Osteoporosis Pseudoglioma
Conditions
Keywords
Osteoporosis-pseudoglioma syndrome, OPPG, LRP5 mutation
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.
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.
Interventions
DRUGLithium
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.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 64 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from patients with OPPG being treated by Dr Streeten and their unaffected family members
Participants by arm
| Arm | Count |
|---|---|
| Lithium 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. | 10 |
| 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. | 16 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | 5 not started, 1 stop due to side effect | 6 | 0 |
Baseline characteristics
| Characteristic | Lithium | Unaffected Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 8 Participants | 15 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 8 Participants | 11 Participants |
| Age, Continuous | 13.4 years STANDARD_DEVIATION 2.5 | 21.8 years STANDARD_DEVIATION 16.5 | 18.8 years STANDARD_DEVIATION 14.1 |
| Race/Ethnicity, Customized Causasian | 10 Participants | 16 Participants | 26 Participants |
| Region of Enrollment United States | 10 participants | 16 participants | 26 participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 16 |
| other Total, other adverse events | 1 / 10 | 0 / 16 |
| serious Total, serious adverse events | 0 / 10 | 0 / 16 |
Outcome results
Primary
pQCT of Lower Leg
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
Population: 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 | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Lithium | pQCT of Lower Leg | Cortical Area Z-score | -2.19 Z-score |
| Lithium | pQCT of Lower Leg | Periosteal circum. Z | -2.09 Z-score |
| Unaffected Controls | pQCT of Lower Leg | Cortical Area Z-score | 0.04 Z-score |
| Unaffected Controls | pQCT of Lower Leg | Periosteal circum. Z | -0.30 Z-score |
Comparison: Cortical area Z-scorep-value: 0.0003t-test, 1 sided
Comparison: Periosteal circumference Z-scorep-value: 0.001t-test, 1 sided
Secondary
pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lithium | pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium | Baseline Z-score SM | -4.96 Z-score | Standard Deviation 0.12 |
| Lithium | pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium | 6 mo Z-score SM | -4.93 Z-score | Standard Deviation 0.64 |