Other Disorders of Bone Development and GrowthPhase 4NCT02367846
Assessing the Impact of Contraceptives on Bone Health Using 41Ca
A Phase 4 study testing Combined Oral Contraceptive (COC) and Contraceptive Vaginal Ring (CVR) in people with Other Disorders of Bone Development and Growth, run by Penn State University at 1 site in United States.
Trial summary
This preclinical randomized crossover study will examine the effects of oral versus non-oral contraceptive therapy on bone turnover in young exercising women. In an effort to expose the route-dependent effects of oral versus non-oral contraceptive therapy on bone turnover, the investigators will examine 1) the effects… Read more about this study
- Who is it for?
- Ages 18 to 25 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Other Disorders of Bone Development and Growth
- What is being tested?
- Combined Oral Contraceptive (COC) and Contraceptive Vaginal Ring (CVR)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2015to Dec 2028
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
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 18 to 25 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Female
- Age 18-25 yrs
- BMI 18-29 kg/m2
- Non-smoking
- Willing to refrain from using hormonal contraceptives for the equilibration + baseline period of the study (~150 days)
- Availability to frequently visit the laboratory in the next 12 months
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- Not currently pregnant nor intending to become pregnant in the next 12 months
- Not lactating
- No apparent metabolic, endocrine, musculoskeletal, or severe psychiatric disease
- Willing to maintain consistent exercise (aerobic, weight-bearing) and dietary habits during pre-intervention and intervention periods
- Willing to refrain from supplements other than those provided by study staff in the next 12 months
- Variable physical activity acceptable, but mode must be primarily weight bearing
- At least 9 menses in the past 12 months
Who cannot join
- Non-weight bearing exercise as primary mode of physical activity
- Resistance exercise training (≥ 2 times 30 minutes per week of resistance exercise)
- Complete seasonal change of impact mode of physical activity
- Known or suspected metabolic or endocrine disease
- Smoking
- Pregnant
Show all 16Show fewer
- Currently consuming large amounts of soy products
- Current clinical eating disorder or other axis 1 psychiatric disorder or bipolar disorders
- Oral or hormonal contraceptive use in the last 6 months
- Hyperparathyroidism
- Liver or renal disease
- Evidence of malabsorption or skeletal disorder
- Thyroid abnormalities (controlled hypothyroidism acceptable)
- Chronic use of non-steroidal anti-inflammatory drugs (NSAIDS)
- Taking medications known to have interactions with oral or vaginal contraceptive therapy
- Other Exclusion Criteria proposed by the World Health Organization COC Contraindications (Grossman et al., 2011).
Trial locations and contacts
1 site in 1 country.
United States1 site
Women's Health and Exercise Laboratories, The Pennsylvania State University
University Park, Pennsylvania, 16802
About this study
Official title: The Effect of Oral vs. Non-oral Contraceptive Therapy on Bone Turnover Using 41Ca Methodology
This preclinical randomized crossover study will examine the effects of oral versus non-oral contraceptive therapy on bone turnover in young exercising women. In an effort to expose the route-dependent effects of oral versus non-oral contraceptive therapy on bone turnover, the investigators will examine 1) the effects of ethinyl estradiol on bone calcium balance using the 41Ca technology and 2) the underlying physiological mechanisms associated with the effects of oral versus non-oral contraceptive therapy on net bone calcium balance.
Read the detailed description
This study is a preclinical, multi-site study (Penn State University and Purdue University) that will determine whether the negative effects of combined oral contraceptive (COC) therapy on bone turnover are dependent on the route of administration such that an attenuation of these effects is observed when a comparable dose of non-oral contraceptive therapy, such as vaginal contraceptive (CVR) therapy is also tested. Millions of women use COC therapy for birth control purposes or regulation of menstrual cycles. CVR therapy is a relatively new FDA-approved contraceptive alternative to COC. The purpose of the proposed project is to investigate whether oral ethinyl estradiol (EE) may negatively impair bone turnover when compared to vaginally-administered EE in young physically-active women.
A novel calcium tracer technology suitable to rapidly assess changes in net bone calcium balance in a small sample size will be applied to evaluate the effects of COC and CVR therapy on bone turnover. The radioisotope Calcium-41 (41Ca) demonstrates increased sensitivity when compared to dual x-ray absorptiometry (DXA) and increased specificity for bone mineralization and precision when compared to biochemical markers of bone turnover. This study will be the first study to examine how the route of estrogen administration affects bone turnover in young physically active women by assessing changes in net bone calcium balance with different forms of contraceptive therapy.
The overall purpose of this study is to explore the effects of oral versus vaginal contraceptive therapy on bone turnover in young exercising women using 41Ca technology. In an effort to expose the route-dependent effects of oral versus non-oral contraceptive therapy on bone turnover, the investigators will examine 1) the effects of ethinyl estradiol on bone calcium balance using the 41Ca technology and 2) the underlying physiological mechanisms associated with the effects of oral versus vaginal contraceptive therapy on net bone calcium balance.
- Being tested
- Combined Oral Contraceptive (COC), Contraceptive Vaginal Ring (CVR)
- Keywords
- Calcium Tracer, Oral Contraceptives, Contraceptive Vaginal Ring, Impact of contraceptives on bone health using 41Ca
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Combined Oral Contraceptive (COC)Drug
Also called Apri (Reclipsen)
The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral vs. non-oral ethinyl estradiol on net bone calcium balance. A prospective crossover study with repeated measures and a simple random assignment will be used to test the effects of 49 days of COC use on bone metabolism using 41Ca to determine net bone calcium balance. Subjects will be randomized to receive COC during either the first or second intervention period.
Contraceptive Vaginal Ring (CVR)Drug
Also called Nuva Ring
The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral vs. non-oral ethinyl estradiol on net bone calcium balance. A prospective crossover study with repeated measures and a simple random assignment will be used to test the effects of 49 days of CVR use on bone metabolism using 41Ca to determine net bone calcium balance. Subjects will be randomized to receive CVR during either the first or second intervention period.
| Study group | Role | What they receive |
|---|---|---|
| Combined Oral Contraceptive (COC) | Experimental | We are testing the effects of a COC (Apri (Reclipsen); 30 µg EE, 150 µg desogestrel). On the first day of the intervention, the participants randomized to COC will begin taking the pill. One pill will be ingested orally at the same time each day for days 1-49 of the intervention. Pills ingested during days 1-21 and during days 29-49 will be active tablets. Pills ingested on days 22-28 will be tablets without active ingredients. Each participant in the COC group will ingest a pill from the first pack each day for the first 28 days then begin the second pack. If a participant is unable to collect a 24-h urine sample on day 49, she will take active tablets from the third pill pack until she has collected the 24-h urine sample. Receives: Drug: Combined Oral Contraceptive (COC) |
| Contraceptive Vaginal Ring (CVR) | Experimental | We are testing the effects of the vaginal ring (Nuva Ring; 15 µg/d EE, 120 µg/d etonogestrel). When randomized to CVR, participants will insert the contraceptive ring into their vagina . The ring will be worn during weeks 1-3, and again during weeks 5-7. During week 4, no ring will be worn to allow for withdrawal bleeding. If a participant is unable to collect a 24-h urine sample on day 49, they will insert a third ring which will remain in the vagina until she has collected a 24-h urine sample. Receives: Drug: Contraceptive Vaginal Ring (CVR) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in 41Ca:Ca ratio
Changes in the 41Ca:Ca ratio in 24-h urine samples measured every 10-14 days during and after oral and non-oral contraceptive therapy as determined by Accelerometer Mass Spectrometry
Measured: 49 days of contraceptive therapy
Secondary outcomes (2)
Changes in serum concentrations of insulin-like growth factor-1 (IGF-1), IGF-binding proteins (IGFBP-1, IGFBP-3), and acid labile subunit (ALS)
Changes in fasting serum concentrations of IGF-1, IGFBP-1, IGFBP-3, and ALS after oral and non-oral contraceptive therapy
Measured: 49 days of contraceptive therapy
Changes in serum concentrations of markers of bone formation and bone resorption
Changes in fasting serum concentrations of markers of bone formation (osteocalcin, P1NP) and bone resorption (CTx) after oral and non-oral contraceptive therapy
Measured: 49 days of contraceptive therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Feb 2015 (estimated)
- Study startJan 2015
- Primary completionDec 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Other Disorders of Bone Development and GrowthStudies of the same condition, open and under way.
- More trials run by Penn State UniversityThe 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
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Penn State University
- Sponsor type
- University, hospital or other
- Collaborators
- Purdue University
- Responsible party
- Principal investigator, Mary Jane DeSouza, Penn State University
- Investigators
- Mary Jane De Souza, PhD, Principal investigator, Penn State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02367846
- Sponsor's protocol ID
- STUDY00000464
- Status last verified
- Jul 2026
- First submitted
- 27 Jan 2015
- Last updated
- 6 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
Publications
Grossman D, White K, Hopkins K, Amastae J, Shedlin M, Potter JE. Contraindications to combined oral contraceptives among over-the-counter compared with prescription users. Obstet Gynecol. 2011 Mar;117(3):558-565. doi: 10.1097/AOG.0b013e31820b0244.
PubMed 21343758Lee WH, Wastney ME, Jackson GS, Martin BR, Weaver CM. Interpretation of 41Ca data using compartmental modeling in post-menopausal women. Anal Bioanal Chem. 2011 Feb;399(4):1613-22. doi: 10.1007/s00216-010-4454-5. Epub 2010 Dec 9.
PubMed 21152905Weaver CM, Martin BR, Jackson GS, McCabe GP, Nolan JR, McCabe LD, Barnes S, Reinwald S, Boris ME, Peacock M. Antiresorptive effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca methodology. J Clin Endocrinol Metab. 2009 Oct;94(10):3798-805. doi: 10.1210/jc.2009-0332. Epub 2009 Jul 7.
PubMed 19584189Denk E, Hillegonds D, Vogel J, Synal A, Geppert C, Wendt K, Fattinger K, Hennessy C, Berglund M, Hurrell RF, Walczyk T. Labeling the human skeleton with 41Ca to assess changes in bone calcium metabolism. Anal Bioanal Chem. 2006 Nov;386(6):1587-602. doi: 10.1007/s00216-006-0795-5. Epub 2006 Oct 11.
PubMed 17033771Ricker EA, De Souza MJ, Stone MS, Jackson GS, McCabe GP, McCabe LD, Weaver CM. Differential bone calcium retention with the use of oral versus vaginal hormonal contraception: A randomized trial using calcium-41 radiotracer. Contraception. 2025 Mar;143:110778. doi: 10.1016/j.contraception.2024.110778. Epub 2024 Nov 28.
PubMed 39615778
Study at a glance
From the registry record, last updated by the sponsor on 6 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Oral vs. Non-oral Contraceptive Therapy on Bone Turnover Using 41Ca Methodology
- ClinicalTrials.gov ID
- NCT02367846
- Acronym / sponsor ID
- STUDY00000464
- Keywords
- Calcium Tracer, Oral Contraceptives, Contraceptive Vaginal Ring, Impact of contraceptives on bone health using 41Ca
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Penn State UniversityUniversity, hospital or other
- Collaborators
- Purdue University
- Study start
- Jan 2015 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 20 Feb 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This preclinical randomized crossover study will examine the effects of oral versus non-oral contraceptive therapy on bone turnover in young exercising women. In an effort to expose the route-dependent effects of oral versus non-oral contraceptive therapy on bone turnover, the investigators will examine 1) the effects of ethinyl estradiol on bone calcium balance using the 41Ca technology and 2) the underlying physiological mechanisms associated with the effects of oral versus non-oral contraceptive therapy on net bone calcium balance.
Detailed description
This study is a preclinical, multi-site study (Penn State University and Purdue University) that will determine whether the negative effects of combined oral contraceptive (COC) therapy on bone turnover are dependent on the route of administration such that an attenuation of these effects is observed when a comparable dose of non-oral contraceptive therapy, such as vaginal contraceptive (CVR) therapy is also tested. Millions of women use COC therapy for birth control purposes or regulation of menstrual cycles. CVR therapy is a relatively new FDA-approved contraceptive alternative to COC. The purpose of the proposed project is to investigate whether oral ethinyl estradiol (EE) may negatively impair bone turnover when compared to vaginally-administered EE in young physically-active women.
A novel calcium tracer technology suitable to rapidly assess changes in net bone calcium balance in a small sample size will be applied to evaluate the effects of COC and CVR therapy on bone turnover. The radioisotope Calcium-41 (41Ca) demonstrates increased sensitivity when compared to dual x-ray absorptiometry (DXA) and increased specificity for bone mineralization and precision when compared to biochemical markers of bone turnover. This study will be the first study to examine how the route of estrogen administration affects bone turnover in young physically active women by assessing changes in net bone calcium balance with different forms of contraceptive therapy.
The overall purpose of this study is to explore the effects of oral versus vaginal contraceptive therapy on bone turnover in young exercising women using 41Ca technology. In an effort to expose the route-dependent effects of oral versus non-oral contraceptive therapy on bone turnover, the investigators will examine 1) the effects of ethinyl estradiol on bone calcium balance using the 41Ca technology and 2) the underlying physiological mechanisms associated with the effects of oral versus vaginal contraceptive therapy on net bone calcium balance.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Combined Oral Contraceptive (COC) | Experimental | Drug: Combined Oral Contraceptive (COC)We are testing the effects of a COC (Apri (Reclipsen); 30 µg EE, 150 µg desogestrel). On the first day of the intervention, the participants randomized to COC will begin taking the pill. One pill will be ingested orally at the same time each day for days 1-49 of the intervention. Pills ingested during days 1-21 and during days 29-49 will be active tablets. Pills ingested on days 22-28 will be tablets without active ingredients. Each participant in the COC group will ingest a pill from the first pack each day for the first 28 days then begin the second pack. If a participant is unable to collect a 24-h urine sample on day 49, she will take active tablets from the third pill pack until she has collected the 24-h urine sample. |
| Contraceptive Vaginal Ring (CVR) | Experimental | Drug: Contraceptive Vaginal Ring (CVR)We are testing the effects of the vaginal ring (Nuva Ring; 15 µg/d EE, 120 µg/d etonogestrel). When randomized to CVR, participants will insert the contraceptive ring into their vagina . The ring will be worn during weeks 1-3, and again during weeks 5-7. During week 4, no ring will be worn to allow for withdrawal bleeding. If a participant is unable to collect a 24-h urine sample on day 49, they will insert a third ring which will remain in the vagina until she has collected a 24-h urine sample. |
Who may qualify
- Ages
- 18 to 25 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- Female
- Age 18-25 yrs
- BMI 18-29 kg/m2
- Non-smoking
- Willing to refrain from using hormonal contraceptives for the equilibration + baseline period of the study (~150 days)
Key exclusion criteria (16 listed)
- Non-weight bearing exercise as primary mode of physical activity
- Resistance exercise training (≥ 2 times 30 minutes per week of resistance exercise)
- Complete seasonal change of impact mode of physical activity
- Known or suspected metabolic or endocrine disease
- Smoking
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 |
|---|---|---|
| Combined Oral Contraceptive (COC)Also: Apri (Reclipsen)The proposed study is a preclinical, multi-site trial comparing the short-term effects of oral vs. non-oral ethinyl estradiol on net bone calcium balance. A prospective crossover study with repeated measures and a simple random assignment will be used to test the effects of 49 days of COC use on bone metabolism using 41Ca to determine net bone calcium balance. Subjects will be randomized to receive COC during either the first or second intervention period. | Drug | Combined Oral Contraceptive (COC) |
| Contraceptive Vaginal Ring (CVR)Also: Nuva RingThe proposed study is a preclinical, multi-site trial comparing the short-term effects of oral vs. non-oral ethinyl estradiol on net bone calcium balance. A prospective crossover study with repeated measures and a simple random assignment will be used to test the effects of 49 days of CVR use on bone metabolism using 41Ca to determine net bone calcium balance. Subjects will be randomized to receive CVR during either the first or second intervention period. | Drug | Contraceptive Vaginal Ring (CVR) |
Primary outcome
Changes in 41Ca:Ca ratio
Time frame: 49 days of contraceptive therapy
Changes in the 41Ca:Ca ratio in 24-h urine samples measured every 10-14 days during and after oral and non-oral contraceptive therapy as determined by Accelerometer Mass Spectrometry
2 secondary outcomes
Changes in serum concentrations of insulin-like growth factor-1 (IGF-1), IGF-binding proteins (IGFBP-1, IGFBP-3), and acid labile subunit (ALS)
Time frame: 49 days of contraceptive therapy
Changes in serum concentrations of markers of bone formation and bone resorption
Time frame: 49 days of contraceptive therapy
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jul 2026.
- Background: PubMed 21343758Grossman D, White K, Hopkins K, Amastae J, Shedlin M, Potter JE. Contraindications to combined oral contraceptives among over-the-counter compared with prescription users. Obstet Gynecol. 2011 Mar;117(3):558-565. doi: 10.1097/AOG.0b013e31820b0244.
- Background: PubMed 21152905Lee WH, Wastney ME, Jackson GS, Martin BR, Weaver CM. Interpretation of 41Ca data using compartmental modeling in post-menopausal women. Anal Bioanal Chem. 2011 Feb;399(4):1613-22. doi: 10.1007/s00216-010-4454-5. Epub 2010 Dec 9.
- Background: PubMed 19584189Weaver CM, Martin BR, Jackson GS, McCabe GP, Nolan JR, McCabe LD, Barnes S, Reinwald S, Boris ME, Peacock M. Antiresorptive effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca methodology. J Clin Endocrinol Metab. 2009 Oct;94(10):3798-805. doi: 10.1210/jc.2009-0332. Epub 2009 Jul 7.
- Background: PubMed 17033771Denk E, Hillegonds D, Vogel J, Synal A, Geppert C, Wendt K, Fattinger K, Hennessy C, Berglund M, Hurrell RF, Walczyk T. Labeling the human skeleton with 41Ca to assess changes in bone calcium metabolism. Anal Bioanal Chem. 2006 Nov;386(6):1587-602. doi: 10.1007/s00216-006-0795-5. Epub 2006 Oct 11.
- Derived from this study: PubMed 39615778Ricker EA, De Souza MJ, Stone MS, Jackson GS, McCabe GP, McCabe LD, Weaver CM. Differential bone calcium retention with the use of oral versus vaginal hormonal contraception: A randomized trial using calcium-41 radiotracer. Contraception. 2025 Mar;143:110778. doi: 10.1016/j.contraception.2024.110778. Epub 2024 Nov 28.
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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.
Mary Jane De Souza, PhD principal investigator
Penn State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Combined Oral Contraceptive (COC) and Contraceptive Vaginal Ring (CVR) in people with Other Disorders of Bone Development and Growth, run by Penn State University at 1 site in United States.
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 13 inclusion and 16 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: under way, not looking for participants, as of the sponsor's last update on 6 Jul 2026. 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 United States. 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.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
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?
Changes in 41Ca:Ca ratio (time frame: 49 days of contraceptive therapy). 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 NCT02367846, which also lists 5 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 6 Jul 2026.