Trial of Lithium Carbonate for Treatment of Osteoporosis-pseudoglioma Syndrome
Study Details
Study Description
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 |
---|---|---|
N/A |
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 Design
Arms and Interventions
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 Names:
|
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. |
Outcome Measures
Primary Outcome Measures
- pQCT of Lower Leg [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
- pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium [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
Eligibility Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Maryland Amish Research Clinic | Lancaster | Pennsylvania | United States | 17601 |
Sponsors and Collaborators
- University of Maryland, Baltimore
Investigators
- Principal Investigator: Elizabeth A Streeten, MD, University of Maryland, College Park
Study Documents (Full-Text)
None provided.More Information
Publications
- Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssière B, Belleville C, Estrera K, Warman ML, Baron R, Rawadi G. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17406-11. Epub 2005 Nov 17.
- Streeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, Donnelly P, Sack P, Morton H. Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone. 2008 Sep;43(3):584-90. doi: 10.1016/j.bone.2008.04.020. Epub 2008 May 7.
- Streeten EA, Ramirez S, Eliades M, Jaimungal S, Chandrasekaran S, Kathleen R, Holmes Morton D, Puffenberger EG, Herskovitz R, Leonard MB. Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure. Bone. 2015 Aug;77:17-23. doi: 10.1016/j.bone.2015.04.007. Epub 2015 Apr 16.
- HP-00040536
Study Results
Participant Flow
Recruitment Details | Participants were recruited from patients with OPPG being treated by Dr Streeten and their unaffected family members |
---|---|
Pre-assignment Detail |
Arm/Group Title | Lithium | Unaffected Controls |
---|---|---|
Arm/Group Description | patients with OPPG will be treated with lithium for 6 months 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. | Family members of patients with OPPG will have DXA and pQCT to compare to OPPG patients. These unaffected participants will not receive lithium. |
Period Title: Overall Study | ||
STARTED | 10 | 16 |
COMPLETED | 4 | 16 |
NOT COMPLETED | 6 | 0 |
Baseline Characteristics
Arm/Group Title | Lithium | Unaffected Controls | Total |
---|---|---|---|
Arm/Group Description | patients with OPPG will be treated with lithium for 6 months 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. | Family members of patients with OPPG will have DXA and pQCT to compare to OPPG patients. These unaffected participants will not receive lithium. | Total of all reporting groups |
Overall Participants | 10 | 16 | 26 |
Age (Count of Participants) | |||
<=18 years |
7
70%
|
8
50%
|
15
57.7%
|
Between 18 and 65 years |
3
30%
|
8
50%
|
11
42.3%
|
>=65 years |
0
0%
|
0
0%
|
0
0%
|
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
13.4
(2.5)
|
21.8
(16.5)
|
18.8
(14.1)
|
Sex: Female, Male (Count of Participants) | |||
Female |
4
40%
|
11
68.8%
|
15
57.7%
|
Male |
6
60%
|
5
31.3%
|
11
42.3%
|
Race/Ethnicity, Customized (Count of Participants) | |||
Causasian |
10
100%
|
16
100%
|
26
100%
|
Region of Enrollment (participants) [Number] | |||
United States |
10
100%
|
16
100%
|
26
100%
|
Outcome Measures
Title | pQCT of Lower Leg |
---|---|
Description | 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. |
Time Frame | Baseline |
Outcome Measure Data
Analysis Population Description |
---|
in OPPG, 2 were too small for pQCT machine and 2 had hardware in legs. For 2 in unaffecteds there were technical difficulties with the pQCT scanner |
Arm/Group Title | Lithium | Unaffected Controls |
---|---|---|
Arm/Group Description | patients with OPPG will be treated with lithium for 6 months 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. | Family members of patients with OPPG will have DXA and pQCT to compare to OPPG patients. These unaffected participants will not receive lithium. |
Measure Participants | 10 | 16 |
Cortical Area Z-score |
-2.19
|
0.04
|
Periosteal circum. Z |
-2.09
|
-0.30
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Lithium, Unaffected Controls |
---|---|---|
Comments | Cortical area Z-score | |
Type of Statistical Test | Equivalence | |
Comments | Continuous variables were expressed as means ± SD or median (range). Group differences in pQCT Z-scores according to genotype T-test was used to compare differences at baseline between affecteds and unaffecteds | |
Statistical Test of Hypothesis | p-Value | 0.0003 |
Comments | ||
Method | t-test, 1 sided | |
Comments | Differences in the two groups were assessed using Student's t-test or the rank-sum test if skewed. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Lithium, Unaffected Controls |
---|---|---|
Comments | Periosteal circumference Z-score | |
Type of Statistical Test | Equivalence | |
Comments | Continuous variables were expressed as means ± SD or median (range). Group differences in pQCT Z-scores according to genotype | |
Statistical Test of Hypothesis | p-Value | 0.001 |
Comments | ||
Method | t-test, 1 sided | |
Comments | Differences in the two groups were assessed using Student's t-test or the rank-sum test if skewed. |
Title | pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium |
---|---|
Description | 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 |
Time Frame | baseline, 6 months |
Outcome Measure Data
Analysis Population Description |
---|
Two OPPG participants who took lithium for 6 months and were able to do pQCT at baseline and 6 months. First number is baseline, 2nd number is 6 months for section modulus |
Arm/Group Title | OPPG Rx With Lithium |
---|---|
Arm/Group Description | Two participants who were treated with lithium and had pQCT done |
Measure Participants | 2 |
Baseline Z-score SM |
-4.96
(0.12)
|
6 mo Z-score SM |
-4.93
(0.64)
|
Adverse Events
Time Frame | 6 months, during the administration of lithium to 5 participants | |||
---|---|---|---|---|
Adverse Event Reporting Description | Two of the participants in the lithium trial also have a severe autistic phenotype. We had hoped that the Lithium might improve their behavior. However, in one of theses 2 participants, his behavior worsened (confirmed by the Vanderbilt standardized behavioral questionnaire and he had to drop out of the study. After stopping Lithium, his behavior promptly returned to his baseline. | |||
Arm/Group Title | Lithium | Unaffected Controls | ||
Arm/Group Description | patients with OPPG will be treated with lithium for 6 months 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. | Family members of patients with OPPG will have DXA and pQCT to compare to OPPG patients. These unaffected participants will not receive lithium. | ||
All Cause Mortality |
||||
Lithium | Unaffected Controls | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/10 (0%) | 0/16 (0%) | ||
Serious Adverse Events |
||||
Lithium | Unaffected Controls | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/10 (0%) | 0/16 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Lithium | Unaffected Controls | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 1/10 (10%) | 0/16 (0%) | ||
Hepatobiliary disorders | ||||
elevated liver function test | 1/10 (10%) | 1 | 0/16 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Elizabeth Streeten, MD |
---|---|
Organization | University of Maryland School of Medicine |
Phone | 410-328-3335 |
estreete@som.umaryland.edu |
- HP-00040536