Predictive Value of Bone Turnover Markers During Discontinuation With Alendronate

An observational study of Osteoporosis, run by Aarhus University Hospital at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Trial summary

The study is a cohort study comprising 136 patients with osteoporosis stopping treatment with alendronate. The study will contribute with new knowledge about biochemical markers of bone turnover as predictors of bone loss after stopping treatment with alendronate. Read more about this study

Who is it for?: Ages 50 years and older
Conditions the study is for: Osteoporosis
What is being tested?: Discontinue alendronate
How many people: 142 participants
Where: 1 siteDenmark
Study dates: 1 Feb 2017to 31 Jan 2019
Phase: Observational
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 50 years and older
All sexes
No healthy volunteers
Adult, Older adult

Study population: 140 patients with osteoporosis stopping treatment with alendronate.

Who may be able to join

Postmenopausal women (postmenopausal for at least two years)
Men above 50 years
Treatment for at least five years with alendronate
BMD T-score total hip > -2.5
BMD T-score lumbar spine (L1-L4) > -4

Who cannot join

Any low-energy fracture within the previous five years during alendronate treatment (not including fingers, toes, or skull)
Low-energy vertebral fracture at any time
Low-energy hip fracture at any time
Ongoing treatment with glucocorticoids
Metabolic bone disease
Hormone replacement therapy
Cancer
Other conditions affecting bone metabolism

Trial locations and contacts

1 site in 1 country.

Denmark1 site

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

Other trials in Denmark

About this study

Read the detailed description

Background:

Osteoporosis increases the risk of fractures. Alendronate reduces the risk of both vertebral- and hip fractures by approximately 50%. It has, however, become evident that long-term anti-resorptive may lead to serious side effects such as atypical femoral fractures or osteonecrosis of the jaw. The alendronate extension study (FLEX) showed that despite stopping treatment after five years the anti-fracture efficacy regarding non-vertebral and radiological vertebral fractures persists for an additional five years in patients with bone mineral density (BMD) T-score > -2.5 at the femoral neck, no fractures during treatment, and no previous vertebral fracture. It is therefore now clinical practice, that treatment is discontinued after five years in patients that fulfil these criteria. Based on the alendronate extension study it was assumed, that bone turnover monitored by biochemical markers would stay suppressed for years after stopping treatment, however, other studies have demonstrated that there is a great variability in the change in bone turnover markers seen after stopping treatment with alendronate in a real-life setting.

Aim:

To investigate the predictive value of markers of bone turnover on bone loss 12 months after stopping alendronate therapy.

Methods:

The study is a cohort study comprising 136 patients with osteoporosis stopping treatment with alendronate.

Perspectives:

The study will contribute with new knowledge about biochemical markers of bone turnover as predictors of bone loss after stopping treatment with alendronate. It will thus be possible to identify patients who will experience a decrease in BMD during treatment break, and for this particular group of patients treatment can be re-initiated earlier so further loss of bone will be avoided. On the other hand, the biochemical markers of bone turnover could also shed light on who can tolerate treatment break, thereby avoid long-term treatment with alendronate, which may be associated with serious side effects. Finally, the use of blood samples rather than DXA will reduce the use of X-rays.

Conditions: Osteoporosis
Being tested: Discontinue alendronate
Keywords: Bone turnover markers, Alendronate, Drug Holiday
Medical subject headings: Osteoporosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Discontinue alendronateDrug
136 patients with osteoporosis stopping treatment with alendronate.

What is being measured

The primary outcome is the main question the study is designed to answer.

If Carboxy-terminal Collagen Crosslinks (CTX) Three and Six Months After Stopping Alendronate Predicted TH BMD (Total Hip BMD) Loss Above the Least Significant Change at Month 12 at the Individual Level.
We constructed receiver operating characteristic (ROC) curves to evaluate if carboxy-terminal collagen crosslinks (CTX) three and six months after stopping alendronate predicted TH BMD loss above the least significant change (LSC) at month 12 at the individual level.
Measured: Baseline and one year after baseline

Secondary outcomes (4)

Percent Change in Bone Turnover Markers Measured Three and Six Months After Stopping Alendronate Treatment and BMD After One and Two Years
We constructed receiver operating characteristic (ROC) curves to evaluate if changes in p-CTX or p-PINP measured three and six months after stopping alendronate predicted TH BMD loss above the least significant change at month 12 and/or month 24 at the individual level.
Measured: one and two years after baseline
Number of Participants in Which CTX Increased Above the Least Significant Change
Number of participants in which CTX increased above the least significant change.
The Department of Clinical Biochemistry, Rigshospitalet, Glostrup, Denmark provided the the least significant change for p-CTX > 30%.
Measured: From baseline to month 24
The Number of Participants Who Lost BMD Beyond the Least Significant Change (LSC) at the Lumbar Spine and Total Hip.
the number of patients who lost BMD beyond the LSC at the lumbar spine (>3%) and total hip (>5%)
Measured: from baseline to month 24
If Baseline Bone Turnover Markers at the Time of Alendronate Discontinuation Predict Changes in BMD After One and Two Years.
We constructed receiver operating characteristic (ROC) curves to evaluate if baseline p-CTX or baseline p-PINP at the time of alendronate discontinuation predicted TH BMD loss above the least significant change at month 12 and/or month 24 at the individual level.
Measured: Changes in TH BMD after one and two years.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Feb 201731 Jan 2019

First posted14 Feb 2017
Study start1 Feb 2017
Primary completion31 Jan 2019
Study completion31 Jan 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (7)Papers the sponsor has linked to this study.
Other trials for OsteoporosisStudies of the same condition, open and under way.
More trials run by Aarhus University HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Observational
Observational model: Cohort
Time perspective: Prospective
Enrolment: 142 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03051620
Sponsor's protocol ID: 2016-003110-27
Other IDs: 2016
Acronym: PROSA
Status last verified: Mar 2021
First submitted: 7 Feb 2017
Last updated: 18 Mar 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Undecided

Publications

Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996 Dec 7;348(9041):1535-41. doi: 10.1016/s0140-6736(96)07088-2.
PubMed 8950879
Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437-43. doi: 10.1056/NEJM199511303332201.
PubMed 7477143
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.
PubMed 20842676
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007 Oct;22(10):1479-91. doi: 10.1359/jbmr.0707onj.
PubMed 17663640
Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927-38. doi: 10.1001/jama.296.24.2927.
PubMed 17190893
Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, Wallace RB, Hochberg MC, Feldstein AC, Lombardi A, Black DM; FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010 May;25(5):976-82. doi: 10.1002/jbmr.11.
PubMed 20200926
Solling AS, Harslof T, Bruun NH, Langdahl B. The predictive value of bone turnover markers during discontinuation of alendronate: the PROSA study. Osteoporos Int. 2021 Aug;32(8):1557-1566. doi: 10.1007/s00198-021-05835-4. Epub 2021 Jan 30.
PubMed 33517477

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 18 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Predictive Value of Bone Turnover Markers During Discontinuation With Alendronate
ClinicalTrials.gov ID: NCT03051620
Acronym / sponsor ID: PROSA / 2016-003110-27
Conditions: Osteoporosis
Keywords: Bone turnover markers, Alendronate, Drug Holiday
Study type: Observational
Recruitment status: Completed
Enrolment: 142 participants (actual)
Lead sponsor: Aarhus University HospitalUniversity, hospital or other
Collaborators: University of Aarhus
Study start: 1 Feb 2017 (actual)
Primary completion: 31 Jan 2019 (actual)
Study completion: 31 Jan 2019 (actual)
First posted: 14 Feb 2017 (actual)
Results: Posted 18 Mar 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Background:

Aim:

To investigate the predictive value of markers of bone turnover on bone loss 12 months after stopping alendronate therapy.

Methods:

The study is a cohort study comprising 136 patients with osteoporosis stopping treatment with alendronate.

Perspectives:

Study design

Observational model: Cohort
Time perspective: Prospective

Who may qualify

Ages: 50 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult
Study population: 140 patients with osteoporosis stopping treatment with alendronate.

Key inclusion criteria (5 listed)

Postmenopausal women (postmenopausal for at least two years)
Men above 50 years
Treatment for at least five years with alendronate
BMD T-score total hip > -2.5
BMD T-score lumbar spine (L1-L4) > -4

Key exclusion criteria (8 listed)

Any low-energy fracture within the previous five years during alendronate treatment (not including fingers, toes, or skull)
Low-energy vertebral fracture at any time
Low-energy hip fracture at any time
Ongoing treatment with glucocorticoids
Metabolic bone disease

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Discontinue alendronate136 patients with osteoporosis stopping treatment with alendronate.	Drug	–

Primary outcome

If Carboxy-terminal Collagen Crosslinks (CTX) Three and Six Months After Stopping Alendronate Predicted TH BMD (Total Hip BMD) Loss Above the Least Significant Change at Month 12 at the Individual Level.
Time frame: Baseline and one year after baseline
We constructed receiver operating characteristic (ROC) curves to evaluate if carboxy-terminal collagen crosslinks (CTX) three and six months after stopping alendronate predicted TH BMD loss above the least significant change (LSC) at month 12 at the individual level.

4 secondary outcomes

Percent Change in Bone Turnover Markers Measured Three and Six Months After Stopping Alendronate Treatment and BMD After One and Two Years
Time frame: one and two years after baseline
Number of Participants in Which CTX Increased Above the Least Significant Change
Time frame: From baseline to month 24
The Number of Participants Who Lost BMD Beyond the Least Significant Change (LSC) at the Lumbar Spine and Total Hip.
Time frame: from baseline to month 24
If Baseline Bone Turnover Markers at the Time of Alendronate Discontinuation Predict Changes in BMD After One and Two Years.
Time frame: Changes in TH BMD after one and two years.

Results and safety

Results posted to the registry on 18 Mar 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Study Population	142	124

Primary outcome: If Carboxy-terminal Collagen Crosslinks (CTX) Three and Six Months After Stopping Alendronate Predicted TH BMD (Total Hip BMD) Loss Above the Least Significant Change at Month 12 at the Individual Level.

Time frame: Baseline and one year after baseline. Mean (Standard Deviation). Unit: percentage change

Measure	Study Population n = 142
Mean change in CTX from baseline to month 3	49 (43)
Mean change in CTX from baseline to month 6	64 (62)
Mean change in TH BMD from baseline to month 12	1.14 (0.14)

Population analysed: None of the ROC curves investigating the ability of change in CTX to predict BMD loss beyond LSC at any site at month 12 at the individual level had AUC above 60% meaning that it was not possible to identify a specific cut-off value that could predict significant bone loss at the individual level.

4 secondary outcomes are reported in the full results.

Adverse events

Time frame: From baseline to month 24. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Study Population	7 of 142 (4.9%)	68 of 142 (47.9%)	0 of 142

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 8950879Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996 Dec 7;348(9041):1535-41. doi: 10.1016/s0140-6736(96)07088-2.
Background: PubMed 7477143Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437-43. doi: 10.1056/NEJM199511303332201.
Background: PubMed 20842676Shane 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.
Background: PubMed 17663640Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007 Oct;22(10):1479-91. doi: 10.1359/jbmr.0707onj.
Background: PubMed 17190893Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927-38. doi: 10.1001/jama.296.24.2927.
Background: PubMed 20200926Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, Wallace RB, Hochberg MC, Feldstein AC, Lombardi A, Black DM; FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010 May;25(5):976-82. doi: 10.1002/jbmr.11.
Derived from this study: PubMed 33517477Solling AS, Harslof T, Bruun NH, Langdahl B. The predictive value of bone turnover markers during discontinuation of alendronate: the PROSA study. Osteoporos Int. 2021 Aug;32(8):1557-1566. doi: 10.1007/s00198-021-05835-4. Epub 2021 Jan 30.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Bente L Langdahl, MD PhD DMSc study director

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

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

An observational study of Osteoporosis, run by Aarhus University Hospital at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

If Carboxy-terminal Collagen Crosslinks (CTX) Three and Six Months After Stopping Alendronate Predicted TH BMD (Total Hip BMD) Loss Above the Least Significant Change at Month 12 at the Individual Level. (time frame: Baseline and one year after baseline). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03051620, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2021.