67 Denosumab Improves Forearm Densitometric, Geometric and Strength Indices as Measured by QCT in Postmenopausal Women With Low BMD

Giuseppe and Toffanin

119

women with established osteoporosis previously treated with antiresorptive drugs. They were given teriparatide (Forsteo, Eli Lilly) by subcutaneous injection, at the dose of 20 mg once daily, plus calcium and Vitamin D. In all subjects BMD at lumbar spine (BMD-LS), femoral neck (BMD-FN) and total femur BMD (BMD-T) was assessed at baseline, and every 6 months for 18 months. At the same time we also performed QUS at phalanxes, by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS, ultrasound bone profile index: UBPI, bone trasmission time: BTT). At baseline and after 18 months vertebral QCT scans of the first, second and third lumbar vertebrae were obtained using a specific software (OSTEO) to quantify the volumetric mineral density (vBMD) of somatic trabecular bone. Teriparatide significantly (p ! 0.001) increased BMD-LS; no significant variation in femoral subregions was found during the study period even though BMD-T tended to increase with the duration of PTH treatment and BMD-FN showed a reduction at month 6 with a progressively return to basal values. No significant changes were observed also for UBPI and AD-SoS, even if the last decreased at month 6 and thereafter it tended to increase. BTT significantly decreased at all time points (p ! 0.05). Teriparatide induced an important and significant (p ! 0.001) increase in vBMD at lumbar spine, as assessed by QCT. Our study shows that in women with established osteoporosis teriparatide determined the expected increase in BMD and vBMD at lumbar spine, with a less strong or negative effect at skeletal sites mainly composed by cortical bone. Further studies in larger population would be necessary to define the clinical role of QUS parameters in patients treated with teriparatide.

64 SIX MONTH PTH 1-84 THERAPY TOLERANCE AND EFFICACY IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS R. Pastore,1 D. Mentuccia,1 C. Moretti,2 S. Castelli,2 A. Pavone,2 and L. Guccione and G. Frajese2,2, 1U.O. Endocrinologia Ospedale S. Giovanni Calibita, Fatebenefratelli, Isola Tiberina, Roma, Italy, 2Dipartimento di Medicina Interna, Universita` di Roma Tor Vergata, Roma, Italy Osteoporosis is characterized by progressive bone loss, it has been established that PTH treatment increases BMD and biomechanical properties of trabecular bone. In the present study we have observed 12 patients, suffering from severe osteoporosis, treated for 6 months with PTH 1-84; the average age at baseline was 71  7.4 and the lumbar spine T-score was 3.34  0.66. At baseline and after 6 months of treatment the following tests have been performed: PTH levels (1565 pg/ml), serum calcium (!10.20 mg/dl), alkaline phosphatase (ALP; 35-104 U/L), osteocalcin (9-46 ng/ml) and b-isomerized type I collagen C-telopeptide breakdown products (b-CTx; ! 730 pg/ml).

baseline 6 month

PTH

Serum calcium

ALP

Osteocalcin

b-CTx

35.88  15.52 27.11  9.55

9.44  0.78 9.59  0.75

110.00  56.25 141.55  45.53

20.04  9.91 109.51  61.02

511.33  156.58 1958.71  1437.77

Results: we have noticed that the PTH levels are unchanged or even lower after 6 months of treatment. The serum calcium levels have been slightly increased, but always under the upper limit of normal; this is consistent with other trials results that underline the importance of having patients with normal calcium levels at baseline and tests to be performed 20 hours after treatment injection. The treatment efficacy is demonstrated by bone turnover markers increase, in particular the anabolic marker osteocalcin average level, has increased more than 5 times from baseline, also the resorption marker b-CTx has raised. These data support the efficacy and safety of PTH 1-84 for the treatment of severe postmenopausal osteoporosis.

65 VIBRATION AS A NON PHARMACOLOGICAL TREATMENT FOR OSTEOPOROSIS

adjunct, or perhaps even alternative, pharmacological treatment of osteoporosis in adults and children. The treatment is particularly attractive for patients who cannot tolerate, or do not want to take, current conventional bone protective therapies. There are two types of devices: those which simulate peak loading to directly improve muscle function (high magnitude, high frequency) and those which induce strains similar to those experienced during postural muscle activity (low magnitude, high frequency). In osteoporotic patients, there are few randomised controlled trials documenting changes in bone outcomes with WBV. The effects of high magnitude, high frequency loading are conflicting, with some studies reporting incremental changes in bone mineral density (BMD), some decremental changes and others no change. The effects of high magnitude, high frequency vibration are much more compelling when studying muscle. The effects of low magnitude, high frequency vibration upon bone have been reported more widely, particularly in children. In post-menopausal women, the treatment reduced bone loss; in children there have been reported incremental change in BMD, bone geometry and muscle mass. Therefore, there is a limited, yet growing, evidencebase for the clinical application of WBV. Effect of WBV is likely to differ depending upon the population being studied and what is to be achieved. For example is it prevention of falls or stimulating bone accretion during growth? Also, the response of bones to loading is likely to depend upon the age of the subject undergoing vibration treatment, with older age diminishing the osteogenic response to loading. Diminishing muscle power during ageing not only exacerbates post-menopausal and age-related bone loss but may also attenuate response to vibration due to changes in muscle stiffness. Therefore, as with physical activity, it is likely that responsiveness to vibration is determined by the age of the individual. More adequately powered trials are required in both types of vibrating technologies. Until then, perhaps use of WBV should be restricted to specialist centres and to research studies until further data are available whereby specific protocols of treatment can be designed.

66 WHOLE-BODY-VIBRATION TRAINING REDUCES FALLS IN POSTMENOPAUSAL WOMEN. PRELININARY 18 MONTHS RESULTS OF THE ERLANGEN LONGITUDINAL VIBRATION STUDY (ELVIS) S. von Stengel W. Kemmler W.A. Kalender and K. Engelke, Institute of Medical Physics, University of Erlangen, Erlangen, Germany; Purpose: To determine the effect of whole body vibration (WBV) within a multi purpose exercise program to influence multiple risk factors of elderly women. Methods: 151 postmenopausal women (age 68.5  3.1) were randomized to a general purpose training group with (VG), or without vibration (TG) or a ‘‘wellness’’ control group (CG). TG and VG performed the same exercise program (twice weekly) consisting of 25 min of aerobic dance and coordination, 20 min of strength training for trunk and upper extremities using elastic bands, and 15 min of strength training for legs on vibration plates (Vibrafit, Sloms, Germany). On the vibration platforms heel rise, one-legged deep squat and leg abduction exercises were carried out. One minute of strength exercise was alternated by one minute of rest with stretching exercises. In VG the plates vibrated at a frequency of 2535 Hz, whereas in TG the plates were switched off. WG performed light exercises and a relaxation program (once weekly). At baseline and after twelve months bone mineral density (BMD) was measured at the hip, lumbar spine and total body using DXA. Falls were recorded daily using the calendar method. Results: After 18 months a significantly higher number of falls were observed in the VG compared with the CG (RR 5 0.42) while no significant effects were observed for the TG. Both training groups significantly gained BMD at the lumbar spine while no changes were observed in WG (TG: 2.1  2.3%; VG: 1.5  2.3%; WG: 0.3  2.2%). At the femoral neck region WG significantly lost BMD ( 1.3  3.3%) while BMD slightly increased in the TG (0.9  4.5%) and was stable in the VG (0.2  2.4%). No vibration related side-effects were reported. Conclusion: These findings suggest that WBV may be an effective approach to reduce the risk of hip fractures by reducing falls. The study was supported by the Elsbeth Bonhoff Foundation, Germany.

K.A. Ward, Imaging Science & Biomedical Engineering, University of Manchester, Manchester, UK; Muscles exert the greatest loads to the skeleton on a daily basis. To prevent damage and fractures, the skeleton responds to loading through alteration in morphology, mass and structure of bones. This interaction between the muscles and bones has led to the development of devices which aim to induce load to the musculoskeletal system by vibrating. The ultimate aim of these whole body vibration (WBV) devices is to provide a non-pharmacological intervention to act as an

Journal of Clinical Densitometry: Assessment of Skeletal Health

67 DENOSUMAB IMPROVES FOREARM DENSITOMETRIC, GEOMETRIC AND STRENGTH INDICES AS MEASURED BY QCT IN POSTMENOPAUSAL WOMEN WITH LOW BMD HK Genant,1,2 K Engelke,2 JP Brown,3 M Omizo,4 HG Bone,5 T Fuerst,2 M Austin,6 H Wang,6 Y Liu,6 and C Libanati6, 1UCSF, San Francisco, CA, USA,

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International Workshop Abstracts

2

Synarc Inc., San Francisco, CA, USA, 3CHUQ, Laval University, Quebec, Canada, 4Oregon Osteoporosis Ctr, Portland, OR, USA, 5Michigan Bone & Mineral Clinic, Detroit, MI, USA, 6Amgen Inc., Thousand Oaks, CA, USA;

% changes  SD from baseline after 12 month# VOI

Denosumab is an investigational fully human monoclonal antibody that specifically targets RANKL to reduce osteoclast formation, function, and survival. Here we describe the effects of denosumab on BMD of the distal region of the forearm as assessed by quantitative computed tomography (QCT). This 2-year randomized, double-blind, phase 3 study was conducted in 332 postmenopausal women with DXA T-scores between 1.0 and 2.5. Subjects were randomized (1:1) to receive subcutaneous denosumab 60 mg every 6 months or placebo. The left forearm was scanned at baseline and months 1, 6, 12, and 24 by QCT using standard whole body spiral CT scanners (120 kV, 1 mm slice thickness, 100 mAs, 10 cm reconstruction field of view). 10 cm of the forearm starting 0.5 cm distally of the radial styloid were scanned. For analysis, Geanie software (Commit Inc. Finland) was used. Custom software allowed extraction of the distal slice at a distance of 20 mm from the styloid process. A dedicated phantom developed in cooperation with QRM GmbH, Germany, was used for simultaneous calibration of the CT values to BMD. Values are reported as least squares mean (95% CI). QCT analysis demonstrated that denosumab significantly increased total BMD of the distal forearm above baseline. A positive change of 2.6% (1.5, 3.8) relative to placebo was reached at 24 months. Significant increases in the cortical 1.7% (1.1, 2.3) and trabecular 9.4% (1.1, 17.6) compartments were also seen. These positive BMD changes were associated with significant improvements in bone geometry and derived indices of bone strength, including cortical thickness and total polar moment of inertia (P ! 0.001). In conclusion, denosumab significantly increased total, cortical, and trabecular BMD at the distal forearm and improved bone geometry and strength parameters. These data expand on the observation that denosumab administration improved DXA BMD at the 1/3 radius, a potentially beneficial effect.

68 REGIONAL DIFFERENCES OF SPINAL BMD CHANGES AFTER ONE YEAR ONCE-MONTHLY IBANDRONATE AS MEASURED BY 3D QCT K. Engelke,1,2 T. Fuerst,1 M.B. Enslin,3 R.Y. Davies,3 L.A. Fitzpatrick,3 D. Ethgen,3 and H. Genant1, 1Synarc Inc. Hamburg, Germany, and San Francisco, CA, USA, 2Institute of Medical Physics, University of Erlangen, Erlangen, Germany, 3GlaxoSmithKline, King of Prussia, PA, USA; Objective: To evaluate local BMD changes in the lumbar vertebrae as measured by 3D QCT in postmenopausal osteoporotic women after one year of oral ibandronate. Methods: In a multi center trial 93 women (age 64  7) were randomized 1:1 to oral once-monthly ibandronate (n 5 47; 150 mg) or placebo (n 5 46); all women received calcium 1000 mg/day and vitamin D 400 mg/ day. 3D QCT of L1 and L2 was performed at baseline and after 12 months. The QCT analysis using MIAF-Spine was based on an automated 3D segmentation of the vertebral bodies and the determination of a vertebral coordinate system relative to which a variety of analysis volumes of interest (VOI) were placed to measure BMD. Here we specifically distinguished the total vertebral body VOI, the 10 mm central (mid) VOI, and the inferior and superior VOIs. Each VOI is further divided into cortical, subcortical and trabecular compartments with the integral compartment being the sum of the three. The extended (ext) cortical compartment comprises of the cortical and the subcortical compartments. For trabecular and cortical analyses the posterior part of the vertebrae was excluded resulting in the so called Osteo VOI. Mean percentage change from baseline to month 12 was calculated in placebo and ibandronate groups, the treatment difference was determined by analysis of variance adjusting for center. All analyses were exploratory; post hoc p values were generated for descriptive purposes only and were not adjusted for multiple comparisons. Results: Scans from 41 (35) subjects in the ibandronate (placebo) group were evaluable at both visits. Average result values of L1 and L2 are shown in the table. Integral BMD treatment differences were comparable in the total vertebra and the mid section. Similar differences were obtained for trabecular BMD in the total vertebra, however, interestingly trabecular treatment differences were higher in the superior and inferior sections than in the mid section, which has been traditionally used for QCT analysis. Treatment differences for the cortical compartment alone were not significant for the mid section probably due to the higher variability associated with a smaller volume but became significant after including the subcortical bone.

Journal of Clinical Densitometry: Assessment of Skeletal Health

Ibandronate

Int BMD total vertebral body 3.0  5.9 Int BMD mid section 2.4  6.8 Trab BMD total vertebral body 1.2  7.7 Trab BMD mid section Osteo 0.5  8.7 Trab BMD inf section Osteo 1.3  9.0 Trab BMD sup section Osteo 1.8  9.8 Cort BMD mid section Osteo 5.2  13.9 ext Cort BMD mid section Osteo 3.5  6.5 Cort BMC mid section Osteo 11.3  27.1

Placebo 1.1  4.1 1.3  4.7 2.8  6.7 2.1  6.6 2.5  8.7 3.4  7.4 1.1  9.4 0.3  4.8 7.8  27.6

% Treatment Diff (95% CI)& 4.4 4.0 4.2 2.3 4.6 4.9 4.4 3.9 3.3

(1.8 to 7.0) (1.0 to 7.0) (0.6 to 7.9) ( 1.6 to 6.2) ( 0.1 to 9.3) (0.4 to 9.4) ( 1.7 to 10.5) (0.8 to 6.9) ( 16.7 to 17.3)

p 0.001 0.011 0.024 0.244 0.055 0.032 0.154 0.014 0.63

#

undajusted means, &adjusted for center

Conclusions: Once-monthly ibandronate increased integral and trabecular BMD of the lumbar spine compared to calcium alone over 12 months. Trabecular changes predominantly occurred in the inferior and superior sections of the vertebrae. Cortical bone was most informative when the subcortical compartment was included. These regional differences contribute to our understanding of the behavior of antiresorptive therapy.

69 THE EFFECTS OF ALENDRONATE ON BONE MINERAL DENSITY IN OSTEOPOROTIC PATIENTS WITH MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE S. Minisola,1 C. Cipriani,1 R. Del Fiacco,1 I. Raso,1 F. Fidanza,1 M. Iorio,1 M.L. Mascia,1 S. Piemonte,1 V. Carnevale,2 A. Scillitani,3 and E. Romagnoli1, 1 Department of Clinical Sciences, University ‘‘La Sapienza’’, Rome, Italy, 2 Departments of Internal Medicine, 3Endocrinology, ‘‘Casa Sollievo della Sofferenza’’ Hospital, San Giovanni Rotondo, Italy Patients with monoclonal gammopathy of undetermined significance (MGUS) may have increased fracture risk, because of raised bone turnover due to an altered RANKL/OPG balance. Thus, a treatment normalizing this negative balance could be of benefit in these patients. We studied 100 patients suffering from de novo MGUS, grouped according to the presence (group A, 50 patients) or absence (group B) of vertebral fractures and/or osteoporosis. The group A was treated with alendronate (70 mg/weekly) plus calcium and cholecalciferol for 18 months, and the group B with calcium and cholecalciferol. In each patient, bone mineral density (BMD) at lumbar and hip level together with bone turnover markers were evaluated every 6 months. After 18 months, the mean bone mineral density of the lumbar spine and total femur had increased by 6.1 and 1.5 percent, respectively, in osteoporotic MGUS patients treated with alendronate. In the nine patients of group A not taking alendronate, BMD values of the lumbar spine and total femur decreased by 1.6 (p  0.001) and 1.3 (p  0.01)%, respectively. In patients of group B, BMD increased by 1.2% at the lumbar spine and decreased by 1.2% at the total femur. Corresponding figures of those patients in the same group non taking calcium and vitamin D supplementation were 0.1 and 1.2%, respectively. In group A, alendronate rapidly induced a marked and persistent decrease of serum ß-CTX, and smaller decreases of the other markers. In group B, bone markers, but sialoprotein, significantly decreased. At 18 months, the difference between the groups was 23.2% for serum isoenzyme of bone alkaline phosphatase (p 0.01), 23.6% for osteocalcin (p 0.01), 35.1% for ßCTX (p 0.001) and e0.47% for BSP (p 5 NS). The increased vertebral BMD and the reduction of bone markers could significantly reduce fracture risk in MGUS patients with osteoporosis treated with alendronate.

70 TERIPARATIDE REDUCES THE SIZE OF REGIONS AT HIGH RISK OF FAILURE AS ASSESSED BY NON-LINEAR FE ANALYSIS IN VIVO C. Graeff,1 Y. Chevalier,2 M. Charlebois,2 P. Varga,2 D. Pahr,2 T.N. Nickelsen,3 C.-C. Gl€ uer,1 and P.K. Zysset2, 1Medical Physics, Clinic of Diagnostic Radiology, University Clinic Schleswig-Holstein, Kiel, Germany, 2Institute for

Volume 12, 2009