Rheumatology 2003;42:743749 doi:10.1093/rheumatology/keg205, available online at www.rheumatology.oupjournals.

org Advance Access publication 16 April 2003

Three-monthly ibandronate bolus injection offers favourable tolerability and sustained efcacy advantage over two years in established corticosteroid-induced osteoporosis
J. D. Ringe, A. Dorst, H. Faber, K. Ibach and J. Preuss
Objective. Corticosteroids are widely prescribed, although treatment-related sideeffects are common. Of these adverse events (AEs), osteoporosis is considered the most serious. Currently, oral bisphosphonates are the standard treatment for corticosteroid-induced osteoporosis (CIO). However, intermittent intravenous (i.v.) therapy may have advantages, including lack of gastrointestinal AEs, improved bioavailability and increased compliance. This study investigated the efcacy and safety of 3-monthly i.v. ibandronate bolus injections in patients with established CIO. The results from a planned 2-yr interim analysis are reported. Method. In this controlled, prospective, open-label, parallel-group study, 104 patients (49 men and 55 women) with established CIO (mean T-score < 22.5 S.D. at the lumbar spine (L2L4) received daily calcium (500 mg) plus either 3-monthly i.v. ibandronate (2 mg) bolus injections or oral daily alfacalcidol (1 mg). The primary end-point was bone mineral density (BMD) change at the lumbar spine, femoral neck and calcaneus after 24 months. Results. Compared with oral daily alfacalcidol, i.v. ibandronate produced signicantly superior gains in mean ("S.D.) BMD at the lumbar spine (2.2"3.1 vs 11.9"7.4%; P< 0.001), femoral neck (1.3"1.8 vs 4.7"4.0%; P< 0.001) and calcaneus (7.6"3.8 vs 15.5"10.7%; P< 0.0001) after 2 yr. Consistent with these BMD gains and, although the study was not powered for fractures, a trend towards a reduction in vertebral fractures and greater back pain relief was seen in the ibandronate group. The overall incidence of AEs was similar in the two treatment arms. Conclusions. Three-monthly i.v. ibandronate bolus injections are signicantly superior to alfacalcidol in the treatment of CIO. These data conrm the potential of ibandronate for the treatment of osteoporosis associated with corticosteroid use. The ease of administration, lack of AEs and good compliance associated with intermittent i.v. ibandronate make it a potentially valuable alternative to oral bisphosphonate therapy for the treatment of CIO.
KEY WORDS: Ibandronate, Bisphosphonate, Alfacalcidol, Corticosteroid-induced osteoporosis, Bone density, Fracture reduction.

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013

Corticosteroids are the rst treatment choice for a number of inammatory and autoimmune syndromes, including asthma, chronic obstructive pulmonary disease,

rheumatoid arthritis and inammatory bowel disease w1, 2x. The signicant benets of corticosteroids mean they have an essential role in clinical practice. However,

Medizinische Klinik IV, Klinikum Leverkusen, University of Cologne, Leverkusen, Germany. Submitted 4 February 2002; revised version accepted 22 November 2002. Correspondence to: J. D. Ringe, Medizinische Klinik IV, Klinikum Leverkusen, University of Cologne, 51375 Leverkusen, Germany. E-mail: ringe@klinikum-lev.de

743 Rheumatology 42 British Society for Rheumatology 2003; all rights reserved

744

J. D. Ringe et al.

treatment-related adverse effects (AEs) are frequent, the most serious and debilitating of which is bone loss that ultimately leads to increased fracture risk w39x. The signicant bone loss associated with corticosteroid therapy is the most frequent form of secondary osteoporosis in both men and women w10x. The prevalence of fractures associated with long-term (05 yr) corticosteroid use is approximately 3050% w6, 7, 11x. Of the various therapeutic options currently available for the treatment of corticosteroid-induced osteoporosis (CIO), the oral bisphosphonates have the most compelling data. These potent inhibitors of bone resorption have demonstrated signicant therapeutic benet in patients with CIO and, in addition, have few AEs w1216x. Notably, recent treatment guidelines from the American College of Rheumatology (ACR) recommend bisphosphonates as rst-line therapy in conjunction with calcium and vitamin D for preventing and treating CIO w17x. Although generally well tolerated, oral bisphosphonates, particularly those containing an amino group, can cause upper gastrointestinal (GI) AEs w1820x. To minimize these AEs and maximize the GI absorption of oral bisphosphonates (< 1%), stringent recommendations have been made regarding posture and the coadministration of medication, food and beverages. These recommendations could lead to poor adherence with therapy and therefore potentially jeopardize clinical outcome w2123x. A true-to-life retrospective study conducted in an osteoporosis clinic found that 17.2% of patients receiving oral bisphosphonate therapy were non-compliant with treatment as a result of either the complexity of the dosing recommendations or GI AEs w24x. Another factor contributing to reduced compliance is the requirement for intake of multiple daily medications w2527x. Several studies have demonstrated that compliance falls as the number of prescribed daily medications increases w2730x. Therefore, prescribing oral bisphosphonates to corticosteroid-treated patients, who may already receive a number of daily medications for their underlying disease, has the potential to decrease compliance. Consequently, when managing patients with CIO, physicians should consider prescribing the most infrequent, effective treatment. Ibandronate is a highly potent nitrogen-containing bisphosphonate that has demonstrated signicant activity in reducing bone turnover in both animal and clinical studies w3143x. To date, studies have demonstrated the efcacy and safety of ibandronate in patients with hypercalcaemia of malignancy w32, 38, 41x, metastatic bone disease w33x and postmenopausal osteoporosis (PMO) w39, 40, 43x. A clinically useful aspect of ibandronate is that it can be administered intermittently by bolus injection w43x. A placebo-controlled, randomized 1-yr dosending study investigated the efcacy and safety of 3-monthly intravenous (i.v.) ibandronate bolus injections in 125 postmenopausal women with osteoporosis w43x. Ibandronate 2 mg i.v. provided the most signicant

and sustained increase in bone mineral density (BMD) and the greatest reduction in bone turnover relative to placebo. Patients who received 2 mg i.v. ibandronate every 3 months achieved a 5.2% increase in lumbar spine BMD after 1 yr of therapy, relative to baseline. Furthermore, 3-monthly i.v. bolus injections of ibandronate were well tolerated, with a similar incidence of AEs to placebo. Three-monthly i.v. ibandronate has now been studied in over 3500 patients with PMO w43; Juttmann JR, Felsenberg D, Halse J et al., unpublished datax. It has been shown that intermittent i.v. ibandronate offers physicians a convenient, effective and well-tolerated alternative to conventional oral bisphosphonate therapy w43; Juttmann JR, Felsenberg D, Halse J et al., unpublished datax. However, thus far, no studies have investigated ibandronate in patients with secondary osteoporosis. Consequently, the aim of the present 3-yr study was to determine the therapeutic efcacy and safety of 3-monthly bolus i.v. injections of ibandronate in patients with established CIO. A planned 2-yr interim analysis of the study data was conducted, the results of which are reported here.

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013

Patients and methods

Study population
Between January 1997 and March 1999, a total of 105 men and women were enrolled in this study, which took place at a single centre in Leverkusen, Germany. All patients were conrmed as having established osteoporosis induced by the long-term administration of high-dose corticosteroids for the treatment of an underlying chronic illness (chronic obstructive lung disease, rheumatoid arthritis or polymyalgia rheumatica). Osteoporosis was dened as a low BMD, of at least 2.5 S.D. below mean young normal values at the lumbar spine (L2L4). Patients enrolled in the study had been receiving chronic uninterrupted corticosteroid therapy for at least 2 yr or had received a corticosteroid dose of at least 7.5 mguday. Patients were excluded from the study if they had hypocalcaemia, suffered from severe renal impairment, had a history of recent major GI tract disease (e.g. oesophagitis or GI ulceration) or had experienced any previous adverse reaction to bisphosphonate therapy. Patients were also excluded if they were receiving other bone-active drugs, such as hormonal replacement therapy, thiazide and diuretics. All participants gave their oral informed consent to participation in this study.

Study design
In this open, parallel-group, controlled study, patients were allocated to receive either 3-monthly bolus injections of ibandronate (2 mg) or daily alfacalcidol (1 mg). In addition, all patients were given a daily calcium supplement (500 mg). The method of allocation to therapy was to nd pairs of patients with similar baseline characteristics and then to assign one member of the matched pair to each treatment group.

Outcome measurements and methods

The primary end-point of the study was the change in BMD at the lumbar spine and femoral neck after 24 months relative to

Ibandronate in corticoid-induced osteoporosis

745

baseline. Secondary efcacy end-points were changes in BMD at the calcaneus, change in back pain intensity and changes in body height during the course of the study. The incidence of new vertebral and non-vertebral fractures was also examined. All efcacy and safety assessments were performed at baseline and every 6 months thereafter. BMD in the lumbar spine, femoral neck and calcaneus was evaluated using dualenergy X-ray absorptiometry (DXA; Lunar Expert, Madison, WI, USA). To ensure standardization and accuracy of BMD results, the same operator, who was unaware of the patients identity and treatment, determined all BMD values, using the same machine. To assess for fractures, lateral X-rays of the thoracic and lumbar spine were obtained. X-ray lms were evaluated by an experienced radiologist who was blinded to patient treatment. To assess back pain we used a simple score based on four categories of pain: 0=none, 1=mild, 2=moderate, 3=severe. Height was measured using a stadiometer.

Statistical analysis
The study was analysed using intention-to-treat (ITT) analysis. One patient withdrew prior to treatment on instruction from her physician and so was not included in the analysis. To compare differences between the two treatment groups, data were analysed using the t-test for continuous variables and the x2 test for ordinal or nominal variables. This statistical analysis was performed using the SPSS for Windows1 software package (release 10.0.7; SPSS Inc., Chicago, IL, USA). Information entered into the software package was independently checked for errors and inconsistencies by an external institute (Institute for Medical Outcome Research, Loerrach, Germany).

age range, sex distribution, height, weight, percentage of underlying diseases, average BMD values, fracture rates and corticosteroid use. At baseline, patients from both treatment groups had a mean lumbar spine wL2L4x BMD T-score of 23.8 ("0.8 and "0.7 in the ibandronate and alfacalcidol groups respectively). In addition, all patients had experienced a similar number of previous vertebral fractures: 4.0"2.7 (mean"S.D.) in the ibandronatetreated patients compared with 3.7"2.5 in those treated with active vitamin D. The mean initial daily corticosteroid (prednisone) dose was 11"6 and 10"4 mg in the ibandronate and alfacalcidol treatment groups respectively. During the course of the study, the mean dose of prednisone decreased by 19% in the ibandronate-treated patients and by 21% in those receiving alfacalcidol. Prior to treatment, patients in the ibandronate group had been receiving corticosteroid therapy for a mean duration of 8"6 yr compared with 7"6 yr in the alfacalcidol group.

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013

Measurements of bone mass

The mean percentage changes in BMD over the 24month treatment period relative to baseline are reported in Table 2. Compared with alfacalcidol treatment, bolus injections of ibandronate produced signicantly superior gains in BMD at the lumbar spine (2.2"3.1 and 11.9"7.4% respectively; P< 0.0001), femoral neck (1.3"1.8 and 4.7"4.0% respectively; P=0.0005) and calcaneus (7.6"3.8 and 15.5"10.7% respectively; P< 0.0001) after 2 yr of treatment. Notably, the ibandronate-related BMD changes at the lumbar spine (Fig. 1), hip (Fig. 2) and calcaneus (Fig. 3) were maintained throughout the study period. The gains in bone mass were consistently greater in the ibandronatetreated patients than in those receiving alfacalcidol, at all measured time points.

Results
Patient characteristics
Of the 104 patients who received therapy, 52 were assigned to receive 2 mg i.v. ibandronate bolus injections every 3 months and 52 were assigned to receive 1 mg oral alfacalcidol daily. The study population included 49 men and 55 women, with a mean age of 64.7 yr. The major clinical baseline characteristics are illustrated in Table 1. The two treatment groups were comparable in terms of
TABLE 1. Patient baseline characteristics (mean"S.D.) Ibandronate (n=52) Men Women Age (yr) Height (cm) Weight (kg) Underlying diseases Chronic obstructive lung disease Rheumatoid arthritis Polymyalgia rheumatica Duration of corticosteroid therapy (yr) Daily corticosteroid dose (mg) BMD T-score Lumbar spine Femoral neck Calcaneus (n=47) Patients with 01 vertebral fracture No. of vertebral fracturesupatient 25 27 64"10 164"9 67"14 28 15 9 8"6 11"6 23.8"0.8 23.0"1.0 22.9"1.0 48 4.0"2.7 Alfacalcidol (n=52) 24 28 66"8 165"10 65"10 26 14 12 7"6 10"4 23.8"0.7 3.1"0.6 22.1"0.9 47 3.7"2.5

Course of back pain

The average back pain score decreased consistently in both groups of patients during the course of the study (Fig. 4). However, a trend towards greater back pain relief was noted in the patients receiving ibandronate. After 24 months of therapy, 84.6% of patients receiving ibandronate experienced a marked improvement in back
TABLE 2. Change in BMD (mean"S.E.) from baseline after 6, 12, 18 and 24 months in patients receiving ibandronate or alfacalcidol Change from baseline (%) Month 6 Ibandronate Lumbar spine Femoral neck Calcaneus Alfacalcidol Lumbar spine Femoral neck Calcaneus 6.2"7.7 1.9"5.9 1.8"10.8 0.6"1.7 0.8"2.9 1.6"4.5 Month 12 8.7"9.0 3.0"5.7 6.9"12.6 1.8"2.8 1.0"2.6 3.1"4.7 Month 18 9.3"5.4 4.7"4.0 9.1"15.5 1.4"2.2 0.8"1.4 3.9"4.1 Month 24 11.9"7.4 4.7"4.0 15.5"10.7 2.2"3.1 1.3"1.8 7.6"3.8

746

J. D. Ringe et al.

FIG. 4. Course of back pain. FIG. 1. Lumbar spine BMD.

TABLE 3. Frequency of patients with one or more vertebral or nonvertebral fractures after 24 months No. of patients Ibandronate (n=52) Vertebral fractures Non-vertebral fractures Alfacalcidol (n=52) Vertebral fractures Non-vertebral fractures 5 9 10 11 Percentage of patients 9.6 17.3 19.2 21.2

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013

New fractures and height loss

In this study, which was not powered to compare reduction in fracture risk, there was a non-signicant trend towards fewer vertebral fractures in the group of patients receiving ibandronate compared with those taking alfacalcidol (Table 3; P=0.264). During the course of the study, new vertebral fractures occurred in ve patients receiving ibandronate (9.6%) vs 10 patients treated with alfacalcidol (19.2%). The incidence of new non-vertebral fractures was similar for the two agents (Table 3): 9 and 11 patients receiving ibandronate and alfacalcidol respectively experienced new non-vertebral fractures. Overall, signicantly more patients in the alfacalcidol treatment group lost body height after 24 months of treatment compared with patients receiving ibandronate (78.8 and 51.9% of patients respectively; P< 0.005). After 2 yr of therapy, the mean loss of body height was 20.27 and 20.98 cm in patients treated with ibandronate and alfacalcidol respectively (P=0.020).

FIG. 2. Femoral neck BMD.

FIG. 3. Calcaneus BMD.

Safety
The incidence of AEs was similar in the 3-monthly i.v. ibandronate and daily oral alfacalcidol groups (Table 4). However, a numerically higher incidence of hypercalcaemiauhypercalciuria was observed in patients taking alfacalcidol compared with those receiving ibandronate (7.6 vs 1.9%). Overall, after 24 months of therapy, 18 and 19 of the ibandronate- and alfacalcidol-treated patients experienced a total of 20 and 23 AEs respectively.

pain (pain score improved by 2 or 3 points) compared with 50.0% of patients receiving alfacalcidol (P=0.086). The trend towards a greater reduction in average back pain score in the ibandronate group was observed after only 6 months of initiating therapy.

Ibandronate in corticoid-induced osteoporosis

747

TABLE 4. Summary of adverse events occurring after 24 months of treatment with ibandronate or alfacalcidol Ibandronate (n=52) Constipation Diarrhoea Epigastric pain Hypercalciuriauhypercalcaemia Arthralgiaumyalgia Nausea Other Total 3 5 1 6 3 2 20 Alfacalcidol (n=52) 2 1 9 4 4 2 1 23

The 2 mg bolus i.v. injection of ibandronate was well tolerated. Most AEs were mild, temporary and manageable, only one patient withdrawing as a result of a treatment-related side-effect. In total, 19.2% of patients receiving ibandronate and 17.3% of those treated with alfacalcidol discontinued the study early. Reasons for patients discontinuing treatment with i.v. ibandronate bolus injections were non-treatment-related death (3.7%), AEs (1.9%), personal reasons unrelated to treatment (11.5%) and missed dose (1.9%). One patient experienced an acute-phase reaction; this was slight to transient.

Discussion
Patients who receive long-term corticosteroid therapy are chronically ill. As a result of their underlying disease, these patients are required to take a number of daily medications and may, therefore, nd it a burden to take further tablets. Unfortunately, however, bone loss associated with long-term corticosteroid use often necessitates the administration of additional supportive drug therapy. At present, oral bisphosphonates are considered to be the standard treatment for patients with CIO. However, an effective therapy that can be administered as a bolus injection and that needs to be given only a few times a year may have several advantages over conventional oral bisphosphonates. Potential benets include increased patient compliance, lack of GI AEs and eliminated risk of reduced enteral absorption due to incorrect intake of beverages. Three-monthly i.v. ibandronate bolus injections have been specically designed to provide an effective therapy for the management of osteoporosis that enhances patient concordance. Studies have demonstrated the potential of ibandronate in PMO w39, 40, 43x. However, the present parallel-group study is the rst to investigate the efcacy and safety of intermittent i.v. ibandronate in patients with established CIO. BMD is the most important predictor of the risk of fracture, regardless of which skeletal site is measured w44, 45x. Therefore, it is universally used as an end-point in studies investigating novel and conventional agents for the treatment of osteoporosis. In this study, 3-monthly administration of 2 mg i.v. ibandronate

signicantly and consistently increased lumbar spine, hip and calcaneus BMD relative to active vitamin D. Other bisphosphonates, including cyclical oral etidronate, intermittent i.v. pamidronate, oral daily alendronate and oral daily risedronate, have been investigated for the treatment of established CIO (BMD T-score < 22.5) w14, 16, 46, 47x. Although direct comparisons are not possible, the percentage BMD increases in lumbar spine in the patients receiving 3-monthly i.v. ibandronate (8.7 and 11.9% at 1 and 2 yr respectively) compare very favourably with those observed with other bisphosphonates (oral etidronate, 5.4% after 2 yr w46x; i.v. infusions of pamidronate, 3.4% increase after 1 yr w47x). In addition to statistically signicant increases in bone mass, patients receiving 3-monthly bolus injections of ibandronate showed a trend towards greater back pain relief than those taking active vitamin D, and also lost signicantly less body height (P=0.020). Furthermore, the signicant increases in BMD observed with 3-monthly ibandronate i.v. bolus injections correlated with a non-signicant trend towards a reduction in the risk of new vertebral fractures. The incidence of nonvertebral fractures was similar in the two treatment groups. The value of biochemical markers of bone turnover is becoming progressively more evident in the management of patients with osteoporosis, with consistent associations being reported between bone marker concentrations and bone loss, as well as fracture risk w4855x. Continuous (oral and weekly) dosing with bisphosphonates is associated with a sustained decrease in the levels of bone markers w56, 57x. Although it is not fully characterized, less frequent dosing schedules produce a more complex time course of bone marker suppression relative to continuous dosing schedules. Levels of biochemical markers of bone turnover, which were not assessed during this study, could have provided further insights into the patterns of bone marker suppression during intermittent i.v. bisphosphonate therapy. Three-monthly i.v. ibandronate was found to be well tolerated in this corticosteroid-treated population, with a similar incidence of AEs compared with daily oral alfacalcidol. Of particular note, i.v. ibandronate was not associated with the GI AEs that have been associated with some orally administered bisphosphonates. Furthermore, compliance with treatment was very high, only one patient discontinuing therapy because of an AE (1.9%) and only one patient missing an injection of ibandronate (1.9%).

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013

Conclusions
For patients with established CIO, 3-monthly administration of i.v. ibandronate bolus injections signicantly increases BMD at the lumbar spine, femoral neck and calcaneus, relative to oral daily alfacalcidol. These 2-yr interim results conrm the ndings from studies conducted in patients with PMO. For the treatment of both PMO and CIO, 3-monthly i.v. ibandronate produces signicant, meaningful increases in BMD. Furthermore,

748

J. D. Ringe et al.

in all studies to date, intermittent i.v. ibandronate has been well tolerated. The ease of administration, scarcity of AEs and good compliance associated with intermittent i.v. ibandronate bolus injections makes this novel treatment approach an interesting and feasible alternative to current oral bisphosphonate therapy for the treatment of patients with CIO.

References
1. Hougardy DM, Peterson GM, Bleasel MD, Randall CT. Is enough attention being given to the adverse effects of corticosteroid therapy? J Clin Pharm Ther 2000;25:2234. 2. Walsh LJ, Wong CA, Pringle M, Tatterseld AE. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. Br Med J 1996;313:346. 3. Adachi JD. Corticosteroid-induced osteoporosis. Am J Med Sci 1997;313:49. 4. Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 1983; 309:268. 5. Cooper C, Coupland C, Mitchell M. Rheumatoid arthritis, corticosteroid therapy and hip fracture. Ann Rheum Dis 1995;54:4952. 6. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis. pathogenesis and management. Ann Intern Med 1990;112:35264. 7. Reid IR. Glucocorticoid osteoporosismechanisms and management. Eur J Endocrinol 1997;137:20917. 8. Sambrook PN, Birmingham J, Kempler S. Corticosteroid effects on proximal femur bone loss. J Bone Miner Res 1990;5:12116. 9. Verstraeten A, Dequeker J. Vertebral and peripheral bone mineral content and fracture incidence in postmenopausal patients with rheumatoid arthritis: effect of low dose corticosteroids. Ann Rheum Dis 1986;45:8527. 10. Ringe JD. Active vitamin D metabolites in glucocorticoidinduced osteoporosis. Calcif Tissue Int 1997;60:1247. 11. Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM, Setoain J. Vertebral fractures in steroid dependent asthma and involutional osteoporosis: a comparative study. Thorax 1991;46:8036. 12. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent CIO. N Engl J Med 1997; 337:3827. 13. Cohen S, Levy RM, Keller M et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999;42:230918. 14. Reid DM, Hughes RA, Laan RF et al. Efcacy and safety of daily risedronate in the treatment of CIO in men and women: a randomized trial. European CIO Treatment Study. J Bone Miner Res 2000;15:100613. 15. Roux C, Oriente P, Laan R et al. Randomized trial of effect of cyclical etidronate in the prevention of corticosteroidinduced bone loss. J Clin Endocrinol Metab 1998;83:112833. 16. Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 1998;339:2929.

17. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoidinduced osteoporosis: 2001 update. Arthritis Rheum 2001; 44:1496503. 18. de Groen PC, Lubbe DF, Hirsch LJ et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996;35:101621. 19. Lufkin EG, Argueta R, Whitaker MD. Pamidronate: an unrecognized problem in gastrointestinal tolerability. Osteoporosis Int 1994;4:32022. 20. Sharpe M, Noble S, Spencer CM. Alendronate. An update of its use in osteoporosis. Drugs 2001;61:9991039. 21. Adami S, Zamberlan N. Adverse effects of bisphosphonates: a comparative review. Drug Safety 1996;14:15870. 22. Adami S. Ibandronate. Drugs 1999;57:109. 23. Rolda n EJA, Negri AL, Gador SA. Short-term compliance to daily alendronate treatment in 1877 patients with osteoporosis. The ECMO study. J Bone Miner Res 2000; 15(Suppl. 1):SU411. 24. Lombas C, Hakim C, Zanchetta JR. Compliance with alendronate treatment in an osteoporosis clinic. J Bone Miner Res 2000;15(Suppl. 1):M406. 25. Colley CA, Lucas LM. Polypharmacy: the cure becomes the disease. J Gen Intern Med 1993;8:27883. 26. Stewart RB, Cooper JW. Polypharmacy in the aged. Practical solutions. Drugs Aging 1994;4:44961. 27. Tashkin DP. Multiple dose regimens. Impact on compliance. Chest 1995;107:176S182S. 28. Gatley MS. To be taken as directed. J R Coll Gen Pract 1968;16:3944. 29. James PN, Anderson JB, Prior JG, White JP, Henry JA, Cochrane GM. Patterns of drug taking in patients with chronic airow obstruction. Postgrad Med J 1985; 61:710. 30. Latiolais CJ, Berry CC. Misuse of prescription medications by outpatients. Drug Intelligence Clin Pharm 1969; 3:27177. 31. Bauss F, Kling L, Sponer G. Comparison of continuous and cyclical administration of ibandronate on bone mass in ovariectomized rats. J Bone Miner Res 1996;11(Suppl. 1): S336. 32. Burckhardt P. Ibandronate in oncology. Cancer 1997; 80(Suppl. 8):16968. 33. Coleman RE, Purohit OP, Black C et al. Double-blind, randomised, placebo-controlled, dose-nding study of oral ibandronate in patients with metastatic bone disease. Ann Oncol 1999;10:3116. 34. Fleisch H. The bisphosphonate ibandronate, given daily as well as discontinuously, decreases bone resorption and increases calcium retention as assessed by calcium kinetics in the intact rat. Osteoporosis Int 1996;6:16670. 35. Lalla S, Hothorn LA, Haag N, Bader R, Bauss F. Lifelong administration of high doses of ibandronate increases bone mass and maintains bone quality of lumbar vertebrae in rats. Osteoporosis Int 1998;8:97103. 36. Monier-Faugere MC, Friedler RM, Bauss F, Malluche HH. A new bisphosphonate, BM 21.0955, prevents bone loss associated with cessation of ovarian function in experimental dogs. J Bone Miner Res 1993;8:134555. 37. Monier-Faugere MC, Geng Z, Paschalis EP et al. Intermittent and continuous administration of the bisphosphonate ibandronate in ovariohysterectomized beagle dogs: effects on bone morphometry and mineral properties. J Bone Miner Res 1999;14:176878.

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013

Ibandronate in corticoid-induced osteoporosis

749

38. Pecherstorfer M, Herrmann Z, Body JJ et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996;14:26876. 39. Ravn P, Clemmesen B, Riis BJ, Christiansen C. The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-nding study. Bone 1996;19:52733. 40. Riis BJ, Ise J, von Stein T, Bagger Y, Christiansen C. Ibandronate: a comparison of oral daily vs intermittent dosing in postmenopausal osteoporosis. J Bone Miner Res 2001;16:18718. 41. Ralston SH, Thiebaud D, Herrmann Z et al. Dose response study of ibandronate in the treatment of cancerassociated hypercalcaemia. Br J Cancer 1997;75:295300. 42. Smith SY, Recker R, Hannan M, Bauss F. Effects of ibandronate treatment on bone mass, architecture and strength in the ovariectomized cynomolgus monkey wAbstract SA370x. J Bone Miner Res 1999;14(Suppl. 1):S402. 43. Thie baud D, Burckhardt P, Kriegbaum H et al. Three monthly i.v. injections of ibandronate in the treatment of postmenopausal osteoporosis. Am J Med 1997;103:298307. 44. Cummings SR, Black DM, Nevitt MC et al. Appendicular bone density and age predict hip fracture in women. The Study of Osteoporotic Fractures Research Group. J Am Med Assoc 1990;263:6658. 45. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of BMD predict occurrence of osteoporotic fractures. Br Med J 1996;312:12549. 46. Adachi JD, Roux C, Pitt PI et al. A pooled data analysis on the use of intermittent cyclical etidronate therapy for the prevention and treatment of corticosteroid induced bone loss. J Rheumatol 2000;27:242431. 47. Gallacher SJ, Fenner JA, Anderson K et al. I.v. pamidronate in the treatment of osteoporosis associated with

48.

49.

50.

51.

52. 53.

54.

55. 56. 57.

corticosteroid dependent lung disease: an open pilot study. Thorax 1992;47:9326. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J. The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientic Advisors of the International Osteoporosis Foundation. Osteoporos Int 2000;11:S217. Garnero P, Hausherr E, Chapuy MC et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 1996; 11:15318. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000;15:152636. Garnero P, Sornay-Rendu E, Duboeuf F, Delmas PD. Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J Bone Miner Res 1999;14:161421. Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. Br Med J 1991;303:9614. Ross PD, Kress BC, Parson RE et al. Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study. Osteoporos Int 2000; 11:7682. Uebelhart D, Schlemmer A, Johansen JS et al. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 1991;72:36773. van Daele PL, Seibel MJ, Burger H et al. Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam study. Br Med J 1996;312:4823. Papapoulos SE. Bisphosphonates in the treatment of osteoporosis. Principles and efcacy. Ann Med Interne 2000;151:50410. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet 2002;359:201826.

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on March 6, 2013