CompletedNCT03087851ZOLARMABUpdated Feb 21, 2021Results posted

Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis

A Phase 4 interventional study of Zoledronic Acid in Osteoporosis, sponsored by Aarhus University Hospital. Completed at 1 site in Denmark. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2021-02-21.

Sponsored by Aarhus University Hospital · Phase 4, Interventional, and Prevention

Phase: Phase 4
Study type: Interventional
Enrollment: 61
Allocation: Randomized
Ages: 50 Years and older
Sex: All

Study 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.

Read the detailed description

Background: Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of osteoclasts. Treatment decreases bone resorption and fracture risk. After discontinuation, however, bone resorption increases and the bone mass gained during 2 years of therapy is lost within 1 year. At present denosumab treatment is considered to be life-long.

Aim: To investigate if infusion of zoledronic acid can prevent increases in bone turnover and bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronic acid at six or nine months after the last injection of denosumab or when bone turnover is increased.

Methods: A randomized open label, interventional study in 60 patients investigating if treatment with zoledronic acid prevents bone loss after denosumab treatment when administrated six or nine months after last injection of deno-sumab or when bone turnover is increased. Forty patients will be allocated to the two intervention groups and 20 patients will be followed without treatment for up to 12 months after the last denosumab treatment. The patients in the observation group and the nine months group will be monitored monthly and if s-carboxy-terminal collagen cross-links (s-CTX) increases above 1.26ug/l (50% above the normal range for postmenopausal women and elderly men) infusion of zoledronic acid will be administered. Furthermore, a DXA scan (lumbar spine and hip sites) will be performed after three months in the observation group. If BMD has decreased more than 5% at any site, infusion of zoledronic acid will be administered. Finally, if a patient in the 9 months group or the in the observation group suffers an osteoporotic clinical vertebral or hip fracture, infusion of zoledronic acid will be administered.

The patients will be monitored with DXA 6, 12 and 24 months after the infusion of zoledronic acid. Zoledronic acid will be re-administered if BMD has decreased more than 5% at the lumbar spine, total hip or femoral neck. If s-CTX in-creases above 1.26 ug/l during the 2nd year a second infusion of zoledronic acid will be administered.

Perspectives: Many patients will reach osteopenic BMD levels on treatment with denosumab, however the treatment effect on bone turnover and BMD has been demonstrated to be reversible and it is therefore important to find out if denosumab treatment can be discontinued and bone mass maintained by other measures. 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. If bone loss can be prevented by zoledronic acid expenses on otherwise life-long denosumab treatment can be saved and long-term side effects of denosumab (atypical femur fractures and osteone-crosis of the jaw) can be prevented.

Conditions studied

Osteoporosis

Browse trials for

Osteoporosis 1,640

Keywords

Denosumab
Bone turnover markers
Bone mineral density

In context

Osteoporosis

1,640 studies on the registry are indexed under Osteoporosis; 212 are open to participants now.

This study's enrollment of 61 is below the median of 95 across 1,133 interventional studies indexed under Osteoporosis.

Browse Osteoporosis studies →

Lead sponsor

Aarhus University Hospital is the lead sponsor of 289 studies on the registry; 79 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 50 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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

Exclusion criteria

Exclusion Criteria:

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

Study design

Phase: Phase 4
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 61 participants (actual)

Study arms

Active comparator
6-month group
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
Active comparator
9-months group
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
Active comparator
Observation group
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

DrugZoledronic Acid
Intravenous infusion of 5 mg zoledronic acid
Also known as: Zoledronate

What researchers measure

Primary outcomes

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.
Time frame: 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
Time frame: 2 years after the first ZOL treatment

Secondary outcomes

Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion.
Changes in lumbar spine BMD from baseline to one year after the zoledronic acid infusion.
Time frame: from baseline to one year after the zoledronic acid infusion
Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion.
Changes in lumbar spine BMD from baseline to two years after the zoledronic acid infusion.
Time frame: 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.
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.
Time frame: from baseline to one year after the zoledronic acid infusion.
Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion.
Changes in p-CTX from baseline to six months after the zoledronic acid infusion.
Time frame: from baseline to six months after the zoledronic acid infusion.
Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion.
Changes in p-CTX from baseline to 12 months after the zoledronic acid infusion.
Time frame: from baseline to 12 months after the zoledronic acid infusion.
Morphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion.
Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) one and two years after the zoledronic acid infusion.
Time frame: one and two years after the zoledronic acid infusion.

Results

Posted Jan 14, 2021

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.

Participant flow

We recruited participants from the Department of Endocrinology, Aarhus University Hospital, Denmark and via advertisements in newspapers and online. The Danish Health Data Authority provided two data extractions, with information on patients living in the Central Region of Denmark, who had redeemed a minimum of 5 prescriptions for denosumab (DMAB) within the last 3 years.

Participant flow — Overall Study
Milestone	6-month Group	9-months Group	Observation Group
Started	20	20	21
Completed	20	19	19
Not completed	0	1	2
Withdrew: Withdraw on medical grounds	0	1	2

Outcome measures

PrimaryChange 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.

Time frame:: baseline to 6 months after the zoledronic acid infusion
Reported as:: Mean · percentage change

Change in Lumbar Spine BMD From Baseline to 6 Months After the Zoledronic Acid Infusion.
percentage change	6-month Group	9-months Group	Observation Group
Change in Lumbar Spine BMD From Baseline to 6 Months After the Zoledronic Acid Infusion.	-2.1 ± 0.9	-4.3 ± 1.1	-3.0 ± 1.1

PrimaryNumber of Participants Who Fail to Maintain BMD

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

Time frame:: 2 years after the first ZOL treatment
Reported as:: Number · participants

Number of Participants Who Fail to Maintain BMD
participants	6-month Group	9-months Group	Observation Group
Number of Participants Who Fail to Maintain BMD	10	5	6

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

Changes in lumbar spine BMD from baseline to one year after the zoledronic acid infusion.

Time frame:: from baseline to one year after the zoledronic acid infusion
Reported as:: Mean · percentage change

Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion.
percentage change	6-month Group	9-months Group	Observation Group
Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion.	-4.8 ± 0.7	-4.1 ± 1.1	-4.7 ± 1.2

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

Changes in lumbar spine BMD from baseline to two years after the zoledronic acid infusion.

Time frame:: from baseline to two years after the zoledronic acid infusion.
Reported as:: Mean · percentage change

Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion.
percentage change	6-month Group	9-months Group	Observation Group
Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion.	-4.0 ± 0.8	-4.1 ± 0.8	-4.3 ± 1.5

SecondaryChanges 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.

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.

Time frame:: from baseline to one year after the zoledronic acid infusion.
Reported as:: Mean · percentage change

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.
percentage change	6-month Group	9-months Group	Observation Group
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.	-2.5 ± 7.4	-1.6 ± 6.7	-4.2 ± 7.2

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

Changes in p-CTX from baseline to six months after the zoledronic acid infusion.

Time frame:: from baseline to six months after the zoledronic acid infusion.
Reported as:: Mean · ug/l

Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion.
ug/l	6-month Group	9-months Group	Observation Group
Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion.	0.60 ± 0.35	0.47 ± 0.24	0.47 ± 0.20

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

Changes in p-CTX from baseline to 12 months after the zoledronic acid infusion.

Time frame:: from baseline to 12 months after the zoledronic acid infusion.
Reported as:: Mean · ug/l

Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion.
ug/l	6-month Group	9-months Group	Observation Group
Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion.	0.58 ± 0.23	0.40 ± 0.20	0.49 ± 0.21

SecondaryMorphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion.

Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) one and two years after the zoledronic acid infusion.

Time frame:: one and two years after the zoledronic acid infusion.
Reported as:: Number · participants

Morphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion.
participants	6-month Group	9-months Group	Observation Group
Morphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion.	0	2	0

Adverse events

Collected over 2 - 2.5 years. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
6-month Group	0/20 (0%)	0/20 (0%)	18/20 (90%)
9-months Group	0/20 (0%)	1/20 (5%)	18/20 (90%)
Observation Group	0/21 (0%)	4/21 (19%)	20/21 (95.2%)

Most frequent serious events

Most frequent serious events
Event	6-month Group	9-months Group	Observation Group
CancerInvestigations	0/20	1/20	4/21

Most frequent other events

Most frequent other events
Event	6-month Group	9-months Group	Observation Group
Infection (unspecified) + Musculoskeletal symptomsInfections and infestations	13/20	18/20	15/21
Flu-like symptoms after ZOL treatmentMusculoskeletal and connective tissue disorders	13/20	8/20	16/21
FractureMusculoskeletal and connective tissue disorders	2/20	2/20	2/21

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	6-month Group	9-months Group	Observation Group	Total
<=18 years	0	0	0	0
Between 18 and 65 years	8	12	7	27
>=65 years	12	8	14	34

Age, Continuous
Age, Continuous(years)	6-month Group	9-months Group	Observation Group	Total
Mean	68 ± 8	65 ± 7	69 ± 9	68 ± 8

Sex: Female, Male
Sex: Female, Male(Participants)	6-month Group	9-months Group	Observation Group	Total
Female	18	17	19	54
Male	2	3	2	7

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	6-month Group	9-months Group	Observation Group	Total
Hispanic or Latino	0	0	0	0
Not Hispanic or Latino	20	20	21	61
Unknown or Not Reported	0	0	0	0

Lumbar spine BMD
Lumbar spine BMD(g/cm^2)	6-month Group	9-months Group	Observation Group	Total
Mean	0,880 ± 0.055	0,878 ± 0,063	0,871 ± 0,089	0,876 ± 0,069

Study locations

1 site

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
Aarhus, 8000, Denmark

References and documents

Publications

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. PubMed 22543469 ↗
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. Erratum In: N Engl J Med. 2009 Nov 5;361(19):1914. PubMed 19671655 ↗
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. PubMed 18539106 ↗
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. PubMed 27098536 ↗
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. PubMed 26510845 ↗
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. PubMed 26694593 ↗
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. Erratum In: J Bone Miner Res. 2011 Aug;26(8):1987. PubMed 20842676 ↗
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. PubMed 33813753 ↗
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. PubMed 32459005 ↗

Study documents

Protocol and statistical analysis plan · Jan 29, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Feb 21, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03087851
Lead sponsor: Aarhus University Hospital
Collaborators: University of Aarhus, Amgen
Responsible party: Anne Sophie Sølling (MD, PhD student, Aarhus University Hospital) — Principal investigator
First posted: Mar 23, 2017
Start date: Mar 13, 2017
Primary completion: Aug 1, 2020
Completion: Aug 1, 2020
Results posted: Jan 14, 2021
Last update: Feb 21, 2021

Study contacts

Bente L Langdahl, MD PhD DMSc

study director · Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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