Long-Term Treatment and Effect of Discontinuation of Calcifediol in Postmenopausal Women with Vitamin D Deficiency: A Randomized Trial.

Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short-term clinical trials, its effects after long-term monthly administration have been studied less extensively. This report describes the results of a 1-year, phase III-IV, double-blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention-to-treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment-related safety issues were reported in any of the groups. The results confirm that long-term treatment with monthly calcifediol in vitamin D-deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long-term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial.

Vitamin D has shown to play a role in multiple diseases due to its skeletal and extraskeletal actions. Furthermore, vitamin D deficiency has become a worldwide health issue. Few supplementation guidelines mention calcifediol treatment, despite being the direct precursor of calcitriol and the biomarker of vitamin D status. This 1-year, phase III-IV, double-blind, randomized, controlled, multicenter clinical trial assessed the efficacy and safety of calcifediol 0.266 mg soft capsules in vitamin D-deficient postmenopausal women, compared to cholecalciferol. Results reported here are from a prespecified interim analysis, for the evaluation of the study's primary endpoint: the percentage of patients with serum 25-hydroxyvitamin D (25(OH)D) levels above 30 ng/ml after 4 months. A total of 303 patients were enrolled, of whom 298 were included in the intention-to-treat (ITT) population. Patients with baseline levels of serum 25(OH)D <20 ng/ml were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months, calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months, and cholecalciferol 25,000 IU/month for 12 months. At month 4, 35.0% of postmenopausal women treated with calcifediol and 8.2% of those treated with cholecalciferol reached serum 25(OH)D levels above 30 ng/ml (p < 0.0001). The most remarkable difference between both drugs in terms of mean change in serum 25(OH)D levels was observed after the first month of treatment (mean ± standard deviation change = 9.7 ± 6.7 and 5.1 ± 3.5 ng/ml in patients treated with calcifediol and cholecalciferol, respectively). No relevant treatment-related safety issues were reported in any of the groups studied. These results thus confirm that calcifediol is effective, faster, and more potent than cholecalciferol in raising serum 25(OH)D levels and is a valuable option for the treatment of vitamin D deficiency. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The role of endothelial function and its assessment in rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population, largely attributable to cardiovascular disease. Factors that contribute to this increased cardiovascular risk include traditional risk factors, which account for only part of the excess, along with manifestations of the disease itself. RA is characterized by inflammation, which also is a key component in the development of atherosclerosis. Inflammation leads to the activation of endothelial cells, which, through an increase in the expression of leukocyte adhesion molecules, promotes a pro-atherosclerotic environment. Endothelial dysfunction is an early preclinical marker of atherosclerosis, and is commonly found in patients with RA. Several methods are available for the assessment of endothelial function, such as flow-mediated dilatation and laser Doppler flowmetry combined with iontophoresis, each with its own advantages and limitations. Studies have shown that endothelial dysfunction in RA is closely associated with inflammation, and therapeutic reduction of inflammation leads to improvements in endothelial function. As such, assessments of endothelial function could prove to be useful tools in the identification and monitoring of cardiovascular risk in patients with RA. Given the increase in cardiovascular mortality associated with RA, effective management must involve prevention of cardiovascular risk, in addition to control of disease activity and inflammation.

Clinical improvement in rheumatoid arthritis is associated with healthier microvascular function in patients who respond to antirheumatic therapy.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) mortality. Microvascular endothelial dysfunction occurs early in the development of CV disease and is worsened by inflammation. The effect of drug treatment for RA on microvascular function has been poorly studied. We assessed the effect of antirheumatic treatment on microvascular endothelial function in patients with RA, particularly to examine responders versus nonresponders to therapy. METHODS: Fifty-one patients with active RA and no previous history of CV disease were assessed at baseline and after 2 and 4 months' therapy with either anti-tumor necrosis factor-alpha drugs (etanercept, n = 27, adalimumab, n = 3) or methotrexate, n = 21. RA disease activity, inflammatory measures, and skin microvascular responses, measured using laser Doppler imaging after iontophoretic delivery of acetylcholine (ACh) and sodium nitroprusside (SNP), were assessed at each study visit. RESULTS: Disease Activity Score (DAS28) decreased significantly from baseline to visit 2 and 3 (6.04 +/- 1.2, 4.34 +/- 1.3, 4 +/- 1.3, respectively; p < 0.0001). Endothelium-dependent (ACh) and independent (SNP) responses for the whole cohort did not improve significantly after drug treatment (p = 0.250, p = 0.062, respectively). When patients who responded to antirheumatic therapy (n = 31) were analyzed, there were significant improvements in both ACh (p = 0.028) and SNP responses (p = 0.019). CONCLUSION: Microvascular endothelial function improves in patients who respond to antirheumatic therapy. These results support the importance of effective therapy for RA patients in terms of CV effects, which might extrapolate to reduced CV events in the future. Clinical trial registration no. ISRCTN57761809.

Etanercept improves inflammation-associated arterial stiffness in rheumatoid arthritis.

OBJECTIVES: Increased arterial stiffness, an independent risk factor for premature coronary artery disease, has been reported in patients with RA. The objectives of this study were first to assess, in patients with RA, the relationship between disease activity, inflammation and augmentation index, which is a combined measure of arterial stiffness and pulse wave reflection. The second objective was to establish any effect anti-rheumatic treatment may have on augmentation index. METHODS: One hundred and forty-eight RA patients with no previous history of cardiovascular disease (CVD) had their augmentation index corrected for a heart rate of 75 beats per minute (AIx@75), and parameters of RA disease activity and CV risk measured. Forty-seven patients were then treated with either MTX (n = 21) or etanercept (ETAN) (n = 26), and assessments were repeated at 2 and 4 months. RESULTS: Patients with high CRP (> 10 mg/l) showed significantly higher mean AIx@75 than those with low CRP (< or = 10 mg/l) (33 +/- 8 vs 30 +/- 8%; P = 0.033). On regression analysis, log(10) CRP (beta = 0.298; P = 0.002), gender (beta = 0.257; P = 0.007), BMI (beta = -0.292; P = 0.004), diastolic blood pressure (beta = 0.260; P = 0.009) and age (beta = 0.194; P = 0.046) were independently associated with AIx@75. Treatment with ETAN (35 +/- 9, 32.5 +/- 1 and 32.5 +/- 8%; P = 0.025) but not MTX (31 +/- 1, 31 +/- 1 and 31 +/- 1%; P = 0.971) attenuated the AIx@75 significantly from baseline to Visits 2 and 3. CONCLUSIONS: Systemic inflammation (CRP) is an independent predictor of arterial stiffness and pulse wave reflection in patients with RA. ETAN but not MTX therapy reduces arterial stiffness and pulse wave reflection and may thus improve CV morbidity in RA.