LAUSR

We read with much interest the article by Sing and colleagues recently published in the Journal. The authors used propensityscore matching to evaluate the risk of cardiovascular (CV) mortality and CV events in amino-bisphosphonate (N-BP) users in a retrospective cohort of patients with newly diagnosed hip fracture. Alendronate treatment was associated with a 67% reduction in the risk of CVmortality and 45% reduction in the risk of myocardial infarction (MI). Similar results were obtainedwhen all N-BP user data were analyzed together. Other cohort studies have reported that alendronate significantly decreases in a dose-dependent fashion the risk of CV events in patients with severe osteoporosis (MI HR 0.35; 95% CI, 0.14 to 0.84; p1⁄4 0.02; stroke HR 0.79; 95% CI, 0.66 to 0.99; p1⁄4 0.005). Patients with osteoporosis and fragility fractures are at increased risk of CV events, such as MI and stroke, than the general population. Recently, during the phase III trial of romosozumab, an antisclerostin humanized monoclonal antibody, there were more adjudicated serious CV adverse events in the romosozumab group than in the alendronate group. Inhibition of sclerostin could potentially alter vascular remodeling, but another possibility is that the comparison drug, alendronate, is cardioprotective. The physiopathology of decreased CV risk associated with NBP is poorly understood. Several potential mechanisms have been investigated, including reduction of serum low-density lipoproteins, halting of plaque formation, inhibition of vascular calcifications, and changes in circulating proinflammatory cytokines. We recently observed that N-BP may have anti-inflammatory and steroid-sparing properties in patients with polymyalgia rheumatica, a common inflammatory disorder. Some years ago our group showed that N-BP could have an immunomodulatory effect on circulating gamma-delta (gd) T cells. In particular, we observed that the number of circulating gd T cells is an important determinant of the occurrence of acute-phase response (APR) and the release of proinflammatory cytokines such as IFN-g and TNF-a after N-BP administration, and that N-BP treatment is associated with a decrease in circulating gd T cells for at least 1 year. This may explain the lower incidence of APR in patients previously exposed to N-BPs, but other clinical implications of this sustained effect of N-BPs on these immuneregulatory cells might also be important. To date, only a few studies have addressed the role of gd T cells in atherosclerosis despite their identification in human atherosclerotic lesions. Nonetheless, gdT cells have been shown to induce apoptosis in cardiac myocytes; they can accumulate in the aortic valve under certain inflammatory stimuli; and they have been found in the proximal aorta of hypercholesteremic mice, where they can promote atherosclerotic lesion progression. Several reports are in keeping with this scenario: gd T cells contribute to the pathogenesis of rheumatoid arthritis (RA), a chronic immune-mediated inflammatory disease characterized by a high CV risk that is strongly modulated by changes in inflammation. The use of N-BP has been associated with reduced risk of MI in RA. Although these very preliminary data need to be confirmed in more robust studies, we hypothesize that the reduction of CV risk in patients exposed to N-BP could be related to an antiinflammatory modulation of gd T cells. We believe further research should be undertaken to elucidate the relationship between gd T cells, N-BP treatment, and CV risk.