Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis

NCT03087851 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: 2015-005529-37
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

Brief Summary

Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of mature osteoclasts. Treatment markedly decrease bone resorption and fracture risk, and many patients will reach osteopenic bone mineral density (BMD) levels on treatment with denosumab. The treatment effect on bone turnover and BMD has, however, been demonstrated to be reversible. This study will show if the bone mass can be maintained by administrating zoledronic acid and if timing of the first dose of zoledronic acid after last dose of denosumab matters.

Conditions

Osteoporosis

Keywords

Denosumab; Bone turnover markers; Bone mineral density

Outcome Measures

Primary Outcomes (2)

• Change in Lumbar Spine BMD From Baseline to 6 Months After the Zoledronic Acid Infusion.

  Change in lumbar spine BMD from baseline to 6 months after the zoledronic acid infusion.

  baseline to 6 months after the zoledronic acid infusion

• Number of Participants Who Fail to Maintain BMD

  Failure is defined as ≥ 3 % BMD loss at the lumbar spine

  2 years after the first ZOL treatment

Secondary Outcomes (6)

• Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion.

  from baseline to one year after the zoledronic acid infusion

• Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion.

  from baseline to two years after the zoledronic acid infusion.

• Changes in Cortical Porosity Measured by High-resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Scan at the Radius and Tibia From Baseline to One Year After the Zoledronic Acid Infusion.

  from baseline to one year after the zoledronic acid infusion.

• Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion.

  from baseline to six months after the zoledronic acid infusion.

• Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion.

  from baseline to 12 months after the zoledronic acid infusion.

Study Arms (3)

6-month group

ACTIVE COMPARATOR

Zoledronic acid will be administered at study day 0. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered.

Drug: Zoledronic Acid

9-months group

ACTIVE COMPARATOR

Zoledronic acid will be administered depending on increase in s-CTX (above 1.26 ug/l) or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 3. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered.

Drug: Zoledronic Acid

Observation group

ACTIVE COMPARATOR

Zoledronic acid will be administered depending on increase in s-CTX (above 1.26 ug/l), decrease in BMD (more than 5% at any site), or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 6. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered.

Drug: Zoledronic Acid

Interventions

Zoledronic Acid DRUG

Intravenous infusion of 5 mg zoledronic acid

Also known as: Zoledronate

6-month group; 9-months group; Observation group

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Postmenopausal women (postmenopausal for at least two years)
• Men above 50 years
• Treatment for at least two years with denosumab
• Last denosumab injection less than five months ago

You may not qualify if:

• Low-energy vertebral fracture at any time
• Low-energy hip fracture within the last 12 months
• BMD T-score \< -2,5 (lumbar spine, total hip or femoral neck)
• Alendronate treatment for more than three years prior to denosumab treatment
• Ongoing treatment with glucocorticoids
• Metabolic bone disease
• Hormone replacement therapy
• Cancer
• Estimated glomerular filtration rate (eGFR) \< 35 mL/min
• Allergy to zoledronic acid
• Hypocalcaemia
• Contraindications for zoledronic acid according to the SPC

Sponsors & Collaborators

• Aarhus University Hospital: lead
• University of Aarhus: collaborator
• Amgen: collaborator

Study Sites (1)

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

Aarhus, 8000, Denmark

Location

Related Publications (9)

• 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 May;11(5):401-19. doi: 10.1038/nrd3705.

  PMID: 22543469 BACKGROUND

• 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 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.

  PMID: 19671655 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

• Koldkjaer Solling AS, Harslof T, Kaal A, Rejnmark L, Langdahl B. Hypercalcemia after discontinuation of long-term denosumab treatment. Osteoporos Int. 2016 Jul;27(7):2383-2386. doi: 10.1007/s00198-016-3535-5. Epub 2016 Apr 20.

  PMID: 27098536 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

• 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

• 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 Nov;25(11):2267-94. doi: 10.1002/jbmr.253.

  PMID: 20842676 BACKGROUND

• Solling AS, Harslof T, Langdahl B. Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study. J Bone Miner Res. 2021 Jul;36(7):1245-1254. doi: 10.1002/jbmr.4305. Epub 2021 Apr 20.

  PMID: 33813753 DERIVED

• Solling AS, Harslof T, Langdahl B. Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial. J Bone Miner Res. 2020 Oct;35(10):1858-1870. doi: 10.1002/jbmr.4098. Epub 2020 Jul 12.

  PMID: 32459005 DERIVED

MeSH Terms

Conditions

Osteoporosis

Interventions

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

Limitations and Caveats

Open-label design, no assessment by VFA or X-ray of VFx at baseline, changes in treatment not in accordance with the protocol. Information about BMD before initiation of DMAB is not available and the BMD loss can therefore not be evaluated in the context of the BMD gain during DMAB. Our p-CTX cutoff was 50% above the normal range for postmenopausal women and elderly men and it cannot be ruled out that the outcome of the study would have been different with a different cutoff.

Results Point of Contact

• Title: MD Anne Sophie Sølling
• Organization: Dep. of Endocrinology and Internal Medicine, Aarhus University Hospital

annesoel@rm.dk

78 45 54 75

Study Officials

• Bente L Langdahl, MD PhD DMSc

  Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD student

Study Record Dates

• First Submitted: March 13, 2017
• First Posted: March 23, 2017
• Study Start: March 13, 2017
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: February 21, 2021
• Results First Posted: January 14, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)