Growth deficiency is a key feature of severe Osteogenesis Imperfecta (OI) and a frequent feature of mild to moderate forms of the disease. The reason that children with OI are short is not fully understood. We do know that details such as the number of fractures suffered or the type of OI do not fully explain the short stature of OI. Growth patterns have been defined for children with OI Types I, III, and IV. At about 12 months of age, children with Types III and IV OI demonstrate a predictable plateau of their linear growth rate. Type IV OI children begin to resume a normal growth rate at about age four to five years, but they will not "catch up" to a normal height, as they have "lost" a significant period of growth. The plateau usually continues for children with Type III OI. The reason for this growth plateau is unknown. There have been no studies which evaluate the growth of OI children in this age range. Our previous studies of growth in OI children have begun at age 5 years.

We have studied growth in OI children for the past 10 years. Different medications have been tried to both stimulate growth and improve bone density. Some children have responded to growth hormone (their growth rate increased by at least 50%) and some did not. The majority of children who did respond were Type IV. However, we need to carefully treat and study more children to try to determine which children will benefit from growth hormone medication.

The Goals of this Study Are:

1. We want to try to find a cause for the growth plateau common in types III and IV OI. Long-term, our goal is to develop a treatment to eliminate this plateau.
2. We want to see how long and how well OI bone will respond to growth stimulation.
3. We hope to find a "predictor" for who will respond to growth hormone and who will not, by measuring your child's endocrine and growth hormone function before receiving any growth hormone treatment.
4. We want to measure the effects of growth stimulation on bone density, and the quality of OI bone.
5. We want to see if there are long term benefits resulting from this treatment in the form of final adult height, trunk height, and possibly improved function of the respiratory system.

Median Subject Age (on p. 1 of webpage): 1-15 years (replaces 0-20)

Growth deficiency is a cardinal feature of severe Osteogenesis Imperfecta (OI) and a frequent feature of mild to moderate forms of this disease. We have previously investigated the status of hormones related to growth in 28 short children with various types of OI. Abnormalities in the endocrine test patterns were found in a subgroup of the children studied. A group of children with decreased responsiveness to GRH also had significantly lower 24 hour time-integrated GH concentrations than children with normal GRH responsiveness.

The protocol has changed to integrate the growth plateau studies that were previously included in 97-CH-0064(I): Evaluation and Intervention for Ambulation, Growth, and Basilar Invagination in Osteogenesis Imperfecta. This protocol will now start at age 1 year, with a complete evaluation of the growth plateau experienced between ages 1 and 4 years in patients with types III and IV OI. It will then continue with a pretreatment year, beginning when the patients exit the growth plateau, usually between ages 4 and 5 years. The pretreatment year will include careful measurements of the growth hormone-somatomedin axis, growth hormone secretion, and determination of the child's baseline growth rate.

We have treated 26 OI children, types III and IV, with synthetic growth hormone under the original version of this protocol, and subsequently treated an additional 10 patients. Overall 19 children responded to treatment which is more than half of those treated. We propose to treat up to an additional 13 children who are responsive to growth hormone until final adult stature is attained, as defined by fusion of growth plates and the plateau of linear growth.

The goals of the study are to determine: 1. the basis of the OI growth plateau, so that a treatment can be proposed to eliminate the growth plateau, 2. the range and duration of growth responsiveness of OI bone, 3. the correlation of this growth responsiveness with the results of endocrine evaluation of the growth hormone-somatomedin axis, 4. the effect of growth hormone on the density and histomorphometric parameters of OI bone, and 5. the long term benefits of this therapy for final stature and trunk length.

Patient recruitment will be stratified by age. Patients age 1 year and older will be recruited into the study of the growth plateau in children with osteogenesis imperfecta. Patients who are approximately 4 years of age, who have begun emerging from the growth plateau, will be recruited for the study of growth hormone treatment in children with osteogenesis imperfecta. Children will be eligible for entry into the growth hormone treatment arm of the protocol until age 8, after which age they will be ineligible. Patients who enroll in the growth hormone treatment trial will be followed until they achieve adult height, approximately age 15 or 16 years.

The first two to three years of participation (approximately ages 1-4 years) will consist of an evaluation of the growth plateau. During these years, visits will be every 4 months to coincide with the schedule for protocol 97-CH-0064. Testing will be distributed over 2 years of visits so as not to exceed the allowed blood withdrawal for the patient's weight according to NIH guidelines.

Once the participants emerge from the growth plateau, they will participate in a pre-treatment year. During that year, we will follow the children every 3 months to conduct the pretreatment endocrine evaluation.

Once patients have completed the pretreatment year, they will receive recombinant human growth hormone (rGH) for at least a period of one year. At the end of one year of treatment, it will be determined whether each individual patient is a responder to rGH. Participants will be treated with 0.06 mg/kg/day rGH, generously donated by Eli Lilly & Co., Indianapolis, IN. Responders will be defined by a sustained 50% increase above baseline growth rate. All participants will be treated for 1 year to identify responders. Only responders will be treated an additional 2 years. After the third year of treatment, responders will be defined as those children who demonstrate a sustained increase of 30% or greater above baseline. These 3-year responders will be treated with growth hormone until final adult height is reached. Eli Lilly & Co. will provide growth hormone for the initial year of treatment, but has not committed to providing growth hormone to treat patients through final height. We will follow all protocol participants, both responders and non-responders, at the NIH until final adult stature is attained.

The iliac crest bone biopsy for direct measurement of bone histology changes will be done at the baseline visit for the treatment phase, when all patients will begin on rGH. We will repeat the bone biopsy after 12 months of treatment, which is the visit when it will be determined whether the patients are responders to growth hormone. This pair of bone biopsies on each patient will allow us to fully evaluate growth and changes in bone quality in this OI population.

• Dwarfism
• Osteogenesis Imperfecta

• Drug: Humatrope
• Drug: GRH
• Drug: Nutropin

• Marini JC, Bordenick S, Heavner G, Rose S, Hintz R, Rosenfeld R, Chrousos GP. The growth hormone and somatomedin axis in short children with osteogenesis imperfecta. J Clin Endocrinol Metab. 1993 Jan;76(1):251-6.
• Prockop DJ, Kivirikko KI. Heritable diseases of collagen. N Engl J Med. 1984 Aug 9;311(6):376-86. Review. No abstract available.
• Rose SR, Municchi G, Barnes KM, Cutler GB Jr. Overnight growth hormone concentrations are usually normal in pubertal children with idiopathic short stature--a Clinical Research Center study. J Clin Endocrinol Metab. 1996 Mar;81(3):1063-8.

• INCLUSION CRITERIA:

Patients will be recruited with the goal of including at least 10 each of individuals with clinical/biochemical criteria of types III and IV OI who are between 1 and 8 years of age.

Height: Individuals with type III OI have severe short stature by definition; individuals with type IV OI recruited to the study will have height less than the 3rd percentile for age. All individuals will be required to furnish growth records, especially height and head circumference, from at least the preceding two years.

Long bone status: Participants must have radiographic evidence that long bone epiphyses have not yet fused. In addition, 60 degrees or greater angulation of a femur will exclude a child, pending surgical management or medical clearance.

Spine: Prospective participants will be evaluated for scoliosis and spinal compressions. Participants with scoliosis greater than 40 degrees will be excluded unless evidence is presented that the scoliosis has been stable for the prior two years. Participants with corrective rods in their spine will be excluded.

Neuro status: All patients will be co-enrolled in 97-CH-0064, and will be screened for Basilar Invagination through that protocol. Children who are initially screened by spiral CT scan with MRI confirmation and determined to have severe BI will be excluded from participation in this study. Severe BI is defined by NIH data as distortion of the angle between the pons and medulla and or compression of posterior fossa contents. We are only beginning to define the parameters of BI in this population, and we do not know why some children with BI progress in severity and some do not. Until those questions are answered, we feel it would not be prudent to stimulate growth in a child we know to have a severe form of BI at enrollment.

Pulmonary status: All children will be co-enrolled in 97-CH-0064, and will have pulmonary function testing and polysomnograms through that protocol. Tests will be scheduled as required for that protocol; namely, PFTs every 2 years if normal, every year if abnormal, and polysomnograms every 4 years if normal, and every 2 years if abnormal.

Potential participants who have not participated in the growth plateau study will still be eligible for participation in the growth hormone treatment trial. These patients, if entering from outside the protocol, must be between age 4 and 8 years, and must have documented growth records that demonstrate that they have emerged from the growth plateau. The first year in the protocol for these patients will be the pretreatment year, in which they will not receive growth hormone but will come to NIH on the schedule for the pretreatment visits.

EXCLUSION CRITERIA:

Patients who develop scoliosis greater than 40 and/or patients who progress to severe basilar invagination during the study will be removed from the study.

Failure to comply with the outlined procedures (blood draws, endocrine testing, bone biopsies, and visit schedule) is also a criterion for withdrawal from the protocol.