Chemical structure of etidronic acid (INN). Created using ACD/ChemSketch and Inkscape. (Photo credit: Wikipedia)
Diagram showing the origins of the main branches of the carotid arteries. (Photo credit: Wikipedia)
Larry H Bernstein, MD, FCAP, Reporter
Vascular Effects of Bisphosphonates—A Systematic Review
- Leyna L. Santos, Taciana B. Cavalcanti and Francisco A. Bandeira
Division of Endocrinology and Diabetes, Agamenon Magalhães Hospital, Ministry of Health, University of Pernambuco
Medical School, Recife, Brazil. Corresponding author email: leynaleite@yahoo.com.br
Abstract
Background: Osteoporosis and cardiovascular disease are interconnected entities with pathophysiological similarities. Bisphosphonates are therapeutic options available for resorptive bone diseases; however, experimental evidence has demonstrated a role for bisphosphonates in the inhibition of atherogenesis.
Methods: A systematic review of the vascular effects of bisphosphonates on atherosclerosis was performed. Vascular effects were evaluated by the thickening of the intima-media of carotid arteries and calcification of the coronary and aorta arteries. Electronic databases PubMed, The Cochrane Library, and Embase from January 1980 to May 2011 were searched.
Results: Of 169 potentially relevant articles, 9 clinical trials were selected. Two articles showed the benefit of the use of etidronate (−0.038 mm, P < 0.005) and alendronate (−0.025 mm, P < 0.05) on carotid artery intima-media thickening (CIMT) after one year.
One article found no changes associated with the use of alendronate. The use of risedronate was associated with a reduction of plaque score on the carotid arteries (decrease of 1% at 1 year, P = 0.015). Of those studies that evaluated the effect on coronary artery calcification (CAC), the results are conflicting: one study showed no changes with use of etidronate and in another, etidronate resulted in inhibition of the process of CAC after 1 year of follow-up (−372 mm3 in CAC score, P , 0.01). Three studies showed positive effects of etidronate on the aortic calcificaton (AC) score, showing no effect with use of ibandronate, and another showed a inhibition in the progression of the abdominal AC score with use of risendronate (P = 0.043).
Conclusion: Bisphosphonates seem to have an inhibitory effect on the atherosclerotic process; however, larger placebo-controlled
studies are needed to better clarify this issue.
Keywords: Bisphosphonates, osteoporosis, atherosclerosis, carotid IMT, aortic calcification
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Bisphosphonates were developed in the 19th century but were first investigated in the 1960s for use in disorders of bone metabolism. Their non-medical use was to soften water in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution of hydroxylapatite, the principal bone mineral, thus arresting bone loss. Only in the 1990s was their actual mechanism of action demonstrated with the initial launch of Fosamax (alendronate) by Merck & Co..
Fleisch H (2002). “Development of bisphosphonates”. Breast Cancer Res 4 (1): 30–4. doi:10.1186/bcr414. PMC 138713. PMID 11879557.
Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-CoA reductase pathway (also known as the mevalonate pathway)
^ van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S (November 2003). “Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates”. Bone 33 (5): 805–11.
http://upload.wikimedia.org/wikipedia/commons/3/39/HMG-CoA_reductase_pathway.png
The idea of preventing dissolution of hydroxyapetite was a naive notion based on no understanding of bone matrix remodeling, concerns we discussed in 1973 at the AFIP. The later notion linked to HMG-CoA-reductase has to be regarded in terms of the role of the osteoclast in removal of bone matrix. The relationship to loss of Ca++ in the subendothelium brings in a whole different perspective. The unintended loss of bone in the jaw of postmenopausal women is loss of membranous bone.