Abstract
We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC ). CTX and mid-tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β=0.19 [0.13, 0.24]) (coefficient=SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β=-0.46 [-0.52,-0.40]) and cortical thickness [β=-0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) (β=0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single-nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p<0.05 cut-off) (n=2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC (n=3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n=938), and the Young Finns Study (YFS) (n=1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p<0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion.
Highlights
Bone size and geometry make a major contribution to fracture risk, reflecting the fact that bending strength of bone is critically dependent on its diameter.[1]
In a large cohort of adolescents, we found CTX to be positively related to periosteal expansion as reflected by periosteal circumference (PC) but inversely related to BMDC and cortical thickness (CT)
A positive relationship was observed between CTX and predicted bone strength as estimated by strength‐strain index (SSI), reflecting the fact that the latter parameter is strongly influenced by bone size
Summary
Bone size and geometry make a major contribution to fracture risk, reflecting the fact that bending strength of bone is critically dependent on its diameter.[1]. Gender differences in periosteal expansion (for example, in expansion of hip circumference during puberty[3]) may help to explain the higher prevalence of hip fractures in women compared with men in later life. Periosteal expansion is thought to continue after longitudinal growth has ceased, this subsequently declines in later life, limiting its ability to compensate for the higher resorption and endocortical expansion that characterizes bone loss in the elderly.[4] This process may potentially protect from bone loss during aging. One factor that may play a largely unrecognized role in periosteal expansion is bone resorption. It is not inconceivable that bone resorption plays a primary role in modeling as well as remodeling, such that periosteal expansion occurs secondary to increased resorption. It has been proposed that periosteal expansion represents part of an overall response intended to retain bone strength in the face of endosteal expansion.[4]
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