Table I.
Calcium metabolism in ankylosing spondylitis patients and in healthy subjects – main studies of calcium supplementation in ankylosing spondylitis
| Calcium metabolism | Healthy subjects | Ankylosing spondylitis patients | Main results of preclinical or clinical studies on calcium metabolism in ankylosing spondylitis | In favor of calcium supplementation in ankylosing spondylitis patients | |
|---|---|---|---|---|---|
| Preclinical models and human laboratory studies | Clinical studies | ||||
| Extracellular calcium concentration | Within the range 1.1–1.3 mmol/l, ionized form | Usually within the range 1.1–1.3 mmol/l, ionized form | – | Normal corrected calcemia in AS and RA patients and hypercalcemia in subjects with polymyalgia rheumatica (Bontoux et al. [25] 1979; case control study) No significant differences in serum calcium levels between AS patients and controls (Cai et al. [26] 2015; meta-analysis) Higher serum calcium levels in AS patients with urolithiasis compared to those without (Gönüllü et al. [58] 2017; prospective case control study) |
No |
| Intracellular calcium concentration | Within the normal range (100 nM) and tightly controlled | Increased in immune cells where it presides over the activation of pro-inflammatory pathways | Enhanced intracellular calcium entrance in neutrophils of AS patients, prevented by treatment with infliximab (Ugan et al. [30] 2016) Anti-inflammatory properties of blockade of IKCa1 lymphocyte potassium channels, which regulate calcium influx in CD4+ and CD8+ T cells of AS patients (Toldi et al. [31] 2016) Loss of physiological intracellular calcium oscillations in peripheral monocytes of patients with SpA (especially AS) compared to controls; possible association with differentiation towards activated phenotypes (Moz et al. [29] 2020) |
– | No |
| Calcium intestinal absorption | 15–30% of the dietary intake, mediated by either active or passive absorption | Reduced in patients with inflammatory bowel diseases, dysbiosis and gut subclinical inflammation | Reduced colonic expression of the L-type calcium channel Cav1.3 in trinitrobenzene sulfonic acid colitis mice; IFN-γ-induced transcriptional and posttranscriptional repression of the Cav1.3 gene in HCT116 cells (Radhakrishnan et al. [19] 2016) Downregulation in duodenal epithelial cells of TNFΔARE mice of the calcium transporters TRPV6, calbindin D9K and PMCA1b, associated with increased trabecular and cortical bone resorption (Huybers et al. [20] 2008) Reduction in colonic inflammation, intestinal permeability and diarrhea in HLA-B27 transgenic rats supplemented with high calcium doses for 7 weeks; reduced expression of mucosal IL-1β and increased expression of ECM remodeling genes in calcium-fed rats compared to controls (Schepens et al. [52] 2010) |
Lower calcium intake in IBD patients resulting from the 22-item quantitative validated frequency food questionnaire compared to controls; association with self-reported lactose intolerance (Vernia et al. [23] 2014; case control study) Higher calcium intake in non-IBD AS patients compared to controls measured through the semi-quantitative food frequency questionnaire (Soleimanifar et al. [24] 2018; case control study) | Yes |
| Calcium resorption from bone | Related to physiologic bone remodeling (about 20% of total bone mass) | Increased in response to pro-inflammatory cytokine secretion | Increased trabecular and cortical bone resorption observed on tomography scanning in TNFΔARE mice, presumably compensating calcium malabsorption or loss in the urinary tract; down-regulation of calbindin-D9K mRNA in bone (Huybers et al. [20] 2008) | Low BMD detected in 13% out of 332 recruited early SpA patients; significant association with inflammatory lesions in MRI, ESR and CRP values and male gender (Briot et al. [47] 2013; longitudinal prospective cohort study) Reduced spinal BMD in patients with nr-axSpA compared to subjects with mechanical low back pain; positive association between low spinal and femoral BMD and lumbar inflammatory findings in MRI in nr-axSpA individuals (Akgöl et al. [46] 2014; case control study) Lower cortical vBMD in radius and lower trabecular vBMD in tibia in AS patients compared to healthy controls detected on HR-pQCT; vertebral fractures associated with lower lumbar cortical vBMD and thinner cortical bone in radius and tibia; inverse correlation between mSASSS and trabecular vBMD in lumbar spine radius and tibia (Klingberg et al. [48] 2013; case control study) Reduced radius cortical vBMD in early nr-axSpA patients versus controls detected through HR-pQCT; lower trabecular vBMD in female gender (Neumann et al. [49] 2018; case control study) |
Yes |
| Calcium resorption from kidney | About 90% of calcium filtered | Unknown (kidney stones related to hypercalciuria?) | Down-regulation of the calcium transporters calbindin-D 28K and NCX1 in kidney epithelial cells of TNFΔARE mice, paralleled by increased trabecular and cortical bone resorption (Huybers et al. [20] 2008) | No difference in urinary calcium excretion between AS patients with and without nephrolithiasis (Rezvani et al. [56] 2018; retrospective cohort study) Renal stones diagnosed in 25% of AS patients versus 3.3% of healthy controls; positive association between the risk of renal stones and patients’ age, disease duration and hypercalciuria (Korkmaz et al. [57] 2005; case control study) No significant association between high urinary calcium excretion and risk of urolithiasis in AS patients (Gönüllü et al. [58] 2017; prospective case control study) |
No |
| Serum PTH levels | Within the range 10–60 pg/ml | Normal or higher | – | No significant differences in serum PTH levels between AS patients and controls (Cai et al. [26] 2015; meta-analysis) No significant differences in serum PTH levels between AS patients and controls; no association with the risk of urolithiasis (Gönüllü et al. [58] 2017; prospective case control study) Higher serum PTH levels in AS patients compared to controls; positive correlation with serum levels of DKK-1 (Orsolini et al. [43] 2018; case control study) Inverse correlation between serum PTH levels and AS disease activity, measured through ESR and CRP values and BASDAI scores (Lange et al. [27] 2001; case control study) Normal serum values of PTH in nr-axSpA patients compared to controls (Akgöl et al. [46] 2014; case control study) |
Yes |
| Serum 25(OH) vitamin D levels | Within the range 30–60 ng/ml | Reduced | – | Reduced serum level of 25(OH) vitamin D in AS patients compared to controls; significant association between lower 25(OH) vitamin D levels and higher ESR values (Cai et al. [26] 2015; meta-analysis) Normal values of serum 25(OH) vitamin D in nr-axSpA patients (Akgöl et al. [46] 2014; case control study) |
Yes |
| Serum 1,25(OH)2 vitamin D levels | Within the range 25–45 pg/ml | Within the range 25–45 pg/ml | – | Normal serum concentration of 1,25(OH)2 vitamin D in AS patients; inverse association with disease activity evaluated through ESR, serum CRP values and BASDAI scores (Cai et al. [26] 2015; meta-analysis) Negative association between serum 1,25(OH)2 vitamin D levels and AS disease activity, measured through ESR and CRP values and BASDAI scores; positive correlation with bone alkaline phosphatase (Lange et al. [27] 2001; case control study) |
No |
AS – ankylosing spondylitis, BASDAI – Bath ankylosing spondylitis disease activity index, BMD – bone mineral density, vBMD – volumetric BMD, CRP – C-reactive protein, ECM – extracellular matrix, ESR – erythrocyte sedimentation rate, HLA-B27 – human leukocyte antigen-B27, HRpQCT – high-resolution peripheral quantitative computed tomography, IBD – inflammatory bowel disease, IFN-γ – interferon-gamma, IL – interleukin, NCX1 – Na+/Ca2+ exchanger, PMCA1b – plasma membrane calcium-transporting ATPase 1b, PTH – parathyroid hormone, RA – rheumatoid arthritis, mSASSS – modified Stoke Ankylosing Spondylitis Spine Score, SpA – spondyloarthritis, nr-axSpA – non-radiographic axial spondyloarthritis, TNF – tumor necrosis factor, TRPV – transient receptors potential vanilloid calcium channel.