Genetic Basis of Skeletal Functionality and Fragility

Fragility fractures occur throughout life and incur tremendous morbidity, mortality, and cost, particularly for the elderly. Over 200 million people worldwide have osteoporosis,¹ with approximately 1.5 million fractures occurring annually in the US² and 3.8 million fractures occurring annually in Europe. ³ These numbers are expected to increase in the next few decades. Clearly, new diagnostic and treatment regimens are needed to reduce fracture incidence on a global basis.

Effectiveness in reducing fracture incidence depends directly on developing a greater understanding of bone fragility and its causes. Fracture resistance is related to bone mass, and can also be examined in engineering terms as being related to its geometry (size and shape) and its intrinsic material properties (tissue quality). The geometry and material properties of bone are largely genetically determined,⁴ and thus likely contribute to the heritability of bone mass⁵ and fracture susceptibility.⁶ Because these physical traits arise directly from tissue growth patterns established before birth and during childhood, bone fragility may be considered a problem of development as much as of aging.⁷ As a result, research directed at understanding the genetic basis of bone fragility will provide new insight into the growth-related causes of variable adult bone morphology and tissue quality, and also identify novel diagnostic and therapeutic targets that can be used to reduce fracture incidence.

Fracture Susceptibility Genes
Bone size and shape vary widely among individuals, and a large fraction of this variation can be attributed to genetic factors. Skeletal traits such as bone mass and bone length are called quantitative traits because they vary in a continuous manner among individuals within a population. The regions of DNA closely linked to the genes underlying a quantitative trait are called quantitative trait loci (QTLs). Genetic analyses identify these chromosomal regions, which tend to correlate strongly with a trait or a disease. The continuous variation in trait values reflects the cumulative effect of a large number of genes, each of which contributes positively or negatively to the trait value in a small way (see Figure 1). Consequently, gene variants that affect the amount or functionality of a protein may slightly increase or decrease the value of a particular trait. How much each gene variant contributes to the trait value varies widely depending on the importance of the protein and the nature of the mutation. Genetic variants affecting type I collagen, for example, havemajor deleterious effects on skeletal fragility, because a mutation affecting the amount and/or quality of collagen severely alters tissue ductility. However, this is generally not the case for common health conditions such as osteoporosis that result from genetic variants that affect bone size, shape, and mass in more subtle ways.⁸ Although many genes have known or suspected roles in regulating various aspects of skeletal traits, many more genes with regulatory functions are yet to be found. Genetic analyses have proved to be a powerful tool for finding novel biological pathways.^9–11

Challenges
A major challenge in understanding why certain individuals are susceptible to common health conditions such as hypertension, arthritis, obesity, and osteoporosis is understanding how genetic and environmental variants compromise the function of these complex systems. For many conditions, genetic background plays a critical role in determining how a system will function under physiological and stressful conditions. For a system such as bone, a critical function is to besufficiently stiff to support the physical forces associated with daily activities and sufficiently strong to resist fracturing. Identifying fracture susceptibility genes that compromise mechanical function is one goal of genetic analyses. However, this is not a simple problem, because complex systems such as bone are considered complex for a reason.

One significant challenge to finding fracture susceptibility genes is that the biological origin of fracture incidence is extremely heterogeneous: that is, individuals may be at risk for fracture for very different biological and thus genetic reasons. Variations in bone strength and toughness, which largely define fracture risk, can arise in many different ways, from reduced bone mass to increased tissue brittleness. This heterogeneity is not unique to bone, but is common to many complex conditions.¹² In bone, a fracture occurs if the forces engendered during an event (e.g. a fall) exceed the load-bearing capacity of the skeleton.¹³ Thus, it is important to identify genetic factors that predispose a bone to be mechanically weaker.

Reduced bone strength may arise in many ways, including excessive bone loss leading to reduced bone mass, ¹⁴ insufficient periosteal expansion to compensate for bone loss,¹⁵ and reduced tissue stiffness and strength resulting from age-related changes in matrix structure and composition. ¹⁶ Fractures may also arise because the skeletal structure has reduced toughness. Toughness is a critical mechanical property characterising the ability of a structure to absorb energy during a fall. Structures with reduced toughness tend to fail in a brittle manner, like chalk. Changes in toughness generally originate as matrix alterations affecting tissue ductility and damageability. This property is often neglected because these matrix changes are difficult to measure non-invasively.

Thus, the strength and toughness of bone are determined by a large number of physical bone traits, each of which may be regulated by different sets of genes. It is therefore important to incorporate the details of bone structure and tissue quality into genetic analyses, because these details provide insight into the biological controls operating on a person by- person basis.