CORRELATION OF VITAMIN D DEFICIENCY AND SUB-CLINICAL OSTEOMALACIA IN AXIAL SPONDYLOARTHROPATHY

* Parminder Virdi 1 , Baljeet Singh 2 , Maninder Kaur 3 and Baldish Singh Oberoi 4 . 1. Senior Resident, Department of Orthopedics, Sri Guru Ram Dass institute of medical sciences and research, Amritsar, India. 2. Professor, Department of Orthopedics, Sri Guru Ram Dass institute of medical sciences and research, Amritsar, India. 3. Senior resident, Medicine Department, Sri Guru Ram Dass Institute of Medical Sciences, Amritsar, India. 4. Graduate N.K.P. Salve institute of medical sciences, India. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History


Results:-
Findings among patients and control subjects:-Patients and controls were well matched for age, gender and daily sun exposure time in two groups. 71(83%)of axSpA patients were HLAB27 positive with a wide variety of disease duration (median date: 3.0, 0.25-20 years). The disease activity ASDAS-CRP were with median scores 2.28, (0.11~5.95), and CRP with median value 5.2, (0.2-847 99.1) mg/L. The bone resorption biomarker sCTX, formation markers OC and ALP in axSpA patients were significantly higher than controls (Table 1). Though no significant difference was observed between the two groups, there were higher adjusted serum calcium and raised PTH in axSpA patients than control (Table 1). Table 1:-Characteristics of the axSpA and healthy controls study population. axSpA: Axial Spondyloarthritis; BMD: Bone Mineral Density; PTH: Parathyroid Hormone; ALP: Alkaline Phosphatase; P1NP: N-amino terminal propeptide of type I collagen; CTX: CrossLaps of type I collagen cross-linked C-telopeptide; OC: Osteocalcin; LS: Lumber Spine Vitamin D levels in axSpA patients and controls: Vitamin D levels in axSpA patients were significantly lower than the control group (p<0.001). However, there were no significant differences with serum calcium, phosphorus and PTH between two groups (Table-2). Femoral BMD T-scores in axSpA patients and controls:-There were higher proportions of osteopenia and osteoporosis in axSpA patients than controls. The femoral neck T and Z scores in axSpA patients were significantly lower than control (Table 3)

Correlation between femoral BMD T-scores and other variables in axSpA patients:
The femoral BMD T-scores were inversely correlated to the disease duration, ASDAS-CRP, spinal stiffness and ALP (

Correlation between vitamin D and other disease variables:
In axSpA patients vitamin D levels were inversely related to the disease duration ( Figure 1A) and positively correlated to daily sunlight exposure time and calcium levels ( Figures 1B and 1C).   Table 5:-Correlation between serum ALP and disease activity, bone biomarkers, BMD in axSpA patients. ASASendorsed disease activity score (ASDAS), osteocalcin (OC), serum C-telopeptides of type collagen (sCTX) were significantly positively correlated whereas femoral BMD Z-score was negatively correlated in axSpA patients.

Discussion:-
Vitamin D deficiency is not only a problem in India but also in countries like Pakistan, China, middle-East and Africa. It is relatively less common in Japan, USA, Canada and South-east Asia [8]. There was a disbelief that Vitamin D (Vit D) deficiency is uncommon in India, however from the data available in the published literature, Vit D deficiency is very common in India in all the age groups and both sex across the country [8]. Furthermore, other cross-sectional studies also describe vitamin D deficiency is prevalent across many urban Indian residents [9]. Evidence also showed that patients with vitamin D deficiency may have an increased risk of immune-mediated inflammatory diseases including AS [10], with further inflammatory activity in SpA patients indirectly linked with vitamin D deficiency and predisposition to the development of osteoporosis, which can be considered as early phase of osteomalacia. Furthermore, some studies also revealed that low plasma levels of serum 25(OH)D were presented in AS patients when compared to healthy control [11,12]. Our study showed 25(OH)D was significantly lower in axSpA patients (25.06 ± 10.06 ng/ml) compared to borderline to the normal level (34.90 ± 12.57 ng/ml) in the control group, consistent with the previous study of Baskan et al. [13]. In our axSpA patients, serum 25(OH)D levels found normal levels in 26 (28%), insufficient in 34 (36%), and deficient in 30 (32%) and severely deficient in 4 (4%) compared with a distribution in healthy controls of 45 (61%), 20 (27%), 8 (11%) and 1 (1%) respectively. Taken together, data suggests that Vitamin D insufficiency is present in axSpA patients from north Indian population.
Recent bone biopsy studies from Germany have shown that as 25(OH)D levels falling below 30 ng/ml suggests rising prevalence of osteomalacia [14]. Furthermore, hypovitaminosis D can lead to hypocalcemia and then elevated PTH level. However, in the early phases of osteomalacia biochemicals such as calcium, phosphate and soluble phosphatase are released in serum because of a low 25(OH)D level, may be lacking due to compensatory changes conversely the PTH may be lifted and it lead to decalcification of the skeleton . AS patients are associated with low vitamin D in serum concentrations are linked with higher disease activity [15]. Although vitamin D concentrations were not associated with higher disease activity in our study, vitamin D levels were significantly lower in axSpA patients. Furthermore, AS patients with osteoporosis it has been shown that the levels of PTH are significantly elevated [13]. In our study axSpA patients serum level of PTH was elevated but not significantly different when compared with healthy control. However, vitamin D levels were inversely related to the disease duration and levels of PTH (Figure 1), which may be due to alteration in vitamin D metabolism and increased bone resorption of prolonged duration. The hypovitaminosis D complicated by secondary hyperparathyroidism is associated with significantly decreased bone mineral density.
The accurate method of detecting osteopenia and osteoporosis may be provided by the measurement of BMD at the femoral neck. Despite the most solid analytic test for osteomalacia is the bone biopsy, Cosman et al. have demonstrated, two decades ago, that significant correlations between histological estimation BMD of the spine and proximal femur in patients with different metabolic bone diseases including osteomalacia [16]. Intriguingly, in our axSpA patients the frequencies of osteopenia and osteoporosis were significantly higher than controls (40% vs 26%, and 9% vs 0) respectively. Consistently, Karberg et al. found that the proportion of osteoporotic patients varies according to the disease duration of AS. In patients with disease duration <5 years, 11% and 15% were osteoporotic at the hip; in patients with disease duration >10 years, 29% were osteoporotic at the hip is assessed by DXA scan. The previous study showed that serum bone formation marker OC and resorption markers sCTX seem to be valuable markers to detect bone loss in AS patients [17]. Interestingly in our axSpA patients serum level of OC and sCTX 850 was significantly increased when compared to healthy control. Besides BMD T/Z-score has significant differences between axSpA patients and healthy control group, furthermore, axSPA patients femoral and lumbar BMD Z-scores were negatively correlated with active inflammatory marker such as CRP, ESR and disease activity ASDAS, bone turnover marker sCTX and OC (Table 4). Consistently, the acute phase reactant ESR and CRP was significantly elevated and inversely correlated with vitamin D levels in AS patients [13], disease activity ASDAS was negatively correlated with BMD because of vitamin D receptor gene may contribute to BMD differences in patients with AS, as gene polymorphisms are also linked to inflammatory activity [18]. Thus, osteoporotic risk may be significantly increased with raised serum levels of bone turnover markers and low levels of vitamin D. Previous study also has shown that the relationship between vitamin D with CRP and ESR, were significantly negatively correlated [19]. In addition, axSpA patients femoral BMD T/Z-score was negatively correlated with ALP, spinal stiffness and BMI. Furthermore, previous study found that serum alkaline phosphates is a sensitive screening tool for the diagnosis of osteomalacia. Hence, these parameters may specify the reasons of early bone loss in axSpA patients and potential immunomodulatory role of vitamin D to prevent osteomalacia in axSpA during active disease condition. In our observational study, axSpA patients had shown lower 25(OH)D levels below 30 ng/ml and higher bone turnover biomarkers than control and net effects of 25(OH)D on bone structure BMD in axSpA are due to vitamin D deficiency and disease activities.
Plasma ALP activity appears to be a sensitive single test in the past which acceptably predicts the presence or absence of histological osteomalacia [20]. We found that the ALP levels were significantly correlated with ASDAS-CRP and bone turnover biomarkers. So increased serum ALP levels were associated with high disease activity, low BMD and higher structural damage scores in axSpA patients. Serum ALP levels does not only reflect the disease activity but also associated with BMD. Our finding is consistent with an earlier result. Serum ALP levels may be a useful marker for predicting bone-related complications such as osteomalacia in axSpA patients. Interestingly, our current study also found that the plasma levels of vitamin D in the axSpA group were significantly lower than control group. Bone resorption biomarker sCTX, bone formation markers OC and ALP were significantly higher in axSpA group than controls. Furthermore, in axSpA patients vitamin D levels were inversely related to the disease duration and positively correlated to daily sunlight exposure time and calcium levels. Consistently, ALP levels significantly correlated with ASDAS-CRP, OC, sCTX), inversely related to the femoral BMD T scores in axSpA patients. Taken together, our data indicate that low Vitamin D levels may lead to subclinical osteomalacia in axSpA patients which is associated with increased PTH and ALP levels, higher bone turnover biomarkers sCTX and OC, low BMD. This evidence shows that axSpA patients may be associated with high rate of development of subclinical osteomalacia.
Limitations:-Limitations of this study are the small number of patients of axSPA. Although, all recruited cases in our study were diagnosed cases of axSPA without any infection and other bone diseases history. We did not perform bone biopsy to confirm the chemical osteomalacia. Low levels of vitamin D can also be found in other conditions including acute myocardial infarction, heart failure, chronic kidney disease, diabetes and infections. However, these conditions are unlikely to be developed in axSpA patients and no evidence was found in our cases.

Conclusion:-
There were significantly lower vitamin D levels in Indian axSpA patients compared to a control group. axSpA patients with low vitamin D, increased PTH and serum ALP levels, higher bone turnover biomarkers sCTX and OC, low BMD indicated that subclinical biochemical osteomalacia is associated with most axSpA patients.