Long-Term Therapy for Postmenopausal Osteoporosis: Stronger Bones but Weaker Arteries?
To the Editor:
The intriguing article by Jono et al1 suggests that long-term supplementation with vitamin D for postmenopausal osteoporosis may increase vascular calcification. This is not a new concept2 and raises important and practical issues.
Alendronate, an inhibitor of osteoclast-mediated bone resorption, is widely promoted for the treatment and prevention of osteoporosis in postmenopausal women.3 This group of women is at higher risk for cardiovascular disease.4 Vascular calcification has many similarities to that of bone,2 and vascular wall macrophages may have both osteoblastic and osteoclastic potential.
Calcification alters the mechanical properties of the atherosclerotic plaque.5 It may lead to increased stress near the shoulder of the plaque, leading to rupture. On the other hand, extensive calcification and fibrosis may stabilize plaque.
Therefore, in addition to vitamin D supplementation, long-term therapy for postmenopausal osteoporosis with alendronate may lead to plaque instability and increased cardiovascular events in a population already at increased risk. Diligent postmarketing surveillance of this drug is necessary to monitor these issues.
It would be unfortunate to make bones stronger at the expense of making arteries weaker.
- Copyright © 1999 by American Heart Association
Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone–related peptide. Circulation. 1998;98:1302–1306.
Demer LL. A skeleton in the atherosclerosis closet. Circulation. 1995;92:2029–2032.
Fosamax (alendronate) [package insert]. West Point, Pa: Merck & Co; 1997.
Mosca L, Manson JE, Sutherland SE, Langer RD, Monolio T, Barrett-Connor E. Cardiovascular disease in women: a statement for healthcare professionals from the American Heart Association. Circulation. 1997;96:2468–2482.
Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, Ramberger J, Stanford W, White R, Taubert K. Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications: a statement for health professionals from the American Heart Association. Circulation. 1996;94:1175–1192.zke
We thank Dr Goldstein for his interesting comments on our recent article describing the mechanism of stimulatory effects of 1α,25-dihydroxyvitamin D3 on in vitro calcification by bovine vascular smooth muscle cells.R1 We agree with Dr Goldstein that long-term therapy for postmenopausal osteoporosis with bisphosphonates including alendronate may lead to plaque instability and cardiovascular events in a population already at increased risk. If calcium content of the calcified plaques is reduced by bisphosphonates, it is likely that the plaques may become more vulnerable to rupture. Because it has been speculated that the vessel is rendered less vulnerable to rupture only when extensive calcification has occurred, the early or intermediate stages of calcification may actually enhance plaque vulnerability.R2 Although there have been no reports concerning adverse events in patients with advanced coronary calcification due to use of bisphosphonates, cautious follow-up may be needed in such cases. However, the role of atherosclerotic calcification in plaque rupture remains unclear. Moreover, bisphosphonates exert both a physicochemical effect, inhibition of calcification, and a biological effect, inhibition of bone resorption. Although the doses required to produce the effect on bone resorption are 1000 times lower than those to inhibit calcification, the compounds may be concentrated in the arterial walls by long-term use of bisphosphonates and modulate arterial functions.R3
The other effect of bisphosphonates on arterial walls should be considered. Some compounds inhibit the development of atherosclerosis in experimental animals without any marked effect on cholesterol metabolism.R4 R5 Therefore, long-term therapy for postmenopausal osteoporosis with bisphosphonates may exert a preventive effect on atherogenesis, at least in a population without any evidence of cardiovascular disease. In any event, it is necessary to evaluate the long-term effect of alendronate on coronary atherosclerosis and calcification.
Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation. 1998;98:1302–1306.
Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, Rumberger J, Stanford W, White R, Taubert K. Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications: a statement for health professionals from the American Heart Association. Circulation.. 1996;94:1175–1192.
Kramsch DM, Aspen AJ, Rozler LJ. Atherosclerosis: prevention by agents not affecting abnormal levels of blood lipids. Science. 1981;213:1511–1512.