The natural history of bone mineral deficits and bone-related disorders has not been characterized fully in females with RTT. In this cross-sectional study, low BMD was common, occurring in 45% of the RTT cohort. However, the variability across the age range studied precluded our ability to identify individual susceptibility. Although absolute BMC and BMD increased with advancing age, BMC and BMD z-scores were lower in older than in younger females. Skeletal fractures and scoliosis also were common, occurring in 28% and 64%, respectively, of the RTT cohort, and were associated with lower total body BMC and BMD. Bone mineral deficits were identified across a broad range of MECP2 mutations. These findings highlight the importance of early diagnosis of bone mineral deficits in RTT and underscore the need to better understand the molecular mechanisms of MECP2 in the regulation of bone mineral metabolism.
BMC in healthy, prepubertal and postpubertal children increases annually by 11 ± 2% and 4 ± 0.5%, respectively (16
). In the present study, the rate of increase in total body BMC and BMD in females with RTT was substantially lower than that of healthy, unaffected girls, ages 8-16 y (9
), but paralleled changes observed in children with other neurological disabilities (15
). Others have reported deficits in cortical bone thickness, radial bone density, and tibial bone strength, measured by skeletal radiographs, densitometry, and ultrasonography in girls with RTT (3
). Histomorphometric studies of trabecular bone in girls with RTT suggest that deficits in BMD may be the consequence of decreased bone formation rather than increased resorption because the number and metabolic activity of osteoblasts are decreased, while the number of osteoclasts may be normal or diminished (20
). Thus, bone mineral deficits in RTT may be a manifestation of growth failure rather than a degenerative disorder (17
Although bone mineral deficits were apparent at an early age, we found marked variability in total body BMC and BMD among the RTT cohort. Genetic factors are thought to be responsible for 70% of the variance in bone mass (21
). However, the variability in total body BMC or BMD in the RTT cohort could not be explained by their mutations because the small number of subjects within each group precluded phenotype-genotype correlations. Others have suggested that R133C and T158M mutations confer a protective effect against bone mineral deficits (19
), but we did not observe such an effect. In the present study, deficits in lean body mass, but not body fat, paralleled bone mineral deficits (22
). Being African-American, as in unaffected individuals, tended to protect against low bone density (9
). BMC and BMD z-scores were lower in individuals who had seizures and received anticonvulsants, both known risk factors (15
Ambulation protects against bone mineral deficits in children with neurological disorders (23
). In children with cerebral palsy, programs using upright stands, load-bearing physical activities, or vibrating platforms improved vertebral, femoral neck, and tibial BMD (24
). In our study, however, total body BMC and BMD z-scores were not significantly different between those who ambulated independently and those who walked with assistance or never walked. The explanation for this finding was not readily apparent although, in contrast to other studies (23
), body size did not differ between our ambulatory and non-ambulatory groups. Despite our findings, we routinely emphasize physical therapy for females with RTT to improve their functional abilities (27
Low BMD is thought to contribute to fracture risk, although prospective measures of BMD in the lumbar spine of children with cerebral palsy did not predict subsequent fracture risk (29
). In healthy girls, each 1 SD reduction of total body BMD doubles the risk for new fractures (30
). The annual fracture rate for healthy females 6 years of age and older is 3 per 100 person-y (28
) and for girls with spastic quadriplegia, 2.7 per 100 person-y (29
). In the present study, one to five skeletal fractures occurred in 28% of the RTT cohort, resulting in a fracture rate of 3.6 per 100 person-y. Scoliosis occurred in 64% of the RTT cohort, a value in the range of other reports (31
). However, we may have underestimated the prevalence of scoliosis and the severity of low bone mineral density in females with RTT because we excluded females with spinal rod placement. Nevertheless, for future DXA applications, the correlation among spine, hip, and total body BMC and BMD in the RTT cohort is of practical importance for those in whom repetitive movements or spinal rod placement preclude total body scans. The associations among low BMC and BMD, fractures, and scoliosis suggest that bone mineral metabolism is important for bone mineral health.
In summary, bone mineral deficits and bone-related disorders were common in RTT. Bone mineral deficits were greater in older than in younger females with RTT. Fractures and scoliosis were associated with lower BMC and BMD. Although factors commonly associated with protection from, or increased risk of, bone mineral deficits were identified, a better understanding of molecular mechanisms that regulate the interaction between MECP2 and bone mineral metabolism is crucial to the development of therapeutic strategies for RTT.