Effect of Combined Treatment With Bisphosphonate and Vitamin D on Atherosclerosis in Patients With Systemic Lupus Erythematosus

A Propensity Score-Based Analysis

Kazumasa Ohmura; Masaru Kato; Toshiyuki Watanabe; Kenji Oku; Toshiyuki Bohgaki; Tetsuya Horita; Shinsuke Yasuda; Yoichi M. Ito; Norihiro Sato; Tatsuya Atsumi


Arthritis Res Ther. 2018;20(72) 

In This Article


To our knowledge, this is the first study to demonstrate that the combination of BP + VD has a potential to retard atherosclerosis in patients with SLE. Our data also showed that BMD correlated negatively with IMT in patients with SLE, as previously reported.[10] Atherosclerosis in SLE could be affected not only by traditional risk factors but also by SLE-related risk factors, such as duration of disease, duration of glucocorticoid use, disease activity, antiphospholipid antibodies, and renal manifestations.[1] Statins have been shown to prevent atherosclerosis in the general population by lowering low-density lipoprotein cholesterol levels and by multiple off-target effects, such as anti-inflammation and proliferation.[11] A prospective randomized trial in 200 patients with SLE, however, failed to show the anti-atherosclerotic effect of the statins, indicating that statins alone may not be sufficient to prevent atherosclerosis in SLE.[12]

Bisphosphonates are expected to inhibit arterial plaque development and calcification through several mechanisms.[13] Nitrogen-containing bisphosphonates and statins inhibit the mevalonate pathway through interaction with farnesyl pyrophosphate synthase to prevent post-translational modification of proteins, resulting in decreased levels of inflammatory cytokines and matrix metalloproteinases.[14,15] Bisphosphonates also decrease a variety of mature vascular cells, which migrate into the vessel walls and injure vascular endothelial cells.[16,17] A clinical trial with elderly osteoporotic women, however, did not show an anti-atherosclerotic effect of ibandronate.[18] A systematic review and meta-analysis recently performed by Kranenburg et al.[19] demonstrated the effect of bisphosphonates on reduction in arterial wall calcification. Of note, treatment with statins in combination with bisphosphonates was more effective in terms of reducing atherosclerotic plaque compared with either monotherapy in patients with hypercholesterolemia,[20] indicating the additive anti-atherosclerotic effect of bisphosphonates with statin therapy.

Vitamin D deficiency is emerging as a novel risk factor for CVD.[5] Vitamin D has been shown to protect endothelial cells from oxidative stress and subsequent apoptosis. Low levels of 25-dehydroxyvitamin D were associated with increased cardiovascular events, whereas the effect of vitamin D supplementation to prevent CVD is now under investigation.[21] Although Vitamin D has been shown to improve SLE disease activity,[22] a prospective randomized trial with 114 postmenopausal women did not demonstrate an anti-atherosclerotic effect of vitamin D.[23] Conversely, Robinson et al.[24] demonstrated that vitamin D status may determine the effect of statin on carotid IMT in juvenile SLE.

Based on these findings, we hypothesized that the combined treatment using bisphosphonates and vitamin D may be more effective compared with bisphosphonate or vitamin D alone in the prevention of atherosclerosis. Furthermore, combination BP + VD is commonly indicated in the treatment of SLE, since most patients require adequate anti-osteoporotic treatment during long-term glucocorticoid use. Subsequently, several issues arise concerning anti-resorptive therapy, including the duration of BP use due to concern about atypical femoral fractures, and the timing of switching to denosumab, teriparatide or other agents due to inadequate efficacy.

This study has some limitations. First, this was a cross-sectional single-center retrospective study in Japanese patients only. As with all retrospective study design, anti-osteoporotic drugs were selected according to the physicians' decision, leading to potential bias in grouping. Although propensity scoring was used to minimize the effect of other confounding factors, further prospective multicenter studies and randomized controlled trials are needed to confirm the results of this analysis. Second, serological data on biomarkers associated with osteoporosis, such as vitamin D status, inflammatory cytokine levels, parathyroid hormone and homocysteine, were not available, due to the absence of measurements. The daily calcium intake also could not be calculated due to the absence of data on supplementation and eating habits. Additional laboratory testing may better elucidate the interplay of specific biomarkers in both osteoporosis and atherosclerosis. Third, at least theoretically, the anti-atherosclerotic effect of a triple combination of statins, bisphosphonates and vitamin D may be more promising but was not well-evaluated herein due to the relatively small sample size. The prevalence of statin use was not different in patients with and without carotid plaques (Table 2).