Pamidronate to Treat Osteogenesis Imperfecta in Children

Osteogenesis imperfecta is an inherited disorder of connective tissue in which affected
individuals synthesize abnormal type I collagen. This results in the formation of abnormal
bone matrix and a predisposition to bony fractures. Many unsuccessful attempts have been
made to increase the bone mineral density of these individuals in the hope that this will
improve the strength of their bones and result in a decreased fracture rate.

Bisphosphonates are synthetic analogs of pyrophosphate which have an affinity for
hydroxyapatite. These drugs act primarily on osteoclasts, impairing the development of
immature osteoclasts and the function of mature osteoclasts, as well as depressing chemical
signaling to adjacent cells, resulting in a shift in the balance of deposition and
resorption in bone. Conditions for which bisphosphonates are being used in children include
four broad categories, 1) a primary defect in bone mineralization 2) bone matrix
abnormalities 3) bone abnormalities due to systemic disease or the effects of treatment of
systemic disease or 4) significant soft tissue calcification with no bone abnormality.

Pamidronate, an aminobisphosphonate, is a potent inhibitor of bone resorption. The purpose
of this protocol is to evaluate the effectiveness of pamidronate in children with types III
and IV osteogenesis imperfecta when the cycle time is varied. We plan to compare children
treated with pamidronate on an every-three-month infusion cycle to children treated every
six months with the same dose per infusion. We also plan to continue to compare children
treated with pamidronate and growth hormone to children treated with pamidronate alone.

INCLUSION CRITERIA:

Children enrolled in this study will be limited to those with Sillence types III and IV
OI, as determined by clinical and genetic criteria.

Most of the children who will be included in this study are already enrolled in the
protocols Evaluation and Intervention for Ambulation, Growth, and Basilar Invagination in
Osteogenesis Imperfecta (97-CH-0064) and Growth Hormone Therapy in Osteogenesis Imperfecta
(92-CH-0034).

Screening of candidates will be based on telephone interviews with a parent, and referral
records to include: AP and lateral radiographs of the lower extremities and spine, and
family, developmental, fracture and medical history. An NIH clinical screening evaluation
will be performed for those children who appear to have a history consistent with OI under
protocol 04-CH-0077, Screening of and Diagnosis of Patients with Connective Tissue
Disorder . Patients admitted for this screening visit who are less than four years of age
as well as those older than 4 years of age but not meeting the criteria for inclusion in
the growth hormone protocol, protocol 92-CH-0034, will be considered for enrollment in
protocol 97-CH-0064 (Evaluation and Intervention for Ambulation, Growth and Basilar
Invagination in OI), those older than four years who meet the criteria will be considered
for co-enrollment in protocol 92-CH-0034.

The inclusion criteria for protocol 92-CH-0034 are as follows: patients must have a
clinical/biochemical diagnosis of osteogenesis imperfecta types III or IV, height less
than third percentile for age, and radiological evidence that long bone epiphyses have not
yet fused.

Patients are excluded from protocol 92-CH-0034 if they have scoliosis of greater than 40
degrees unless scoliosis has been stable over the past two years, or evidence of severe
basilar invagination.

Patients with previous exposure to bisphosphonates in outside trials will be considered
for participation in this trial.

EXCLUSION CRITERIA:

Inability to comply with the visit schedule, maintenance of the physical therapy program,
and ability to administer and comply with GH injections are central to our analysis of the
outcomes of this study. Failure to comply with these conditions will constitute exclusion
criteria.

Pregnancy.

Patients that have had or will have surgery to place instrumentation in the spine (i.e.
result of spine fusion).