Romosozumab improves lumbar spine bone mass and bone strength parameters relative to alendronate in postmenopausal women: results from the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial

Jacques P Brown, Klaus Engelke, Tony M Keaveny, Arkadi Chines, Roland Chapurlat, A Joseph Foldes, Xavier Nogues, Roberto Civitelli, Tobias De Villiers, Fabio Massari, Cristiano A F Zerbini, Zhenxun Wang, Mary K Oates, Christopher Recknor, Cesar Libanati, Jacques P Brown, Klaus Engelke, Tony M Keaveny, Arkadi Chines, Roland Chapurlat, A Joseph Foldes, Xavier Nogues, Roberto Civitelli, Tobias De Villiers, Fabio Massari, Cristiano A F Zerbini, Zhenxun Wang, Mary K Oates, Christopher Recknor, Cesar Libanati

Abstract

The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://ichgcp.net/clinical-trials-registry/NCT01631214) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: BONE MINERAL CONTENT; BONE STRENGTH; FINITE ELEMENT ANALYSIS; POSTMENOPAUSAL OSTEOPOROSIS; QUANTITATIVE COMPUTED TOMOGRAPHY.

© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Figures

FIGURE 1
FIGURE 1
Least squares mean aBMD percentage change from baseline at the lumbar spine with romosozumab or alendronate treatment at months 6, 12, 18, and 24 by DXA. n = number of randomized patients enrolled in the QCT/FEA imaging component of the ARCH substudy with values at baseline and one or more postbaseline DXA visit at month 6 or month 18 and with values at baseline and one or more postbaseline QCT visit; n1 = number of patients with values at that time point. Month 6 and month 12 measurements were during the double‐blind period when patients received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months; month 18 and month 24 measurements were during the open‐label period when patients received weekly oral open‐label alendronate 70 mg for 12 months. Data were based on ANCOVA model, adjusting for presence of severe vertebral fracture at baseline, baseline aBMD value, machine type, and baseline aBMD value‐by‐machine type interaction. Missing values were imputed by carrying forward the last nonmissing postbaseline value prior to the missing value and within the treatment period. Abbreviations: aBMD, areal bone mineral density; ALN, alendronate; ANCOVA, analysis of covariance; ARCH, Active‐Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk; Diff, difference between the treatment groups; DXA, dual‐energy x‐ray absorptiometry; FEA, finite element analysis; QCT, quantitative computed tomography; ROMO, romosozumab.
FIGURE 2
FIGURE 2
Least squares mean vBMD percentage change from baseline at the lumbar spine with romosozumab or alendronate treatment at months 6, 12, and 24 by QCT: integral vBMD (A), cortical vBMD (B), and trabecular vBMD (C). n = number of randomized patients enrolled in the QCT/FEA imaging component of the ARCH substudy with values at baseline and one or more postbaseline visits; n1 = number of patients with values at that time point. Month 6 and month 12 measurements were during the double‐blind period when patients received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months; month 24 measurements were during the open‐label period when patients received open‐label weekly oral alendronate 70 mg for 12 months. Data were based on ANCOVA model, adjusting for presence of severe vertebral fracture at baseline and baseline vBMD value. Missing values were imputed by carrying forward the last nonmissing postbaseline value prior to the missing value and within the treatment period. Abbreviations: ALN, alendronate; ANCOVA, analysis of covariance; ARCH, Active‐Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk; Diff, difference between the treatment groups; FEA, finite element analysis; QCT, quantitative computed tomography; ROMO, romosozumab; vBMD, volumetric bone mineral density.
FIGURE 3
FIGURE 3
Least squares mean bone strength percentage change from baseline at the lumbar spine with romosozumab or alendronate treatment at months 6, 12, and 24 by FEA: integral bone strength (A), cortical bone strength (B), and trabecular bone strength (C). n = number of randomized patients enrolled in the QCT/FEA imaging component of the ARCH substudy with values at baseline and one or more postbaseline visits; n1 = number of patients with values at that time point. Month 6 and month 12 measurements were during the double‐blind period where patients received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months; month 24 measurements were during the open‐label period when patients received weekly oral open‐label alendronate 70 mg for 12 months. Data were based on ANCOVA model, adjusting for presence of severe vertebral fracture at baseline and baseline FEA value. Missing values were imputed by carrying forward the last nonmissing postbaseline value prior to the missing value and within the treatment period. Abbreviations: ALN, alendronate; ANCOVA, analysis of covariance; ARCH, Active‐Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk; Diff, difference between the treatment groups; FEA, finite element analysis; QCT, quantitative computed tomography; ROMO, romosozumab.
FIGURE 4
FIGURE 4
Correlation of postbaseline absolute changes in integral FEA bone strength and postbaseline absolute changes in integral DXA aBMD (A) and integral QCT vBMD (B) at the lumbar spine for romosozumab‐to‐alendronate and alendronate‐to‐alendronate groups through month 24. Includes randomized patients enrolled in the QCT/FEA imaging component of the ARCH substudy with baseline and one or more postbaseline reported results for the parameters of interest. n1 = number of evaluable measurements, with one or more measurements per patient. Month 6 and month 12 measurements were during the double‐blind period where patients received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months; month 24 measurements were during the open‐label period when patients received open‐label weekly oral alendronate 70 mg for 12 months. Abbreviations: aBMD, areal bone mineral density; ALN, alendronate; ARCH, Active‐Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk; DXA, dual‐energy x‐ray absorptiometry; FEA, finite element analysis; QCT, quantitative computed tomography; R, Spearman's correlation coefficient; ROMO, romosozumab; vBMD, volumetric bone mineral density.

References

    1. Morgan EF, Unnikrisnan GU, Hussein AI. Bone mechanical properties in healthy and diseased states. Annu Rev Biomed Eng. 2018;20:119‐143.
    1. Bouxsein ML, Seeman E. Quantifying the material and structural determinants of bone strength. Best Pract Res Clin Rheumatol. 2009;23:741‐753.
    1. Warriner AH, Patkar NM, Curtis JR, et al. Which fractures are most attributable to osteoporosis? J Clin Epidemiol. 2011;64:46‐53.
    1. Kendler DL, Bauer DC, Davison KS, et al. Vertebral fractures: clinical importance and management. Am J Med. 2016;129:221.e1‐‐e10.
    1. Austin M, Yang Y‐C, Vittinghoff E, et al. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res. 2012;27:687‐693.
    1. Cosman F, Crittenden DB, Ferrari S, et al. FRAME study: the foundation effect of building bone with 1 year of romosozumab leads to continued lower fracture risk after transition to denosumab. J Bone Miner Res. 2018;33:1219‐1226.
    1. Ferrari S, Adachi JD, Lippuner K, et al. Further reductions in nonvertebral fracture rate with long‐term denosumab treatment in the FREEDOM open‐label extension and influence of hip bone mineral density after 3 years. Osteoporos Int. 2015;26:2763‐2771.
    1. Kendler DL, Marin F, Zerbini CAF, et al. Effects of teriparatide and risedronate on new fractures in post‐menopausal women with severe osteoporosis (VERO): a multicentre, double‐blind, double‐dummy, randomised controlled trial. Lancet. 2018;391:230‐240.
    1. Saag KG, Zanchetta JR, Devogelaer J‐P, et al. Effects of teriparatide versus alendronate for treating glucocorticoid‐induced osteoporosis: thirty‐six‐month results of a randomized, double‐blind, controlled trial. Arthritis Rheum. 2009;60:3346‐3355.
    1. Langdahl BL, Libanati C, Crittenden DB, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open‐label, phase 3 trial. Lancet. 2017;390:1585‐1594.
    1. Cosman F, Miller PD, Williams GC, et al. Eighteen months of treatment with subcutaneous abaloparatide followed by 6 months of treatment with alendronate in postmenopausal women with osteoporosis: results of the ACTIVExtend trial. Mayo Clin Proc. 2017;92:200‐210.
    1. Bouxsein ML, Eastell R, Lui L‐Y, et al. Change in bone density and reduction in fracture risk: a meta‐regression of published trials. J Bone Miner Res. 2019;34:632‐642.
    1. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532‐1543.
    1. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377:1417‐1427.
    1. Keaveny TM, McClung MR, Genant HK, et al. Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. J Bone Miner Res. 2014;29:158‐165.
    1. Bauer JS, Kohlmann S, Eckstein F, et al. Structural analysis of trabecular bone of the proximal femur using multislice computed tomography: a comparison with dual x‐ray absorptiometry for predicting biomechanical strength in vitro. Calcif Tissue Int. 2006;78:78‐89.
    1. Nawathe S, Akhlaghpour H, Bouxsein ML, Keaveny TM. Microstructural failure mechanisms in the human proximal femur for sideways fall loading. J Bone Miner Res. 2014;29:507‐515.
    1. Fields AJ, Lee GL, Liu XS, et al. Influence of vertical trabeculae on the compressive strength of the human vertebra. J Bone Miner Res. 2011;26:263‐269.
    1. Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporos Int. 2003;14:S13‐S18.
    1. Osterhoff G, Morgan EF, Shefelbine SJ, et al. Bone mechanical properties and changes with osteoporosis. Injury. 2016;47(Suppl 2):S11‐S20.
    1. Keaveny TM. Biomechanical computed tomography—noninvasive bone strength analysis using clinical computed tomography scans. Ann N Y Acad Sci. 2010;1192:57‐65.
    1. Amgen Inc. EVENITY® (romosozumab‐aqqg) US prescribing information. Amgen Inc., Thousand Oaks, CA, US; 2019. . Accessed July 12, 2021.
    1. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370:412‐420.
    1. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26:19‐26.
    1. McClung MR, Brown JP, Diez‐Perez A, et al. Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double‐blind, phase 2, parallel group study. J Bone Miner Res. 2018;33:1397‐1406.
    1. Engelke K, Mastmeyer A, Bousson V, et al. Reanalysis precision of 3D quantitative computed tomography (QCT) of the spine. Bone. 2009;44:566‐572.
    1. Genant HK, Engelke K, Bolognese MA, et al. Effects of romosozumab compared with teriparatide on bone density and mass at the spine and hip in postmenopausal women with low bone mass. J Bone Miner Res. 2017;32:181‐187.
    1. Mastmeyer A, Engelke K, Fuchs C, Kalender WA. A hierarchical 3D segmentation method and the definition of vertebral body coordinate systems for QCT of the lumbar spine. Med Image Anal. 2006;10:560‐577.
    1. Prevrhal S, Engelke K, Kalender WA. Accuracy limits for the determination of cortical width and density: the influence of object size and CT imaging parameters. Phys Med Biol. 1999;44:751‐764.
    1. Keaveny TM, Crittenden DB, Bolognese MA, et al. Greater gains in spine and hip strength for romosozumab compared with teriparatide in postmenopausal women with low bone mass. J Bone Miner Res. 2017;32:1956‐1962.
    1. Lee DC, Hoffmann PF, Kopperdahl DL, Keaveny TM. Phantomless calibration of CT scans for measurement of BMD and bone strength—inter‐operator reanalysis precision. Bone. 2017;103:325‐333.
    1. Allaire BT, Lu D, Johannesdottir F, et al. Prediction of incident vertebral fracture using CT‐based finite element analysis. Osteoporos Int. 2019;30:323‐331.
    1. Kopperdahl DL, Aspelund T, Hoffmann PF, et al. Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans. J Bone Miner Res. 2014;29:570‐580.
    1. Lewiecki EM, Keaveny TM, Kopperdahl DL, et al. Once‐monthly oral ibandronate improves biomechanical determinants of bone strength in women with postmenopausal osteoporosis. J Clin Endocrinol Metab. 2009;94:171‐180.
    1. Silva MJ, Wang C, Keaveny TM, Hayes WC. Direct and computed tomography thickness measurements of the human, lumbar vertebral shell and endplate. Bone. 1994;15:409‐414.
    1. Prevrhal S, Fox JC, Shepherd JA, Genant HK. Accuracy of CT‐based thickness measurement of thin structures: modeling of limited spatial resolution in all three dimensions. Med Phys. 2003;30:1‐8.
    1. Eswaran SK, Gupta A, Adams MF, Keaveny TM. Cortical and trabecular load sharing in the human vertebral body. J Bone Miner Res. 2006;21:307‐314.
    1. Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104:1595‐1622.
    1. Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587‐594.
    1. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis–2020 update–Executive Summary. Endocr Pract. 2020;26(5):564‐570.
    1. Lee DC, Varela A, Kostenuik PJ, Ominsky MS, Keaveny TM. Finite element analysis of denosumab treatment effects on vertebral strength in ovariectomized cynomolgus monkeys. J Bone Miner Res. 2016;31:1586‐1595.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit