engstrӧm 2009, Sweden (Malmo Diet and Cancer study)30	CH	5171	Hip, knee	Arthroplasty	Mean BMI OA: 28.9±4.6 kg/m2 Non-OA: 25.7±3.9 kg/m2	Age, sex, BMI and other variables	***	BMI (^∅) Age (^∅)	***	No significant risk of hip and knee OA, comparing DM to non-DM. Hip OA: adj RR=0.7 (95% CI 0.4 to 1.2) Knee OA: adj RR=1.4 (95% CI 0.9 to 2.4)
Frey 1996, USA31	CH	1514	Not specified	Self -reported	Mean BMI men. OA: 26.3±0.2 kg/m² Non-OA: 26.0±0.2 kg/m² Mean BMI women: OA: 25.1±0.2 kg/m² Non-OA: 24.3±0.2 kg/m²	Age, weight, BMI, max life time weight	**	BMI* Age (^∅)	**	No significant difference in glucose levels or prevalence of DM, compare OA to non-OA. IGT and DM was not associated with a history of OA
Driban 2017, USA OAI dataset32	CH	162	Knee OA progression	X-ray	Mean BMI Advanced OA:28.9±4.7 kg/m² OA: 27.9±4.6 kg/m² Non-OA:27.3±4.9 kg/m²	Age, and BMI	****	BMI (^∅) Age (^∅)	**	Glucose, glycated serum protein and C reactive protein were not significantly associated with incident or accelerated knee OA.
Cross-sectionalstudies
Anderson 1988 USA (HANES I)36	CS	5193	Knee	X-ray	Not available	age	****	Age*	nil	No significant risk of knee OA, comparing DM to non-DM Age adj OR, men=2.14 (95% CI 0.92 to 4.96) Age adj OR women=1.02 (95% CI 0.52 to 2.00) Null association in multi-variable regression model (data not shown)
Dahaghin 2007, Netherlands (Rotterdam study)46	CS	3585	Hand	X-day	Significant association between Hand OA and BMI >27.4 kg/m², OR=1.4 (95% CI 1.2 to 1.7)	Age, sex, BMI and other variables	***	BMI (^∅) Age (^∅)	**	No significant risk for hand OA, comparing DM to non-DM adj OR=1.2 (95% CI 0.9 to 1.6)
Sturmer 2001 Germany (Ulm OA study)38	CS	809	Bilateral OA or Generalised OA	X-ray and physical examination	Prevalence of obesity (BMI ≥30 kg/m²) DM 52.3% Non-DM 29.3%	Age, sex, BMI and other variables	**	BMI (^∅) Age (^∅)	***	For patients undergoing hip/knee arthroplasty, DM was not associated with: Bilateral OA: adj OR=2.21 (95% CI 0.77 to 6.41) Generalised OA: adj OR=0.97 (95% CI 0.50 to 1.86)
Martin 1997, USA (Baltimore longitudinal study of ageing)47	CS	739	Knee	X-ray	Mean BMI for men KL0: 26±4 kg/m² KL2+: 26±4 kg/m² Mean BMI for women KL0: 24±4 kg/m² KL2+: 26±5 kg/m² (p=0.0007)	Age and BMI	***	BMI (^∅) Age (^∅)	***	No significant risk of knee OA, comparing DM to non-DM. Men: adj OR=0.74 (95% CI 0.35 to 1.57) Women: adj OR=0.56 (95% CI 0.14 to 2.24)
Bagge 1991, Sweden (70 year old people in Goteborg)48	CS data from prospective cohort	340	Knee and hand	X-ray	Significant association between: BMI and knee OA BMI and hand OA (women only)	BMI	***	BMI (^∅) Age*	***	No significant risk of knee OA, comparing DM and non-DM. Women: RR=1.44 (95% CI 0.54 to 3.0); Men: adj RR=1.08 (95% CI 0.51 to 2.28); Both sex: adj RR=1.22 (95% CI 0.72 to 2.07). Null association for Hand OA (data not shown)
Case-controlstudies
Nielen 2016, UK12	CC	Hip: 99 682 Knee: 89 536	Hip and knee	Arthroplasty	Mean BMI for hip OA OA: 27.6±5.0 kg/m² Non-OA: 26.8±5.0 kg/m² Mean BMI for knee OA OA: 29.7±5.2 kg/m² Non-OA: 27.0±5.1 kg/m²	Matched age and sex. Adjusted for: BMI and smoking	**	BMI* Age (^∅)	**	No significant risk of hip/knee OA, comparing DM to non-DM. Hip: adj OR=0.87 (95% CI 0.82 to 0.93) Knee: adj OR=0.85 (95%CI 0.77 to 0.94) Current antidiabetic drug use and increasing HbA1c associated with lower risk of hip/ knee arthroplasty
Han 2013, Korea (Korea National Health and Nutrition Examination Survey)34	CC	2234	Knee	Self-reported +symptoms	Mean BMI OA: 24.6±3.3 kg/m² Non-OA: 23.8±3.1 kg/m²	Age, height exercise, alcohol intake and smoking	**	BMI* Age (^∅)	**	No significant difference in fasting blood glucose, compare OA vs non-OA No significant risk of knee OA, comparing DM to non-DM Men: adj OR=1.458 (95% CI 0.748 to 2.839) Women: adj OR=0.822 (95% CI 0.591 to 1.143)
Al-Jarallah 2016, Kuwait13	CC	311	Knee	X-ray	Prevalence of BMI≥30 mg/kg²: DM: 64.4% Non-DM: 45.1%	Age, sex, BMI	***	BMI (^∅) Age (^∅)	**	No significant association with presence of osteophytes, comparing DM and non-DM, adj OR=0.098 (95% CI 0.042 to 0.230)
Magnusson 2017, Norway35	CC	165	Hand	X-ray	Mean BMI OA: 26.2±4.0 kg/m² Non-OA: 25.8±4.3 kg/m²	Age, sex, waist circumference and education	***	BMI* Age*	**	No significant risk of radiographic OA or erosive hand OA, comparing type 1 DM to non-DM Radiographic hand OA: adj OR=1.11 (95% CI 0.55 to 2.26) Erosive hand OA: adj OR=2.96 (95% CI 0.82 to 10.64). Among subjects with long-term type 1 DM, hyperglycaemic burden (mean time weighted HbA1c) not associated with radiographic hand OA and erosive hand OA
Horn 1992, USA33	CC	73	Knee	X-ray and symptoms	Mean weight DM: 98.7±18.3 kg Non-DM: 95.3±19.0 kg	Matched age and BMI in case/ control	*	BMI* Age*	**	Significant lower prevalence of osteophytosis, comparing DM to non-DM women: DM, osteophytosis 84% vs Non-DM, osteophytosis 98% P=0.0044

*§Comparability scoring is given as full star (*) to comparable BMI and age at baseline; and half star (denoted by (^∅)) if BMI and age was adjusted with statistical modelling.
adj, adjusted; BMI, body mass index; CC, case-control study; CH, prospective cohort study; CI, confidence intervals; CS, cross-sectional study; DM, diabetes mellitus; HbA1c, glycated haemoglobin; HOMA-IR, homeostasis model assessment-estimated insulin resistance; HR, HR ratio; HANES I, the United States first national Health and Nutrition Examination Survey of 1971–1975 (HANES I); IGT, impaired glucose tolerance; KOA, knee osteoarthritis; MetS, metabolic syndrome; n, sample size; OA, osteoarthritis; OAI, Osteoarthritis initiatives; OR, odd ratio; RR, relative risk; T2, T2-weighted MRI scan; X-ray, radiographic.