ZOLARMAB: Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis

• Sponsor: Aarhus University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03087851
• Collaborator: University of Aarhus (Other), Amgen (Industry)
• Enrollment: 61
• Location: 1
• Arms: 3
• Actual Duration (Months): 40.6
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis	Drug: Zoledronic Acid	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis
• Actual Study Start Date: Mar 13, 2017
• Actual Primary Completion Date: Aug 1, 2020
• Actual Study Completion Date: Aug 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
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; Intravenous infusion of 5 mg zoledronic acid; Other Names: Zoledronate
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; Intravenous infusion of 5 mg zoledronic acid; Other Names: Zoledronate
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; Intravenous infusion of 5 mg zoledronic acid; Other Names: Zoledronate

Outcome Measures

Primary Outcome Measures

1. Change in Lumbar Spine BMD From Baseline to 6 Months After the Zoledronic Acid Infusion. [baseline to 6 months after the zoledronic acid infusion]

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

2. Number of Participants Who Fail to Maintain BMD [2 years after the first ZOL treatment]

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

Secondary Outcome Measures

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

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

3. 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 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.

4. 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 six months after the zoledronic acid infusion.

5. Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion. [from baseline to 12 months after the zoledronic acid infusion.]

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

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: 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:

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark	Aarhus		Denmark	8000

Sponsors and Collaborators

• Aarhus University Hospital
• University of Aarhus
• Amgen

Investigators

• Study Director: Bente L Langdahl, MD PhD DMSc, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 29, 2018

More Information

Publications

• 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.
• 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.
• 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.
• Koldkjær Sølling AS, Harsløf 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.
• 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. Review.
• 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.
• 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.

• Responsible Party: Anne Sophie Sølling, MD, PhD student, Aarhus University Hospital
• ClinicalTrials.gov Identifier: NCT03087851
• Other Study ID Numbers: 2015-005529-37
• First Posted: Mar 23, 2017
• Last Update Posted: Feb 21, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Anne Sophie Sølling, MD, PhD student, Aarhus University Hospital: Denosumab; Bone turnover markers; Bone mineral density
• Additional relevant MeSH terms: Osteoporosis; Zoledronic Acid

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	Zoledronate: administrated at baseline. Zoledronate re-adminisrated: If p-C-terminal telopeptide of type 1 collagen (p-CTX) increases above 1.26 ug/l or bone mineral density (BMD) decreases more than 5% at any site.	Zoledronate: administrated depending on increase in p-CTX (above 1.26 ug/l) or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 3. Zoledronate re-administrated: If p-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site.	Zoledronate: administrated depending on increase in p-CTX (above 1.26 ug/l), decrease in BMD (more than 5%), or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 6. Zoledronate re-administrated: If p-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site.
Period Title: Overall Study
STARTED	20	20	21
COMPLETED	20	19	19
NOT COMPLETED	0	1	2

Baseline Characteristics

Arm/Group Title	6-month Group	9-months Group	Observation Group	Total
Arm/Group Description	Treated with zoledronate 5 mg	Treated with zoledronate 5 mg	Treated with zoledronate 5 mg	Total of all reporting groups
Overall Participants	20	20	21	61
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 40%	12 60%	7 33.3%	27 44.3%
>=65 years	12 60%	8 40%	14 66.7%	34 55.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68 (8)	65 (7)	69 (9)	68 (8)
Sex: Female, Male (Count of Participants)
Female	18 90%	17 85%	19 90.5%	54 88.5%
Male	2 10%	3 15%	2 9.5%	7 11.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	20 100%	20 100%	21 100%	61 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Lumbar spine BMD (g/cm^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/cm^2]	0,880 (0.055)	0,878 (0,063)	0,871 (0,089)	0,876 (0,069)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Mean (Standard Error) [percentage change]	-2.1 (0.9)	-4.3 (1.1)	-3.0 (1.1)

2. Primary Outcome

Title	Number of Participants Who Fail to Maintain BMD
Description	Failure is defined as ≥ 3 % BMD loss at the lumbar spine
Time Frame	2 years after the first ZOL treatment

Outcome Measure Data

Analysis Population Description

Number of Participants Who Fail to Maintain lumbar spine BMD from baseline to 24 months after the first ZOL

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Number [participants]	10 50%	5 25%	6 28.6%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Mean (Standard Error) [percentage change]	-4.8 (0.7)	-4.1 (1.1)	-4.7 (1.2)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Mean (Standard Error) [percentage change]	-4.0 (0.8)	-4.1 (0.8)	-4.3 (1.5)

5. Secondary Outcome

Title	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.
Description	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.

Outcome Measure Data

Analysis Population Description

Changes in cortical porosity at the radius from baseline to one year after the zoledronic acid infusion.

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Mean (Standard Error) [percentage change]	-2.5 (7.4)	-1.6 (6.7)	-4.2 (7.2)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Mean (Standard Deviation) [ug/l]	0.60 (0.35)	0.47 (0.24)	0.47 (0.20)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Mean (Standard Deviation) [ug/l]	0.58 (0.23)	0.40 (0.20)	0.49 (0.21)

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	6-month Group	9-months Group	Observation Group
Arm/Group Description	n=20	n=20	n=21
Measure Participants	20	20	21
Number [participants]	0 0%	2 10%	0 0%

Adverse Events

Time Frame	2 - 2.5 years
Arm/Group Title	6-month Group		9-months Group		Observation Group
Arm/Group Description	Zoledronate: administrated at baseline. Zoledronate re-administrated: If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site.		Zoledronate: administrated 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. Zoledronate re-administrated: If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site.		Zoledronate: administrated 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. Zoledronate re-administrated: If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site.
All Cause Mortality
	6-month Group		9-months Group		Observation Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/21 (0%)
Serious Adverse Events
	6-month Group		9-months Group		Observation Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		1/20 (5%)		4/21 (19%)
Investigations
Cancer	0/20 (0%)	0	1/20 (5%)	1	4/21 (19%)	4
Other (Not Including Serious) Adverse Events
	6-month Group		9-months Group		Observation Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/20 (90%)		18/20 (90%)		20/21 (95.2%)
Infections and infestations
Infection (unspecified) + Musculoskeletal symptoms	13/20 (65%)	13	18/20 (90%)	18	15/21 (71.4%)	15
Musculoskeletal and connective tissue disorders
Flu-like symptoms after ZOL treatment	13/20 (65%)	13	8/20 (40%)	8	16/21 (76.2%)	16
Fracture	2/20 (10%)	2	2/20 (10%)	2	2/21 (9.5%)	2

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.