Arjan P. Bergink

Cdx-2 Polymorphism in the Promoter Region of the Human Vitamin D Receptor Gene Determines Susceptibility to Fracture in the Elderly

A Cdx‐2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A‐allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism.

Vitamin D Status, Bone Mineral Density, and the Development of Radiographic Osteoarthritis of the Knee: The Rotterdam Study

Objective:To study the association between baseline vitamin D status, bone mineral density (BMD), and the development of radiographic osteoarthritis (ROA) of the knee in a large population-based cohort of men and women. Methods:A sample of 1248 subjects (728 women and 520 men) was drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. At baseline, vitamin D dietary intake was determined, and BMD and 25-hydroxy vitamin D (25(OH)D) serum levels were measured. After a mean follow-up time of 6.5 years incidence and progression of knee ROA of was assessed. Results:The mean vitamin D intake in our study population was 64 IU/d and the mean 25(OH)D level 66 nmol/L. Vitamin D levels were associated with baseline BMD, particularly in subjects with baseline knee ROA. Progressive ROA occurred in 5.1% of the participants in the highest tertile of vitamin D intake against 12.6% in the lowest tertile, resulting in an adjusted odds ratio of 7.7 (95% CI: 1.3–43.5). Both intake and levels of 25(OH)D were not significantly related to incident ROA. However, we found a significant interaction between vitamin D intake and BMD in the association with incident knee ROA (P = 0.03): in subjects with low lumbar spine BMD at baseline we observe an increasing incidence of knee ROA with decreasing vitamin D intake and serum levels. Conclusions:Low dietary vitamin D intake increases the risk of progression of knee ROA. Particularly in subjects with low baseline BMD, vitamin D status seems to influence the incidence and progression of knee ROA. Thus, improving the vitamin D status in the elderly could protect against the development and worsening of knee OA, especially in those with low BMD.

The role of vitamin D receptor gene polymorphisms in bone biology

The role of vitamin D and its receptor (VDR) in skeletal metabolism is well known but the vitamin D endocrine system seems to play an important role in other metabolic pathways as well, such as those involved in osteoarthritis, the immune response and cancer. One approach to understand the vitamin D endocrine system is to study the influence of variations in the DNA sequence of important proteins of this system. For example, deleterious mutations in the VDR gene cause 1,25-dihydroxyvitamin D-resistant rickets, a rare monogenetic disease. More subtle sequence variations (polymorphisms) in the VDR gene occur much more frequently but their effects are poorly understood. Their influence on the vitamin D endocrine system is currently under scrutiny in relation to a number of so-called complex diseases and traits such as osteoporosis. The interpretation of polymorphic variations in the VDR gene is severely hindered by the fact that several of the polymorphisms used have unknown effects. However, current data indicate that dozens of additional polymorphic variations exist in the VDR gene that could each have different types of consequences. Therefore, efforts are focussed on finding novel sequence variations and to study their interaction in molecular- and cell-biological experiments as well as in genomic epidemiological studies. The ultimate goal of this approach is to identify the combinations of functional sequence variants that modulate the vitamin D endocrine system and confer risk of disease.

25-Hydroxyvitamin D and osteoarthritis: A meta-analysis including new data

OBJECTIVES To study the relationship between 25-hydroxy (OH) vitamin D serum levels and osteoarthritis (OA) of the knee, hip, and hand in a meta-analysis, with updated and expanded results of our previous study. METHODS Pubmed was searched from February 1975 to December 2014 for articles assessing the relationship between vitamin D levels and OA. In our meta-analysis, 6 cross-sectional and 6 longitudinal studies were included. The number of subjects in these studies ranged from 99 to 1248 subjects. The latter 1248 subjects (58% women) were drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. At baseline, 25(OH) vitamin D serum levels were measured and prevalent OA of knees, hips and hands was scored by the Kellgren-Lawrence grading system. After a mean follow-up time was 8.4 years, incidence and progression of OA were assessed. RESULTS No clear association between vitamin serum levels and prevalent, incident or progressive knee, hip or hand OA was observed. The quality of most studies was low, and the results were conflicting. Meta-analysis of 3 cross-sectional studies on vitamin D levels and knee joint space narrowing (JSN) showed an increased risk of prevalent JSN with decreasing vitamin D levels (OR = 1.52, 95% CI: 1.15-2.01). The association observed in the meta-analysis of 3 studies on low vitamin D levels and incident and progressive knee OA was not significant (OR = 1.37, 95% CI: 0.97-1.92); however, when considering solely progressive knee OA, the risk was significantly increased (OR = 2.40, 95% CI: 1.22-4.72). CONCLUSIONS Epidemiological studies do not provide evidence of an independent association between 25(OH) vitamin D serum levels with hip or hand OA. When analyzing subgroups of knee OA, significant associations of low vitamin D levels with prevalent knee JSN and with progressive knee OA were observed. Overall, the results of this study do not support the advice to supplement vitamin D to prevent the onset or worsening of osteoarthritis, except perhaps for progressive knee OA.

Are bone mineral density and fractures related to the incidence and progression of radiographic osteoarthritis of the knee, hip and hand in elderly men and women? the rotterdam study

To examine the longitudinal relationship between bone mineral density (BMD) and the incidence and progression of knee, hip, and hand osteoarthritis (OA), and to examine the relationship between prevalent vertebral and nonvertebral fractures and the incidence and progression of OA in elderly men and women in the Rotterdam Study.

Varus Alignment Was Associated with an Increased Risk of Osteoarthritis of the Knee

Question: Is malalignment associated with the development of osteoarthritis of the knee? Design: Cohort population-based study. Setting: Rotterdam, The Netherlands. Patients: 1501 participants (3002 knees) ≥55 years of age (mean age, 66 y; 60% women) were randomly selected from 3585 participants who completed 6.6 years of follow-up. Of the 3002 knees, 2664 had legible radiographs. Assessment of risk factors: Knees were categorized as having normal alignment (medial angle formed by the femur and tibia [FT angle] = 182° to 184°), varus alignment (FT angle 184°). Main outcome measures: Osteoarthritis of the knee (confirmed by Kellgren-Lawrence radiographic score). Two readers who were blinded to the clinical status of patients assessed the radiographs of the knee. Main results: At baseline, 2290 knees showed no osteoarthritis (Kellgren-Lawrence score 184°) were at higher risk for the development of osteoarthritis of the knee.