- Email: [email protected]
Association of vitamin D and knee osteoarthritis – A review
APME-402; No. of Pages 5 apollo medicine xxx (2017) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/apme
Review Article
Association of vitamin D and knee osteoarthritis – A review Raju Vaishya a, Vipul Vijay b,*, Syed Mustafa Hussaini c, Amit K. Agarwal b a
Professor & Senior Consultant, Department of Orthopaedics, Indraprastha Apollo Hospital, New Delhi, India Associate Professor & Consultant, Department of Orthopaedics, Indraprastha Apollo Hospital, New Delhi, India c DNB Trainee, Orthopaedics, Department of Orthopaedics, Indraprastha Apollo Hospital, New Delhi, India b
article info
abstract
Article history:
Osteoarthritis (OA) is a progressively degenerating joint disease primarily affecting the
Received 25 January 2017
weight-bearing joints of the body. The precise etiopathogenesis and mechanism of progres-
Accepted 31 January 2017
sion of osteoarthritis still remain elusive. However, many known risk factors such as vitamin
Available online xxx
D deficiency, obesity, genetics, and trauma, etc. have been studied and hypothesized to play a significant role in its occurrence and progression. Studies into the effects of low vitamin D
Keywords:
levels on pain and joint function to date have yielded equivocal results. Due to the apparent
Vitamin D
conflicting effects of vitamin D in knee OA, further research is required to fully elucidate its
Cartilage
role in the development and progression of the disease. © 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
Knee Osteoarthritis
1.
Introduction
Osteoarthritis (OA) is a chronic progressive and degenerative joint disease which commonly affects weight bearing synovial joints. It is characterized by gradual degradation and subsequent loss of articular cartilage, abnormal subchondral bone growth, and remodeling, and, in early stages also causes inflammation of the synovium. The complexity of OA has hindered attempts to understand its etiology and pathogenesis which still remains equivocal.1 There are, however, a range of risk factors which are known to associate with OA including age, gender, obesity, previous joint trauma, and genetics.2 Historically, it was assumed that only cartilage contributed to the progression of OA, but all tissues within the joint structure are now known to be involved. In osteoarthritic
knees, the most common location of OA, the subchondral tibial and femoral bones play central roles in the pathology of joint degeneration.3 Vitamin D has recently found focus due to its widespread effects on the musculoskeletal system. Also, the prevalence of vitamin D deficiency has consistently been on the rise.4 These two factors have led to an increased focus on the effect of vitamin D deficiency on the incidence and progression of OA, especially in the weight bearing joints like hip and knee.
2.
Role of vitamin D deficiency in OA
Vitamin D (25-dihydroxy-cholecalciferol) is a steroidal hormone that has diverse biological functions in target tissues.5 The primary functions of vitamin D are calcium homeostasis
* Corresponding author at: Consultant, Room No. 1210, Department of Orthopaedics, Joint Replacement & Arthroscopy, Indraprastha Apollo Hospital, New Delhi 110076, India. Tel.: +91 11 29871210. E-mail address: [email protected] (V. Vijay). http://dx.doi.org/10.1016/j.apme.2017.01.011 0976-0016/© 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5
2
apollo medicine xxx (2017) xxx–xxx
and regulation of bone metabolism; however, the full extent of vitamin D's biological action remains to be determined with a broad range of effects on different cell and tissue types being reported. Vitamin D deficiency results in hypocalcemia, and hypophosphatemia and also causes an increase in PTH secretion.5 Hypovitaminosis D, generally (though not universally) defined as circulating serum 25(OH)D3 levels of <20 ng/ ml and frequently found to coexist with OA, particularly in the elderly patients.6 Acting via the vitamin D receptor (VDR), vitamin D regulates circulating calcium and phosphate homeostasis through altering kidney reabsorption and intestinal absorption.7 Low vitamin D leads to vascular smooth muscle proliferation, endothelial cell dysfunction and increased inflammation.8 In the etiopathogenesis of OA, vitamin D has recently gained focus. The receptors of vitamin D have been found in chondrocytes.9 Vitamin D acts through controlling the matrix metalloproteinase and prostaglandin E2 secretion.8 Vitamin D has also been shown to affect the production of proteoglycans which are necessary for maintaining cartilage health.10 The bone remodeling is also inhibited by vitamin D, and hence it plays a major role in the metabolism of the subchondral bone.11,12
Muraki et al. conducted a cross-sectional study consisting of 787 participants, with a baseline age of 65.6 2.7, and baseline vitamin D levels of 42.5 ng/ml. OA assessment was done using Kellegren and Lawrence Grading.13 The results showed that there was no significant association between a polymorphism of VDR with radiological knee OA. However, a low tertile level vitamin D was associated with knee pain than with a high tertile. Hence, the study concluded that vitamin D deficiency was showed more significant association with knee pain rather than radiographic knee OA. In a cohort study conducted by Ding et al., there were 880 participants with male, the female ratio of 50:50. The mean age was 61 years and baseline vitamin D levels were52.8 ng/ml.14 It was found that there was a significant association of vitamin D deficiency with knee cartilage loss as evidenced by JSN (joint space narrowing). However, it showed no direct correlation with radiographic knee OA as assessed by osteophytes on plain radiograph. Consequently, the study concluded that vitamin D and sun exposure was helpful in reducing knee cartilage loss.
2.1. Vitamin D deficiency and prevalence of radiographic knee OA
There have also been longitudinal studies where patients with vitamin D deficiency were followed in a prospective manner to assess the incidence of radiographic knee OA. A prospective cohort study conducted by Berginik et al. included 1248 participants with an average age of 66.2 and a male to female ratio of 58:42. Their mean vitamin D levels were 26.4 ng/ml.15 Radiographic assessment was done using Kellgren and Lawrence Grading. The results showed that a low tertile level vitamin D showed significant association to JSN and radiographic progression of knee OA. Hence the study
Vitamin D deficiency has long being speculated to be a profound risk factor for the occurrence and progression of knee OA, but its objective evidence till date remains bleak. However, several major studies, both cross sectional and longitudinal, have since been done which has enhanced our understanding its actual underlying pathophysiology (Tables 1 and 2).
2.2. Vitamin D deficiency and incidence of radiographic knee OA
Table 1 – Cross sectional and cohort studies studying the association of vitamin D with knee osteoarthritis. Author and year of study
Age Type of study Number of participants (years) (n)
Malas et al. (2013),17 UK
Cross sectional study
80
20–45
0:100
20
Ding et al. (2009),14 Australia
Cohort study
880
61
50:50 (440/440)
52.8
Muraki et al. (2011),13 Japan
Cross sectional study
787
65.6 2.7
49:51 (388/399)
42.5
Bergink et al. (2009),15 Netherlands
Cohort Study
1248
66.2 (6.7)
58:42 (728/520)
26.4 (10.8)
Male: female
Mean vitamin D levels in ng/ml
Outcome
Clinical conclusion
Patients with vitamin D level (<10 ng/ml) showed a thinner distal femur cartilage when compared to patients with vitamin D level (>10 ng/ml) Vitamin D and sunlight exposure showed no concise correlation to knee ROA Low levels of vitamin D were associated with knee pain, however polymorphism of vitamin D receptor showed no association with radiological OA JSN and radiographic OA had significant association to a low vitamin D level
Vitamin D deficiency is clinically responsible for thinning of distal femoral cartilage
Vitamin D deficiency showed more correlation to knee cartilage loss than radiographic knee OA Vitamin D deficiency was more correspondent to knee pain than radiographic OA. Also, vitamin D receptor polymorphism and knee OA showed no association. Patients with low vitamin D intake showed increased of radiographic knee OA
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5
3
apollo medicine xxx (2017) xxx–xxx
Table 2 – Longitudinal studies assessing the association of vitamin D and knee OA. Author
Country of study and year
Zhang et al.19
USA, 2015
Ding et al.14
Australia, 2009
Felson et al.18
USA, 2007
Bergink et al.15
Netherlands, 2009
Demography:mean age (years) and male:female ratio Sample size (n)
Baseline vitamin D levels (ng/ml)
61 9.2 46.6:53.4 (223/195) N = 418 61 50:50 (440/440) N = 880 53.1 8.7 46.9:53.1 N = 992 66.2 (6.7) 58:42 (728/520) N = 1248
26.2 10.3
Risk of progression of OA doubled in participants with low levels of vitamin D
52.8
Vitamin D deficiency showed more correlation to Knee cartilage loss than radiographic knee OA
19.7 7.4
Knee cartilage volume loss had no significant association with vitamin D deficiency
26.4 (10.8)
Patients with low vitamin D intake showed increased of radiographic knee OA
concluded that diet poor in vitamin D intake increased the risk of progression of radiographic knee OA as evidenced by JSN. McAlindon et al. conducted a randomized control trial where they 146 female patients with symptomatic OA as assessed by KL grading were randomly assigned into treatment and placebo groups.16 The mean age was 62.4 years. The baseline vitamin D levels in the placebo group were 37.52 = 7.53, and vitamin D group was 37.03 = 7.54 g/ml. The treatment group received vitamin D supplementation for 2 years. The results showed that after 2 years of follow-up, there was worsening of knee pain and function in both treatment and the placebo group. Hence it was concluded that vitamin D supplementation showed no role in reducing knee pain and preventing knee cartilage loss in patients with symptomatic knee OA.
2.3. Vitamin D deficiency and distal femur cartilage thickness Malas et al. conducted a cross-sectional study where 80 female patients aged between 20 and 45 years were evaluated for distal femoral cartilage thickness as measured by ultrasound.17 The mean vitamin D levels were 20 ng/ml. It was found that patients with vitamin D levels of <10 ng/ml showed significant thinning of distal femur cartilage than compared to patients with a level of >10 ng/ml. Therefore, it was concluded that vitamin D deficiency was associated with thinning of distal femoral cartilage.
2.4.
Vitamin D deficiency and radiographic OA progression
Several cohort studies have been done where the association of vitamin D and radiographic progression of OA was explored. A randomized control trial conducted by McAlindon et al. evaluated the relationship of vitamin D supplementation on radiographic progression of knee OA as measured by cartilage volume loss.15 It concluded that vitamin D supplementation had no role in reducing knee pain or cartilage volume loss in symptomatic knee OA at 2 years. A prospective cohort study conducted by Felson et al. evaluated 992 patients for evidence of radiographic progression.18 The mean vitamin D level was 19.7 7.4 ng/ml. It was
Conclusion
found that there were no significant association vitamin D deficiency and knee cartilage loss. A cohort study conducted by Zhang et al. included 418 participants with a mean age of 61 9.2 years and average Vitamin d levels of 26.2 ng/ml.19 The study concluded that the risk of progression of radiographic OA doubled in patients with vitamin D deficiency.
2.5.
Vitamin D deficiency and cartilage defect progression
Cohort study conducted by Ding et al. included 880 participants with mean age of 61 years and average vitamin D of 52.8 ng/ml. It was found that vitamin D had a protective effect against cartilage defect progression.13
2.6. Vitamin D deficiency and cartilage volume loss progression Ding et al. conducted a cohort study consisting of 880 participants of whom 50% were male. The mean age was 61 years, and the average vitamin D level was 52.8 ng/ml. Results showed that there was no significant association between vitamin D and sunlight exposure in knee ROA. However, the significance of vitamin D deficiency with knee cartilage loss was substantial.13
2.7.
Future areas of study
Vitamin D deficiency is prevalent worldwide. In the adult population, it has been implicated to be one the profound causative factors of knee OA. Nevertheless, substantial evidence concerning vitamin D deficiency and knee OA is lacking. Hence, in future, there is a requirement for vigorously designed RCTs with large scale sample size to finally conclude the real correlation of vitamin D deficiency with the disease process.
3.
Discussion
OA is the most common joint disease in the world, with an ageassociated increase in both incidence and prevalence. OA is
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5
4
apollo medicine xxx (2017) xxx–xxx
one of the leading causes of disability in the world, with more than 10% of the elderly population having symptomatic disease.20 The outcome of this review establishes that while there was limited or contrasting evidence suggesting that low serum levels of 25-(OH)D were affiliated with the incidence and progression of individual attributes of knee OA, there was moderate evidence suggesting that low 25-(OH)D levels were associated with progression of knee ROA.13 A compelling degree of evidence was distinctly apparent when JSN (incident and progressive) and changes in cartilage volume coalesced as the outcome of cartilage loss.14 These signify that an intervention to improve vitamin D level in OA warrants further analysis. However, different outcome measures used in knee OA may ensue unpredictable results. Some had a significant positive association with vitamin D deficiency, whereas others failed to show the significant correlation. Both JSN and osteophytes are key elements of ROA. Although we found moderate evidence for 25-(OH)D and progression of ROA (assessed by KL), evidence for the associations between 25(OH)D and progression of osteophytes or JSN alone was inconsistent.14 Progression of knee ROA assessed by the KL scoring system is usually defined as an increase of at least 1 grade of JSN in knees with prevalent disease (grade 2 is defined as the presence of definite osteophytes with possible JSN); therefore progression of ROA actually reflects loss of joint space in those with established osteophytes.21 The superior level of evidence for the association of 25-(OH)D with the progression of ROA than with progression of JSN or osteophytes suggests that vitamin D deficiency may be associated with cartilage loss (reflected by loss of joint space) mainly in those with subchondral bone overgrowth.14 There was moderate evidence indicating that vitamin D deficiency was not associated with the incidence of knee ROA.16 There is no doubt that RCTs are the preferred approach to determining whether interventions to correct vitamin D deficiency will prevent the progression of OA. To validate whether correction of vitamin D deficiency is plausible in the treatment of OA, future conscientiously designed RCTs with careful consideration of variables including vitamin D-deficient participants, sufficient duration, and sensitive outcome measures are required. In summary, 25-(OH)D3 appears to be implicated in knee OA about structural change rather than symptoms; further well-designed RCTs are needed to determine whether vitamin D supplementation can slow disease progression.
Author contributions RV helped in the conceptualization of the study and helped in the preparation and review of the manuscript. VV was one of the prinicipal investigators. He helped in the collection of data, statistical analysis, preparation and review of the manuscript. EE was one of the prinicipal investigators. He helped in the collection of data, statistical analysis, preparation and review of the manuscript.
AKA helped in the preparation and review of the manuscript.
Conflicts of interest The authors have none to declare.
references
1. Mabey T. Role of vitamin D in osteoarthritis: molecular, cellular and clinical perspectives. Int J Endocrinol. 2015;383918. http://dx.doi.org/10.1155/2015/383918. 2. Pal CP, Singh P, Chaturvedi S, Pruthi KK, Vij A. Epidemiology of knee osteoarthritis in India and related factors. Indian J Orthop. 2016;50(5):518–522. 3. Li G, Yin J, Gao J, et al. Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Res Ther. 2013;15(6):223. http://dx.doi.org/10.1186/ ar4405. 4. Pal CP, Kumar H, Kumar D, et al. Prevalence of vitamin D deficiency in orthopaedic patients – a single centre study. J Clin Orthop Trauma. 2016;7(suppl 2):143–146. http://dx.doi. org/10.1016/j.jcot.2016.06.009. 5. Vaishya R, Vijay V, Agarwal AK, Jahangir J. Resurgence of vitamin D: old wine in new bottle. J Clin Orthop Trauma. 2015;6(3):173–183. http://dx.doi.org/10.1016/j. jcot.2015.02.002. 6. Hollis BW, Wagner CL. Assessment of dietary VD requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79:717–726. 7. Lee SM, Riley EM, Meyer MB, et al. 1,25-Dihydroxyvitamin D3 controls a cohort of vitamin D receptor target genes in the proximal intestine that is enriched for calcium-regulating components. J Biol Chem. 2015;290(29):18199–18215. http://dx. doi.org/10.1074/jbc.M115.665794. 8. Santoro D, Pellicanò V, Cernaro V, et al. Role of vitamin D in vascular complications and vascular access outcome in patients with chronic kidney disease. Curr Med Chem. 2016;23 (17):1698–1707. 9. Wang Y, Zhu J, DeLuca HF. Identification of the vitamin D receptor in osteoblasts and chondrocytes but not osteoclasts in mouse bone. J Bone Miner Res. 2014;29(3):685–692. http://dx. doi.org/10.1002/jbmr.2081. 10. Corvol MT, Dumontier MF, Tsagris L, Lang F, Bourguignon J. Cartilage and vitamin D in vitro (author's transl). Ann Endocrinol (Paris). 1981;42(4–5):482–487. 11. McAlindon TE. Nutraceuticals: do they work and when should we use them? Best Pract Res Clin Rheumatol. 2006;20:99–115. 12. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353–373. 13. Muraki S, Dennison E, Jameson K, et al. Association of vitamin D status with knee pain and radiographic knee osteoarthritis. Osteoarthritis Cartilage. 2011;19:1301–1306. http://dx.doi.org/10.1016/j.joca.2011.07.017. 14. Ding C, Cicuttini F, Parameswaran V, et al. Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study. Arthritis Rheum. 2009;60:1381–1389. http://dx.doi.org/10.1002/ art.24486. 15. Bergink AP, Uitterlinden AG, Van Leeuwen JP, et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: the Rotterdam
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5 apollo medicine xxx (2017) xxx–xxx
Study. J Clin Rheumatol. 2009;15:230–237. http://dx.doi.org/ 10.1097/RHU.0b013e3181b08f20. 16. McAlindon T, LaValley M, Schneider E, et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis a randomized controlled trial. JAMA. 2013;309 (2):155–162. http://dx.doi.org/10.1001/jama.2012.164487. 17. Malas F&u, Kara M, Ersöz LAM, et al. Does vitamin D affect femoral cartilage thickness? An ultrasonographic study. Clin Rheumatol. 2014;33(9):1331–1334. http://dx.doi.org/10.1007/ s10067-013-2432-y. 18. Felson DT, Niu J, Clancy M, et al. Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies. Arthritis Rheum. 2007;56:129–136.
19. Zhang FF, Driban JB, Grace HL, et al. Vitamin D deficiency is associated with progression of knee osteoarthritis. J Nutr. 2014;144:2002–2008. http://dx.doi.org/ 10.3945/jn.114.193227. 20. Heidari B, Heidari P, Hajian-Tilaki K. Association between serum vitamin D deficiency and knee osteoarthritis. Int Orthop (SICOT). 2011;35:1627–1631. http://dx.doi.org/10.1007/ s00264-010-1186-2. 21. Yuelong C, Tania W, Kay N, et al. Association between serum levels of 25-hydroxyvitamin D and osteoarthritis: a systematic review. Rheumatology (Oxford). 2013;52:1323–1334. http://dx.doi.org/10.1093/ rheumatology/ket132.
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/apme
Review Article
Association of vitamin D and knee osteoarthritis – A review Raju Vaishya a, Vipul Vijay b,*, Syed Mustafa Hussaini c, Amit K. Agarwal b a
Professor & Senior Consultant, Department of Orthopaedics, Indraprastha Apollo Hospital, New Delhi, India Associate Professor & Consultant, Department of Orthopaedics, Indraprastha Apollo Hospital, New Delhi, India c DNB Trainee, Orthopaedics, Department of Orthopaedics, Indraprastha Apollo Hospital, New Delhi, India b
article info
abstract
Article history:
Osteoarthritis (OA) is a progressively degenerating joint disease primarily affecting the
Received 25 January 2017
weight-bearing joints of the body. The precise etiopathogenesis and mechanism of progres-
Accepted 31 January 2017
sion of osteoarthritis still remain elusive. However, many known risk factors such as vitamin
Available online xxx
D deficiency, obesity, genetics, and trauma, etc. have been studied and hypothesized to play a significant role in its occurrence and progression. Studies into the effects of low vitamin D
Keywords:
levels on pain and joint function to date have yielded equivocal results. Due to the apparent
Vitamin D
conflicting effects of vitamin D in knee OA, further research is required to fully elucidate its
Cartilage
role in the development and progression of the disease. © 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
Knee Osteoarthritis
1.
Introduction
Osteoarthritis (OA) is a chronic progressive and degenerative joint disease which commonly affects weight bearing synovial joints. It is characterized by gradual degradation and subsequent loss of articular cartilage, abnormal subchondral bone growth, and remodeling, and, in early stages also causes inflammation of the synovium. The complexity of OA has hindered attempts to understand its etiology and pathogenesis which still remains equivocal.1 There are, however, a range of risk factors which are known to associate with OA including age, gender, obesity, previous joint trauma, and genetics.2 Historically, it was assumed that only cartilage contributed to the progression of OA, but all tissues within the joint structure are now known to be involved. In osteoarthritic
knees, the most common location of OA, the subchondral tibial and femoral bones play central roles in the pathology of joint degeneration.3 Vitamin D has recently found focus due to its widespread effects on the musculoskeletal system. Also, the prevalence of vitamin D deficiency has consistently been on the rise.4 These two factors have led to an increased focus on the effect of vitamin D deficiency on the incidence and progression of OA, especially in the weight bearing joints like hip and knee.
2.
Role of vitamin D deficiency in OA
Vitamin D (25-dihydroxy-cholecalciferol) is a steroidal hormone that has diverse biological functions in target tissues.5 The primary functions of vitamin D are calcium homeostasis
* Corresponding author at: Consultant, Room No. 1210, Department of Orthopaedics, Joint Replacement & Arthroscopy, Indraprastha Apollo Hospital, New Delhi 110076, India. Tel.: +91 11 29871210. E-mail address: [email protected] (V. Vijay). http://dx.doi.org/10.1016/j.apme.2017.01.011 0976-0016/© 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5
2
apollo medicine xxx (2017) xxx–xxx
and regulation of bone metabolism; however, the full extent of vitamin D's biological action remains to be determined with a broad range of effects on different cell and tissue types being reported. Vitamin D deficiency results in hypocalcemia, and hypophosphatemia and also causes an increase in PTH secretion.5 Hypovitaminosis D, generally (though not universally) defined as circulating serum 25(OH)D3 levels of <20 ng/ ml and frequently found to coexist with OA, particularly in the elderly patients.6 Acting via the vitamin D receptor (VDR), vitamin D regulates circulating calcium and phosphate homeostasis through altering kidney reabsorption and intestinal absorption.7 Low vitamin D leads to vascular smooth muscle proliferation, endothelial cell dysfunction and increased inflammation.8 In the etiopathogenesis of OA, vitamin D has recently gained focus. The receptors of vitamin D have been found in chondrocytes.9 Vitamin D acts through controlling the matrix metalloproteinase and prostaglandin E2 secretion.8 Vitamin D has also been shown to affect the production of proteoglycans which are necessary for maintaining cartilage health.10 The bone remodeling is also inhibited by vitamin D, and hence it plays a major role in the metabolism of the subchondral bone.11,12
Muraki et al. conducted a cross-sectional study consisting of 787 participants, with a baseline age of 65.6 2.7, and baseline vitamin D levels of 42.5 ng/ml. OA assessment was done using Kellegren and Lawrence Grading.13 The results showed that there was no significant association between a polymorphism of VDR with radiological knee OA. However, a low tertile level vitamin D was associated with knee pain than with a high tertile. Hence, the study concluded that vitamin D deficiency was showed more significant association with knee pain rather than radiographic knee OA. In a cohort study conducted by Ding et al., there were 880 participants with male, the female ratio of 50:50. The mean age was 61 years and baseline vitamin D levels were52.8 ng/ml.14 It was found that there was a significant association of vitamin D deficiency with knee cartilage loss as evidenced by JSN (joint space narrowing). However, it showed no direct correlation with radiographic knee OA as assessed by osteophytes on plain radiograph. Consequently, the study concluded that vitamin D and sun exposure was helpful in reducing knee cartilage loss.
2.1. Vitamin D deficiency and prevalence of radiographic knee OA
There have also been longitudinal studies where patients with vitamin D deficiency were followed in a prospective manner to assess the incidence of radiographic knee OA. A prospective cohort study conducted by Berginik et al. included 1248 participants with an average age of 66.2 and a male to female ratio of 58:42. Their mean vitamin D levels were 26.4 ng/ml.15 Radiographic assessment was done using Kellgren and Lawrence Grading. The results showed that a low tertile level vitamin D showed significant association to JSN and radiographic progression of knee OA. Hence the study
Vitamin D deficiency has long being speculated to be a profound risk factor for the occurrence and progression of knee OA, but its objective evidence till date remains bleak. However, several major studies, both cross sectional and longitudinal, have since been done which has enhanced our understanding its actual underlying pathophysiology (Tables 1 and 2).
2.2. Vitamin D deficiency and incidence of radiographic knee OA
Table 1 – Cross sectional and cohort studies studying the association of vitamin D with knee osteoarthritis. Author and year of study
Age Type of study Number of participants (years) (n)
Malas et al. (2013),17 UK
Cross sectional study
80
20–45
0:100
20
Ding et al. (2009),14 Australia
Cohort study
880
61
50:50 (440/440)
52.8
Muraki et al. (2011),13 Japan
Cross sectional study
787
65.6 2.7
49:51 (388/399)
42.5
Bergink et al. (2009),15 Netherlands
Cohort Study
1248
66.2 (6.7)
58:42 (728/520)
26.4 (10.8)
Male: female
Mean vitamin D levels in ng/ml
Outcome
Clinical conclusion
Patients with vitamin D level (<10 ng/ml) showed a thinner distal femur cartilage when compared to patients with vitamin D level (>10 ng/ml) Vitamin D and sunlight exposure showed no concise correlation to knee ROA Low levels of vitamin D were associated with knee pain, however polymorphism of vitamin D receptor showed no association with radiological OA JSN and radiographic OA had significant association to a low vitamin D level
Vitamin D deficiency is clinically responsible for thinning of distal femoral cartilage
Vitamin D deficiency showed more correlation to knee cartilage loss than radiographic knee OA Vitamin D deficiency was more correspondent to knee pain than radiographic OA. Also, vitamin D receptor polymorphism and knee OA showed no association. Patients with low vitamin D intake showed increased of radiographic knee OA
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5
3
apollo medicine xxx (2017) xxx–xxx
Table 2 – Longitudinal studies assessing the association of vitamin D and knee OA. Author
Country of study and year
Zhang et al.19
USA, 2015
Ding et al.14
Australia, 2009
Felson et al.18
USA, 2007
Bergink et al.15
Netherlands, 2009
Demography:mean age (years) and male:female ratio Sample size (n)
Baseline vitamin D levels (ng/ml)
61 9.2 46.6:53.4 (223/195) N = 418 61 50:50 (440/440) N = 880 53.1 8.7 46.9:53.1 N = 992 66.2 (6.7) 58:42 (728/520) N = 1248
26.2 10.3
Risk of progression of OA doubled in participants with low levels of vitamin D
52.8
Vitamin D deficiency showed more correlation to Knee cartilage loss than radiographic knee OA
19.7 7.4
Knee cartilage volume loss had no significant association with vitamin D deficiency
26.4 (10.8)
Patients with low vitamin D intake showed increased of radiographic knee OA
concluded that diet poor in vitamin D intake increased the risk of progression of radiographic knee OA as evidenced by JSN. McAlindon et al. conducted a randomized control trial where they 146 female patients with symptomatic OA as assessed by KL grading were randomly assigned into treatment and placebo groups.16 The mean age was 62.4 years. The baseline vitamin D levels in the placebo group were 37.52 = 7.53, and vitamin D group was 37.03 = 7.54 g/ml. The treatment group received vitamin D supplementation for 2 years. The results showed that after 2 years of follow-up, there was worsening of knee pain and function in both treatment and the placebo group. Hence it was concluded that vitamin D supplementation showed no role in reducing knee pain and preventing knee cartilage loss in patients with symptomatic knee OA.
2.3. Vitamin D deficiency and distal femur cartilage thickness Malas et al. conducted a cross-sectional study where 80 female patients aged between 20 and 45 years were evaluated for distal femoral cartilage thickness as measured by ultrasound.17 The mean vitamin D levels were 20 ng/ml. It was found that patients with vitamin D levels of <10 ng/ml showed significant thinning of distal femur cartilage than compared to patients with a level of >10 ng/ml. Therefore, it was concluded that vitamin D deficiency was associated with thinning of distal femoral cartilage.
2.4.
Vitamin D deficiency and radiographic OA progression
Several cohort studies have been done where the association of vitamin D and radiographic progression of OA was explored. A randomized control trial conducted by McAlindon et al. evaluated the relationship of vitamin D supplementation on radiographic progression of knee OA as measured by cartilage volume loss.15 It concluded that vitamin D supplementation had no role in reducing knee pain or cartilage volume loss in symptomatic knee OA at 2 years. A prospective cohort study conducted by Felson et al. evaluated 992 patients for evidence of radiographic progression.18 The mean vitamin D level was 19.7 7.4 ng/ml. It was
Conclusion
found that there were no significant association vitamin D deficiency and knee cartilage loss. A cohort study conducted by Zhang et al. included 418 participants with a mean age of 61 9.2 years and average Vitamin d levels of 26.2 ng/ml.19 The study concluded that the risk of progression of radiographic OA doubled in patients with vitamin D deficiency.
2.5.
Vitamin D deficiency and cartilage defect progression
Cohort study conducted by Ding et al. included 880 participants with mean age of 61 years and average vitamin D of 52.8 ng/ml. It was found that vitamin D had a protective effect against cartilage defect progression.13
2.6. Vitamin D deficiency and cartilage volume loss progression Ding et al. conducted a cohort study consisting of 880 participants of whom 50% were male. The mean age was 61 years, and the average vitamin D level was 52.8 ng/ml. Results showed that there was no significant association between vitamin D and sunlight exposure in knee ROA. However, the significance of vitamin D deficiency with knee cartilage loss was substantial.13
2.7.
Future areas of study
Vitamin D deficiency is prevalent worldwide. In the adult population, it has been implicated to be one the profound causative factors of knee OA. Nevertheless, substantial evidence concerning vitamin D deficiency and knee OA is lacking. Hence, in future, there is a requirement for vigorously designed RCTs with large scale sample size to finally conclude the real correlation of vitamin D deficiency with the disease process.
3.
Discussion
OA is the most common joint disease in the world, with an ageassociated increase in both incidence and prevalence. OA is
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5
4
apollo medicine xxx (2017) xxx–xxx
one of the leading causes of disability in the world, with more than 10% of the elderly population having symptomatic disease.20 The outcome of this review establishes that while there was limited or contrasting evidence suggesting that low serum levels of 25-(OH)D were affiliated with the incidence and progression of individual attributes of knee OA, there was moderate evidence suggesting that low 25-(OH)D levels were associated with progression of knee ROA.13 A compelling degree of evidence was distinctly apparent when JSN (incident and progressive) and changes in cartilage volume coalesced as the outcome of cartilage loss.14 These signify that an intervention to improve vitamin D level in OA warrants further analysis. However, different outcome measures used in knee OA may ensue unpredictable results. Some had a significant positive association with vitamin D deficiency, whereas others failed to show the significant correlation. Both JSN and osteophytes are key elements of ROA. Although we found moderate evidence for 25-(OH)D and progression of ROA (assessed by KL), evidence for the associations between 25(OH)D and progression of osteophytes or JSN alone was inconsistent.14 Progression of knee ROA assessed by the KL scoring system is usually defined as an increase of at least 1 grade of JSN in knees with prevalent disease (grade 2 is defined as the presence of definite osteophytes with possible JSN); therefore progression of ROA actually reflects loss of joint space in those with established osteophytes.21 The superior level of evidence for the association of 25-(OH)D with the progression of ROA than with progression of JSN or osteophytes suggests that vitamin D deficiency may be associated with cartilage loss (reflected by loss of joint space) mainly in those with subchondral bone overgrowth.14 There was moderate evidence indicating that vitamin D deficiency was not associated with the incidence of knee ROA.16 There is no doubt that RCTs are the preferred approach to determining whether interventions to correct vitamin D deficiency will prevent the progression of OA. To validate whether correction of vitamin D deficiency is plausible in the treatment of OA, future conscientiously designed RCTs with careful consideration of variables including vitamin D-deficient participants, sufficient duration, and sensitive outcome measures are required. In summary, 25-(OH)D3 appears to be implicated in knee OA about structural change rather than symptoms; further well-designed RCTs are needed to determine whether vitamin D supplementation can slow disease progression.
Author contributions RV helped in the conceptualization of the study and helped in the preparation and review of the manuscript. VV was one of the prinicipal investigators. He helped in the collection of data, statistical analysis, preparation and review of the manuscript. EE was one of the prinicipal investigators. He helped in the collection of data, statistical analysis, preparation and review of the manuscript.
AKA helped in the preparation and review of the manuscript.
Conflicts of interest The authors have none to declare.
references
1. Mabey T. Role of vitamin D in osteoarthritis: molecular, cellular and clinical perspectives. Int J Endocrinol. 2015;383918. http://dx.doi.org/10.1155/2015/383918. 2. Pal CP, Singh P, Chaturvedi S, Pruthi KK, Vij A. Epidemiology of knee osteoarthritis in India and related factors. Indian J Orthop. 2016;50(5):518–522. 3. Li G, Yin J, Gao J, et al. Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Res Ther. 2013;15(6):223. http://dx.doi.org/10.1186/ ar4405. 4. Pal CP, Kumar H, Kumar D, et al. Prevalence of vitamin D deficiency in orthopaedic patients – a single centre study. J Clin Orthop Trauma. 2016;7(suppl 2):143–146. http://dx.doi. org/10.1016/j.jcot.2016.06.009. 5. Vaishya R, Vijay V, Agarwal AK, Jahangir J. Resurgence of vitamin D: old wine in new bottle. J Clin Orthop Trauma. 2015;6(3):173–183. http://dx.doi.org/10.1016/j. jcot.2015.02.002. 6. Hollis BW, Wagner CL. Assessment of dietary VD requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79:717–726. 7. Lee SM, Riley EM, Meyer MB, et al. 1,25-Dihydroxyvitamin D3 controls a cohort of vitamin D receptor target genes in the proximal intestine that is enriched for calcium-regulating components. J Biol Chem. 2015;290(29):18199–18215. http://dx. doi.org/10.1074/jbc.M115.665794. 8. Santoro D, Pellicanò V, Cernaro V, et al. Role of vitamin D in vascular complications and vascular access outcome in patients with chronic kidney disease. Curr Med Chem. 2016;23 (17):1698–1707. 9. Wang Y, Zhu J, DeLuca HF. Identification of the vitamin D receptor in osteoblasts and chondrocytes but not osteoclasts in mouse bone. J Bone Miner Res. 2014;29(3):685–692. http://dx. doi.org/10.1002/jbmr.2081. 10. Corvol MT, Dumontier MF, Tsagris L, Lang F, Bourguignon J. Cartilage and vitamin D in vitro (author's transl). Ann Endocrinol (Paris). 1981;42(4–5):482–487. 11. McAlindon TE. Nutraceuticals: do they work and when should we use them? Best Pract Res Clin Rheumatol. 2006;20:99–115. 12. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353–373. 13. Muraki S, Dennison E, Jameson K, et al. Association of vitamin D status with knee pain and radiographic knee osteoarthritis. Osteoarthritis Cartilage. 2011;19:1301–1306. http://dx.doi.org/10.1016/j.joca.2011.07.017. 14. Ding C, Cicuttini F, Parameswaran V, et al. Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study. Arthritis Rheum. 2009;60:1381–1389. http://dx.doi.org/10.1002/ art.24486. 15. Bergink AP, Uitterlinden AG, Van Leeuwen JP, et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: the Rotterdam
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
APME-402; No. of Pages 5 apollo medicine xxx (2017) xxx–xxx
Study. J Clin Rheumatol. 2009;15:230–237. http://dx.doi.org/ 10.1097/RHU.0b013e3181b08f20. 16. McAlindon T, LaValley M, Schneider E, et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis a randomized controlled trial. JAMA. 2013;309 (2):155–162. http://dx.doi.org/10.1001/jama.2012.164487. 17. Malas F&u, Kara M, Ersöz LAM, et al. Does vitamin D affect femoral cartilage thickness? An ultrasonographic study. Clin Rheumatol. 2014;33(9):1331–1334. http://dx.doi.org/10.1007/ s10067-013-2432-y. 18. Felson DT, Niu J, Clancy M, et al. Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies. Arthritis Rheum. 2007;56:129–136.
19. Zhang FF, Driban JB, Grace HL, et al. Vitamin D deficiency is associated with progression of knee osteoarthritis. J Nutr. 2014;144:2002–2008. http://dx.doi.org/ 10.3945/jn.114.193227. 20. Heidari B, Heidari P, Hajian-Tilaki K. Association between serum vitamin D deficiency and knee osteoarthritis. Int Orthop (SICOT). 2011;35:1627–1631. http://dx.doi.org/10.1007/ s00264-010-1186-2. 21. Yuelong C, Tania W, Kay N, et al. Association between serum levels of 25-hydroxyvitamin D and osteoarthritis: a systematic review. Rheumatology (Oxford). 2013;52:1323–1334. http://dx.doi.org/10.1093/ rheumatology/ket132.
Please cite this article in press as: Vaishya R, et al. Association of vitamin D and knee osteoarthritis – A review, Apollo Med. (2017), http://dx. doi.org/10.1016/j.apme.2017.01.011
5