Safety and Effectiveness of Oral Alendronate Therapy on Bone Mineral Density in HIV-infected Children and Adolescents With Low Bone Mineral Density

Condition(s) targeted: HIV Infections

Intervention: Alendronate (Drug); Alendronate placebo (Drug); Calcium carbonate/vitamin D (Dietary Supplement)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
George K. Siberry, MD, Study Chair, Affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

HIV-infected children, youth, and adults have lower bone mineral density (BMD) than would be expected for HIV-uninfected people of similar age, weight and race. As the majority of perinatally HIV-infected U. S. children are entering or in adolescence, the potential for HIV-related impaired BMD during the adolescent peak of bone mass acquisition is of particular concern. The primary purpose of this study is to compare changes from pre-treatment levels of BMD of the lumbar spine after 24 and 48 weeks of alendronate treatment with placebo in HIV-infected children and adolescents.

Official title: Impact of Oral Alendronate Therapy on Bone Mineral Density in HIV-infected Children and Adolescents With Low Bone Mineral Density

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Primary outcome:

Pre-treatment levels of BMD of the lumbar spine after 24 and 48 weeks of alendronate treatment versus placebo, as measured by Hologic bone densitometers

Safety of of alendronate use as measured by the incidence of new hematology or chemistry laboratory values greater than or equal to Grade 3; signs or symptoms; or new cases of jaw osteonecrosis, atrial fibrillation, or non-healing fractures

Secondary outcome:

Changes from pre-treatment levels of whole body BMD after alendronate treatment versus placebo

Changes from pre-treatment levels of whole body and lumbar spine BMD alendronate treatment versus 48 weeks of alendronate followed by 48 weeks of placebo

Effect of other known bone mineral determinants (age, gender, race/ethnicity, steroid use, Depo-Provera, tenofovir, pubertal stage, bone age, vitamin D status) and inflammatory cytokine levels on changes in BMD after alendronate treatment

Changes in BMD after completion of 48 weeks of alendronate therapy

Alterations in pre-treatment bone marker turnover, receptor activator of nuclear factor kappa-B ligand/osteoprotegerin (RANKL/OPG) ratio, central fat content, and determination of whether the changes in these outcomes correlate with changes in BMD

Effect of alendronate therapy on changes in HIV status (as measured by changes in viral load, CD4% and CDC disease category) and determination whether the changes in these outcomes correlate with changes in BMD

Duration of detectable urinary alendronate in adolescent participants who have completed 48 and 96 weeks of alendronate therapy

Detailed description: Puberty is a time when the foundation is laid for healthy bone mass. Over the course of puberty, 26% of bone mass is established in the 4-year period of peak height velocity and up to 60% of adult peak bone mass is established. Factors that affect normal bone mineralization include calcium intake, vitamin D status, degree of physical and weight bearing activities, hormones, genetics, body weight, and general health and nutrition status. HIV-infected children, youth, and adults have lower bone mineral density (BMD) than would be expected for healthy people of similar age, weight, and race. As the majority of perinatally HIV-infected U. S. children are entering or in adolescence, the potential for HIV-related impaired BMD during the adolescent peak of bone mass acquisition is of particular concern. The purpose of this study is to compare changes from pretreatment levels of BMD of the lumbar spine after 24 and 48 weeks of alendronate treatment with placebo in HIV-infected children and adolescents. This study will last approximately 144 weeks. Participants will be randomized into one of three groups. Participants in Group 1 will receive alendronate for 96 weeks. Participants in Group 2 will receive alendronate for 48 weeks and alendronate placebo for an additional 48 weeks. Participants in Group 3 will receive placebo for 48 weeks followed by alendronate for 48 weeks. All three groups will be followed off treatment for an additional 48 weeks. All participants will receive vitamin D/calcium for the duration of the study. There will be 13 study visits for each participant. They will occur at study entry and Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144. A physical exam, targeted events history, and adherence questionnaire will occur at all visits. Blood and urine collection, Tanner stage assessment, DXA scan, and radiograph will occur at most visits. Participants will also complete a questionnaire about smoking behavior at screening. Participants will be contacted by telephone 7 times throughout the study at Weeks 1, 4, 28, 49, 52, 76, and 100 to screen for adverse events, assess adherence, and reinforce study instructions. Information provided by adolescent participants about sexual activity, pregnancy, and smoking and alcohol use will not be shared without the participants' permission.

Minimum age: 11 Years. Maximum age: 24 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Documentation of HIV-1 infection is defined as positive results from two samples

collected at different time points. All samples tested must be whole blood, serum, or plasma. For studies conducted under an IND, all test methods should be FDA-approved if available. If FDA-approved methods are not available, test methods should be verified according to GCLP and approved by the IMPAACT central laboratory. Results documented in the clinical record from past testing may be used to satisfy the criteria for documentation of HIV-1 infection. More information on this criterion can be found in the protocol.

- HIV-infected. Infection must have been acquired prior to puberty.

- For participants receiving antiretroviral therapy, antiretroviral agents must be

steady for at least 12 weeks prior to study entry and have a viral load less than 10,000 copies/mL

- Lumbar spine DXA BMD z-score lower than -1. 5 OR history of fragility fracture within

the prior 12 months (regardless of DXA result). More information about this criterion can be found in the protocol.

- Available for routine dental exam and care every 6 months

- Demonstrates ability and willingness to swallow study medications

- For females, participants must agree to use at least two forms of accepted

contraceptives. More information about this criterion can be found in the protocol. Exclusion Criteria:

- Body weight of more than 300 lbs.

- For female participants, received Depo-Provera for less than 1 full year during the

year prior to study entry. More information about this criterion can be found in the protocol.

- Anticonvulsant therapy

- Proven growth hormone deficiency

- Use of growth hormone in the 12 months prior to entry

- Primary hyperparathyroidism

- Hypoparathyroidism

- Renal failure

- Cushing syndrome

- Active dental infection

- Dental or periodontal disease that is expected to require more than basic restorative

care

- Esophageal or gastric ulcer, chronic nonsteroidal anti-inflammatory drug (NSAID) use,

aspirin use

- Tenofovir disoproxil fumarate (TDF) taken by participants for less than 24 weeks

during the 24 weeks prior to study entry. More information about this criterion can be found in the protocol.

- Hemoglobin less than 10 g/dL

- Any past pharmacologic treatment (except vitamin D and/or calcium supplementation)

for low bone density

- Inability to stand or sit upright for at least 30 minutes

- Hypersensitivity to any component of alendronate

- Hypocalcemia (less than the lower limit of normal established by the local laboratory

in which it is performed)

- Known abnormalities of the esophagus that delay esophageal emptying such as stricture

or achalasia

- 25-OH vitamin D less than 10 ng/mL

- Pregnant or breastfeeding

Univ. of Sao Paulo Brazil NICHD CRS, Sao Paulo 14049-900, Brazil

San Juan City Hosp. PR NICHD CRS, San Juan 00936, Puerto Rico

David Geffen School of Medicine at UCLA NICHD CRS, Los Angeles, California 90095-1752, United States

Pediatric Perinatal HIV Clinical Trials Unit CRS, Miami, Florida 33136, United States

USF - Tampa NICHD CRS, Tampa, Florida 33606, United States

Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS, Chicago, Illinois 60614, United States

Johns Hopkins Univ. Baltimore NICHD CRS, Baltimore, Maryland 21287, United States

WNE Maternal Pediatric Adolescent AIDS CRS, Worcester, Massachusetts 01605, United States

SOM Federal University Minas Gerais Brazil NICHD CRS, Belo Horizonte, Minas Gerais 30130-100, Brazil

St. Jude Children's Research Hospital CRS, Memphis, Tennessee 38105, United States

Related publications:

Clay PG, Voss LE, Williams C, Daume EC. Valid treatment options for osteoporosis and osteopenia in HIV-infected persons. Ann Pharmacother. 2008 May;42(5):670-9. doi: 10.1345/aph.1K465. Epub 2008 Apr 15. Review.

McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, Suckow C, Gopalakrishnan G, Benson C, Wohl DA. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS. 2007 Nov 30;21(18):2473-82.

Stoch SA, Saag KG, Greenwald M, Sebba AI, Cohen S, Verbruggen N, Giezek H, West J, Schnitzer TJ. Once-weekly oral alendronate 70 mg in patients with glucocorticoid-induced bone loss: a 12-month randomized, placebo-controlled clinical trial. J Rheumatol. 2009 Aug;36(8):1705-14. doi: 10.3899/jrheum.081207. Epub 2009 Jun 1.

Starting date: August 2009
Last updated: October 7, 2014