To the Editor:
The guest editorial “Current Controversies in Bisphosphonate Therapy” (32:473-475) describing the benefits of bisphosphonates on bone mass is misleading, if not erroneous.
Bisphosphonates do not increase bone mass, as Dr Kamath states. Bisphosphonates retard the osteoclast-induced resorption of bone, thereby lessening bone loss.
G. Richard Paul, MD
By blunting the effects of osteoclasts, bisphosphonates indirectly preserve bone mass through a net positive increase in bone production by osteoblasts. Therefore, the overall balance between bone breakdown and buildup is swung in favor of bone buildup, resulting in net positive bone balance1 or net positive bone mass.2 The therapeutic advances seen from first- to third-generation bisphosphonates are based largely on the potency and selectivity of bisphosphonates for the inhibition of bone resorption.3
While traditional understanding is that bisphosphonates affect osteoclasts, the mevalonate-associated mechanism of action of bisphosphonates is not specific to osteoclasts alone: as Morris and Einhorn4 note, it is unclear to what extent other cell lines are affected by bisphosphonates, and more studies need to be done to examine the potential osteogenic/anabolic effects of bisphosphonates. Preliminary data from basic science studies suggest bisphosphonates may play a more direct, anabolic role in osteoblast differentiation5-8 and may upregulate bone morphogenetic protein 2 production.2
While the antiresorptive benefits of bisphosphonates have been clearly established, time and further basic science/clinical studies will shed more light on the other mechanistic actions of bisphosphonates. Harnessing potential osteogenic effects of bisphosphonates may be clinically important.
Atul F. Kamath, MD
- Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest. 1996; 97(12):2692-2696.
- Shanbhag AS. Use of bisphosphonates to improve the durability of total joint replacements. J Am Acad Orthop Surg. 2006; 14(4):215-225.
- Lin JT, Lane JM. Bisphosphonates. J Am Acad Orthop Surg. 2003; 11(1):1-4.
- Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005; 87(7):1609-1618.
- Tsuchimoto M, Azuma Y, Higuchi O, et al. Alendronate modulates osteogenesis of human osteoblastic cells in vitro. Jpn J Pharmacol. 1994; 66(1):25-33.
- Giuliani N, Pedrazzoni M, Negri G, Passeri G, Impicciatore M, Girasole G. Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone. 1998; 22(5):455-461.
- Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS. Osteoblast proliferation and maturation by bisphosphonates. Biomaterials. 2004; 25(18):4105-4115.
- von Knoch F, Jaquiery C, Kowalsky M, et al. Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials. 2005; 26(34):6941-6949.