Use Of Bisphosphonates For The Treatment Of Osteogenesis Imperfecta.

Horacio Plotkin(*), M.D. and Francis H. Glorieux(*,#), M.D., Ph.D.
(*)Genetics Unit, Shriners Hospital for Children,
(#) Departments of Surgery and Pediatrics, McGill University, Montréal, Québec, Canada

Medical treatment has long been largely ineffective in altering the course of osteogenesis imperfecta (OI). Recently, cyclical intravenous treatment with pamidronate (3-amino-1- hydroxypropylidene-bisphosphonate) has proven of benefit to children with severe forms of OI (1). Bone mineral density (BMD) and physical activity increased markedly in these patients and fracture rate decreased.

Bisphosphonates are synthetic analogs of pyrophosphate, and are potent inhibitors of bone resorption (2). These compounds are widely used for the treatment of adults suffering from bone loss and increased bone fragility (3-5) and there is increasing experience on the effect of these drugs in children (1, 6-9).

We are currently treating with pamidronate more than 140 children with OI, and some of them have been receiving treatment for more than six years. Analysis of the results of the first 30 children that have received the treatment (7.5 mg/kg/year intravenously at 4 to 6 month intervals) for between 1 and 4 years 1 showed that after the initial infusion cycle, biochemical markers of bone resorption fell sharply, the bone mineral density (BMD) increased 41.9 ±29 percent, and the deviation from normal, as indicated by Z-score, increased from -5.3 ±1.2 to -3.4 ±1.5. Metacarpal cortical width increased by 27.0 ±20.2 percent in the first year of treatment, and lateral spine radiographs suggested new bone formation in 25 children. The incidence of radiologically confirmed fractures fell by 1.7 fractures per year. Treatment did not alter fracture healing, growth rate or growth plate appearances. Dependence on mobility aids was reduced in 16 children, and remained unchanged in the other 14. All subjects reported substantial relief of chronic pain and fatigue.

A particular interesting group of patients is that of children under two years of age since its characteristic rapid bone turnover is likely to potentiate the effect of the drug. Pamidronate was administered intravenously in cycles of three consecutive days. We treated for one year nine subjects who were compared to an historical control group consisting of ten age-matched severely affected OI patients, who had not received any treatment 10. Under cyclical treatment BMD increased between 65% and 227%, and the Z score diminished from -6.9±2.0 to -2.3±1.6. In the control group there was no change in the BMD Z score. In the treated patients, fracture rate decreased from 2.0±2.6 to 0.2±0.2 fractures/month, and mobility improved significantly. No adverse side effects were noted apart from the well-known acute phase reaction during the first infusion cycle. In this group of patients under two years of age, the response to treatment appeared to be faster and more pronounced than what we had observed in older children. Signs of bone pain (e.g. crying while being handled) disappeared within days and an increase in BMD was evident as early as six weeks after the start of treatment. Without exception the gain in BMD was greater than the increase expected in healthy children. In contrast, no changes in BMD occurred in the untreated controls. Vertebral size increased in all treated children, as should be expected in growing individuals. In contrast, a decrease in vertebral size was noted in half of the untreated children, indicating that vertebral collapse had occurred in these patients. Thus, it appears that pamidronate infusions not only increased lumbar spine BMD, but also protected bone integrity. This view is further strengthened by the readily apparent reshaping of both vertebrae and long bones.

The effect of bisphosphonate therapy on growth has been a matter of concern before the treatment was used in children. In animal studies long-term treatment with bisphosphonates did not affect linear growth, unless very high doses were administered (11). In our group of patients, pamidronate did not have a detrimental effect on growth. The height Z-score increased in six of the nine children under two years of age, and there was no arrest of growth in any of the patients.

Bisphosphonates are not a cure for OI, as they do not alter the genetic defect causing the disease. It is unclear at present how long this treatment should be continued, and which is the optimal treatment schedule and dosage. There were no significant side effects after up to seven years of treatment, but longer surveillance is under way. New bisphosphonates are under investigation to compare their effects to those of pamidronate (8). Further research is warranted to find the "ideal" treatment for OI.

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Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999.