Background: To compare height-adjusted fat and fat-free mass components of body composition in girls with adolescent idiopathic scoliosis to young adolescents with eating disorders. Adolescent idiopathic scoliosis (AIS) has been linked with low bone densities. Animal and human studies have shown that bone densities are influenced by a wide variety of inter-related factors that includes body fat, oestrogen levels, nutritional status and energy balance. Anthropometric studies have reported girls with AIS as being taller and more slender than their age-matched peers and that they also exhibit complex patterns of body asymmetry, particularly in the upper limb. There are also some studies report eating disorders in this population.

Methods: Height-adjusted fat and fat-free mass components of body composition were examined. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated and normalised for height and were superimposed onto UK 1990 growth reference data. The data for left and right limb length was also compared. A sample of 325 girls with AIS referred to the specialist spinal unit in Liverpool during the period 1970–1990.

Results: The fat mass index and fat-free mass index were reduced in this sample of AIS subjects compared with normal reference children, but were similar to those diagnosed with eating disorders (anorexia nervosa). The cohort also exhibited significant upper limb asymmetry.

Conclusion: The findings suggest that this population has significantly low fat mass compared to normal, healthy reference values. Since fat mass reflects energy balance, nutritional status (possibly eating disorders) and is closely linked to endocrine function, the implications of reduced fat mass on growth, bone mass accretion and the aetiology of AIS merit further investigation.

Objective. Despite the current revolution in molecular medicine that has benefitted the treatment of certain diseases (Ross 2002), idiopathic scoliosis has resisted attempts to understand the molecular basis of its curve development. Lowe et al (2002) in a longitudinal study of 55 AIS patients concluded that platelet calmodulin levels correlate closely with curve progression and stabilization by bracing or spine fusion. They suggest that the platelet is a “minimuscle” with a protein contractile system (actin and myosin) similar to that of skeletal muscle. Using Lowe’s data we found that percentage platelet calmodulin change correlates significantly with percentage Cobb angle change (ANOVA, p=0.0003, n=54) that led us to suggest a platelet/skeletal hypothesis to account for their findings as part of a cascade concept for the pathogenesis of AIS.

Hypothesis. The human immature vertebral body is unusual among mammals in lacking epiphyses. This may explain why an axial load transmitted directly from the intervertebral disc deforms mature vertebral body end-plates as an axial inward bulge (Brinckmann et al 1983). In immature normal vertebral bodies vascular “lakes” (resembling bunches of grapes) have been found adjacent to the disc growth plates in subjects aged 9 to 13 years of age (Mineiro 1965). These “lakes” may provide a susceptibility to platelet activation from vascular stasis and shear stresses. In addition to their role in hemostasis platelets contain many growth factors including TGF-βs in α-granules that are secreted at a fracture site (Bolander 1992). TGF-βs are found in human neonatal rib growth plates (Horner et al 1998) but, like estrogen receptors, have not yet been sought in human intervertebral disc growth plates. We hypothesize that in the presence of a small scoliosis curve (from unknown causes ?spine, rib, muscle, or nervous system) platelets, as they circulate through vessels in eccentrically-loaded and deforming immature vertebral bodies particularly about the curve apex in the presence of a basic defect, are activated also by repeated axial inward bulges of disc growth plates causing mechanical micro-insults with endothelial cell desquamation and the formation of a calcium-cadmodulin complex. The latter is associated with platelet contraction (shape change) and the secretion from α-granules of various growth factors including angiogenic regulators (platelet release reaction, Hartwig 2003, Reed 2002, Rendu and Brohard-Bohn 2002). These growth factors abet the hormone-driven growth of the already mechanically-compromised disc growth plates and induce anterior spinal overgrowth and curve progression. The basic defect in AIS could be 1) a platelet, endothelial, or subendothelial anomaly, defect, or functional (?hormonal) disorder, and 2) one or more genetic polymorphisms that involve platelet receptors (Afshar-Kharghan and Bray 2002) and putative estrogen receptors in vertebral disc growth plates (Inoue et al 2002ab). The predilection of progressive AIS for girls may be related to the cyclical platelet functions in women associated with normal uterine function (Jones et al 1983, Pansini et al 1986, Tarantino et al 1994, Faraday et 1997). Curve laterality is determined by factors that initiate curve progression. Low plasma melatonin of progressive AIS may act both by a reduced antagonism to calmodulin (Lowe 2000, Dubousset and Machida 2001) and facilitating platelet aggregation with secretion of growth factors from α-granules.

Conclusions. The platelet/skeletal hypothesis for progressive AIS and the cascade concept suggests much new research. The hypothesis has genetic, diagnostic, prognostic and potential therapeutic implications. It raises questions about the possibility of changes in platelet calmodulin levels in other progressive and resolving deformities that occur in the immature and adult skeleton.

Nachemson (1996), drawing upon the theses of Sahlstrand (1977) and Lidström (1988), articulated the view there are more girls than boys with progressive AIS for the following reason. The maturation of postural mechanisms in the nervous system is complete about the same time in boys and girls. Girls enter their skeletal adolescent growth spurt with immature postural mechanisms – so that if they have a predisposition to develop a scoliosis curve, the spine deforms. In contrast boys enter their adolescent growth spurt with mature postural mechanisms so that they are protected from developing a scoliosis curve. There is evidence that postural sway improves with age in boys and girls until about 10 years of age after which it is similar between the sexes (Hirashawa 1973, Odenrick and Sandstedt 1984) findings which need further evaluation. We term Nachemson’s concept the neuro-ossesous timing of maturation (NOTOM) hypothesis. It may have an evolutionary basis through natural selection towards sexual and skeletal development during adolescence being earlier in girls and later in boys.

The NOTOM hypothesis suggests a treatment to prevent progression of late-juvenile idiopathic scoliosis, early-AIS, and some secondary scolioses based on delaying the onset of puberty used therapeutically in girls with idiopathic precocious puberty (IPP, Grumbach and Styne 1998). The proposal is to administer a gonadorelin analogue which in the pituitary down-regulates the receptors to hypothalamic gonadotropin-releasing hormone (GnRH) causing a fall in both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn causes a fall in oestrogens and androgens, and thereby delays or stops menarche and slows bone growth – as in girls and boys with IPP (Galluzzi et al 1998). Expert scrutiny of this therapeutic proposal is currently in progress.

1. The case is reported of a girl born by normal delivery whose right lower limb showed reduplication of the femur below the single femoral head.

2. The tibia was absent but the ossific centres in the foot appeared to be normal. We are grateful to Processor Robert Roeaf for permission to publish details of this patient.