Oral Ibandronate Preserves Trabecular Microarchitecture: Micro-Computed Tomography Findings From the Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe Study

Journal of Clinical Densitometry: Assessment of Skeletal Health, vol. 12, no. 1, 71e76, 2009 Ó Copyright 2009 by The International Society for Clinical Densitometry 1094-6950/08/12:71e76/$36.00 DOI: 10.1016/j.jocd.2008.10.006

Original Article

Oral Ibandronate Preserves Trabecular Microarchitecture: Micro-Computed Tomography Findings From the Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe Study Robert R. Recker,*,1 Louis-Georges Ste-Marie,2 Bente Langdahl,3 Daiva Masanauskaite,4 Dominique Ethgen,5 and Pierre D. Delmas6 1

Osteoporosis Research Center, Creighton University, Omaha, Nebraska, USA; 2CHUM Universit e de Montreal, Centre de Recherche H^ opital Saint-Luc, 264 Ren e L evesque Blvd East, Montr eal, Qu ebec, H2X 1P1 Canada; 3Aarhus University Hospital, Aarhus Sygehus THG, DK-8000 Aarhus C, Denmark; 4F. Hoffmann-La Roche Ltd, Grenzacherstrasse, Basel, Switzerland; 5GlaxoSmithKline, Collegeville, Philadelphia, USA; and 6Universit e de Lyon and Institut National de la Sant e et de la Recherche M edicale (INSERM) Research Unit 831, Lyon Cedex, France

Abstract Micro-computed tomography (micro-CT) is a quantitative 3-dimensional (3D) scanning procedure used to assess trabecular architecture. In the 3-yr oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) study, it was found that oral ibandronate administered daily (2.5 mg) or intermittently (20 mg) significantly reduced vertebral fracture risk by 62% ( p 5 0.0001) and 50% ( p 5 0.0006), respectively, vs placebo. Twodimensional histomorphometric analysis of BONE study biopsies indicated that newly formed bone was of normal quality. In the current analysis, micro-CT was used to assess 3D trabecular microarchitecture. Rod and plate distribution was quantified by differential analysis of the triangulated bone surface. Biopsies were obtained from 110 patients, with 84 evaluable by micro-CT. Median structural model index (SMI; a lower SMI indicates an increased ratio of plates to rods and thus, improved trabecular microarchitecture) was 1.001 with ibandronate vs 1.365 with placebo (90% confidence interval [CI] for difference in medians: e0.626, e0.033), and connectivity density was higher in ibandronate-treated patients (median: 3.904 vs 3.112/mm3, 90% CI for difference in medians: 0.159, 1.517). This indicates that trabecular microarchitecture was better preserved in patients receiving ibandronate than placebo. Taken together with previous results from BONE, these findings indicate that ibandronate treatment preserves bone strength by maintaining good quality trabecular microarchitecture in women with postmenopausal osteoporosis. Key Words: Ibandronate; Micro-computed tomography; Postmenopausal osteoporosis; Trabecular architecture.

the risk of fractures (1e5). Fracture protection is achieved by improving overall bone strength, and an important element of this, in addition to BMD and bone turnover, is the material and structural properties of bone. The features of bone microarchitecture, in particular, the size and shape of trabeculae, and their connectivity and orientation, contribute to bone strength (6,7). Alterations in bone microarchitecture may not always be captured by BMD measurements. Some architectural features can be assessed in histological sections of bone biopsy

Introduction The nitrogen-containing bisphosphonates increase bone mineral density (BMD), reduce bone turnover, and reduce Received 02/26/08; Revised 10/10/08; Accepted 10/20/08. *Address correspondence to: Robert R. Recker, MD, MACP, FACE, Osteoporosis Research Center, School of Medicine, Creighton University, 601 N, 30th Street #5766, Omaha, NE 68131. E-mail: rrecker@ creighton.edu

71

72 specimens using 2-dimensional (2D) approaches, such as histomorphometry (8). More sophisticated methods have now been developed, however, which enable 3-dimensional (3D) visualization and quantification of bone microstructure (9). One such method is micro-computed tomography (microCT), a quantitative 3D scanning method that can be used to assess trabecular architecture (10,11), providing information that is not available with histomorphometry. During microCT, the specimen is rotated at various angles in an X-ray beam, and a 3D image is built up from planar sections. Processing of the 3D image allows direct quantification of unbiased morphometric variables, such as area, volume, and surface determination, and assessments of thickness and connectivity. Importantly, micro-CT scanning is a nondestructive technique, unlike traditional 2D histomorphometry, thus allowing multiple tests to be carried out on a single sample. Furthermore, availability of desktop micro-CT devices mean that the technique is now widely used in investigations of bone samples from clinical and preclinical studies. The ability of bone to resist fracture is a function of its architecture and material properties. Therefore, 3D assessment of structural characteristics may improve efficacy testing of treatments for osteoporosis. When used for investigating the role of bone architecture in osteoporotic fractures and evaluating osteoporosis therapies, micro-CT has the advantage that multiple variables related to bone surface, volume, and trabecular architecture can be measured. Overall, bone deterioration resulting from osteoporosis is characterized by a change from plate to rod elements in trabecular structure. In micro-CT, the structural model index (SMI), using a 3D view, quantifies the bone structure in terms of the ratio between rods and plates; a larger proportion of plates is indicative of a stronger bone structure as opposed to a larger proportion of rods. The SMI value is 0 for an ideal plate structure, and 3 for a perfect rod-based structure. For a structure with both plates and rods of equal thickness, the SMI value lies between 0 and 3, depending on the volume ratio of rods and plates. The oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) study was a 3-yr, randomized, double-blind trial of placebo vs daily oral ibandronate (2.5 mg) or intermittent oral ibandronate (20 mg every other day for 12 doses every 3 mo) in women with postmenopausal osteoporosis (2,12). Results showed that daily and intermittent oral ibandronate significantly increased lumbar spine ( p ! 0.0001) and proximal femur ( p ! 0.0001) BMD vs placebo, and reduced bone turnover, leading to a significant reduction in vertebral fracture risk (relative risk reduction: 62%, p 5 0.0001 and 50%, p 5 0.0006, respectively). Histomorphometric analyses of bone biopsies taken after 2e3 yr of treatment with oral ibandronate in the BONE study showed that the newly formed bone retained a normal structure, with no signs of woven bone or adverse effects on mineralization (13). Quantitative assessment demonstrated no impairment in bone mineralization, and all quantitative efficacy and safety variables were consistent with the production of normalquality, newly formed bone and a reduction in bone turnover Journal of Clinical Densitometry: Assessment of Skeletal Health

Recker et al. with both ibandronate regimens relative to placebo. Moreover, histomorphometric variables were normalized to values seen in healthy premenopausal women (14); notably, activation frequency was reduced significantly with oral ibandronate compared with placebo to levels consistent with those in premenopausal women (14). Similar results were obtained from histomorphometric analysis of bone biopsies taken during the Dosing IntraVenous Administration study, a randomized, double-blind trial that compared 2 intermittent intravenous ibandronate injection regimens (2 mg every 2 mo and 3 mg every 3 mo) with 2.5 mg daily oral ibandronate (15). Newly formed bone was again of normal lamellar structure, with no evidence of marrow fibrosis, cellular toxicity, or mineralization defects, and activation frequency and mineralizing surface in all 3 groups of ibandronate-treated patients were similar to those reported in healthy premenopausal women (14). Results are presented here from micro-CT analysis of bone biopsy samples collected during the 3-yr BONE study.

Subjects and Methods Study Design and Participants The BONE study was a randomized, double-blind, placebo-controlled, parallel-group trial that enrolled 2946 postmenopausal women with a lumbar spine BMD Tscore  e2.0 in at least 1 vertebra (L1eL4) and 1e4 prevalent vertebral fractures (T4eL4), and has previously been reported in detail (2). Briefly, patients received placebo or oral ibandronate either daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 mo), and all patients also received daily calcium (500 mg) and vitamin D (400 IU) supplements. Major exclusion criteria included a lumbar spine BMD T-score ! e5.0; more than 2 prevalent fractures of the lumbar spine; diseases or therapy (within the previous 6 mo) known to affect bone metabolism; previous bisphosphonate treatment; fluoride treatment within the last 12 mo or for a total duration of more than 2 yr; renal impairment; contraindications to calcium or vitamin D therapy; and hyperor hypocalcaemia. The study was conducted in accordance with the principles of the Declaration of Helsinki; the Institutional Review Boards of the participating centers approved the study, and all patients provided written informed consent.

Bone Biopsy Procedure Horizontal transiliac bone biopsies were obtained after 22 or 34 mo of treatment, as per previously published methods (13). Patients received tetracycline (1 g/d) over 2 d, given 12 d apart to ensure double-labeling of the bone, and biopsies were taken 3e8 d after the second tetracycline dosing interval using a trephine of 7.5-mm inner diameter. Evaluable biopsy cores were those that were unbroken. The biopsy was included if it had only 1 cortex as long as there was enough tissue and no artifact that would interfere with the analysis. Biopsies that had insufficient tissue or too much artifact were not included. The number of cortices was not used as an inclusion criterion. Volume 12, 2009

Oral Ibandronate Preserves Trabecular Microarchitecture Micro-Computed Tomography Procedure Micro-CT analysis was carried out in a single laboratory (Creighton University, Omaha, Nebraska) with a Scanco mCT 40 scanner (Scanco Medical, Bassersdorf, Switzerland). Rod and plate distributions in the trabeculae were quantified from the 3D scan by differential analysis of the triangulated bone surface to determine its SMI. A change from plates to rods, characteristic of osteoporosis, signifies a reduction in the quality of the trabecular structure. The number of trabecular connections per mm3 was estimated in terms of connectivity density. The connectivity (c) of a 2-component system, such as bone and marrow, can be derived from the Euler characteristic (e) by the equation c 5 1 e e, if all the trabeculae and bone marrow cavities are connected. A marching cube algorithm was used for the generation of 3D bone structure images from micro-CT images, with the smooth surface of 3D polygonal representation consisting entirely of triangles. Bone surface area (mm2) was determined using the marching cubes method to triangulate the surface of the mineralized bone phase. Bone volume (mm3) was calculated using tetrahedrons corresponding to the enclosed volume of the triangulated surface; total volume was defined as the volume of the sample that was examined. Trabecular thickness (mm) was calculated as the average diameter of the largest nonoverlapping spheres that fit inside the trabecular bone throughout the volume of interest; trabecular separation (mm) was measured the same way, but using the marrow space instead of the trabecular bone. Trabecular number (per mm) was defined as the inverse of the diameter of the largest nonoverlapping spheres that fit inside the marrow space where the trabecular bone is only represented by its centerline.

73

obvious differences in baseline characteristics between the 2 ibandronate arms (2.5 mg daily or 20 mg every other day for 12 doses every 3 mo), data were pooled to provide a larger sample size. This was also considered appropriate as results from the BONE study showed that the efficacy of the 2 regimens is similar in terms of improvements in BMD, bone turnover, and fracture risk (2). This was an exploratory analysis; therefore, no formal testing for homogeneity was performed before pooling the ibandronate arms. With the large number of endpoints analyzed, there was an increased risk of seeing ‘‘false positive’’ results. As such, it was considered more appropriate to limit this analysis to looking for ‘‘trends’’ in significance using 90% CIs, and then, to infer statistical significance at an increased alpha level ( p ! 0.1). If the 90% CI for the difference in medians did not encompass zero, a statistically significant difference was inferred post hoc at a 5 0.10, although this does not imply statistical significance at a 5 0.05. The actual p values were not calculated. A truly statistically significant result would require a very high level of significance ( p ! 0.05) because of the number of endpoints tested. This was not the intention of this analysis.

Results Patient Disposition and Baseline Characteristics In total, 110 single transiliac bone biopsies were obtained after 22 or 34 mo of treatment in the BONE study. Of these, 100 were evaluable for histomorphometry (i.e., they were not damaged), and 84 out of these 100 were suitable for microCT evaluation (placebo arm: n 5 28; pooled ibandronate arms: n 5 56). Baseline data for the 110 patients who provided samples were well balanced across the 3 treatment arms of the original BONE study (Table 1).

Statistical Analysis The number of bone biopsies performed was based on sample size requirements for a preplanned, previously published histomorphometry analysis (13). This micro-CT analysis was not preplanned. Therefore, this analysis was not powered to test hypotheses on individual parameters, and a primary endpoint was not specified. As there were no

Micro-Computed Tomography Analysis Results of the micro-CT analysis are summarized in Table 2. Median SMI values were significantly lower (a ! 0.10, based on the 90% CI) in the pooled ibandronate arm than in the placebo arm, signifying a higher plate-to-rod ratio in trabecular bone (Fig. 1). This indicates preservation of the architecture of

Table 1 Baseline Characteristics of Patients Providing Bone Biopsies Variables Age (yr) Weight (kg) Height (cm) Body mass index (kg/m2) Time since menopause (yr) Lumbar spine (L2eL4) BMD (T-score) Total hip BMD (T-score)

Placebo (n 5 36) Mean  SD

Daily ibandronate (n 5 40) Mean  SD

Intermittent ibandronate (n 5 34) Mean  SD

66.44  5.56 67.60  9.28 160.26  6.64 26.35  3.53 17.56  5.99 e2.86  0.64 e1.63  0.87

66.13  5.98 69.25  12.95 160.76  5.78 26.88  5.41 19.65  7.09 e2.50  0.77 e1.53  1.04

65.85  5.48 71.42  13.32 160.56  5.87 27.67  4.70 17.70  7.11 e2.58  0.72 e1.62  0.96

Abbr: SD, standard deviation; BMD, bone mineral density. Journal of Clinical Densitometry: Assessment of Skeletal Health

Volume 12, 2009

74

Recker et al. Table 2 Results of Micro-CT Variables Analyzed Placebo (n 5 28) Median (90% CI)

Variables Bone volume/total volume Connectivity density (1/mm3) Structural model index Trabecular number (1/mm) Trabecular thickness (mm) Trabecular separation (mm)

0.1470 3.1122 1.3648 1.1845 0.1598 0.7842

(0.1379, (2.8056, (1.0528, (1.1239, (0.1460, (0.7243,

0.1777) 3.6852) 1.6091) 1.2673) 0.1935) 0.8396)

Pooled ibandronate (n 5 56) Median (90% CI) 0.1741 3.9036 1.0008 1.2722 0.1684 0.7284

(0.1512, (3.4637, (0.8667, (1.1877, (0.1536, (0.7020,

0.1908) 4.5910) 1.2658) 1.3179) 0.1807) 0.7903)

Difference in medians 0.0271 0.7914 e0.3640 0.0878 0.0086 e0.0557

(e0.0061, 0.0431) (0.1589, 1.5174)* (e0.6255, e0.0332)* (e0.0284, 0.1534) (e0.0290, 0.0272) (e0.1183, 0.0178)

Abbr: CT, computed tomography; CI, confidence interval. *a ! 0.10.

trabecular bone in the ibandronate group. Ibandronate treatment was also associated with a significantly higher (a ! 0.10, based on the 90% CI) connectivity density of the trabeculae compared with placebo, again indicating preservation of trabecular architecture with ibandronate treatment (Fig. 2). Although not statistically significant, a higher bone volume/total volume was reported with ibandronate vs placebo (Table 2). Consistently, trabecular number and trabecular thickness were slightly higher with ibandronate, and trabecular separation was lower with ibandronate vs placebo (Table 2). These measurements indicate that ibandronate treatment generates a consistent and beneficial trend on multiple parameters of bone structure and architecture when compared with placebo. Overall, micro-CT analysis of structural elements associated with bone strength showed greater preservation of trabecular bone after ibandronate treatment compared with placebo. Micro-CT images from osteoporotic bone after treatment with ibandronate or placebo are shown in Fig. 3.

Discussion The results of this micro-CT analysis showed that SMI values were lower in the pooled ibandronate arms than in the

placebo arm. This shows a higher plate-to-rod ratio in the trabecular bone of ibandronate-treated patients, indicating preservation of the architecture of trabecular bone in the ibandronate group. Ibandronate treatment was also associated with a higher connectivity density than placebo, confirming preservation of trabecular architecture with ibandronate treatment. Analysis of individual structural elements associated with bone strength also showed greater preservation of trabecular bone after ibandronate treatment compared with placebo. All of the 3D measures from micro-CT demonstrate better microstructure in the pooled ibandronate treatment group compared with the placebo group. In the pooled treatment group, bone volume, connectivity density, trabecular number, and trabecular thickness were all greater than in the placebo group. The SMI was lower in the ibandronate-treated group, indicating preservation of the plate model. In addition, trabecular separation was lower, indicating maintenance of trabecular elements. Overall, these results suggest that bone strength is increased after ibandronate treatment compared with placebo, and that ibandronate preserves bone quality with no adverse impact on bone microarchitecture after up to 3 yr of treatment. The findings of this micro-CT analysis of samples from the BONE study are consistent with previously reported findings

1.6 4.5 4.0

Connectivity density (per mm3; 90% CI)

SMI (90% CI)

1.2

0.8

0.4

3.5 3.0 2.5 2.0 1.5 1.0 0.5

0 Ibandronate (n=56)

Placebo (n=28)

Fig. 1. Median (90% confidence interval) structural model index values show a higher plate-to-rod ratio in trabecular bone, indicating an improvement in trabecular bone architecture in the ibandronate group. Journal of Clinical Densitometry: Assessment of Skeletal Health

0 Ibandronate (n=56)

Placebo (n=28)

Fig. 2. Median (90% confidence interval) connectivity density (per mm3) indicating preservation of trabecular architecture with ibandronate treatment. Volume 12, 2009

Oral Ibandronate Preserves Trabecular Microarchitecture

75

Fig. 3. Micro-computed tomography images of osteoporotic bone from: (A) a patient receiving ibandronate (bone volume/ total volume: 0.19; connectivity density [1/mm3]: 4.22; structural model index: 0.72; trabecular number [1/mm]: 1.31; trabecular thickness [mm]: 0.16; trabecular separation [mm]: 0.71), and (B) a patient receiving placebo (bone volume/total volume: 0.12; connectivity density [1/mm3]: 5.26; structural model index: 1.49; trabecular number [1/mm]: 1.34; trabecular thickness [mm]: 0.12; trabecular separation [mm]: 0.69).

from the study. During 3 yr of daily or intermittent ibandronate therapy, beneficial changes in bone turnover, BMD, and fracture risk were observed (2). In addition, hip structural variables were stable or degraded in the placebo group, but showed statistically significant differences vs placebo after treatment with ibandronate (16). Qualitative histological analysis of bone biopsies from patients enrolled in the BONE study showed that newly formed trabecular bone retained its lamellar structure with no evidence of woven bone, marrow fibrosis, or cellular toxicity (13). Similarly, quantitative histomorphometric analysis demonstrated no impairment in mineralization of bone matrix (13). Moreover, the reduction in bone turnover seen with oral ibandronate was associated with signs of improved microarchitecture and connectivity (13). The results of the micro-CT analysis are also consistent with preclinical histomorphometry findings with ibandronate in a number of animal models. For example, studies in ovariectomized rats have shown that ibandronate treatment leads to improvements in bone variables, including trabecular bone volume, trabecular number, load to failure (Fmax) and yield load in long bones and vertebrae (17,18). Similar results have been observed in ovariohysterectomized dogs (19) and ovariectomized nonhuman primates (20,21). The results of the present analysis are also consistent with micro-CT data published for the other nitrogen-containing bisphosphonates, alendronate, and risedronate. In a small, 1-yr placebo-controlled study in women with postmenopausal osteoporosis, risedronate therapy (5 mg daily; n 5 14) was associated with significant benefits over placebo (n 5 12) with regard to bone volume, trabecular thickness, trabecular number, percent plate, and trabecular separation (22). A follow-up biopsy obtained after up to 5 yr of treatment in 7 patients showed that changes were maintained (23). A micro-CT study of bone biopsies (n 5 88) taken at the end of multiple alendronate clinical trials showed that bone volume and trabecular number were significantly greater in patients who had received alendronate (n 5 29) compared with placebo (n 5 59) (24). As in the present study, micro-CT results for Journal of Clinical Densitometry: Assessment of Skeletal Health

risedronate (with synchrotron radiation: n 5 19) and alendronate were consistent with quantitative histomorphometric analysis in the same patients (24,25). A limitation of the present study is that, because of a single biopsy being taken at the end of the treatment period, comparisons cannot be made with baseline values for the same patient taken as their own control, and also means that the standard deviation of the baseline bone status in each of the treatment groups cannot be taken into account. Even with this limitation, however, significant differences at a 5 0.10 could be observed between groups at the end of treatment on selected variables, indicating increased bone strength. The present analysis includes pooled data from 2 different ibandronate regimens; this was considered appropriate as results from the BONE study showed that the efficacy of the 2 regimens is similar in terms of improvements in BMD, bone turnover, and fracture risk (2). In conclusion, the reduction in fracture incidence achieved with ibandronate therapy is accompanied by an overall improvement in trabecular bone architecture and structural variables measured by micro-CT, which are indicative of better bone strength compared with placebo. Trabecular architecture was better preserved after 2e3 yr of treatment with ibandronate than with placebo, and the results of this micro-CT analysis are consistent with those of the quantitative histomorphometric analysis of biopsy data from the BONE study. Overall, micro-CT analysis supports the results obtained for BMD, bone turnover, and hip structural analysis observed in the BONE study.

Acknowledgment Funding for this study was provided by F. Hoffmann-La Roche Ltd. This analysis was sponsored by F. Hoffmann-La Roche Ltd and GlaxoSmithKline. The authors would also like to acknowledge medical writing assistance provided by Charlotte Kennerley and Catherine Lee (Gardiner-Caldwell Communications) in the preparation of this manuscript. Volume 12, 2009

76

Recker et al.

References 1. Black DM, Cummings SR, Karpf DB, et al. 1996 Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535e1541. 2. Chesnut CH, Skag A, Christiansen C, et al. 2004 Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 19: 1241e1249. 3. Cummings SR, Black DM, Thompson DE, et al. 1998 Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077e2082. 4. Harris ST, Watts NB, Genant HK, et al. 1999 Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282:1344e1352. 5. Reginster JY, Minne HW, Sorensen OH, et al. 2000 Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11:83e91. 6. Dalle CL, Giannini S. 2004 Bone microarchitecture as an important determinant of bone strength. J Endocrinol Invest 27: 99e105. 7. Seeman E, Delmas PD. 2006 Bone qualitydthe material and structural basis of bone strength and fragility. N Engl J Med 354:2250e2261. 8. Croucher PI, Garrahan NJ, Compston JE. 1996 Assessment of cancellous bone structure: comparison of strut analysis, trabecular bone pattern factor, and marrow space star volume. J Bone Miner Res 11:955e961. 9. Jarvinen TL, Sievanen H, Jokihaara J, Einhorn TA. 2005 Revival of bone strength: the bottom line. J Bone Miner Res 20:717e720. 10. Jiang Y, Zhao J, Liao EY, et al. 2005 Application of micro-CT assessment of 3-D bone microstructure in preclinical and clinical studies. J Bone Miner Metab 23(Suppl):122e131. 11. Borah B, Gross GJ, Dufresne TE, et al. 2001 Three-dimensional microimaging (MRmicroI and microCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis. Anat Rec 265:101e110. 12. Delmas PD, Recker RR, Chesnut CH III, et al. 2004 Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int 15:792e798. 13. Recker RR, Weinstein RS, Chesnut CH III, et al. 2004 Histomorphometric evaluation of daily and intermittent oral ibandronate

Journal of Clinical Densitometry: Assessment of Skeletal Health

14.

15.

16. 17.

18.

19.

20.

21.

22.

23.

24. 25.

in women with postmenopausal osteoporosis: results from the BONE study. Osteoporos Int 15:231e237. Recker RR, Lappe J, Davies KM, Heaney R. 2004 Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res 19:1628e1633. Recker RR, Ste-Marie LG, Czerwinski E, et al. 2006 Intermittent intravenous ibandronate injections have a similar bone safety profile to daily oral dosing. Calcif Tissue Int 6(Suppl. 1):78. Abstract P455. Fuerst T, Beck TJ, Gaither K, et al. 2006 Effect of oral ibandronate on hip structure: results from the BONE study. J Bone Miner Res 21(Suppl. 1):S287. Abstract SU323. Bauss F, Lalla S, Endele R, Hothorn LA. 2002 Effects of treatment with ibandronate on bone mass, architecture, biomechanical properties, and bone concentration of ibandronate in ovariectomized aged rats. J Rheumatol 29:2200e2208. Lalla S, Hothorn LA, Haag N, et al. 1998 Lifelong administration of high doses of ibandronate increases bone mass and maintains bone quality of lumbar vertebrae in rats. Osteoporos Int 8: 97e103. Monier-Faugere MC, Geng Z, Paschalis EP, et al. 1999 Intermittent and continuous administration of the bisphosphonate ibandronate in ovariohysterectomized beagle dogs: effects on bone morphometry and mineral properties. J Bone Miner Res 14: 1768e1778. M€ uller R, Hannan M, Smith S, Bauss F. 2004 Intermittent ibandronate preserves bone quality and bone strength in the lumbar spine after 16 months of treatment in the ovariectomized cynomolgus monkey. J Bone Miner Res 19:1787e1796. Smith SY, Recker RR, Hannan M, et al. 2003 Intermittent intravenous administration of the bisphosphonate ibandronate prevents bone loss and maintains bone strength and quality in ovariectomized cynomolgus monkeys. Bone 32:45e55. Dufresne TE, Chmielewski PA, Manhart MD, et al. 2003 Risedronate preserves bone architecture in early postmenopausal women in 1 year as measured by three-dimensional microcomputed tomography. Calcif Tissue Int 73:423e432. Borah B, Dufresne TE, Ritman EL, et al. 2006 Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone 39:345e352. Recker R, Masarachia P, Santora A, et al. 2005 Trabecular bone microarchitecture after alendronate treatment of osteoporotic women. Curr Med Res Opin 21:185e194. Borah B, Ritman EL, Dufresne TE, et al. 2005 The effect of risedronate on bone mineralization as measured by microcomputed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover. Bone 37:1e9.

Volume 12, 2009