Bisphosphonates for Prevention of Post-Denosumab Bone Loss

NCT03396315 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: AAAR5220
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

Brief Summary

The primary goal of the study is to assess the extent to which bisphosphonate therapy will prevent decreases in bone mass that may occur after cessation of denosumab in premenopausal women with idiopathic osteoporosis (IOP) enrolled in AAAN0161 (FD05114) "Denosumab for the prevention of post-teriparatide bone loss in premenopausal women with idiopathic osteoporosis". In addition, the investigator will observe participants for a second year off bisphosphonate therapy to assess duration of response. The hypothesis is that bisphosphonate therapy with alendronate or zoledronic acid, initiated after recovery of bone remodeling activity, will prevent significant bone loss after discontinuing denosumab.

Conditions

IOP; Osteoporosis

Keywords

premenopausal women

Outcome Measures

Primary Outcomes (1)

• Difference in BMD at the Lumbar Spine (L1-4) Within Group

  Within-group difference (percent change) in BMD at the lumbar spine (L1-4) will be measured by Dual-energy X-ray absorptiometry (DXA) and calculated.

  Baseline, 12 month

Study Arms (2)

alendronate

ACTIVE COMPARATOR

Subjects will receive oral alendronate

Drug: Alendronate

zoledronic acid

ACTIVE COMPARATOR

Subjects will receive zoledronic acid

Drug: Zoledronic Acid

Interventions

Alendronate DRUG

oral alendronate 70 mg weekly for 12 months will be given for the prevention of osteoporosis

Also known as: fosamax

alendronate

Zoledronic Acid DRUG

single intravenous dose of zoledronic acid 5 mg will be given for the prevention of osteoporosis

Also known as: Reclast

zoledronic acid

Eligibility Criteria

• Age: 20 Years - 55 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• All women completing at least 12 months of Forteo treatment and at least 12 months of denosumab under previous research studies who remain without a diagnosis of an excluded medical condition and medication exposures as detailed below, will be offered enrollment into this study.

You may not qualify if:

• Known intolerance to calcium supplements
• Contraindications to bisphosphonate treatment:
• Hypocalcemia
• Pregnancy
• Known hypersensitivity to bisphosphonates
• History of osteomalacia
• History of osteonecrosis of the jaw
• History of dental extraction or other invasive dental surgery within the prior 4 weeks
• Invasive dental work planned in the next 12 months
• Any condition or illness (acute, chronic, or history), which in the opinion of the Investigator might interfere with the evaluation of efficacy and safety during the study or may otherwise compromise the safety of the subject
• Self-reported or known alcohol or drug abuse within the previous 12 months
• Current or recent (within 1 year of enrollment) inflammatory bowel disease or malabsorption
• Abnormal laboratory tests performed during Visit 1
• Renal insufficiency or liver disease: estimated glomerular filtration rate (eGFR) \< 35 ml/min, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>50% above upper limit of normal
• Hypercalcemia, hypocalcemia

Sponsors & Collaborators

• Columbia University: lead
• Amgen: collaborator

Study Sites (2)

Creighton University

Omaha, Nebraska, 68131, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Publications (23)

• Cohen A, Recker RR, Lappe J, Dempster DW, Cremers S, McMahon DJ, Stein EM, Fleischer J, Rosen CJ, Rogers H, Staron RB, Lemaster J, Shane E. Premenopausal women with idiopathic low-trauma fractures and/or low bone mineral density. Osteoporos Int. 2012 Jan;23(1):171-82. doi: 10.1007/s00198-011-1560-y. Epub 2011 Mar 2.

  PMID: 21365462 BACKGROUND

• Cohen A, Dempster DW, Recker RR, Stein EM, Lappe JM, Zhou H, Wirth AJ, van Lenthe GH, Kohler T, Zwahlen A, Muller R, Rosen CJ, Cremers S, Nickolas TL, McMahon DJ, Rogers H, Staron RB, LeMaster J, Shane E. Abnormal bone microarchitecture and evidence of osteoblast dysfunction in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2011 Oct;96(10):3095-105. doi: 10.1210/jc.2011-1387. Epub 2011 Aug 10.

  PMID: 21832117 BACKGROUND

• Cohen A, Lang TF, McMahon DJ, Liu XS, Guo XE, Zhang C, Stein EM, Dempster DW, Young P, Saeed I, Lappe JM, Recker RR, Shane E. Central QCT reveals lower volumetric BMD and stiffness in premenopausal women with idiopathic osteoporosis, regardless of fracture history. J Clin Endocrinol Metab. 2012 Nov;97(11):4244-52. doi: 10.1210/jc.2012-2099. Epub 2012 Sep 7.

  PMID: 22962425 BACKGROUND

• Cohen A, Liu XS, Stein EM, McMahon DJ, Rogers HF, Lemaster J, Recker RR, Lappe JM, Guo XE, Shane E. Bone microarchitecture and stiffness in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2009 Nov;94(11):4351-60. doi: 10.1210/jc.2009-0996. Epub 2009 Oct 16.

  PMID: 19837923 BACKGROUND

• Cohen A, Stein EM, Recker RR, Lappe JM, Dempster DW, Zhou H, Cremers S, McMahon DJ, Nickolas TL, Muller R, Zwahlen A, Young P, Stubby J, Shane E. Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study. J Clin Endocrinol Metab. 2013 May;98(5):1971-81. doi: 10.1210/jc.2013-1172. Epub 2013 Mar 29.

  PMID: 23543660 BACKGROUND

• Nishiyama K, Wang J, Young P, et al. Teriparatide Is Associated with Improved Microarchitecture and Estimated Bone Strength in Premenopausal Women with Idiopathic Osteoporosis: An HR-pQCT Study. American Society for Bone and Mineral Research Annual Meeting; 2013; Baltimore, MD: American Society for Bone and Mineral Research

  BACKGROUND

• Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, Lindsay R. 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 May;16(5):925-31. doi: 10.1359/jbmr.2001.16.5.925.

  PMID: 11341338 BACKGROUND

• Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest. 1998 Oct 15;102(8):1627-33. doi: 10.1172/JCI3914.

  PMID: 9788977 BACKGROUND

• Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial. J Bone Miner Res. 2000 May;15(5):944-51. doi: 10.1359/jbmr.2000.15.5.944.

  PMID: 10804025 BACKGROUND

• Finkelstein JS, Arnold AL. Increases in bone mineral density after discontinuation of daily human parathyroid hormone and gonadotropin-releasing hormone analog administration in women with endometriosis. J Clin Endocrinol Metab. 1999 Apr;84(4):1214-9. doi: 10.1210/jcem.84.4.5643.

  PMID: 10199756 BACKGROUND

• Cohen A, Kamanda-Kosseh M, Recker RR, Lappe JM, Dempster DW, Zhou H, Cremers S, Bucovsky M, Stubby J, Shane E. Bone Density After Teriparatide Discontinuation in Premenopausal Idiopathic Osteoporosis. J Clin Endocrinol Metab. 2015 Nov;100(11):4208-14. doi: 10.1210/jc.2015-2829. Epub 2015 Sep 10.

  PMID: 26358172 BACKGROUND

• Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC. 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. 2011 Apr;96(4):972-80. doi: 10.1210/jc.2010-1502. Epub 2011 Feb 2.

  PMID: 21289258 BACKGROUND

• Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. 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. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.

  PMID: 18539106 BACKGROUND

• Anastasilakis AD, Makras P. Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int. 2016 May;27(5):1929-30. doi: 10.1007/s00198-015-3459-5. Epub 2015 Dec 22. No abstract available.

  PMID: 26694593 BACKGROUND

• Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical Features of 24 Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases. J Bone Miner Res. 2017 Jun;32(6):1291-1296. doi: 10.1002/jbmr.3110. Epub 2017 Mar 13.

  PMID: 28240371 BACKGROUND

• Anastasilakis AD, Yavropoulou MP, Makras P. Bisphosphonates or denosumab discontinuation and risk of fractures. Maturitas. 2017 Aug;102:75. doi: 10.1016/j.maturitas.2017.04.016. Epub 2017 Apr 27. No abstract available.

  PMID: 28495014 BACKGROUND

• Anastasilakis AD, Yavropoulou MP, Makras P, Sakellariou GT, Papadopoulou F, Gerou S, Papapoulos SE. Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment. Eur J Endocrinol. 2017 Jun;176(6):677-683. doi: 10.1530/EJE-16-1027. Epub 2017 Mar 10.

  PMID: 28283537 BACKGROUND

• Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. 2016 May;27(5):1923-5. doi: 10.1007/s00198-015-3380-y. Epub 2015 Oct 28.

  PMID: 26510845 BACKGROUND

• Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: 9 Clinical Cases Report. J Clin Endocrinol Metab. 2017 Feb 1;102(2):354-358. doi: 10.1210/jc.2016-3170.

  PMID: 27732330 BACKGROUND

• Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics. Osteoporos Int. 2016 May;27(5):1917-21. doi: 10.1007/s00198-015-3458-6. Epub 2015 Dec 22.

  PMID: 26694598 BACKGROUND

• Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL; DAPS Investigators. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012 Jan;23(1):317-26. doi: 10.1007/s00198-011-1780-1. Epub 2011 Sep 17.

  PMID: 21927922 BACKGROUND

• Reid IR, Horne AM, Mihov B, Gamble GD. Bone Loss After Denosumab: Only Partial Protection with Zoledronate. Calcif Tissue Int. 2017 Oct;101(4):371-374. doi: 10.1007/s00223-017-0288-x. Epub 2017 May 13.

  PMID: 28500448 BACKGROUND

• Cohen A, Kamanda-Kosseh M, Rawal R, Agarwal S, Barry J, Shiau S, Colon I, Bucovsky M, Lappe JM, Shane E. Bone density and remodeling after discontinuation of sequential therapy for premenopausal idiopathic osteoporosis. Osteoporos Int. 2025 Dec 14. doi: 10.1007/s00198-025-07755-z. Online ahead of print.

  PMID: 41392041 DERIVED

Related Links

• Department of Endocrinology at Columbia University

MeSH Terms

Conditions

Osteoporosis

Interventions

Alendronate; Zoledronic Acid

Condition Hierarchy (Ancestors)

Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Mariana Bucovsky
• Organization: Columbia University

mb3523@cumc.columbia.edu

12123057225

Study Officials

• Elizabeth Shane, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: open-label study in which they would choose whether to take oral alendronate 70 mg weekly for 12 months or a single intravenous dose of zoledronic acid 5 mg.

Study Record Dates

• First Submitted: January 5, 2018
• First Posted: January 10, 2018
• Study Start: January 29, 2018
• Primary Completion: June 9, 2023
• Study Completion: June 9, 2023
• Last Updated: May 8, 2024
• Results First Posted: May 8, 2024

Record last verified: 2024-04

Locations

US (2)