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Trial of Lithium Carbonate for Treatment of Osteoporosis-pseudoglioma Syndrome

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ClinicalTrials.gov Identifier: NCT01108068
Recruitment Status : Completed
First Posted : April 21, 2010
Results First Posted : April 27, 2018
Last Update Posted : April 27, 2018
Sponsor:
Information provided by (Responsible Party):
Elizabeth Streeten, University of Maryland

Brief Summary:
This was a pilot study of 10 patients with Osteoporosis-pseudoglioma syndrome (OPPG) from the Old Order Mennonite community and 16 controls, who did not have OPPG. Five of the 10 OPPG patient elected to participate in the Lithium trial and 5 participated only in baseline data (labs, pQCT). The 5 with OPPG who were given lithium for 6 months had both dual energy xray absorptiometry (DXA), peripheral quantitative computerized tomography (pQCT) and lab assessment at baseline and 6 months. Studies in the mouse model of OPPG showed that lithium normalized their bone strength. Controls (n=16) were recruited from the Old Order Mennonite community, to minimize the effects of environmental and lifestyle factors. The controls were not be given lithium. The age range of participants was 4-64 years.

Condition or disease Intervention/treatment Phase
Osteoporosis Pseudoglioma Drug: Lithium Not Applicable

Detailed Description:

Osteoporosis-pseudoglioma (OPPG) syndrome is a very rare genetic disorder (approximately 50 cases have been reported worldwide) due to mutations in the LRP5 gene, causing blindness from birth and fragile bones (osteoporosis)in early childhood. The bony fragility can lead to recurrent fractures of major bones such as the hip (femur) and spine, leaving some children in wheelchairs.

Treatment to strengthen the bones in OPPG has primarily been with osteoporosis medications used in other fragile bone disorders of childhood and in adults, namely the bisphosphonates (eg. pamidronate, alendronate). These drugs have helped the bone strength in OPPG somewhat but have not prevented all fractures. We have observed fractures of the hip in 3 children with OPPG who we have treated, in spite of their attaining normal bone density (determined by DXA, dual xray absorptiometry) with bisphosphonates. Therefore, new treatments for OPPG are greatly needed and new methods besides DXA are needed to monitor bone strength on treatment.

A mouse model of OPPG has been created. In the mouse model of OPPG, lithium dramatically improved their bones, returning them to normal strength and preventing fractures. Lithium, which is used for people with psychiatric disease, is known to lead to higher bone strength and reduced fractures in people who are on it for psychiatric disease. Lithium has been used safely and is approved for children 12 and above. The theory is that lithium will improve bone strength in OPPG in humans, as it has in the mouse, by stimulating bone production bypassing the genetic defect in OPPG.

In this study, we recruited 10 patients with OPPG and treated those who agreed (n=5) with lithium for 6 months, monitoring the response of the bones by both DXA and pQCT (peripheral quantitative computed tomography), the latter which gives information about bone quality. An IND was obtained to use lithium in this study.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Trial of Lithium Carbonate for Treatment of Osteoporosis Pseudoglioma Syndrome
Study Start Date : July 2010
Actual Primary Completion Date : July 2014
Actual Study Completion Date : July 2014


Arm Intervention/treatment
Experimental: Lithium
patients with OPPG will be treated with lithium for 6 months
Drug: Lithium
lithium will be given for 6 months to patients with OPPG, starting at a low dose of 2.5 mg/kg daily, gradually increasing until a lithium blood level of 0.3-0.6 ng/dl is achieved.
Other Name: lithium carbonate or lithium citrate will be used

No Intervention: Unaffected controls
Family members of patients with OPPG will have DXA and pQCT to compare to OPPG patients. These unaffected participants will not receive lithium.



Primary Outcome Measures :
  1. pQCT of Lower Leg [ Time Frame: Baseline ]
    pQCT will be done at baseline for all OPPG participants and unaffecteds. The Z-score indicates the number of standard deviations away from the mean of age matched controls. A Z-score of 0 is equal to the mean, with negative numbers indicating values lower than the mean and positive values higher. A positive change in Z-score indicates a favorable outcome.


Secondary Outcome Measures :
  1. pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium [ Time Frame: baseline, 6 months ]
    The Z-score indicates the number of standard deviations away from the mean of age matched controls. A Z-score of 0 is equal to the mean, with negative numbers indicating values lower than the mean and positive values higher. A positive change in Z-score indicates a favorable outcome.Z-score of pQCT variable was noted for the in two OPPG participants who received lithium and were also able to get pQCT scans. The "n" of 2 was too small to do statistical analyses. Of the 5 OPPG who were on lithium, 2 were too small for the machine (eventhough over age 4) and 1 had rods in his legs and couldn't have pQCT



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Ages Eligible for Study:   4 Years to 64 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Eligibility Criteria

Inclusion Criteria

  • Age 4 years or greater
  • Diagnosed with osteoporosis pseudoglioma syndrome (OPPG) or a first degree relative of someone with OPPG. For diagnosis of OPPG, one of the following is required: (1) congenital blindness in a child born into a family with known OPPG where at least one affected family member has had an LRP5 mutation demonstrated or (2) a child with no known family members with OPPG who has congenital blindness, DXA Z-score < -2.0 and mutation in LRP5 documented
  • No contraindications to lithium carbonate
  • For women of child bearing age, willing to undergo urine pregnancy test

Exclusion Criteria

  • Age under 4 years
  • Not diagnosed with osteoporosis pseudoglioma (OPPG) syndrome or a first degree relative of someone with OPPG, or a member of the Old Order Mennonite community
  • Pregnant
  • For women of childbearing age, not willing to undergo urine pregnancy test
  • Contraindication to Lithium (serum creatinine > 1.3, known cardiovascular disease [history of myocardial infarction, heart failure], currently on diuretic or ACE inhibitor)
  • Glomerular filtration rate below 80 cc/min

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01108068


Locations
United States, Pennsylvania
University of Maryland Amish Research Clinic
Lancaster, Pennsylvania, United States, 17601
Sponsors and Collaborators
University of Maryland
Investigators
Principal Investigator: Elizabeth A Streeten, MD University of Maryland

Publications:
Responsible Party: Elizabeth Streeten, Clinical Professor of Medicine, University of Maryland
ClinicalTrials.gov Identifier: NCT01108068     History of Changes
Other Study ID Numbers: HP-00040536
First Posted: April 21, 2010    Key Record Dates
Results First Posted: April 27, 2018
Last Update Posted: April 27, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Elizabeth Streeten, University of Maryland:
Osteoporosis-pseudoglioma syndrome, OPPG, LRP5 mutation

Additional relevant MeSH terms:
Osteoporosis
Blindness
Spasms, Infantile
Genetic Diseases, X-Linked
Osteogenesis Imperfecta
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Vision Disorders
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Eye Diseases
Signs and Symptoms
Epilepsy, Generalized
Epilepsy
Brain Diseases
Central Nervous System Diseases
Genetic Diseases, Inborn
Osteochondrodysplasias
Bone Diseases, Developmental
Collagen Diseases
Connective Tissue Diseases
Lithium Carbonate
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents