CLINICIAN’S CORNER Bisphosphonate treatment: An orthodontic concern calling for a proactive approach James J. Zahrowski Tustin, Calif The purpose of this article is to raise awareness among orthodontists of the effects of bisphosphonates, a commonly prescribed type of drug that can inhibit tooth movement and increase serious osteonecrosis risks in the alveolar bones of the maxilla and the mandible. Common medical uses of bisphosphonates, applicable pharmacology, pharmacokinetics, reports of impaired bone healing and induced osteonecrosis, and a drug effect accumulation theory are reviewed. Potential orthodontic issues and proposed orthodontic recommen- dations for intravenous and oral bisphosphonate treatments are discussed. Bisphosphonate medication screening, patient counseling, informed consent, and, perhaps, changes in treatment planning might be considered. (Am J Orthod Dentofacial Orthop 2007;131:311-20) isphosphonates are drugs used to treat bone biphosphonates are up to 12 times greater than from metabolism disorders such as osteoporosis, oral uses.1,3 This higher drug level greatly decreases Bbone diseases, and bone pain from some types bone turnover to limit bone destruction, fractures, of cancer. Because bisphosphonates work by inhibiting hypercalcemia, and pain from multiple myeloma and bone resorption by osteoclasts, they can have side might decrease bone formation to slow cancers from effects in dental treatment, including inhibited tooth metastasizing into the bone.4,5 These bisphosphonates movement, impaired bone healing, and induced osteo- have been given to children for osteoporotic or lytic necrosis in the maxilla and the mandible. As orthodon- bone conditions such as osteogenesis imperfecta, fi- tists, we need to know the pharmacology of drugs that brous dysplasia, juvenile or glucocorticoid osteoporo- can change bone physiology because they can hinder sis, and Gaucher’s disease.6 treatment and increase morbidity. These effects could Alendronate, risedronate, and ibandronate are com- mean additional patient counseling is needed, along monly administered orally to treat osteoporosis and with informed consent, enhanced monitoring tech- osteopenia in peri- and postmenopausal women.1 Os- niques, reporting of side effects, and, perhaps, changes teoporosis affects 8 million women and 2 million men in treatment planning. in the United States. Osteoporosis is defined as bone Bisphosphonate types include alendronate (Fosa- density of 2.5 SD below the mean or the presence of a max and Fosamax Plus D, Merck, Whitehouse Station, fragility fracture.7,8 Osteopenia is bone density between NJ) tablets; etidronate (Didronel, Procter & Gamble, 1 and 2.5 SD below the mean.8 At least 1.5 million Cincinnati, Ohio) tablets and intravenous (IV); ibandr- bone fractures occur each year in the United States onate (Boniva, Roche, Basel, Switzerland) tablets and from osteoporosis. Vertebral, thoracic, pelvic, hip, and IV; pamidronate (Aredia, Novartis, Basel, Switzerland) humerus fractures are associated with long-term mor- IV; risedronate (Actonel, Procter & Gamble, Cincin- bidity and sometimes mortality. Oral bisphosphonates nati, Ohio) tablets; tiludronate (Skelid, Sanofi-Aventis, have been shown to decrease fractures up to 50%.7 Paris, France) tablets; and zoledronic acid (Zometa, Nitrogen-containing bisphosphonates can cause esoph- Novartis, Basel, Switzerland) IV.1,2 agitis and limit their oral use if not taken properly.9 Bisphosphonates are administered intravenously to In 2005, alendronate was the 15th most commonly treat severe medical conditions such as multiple my- prescribed drug, with approximately 18 million pre- eloma, bone metastases of various cancers, hypercalce- scriptions, and risedronate was 37th, with almost 10 mia, and severe Paget’s disease.1 Systemic levels of million prescriptions.10 A 40% increase in the use of risedronate for the treatment of osteoporosis has oc- Private practice, Tustin, Calif. curred since 2003.11 Reprint requests to: James J. Zahrowski, 13372 Newport Ave, #E, Tustin, CA 92780; e-mail, [email protected]. Submitted, June 2006; revised and accepted, September 2006. PHARMACOLOGY OF BISPHOSPHONATES 0889-5406/$32.00 Copyright © 2007 by the American Association of Orthodontists. Bisphosphonates, analogues of inorganic pyrophos- doi:10.1016/j.ajodo.2006.09.035 phates, have a high affinity to calcium and are targeted 311 312 Zahrowski American Journal of Orthodontics and Dentofacial Orthopedics March 2007 to areas of bone turnover having preferential uptake on thetase and geranylgeranyl pyrophosphatase in the the exposed hydroxyapatite actively undergoing bone mevalonate pathway responsible for the prenylation of resorption.12,13 small GTP-binding proteins that are responsible for The major action of bisphosphonates is to decrease cytoskeletal integrity and intracellular signaling.12,14 the resorption of bone by directly inhibiting osteoclastic Bisphosphonates might also prevent osteoclast activat- activity.2 The antiresorption effect on bone is mediated ing factors, such as receptor activator of nuclear factor by intracellular uptake of the drug, which decreases KB ligand (RANKL), the primary mediator of oste- osteoclastic cell function.12,14 The antiresorptive action oclastic differentiation, activation, and survival.21 His- to bone is the premise for the lower doses of oral tologically, the osteoclasts lose their ruffled borders, bisphosphonate used to treat osteoporosis.7,9 This anti- become inactive, and undergo programmed cellular resorption action was also demonstrated with acute IV death, or apoptosis.12,14 pamidronate administration to rats over 5 days to Tooth movement was decreased by 40% after decrease bone resorption and increase bone formation administration of subcutaneous bisphosphonate was by 20% to 30% during osseous distraction of the given every other day for 3 weeks in rats.25 After a mandible.15 After 6 to 12 months of oral bisphospho- single dose of IV pamidronate during tooth movement, nate administration, a clinical improvement of peri- fewer osteoclasts were observed in the alveolar bone odontal disease occurred.16,17 An expected decrease in next to the periodontal ligament.26 Histologic degener- N-telopeptide, a bone marker for resorption, and an ative structural changes, such as loss of ruffled borders, increase in bone mineral density were found after 6 were observed in osteoclasts and attributed to loss of months of oral bisphosphonates.16 At 2 years of oral function.26 It appears that a decrease in osteoclastic bisphosphonate treatment, periodontal patients showed activity occurs early in the bisphosphonate accumula- improvement compared with controls.18 tion effect and can be observed as decreased tooth Other articles discuss the complex mechanisms of movement. bone regulation and metabolism that are not included Bisphosphonates have antiangiogenic properties here.19,20 that inhibit endothelial proliferation and decrease cap- As bisphosphonates are given in higher, more illary formation.27,28 The high concentrations of potent IV doses for longer periods of time, osteoclastic bisphosphonates in bone were sufficient to have anti- activity becomes much decreased. Hence, these drugs angiogenic properties.27 In alveolar bone, overaccumu- are used to treat severe bone disorders such as multiple lation of bisphosphonates might cause lack of capillary myeloma and bone metastases from other can- formation and decreased blood flow, and contribute to cers.1,5,21,22 IV pamidronate given to stage 4 breast the avascular condition in osteonecrosis.22 Because of cancer patients showed decreases in bone pain and the short half-life of the drug in the plasma, it is healing of lytic bone lesions, whereas the bone-specific unlikely that the low transient levels found in soft alkaline phosphatase, a marker of bone formation, tissues (noncalcified) affect endothelial proliferation.27 decreased by 41%.23 During the oral alendronate phase In patients taking long-term bisphosphonates, it appears III clinical trials for osteoporosis, after 3 years, a that we should be concerned about possible decreased decrease in bone formation was found based on bio- blood flow during new bone formation. chemical bone markers.24 When bisphosphonates are given long term, it was suggested that, when osteoclas- PHARMACOKINETICS OF BISPHOSPHONATES tic activity decreases sufficiently, decreased osteoblas- Pharmacokinetics is the study of a drug’s action tic activity might follow, caused by the coupling effect in the human body, including absorption, distribution through intercellular mediators. into tissues, metabolism, and elimination.29 The relative potencies of osteoclastic inhibition for Bioavailability is the fraction of the drug that bisphosphonates are etidronate, 1; tiludronate, 10; pam- reaches systemic circulation after oral intake, and it idronate, 100; alendronate, 100-1000; risedronate, 1000- depends on the amount absorbed and the amount that 10,000; ibandronate, 1000-10,000; and zoledronic acid, escapes the first-pass liver metabolism.29 The bioavail- 10,000ϩ.2 The chemical structures of bisphosphonates ability of oral bisphosphonates is very low, usually less and the different nitrogen side groups that determine than 2%; that of a standard IV dose is 100%.2,29 The potency have been known for many years.9 Nitrogen in drugs are poorly absorbed in the upper portion of the the side groups, especially a cyclic nitrogen group, has a small intestine because of their low lipophilicity, which major role to