Variation in tibial functionality and fracture susceptibility among healthy, young adults arises from the acquisition of biologically distinct sets of traits

Abstract

Physiological systems like bone respond to many genetic and environmental factors by adjusting traits in a highly coordinated, compensatory manner to establish organ-level function. To be mechanically functional, a bone should be sufficiently stiff and strong to support physiological loads. Factors impairing this process are expected to compromise strength and increase fracture risk. We tested the hypotheses that individuals with reduced stiffness relative to body size will show an increased risk of fracturing and that reduced strength arises from the acquisition of biologically distinct sets of traits (ie, different combinations of morphological and tissue-level mechanical properties). We assessed tibial functionality retrospectively for 336 young adult women and men engaged in military training, and calculated robustness (total area/bone length), cortical area (Ct.Ar), and tissue-mineral density (TMD). These three traits explained 69% to 72% of the variation in tibial stiffness (p < 0.0001). Having reduced stiffness relative to body size (body weight  bone length) was associated with odds ratios of 1.5 (95% confidence interval [CI], 0.5-4.3) and 7.0 (95% CI, 2.0-25.1) for women and men, respectively, for developing a stress fracture based on radiography and scintigraphy. K-means cluster analysis was used to segregate men and women into subgroups based on robustness, Ct.Ar, and TMD adjusted for body size. Stiffness varied 37% to 42% among the clusters (p < 0.0001, ANOVA). For men, 78% of stress fracture cases segregated to three clusters (p < 0.03, chi-square). Clusters showing reduced function exhibited either slender tibias with the expected Ct.Ar and TMD relative to body size and robustness (ie, well-adapted bones) or robust tibias with reduced residuals for Ct.Ar or TMD relative to body size and robustness (ie, poorly adapted bones). Thus, we show there are multiple biomechanical and thus biological pathways leading to reduced function and increased fracture risk. Our results have important implications for developing personalized preventative diagnostics and treatments.

Increased density and periosteal expansion of the tibia in young adult men following short-term arduous training

“…Bone tissue is brittle in narrower tibia, supporting the notion that increased Ct.Dn is a compensatory mechanism for a structurally weaker bone, as shown in male cadaveric specimens [50], in vivo in women [37], and in stress fracture cases [51,52]. In support of these previous findings, volumetric Ct.Dn was inversely related to periosteal (and endosteal) perimeter at Baseline, indicating that those with lower crosssectional area had higher Ct.Dn.…”

How Does Bone Strength Compare Across Sex, Site, and Ethnicity?

“…Previously, we showed that men and women of both ethnicities demonstrated natural variation in the manner to which robustness, cortical area, and tissue mineral density are associated with one another across long bones [11,12,20,21]. Slender bones are 30% to 180% less stiff and strong than robust bones, relative to body size, with a lower bone strength index, narrower diameter, and lower cortical area [20].…”

“…Thus, there would appear to be a biological constraint in the level to which cellular processes (eg, osteoclastic/osteoblastic-driven modeling and remodeling) can be adjusted to mechanically compensate for the natural variation in robustness. It is well known that women tend to have more slender bones than men for a given body size [1,18,19,22], putting them at greater risk of fracturing under extreme loading conditions (eg, military training and falls among the elderly) [1,11,12,17]. However, it had yet to be determined whether this difference in strength is the result of fundamental differences in the manner by which men and women construct bone.…”

Fundamental differences in axial and appendicular bone density in stress fractured and uninjured Royal Marine recruits — A matched case–control study

“…Findings from the present study indicated that recruits with narrower tibiae were at a greater risk of stress fracture, independent of body size. A slender tibia has previously been identified as a risk factor for stress fracture in male military recruits [7,8,31]. There is some evidence that bone attempts to compensate for this functional inequivalence by increased bone mineralisation [32].…”