Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis

David W Dempster, Jacques P Brown, Astrid Fahrleitner-Pammer, David Kendler, Sebastien Rizzo, Ivo Valter, Rachel B Wagman, Xiang Yin, Susan V Yue, Georges Boivin, David W Dempster, Jacques P Brown, Astrid Fahrleitner-Pammer, David Kendler, Sebastien Rizzo, Ivo Valter, Rachel B Wagman, Xiang Yin, Susan V Yue, Georges Boivin

Abstract

Context: Denosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis.

Objective: Determine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics.

Design and setting: International, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension.

Patients: Postmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points.

Interventions: FREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years.

Outcomes: Bone histology, histomorphometry, matrix mineralization.

Results: Ten-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter.

Conclusions: Denosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.

Trial registration: ClinicalTrials.gov NCT00089791.

Figures

Figure 1.
Figure 1.
Percentage of bone biopsies with any fluorochrome on trabecular, cortical, and trabecular or cortical bone. n, number of biopsies with any label; N, number of evaluable biopsies.
Figure 2.
Figure 2.
Bone histomorphometry results for iliac crest bone biopsies from FREEDOM and the extension. All parameters except cortical width were obtained from cancellous bone. Data represent median and interquartile range, n = number of subjects with observed data; N = number of randomized subjects who enrolled in the bone biopsy substudy who received at least 1 dose of investigational product during FREEDOM (for the FREEDOM groups) and during extension (for the extension groups), and had at least one evaluable biopsy. *P < 0.05 vs placebo years 2/3; †P < 0.05 vs denosumab year 2/3; §P < 0.05 vs denosumab year 5, by two-sided Wilcoxon rank-sum test. BFR, bone formation rate; TV, tissue volume.
Figure 3.
Figure 3.
Digitized microradiographs of single cortices of iliac crest bone biopsies representative of placebo (PBO) year 2 group and denosumab (DMAb) years 2, 5, and 10. Samples were selected based on cortical DMB and HI values (bottom) similar to their respective group’s median values (in parentheses). For the year 2 PBO and DMAb samples, the group median values (in parentheses) represent values for years 2 and 3 combined.
Figure 4.
Figure 4.
DMB and HI for iliac crest bone biopsies. Note that the y-axis scales are truncated. For the box-and-whisker plots, the box’s lower bound represents the first quartile (Q1), its upper bound represents the third quartile (Q3), the line is the median, the diamond is the mean, and the circles are outliers. The gray bands with dashed lines represent the interquartile range (Q1–Q3) and median value, respectively, for the premenopausal reference group (n = 42), from which endocortical and periosteal subcompartment mineralization data were not obtained. *P < 0.05 vs placebo years 2/3, †P < 0.05 vs denosumab years 2/3, §P < 0.05 vs premenopausal reference group, by two-sided Wilcoxon rank-sum test for between-group comparisons. n = number of subjects with observed data.
Figure 5.
Figure 5.
Additional DMB and HI results for denosumab-treated subjects. Note that the x-axis scales are truncated. (A) Results for sequential biopsies from 11 denosumab-treated subjects that provided serial bone biopsy samples. (B) DMB and HI results in total bone for subjects with and without fluorochrome labels. The box-and-whisker plots and n values are explained in the Fig 4. legend.

References

    1. Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, San Martin J, Dansey R. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11(5):401–419.
    1. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial . Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.
    1. Reid IR, Miller PD, Brown JP, Kendler DL, Fahrleitner-Pammer A, Valter I, Maasalu K, Bolognese MA, Woodson G, Bone H, Ding B, Wagman RB, San Martin J, Ominsky MS, Dempster DW; Denosumab Phase 3 Bone Histology Study Group . Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res. 2010;25(10):2256–2265.
    1. Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS. Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone. 2011;49(2):151–161.
    1. Brown JP, Reid IR, Wagman RB, Kendler D, Miller PD, Jensen JE, Bolognese MA, Daizadeh N, Valter I, Zerbini CA, Dempster DW. Effects of up to 5 years of denosumab treatment on bone histology and histomorphometry: the FREEDOM study extension. J Bone Miner Res. 2014;29(9):2051–2056.
    1. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwiński E, Krieg MA, Man Z, Mellström D, Radominski SC, Reginster JY, Resch H, Román Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012;27(3):694–701.
    1. Ferrari S, Adachi JD, Lippuner K, Zapalowski C, Miller PD, Reginster JY, Törring O, Kendler DL, Daizadeh NS, Wang A, O’Malley CD, Wagman RB, Libanati C, Lewiecki EM. 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(12):2763–2771.
    1. Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, Brandi ML, Czerwiński E, Franek E, Lakatos P, Mautalen C, Minisola S, Reginster JY, Jensen S, Daizadeh NS, Wang A, Gavin M, Libanati C, Wagman RB, Bone HG. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int. 2015;26(12):2773–2783.
    1. Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513–523.
    1. Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, Kostenuik PJ. Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone. 2011;49(2):162–173.
    1. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90(3):1294–1301.
    1. Miyazaki T, Tokimura F, Tanaka S. A review of denosumab for the treatment of osteoporosis. Patient Prefer Adherence. 2014;8:463–471.
    1. Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, Lorich DG, Lane JM, Boskey AL. Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res. 2012;27(3):672–678.
    1. Allen MR, Burr DB. Mineralization, microdamage, and matrix: how bisphosphonates influence material properties of bone. Bonekey Osteovision. 2007;4(2):49–60.
    1. Kostenuik PJ, Nguyen HQ, McCabe J, Warmington KS, Kurahara C, Sun N, Chen C, Li L, Cattley RC, Van G, Scully S, Elliott R, Grisanti M, Morony S, Tan HL, Asuncion F, Li X, Ominsky MS, Stolina M, Dwyer D, Dougall WC, Hawkins N, Boyle WJ, Simonet WS, Sullivan JK. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res. 2009;24(2):182–195.
    1. Bonnet N, Gerbaix M, Ominsky M, Ammann P, Kostenuik PJ, Ferrari SL. Influence of fatigue loading and bone turnover on bone strength and pattern of experimental fractures of the tibia in mice. Calcif Tissue Int. 2016;99(1):99–109.
    1. Norman TL, Yeni YN, Brown CU, Wang Z. Influence of microdamage on fracture toughness of the human femur and tibia. Bone. 1998;23(3):303–306.
    1. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000;27(5):687–694.
    1. Zoehrer R, Roschger P, Paschalis EP, Hofstaetter JG, Durchschlag E, Fratzl P, Phipps R, Klaushofer K. Effects of 3- and 5-year treatment with risedronate on bone mineralization density distribution in triple biopsies of the iliac crest in postmenopausal women. J Bone Miner Res. 2006;21(7):1106–1112.
    1. Misof BM, Roschger P, Gabriel D, Paschalis EP, Eriksen EF, Recker RR, Gasser JA, Klaushofer K. Annual intravenous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort. J Bone Miner Res. 2013;28(3):442–448.
    1. Valenta A, Roschger P, Fratzl-Zelman N, Kostenuik PJ, Dunstan CR, Fratzl P, Klaushofer K. Combined treatment with PTH (1-34) and OPG increases bone volume and uniformity of mineralization in aged ovariectomized rats. Bone. 2005;37(1):87–95.
    1. Ross AB, Bateman TA, Kostenuik PJ, Ferguson VL, Lacey DL, Dunstan CR, Simske SJ. The effects of osteoprotegerin on the mechanical properties of rat bone. J Mater Sci Mater Med. 2001;12(7):583–588.
    1. Misof BM, Roschger P, Ominsky MS, Messmer P, Kostenuik P, Klaushofer K. The effect of denosumab on bone matrix mineralization in mice [abstract]. J Bone Miner Res. 2011;26(Suppl. 1):S94. Abstract 0058.
    1. Meunier PJ, Boivin G. Bone mineral density reflects bone mass but also the degree of mineralization of bone: therapeutic implications. Bone. 1997;21(5):373–377.
    1. Follet H, Boivin G, Rumelhart C, Meunier PJ. The degree of mineralization is a determinant of bone strength: a study on human calcanei. Bone. 2004;34(5):783–789.
    1. Bala Y, Farlay D, Delmas PD, Meunier PJ, Boivin G. Time sequence of secondary mineralization and microhardness in cortical and cancellous bone from ewes. Bone. 2010;46(4):1204–1212.
    1. Turner CH. Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int. 2002;13(2):97–104.
    1. Lloyd AA, Gludovatz B, Riedel C, Luengo EA, Saiyed R, Marty E, Lorich DG, Lane JM, Ritchie RO, Busse B, Donnelly E. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci USA. 2017;114(33):8722–8727.
    1. Boskey AL, Spevak L, Weinstein RS. Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int. 2009;20(5):793–800.
    1. Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2–17.
    1. Montagner F, Kaftandjian V, Farlay D, Brau D, Boivin G, Follet H. Validation of a novel microradiography device for characterization of bone mineralization. J XRay Sci Technol. 2015;23(2):201–211.
    1. Parisien M, Cosman F, Morgan D, Schnitzer M, Liang X, Nieves J, Forese L, Luckey M, Meier D, Shen V, Lindsay R, Dempster DW. Histomorphometric assessment of bone mass, structure, and remodeling: a comparison between healthy black and white premenopausal women. J Bone Miner Res. 1997;12(6):948–957.
    1. Roschger P, Gupta HS, Berzlanovich A, Ittner G, Dempster DW, Fratzl P, Cosman F, Parisien M, Lindsay R, Nieves JW, Klaushofer K. Constant mineralization density distribution in cancellous human bone. Bone. 2003;32(3):316–323.
    1. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ; AMG 162 Bone Loss Study Group . Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821–831.
    1. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte M; American Society for Bone and Mineral Research . Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25(11):2267–2294.
    1. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24(1):153–161.
    1. Miller P, Pannacciulli N, Malouf-Sierra J, Singer A, Czerwinski E, Bone HG, Wang C, Wagman RB, Brown JP. A meta-analysis of four clinical trials of denosumab compared with bisphosphonates in postmenopausal women previously treated with oral bisphosphonates. J Bone Miner Res. 2017;32(Suppl 1):S271.
    1. Currey JD. The effect of porosity and mineral content on the Young’s modulus of elasticity of compact bone. J Biomech. 1988;21(2):131–139.
    1. Marotti G, Favia A, Zallone AZ. Quantitative analysis on the rate of secondary bone mineralization. Calcif Tissue Res. 1972;10(1):67–81.
    1. Farlay D, Armas LA, Gineyts E, Akhter MP, Recker RR, Boivin G. Nonenzymatic glycation and degree of mineralization are higher in bone from fractured patients with type 1 diabetes mellitus. J Bone Miner Res. 2016;31(1):190–195.
    1. Mailhot G, Dion N, Farlay D, Rizzo S, Bureau NJ, Jomphe V, Sankhe S, Boivin G, Lands LC, Ferraro P, Ste-Marie LG. Impaired rib bone mass and quality in end-stage cystic fibrosis patients. Bone. 2017;98:9–17.
    1. Bala Y, Depalle B, Farlay D, Douillard T, Meille S, Follet H, Chapurlat R, Chevalier J, Boivin G. Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. J Bone Miner Res. 2012;27(4):825–834.
    1. Roschger P, Lombardi A, Misof BM, Maier G, Fratzl-Zelman N, Fratzl P, Klaushofer K. Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data from the fracture intervention trial long-term extension (FLEX). J Bone Miner Res. 2010;25(1):48–55.
    1. Ferrari S, Butler P, Kendler DL, Miller PD, Roux C, Wang AT, Wagman RB, Lewiecki EM. Ten-year continued nonvertebral fracture reduction in postmenopausal women with denosumab treatment. J Bone Miner Res. 2017;32:S25.
    1. Ominsky MS, Libanati C, Niu QT, Boyce RW, Kostenuik PJ, Wagman RB, Baron R, Dempster DW. Sustained modeling-based bone formation during adulthood in cynomolgus monkeys may contribute to continuous BMD gains with denosumab. J Bone Miner Res. 2015;30(7):1280–1289.
    1. Dempster D, Zhou H, Recker R, Brown J, Recknor C, Lewiecki EM, Miller P, Rao S, Kendler D, Lindsay R, Krege JH, Alam J, Taylor K, Ruff VA. Longitudinal changes in modeling- and remodeling-based bone formation with an anabolic vs. an antiresorptive agent in the AVA osteoporosis study. J Bone Miner Res. 2016;31:S51.
    1. Recker RR, Kimmel DB, Parfitt AM, Davies KM, Keshawarz N, Hinders S. Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. J Bone Miner Res. 1988;3(2):133–144.

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