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Bone safety with risedronate: histomorphometric studies at different dose levels and exposure

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Abstract

Summary

This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens.

Introduction

The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate.

Methods

Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated.

Results

Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women.

Conclusions

Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.

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References

  1. Heaney RP (2003) Remodeling and skeletal fragility. Osteoporos Int 14(Suppl 5):S12–S15

    Google Scholar 

  2. Russell RG, Mühlbauer RC, Bisaz S, Williams DA, Fleisch H (1970) The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calcif Tissue Res 6:183–196

    Article  CAS  PubMed  Google Scholar 

  3. Recker RR, Kimmel DB, Parfitt AM, Davies KM, Keshawarz N, Hinders S (1988) Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. J Bone Miner Res 3:133–144

    Article  CAS  PubMed  Google Scholar 

  4. Frost HM (1969) Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res 3:211–237

    Article  CAS  PubMed  Google Scholar 

  5. Bone HG, Downs RW Jr, Tucci JR, Harris ST, Weinstein RS, Licata AA, McClung MR, Kimmel DB, Gertz BJ, Hale E, Polvino WJ (1997) Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers. J Clin Endocrinol Metab 82:265–274

    CAS  PubMed  Google Scholar 

  6. Chavassieux PM, Arlot ME, Roux JP, Portero N, Daifotis A, Yates AJ, Hamdy NA, Malice MP, Freedholm D, Meunier PJ (2000) Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies. J Bone Miner Res 15:754–762

    Article  CAS  PubMed  Google Scholar 

  7. Reszka AA, Rodan GA (2003) Bisphosphonate mechanism of action. Curr Rheumatol Rep 5:65–74

    Article  PubMed  Google Scholar 

  8. Recker RR, Ste-Marie LG, Langdahl B, Czerwinski E, Bonvoisin B, Masanauskaite D, Rowell L, Felsenberg D (2010) Effects of intermittent intravenous ibandronate injections on bone quality and micro-architecture in women with postmenopausal osteoporosis: the DIVA study. Bone 46:660–665

    Article  CAS  PubMed  Google Scholar 

  9. Recker RR, Delmas PD, Halse J, Reid IR, Boonen S, Garcia-Hernandez PA, Supronik J, Lewiecki EM, Ochoa L, Miller P, Hu H, Mesenbrink P, Hartl F, Gasser J, Eriksen EF (2008) Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. J Bone Miner Res 23:6–16

    Article  CAS  PubMed  Google Scholar 

  10. Ott SM, Oleksik A, Lu Y, Harper K, Lips P (2002) Bone histomorphometric and biochemical marker results of a 2-year placebo-controlled trial of raloxifene in postmenopausal women. J Bone Miner Res 17:341–348

    Article  CAS  PubMed  Google Scholar 

  11. Lewiecki EM (2010) Treatment of osteoporosis with denosumab. Maturitas 66:182–186

    Article  CAS  PubMed  Google Scholar 

  12. Burr DB (2002) Targeted and nontargeted remodeling. Bone 30:2–4

    Article  CAS  PubMed  Google Scholar 

  13. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Investig 100:1475–1480

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD (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 282:1344–1352

    Article  CAS  PubMed  Google Scholar 

  15. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R (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 11:83–91

    Article  CAS  PubMed  Google Scholar 

  16. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier PJ, Reginster JY, Hip Intervention Program Study Group (2001) Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 344:333–340

    Article  CAS  PubMed  Google Scholar 

  17. Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP (2004) Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin 20:757–764

    Article  CAS  PubMed  Google Scholar 

  18. Eriksen EF, Melsen F, Sod E, Barton I, Chines A (2002) Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis. Bone 31:620–625

    Article  CAS  PubMed  Google Scholar 

  19. Ste-Marie LG, Sod E, Johnson T, Chines A (2004) Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis. Calcif Tissue Int 75:469–476

    Article  CAS  PubMed  Google Scholar 

  20. McClung MR, Benhamou CL, Man Z, Tlustochowicz W, Zanchetta JR, Eusebio R, Balske AM, Matzkin E, Olszynski WP, Recker R, Delmas PD (2013) A novel monthly dosing regimen of risedronate for the treatment of postmenopausal osteoporosis: 2-year data. Calcif Tissue Int 92:59–67

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. McClung MR, Zanchetta JR, Racewicz A, Roux C, Benhamou CL, Man Z, Eusebio RA, Beary JF, Burgio DE, Matzkin E, Boonen S, Delmas P (2013) Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data. Osteoporos Int 24:293–299

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. McClung MR, Miller PD, Brown JP, Zanchetta J, Bolognese MA, Benhamou CL, Balske A, Burgio DE, Sarley J, McCullough LK, Recker RR (2012) Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet. Osteoporos Int 23:267–276

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Keshawarz NM, Recker RR (1984) Expansion of the medullary cavity at the expense of cortex in postmenopausal osteoporosis. Metab Bone Dis Relat Res 5:223–228

    Article  CAS  PubMed  Google Scholar 

  24. Eriksen EF (1986) Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. Endocr Rev 7:379–408

    Article  CAS  PubMed  Google Scholar 

  25. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker R (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610

    Article  CAS  PubMed  Google Scholar 

  26. Recker RR, Sod EW, Li Z, Chines AA (2003) Bone histology and histomorphometry in a 2-year risedronate study comparing daily and weekly dosing [poster P-149]. Calcif Tissue Int 72:279–313

    Article  Google Scholar 

  27. Chavassieux P, Portero N, Xu S, Eusebio R, Delmas P, Zanchetta J, Valter I, Recker R (2009) Comparison between 150 mg monthly and 5 mg daily risedronate in postmenopausal osteoporosis; effects on bone quality and bone remodelling [abstract P485]. Bone 44(Suppl 2):S439

    Article  Google Scholar 

  28. McClung M, Bolognese M, Miller P, Sarley J, McCullough L, Brown JP, Recker RR (2010) BMD response to a novel delayed-release risedronate 35 mg once-a-week formulation taken with or without breakfast: one year results [abstract FR0388]. J Bone Miner Res 25(Suppl 1):S124

    Google Scholar 

  29. Recker R, Valter I, Maasalu K, Magaril C, Man Z, Zanchetta JR, Mautalen C, Vahula KL, Miller P, Wenderoth D, McClung M (2011) Bone safety of a novel delayed-release risedronate 35 mg once-a-week assessed by bone histology and histomorphometry [abstract SU0421]. J Bone Miner Res 26(Suppl 1). http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=fc92145a-455a-418a-ae06-126ea280ab18. Accessed 26 Nov 2013

  30. Recker R, 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 19:1628–1633

    Article  PubMed  Google Scholar 

  31. Recker RR, Kimmel DB, Dempster D, Weinstein RS, Wronski TJ, Burr DB (2011) Issues in modern bone histomorphometry. Bone 49:955–964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Recker RR, Ste-Marie L, Chavassieux P, Borah B (2010) Multiple studies with risedronate demonstrate consistent bone turnover regardless of dose [abstract P491]. Osteoporos Int 21(Suppl 1):S202

    Google Scholar 

  33. Kimmel DB, Recker RR, Gallagher JC, Vaswani AS, Aloia JF (1990) A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects. Bone Miner 11:217–235

  34. Recker RR, Weinstein RS, Chesnut CH 3rd, Schimmer RC, Mahoney P, Hughes C, Bonvoisin B, Meunier PJ (2004) Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study. Osteoporos Int 15:231–237

    Article  CAS  PubMed  Google Scholar 

  35. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301

    Article  CAS  PubMed  Google Scholar 

  36. Felsenberg D, Boonen S (2005) The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 27:1–11

    Article  PubMed  Google Scholar 

  37. Parfitt AM (1992) Implications of architecture for the pathogenesis and prevention of vertebral fracture. Bone 13(Suppl 2):S41–S47

    Article  PubMed  Google Scholar 

  38. Borah B, Dufresne TE, Chmielewski PA, Johnson TD, Chines A, Manhart MD (2004) Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone 34:736–746

    Article  CAS  PubMed  Google Scholar 

  39. Borah B, Dufresne T, Nurre J, Phipps R, Chmielewski P, Wagner L, Lundy M, Bouxsein M, Zebaze R, Seeman E (2010) Risedronate reduces intracortical porosity in women with osteoporosis. J Bone Miner Res 25:41–47

    Article  CAS  PubMed  Google Scholar 

  40. Prolia® (denosumab). Prescribing information, revised July 2013. http://pi.amgen.com/united_states/prolia/prolia_pi.pdf. Accessed 26 Nov 2013

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Acknowledgments

The study, as well as writing and editorial support, was funded by Warner Chilcott (US) LLC and Sanofi. The authors had full access to the data and were involved in the preparation of the manuscript. The authors played a significant role in writing this manuscript, critically reviewed all versions of the manuscript, and take full responsibility for all content and the decision to submit the manuscript. None of the authors received any form of compensation related to the development of this manuscript. This manuscript was prepared conforming to the guidelines of the International Committee of Medical Journal Editors. The authors would like to thank Tam Vo, PhD, from Excerpta Medica for providing editorial and writing assistance in the preparation of this manuscript.

Conflicts of interest

Dr Recker is a paid consultant for Merck, Lilly, Amgen, and Novartis, and has received grant/research support from Merck, Lilly, Wyeth, Procter & Gamble, Amgen, Roche, GlaxoSmithKline, Novartis, and Sanofi through grants to his institution. Dr Ste-Marie is a paid consultant for Merck, Lilly, Procter & Gamble, Amgen, and Novartis, and has received grants/research support to his institution from Lilly, Wyeth, Procter & Gamble, Amgen, Novartis, and Pfizer. Dr Chavassieux has no conflict of interest. Dr McClung is a paid consultant for Amgen, Lilly, and Merck, and has received grant/research support from Amgen and Merck. Dr Lundy served as a consultant for Warner Chilcott Pharmaceuticals Inc.

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Authors and Affiliations

  1. Osteoporosis Research Center, Creighton University School of Medicine, 601 N. 30th Street Suite 4820, Omaha, NE, 68131, USA

    R. R. Recker

  2. Université de Montréal, CHUM Hôpital Saint-Luc, Montréal, QC, Canada

    L.-G. Ste-Marie

  3. INSERM U1033, Université de Lyon, Lyon, France

    P. Chavassieux

  4. Oregon Osteoporosis Center, Portland, OR, USA

    M. R. McClung

  5. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    M. W. Lundy

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  1. R. R. Recker
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  2. L.-G. Ste-Marie
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  3. P. Chavassieux
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  4. M. R. McClung
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  5. M. W. Lundy
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Correspondence to R. R. Recker.

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Recker, R.R., Ste-Marie, LG., Chavassieux, P. et al. Bone safety with risedronate: histomorphometric studies at different dose levels and exposure. Osteoporos Int 26, 327–337 (2015). https://doi.org/10.1007/s00198-014-2850-y

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