Clinical trial NCT00921557: Safety and Effectiveness of Alendronate for Bone Mineral Density 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infection
Keywords: Bone mineral density
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2009-06-16
Enrollment: 52
Sex: ALL
Minimum age (years): 11
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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 was 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.

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 was to compare changes in BMD of the lumbar spine from pre-treatment levels to 24 and 48 weeks after alendronate treatment or placebo in HIV-infected children and adolescents.

Participants were randomized equally into one of three groups: Group 1A received alendronate for 96 weeks; Group 1B received alendronate for 48 weeks followed by placebo for 48 weeks; Group 2 received placebo for 48 weeks followed by alendronate for 48 weeks. All three groups were followed off treatment for an additional 48 weeks. Participants also received vitamin D/calcium for the duration of the study and were asked to perform 60 minutes of weight-bearing exercise each day.

Clinic visits were scheduled every 12 weeks after entry, with telephone contact visits one, four, and 28 weeks after entry and the week 48 visit. A physical exam and dental assessment was conducted at each clinic visit, and a history of adverse events collected. Dual Energy X-ray absorptiometry (DXA), hematology and chemistry panels were conducted at entry and weeks 24, 48, 72, 96 and 144. Lumbar spine and whole body (with head) BMD was measured using Hologic DXA scanners (QDR4500A, QDR4500W or Delphi A models).

The primary analysis compared changes from entry to 24 and 48 weeks in lumbar spine BMD between Groups 1A and 1B combined (both on alendronate for initial 48 weeks) vs. Group 2 (on placebo for 48 weeks). Study participants were unblinded after 96 weeks of follow-up (the primary completion date) but remained on study, off study treatment, for an additional 48 weeks.

Secondary laboratory outcomes listed in the protocol (bone marker turnover and Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin (RANKL/OPG) Ratio) and central fat content, which required application for additional funding for laboratory testing, will not be performed and no results will be available.

Eligibility criteria: Inclusion Criteria (Version 2.0 of protocol):

* Documentation of HIV-1 infection
* HIV-infection acquired before puberty
* For participants receiving antiretroviral therapy, must have been on the same antiretroviral agents for at least 12 weeks prior to study entry and have a viral load less than 10,000 copies/mL. For participants not receiving antiretroviral therapy, must have not been on antiretroviral agents for at least 12 weeks prior to study entry and have no indication for therapy
* Lumbar spine DXA BMD z-score less than -1.5 or history of fragility fracture within the prior 12 months (regardless of DXA result).
* Available for routine dental exam and care every 6 months
* Demonstrated ability and willingness to swallow study medications
* Females of reproductive potential must have had a negative pregnancy test at screening and within 48 hours prior to study entry. They must also have agreed to avoid pregnancy while on the study and if engaging in sexual activity, use at least two forms of contraception.
* Parent or legal guardian able and willing to provide signed informed consent for children who could not provide consent for themselves.

Exclusion Criteria (Version 2.0 of protocol):

* Body weight more than 300 lbs.
* For female participants: if on Depo-Provera, they must have been on it for at least 1 year prior to study entry; if not on Depa-Provera, they must have not been on it for at least 1 year prior to study entry.
* 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 expected to require more than basic restorative care
* Pregnancy or lactation
* Esophageal or gastric ulcer, chronic nonsteroidal anti-inflammatory drug (NSAID) use, or aspirin use
* Tenofovir disoproxil fumarate (TDF): if on TDF, they must have been on it for at least 6 months prior to study entry; if not on TDF, they must have not been on it for at least 6 months prior to study entry.
* 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 was performed)
* Known abnormalities of the esophagus that delay esophageal emptying such as stricture or achalasia
* 25-OH vitamin D less than 10 ng/mL in combination with elevated intact PTH above the upper limit of normal for the local laboratory in which it was performed

Primary outcomes:
measure: Percent Change From Baseline to Weeks 24 and 48 in Lumbar Spine BMD
timeFrame: Weeks 0, 24 and 48
measure: Percentage of Participants Developing New Signs, Symptoms, Hematology or Chemistry Laboratory Values Greater Than or Equal to Grade 3 or New Cases of Jaw Osteonecrosis, Atrial Fibrillation, or Non-healing Fractures
timeFrame: Week 0 to 48
Secondary outcomes:
measure: Percent Change From Baseline to Weeks 24 and 48 in Whole Body (With Head) BMD
timeFrame: Weeks 0, 24 and 48
measure: Percent Change From Baseline to Week 96 in Lumbar Spine BMD
timeFrame: Weeks 0 and 96
measure: Percent Change From Baseline to Week 96 in Whole Body (With Head) BMD
timeFrame: Weeks 0 and 96
measure: Safety as Measured by the Incidence of New Signs, Symptoms, Hematology or Chemistry Laboratory Values Greater Than or Equal to Grade 3 or New Cases of Jaw Osteonecrosis, Atrial Fibrillation, or Non-healing Fractures
timeFrame: Weeks 0 to 144
measure: 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 Lumbar Spine BMD
timeFrame: Weeks 0, 24 and 48
measure: 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 Whole Body (With Head) BMD.
timeFrame: Weeks 0, 24 and 48
measure: Percent Change From Week 48 to Week 96 (Group 1B), Week 48 to Week 144 (Group 1B), and Week 96 to 144 (Group 2) in Lumbar Spine BMD
timeFrame: Weeks 48, 96 and 144
measure: Percent Change From Week 48 to Week 96 (Group 1B), Week 48 to Week 144 (Group 1B), and Week 96 to 144 (Group 2) in Whole Body (With Head) BMD
timeFrame: Weeks 48, 96 and 144
measure: Change From Baseline to Week 48 in Bone Marker Turnover
timeFrame: Weeks 0 and 48
measure: Correlation of Changes in Bone Marker Turnover With Changes in Lumbar Spine and Whole Body (With Head) BMD
timeFrame: Weeks 0 and 48
measure: Change From Baseline to Week 48 in Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin (RANKL/OPG) Ratio
timeFrame: Weeks 0 and 48
measure: Correlation of Changes in RANKL/OPG Ratio With Changes in Lumbar Spine and Whole Body (With Head) BMD
timeFrame: Weeks 0 and 48
measure: Change From Baseline to Week 48 in Central Fat Content
timeFrame: Weeks 0 and 48
measure: Correlation of Changes in Central Fat Content With Changes in Lumbar Spine and Whole Body (With Head) BMD
timeFrame: Weeks 0 and 48
measure: Percent of Participants With HIV-1 RNA <= 400 Copies/ml
timeFrame: Weeks 0, 48, 96 and 144
measure: Change in CD4 Percent From Baseline
timeFrame: Weeks 0, 48, 96 and 144
measure: Change in Centers for Disease Control (CDC) HIV Disease Category
timeFrame: Weeks 144
measure: Percent of Participants With Detectable Urinary Alendronate
timeFrame: Weeks 48, 96 and 144
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA NICHD CRS
state: California
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit CRS
state: Florida
city: Tampa
country: United States
facility: USF - Tampa NICHD CRS
state: Florida
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago (LCH) CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: George K. Siberry, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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. doi: 10.1097/QAD.0b013e3282ef961d.
citation: 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.
citation: The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).
citation: Jacobson DL, Lindsey JC, Gordon C, Hazra R, Spiegel H, Ferreira F, Amaral FR, Pagano-Therrien J, Gaur A, George K, Benson J, Siberry GK. Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age. Clin Infect Dis. 2020 Aug 22;71(5):1281-1288. doi: 10.1093/cid/ciz957.