Clinical trial NCT01108068: Trial of Lithium Carbonate for Treatment of Osteoporosis-pseudoglioma Syndrome
Official title: Trial of Lithium Carbonate for Treatment of Osteoporosis Pseudoglioma Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Osteoporosis Pseudoglioma
Keywords: Osteoporosis-pseudoglioma syndrome, OPPG, LRP5 mutation
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2010-04-21
Enrollment: 26
Sex: ALL
Minimum age (years): 4
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: pQCT of Lower Leg
timeFrame: Baseline
Secondary outcomes:
measure: pQCT Z-score in OPPG Participants at Baseline and 6 Months After Lithium
timeFrame: baseline, 6 months
Other outcomes:
Locations:
city: Lancaster
country: United States
facility: University of Maryland Amish Research Clinic
state: Pennsylvania
Study officials:
affiliation: University of Maryland, College Park
name: Elizabeth A Streeten, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Clement-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssiere 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. doi: 10.1073/pnas.0505259102. Epub 2005 Nov 17.
citation: 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.