Bisphosphonates: Mechanism of Action and Role in Clinical Practice
2008; Elsevier BV; Volume: 83; Issue: 9 Linguagem: Inglês
10.4065/83.9.1032
ISSN1942-5546
AutoresMatthew T. Drake, B.L. Clarke, Sundeep Khosla,
Tópico(s)Radiopharmaceutical Chemistry and Applications
ResumoBisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. In addition to currently approved uses, bisphosphonates are commonly prescribed for prevention and treatment of a variety of other skeletal conditions, such as low bone density and osteogenesis imperfecta. However, the recent recognition that bisphosphonate use is associated with pathologic conditions including osteonecrosis of the jaw has sharpened the level of scrutiny of the current widespread use of bisphosphonate therapy. Using the key words bisphosphonate and clinical practice in a PubMed literature search from January 1, 1998, to May 1, 2008, we review current understanding of the mechanisms by which bisphosphonates exert their effects on osteoclasts, discuss the role of bisphosphonates in clinical practice, and highlight some areas of concern associated with bisphosphonate use. Bisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. In addition to currently approved uses, bisphosphonates are commonly prescribed for prevention and treatment of a variety of other skeletal conditions, such as low bone density and osteogenesis imperfecta. However, the recent recognition that bisphosphonate use is associated with pathologic conditions including osteonecrosis of the jaw has sharpened the level of scrutiny of the current widespread use of bisphosphonate therapy. Using the key words bisphosphonate and clinical practice in a PubMed literature search from January 1, 1998, to May 1, 2008, we review current understanding of the mechanisms by which bisphosphonates exert their effects on osteoclasts, discuss the role of bisphosphonates in clinical practice, and highlight some areas of concern associated with bisphosphonate use. Since their introduction to clinical practice more than 3 decades ago, bisphosphonates have been increasingly used for an array of skeletal disorders. Bisphosphonates are now used to treat such varied conditions as heritable skeletal disorders in children, postmenopausal and glucocorticoid-induced osteoporosis (GIO), and bone metastases in patients with malignancies. Bisphosphonates can offer substantial clinical benefit in conditions in which an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption underlies disease pathology; however, the more recently recognized association of bisphosphonate use with pathologic conditions, including low bone turnover states with resultant pathologic fractures, osteonecrosis of the jaw (ONJ), and an increased incidence of atrial fibrillation, has brought increased scrutiny to the current broad use of bisphosphonate therapy. PubMed literature from January 1, 1998, to May 1, 2008, was reviewed using bisphosphonate and clinical practice as search terms. Additional articles not obtained in the primary search were identified by assessment of literature referenced in the reviewed articles. We present data on the development of bisphosphonates as therapeutic agents, the proposed mechanisms by which these agents exert their effects, and the current roles for bisphosphonate therapy in clinical practice. Additionally, we address some areas of concern for clinicians and draw attention to some currently unresolved issues associated with bisphosphonate use. Structurally, bisphosphonates are chemically stable derivatives of inorganic pyrophosphate (PPi), a naturally occurring compound in which 2 phosphate groups are linked by esterification (Figure 1, A). Within humans, PPi is released as a by-product of many of the body's synthetic reactions; thus, it can be readily detected in many tissues, including blood and urine.1Russell RG Bisphosphonates: from bench to bedside.Ann N Y Acad Sci. 2006; 1068: 367-401Crossref PubMed Scopus (155) Google Scholar Pioneering studies from the 1960s demonstrated that PPi was capable of inhibiting calcification by binding to hydroxyapatite crystals, leading to the hypothesis that regulation of PPi levels could be the mechanism by which bone mineralization is regulated.2Fleisch H Russell RG Straumann F Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis.Nature. 1966; 212: 901-903Crossref PubMed Scopus (132) Google Scholar Like their natural analogue PPi, bisphosphonates have a very high affinity for bone mineral because they bind to hydroxyapatite crystals. Accordingly, bisphosphonate skeletal retention depends on availability of hydroxyapatite binding sites. Bisphosphonates are preferentially incorporated into sites of active bone remodeling, as commonly occurs in conditions characterized by accelerated skeletal turnover. Bisphosphonate not retained in the skeleton is rapidly cleared from the circulation by renal excretion. In addition to their ability to inhibit calcification, bisphosphonates inhibit hydroxyapatite breakdown, thereby effectively suppressing bone resorption.3Russell RG Muhlbauer RC Bisaz S Williams DA Fleisch H The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats.Calcif Tissue Res. 1970; 6: 183-196Crossref PubMed Scopus (94) Google Scholar This fundamental property of bisphosphonates has led to their utility as clinical agents. More recently, it has been suggested that bisphosphonates also function to limit both osteoblast and osteocyte apoptosis.4Plotkin LI Weinstein RS Parfitt AM Roberson PK Manolagas SC Bellido T Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin.J Clin Invest. 1999; 104: 1363-1374Crossref PubMed Google Scholar, 5Plotkin LI Aguirre JI Kousteni S Manolagas SC Bellido T Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation.J Biol Chem. 2005 Feb 25; 280 (Epub 2004 Dec 6.): 7317-7325Crossref PubMed Scopus (112) Google Scholar The relative importance of this function for bisphosphonate activity is currently unclear. Modification of the chemical structure of bisphosphonates has widened the differences between the effective bisphosphonate concentrations needed for antiresorptive activity relative to those that inhibit bone matrix mineralization, making the circulating concentrations of all bisphosphonates currently used in clinical practice active essentially only for the inhibition of skeletal resorption.1Russell RG Bisphosphonates: from bench to bedside.Ann N Y Acad Sci. 2006; 1068: 367-401Crossref PubMed Scopus (155) Google Scholar As shown in Figure 1, A, the core structure of bisphosphonates differs only slightly from PPi in that bisphosphonates contain a central nonhydrolyzable carbon; the phosphate groups flanking this central carbon are maintained. As detailed in Figure 1, B, and distinct from PPi, nearly all bisphosphonates in current clinical use also have a hydroxyl group attached to the central carbon (termed the R1 position). The flanking phosphate groups provide bisphosphonates with a strong affinity for hydroxyapatite crystals in bone (and are also seen in PPi), whereas the hydroxyl motif further increases a bisphosphonate's ability to bind calcium. Collectively, the phosphate and hydroxyl groups create a tertiary rather than a binary interaction between the bisphosphonate and the bone matrix, giving bisphosphonates their remarkable specificity for bone.1Russell RG Bisphosphonates: from bench to bedside.Ann N Y Acad Sci. 2006; 1068: 367-401Crossref PubMed Scopus (155) Google Scholar Although the phosphate and hydroxyl groups are essential for bisphosphonate affinity for bone matrix, the final structural moiety (in the R2 position) bound to the central carbon is the primary determinant of a bisphosphonate's potency for inhibition of bone resorption. The presence of a nitrogen or amino group increases the bisphosphonate's antiresorptive potency by 10 to 10,000 relative to early non-nitrogen-containing bisphosphonates, such as etidronate.1Russell RG Bisphosphonates: from bench to bedside.Ann N Y Acad Sci. 2006; 1068: 367-401Crossref PubMed Scopus (155) Google Scholar, 6Dunford JE Thompson K Coxon FP et al.Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.J Pharmacol Exp Ther. 2001; 296: 235-242PubMed Google Scholar Recent studies (described subsequently) delineate the molecular mechanism by which nitrogen-containing bisphosphonates inhibit osteoclast activity. A critical pharmacological feature of all bisphosphonates is their extremely high affinity for, and consequent deposition into, bone relative to other tissues. This high affinity for bone mineral allows bisphosphonates to achieve a high local concentration throughout the entire skeleton. Accordingly, bisphosphonates have become the primary therapy for skeletal disorders characterized by excessive or imbalanced skeletal remodeling, in which osteoclast and osteoblast activities are not tightly coupled, leading to excessive osteoclast-mediated bone resorption. Early non-nitrogen-containing bisphosphonates (etidronate, clodronate, and tiludronate) (Figure 1, B) are considered first-generation bisphosphonates. Because of their close structural similarity to PPi, non-nitrogen-containing bisphosphonates become incorporated into molecules of newly formed adenosine triphosphate (ATP) by the class II aminoacyl-transfer RNA synthetases after osteoclast-mediated uptake from the bone mineral surface.1Russell RG Bisphosphonates: from bench to bedside.Ann N Y Acad Sci. 2006; 1068: 367-401Crossref PubMed Scopus (155) Google Scholar Intracellular accumulation of these nonhydrolyzable ATP analogues is believed to be cytotoxic to osteoclasts because they inhibit multiple ATP-dependent cellular processes, leading to osteoclast apoptosis. Unlike early bisphosphonates, second- and third-generation bisphosphonates (alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid) have nitrogen-containing R2 side chains (Figure 1, C). The mechanism by which nitrogen-containing bisphosphonates promote osteoclast apoptosis is distinct from that of the non-nitrogen-containing bisphosphonates. As elegantly illustrated in recent studies, nitrogen-containing bisphosphonates bind to and inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway critical to the production of cholesterol, other sterols, and isoprenoid lipids6Dunford JE Thompson K Coxon FP et al.Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.J Pharmacol Exp Ther. 2001; 296: 235-242PubMed Google Scholar, 7Kavanagh KL Guo K Dunford JE et al.The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.Proc Natl Acad Sci U S A. 2006 May 16; 103 (Epub 2006 May 9.): 7829-7834Crossref PubMed Scopus (221) Google Scholar (Figure 2, A). As such, the posttranslational modification (isoprenylation) of proteins (including the small guanosine triphosphate-binding proteins Rab, Rac, and Rho, which play central roles in the regulation of core osteoclast cellular activities including stress fiber assembly, membrane ruffling, and survival) is inhibited,8Hall A Rho GTPases and the actin cytoskeleton.Science. 1998; 279: 509-514Crossref PubMed Scopus (4020) Google Scholar ultimately leading to osteoclast apoptosis.9Luckman SP Hughes DE Coxon FP Graham R Russell G Rogers MJ Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras.J Bone Miner Res. 1998; 13: 581-589Crossref PubMed Scopus (758) Google Scholar Interestingly, whereas farnesyl pyrophosphate synthase is ubiquitously expressed in mammalian cells and has a critical role in lipid production, cellular apoptosis induced by nitrogen-containing bisphosphonates appears to occur only in osteoclasts. This is likely a direct function of the ability of bisphosphonates to selectively adhere to and be retained within bone before endocytosis within osteoclasts during osteoclast-mediated bone mineral dissolution and matrix digestion (Figure 2, B). Given the fact that nearly all patients now receive treatment with the more potent nitrogen-containing bisphosphonates rather than the earlier non-nitrogen-containing bisphosphonates, the remainder of this review focuses on this more recent class of bisphosphonates. Although bisphosphonate-mediated induction of osteoclast apoptosis cannot be measured directly within the clinical setting, a temporal reduction in biochemical markers of bone resorption (namely amino- and carboxyl-terminal breakdown products of type 1 collagen in serum and urine) after bisphosphonate initiation is considered a reasonably reliable surrogate of bisphosphonate efficacy and potency. Maximum suppression of bone resorption occurs within approximately 3 months of initiation of oral bisphosphonate therapy given daily, weekly, or monthly and remains roughly constant with continuation of treatment.10Rizzoli R Greenspan SL Bone GIII Alendronate Once-Weekly Study Group et al.Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis.J Bone Miner Res. 2002; 17: 1988-1996Crossref PubMed Google Scholar, 11Brown JP Kendler DL McClung MR et al.The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis.Calcif Tissue Int. 2002 Aug; 71 (Epub 2002 Jun 27.): 103-111Crossref PubMed Scopus (244) Google Scholar, 12Cremers SC Pillai G Papapoulos SE Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis.Clin Pharmacokinet. 2005; 44: 551-570Crossref PubMed Scopus (92) Google Scholar Resorption is suppressed more rapidly after intravenous (IV) bisphosphonate administration than after oral bisphosphonate therapy. As might be anticipated, length of suppression is largely a function of bisphosphonate potency for mineral matrix binding, such that the most potent bisphosphonate, zoledronic acid, at a dose of either 4 mg13Reid IR Brown JP Burckhardt P et al.Intravenous zoledronic acid in postmenopausal women with low bone mineral density.N Engl J Med. 2002; 346: 653-661Crossref PubMed Scopus (565) Google Scholar or 5 mg (the dose approved by the Food and Drug Administration [FDA] for osteoporosis),14Black DM Delmas PD Eastell R HORIZON Pivotal Fracture Trial et al.Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.N Engl J Med. 2007; 356: 1809-1822Crossref PubMed Scopus (1040) Google Scholar effectively suppresses biochemical markers of bone resorption for up to 1 year in women with postmenopausal osteoporosis. Although the precise biologic half-lives of the currently used nitrogen-containing bisphosphonates remain the subject of debate largely because of technical challenges required to determine bisphosphonate levels in urine and serum, estimates for the potent bisphosphonate alendronate suggest a biologic half-life of more than 10 years after single-dose IV administration.15Khan SA Kanis JA Vasikaran S et al.Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis.J Bone Miner Res. 1997; 12: 1700-1707Crossref PubMed Scopus (140) Google Scholar A critical feature governing the clinical pharmacology of bisphosphonates is their bioavailability. As a class, bisphosphonates are very hydrophilic. Accordingly, they are poorly absorbed from the gastrointestinal tract after oral administration (generally with absorption of <1% for an oral dose), instead undergoing paracellular transport because they are not lipophilic.16Lin JH Bisphosphonates: a review of their pharmacokinetic properties.Bone. 1996; 18: 75-85Abstract Full Text PDF PubMed Scopus (466) Google Scholar Further, only about 50% of the absorbed drug is selectively retained in the skeleton, whereas the remainder is eliminated in the urine without being metabolized. Skeletal uptake and retention are primarily dependent on host factors (renal function, prevalent rate of bone turnover, and binding site availability) and bisphosphonate potency for bone matrix.12Cremers SC Pillai G Papapoulos SE Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis.Clin Pharmacokinet. 2005; 44: 551-570Crossref PubMed Scopus (92) Google Scholar The amount of bisphosphonate retained after either oral or IV administration varies widely both between patients and across clinical conditions and is primarily believed to reflect variations in bone turnover.12Cremers SC Pillai G Papapoulos SE Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis.Clin Pharmacokinet. 2005; 44: 551-570Crossref PubMed Scopus (92) Google Scholar A previous impediment for many patients prescribed oral bisphosphonate therapy was the inconvenience associated with daily oral administration (requiring patients to remain upright for 30 minutes and refrain from eating any food both 2 hours before and at least 30 minutes after pill ingestion) and the relatively common association with gastrointestinal symptoms. The more recent development of pharmacologically equivalent preparations allowing for once-weekly (alendronate or risedronate) or even monthly (ibandronate or risedronate) oral administration has profoundly affected bisphosphonate delivery for most patients for whom convenience (and thus adherence to therapy) was an issue and has correspondingly lead to higher rates of adherence.17Penning-van Beest FJ Goettsch WG Erkens JA Herings RM Determinants of persistence with bisphosphonates: a study in women with postmenopausal osteoporosis.Clin Ther. 2006; 28: 236-242Abstract Full Text PDF PubMed Scopus (80) Google Scholar, 18Rossini M Bianchi G Di Munno O Osteoporosis in Clinical Practice (TOP) Study Group et al.Determinants of adherence to osteoporosis treatment in clinical practice.Osteoporos Int. 2006; 17 (Epub 2006 Mar 15.): 914-921Crossref PubMed Scopus (160) Google Scholar Further, the availability of IV preparations (pamidronate, ibandronate, and zoledronic acid), which for most clinical conditions require even less frequent dosing, has eliminated the gastrointestinal adverse effects incurred by some patients managed with oral bisphosphonates, although the rate of acute phase reactions characterized by flulike symptoms (low-grade fever, myalgias and arthralgias, or headache) is increased in patients receiving IV rather than oral bisphosphonate treatment.14Black DM Delmas PD Eastell R HORIZON Pivotal Fracture Trial et al.Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.N Engl J Med. 2007; 356: 1809-1822Crossref PubMed Scopus (1040) Google Scholar As aforementioned, bisphosphonates promote the apoptosis of osteoclasts actively engaged in the degradation of mineral on the bone surface. Accordingly, bisphosphonates have become the primary therapy for managing skeletal conditions characterized by increased osteoclast-mediated bone resorption. Such excessive resorption underlies several pathologic conditions for which bisphosphonates are now commonly used, including multiple forms of osteoporosis (juvenile, postmenopausal or involutional [senile], glucocorticoid-induced, transplant-induced, immobility-induced, and androgen-deprivation-related), Paget disease of bone, osteogenesis imperfecta (OI), hypercalcemia, and malignancy metastatic to bone. Although each of the nitrogen-containing bisphosphonates is more potent than the non-nitrogen-containing bisphosphonates, their ability to suppress osteoclast activity (as measured by biochemical markers of bone turnover) varies. However, whether superior suppression of bone turnover is relevant for fracture prevention remains to be determined. Indeed, data suggest that adherence to long-term bisphosphonate therapy, rather than the specific bisphosphonate used, is the most important factor in determining the effectiveness of treatment for limiting fracture risk.19Yood RA Emani S Reed JI Lewis BE Charpentier M Lydick E Compliance with pharmacologic therapy for osteoporosis.Osteoporos Int. 2003 Dec; 14 (Epub 2003 Sep 19.): 965-968Crossref PubMed Scopus (153) Google Scholar, 20Siris ES Harris ST Rosen CJ et al.Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases.Mayo Clin Proc. 2006; 81: 1013-1022Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar Accordingly, studies examining bisphosphonate therapy adherence suggest that, by addressing patient concerns of medication safety and timing, clinicians can significantly improve adherence.21Carr AJ Thompson PW Cooper C Factors associated with adherence and persistence to bisphosphonate therapy in osteoporosis: a cross-sectional survey.Osteoporos Int. 2006; 17 (Epub 2006 Aug 1.): 1638-1644Crossref PubMed Scopus (61) Google Scholar Whether weekly or monthly oral bisphosphonate dosing leads to higher rates of adherence to therapy is currently unknown. The most common clinical condition for which bisphosphonate therapy is used is osteoporosis, a skeletal condition characterized by compromised bone strength resulting in an increased risk of fracture. As previously noted, osteoporosis is a clinically heterogeneous disease with a range of origins, including hormone loss (postmenopausal and androgen-deprivation), iatrogenic (glucocorticoid-induced and transplant-related), physical (immobility), and genetic (eg, juvenile and OI-associated). Often these conditions overlap within individual patients. Postmenopausal osteoporosis is characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation such that bone resorption is increased. This relative imbalance leads to diminution of skeletal mass, deterioration of bone microarchitecture, and increased fracture risk. During the past 2 decades, bisphosphonate therapy has become the leading clinical intervention for postmenopausal osteoporosis because of the ability of bisphosphonates to selectively suppress osteoclast activity and thereby retard bone resorption. The fracture reduction and concomitant increases in bone density generally seen with bisphosphonate use are believed to result from a decline in the activation frequency of new remodeling units formed by osteoclasts, with relative preservation (at least initially) of osteoblast activity. As such, the initial stabilization and retention of trabecular connectivity allow the duration of secondary mineral deposition on the structural scaffold to be prolonged, thereby increasing the percentage of bone structural units that reach a maximum degree of mineralization.22Boivin GY Chavassieux PM Santora AC Yates J Meunier PJ Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women.Bone. 2000; 27: 687-694Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar This increase in the mean degree of skeletal mineralization underlies both improvements in bone density and reductions in fracture risk after bisphosphonate therapy. Importantly, this role for bisphosphonates was indirectly buttressed by the early termination of the estrogen and progesterone arm of the Women's Health Initiative (WHI), because of concern about increased rates of coronary artery disease and breast cancer among women receiving hormonal therapy. For most practitioners and patients, the WHI results effectively limited the practice of treating postmenopausal osteoporosis with hormone replacement therapy, despite the strong evidence provided in the WHI and previous studies that estrogen is highly effective in preventing fractures.23Rossouw JE Anderson GL Prentice RL Writing Group for the Women's Health Initiative Investigators et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Google Scholar Among the oral bisphosphonates, both alendronate and risedronate have been conclusively demonstrated to reduce the number of vertebral24Black DM Cummings SR Karpf DB Fracture Intervention Trial Research Group et al.Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.Lancet. 1996; 348: 1535-1541Abstract Full Text Full Text PDF PubMed Scopus (2435) Google Scholar, 25Cummings SR Black DM Thompson DE et al.Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.JAMA. 1998; 280: 2077-2082Crossref PubMed Scopus (1503) Google Scholar, 26Harris ST Watts NB Genant HK Vertebral Efficacy With Risedronate Therapy (VERT) Study Group et al.Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial.JAMA. 1999; 282: 1344-1352Crossref PubMed Scopus (1636) Google Scholar and hip fractures,24Black DM Cummings SR Karpf DB Fracture Intervention Trial Research Group et al.Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.Lancet. 1996; 348: 1535-1541Abstract Full Text Full Text PDF PubMed Scopus (2435) Google Scholar, 27McClung MR Geusens P Miller PD Hip Intervention Program Study Group et al.Effect of risedronate on the risk of hip fracture in elderly women.N Engl J Med. 2001; 344: 333-340Crossref PubMed Scopus (1290) Google Scholar progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.28Liberman UA Weiss SR Broll J Alendronate Phase III Osteoporosis Treatment Study Group et al.Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis.N Engl J Med. 1995; 333: 1437-1443Crossref PubMed Scopus (1704) Google Scholar Ibandronate, developed more recently and available in both oral and IV preparations, has been demonstrated to reduce only the risk of vertebral fracture,29Delmas PD Recker RR Chesnut III, CH et al.Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study.Osteoporos Int. 2004 Oct; 15 (Epub 2004 Apr 8.): 792-798Crossref PubMed Scopus (179) Google Scholar, 30Chesnut III, IC Skag A Christiansen C Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) et al.Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.J Bone Miner Res. 2004 Aug; 19 (Epub 2004 Mar 29.): 1241-1249Crossref PubMed Scopus (659) Google Scholar although the sample size estimates used did not allow sufficient power to detect an effect on nonvertebral or hip fractures. The relative fracture risk reduction in vertebral, hip, and nonvertebral sites in postmenopausal women with known osteoporosis after 3 years of bisphosphonate treatment is compared in the Table.TABLE 1Relative Risk Reduction for Vertebral, Hip, or Nonvertebral Fractures in Postmenopausal Women With Known Osteoporosis After 3 Years of Daily Oral Bisphosphonate TreatmentaNS = not significant.BisphosphonateType of fractureRisedronate26Harris ST Watts NB Genant HK Vertebral Efficacy With Risedronate Therapy (VERT) Study Group et al.Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial.JAMA. 1999; 282: 1344-1352Crossref PubMed Scopus (1636) Google Scholar, 27McClung MR Geusens P Miller PD Hip Intervention Program Study Group et al.Effect of risedronate on the risk of hip fracture in elderly women.N Engl J Med. 2001; 344: 333-340Crossref PubMed Scopus (1290) Google ScholarAlendronate24Black DM Cummings SR Karpf DB Fracture Intervention Trial Research Group et al.Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.Lancet. 1996; 348: 1535-1541Abstract Full Text Full Text PDF PubMed Scopus (2435) Google ScholarIbandronate30Chesnut III, IC Skag A Christiansen C Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) et al.Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.J Bone Miner Res. 2004 Aug; 19 (Epub 2004 Mar 29.): 1241-1249Crossref PubMed Scopus (659) Google ScholarVertebral414762Hip4051NSNonvertebral3920NSa NS = not significant. Open table in a new tab Reductions in fracture incidence occur before demonstrable changes (measured by dual-energy x-ray absorptiometry [DXA]) in bone mineral density (BMD), suggesting that stabilization of existing skeletal microarchitecture or decreased bone turnover is sufficient for fracture risk reduction.31Riggs BL Melton III, LJ Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density [editorial].J Bone Miner Res. 2002; 17: 11-14Crossref PubMed Google Scholar Daily alendronate use at doses of 10 mg for up t
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