Abstract
Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients’ age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population.
Highlights
Down syndrome (DS) was initially described in 1866 [1], the pathophysiology of many clinical aspects of the DS phenotype have not been elucidated
The skeletal effects of trisomy in Ts65Dn mice are decreased trabecular bone volume and architecture, as well as changes in cortical parameters that result in decreased overall bone stiffness and bone strength
The low bone mass phenotype is consistent with the human DS population that displays a low bone mineral density (BMD) due to decreased bone turnover [13]
Summary
Down syndrome (DS) was initially described in 1866 [1], the pathophysiology of many clinical aspects of the DS phenotype have not been elucidated. Low bone mass and the associated increased fracture rates are clinical features that complicate DS [2]. As the life expectancy of individuals with DS has increased to greater than age 50 [3,4], the bone health of adolescent and adult DS patients has become an important medical issue. Several investigators, including ourselves have reported that adults (and children) with DS have lower bone mass, expressed as BMD, especially in the lumbar spine, compared with their peers without mental retardation or with mental retardation but without DS [5,10,11,12,13]. Low sunlight exposure and anti-convulsant use have been associated with decreased bone mass but these are not consistent risk factors in DS, leaving the underlying pathophysiology unknown [2]. No bone anabolic therapies have been evaluated in DS
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