Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis (ZOLARMAB)

• ClinicalTrials.gov Identifier: NCT03087851
• Recruitment Status: Active, not recruiting
• First Posted: March 23, 2017
• Last Update Posted: April 3, 2019
• Sponsor: Aarhus University Hospital
• Collaborators: University of Aarhus; Amgen
• Information provided by (Responsible Party): Anne Sophie Sølling, Aarhus University Hospital

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 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 re-cruitment and differentiation of osteoclasts. Treatment decreases bone resorption and fracture risk. After discontinu-ation, 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 per-formed 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 (Clinical Trial)
• Actual Enrollment: 60 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: March 13, 2017
• Estimated Primary Completion Date: September 1, 2020
• Estimated Study Completion Date: December 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
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
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

Outcome Measures

Primary Outcome Measures :

1. BMD lumbar spine [ Time Frame: 6 months ]
   Change in lumbar spine BMD from baseline to 6 months after the zoledronic acid infusion.
2. BMD total hip, femoral neck and spine [ Time Frame: Two years ]
   The proportion of patients who fails to maintain BMD (total hip, femoral neck and spine). Failure is defined as ≥ 3 % BMD loss at the lumbar spine or ≥ 5 % BMD loss at the femoral neck or total hip.

Secondary Outcome Measures :

1. BMD total hip and femoral neck [ Time Frame: One year ]
   Changes in total hip, femoral neck and lumbar spine BMD from baseline to one year after the zoledronic acid infusion.
2. BMD total hip, femoral neck and lumbar spine [ Time Frame: Two years ]
   Changes in total hip, femoral neck and lumbar spine BMD from baseline to two years after the zoledronic acid infusion.
3. Bone microarchitecture: Trabecular bone volume fraction and cortical porosity [ Time Frame: One year ]
   Changes in trabecular bone volume fraction and 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. Bone turnover markers: S-carboxy-terminal collagen crosslinks (CTX) and s-procollagen type I N-terminal propeptide (PINP) [ Time Frame: Six months ]
   Changes in CTX and PINP from baseline to six months after the zoledronic acid infusion.
5. Bone turnover markers: S-carboxy-terminal collagen crosslinks (CTX) and s-procollagen type I N-terminal propeptide (PINP) [ Time Frame: One year ]
   Changes in CTX and PINP from baseline to 12 months after the zoledronic acid infusion.
6. Morphometric vertebral fractures [ Time Frame: One and two years ]
   Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) one and two years after the zoledronic acid infusion.

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Denmark

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

More Information

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. Review.

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.

Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J; Amg Bone Loss Study Group. 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):222-9. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.

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.

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.

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.

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 History of Changes
• Other Study ID Numbers: 2015-005529-37
• First Posted: March 23, 2017
• Last Update Posted: April 3, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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, Aarhus University Hospital:

Denosumab; Bone turnover markers; Bone mineral density

Additional relevant MeSH terms:

Osteoporosis; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Zoledronic Acid; Denosumab; Bone Density Conservation Agents; Physiological Effects of Drugs