Juvenile primary osteoporosis, unless diagnosed as osteogenesis imperfecta, has previously been considered a sporadic and self-limiting disease. New genetic findings, including osteoporosis-causing mutations in the LDL-receptor related protein (LRP) 5 and LRP6 genes, challenge this view. The pathogenesis of juvenile osteoporosis still remains largely unknown. We describe findings in a three-generation pedigree with a new form of autosomal dominant osteoporosis.
The proband, at age 35, presented with multiple painful thoracic vertebral compression fractures causing a loss of 7 cm of her adult height. Secondary causes of osteoporosis were excluded. She has no features of OI and no peripheral fractures. The lumbar bone mineral density (BMD) Z-score is −2.9. Assessment of the pedigree revealed osteoporosis in eight additional family members, many with asymptomatic compression fractures. The youngest is a boy of 12 years with asymptomatic compression fractures in his thoracic spine and a lumbar BMD Z-score of −1.7. Transilial bone biopsies from two treatment-naïve adult family members revealed severe low-turnover osteoporosis with low trabecular bone volume, decreased osteoid and low numbers of osteoblasts. Mineralization and resorption rates were normal.
A genome-wide micro-satellite analysis yielded a maximum lod score of 2.8 and further analyses are under way to identify the disease-causing genetic defect. No linkage was found in areas encoding type 1 collagen. Genetic testing for mutations in LRP5 and LRP6 was negative.
The described three-generation family represents a new form of autosomal dominant early onset primary osteoporosis. The discovery of the underlying genetic defect may provide important new information about the biological and pathogenetic mechanisms of osteoporosis.