Advertisement

Current Osteoporosis Reports

, Volume 15, Issue 4, pp 343–352 | Cite as

Using Osteoporosis Therapies in Combination

  • Michael R. McClungEmail author
Therapeutics and Medical Management (S Jan de Beur and B Clarke, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Therapeutics and Medical Management

Abstract

Purpose of review

The objective of this review is to update evidence regarding the use of osteoporosis drugs in sequence or in combination to optimize increases in bone mass and strength.

Recent findings

Simultaneous use of denosumab plus teriparatide produces larger increases in BMD than does monotherapy. The use of bisphosphonates or denosumab after teriparatide results in progressive gains in BMD. When switching from bisphosphonates and especially denosumab to teriparatide, an overlap of 6-12 months may prevent the transient loss of BMD in cortical sites. Phase 3 trials document fracture risk reduction with anabolic therapy for 12-18 months followed by an anti-remodeling drug.

Summary

With the exception of adding teriparatide to ongoing denosumab therapy, there is little evidence to support the use of more than one osteoporosis drug at a time. In contrast, sequential therapy regimens of anabolic drugs followed by potent anti-remodeling agents will be the new standard for treating patients at imminent risk of fracture.

Keywords

Osteoporosis anabolic anti-remodeling combination sequential 

Notes

Compliance with Ethical Guidelines

Conflict of Interest

Michael McClung reports receiving payment from Amgen, Merck, and Radius Health as a member of their scientific advisory boards and for speaking at scientific meetings.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Parfitt AM. Age-related structural changes in trabecular and cortical bone: cellular mechanisms and biomechanical consequences. Calcif Tissue Int. 1984;36(Suppl 1):S123–8.CrossRefGoogle Scholar
  2. 2.
    McClung MR, San Martin J, Miller PD, Civitelli R, Bandeira F, Omizo M, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165:1762–8.CrossRefGoogle Scholar
  3. 3.
    Arlot M, Meunier PJ, Boivin G, Haddock L, Tamayo J, Correa-Rotter R, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res. 2005;20:1244–53.CrossRefGoogle Scholar
  4. 4.
    Reeve J, Bradbeer JN, Arlot M, Davies UM, Green JR, Hampton L, et al. hPTH 1-34 treatment of osteoporosis with added hormone replacement therapy: biochemical, kinetic and histological responses. Osteoporos Int. 1991;1:162–70.CrossRefGoogle Scholar
  5. 5.
    Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet. 1997;350:550–5.CrossRefGoogle Scholar
  6. 6.
    •• Cosman F. Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches. Curr Osteoporos Rep. 2014;12:385–95. This commentarythoroughly summarizes the extensive knowledge about combined and sequential therapy as of 2014 CrossRefGoogle Scholar
  7. 7.
    •• Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532–43. In this phase 3 fracture endpoint trial, romosozumab was administered for one year followed by denosumab for an additional 12 months. The substantial reduction in vertebral fracture risk achieved with romosozumab during your one was maintained in year two compared to the effect of placebo followed by denosumab CrossRefGoogle Scholar
  8. 8.
    •• Cosman F, Miller PD, Williams GC, Hattersley G, Hu MY, Valter I, 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;92:200–10. This is the extension of the phase 3 fracture endpoint trial with abaloparatide in which 6 months of alendronate therapy after 18 months of abaloparatide maintained the reduction in fracture risk CrossRefGoogle Scholar
  9. 9.
    Sims NA, Martin TJ. Coupling signals between the osteoclast and osteoblast: how are messages transmitted between these temporary visitors to the bone surface? Front Endocrinol (Lausanne). 2015;24:6–41. doi: 10.3389/fendo.2015.00041.CrossRefGoogle Scholar
  10. 10.
    Borah B, Dufresne TE, Chmielewski PA, Johnson TD, Chines A, Manhart MD. Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone. 2004;34:736–46.CrossRefGoogle Scholar
  11. 11.
    Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev. 2005;26:688–703.CrossRefGoogle Scholar
  12. 12.
    Dempster DW, Roschger P, Misof BM, Zhou H, Paschalis EP, Alam J, et al. Differential effects of teriparatide and zoledronic acid on bone mineralization density distribution at 6 and 24 months in the SHOTZ Study. J Bone Miner Res. 2016;31:1527–35.CrossRefGoogle Scholar
  13. 13.
    •• Seeman E, Martin TJ. Co-administration of antiresorptive and anabolic agents: a missed opportunity. J Bone Miner Res. 2015;30:753–64. This commentary reviews the physiological basis for the simultaneous use of anabolic and anti-remodeling agents, explains the limitation of areal BMD by DXA to evaluate the effectiveness of such combinations and urges more reliance on new imaging techniques to assess changes in structure and strength CrossRefGoogle Scholar
  14. 14.
    Austin M, Yang YC, Vittinghoff E, Adami S, Boonen S, Bauer DC, et al. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res. 2012;27:687–93.CrossRefGoogle Scholar
  15. 15.
    Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW, et al. Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab. 2000;85:720–6.PubMedGoogle Scholar
  16. 16.
    Greenspan SL, Emkey RD, Bone HG, Weiss SR, Bell NH, Downs RW, et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137:875–83.CrossRefGoogle Scholar
  17. 17.
    Greenspan SL, Resnick NM. Parker RA Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. JAMA. 2003;28:2525–33.CrossRefGoogle Scholar
  18. 18.
    Harris ST, Eriksen EF, Davidson M, Ettinger MP, Moffett AH Jr, Baylink DJ, et al. Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2001;8:1890–7.Google Scholar
  19. 19.
    Min YK, Lee DY, Choi SJ, Kim JH, Choi D, Yoon BK. Effects of adding alendronate to ongoing hormone therapy on bone mineral density in postmenopausal Korean women: a randomized, double-blind, placebo-controlled clinical trial. Menopause. 2013;20:761–6.CrossRefGoogle Scholar
  20. 20.
    Ste-Marie LG, Schwartz SL, Hossain A, Desaiah D, Gaich GA. Effect of teriparatide [rhPTH(1–34)] on BMD when given to postmenopausal women receiving hormone replacement therapy. J Bone Miner Res. 2006;21:283–91.CrossRefGoogle Scholar
  21. 21.
    Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res. 2001;16:925–31.CrossRefGoogle Scholar
  22. 22.
    Deal C, Omizo M, Schwartz EN, Eriksen EF, Cantor P, Wang J, et al. Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J Bone Miner Res. 2005;20:1905–11.CrossRefGoogle Scholar
  23. 23.
    Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207–15.CrossRefGoogle Scholar
  24. 24.
    Schafer AL, Sellmeyer DE, Palermo L, Hietpas J, Eastell R, Shoback DM, et al. Six months of parathyroid hormone (1–84) administered concurrently vs sequentially with monthly ibandronate over two years: the PTH and ibandronate combination study (PICS) randomized trial. J Clin Endocrinol Metab. 2012;97:3522–9.CrossRefGoogle Scholar
  25. 25.
    Walker MD, Cusano NE, Sliney J Jr, Romano M, Zhang C, DJ MM, et al. Combination therapy with risedronate and teriparatide in male osteoporosis. Endocrine. 2013;44:237–46.CrossRefGoogle Scholar
  26. 26.
    Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003;349:1216–26.CrossRefGoogle Scholar
  27. 27.
    Finkelstein JS, Wyland JJ, Lee H, Neer RM. Effects of teriparatide, alendronate, or both in women with postmenopausal osteoporosis. J Clin Endocrinol Metab. 2010;95:1838–45.CrossRefGoogle Scholar
  28. 28.
    Cosman F, Wermers RA, Recknor C, Mauck KF, Xie L, Glass EV, et al. Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive agent. J Clin Endocrinol Metab. 2009;94:3772–80.CrossRefGoogle Scholar
  29. 29.
    Cosman F, Keaveny TM, Kopperdahl D, Wermers RA, Wan X, Krohn KD, et al. Hip and spine strength effects of adding vs switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene. J Bone Miner Res. 2013;28:1328–36.CrossRefGoogle Scholar
  30. 30.
    Muschitz C, Kocijan R, Fahrleitner-Pammer A, Lung S, Resch H. Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density. J Bone Miner Res. 2013;28:196–205.CrossRefGoogle Scholar
  31. 31.
    Cosman F, Eriksen EF, Recknor C, Miller PD, Guañabens N, Kasperk C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J Bone Miner Res. 2011;26:503–11.CrossRefGoogle Scholar
  32. 32.
    •• Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet. 2013;382(9886):50–6. This and the follow-up 2 year study (Leder, reference 33) demonstrated a BMD advantage in patients receiving combined therapy with denosumab and teriparatide compared to either therapy alone CrossRefGoogle Scholar
  33. 33.
    •• Leder BZ, Tsai JN, Uihlein AV, Burnett-Bowie SA, Zhu Y, Foley K, et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial. J Clin Endocrinol Metab. 2014;99:1694–700. The two-year extension of the DATA trial provides evidence that following teriparatide with denosumab is beneficial while beginning teriparatide when denosumab is discontinued, without an overlap of both drugs, should be avoided CrossRefGoogle Scholar
  34. 34.
    Idolazzi L, Rossini M, Viapiana O, Braga V, Fassio A, Benini C, et al. Teriparatide and denosumab combination therapy and skeletal metabolism. Osteoporos Int. 2016;27:3301–7.CrossRefGoogle Scholar
  35. 35.
    Tsai JN, Uihlein AV, Burnett-Bowie SA, Neer RM, Zhu Y, Derrico N, et al. Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT Study. J Bone Miner Res. 2015;30:39–45.CrossRefGoogle Scholar
  36. 36.
    • Tsai JN, Uihlein AV, Burnett-Bowie SM, Neer RM, Derrico NP, Lee H, et al. Effects of two years of teriparatide, denosumab, or both on bone microarchitecture and strength (DATA-HRpQCT study). J Clin Endocrinol Metab. 2016;101:2023–30. Using high resolution QCT analysis in the day to trial, combined with therapy with denosumab plus teriparatide resulted in larger increments in trabecular and cortical bone mass and strength then did teriparatidemonotherapy, but the advantage of combined therapy over denosumab alone was small CrossRefGoogle Scholar
  37. 37.
    • Eriksen EF, Brown JP. Commentary: Concurrent administration of PTH and antiresorptives: additive effects or DXA cosmetics. Bone. 2016;86:139–42. This commentary suggests that the apparent BMD advantage of combining denosumab and teriparatide should be interpreted cautiously without more convincing evidence of a clinical advantage CrossRefGoogle Scholar
  38. 38.
    Cosman F, Nieves JW, Dempster DW. Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res. 2017;32:198–202.CrossRefGoogle Scholar
  39. 39.
    McClung M, Recker R, Miller P, Fiske D, Minkoff J, Kriegman A, et al. Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate. Bone. 2007;41:122–8.CrossRefGoogle Scholar
  40. 40.
    Wasnich RD, Bagger YZ, Hosking DJ, McClung MR, Wu M, Mantz AM, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11(6 Pt 1):622–30.CrossRefGoogle Scholar
  41. 41.
    McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM. Observations following discontinuation of long-term denosumab therapy. Osteoporos Int. 2017;28:1723–32.CrossRefGoogle Scholar
  42. 42.
    Ascott-Evans BH, Guanabens N, Kivinen S, Stuckey BG, Magaril CH, Vandormael K, et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial. Arch Intern Med. 2003;163:789–94.CrossRefGoogle Scholar
  43. 43.
    Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti SB. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012;23:317–26.CrossRefGoogle Scholar
  44. 44.
    Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures following denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. 2017; doi: 10.1002/jbmr.3110.CrossRefGoogle Scholar
  45. 45.
    Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1729–38.CrossRefGoogle Scholar
  46. 46.
    Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036–45.CrossRefGoogle Scholar
  47. 47.
    LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;6(305):1305–14.CrossRefGoogle Scholar
  48. 48.
    Brown JP, Roux C, Törring O, Ho PR, Beck Jensen JE, Gilchrist N, et al. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013;28:746–52.CrossRefGoogle Scholar
  49. 49.
    McClung MR. Cancel the denosumab holiday. Osteoporos Int. 2016;27:1677–82.CrossRefGoogle Scholar
  50. 50.
    Prolia Prescribing Information. http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/prolia/prolia_pi.ashx. 2017, page 8. Accessed 26 February 2017.
  51. 51.
    Kendler DL, Roux C, Benhamou CL, Brown JP, Lillestol M, Siddhanti S, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res. 2010;25:72–81.CrossRefGoogle Scholar
  52. 52.
    Roux C, Hofbauer LC, Ho PR, Wark JD, Zillikens MC, Fahrleitner-Pammer A, et al. Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study. Bone. 2014;58:48–54.CrossRefGoogle Scholar
  53. 53.
    Recknor C, Czerwinski E, Bone HG, Bonnick SL, Binkley N, Palacios S, et al. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol. 2013;121:1291–9.CrossRefGoogle Scholar
  54. 54.
    Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab. 2016;101:3163–70.CrossRefGoogle Scholar
  55. 55.
    Cummings SR, Cosman F, Lewiecki EM, Schousboe JT, Bauer DC, Black DM, et al. Goal-directed treatment for osteoporosis: a progress report from the ASBMR-NOF Working Group on goal-directed treatment for osteoporosis. J Bone Miner Res. 2017;32:3–10.CrossRefGoogle Scholar
  56. 56.
    Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015;30:934–44.CrossRefGoogle Scholar
  57. 57.
    Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 2000;85:2129–34.PubMedGoogle Scholar
  58. 58.
    Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, et al. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med. 2005;353:555–65.CrossRefGoogle Scholar
  59. 59.
    Miller PD, Delmas PD, Lindsay R, Watts NB, Luckey M, Adachi J, et al. Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J Clin Endocrinol Metab. 2008;93:3785–93.CrossRefGoogle Scholar
  60. 60.
    Boonen S, Marin F, Obermayer-Pietsch B, Simões ME, Barker C, Glass EV, et al. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2008;93:852–60.CrossRefGoogle Scholar
  61. 61.
    Muschitz C, Kocijan R, Fahrleitner-Pammer A, Pavo I, Haschka J, Schima W, et al. Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density--the CONFORS Study. J Bone Miner Res. 2014;29:1777–85.CrossRefGoogle Scholar
  62. 62.
    Stepan JJ, Burr DB, Li J, Ma YL, Petto H, Sipos A, et al. Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis. Osteoporos Int. 2010;21:2027–36.CrossRefGoogle Scholar
  63. 63.
    Fahrleitner-Pammer A, Burr D, Dobnig H, Stepan JJ, Petto H, Li J, et al. Improvement of cancellous bone microstructure in patients on teriparatide following alendronate pretreatment. Bone. 2016;89:16–24.CrossRefGoogle Scholar
  64. 64.
    Ma YL, Zeng QQ, Chiang AY, Burr D, Li J, Dobnig H, et al. Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment. Bone. 2014;59:139–47.CrossRefGoogle Scholar
  65. 65.
    Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;20(361):756–65.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Institute of Health and AgeingAustralian Catholic UniversityMelbourneAustralia
  2. 2.Oregon Osteoporosis CenterPortlandUSA

Personalised recommendations