Top

Osteoporosis International

Published in:

Open Access 01-05-2017 | Original Article

Observations following discontinuation of long-term denosumab therapy

Authors: M. R. McClung, R. B. Wagman, P. D. Miller, A. Wang, E. M. Lewiecki

Published in: Osteoporosis International | Issue 5/2017

Abstract

Summary

Stopping denosumab after 8 years of continued treatment was associated with bone loss during a 1-year observation study in patients who were not prescribed osteoporosis treatment. Bone loss was attenuated in patients who began another osteoporosis therapy. Treatment to prevent bone loss upon stopping denosumab should be considered.

Introduction

This study aimed to understand osteoporosis management strategies during a 1-year observational follow-up after up to 8 years of denosumab treatment in a phase 2 study.

Methods

During the observational year, patients received osteoporosis management at the discretion of their physician and returned to the clinic for BMD assessment and completion of an osteoporosis management questionnaire. Incidence of serious adverse events and fractures was collected. Analyses were descriptive.

Results

Of 138 eligible patients, 82 enrolled in and completed the observation study. Most (65 [79%]) did not receive prescription osteoporosis medication, with “my doctor felt I no longer needed a medication” being the most common reason (23 [35%]). Of the 17 patients who took osteoporosis medications, 8 discontinued therapy during the observation study. In patients treated with denosumab for 8 years (N = 52), BMD decreased during the 1-year observation study (6.7% [lumbar spine], 6.6% [total hip]). Those who took osteoporosis medication during the observation study showed a smaller decline in BMD than those who did not. No new safety concerns were identified. Eight patients (9.8%), all of whom had at least one predisposing risk factor, experienced 17 fractures. This included seven patients who experienced one or more vertebral fractures.

Conclusions

Consistent with denosumab’s mechanism of action, treatment cessation led to reversal of the drug’s effect on BMD and perhaps fracture risk. For patients who took osteoporosis therapy, bone loss was attenuated. For patients at high fracture risk, switching to another osteoporosis therapy if denosumab is discontinued seems appropriate.

Available only for authorised users

Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney RJ, Pignolo RJ, Sellmeyer DE (2016) Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 31:16–35CrossRefPubMedPubMedCentral

Whitaker M, Guo J, Kehoe T, Benson G (2012) Bisphosphonates for osteoporosis—where do we go from here? N Engl J Med 366:2048–2051CrossRefPubMed

Diab DL, Watts NB (2014) Use of drug holidays in women taking bisphosphonates. Menopause 21:195–197CrossRefPubMed

McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, Hanley DA, Kendler DL, Yuen CK, Lewiecki EM (2013) Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 126:13–20CrossRefPubMed

Banks E, Beral V, Reeves G, Balkwill A, Barnes I, Million Women Study Collaborators (2004) Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 291:2212–2220CrossRefPubMed

Barrett-Connor E, Wehren LE, Siris ES, Miller P, Chen YT, Abbott TA, Berger ML, Santora AC, Sherwood LM (2003) Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study. Menopause 10:412–419CrossRefPubMed

Yates J, Barrett-Connor E, Barlas S, Chen YT, Miller PD, Siris ES (2004) Rapid loss of hip fracture protection after estrogen cessation: evidence from the National Osteoporosis Risk Assessment. Obstet Gynecol 103:440–446CrossRefPubMed

Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, Chlebowski RT, Gass M, LaCroix A, Manson JE, Prentice RL, Rossouw J, Stefanick ML, WHI Investigators (2008) Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 299:1036–1045CrossRefPubMed

Lindsay R, Scheele WH, Neer R, Pohl G, Adami S, Mautalen C, Reginster JY, Stepan JJ, Myers SL, Mitlak BH (2004) Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med 164:2024–2030CrossRefPubMed

10.

Prince R, Sipos A, Hossain A, Syversen U, Ish-Shalom S, Marcinowska E, Halse J, Lindsay R, Dalsky GP, Mitlak BH (2005) Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res 20:1507–1513CrossRefPubMed

11.

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 (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765CrossRefPubMed

12.

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 (2012) Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 27:694–701CrossRefPubMed

13.

Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellstrom D, Radominski SC, Reginster JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S (2013) The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 98:4483–4492CrossRefPubMedPubMedCentral

14.

Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, Brandi ML, Czerwinski 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 (2015) The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int 26:2773–2783CrossRefPubMedPubMedCentral

15.

Bone HG, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwinski E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Dakin P, Wagman RB, Papapoulos S (2015) Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension Trial. J Bone Miner Res (ASBMR Annual Meeting Abstracts) 30(Suppl 1):S471

16.

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 (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821–831CrossRefPubMed

17.

Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, Wang A, Siddhanti S, Fitzpatrick LA, AMG 162 Bone Loss Study Group (2007) Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 22:1832–1841CrossRefPubMed

18.

Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J, AMG 162 Bone Loss Study Group (2008) Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43:222–229CrossRefPubMed

19.

Miller PD, Wagman RB, Peacock M, Lewiecki EM, Bolognese MA, Weinstein RL, Ding B, San Martin J, McClung MR (2011) Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin Endocrinol Metab 96:394–402CrossRefPubMed

20.

McClung MR, Lewiecki EM, Geller ML, Bolognese MA, Peacock M, Weinstein RL, Ding B, Rockabrand E, Wagman RB, Miller PD (2013) Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos Int 24:227–235CrossRefPubMed

21.

Greenspan SL, Emkey RD, Bone HG, Weiss SR, Bell NH, Downs RW, McKeever C, Miller SS, Davidson M, Bolognese MA, Mulloy AL, Heyden N, Wu M, Kaur A, Lombardi A (2002) 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 137:875–883CrossRefPubMed

22.

Wasnich RD, Bagger YZ, Hosking DJ, McClung MR, Wu M, Mantz AM, Yates JJ, Ross PD, Alexandersen P, Ravn P, Christiansen C, Santora AC, Early Postmenopausal Intervention Cohort Study Group (2004) Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause 11:622–630CrossRefPubMed

23.

Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC (2011) Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab 96:972–980CrossRefPubMed

24.

Eisman JA, Bone HG, Hosking DJ, McClung MR, Reid IR, Rizzoli R, Resch H, Verbruggen N, Hustad CM, DaSilva C, Petrovic R, Santora AC, Ince BA, Lombardi A (2011) Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 26:242–251CrossRefPubMed

25.

Ascott-Evans BH, Guanabens N, Kivinen S, Stuckey BG, Magaril CH, Vandormael K, Stych B, Melton ME (2003) Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial. Arch Intern Med 163:789–794CrossRefPubMed

26.

Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, Lang TF, McGowan JA, Rosen CJ, PaTH Study Investigators (2005) One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 353:555–565CrossRefPubMed

27.

Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL, DAPS Investigators (2012) Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int 23:317–326CrossRefPubMed

28.

Boonen S, Ferrari S, Miller PD, Eriksen EF, Sambrook PN, Compston J, Reid IR, Vanderschueren D, Cosman F (2012) Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective. J Bone Miner Res 27:963–974CrossRefPubMed

29.

Ivaska KK, Gerdhem P, Väänänen HK, Akesson K, Obrant KJ (2010) Bone turnover markers and prediction of fracture: a prospective follow-up study of 1040 elderly women for a mean of 9 years. J Bone Miner Res 25:393–403CrossRefPubMed

30.

Brown JP, Roux C, Törring O, Ho PR, Beck Jensen JE, Gilchrist N, Recknor C, Austin M, Wang A, Grauer A, Wagman RB (2013) 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 28:746–752CrossRefPubMedPubMedCentral

31.

Egerdie BR, Tammela T, Sieber P, Lamy O, Ke C, Warner D (2015) Denosumab treatment for bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer: 5-year safety follow-up. Can Urol Assoc J (CUA Annual Meeting Abstracts) 9(5–6 Suppl 2):S91

32.

Anastasilakis AD, Makras P (2016) Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int 27:1929–1930CrossRefPubMed

33.

Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O (2016) Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int 27:1923–1925CrossRefPubMed

34.

Popp AW, Zysset PK, Lippuner K (2016) Rebound-associated vertebral fractures after discontinuation of denosumab—from clinic and biomechanics. Osteoporos Int 27:1917–1921CrossRefPubMed

35.

Black DM, Rosen CJ (2016) Postmenopausal osteoporosis. N Engl J Med 374:2096–2097PubMed

Title: Observations following discontinuation of long-term denosumab therapy
Authors: M. R. McClung
R. B. Wagman
P. D. Miller
A. Wang
E. M. Lewiecki
Publication date: 01-05-2017
Publisher: Springer London
Published in: Osteoporosis International / Issue 5/2017
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-017-3919-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Observations following discontinuation of long-term denosumab therapy

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2017

Hyponatremia and fractures: should hyponatremia be further studied as a potential biochemical risk factor to be included in FRAX algorithms?

Socioeconomic status and bone mineral density in adults by race/ethnicity and gender: the Louisiana osteoporosis study

Significant improvement of bone mineral density and bone turnover markers by denosumab therapy in bisphosphonate-unresponsive patients: response to comments

Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation

Response to: A role for thiazide diuretic therapy in preventing bone loss, fracture and nephrolithiasis in individuals with thalassemia and hypercalciuria?

Dietary potassium intake is beneficial to bone health in a low calcium intake population: the Korean National Health and Nutrition Examination Survey (KNHANES) (2008–2011)