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

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.

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