effect of vitamin d supplementation on tibial cartilage ......1. to evaluate the efficacy of vitamin...

Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain among Patients with

Symptomatic Knee Osteoarthritis:a Randomized Controlled Trial

Xingzhong (Jason) JinResearch 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


Background

Knee osteoarthritis (KOA)• 10% men and 13% women aged over 60 years.• 11th leading cause of global disability.• 1.0-2.5% of GDP in developed countries.

(Source: the global burden of disease 2010 study)


Vitamin D and OAØ Epidemiologic evidence (longitudinal studies)


Laslett et al (2013) Moderate deficiency associated with increased knee pain

Vitamin D and OA


Is vitamin D supplementation a cost-effective way to treat knee OA??Have we finally found the holy grail??

Randomized controlled trials

INSERT FACULTY NAME IN FOOTER 7

Sample size: 146 participants with symptomatic knee OA

Intervention: Vitamin D3 2000IU per day for 2 years

Outcomes: WOMAC pain, cartilage volume by MRI



Sample size: 107 participants with knee OA with 25(OH)D ≤ 50nmol/L

Intervention: Vitamin D3 60,000IU/day for 10 days + 60,000IU/month for 1 year

Outcomes: WOMAC pain and function



Conclusions: There is a small but statistically significant clinical benefit to

vitamin D treatment in patients with knee OA.


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.


Systematic Review


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

①Vitamin D3 50,000 IU/month for 24 months

② Identical inert placebo


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.


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)


Cartilage volume Cartilage defects Bone marrow lesions(BMLs)

* Western Ontario and McMaster Universities Arthritis Index

† Whole-Organ Magnetic Resonance Imaging Score

VIDEO study


Study Timeline

Flowchart


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/m2) 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 (cm3) 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.

Serum 25(OH)D levels



Primary endpoint:WOMAC knee pain

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.


Two year change in cartilage volume between vitamin D and placebo [mean].

Vitamin D (n=209)

Placebo (n=204)


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.

• Total tibial cartilage volume: • Vitamin D group: -121.29 mm3 p.a.• Placebo group: -150.68 mm3 p.a.

Primary endpoint:Tibial cartilage volume

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.


‘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.



The publication journey for the VIDEO study

• New England Journal of Medicine (NEJM)Submitted on 25th July 2015, rejected on 7th August

• Lancet Submitted on 21st August, rejected on 27th August

• JAMASubmitted on 2nd September 2015, accepted on 11th February 2016

Is it really ‘Negative’?


• Taber’s Cyclopedic Medical Dictionary 20th 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’.

‘Negative’ trial – What next?


• There are ALWAYS something we could learn from a ‘negative’ trial.


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?



Is there some indication of potential benefits?


Change in knee pain over 24 months follow-up [mean].

Vitamin D

(n=209) Placebo (n=204)


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)


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.

Post-hoc analyses:VAS & WOMAC scores

Change in study endpoints over 2 years between vitamin D and placebo [mean (95% CI)].

Vitamin D (n = 209) Placebo (n = 204)Between-group

difference P-valueVAS 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) 0.313WOMAC, 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.


Was the primary outcome appropriate?

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.


35%

25%

Vitamin D

Placebo

P = 0.029

Secondary endpoints:Cartilage defects & BMLs


Vitamin D (n=209)

Placebo (n=204)


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

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.

The effects sizes on cartilage defects and BMLs slightly favour vitamin D supplementation, although they are not statistically significant.

Secondary endpoints:Effusion-synovitis


Vitamin D Mean (95% CI)

Placebo Mean (95% CI)

Between-group Difference

Mean (95% CI)P value

Total volume of whole joint

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

Absolute change (ml) 0.04 (-1.46, 1.53) 2.53 (0.84, 4.22) -2.49 (-4.74, -0.25) 0.03

Adverse events


Vitamin D(N=209)

Placebo(N=204)

No. of patients (%)

No. of patients (%)

Adverse EventsDeath 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.

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.


Acknowledgements


Chief investigators

• Prof. Changhai Ding• Prof. Graeme Jones• Prof. Flavia Cicuttini

• Prof. Anita Wluka• Prof. Tania Winzenberg• Prof. Leigh Blizzard

Research team

• Robert Warren• Zhaohua Zhu• Weiyu Han • Benny Antony• Xia Wang

This study is supported by the National Health & Medical Research Council (NHMRC ID 605501)

Special thanks

• Jodi Barling• Kay Nguo• Yuelong Cao• Alice Noone• Judy Hankin

VIDEO study participants

effect of vitamin d supplementation on tibial cartilage ......1. to evaluate the efficacy of vitamin...

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