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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK062249 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| The Hospital for Sick Children | OTHER |
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This study is to determine the effects of anorexia nervosa on bone mass and hormone levels in adolescents. Whether administration of estrogen, a normal hormone present during puberty, can help maintain bone development in girls with anorexia nervosa will be determined.
Adolescence is a critical time for bone mineral accretion as between 60-90% of peak bone mass is established during this period, and peak bone mass is a major determinant of bone density and osteoporosis risk during adulthood. Anorexia nervosa (AN) is the third most common chronic illness among adolescent girls, with a prevalence of 0.2-1.0%. Therefore, AN occurs at a time during which patients are the most vulnerable to disruption of bone mineral accretion. Osteopenia is a major co-morbid complication of AN in 50-75% of female adolescents and adult women with this eating disorder. Women with the onset of the disorder during adolescence have more severe osteopenia than women with onset during adulthood. Little is known about the pathogenesis of osteopenia in this adolescent population and there are no established therapies. Improved understanding of bone mineral metabolism and factors which predict recovery of bone mineral accretion are critical in the development of therapeutic strategies to preserve and maximize bone mass in girls with the onset of AN during adolescence. Estrogen is known to be a critical factor in the development of peak bone mass. Although AN is associated with profound estrogen deficiency, there are no controlled studies investigating the effects of estrogen administration in this population.
This research proposal will address critical unanswered questions regarding bone abnormalities in adolescents with anorexia nervosa. Defining changes in bone formation with weight recuperation and hormonal variables would provide insight into the factors essential for bone mineral accretion during adolescence, as well as those that predict recovery. Determination of dose-dependent estrogen effects in this population will be key in targeting interventions during the time of active disease, with the long-term goal of preserving peak bone mass accretion in this vulnerable group of patients. Data obtained from women with post-menopausal osteoporosis or from women with AN cannot be extrapolated to adolescent patients who are in an active period of bone growth and mineralization as well as remodeling. Given the increasing prevalence of AN and its profound consequences on bone health, these studies will provide much needed data to enable treatment strategies for this severe co-morbid disease.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Physiologic estrogen replacement | Experimental | Mature girls with anorexia nervosa (AN) (bone age 15 or greater): Transdermal estradiol (100 mcg) with cyclic progesterone (days 1-10 of each month). Immature girls with AN (bone age less than 15 years): Ethinyl estradiol (3.75 mcg daily for the first 6 months, 7.5 mcg daily for the next 6 months, and 11.25 mcg daily for the final 6 months of the study |
|
| Placebo | Placebo Comparator | Placebo patches or pills |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Physiologic Estrogen/progesterone | Drug | Vivelle Dot patch 100 mcg twice weekly; Provera 2.5 mg daily for the first 10 days of the month |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Spine Bone Density Over the Study Duration (18 Months) | Bone density at the spine (lumbar 1-4 vertebrae) was measured using dual energy x-ray absorptiometry (DXA) at baseline, 6 months, 12 months and 18 months. The primary outcome was the percent change in bone density at the spine from baseline to 18 months. Areal bone density is measured as g/cm2. The unit of measure for the percent change in bone density is 'percent' Percent change in bone density= [[Bone density at 18 months- Bone density at baseline)*100/Bone density at baseline]%](streamdown:incomplete-link) | Baseline and 18 months |
| Change in Spine Bone Mineral Density Z-scores Over the Study Duration (18 Months) | Bone density at the spine (lumbar 1-4 vertebrae) was measured using dual energy x-ray absorptiometry (DXA) at baseline, 6 months, 12 months and 18 months. The other primary outcome was the change in spine bone density Z-score from baseline to 18 months. The bone density Z-score is a standard deviation score that compares one's bone density to the mean for age and gender, and the Z-score, therefore, does not have any units. It is simply referred to as a Z-score. Change in bone density Z-score= [Bone density Z-score at 18 months- Bone density Z-score at baseline] | Baseline and 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in N-terminal Propeptide of Type 1 Procollagen (P1NP) Over the Study Duration (18 Months) | P1NP is a surrogate marker of bone formation that is measured in serum. P1NP levels were measured at baseline, 6, 12 and 18 months. A secondary outcome was the change in P1NP levels from baseline to 18 months: [P1NP at 18 months - P1NP at baseline). The unit is ng/ml](streamdown:incomplete-link) | Baseline and 18 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Madhusmita Misra, MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21698665 | Result | Misra M, Katzman D, Miller KK, Mendes N, Snelgrove D, Russell M, Goldstein MA, Ebrahimi S, Clauss L, Weigel T, Mickley D, Schoenfeld DA, Herzog DB, Klibanski A. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011 Oct;26(10):2430-8. doi: 10.1002/jbmr.447. | |
| 24021517 | Derived | Misra M, Katzman DK, Estella NM, Eddy KT, Weigel T, Goldstein MA, Miller KK, Klibanski A. Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial. J Clin Psychiatry. 2013 Aug;74(8):e765-71. doi: 10.4088/JCP.13m08365. |
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Reasons for enrolled participants being excluded from the trial before assignment to groups primarily included identification of exclusion criteria, loss of interest on the part of the participant, and loss to follow-up.
Period of recruitment: 2003-2009. Location: Massachusetts General Hospital (Boston) and Hospital for Sick Children (Toronto).
We screened 150 girls with anorexia nervosa (AN) (110 at MGH and 40 at SickKids) and 88 normal-weight controls 12-18 years. Following the screen, 110 AN and 40 controls were enrolled for the prospective study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Physiologic Estrogen Replacement | Mature girls with anorexia nervosa (bone age 15 or greater): Transdermal estradiol (100 mcg) with cyclic progesterone (days 1-10 of each month). Immature girls with anorexia nervosa (bone age less than 15 years): Ethinyl estradiol (3.75 mcg daily for the first 6 months, 7.5 mcg daily for the next 6 months, and 11.25 mcg daily for the final 6 months of the study |
| FG001 | Placebo | Mature girls with anorexia nervosa with a bone age of 15 years of greater: Placebo patches; Immature girls with anorexia nervosa with a bone age of less than 15 years: Placebo pills |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Physiologic Estrogen Replacement | Mature girls with anorexia nervosa (bone age 15 or greater): Transdermal estradiol (100 mcg) with cyclic progesterone (days 1-10 of each month). Immature girls with anorexia nervosa (bone age less than 15 years): Ethinyl estradiol (3.75 mcg daily for the first 6 months, 7.5 mcg daily for the next 6 months, and 11.25 mcg daily for the final 6 months of the study |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change in Spine Bone Density Over the Study Duration (18 Months) | Bone density at the spine (lumbar 1-4 vertebrae) was measured using dual energy x-ray absorptiometry (DXA) at baseline, 6 months, 12 months and 18 months. The primary outcome was the percent change in bone density at the spine from baseline to 18 months. Areal bone density is measured as g/cm2. The unit of measure for the percent change in bone density is 'percent' Percent change in bone density= [[Bone density at 18 months- Bone density at baseline)*100/Bone density at baseline]%](streamdown:incomplete-link) | The number of participants was determined using power calculations based on preliminary data. For our primary longitudinal analysis, bone mineral density (BMD) changes were analyzed using a mixed model analysis of variance (intent-to-treat model). For secondary analysis, we examined BMD changes after controlling for age and weight changes. | Posted | Mean | Standard Deviation | Percent change | Baseline and 18 months |
|
18 months for each subject(AN E+ versus AN E-)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Physiologic Estrogen Replacement | Mature girls with anorexia nervosa (bone age 15 or greater): Transdermal estradiol (100 mcg) with cyclic progesterone (days 1-10 of each month). Immature girls with anorexia nervosa (bone age less than 15 years): Ethinyl estradiol (3.75 mcg daily for the first 6 months, 7.5 mcg daily for the next 6 months, and 11.25 mcg daily for the final 6 months of the study |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalizations for low weight and/or bradycardia | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea/vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Anne Klibanski | Massachusetts General Hospital | 617-726-3870 | aklibanski@partners.org |
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| ID | Term |
|---|---|
| D000856 | Anorexia Nervosa |
| D000568 | Amenorrhea |
| ID | Term |
|---|---|
| D001068 | Feeding and Eating Disorders |
| D001523 | Mental Disorders |
| D008599 | Menstruation Disturbances |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D011374 | Progesterone |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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|
| Placebo | Other | Placebo patches twice weekly; Placebo pills daily for the first 10 days of every month |
|
| 22728230 | Derived | Faje AT, Fazeli PK, Katzman DK, Miller KK, Breggia A, Rosen CJ, Mendes N, Klibanski A, Misra M. Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls. Bone. 2012 Sep;51(3):474-9. doi: 10.1016/j.bone.2012.06.006. Epub 2012 Jun 15. |
| Lost to Follow-up |
|
| BG001 | Placebo | Mature girls with anorexia nervosa with a bone age of 15 years of greater: Placebo patches; Immature girls with anorexia nervosa with a bone age of less than 15 years: Placebo pills |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Mature girls with anorexia nervosa (AN) (bone age ≥15 years) randomized this arm received transdermal 17-β estradiol (100 mcg patch applied twice weekly) continuously over the study duration. Girls randomized to the active estradiol patch also received medroxyprogesterone 2.5 mg daily for 10 days each month. Immature girls with AN (bone age<15 years, N=14) randomized to this arm received escalating doses of oral ethinyl estradiol (3.75 mcg daily for the first 6 months, 7.5 mcg daily for the second 6 months, and 11.25 mcg daily for the last 6 months). All subjects were given 1200 mg calcium carbonate and 400 IU vitamin D daily. |
| OG001 | Placebo | Mature girls with anorexia nervosa (AN) randomized to this arm received placebo patches and cyclic placebo pills. Immature girls with AN randomized to this arm received placebo pills. All subjects received supplemental calcium (1200 mg) and vitamin D (400 IU) daily |
|
|
|
| Secondary | Change in N-terminal Propeptide of Type 1 Procollagen (P1NP) Over the Study Duration (18 Months) | P1NP is a surrogate marker of bone formation that is measured in serum. P1NP levels were measured at baseline, 6, 12 and 18 months. A secondary outcome was the change in P1NP levels from baseline to 18 months: [P1NP at 18 months - P1NP at baseline). The unit is ng/ml](streamdown:incomplete-link) | The number of participants was determined based on our preliminary data. This analysis was based on completers only. | Posted | Mean | Standard Deviation | ng/ml | Baseline and 18 months |
|
|
|
|
| Primary | Change in Spine Bone Mineral Density Z-scores Over the Study Duration (18 Months) | Bone density at the spine (lumbar 1-4 vertebrae) was measured using dual energy x-ray absorptiometry (DXA) at baseline, 6 months, 12 months and 18 months. The other primary outcome was the change in spine bone density Z-score from baseline to 18 months. The bone density Z-score is a standard deviation score that compares one's bone density to the mean for age and gender, and the Z-score, therefore, does not have any units. It is simply referred to as a Z-score. Change in bone density Z-score= [Bone density Z-score at 18 months- Bone density Z-score at baseline] | Posted | Mean | Standard Deviation | Z -scores | Baseline and 18 months |
|
|
|
|
| 12 |
| 55 |
| 18 |
| 55 |
| EG001 | Placebo | Mature girls with anorexia nervosa with a bone age of 15 years of greater: Placebo patches; Immature girls with anorexia nervosa with a bone age of less than 15 years: Placebo pills | 16 | 55 | 20 | 55 |
| Increased vaginal bleeding | Reproductive system and breast disorders | Systematic Assessment |
|
| Erythema at patch application site | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pregnancy | Reproductive system and breast disorders | Systematic Assessment |
|
| Suicidal ideation | Psychiatric disorders | Systematic Assessment |
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| Dizziness | Vascular disorders | Systematic Assessment |
|
| Headaches | Nervous system disorders | Systematic Assessment |
|
| Bloating | Gastrointestinal disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Breast tenderness | Reproductive system and breast disorders | Systematic Assessment |
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| Increased vaginal discharge | Reproductive system and breast disorders | Systematic Assessment |
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| Increased uterine bleeding | Reproductive system and breast disorders | Systematic Assessment |
|
| Irritation from contact lenses | Eye disorders | Systematic Assessment |
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| Perceived increase in facial hair | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Perceived loss of scalp hair | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Worsening depression | Psychiatric disorders | Systematic Assessment |
|
| Erythema at patch application site | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
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| D013568 | Pathological Conditions, Signs and Symptoms |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D003339 | Corpus Luteum Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045167 | Progesterone Congeners |
| D012739 | Gonadal Steroid Hormones |