The Effects of Estrogen Replacement Therapy in Postmenopausal Women With Hypercalciuria and Low Bone Mass

Phase 2

Terminated

• Conditions: Hypercalciuria; Hypercalciuria, Familial Idiopathic; Osteopenia; Osteoporosis
• Interventions: Drug: Transdermal estradiol

• Registration Number: NCT01928082
• Lead Sponsor: University of Chicago

Brief Summary

The purpose of this study is to assess if estrogen replacement normalizes urinary calcium excretion in postmenopausal women with hypercalciuria and low bone mass and to assess for differences in response to estrogen replacement in women with familial hypercalciuria compared to nonfamilial hypercalciuria.

Detailed Description

Subjects will primarily be recruited from the subjects of protocol 12-1421. Subjects may also be identified through chart review of patients seen by Dr. Favus in the Bone Clinic at the University of Chicago. These subjects will be mailed a letter describing the study and a request to contact us if they are willing to participate in the study.

We plan to enroll 20 subjects to obtain complete data on 16 subjects. We aim to have 10 subjects who will have confirmed familial idiopathic hypercalciuria (IH) and 10 subjects who will have no family history of hypercalciuria.

Subjects will be brought into the Clinical Research Center at the University of Chicago where blood samples will be collected by phlebotomy to obtain the following screening tests: complete metabolic panel; including calcium, phosphate, magnesium, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin; parathyroid hormone, 25-hydroxyvitamin D, follicle stimulating hormone (FSH), and estradiol. A twenty-four hour urine collection starting with second void of the day will be collected for calcium, phosphate, magnesium, citrate, oxalate, sodium, ammonia, sulfate, and creatinine. Subjects on diuretics will be screened after a 2 week washout period, provided this can be discontinued safely. If subjects have participated in study protocol number 12-1421, these screening tests do not have to be repeated and the results from protocol number 12-1421 will be used to determine eligibility.

Screening subjects who meet inclusion criteria can proceed to the observational study. Screening subjects who are vitamin D depleted (serum 25-hydroxyvitamin D less than 35 ng/mL) may be rescreened after repletion of vitamin D.

A letter describing the study aims, protocols, and risks and benefits will be sent to their primary care physicians and gynecologists. Upon completion of the study, a summary letter will be sent as well.

Prior to the baseline visit a twenty-four hour urine collection starting with the second void of the day will be collected for calcium, phosphate, magnesium, citrate, oxalate, sodium, ammonia, sulfate, and creatinine. Subjects on diuretics will require a 2 week washout period, provided this can be discontinued safely. During the baseline visit a medical history will be taken and a physical exam will be performed. Venous blood will be collected for 1,25-dihydroxyvitamin D3, osteocalcin, bone-specific alkaline phosphatase, C-telopeptides of type 1 collagen (CTX), procollagen type 1 N-terminal propeptide (P1NP), bone morphogenetic protein 2 (BMP-2), and sclerostin. If the subject has had these blood tests performed in the preceding four months for protocol 12-1421, the blood tests will not be repeated. 18F sodium fluoride PET/CT bone scan will be performed. The protocol for the radionuclide imaging is attached.

All subjects will be started on transdermal 17-beta-estradiol 0.05 mg/d, which is equivalent to the standard dose of conjugated estrogen dose of 0.625 mg, for 4 weeks and increased to 0.1 mg for subsequent 4 weeks. Given the short duration of this study, progesterone will not be provided, as 8 weeks is not of sufficient duration to significantly increase the risk of endometrial cancer (Strom, Schinnar et al. 2006).

For the entire study, diuretics will be discontinued if it has been deemed safe to do so by the principle investigator or prescribing physician. Throughout the study, subject will maintain 900-1200 mg of dietary calcium daily. To monitor dietary calcium intake, a 5 day diet diary will be kept from Sunday to Thursday of the fourth week of each medication dose. Compliance of the study medication will be assessed by estrogen patch counts.

The following blood tests will be repeated 4 and 8 weeks after starting estradiol patch: complete metabolic panel (including calcium, phosphate, potassium, bicarbonate, chloride, magnesium, creatinine, and albumin), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, parathyroid hormone, estradiol, osteocalcin, bone-specific alkaline phosphatase, C-telopeptides of type 1 collagen (CTX), procollagen type 1 N-terminal propeptide (P1NP), bone morphogenetic protein 2 (BMP-2), and sclerostin. In addition, 4 and 8 weeks after starting estradiol patch, 24 hour urine collection will be performed for calcium, phosphate, magnesium, citrate, oxalate, sodium, ammonia, sulfate, and creatinine.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2013-08-01
• Study First Submitted: 2013-08-20
• Study First Submitted QC: 2013-08-20
• Study First Posted: 2013-08-23
• Primary Completion: 2014-08-01
• Study Completion: 2014-08-01
• Results First Submitted: 2017-10-12
• Results First Submitted QC: 2018-02-05
• Results First Posted: 2018-03-07
• Status Verified: 2018-10
• Last Update Submitted: 2018-12-07
• Last Update Posted: 2018-12-10

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 1

Inclusion Criteria

• Postmenopausal women
• Diagnosis of hypercalciuria
• Diagnosis of low bone mass
• Vitamin D replete (serum 25-hydroxyvitamin D level >35 ng/mL)

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Exclusion Criteria

• Secondary causes of hypercalciuria (primary hyperparathyroidism, sarcoidosis, vitamin D excess, malignant neoplasm, and renal tubular acidosis)
• Other metabolic bone disease (primary hyperparathyroidism, hyperthyroidism, hypercortisolemia, severe gastrointestinal disorders, liver cirrhosis, renal failure (Cr >1.5), active malignancy including multiple myeloma, rheumatological diseases, and Paget's disease of bone)
• Use of medications affecting bone and calcium metabolism (corticosteroids in the previous 3 months, suppressive dose of thyroid hormone, calcium channel blockers, anti-convulsants, aromatase inhibitors, thiazolidinediones, and cyclosporine A)
• History of coronary artery disease
• Breast cancer or suspected estrogen-dependent neoplasia
• Previous venous thromboembolic event
• Stroke
• Active liver disease
• Tobacco use within the past 6 months
• Negative colonoscopy within the previous 10 years or sigmoidoscopy within the previous 5 years
• Negative mammogram within the previous 2 years
• Negative Pap smear within the previous 3 years in women < or = 65 years old with an intact cervix
• No vaginal bleeding within the prior 5 months.
• Age > or = 70
• > or = 20 years since last menstrual period or use of hormone replacement therapy

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Transdermal estradiol	Transdermal estradiol	Transdermal estradiol 0.05 mg/day for 4 weeks, followed by 0.10 mg/day for 4 weeks

Primary Outcome Measures

Name	Time	Method
Absolute Change in 24 Hour Urinary Calcium Excretion	4 weeks, 8 weeks	0 participants were measured because the study was terminated

Secondary Outcome Measures

Name	Time	Method
Serum Bone Morphogenetic Protein 2	4 weeks, 8 weeks	Not available because the study was terminated
Serum 1,25-dihydroxyvitamin D3	4 weeks, 8 weeks	0 participants were analyzed because the study was terminated
Serum Sclerostin	4 weeks, 8 weeks	Not available because the study was terminated

Trial Locations

Locations (1)

The University of Chicago; 🇺🇸 Chicago, Illinois, United States