Bone Loss in Women With Anorexia Nervosa

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00089843
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 77
• Location: 1
• Arms: 4
• Duration (Months): 58
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Women with Anorexia Nervosa have been found to have low bone density. The study will determine whether administration of low doses of a natural hormone, testosterone and/or risedronate, a medication to help prevent bone breakdown will improve or prevent bone loss in this condition.

Condition or Disease	Intervention/Treatment	Phase
Anorexia Nervosa	Drug: Testosterone; Drug: Actonel (risedronate); Drug: Placebo Actonel (risedronate); Drug: Placebo testosterone	Phase 2/Phase 3

Detailed Description

1. SPECIFIC AIMS

Severe osteopenia is a prevalent complication of anorexia nervosa (AN), affecting over half of all women with this disease. Loss of 25-50% of total bone mass occurs frequently and is often permanent. Although anorexia nervosa affects from 0.5-1.0% of college age women, no successful therapeutic interventions have been developed for osteoporosis in this population. Bone loss in anorexia nervosa is characterized by reduced bone formation coupled with increased bone resorption. Anorexia nervosa results in a deficiency of testosterone. Testosterone administration reduces bone resorption and data suggest that low-dose testosterone replacement therapy can increase surrogate markers of bone formation. Bisphosphonates are now well established to decrease bone resorption and improve bone density in severely osteopenic postmenopausal women. However, there are few data regarding the use of this antiresorptive therapy in women with severe pre-menopausal bone loss. Our preliminary data demonstrate that administration of a bisphosphonate decreases bone resorption and increases bone mass in women with AN after 6 and 9 months. These are the first data to demonstrate a striking increase in bone density in such women. We will test the hypothesis that a combined strategy to increase bone formation and decrease bone resorption by combining testosterone with a bisphosphonate will increase bone mass in anorexia nervosa.

The following hypotheses will be tested:

Specific Aim 1. Testosterone, a nutritionally dependent bone trophic factor, is a critical determinant of decreased bone formation in anorexia nervosa, and administration of physiologic testosterone will increase bone formation and lean body mass in this disease

We will investigate in women with anorexia nervosa whether:

1. Bone formation is reduced in association with low serum testosterone B. Testosterone deficiency is due to a combination of ovarian and adrenal defects resulting from undernutrition C. Testosterone administration reverses testosterone deficiency leading to an acute and sustained increase in bone formation and a decrease in bone resorption D. Administration of physiologic testosterone replacement stimulates increases in IGF-I levels in women with anorexia nervosa, a mechanism for increased bone formation and bone density E. Administration of physiologic testosterone replacement increases lean body mass, a major determinant of bone density

Specific Aim 2. Long-term (12 months) physiologic testosterone administration combined with a bisphosphonate increases bone density by a dual anabolic and anti-resorptive strategy

We will investigate in women with anorexia nervosa whether:

1. Physiologic testosterone administration increases bone density B. Administration of a bisphosphonate decreases the excessive state of bone resorption and increases bone density C. Co-administration of physiologic testosterone replacement and a bisphosphonate increases bone density to a greater degree than testosterone or a bisphosphonate alone by increasing bone formation and decreasing bone resorption

Study Design

• Study Type: Interventional
• Actual Enrollment: 77 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: IGF-1 and Bone Loss in Women Anorexia Nervosa
• Study Start Date: Jun 1, 2003
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 2 Placebo Actonel (risedronate) and active testosterone patch	Drug: Testosterone; Testosterone patch 150mcg daily; Other Names: Intrinsa ; Drug: Placebo Actonel (risedronate); Placebo tablet identical in appearance to active Actonel (risedronate) tablet
Active Comparator: 3 Active Actonel (risedronate) and active testosterone patch	Drug: Testosterone; Testosterone patch 150mcg daily; Other Names: Intrinsa ; Drug: Actonel (risedronate); Actonel (risedronate) 35mg PO one time weekly; Other Names: Actonel
Active Comparator: 4 Active Actonel (risedronate) and placebo testosterone	Drug: Actonel (risedronate); Actonel (risedronate) 35mg PO one time weekly; Other Names: Actonel ; Drug: Placebo testosterone; Placebo patch identical in appearance to testosterone patch
Placebo Comparator: 1 Placebo testosterone patch and placebo Actonel (risedronate)	Drug: Placebo Actonel (risedronate); Placebo tablet identical in appearance to active Actonel (risedronate) tablet; Drug: Placebo testosterone; Placebo patch identical in appearance to testosterone patch

Outcome Measures

Primary Outcome Measures

1. Bone Mineral Density [Baseline and 12 months]

   Percent change in postero-anterior (PA) spine bone mineral density as measured by dual energy x-ray absorptiometry (DXA)over a 12-month period. The differences in log-transformed values are reported as percent change.

Secondary Outcome Measures

1. Markers of Bone Metabolism [Baseline to 12 months]

   type 1 collagen C-telopeptide(CTX); The differences in log-transformed values are reported as percent change.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Anorexia Nervosa,

• Over 18,

• Female,

• Decreased bone density

Exclusion Criteria:

• Medications to increase bone density

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Anne Klibanski, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Karen Klahr Miller, MD, Chief, Neuroendocrine Unit, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00089843
• Other Study ID Numbers: 5 R01 DK052625 (completed); R01DK052625; 1UL1RR025758
• First Posted: Aug 17, 2004
• Last Update Posted: Sep 2, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Karen Klahr Miller, MD, Chief, Neuroendocrine Unit, Massachusetts General Hospital: Eating Disorders; Osteopenia
• Additional relevant MeSH terms: Anorexia; Anorexia Nervosa; Risedronic Acid; Etidronic Acid; Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate

Study Results

Participant Flow

Arm/Group Title	Placebo Actonel and Active Testosterone Patch	Active Actonel and Active Testosterone Patch	Active Actonel and Placebo Testosterone	Placebo Testosterone Patch and Placebo Actonel
Arm/Group Description	Placebo Actonel tablet weekly and active testosterone patch (starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)	Active Actonel tablet (35 mg weekly) and Active Testosterone patch (starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)	Active Actonel tablet (35 mg weekly) and Placebo Testosterone Patch	Placebo Testosterone Patch and placebo Actonel tablet
Period Title: Overall Study
STARTED	19	20	20	18
COMPLETED	17	16	15	11
NOT COMPLETED	2	4	5	7

Baseline Characteristics

Arm/Group Title	Placebo Actonel and Active Testosterone Patch	Active Actonel and Active Testosterone Patch	Active Actonel and Placebo Testosterone	Placebo Testosterone Patch and Placebo Actonel	Total
Arm/Group Description	Placebo Actonel tablet weekly and active testosterone patch (starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)	Active Actonel tablet (35 mg weekly) and Active Testosterone patch (starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)	Active Actonel tablet (35 mg weekly) and Placebo Testosterone Patch	Placebo Testosterone Patch and placebo Actonel tablet	Total of all reporting groups
Overall Participants	19	20	20	18	77
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	19 100%	20 100%	20 100%	18 100%	77 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.1 (7.3)	25.2 (6.2)	25.3 (6.3)	26.9 (7.2)	26.1 (6.7)
Sex: Female, Male (Count of Participants)
Female	19 100%	20 100%	20 100%	18 100%	77 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	19 100%	20 100%	20 100%	18 100%	77 100%

Outcome Measures

1. Primary Outcome

Title	Bone Mineral Density
Description	Percent change in postero-anterior (PA) spine bone mineral density as measured by dual energy x-ray absorptiometry (DXA)over a 12-month period. The differences in log-transformed values are reported as percent change.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

1 subject was excluded from analysis. A factorial analysis was performed and determines the effect of each intervention separately, whether or not a subject received the 2nd intervention. Therefore, data from all 76 subjects who participated were used to determine the effect of each intervention on our endpoints.

Arm/Group Title	Actonel (Risedronate) 35 mg Weekly	Testosterone
Arm/Group Description	Actonel (risedronate) 35 mg, 1 tablet weekly	Testosterone, initial dose 150 mcg transdermal daily, increased to 300 mcg daily in women with free testosterone levels below the median (n=25 women)
Measure Participants	40	39
Mean (95% Confidence Interval) [percent change]	3.2	-0.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Actonel (Risedronate) 35 mg Weekly
	Comments	Factorial analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This p value was for the effect of Actonel (risedronate) on bone mineral density of the spine.
	Method	Factorial analysis
	Comments
Method of Estimation	Estimation Parameter	Percent change between 0 and 12 months
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; 1.8 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Testosterone
	Comments	Factorial analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments	This p value was for the effect of testosterone on bone mineral density of the spine.
	Method	Factorial analysis
	Comments
Method of Estimation	Estimation Parameter	Percent change between 0 and 12 months
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -2.0 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Markers of Bone Metabolism
Description	type 1 collagen C-telopeptide(CTX); The differences in log-transformed values are reported as percent change.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

1 subject was excluded from analysis. A factorial analysis was performed and determines the effect of each intervention separately, whether or not a subject received the 2nd intervention. Therefore, data from all 76 subjects who participated were used to determine the effect of each intervention on our endpoints.

Arm/Group Title	Actonel (Risedronate)	Testosterone
Arm/Group Description	Actonel (risedronate) 35 mg tablet weekly	Testosterone patch(starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)
Measure Participants	40	39
Mean (95% Confidence Interval) [percent change of CTX]	-41	-11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Actonel (Risedronate) 35 mg Weekly
	Comments	Factorial analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	This p value was for the effect of Actonel (risedronate).
	Method	Factorial analysis
	Comments
Method of Estimation	Estimation Parameter	Percent change between 0 and 12 months
	Estimated Value	-41
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Testosterone
	Comments	Factorial analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments	This p value was for the effect of testosterone.
	Method	Factorial analysis
	Comments
Method of Estimation	Estimation Parameter	Percent change between 0 and 12 months
	Estimated Value	-11
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Placebo Actonel and Active Testosterone Patch		Active Actonel and Active Testosterone Patch		Active Actonel and Placebo Testosterone		Placebo Testosterone Patch and Placebo Actonel
Arm/Group Description	Placebo Actonel tablet weekly and active testosterone patch (starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)		Active Actonel tablet (35 mg weekly) and Active Testosterone patch (starting dose 150 mcg daily; increased to 300 mcg daily in subjects whose levels remained below the median on the initial dose)		Active Actonel tablet (35 mg weekly) and Placebo Testosterone Patch		Placebo Testosterone Patch and placebo Actonel tablet
All Cause Mortality
	Placebo Actonel and Active Testosterone Patch		Active Actonel and Active Testosterone Patch		Active Actonel and Placebo Testosterone		Placebo Testosterone Patch and Placebo Actonel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Actonel and Active Testosterone Patch		Active Actonel and Active Testosterone Patch		Active Actonel and Placebo Testosterone		Placebo Testosterone Patch and Placebo Actonel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/19 (31.6%)		1/20 (5%)		5/20 (25%)		2/18 (11.1%)
Psychiatric disorders
Hospitalization related to underlying condition (anorexia nervosa)	6/19 (31.6%)	16	1/20 (5%)	11	5/20 (25%)	13	2/18 (11.1%)	3
Other (Not Including Serious) Adverse Events
	Placebo Actonel and Active Testosterone Patch		Active Actonel and Active Testosterone Patch		Active Actonel and Placebo Testosterone		Placebo Testosterone Patch and Placebo Actonel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/19 (63.2%)		16/20 (80%)		16/20 (80%)		12/18 (66.7%)
Gastrointestinal disorders
Reflux	5/19 (26.3%)	8	3/20 (15%)	8	1/20 (5%)	3	6/18 (33.3%)	11
Musculoskeletal and connective tissue disorders
Myalgias	3/19 (15.8%)	3	1/20 (5%)	2	2/20 (10%)	2	0/18 (0%)	0
Skin and subcutaneous tissue disorders
Mild irritation at patch site	9/19 (47.4%)	18	11/20 (55%)	27	8/20 (40%)	29	7/18 (38.9%)	15
Mild increase in acne or oily skin	8/19 (42.1%)	21	13/20 (65%)	28	13/20 (65%)	33	12/18 (66.7%)	33
Mild increase in body hair growth	6/19 (31.6%)	11	7/20 (35%)	12	3/20 (15%)	4	3/18 (16.7%)	14

Limitations/Caveats

[Not Specified]

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.