Xingzhong (Jason) Jin

Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain among Patients with Symptomatic Knee Osteoarthritis: a Randomized Controlled Trial Xingzhong (Jason) Jin Research Fellow, NDARC, UNSW Graeme Jones, Flavia Cicuttini, Anita Wluka, Zhaohua Zhu, Weiyu Han, Benny Antony, Xia Wang, Tania Winzenberg, Leigh Blizzard, Changhai Ding

Outline Overview of the VIDEO study Lessons leaned from a negative trial MENZIES INSTITUTE FOR MEDICAL RESEARCH 2

Declaration No conflict of interests MENZIES INSTITUTE FOR MEDICAL RESEARCH 3

Background Knee osteoarthritis (KOA) 10% men and 13% women aged over 60 years. 11 th leading cause of global disability. 1.0-2.5% of GDP in developed countries. (Source: the global burden of disease 2010 study) MENZIES INSTITUTE FOR MEDICAL RESEARCH 4

Vitamin D and OA Ø Epidemiologic evidence (longitudinal studies) Laslett et al (2013) Moderate deficiency associated with increased knee pain MENZIES INSTITUTE FOR MEDICAL RESEARCH 5

Vitamin D and OA Is vitamin D supplementation a cost-effective way to treat knee OA?? Have we finally found the holy grail?? MENZIES INSTITUTE FOR MEDICAL RESEARCH 6

Randomized controlled trials Sample size: 146 participants with symptomatic knee OA Intervention: Vitamin D 3 2000IU per day for 2 years Outcomes: WOMAC pain, cartilage volume by MRI INSERT FACULTY NAME IN FOOTER 7

Randomized controlled trials INSERT FACULTY NAME IN FOOTER 8

Randomized controlled trials Sample size: 107 participants with knee OA with 25(OH)D 50nmol/L Intervention: Vitamin D 3 60,000IU/day for 10 days + 60,000IU/month for 1 year Outcomes: WOMAC pain and function INSERT FACULTY NAME IN FOOTER 9

Randomized controlled trials Conclusions: There is a small but statistically significant clinical benefit to vitamin D treatment in patients with knee OA. INSERT FACULTY NAME IN FOOTER 10

Randomized controlled trials ØWeakness in design Include both vitamin D sufficiency and deficiency. Recruit patients of severe disease stage. Relative small sample size to detect the true effects. Relative short follow-up time. MENZIES INSTITUTE FOR MEDICAL RESEARCH 11

Systematic Review MENZIES INSTITUTE FOR MEDICAL RESEARCH 12

VIDEO study Ø A multicentre, randomized, double-blind, placebo-controlled trial. Ø Objectives 1. To evaluate the efficacy of vitamin D supplementation on knee pain and cartilage volume loss in symptomatic KOA patients with low vitamin D levels. 2. To determine whether vitamin D prevent the progression of other knee structural abnormalities. Ø Interventions 1 Vitamin D 3 50,000 IU/month for 24 months 2 Identical inert placebo MENZIES INSTITUTE FOR MEDICAL RESEARCH 13

VIDEO study Inclusion criteria Age 50 ~ 79; symptomatic knee OA for 6 months (ACR criteria). Serum 25(OH)D, 12.5 nmol/l ~ 60 nmol/l. Visual analogue scale (VAS) for knee pain, 20 mm ~ 80 mm. Exclusion criteria Grade 3 radiographic OA (Altman s atlas). Contraindications to MRI. Other conditions, e.g. inflammatory arthritis, lupus, cancer, etc. MENZIES INSTITUTE FOR MEDICAL RESEARCH 14

VIDEO study Primary endpoints WOMAC knee pain over 24 months Tibial cartilage volume change (% p.a.) Secondary endpoints Tibiofemoral cartilage defects (modified Outerbridge, range 0-4) Tibiofemoral bone marrow lesions (modified WORMS, range 0-3) * Western Ontario and McMaster Universities Arthritis Index Cartilage volume Cartilage defects Bone marrow lesions (BMLs) Whole-Organ Magnetic Resonance Imaging Score MENZIES INSTITUTE FOR MEDICAL RESEARCH 15

VIDEO study Study Timeline MENZIES INSTITUTE FOR MEDICAL RESEARCH 16

Flowchart MENZIES INSTITUTE FOR MEDICAL RESEARCH 17

Baseline characteristics Vitamin D (n = 209) Placebo (n = 204) Hobart 129 (61%) 132 (64%) Melbourne 80 (38%) 72 (35%) Age (years) 63.5 (6.9) 62.9 (7.2) Female (%) 106 (50%) 102 (50%) Body mass index (kg/m 2 ) 29.6 (5.4) 29.6 (4.6) Serum 25OHD (nmol/l) 43.7 (11.8) 43.8 (12.7) Radiographic OA (%) 163 (96%) 157 (96%) Total WOMAC score (0-2400) 687.3 (426.3) 664.7 (390.8) Pain (0-500) 137.8 (88.9) 134.4 (83.2) Stiffness (0-200) 61.5 (41.6) 61.7 (40.1) Function (0-1700) 487.9 (318.1) 467.6 (292.8) VAS pain (0-100) 51.4 (18.8) 49.6 (17.8) Tibial cartilage volume (cm 3 ) 3.47 (1.04) 3.64 (1.04) 25OHD, 25-hydroxyvitamin D; OA, osteoarthritis; WOMAC, Western Ontario and McMaster University Index; VAS, visual analogue scale. MENZIES INSTITUTE FOR MEDICAL RESEARCH 18

Serum 25(OH)D levels MENZIES INSTITUTE FOR MEDICAL RESEARCH 19

Primary endpoint: WOMAC knee pain MENZIES INSTITUTE FOR MEDICAL RESEARCH 20

Primary endpoint: WOMAC knee pain Change in knee pain over 24 months follow-up [mean]. Vitamin D (n=209) Placebo (n=204) Between-group difference p-value WOMAC Pain (0-500) -49.9-35.1-14.8 0.102 Walking on flat surface (0-100) -8.5-6.1-2.4 0.244 Going up/down stairs (0-100) -12.2-9.2-3.0 0.252 Standing upright (0-100) -8.8-5.3-3.5 0.104 Sitting (0-100) -9.5-5.6-3.9 0.072 Pain at night (0-100) -10.9-9.0-1.9 0.430 The result in this table is generated from mixed models adjusted for age, sex, BMI, centre, and month. All analyses compare baseline versus 24 months. MENZIES INSTITUTE FOR MEDICAL RESEARCH 21

Primary endpoint: Tibial cartilage volume Total tibial cartilage volume: Vitamin D group: -121.29 mm 3 p.a. Placebo group: -150.68 mm 3 p.a. Two year change in cartilage volume between vitamin D and placebo [mean]. Vitamin D (n=209) Placebo (n=204) Between-group difference p-value Tibial cartilage volume (% p.a.) -3.44-4.23 0.78 0.132 Medial tibial cartilage volume -3.29-4.39 1.10 0.119 Lateral tibial cartilage volume -3.44-4.09 0.65 0.290 The result in this table in generated by comparing baseline versus 24 months from multiple imputed datasets. All analyses compare baseline versus 24 months. MENZIES INSTITUTE FOR MEDICAL RESEARCH 22

Conclusion o Vitamin D at 50,000 IU/month over 2 years did not meet the primary endpoints in this RCT. o There may be moderate effects on knee pain, physical function, BMLs and effusion-synovitis. o The clinical importance of the effects should be determined on individual patient improvement. MENZIES INSTITUTE FOR MEDICAL RESEARCH 23

Negative trial MENZIES INSTITUTE FOR MEDICAL RESEARCH 24

Negative trial An editorialist in the British Medical Journal observed in 1987: Negative results have never made riveting reading! 50% of clinical trials have never published results. Positive trials were 2 times more likely to be published as those with negative results. MENZIES INSTITUTE FOR MEDICAL RESEARCH 25

Negative trial The publication journey for the VIDEO study New England Journal of Medicine (NEJM) Submitted on 25 th July 2015, rejected on 7 th August Lancet Submitted on 21 st August, rejected on 27 th August JAMA Submitted on 2 nd September 2015, accepted on 11 th February 2016 MENZIES INSTITUTE FOR MEDICAL RESEARCH 26

Is it really Negative? Taber s Cyclopedic Medical Dictionary 20 th Edition: An investigation in which no benefit of a treatment, or no association between a risk factor and an outcome, is demonstrated; also called negative trial The term negative is a misnomer and is commonly defined as those where the difference for the primary endpoint has a P value greater than or equal to 0.05 (P 0.05), that is, where the null hypothesis is not rejected. The correct term should be an inconclusive trial or nonsignificant trial. MENZIES INSTITUTE FOR MEDICAL RESEARCH 27

Negative trial What next? There are ALWAYS something we could learn from a negative trial. MENZIES INSTITUTE FOR MEDICAL RESEARCH 28

Negative trial What next? 1. Is there some indication of potential benefits? 2. Was the trial underpowered? 3. Was the primary outcome appropriate? 4. Was the population appropriate? 5. Was the treatment regiment appropriate? 6. Were there deficiencies in trial conduct? 7. Is a claim of non-inferioirty of value? 8. Do subgroup findings elicit positive signals? 9. Do secondary outcomes reveal positive findings? 10. Can alternative analyses help? 11. Does more positive external evidence exist? 12. Is there a strong biologic rationale that favors the treatment? INSERT FACULTY NAME IN FOOTER 29

Negative trial What next? Is there some indication of potential benefits? Change in knee pain over 24 months follow-up [mean]. Vitamin D (n=209) Placebo (n=204) Between-group difference p-value WOMAC Pain (0-500) -49.9-35.1-14.8 0.102 Walking on flat surface (0-100) -8.5-6.1-2.4 0.244 Going up/down stairs (0-100) -12.2-9.2-3.0 0.252 Standing upright (0-100) -8.8-5.3-3.5 0.104 Sitting (0-100) -9.5-5.6-3.9 0.072 Pain at night (0-100) -10.9-9.0-1.9 0.430 The result in this table is generated from mixed models adjusted for age, sex, BMI, centre, and month. All analyses compare baseline versus 24 months. Two year change in cartilage volume between vitamin D and placebo [mean]. Vitamin D (n=209) Placebo (n=204) Between-group difference p-value Tibial cartilage volume (% p.a.) -3.44-4.23 0.78 0.132 Medial tibial cartilage volume -3.29-4.39 1.10 0.119 Lateral tibial cartilage volume -3.44-4.09 0.65 0.290 The result in this table in generated by comparing baseline versus 24 months from multiple imputed datasets. All analyses compare baseline versus 24 months. MENZIES INSTITUTE FOR MEDICAL RESEARCH 30

Post-hoc analyses: VAS & WOMAC scores Was the primary outcome appropriate? Change in study endpoints over 2 years between vitamin D and placebo [mean (95% CI)]. Between-group Vitamin D (n = 209) Placebo (n = 204) difference P-value VAS Pain (0-100) -14.8-9.4-5.4 0.048 * WOMAC total (0-2400) -239.2 (-290.5, -188.0) -147.8 (-200.8, -94.9) -91.4 (-165.1, 17.7) 0.015 * Function (0-1700) -170.2 (-207.4, -133.0) -97.3 (-135.7, -58.8) -72.9 (-126.4, 19.4) 0.008 * Stiffness (0-200) -19.7 (-25.4, -13.9) -15.4 (-21.3, -9.5) -4.2 (-12.5, 4.0) 0.313 WOMAC, Western Ontario and McMaster University Index; VAS, visual analogue scale; p.a., per annum. WOMAC scores and VAS pain results are generated from mixed models adjusted for age, sex, body mass index, centre and month. Cartilage volume, cartilage defect and bone marrow lesion results are generated from multiple imputed datasets. All analyses compare baseline versus 24 months. Asterisk signs indicate statistical significance. MENZIES INSTITUTE FOR MEDICAL RESEARCH 31

Post-hoc analyses: OMERACT-OARSI response OMERACT-OARSI (Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International) Improvement 50% and an absolute change 20 points, in either WOMAC pain or function score. Improvement 20% and an absolute change 10 points in both WOMAC pain and function score. Vitamin D 35% Placebo P = 0.029 25% MENZIES INSTITUTE FOR MEDICAL RESEARCH 32

Secondary endpoints: Cartilage defects & BMLs Do secondary outcomes reveal positive findings? The conclusion of a trial should be made considering not only primary outcomes, but also secondary outcomes and adverse events. Vitamin D (n=209) Placebo (n=204) Between-group difference p-value Tibiofemoral cartilage defects 0.29 0.47-0.19 0.159 Medial tibiofemoral defects 0.21 0.33-0.12 0.215 Lateral tibiofemoral defects 0.08 0.15-0.08 0.400 Tibiofemoral bone marrow lesion -0.59-0.21-0.38 0.087 Medial tibiofemoral lesion -0.57-0.42-0.15 0.355 Lateral tibiofemoral lesion -0.05 0.17-0.22 0.087 The effects sizes on cartilage defects and BMLs slightly favour vitamin D supplementation, although they are not statistically significant. MENZIES INSTITUTE FOR MEDICAL RESEARCH 33

Secondary endpoints: Effusion-synovitis Total volume of whole joint Vitamin D Mean (95% CI) Placebo Mean (95% CI) Between-group Difference Mean (95% CI) Absolute change (ml) 0.26 (-0.82, 1.34) 2.20 (1.01, 3.38) -1.94 (-3.54, -0.33) 0.02 Suprapatellar pouch P value Absolute change (ml) 0.04 (-1.46, 1.53) 2.53 (0.84, 4.22) -2.49 (-4.74, -0.25) 0.03 MENZIES INSTITUTE FOR MEDICAL RESEARCH 34

Adverse events Vitamin D (N=209) No. of patients (%) Placebo (N=204) No. of patients (%) Adverse Events Death 1 (0.5) 0 (0.0) Malignancy 4 (1.9) 2 (1.0) Coronary artery disease 1 (0.5) 1 (0.5) Severe infection 0 (0.0) 3 (1.8) Major depression 1 (0.5) 0 (0.0) Nephrolithiasis 1 (0.5) 1 (0.5) Hypercalceamia 3 (1.4) 2 (1.0) Hyperparathyroidism 1 (0.5) 0 (0.0) Hospitalization * 3 (1.4) 0 (0.0) * Two were admitted to hospital after a fall and one was due to severe diarrhoea. MENZIES INSTITUTE FOR MEDICAL RESEARCH 35

Conclusion o Vitamin D at 50,000 IU/month over 2 years did not meet the primary endpoints in this RCT. o There may be moderate effects on knee pain, physical function, BMLs and effusion-synovitis. o The clinical importance of the effects should be determined on individual patient improvement. MENZIES INSTITUTE FOR MEDICAL RESEARCH 36

Acknowledgements Chief investigators Prof. Changhai Ding Prof. Graeme Jones Prof. Flavia Cicuttini Prof. Anita Wluka Prof. Tania Winzenberg Prof. Leigh Blizzard Robert Warren Zhaohua Zhu Weiyu Han Benny Antony Xia Wang Research team Special thanks VIDEO study participants Jodi Barling Kay Nguo Yuelong Cao Alice Noone Judy Hankin This study is supported by the National Health & Medical Research Council (NHMRC ID 605501) MENZIES INSTITUTE FOR MEDICAL RESEARCH 37

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