Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

Background-Matrix metalloproteinases (MMPs) are critically involved in the development of unstable plaques. Although arteriosclerotic lesions in patients with diabetes mellitus are more unstable than those of nondiabetic subjects, nothing is known about serum levels of MMPs in these patients or about mechanisms to modulate MMP levels. We investigated MMP levels in diabetic and nondiabetic coronary artery disease (CAD) patients and performed a clinical trial to assess the effect of the PPAR␥-activating, antidiabetic thiazolidinedione rosiglitazone on MMP levels in diabetic CAD patients. Methods and Results-In CAD patients, MMP-2, -8, and -9 serum levels were significantly higher in type 2 diabetic subjects compared with age-, sex-, and body mass index-matched nondiabetics. Thirty-nine diabetic patients with CAD were randomized to receive rosiglitazone 4 mg (twice daily) or placebo for 12 weeks. Rosiglitazone treatment, but not placebo, significantly reduced MMP-9 levels already after 2 weeks by Ϫ19.6% (Ϫ38.3% to 8.6%, PϽ0.05), and levels remained suppressed until the end of the study. In addition, rosiglitazone significantly decreased serum amyloid A (SAA) and tumor necrosis factor-␣ levels. Conclusion-MMP-9 levels are increased in type 2 diabetic patients with CAD, and treatment of these patients with the antidiabetic PPAR␥-activator rosiglitazone significantly reduces MMP-9, tumor necrosis factor-␣, and SAA serum levels. These data support anti-inflammatory and potential antiatherogenic effects of thiazolidinediones.

Background-Interaction of CD40L with its receptor CD40 is critically involved in inflammatory cell activation in atherogenesis. In addition, serum levels of soluble CD40L are elevated in acute coronary syndromes and have been associated with increased cardiovascular risk in healthy subjects, thus making sCD40L an intriguing target to modulate the inflammatory response in the vasculature. PPAR␥-activating thiazolidinediones, novel insulin-sensitizing antidiabetic agents, have recently been shown to exhibit antiinflammatory effects in the vessel wall. To examine whether thiazolidinedione treatment might modulate serum levels of sCD40L in high-risk patients, we performed a randomized, placebo-controlled, single-blinded trial to assess the effect of rosiglitazone on sCD40L levels in patients with type 2 diabetes and coronary artery disease (CAD). Methods and Results-Thirty-nine patients with diabetes and angiographically proven CAD were randomized to receive rosiglitazone (4 mg BID) or placebo for 12 weeks. Baseline parameters did not significantly differ between groups. Rosiglitazone treatment, but not placebo, significantly reduced sCD40L serum levels within the first 2 weeks by 8. Interaction of the multipotent immunomodulator CD40 ligand (CD40L or CD154) with its receptor CD40 has emerged as an important contributor to this inflammatory process in the vessel wall. CD40 and CD40L are expressed on endothelial cells, vascular smooth muscle cells, mononuclear cells, and platelets, and CD40 -CD40L interaction has been shown to exhibit proinflammatory and proatherogenic effects in vitro and in vivo. 3,4 In addition to the cell-associated form, CD40L also exists in a soluble, biologically active form (sCD40L), which has similar proinflammatory effects on vascular cells. 5 Interestingly, sCD40L is associated with acute coronary syndromes 6 as well as hypercholesterolemia, 7 and elevated sCD40L levels predict an increased cardiovascular risk in healthy subjects. 8 Therefore, CD40L has been suggested as a potential therapeutical target to modulate vascular inflammation and possibly influence cardiovascular risk. However, limited studies exist on such a counterbalancing mechanism, with conflicting data on the role of statins in sCD40L lowering. 7,9 Still, nothing is known about sCD40L levels in patients with diabetes or about mechanisms to modulate sCD40L levels in this high-risk group.Recent experimental data suggest that a novel group of antidiabetic agents, thiazolidinediones (TZDs; glitazones), like rosiglitazone or pioglitazone, might-in addition to their metabolic effects-exhibit antiinflammatory properties in the vessel wall. These agents, used clinically to treat patients with type 2 diabetes mellitus, act via the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR␥), thus regulating the expression of various target Therefore, we performed a randomized, placebo-controlled trial to examine the effect of rosiglitazone treatment on sCD40L serum levels in patients with type 2 diabetes a...