Understanding Bone Strength is not Enough

Abstract

Increases in fracture risk beyond what are expected from bone mineral density (BMD) are often attributed to poor “bone quality” such as impaired bone tissue strength. Recent studies, however, have highlighted the importance of tissue material properties other than strength, such as fracture toughness. Here we review the concepts behind failure properties other than strength and the physical mechanisms through which they cause mechanical failure: strength describes failure from a single overload; fracture toughness describes failure from a modest load combined with a pre-existing flaw or damage; and fatigue strength describes failure from thousands to millions of cycles of small loads. In bone, these distinct failure mechanisms appear to be more common in some clinical fractures than others. For example, wrist fractures are usually the result of a single overload, the failure mechanism dominated by bone strength, while spinal fractures are rarely the result of a single overload, implicating multiple loading cycles and increased importance of fatigue strength. The combination of tissue material properties and failure mechanisms that lead to fracture represent distinct mechanistic pathways, analogous to molecular pathways used to describe cell signaling. Understanding these distinct mechanistic pathways is necessary because some characteristics of bone tissue can increase fracture risk by impairing fracture toughness or fatigue strength without impairing bone tissue strength. Additionally, mechanistic pathways to failure associated with fracture toughness and fatigue involve multiple loading events over time, raising the possibility that a developing fracture could be detected and interrupted before overt failure of a bone. Over the past two decades there have been substantial advancements in fracture prevention by understanding bone strength and fractures caused by a single load, but if we are to improve fracture risk prevention beyond what is possible now, we must consider material properties other than strength.

I. Introduction

Osteoporosis is characterized by reduced bone mass and density leading to increased risk of fragility fracture. For over 20 years, bone mineral density (BMD) has been the primary method of identifying individuals with high fracture risk. Although BMD is a useful indicator of fracture risk, its ability to predict fracture has well recognized limitations. For example, in some clinical studies, fractures were observed more frequently in patients who would not be characterized as “high-risk” based on BMD ⁽¹⁾. Additionally, fracture risk is greater than would be expected from BMD in older patients, ⁽²⁾ those with diabetes ⁽³⁾, and those undergoing treatment with glucocorticoids ⁽⁴⁾. Changes in fracture risk that are greater than expected from BMD are attributed to impaired “bone quality” – a term that is used to refer to characteristics of bone that influence mechanical performance but are not well described by BMD including bone morphology, internal architecture and impaired bone tissue material properties ^(5,6).

Clinical fracture occurs when loading conditions exceed the capacity of the bone. The ability of a whole bone to resist mechanical failure is a combination of bone density, bone morphology and bone tissue mechanical properties. Bone density and morphology are strongly correlated with BMD measures. When fracture risk is greater than expected from BMD, alterations in tissue material properties are often implicated. Recent studies and review articles have noted that tissue material properties other than strength influence fracture risk. Fracture toughness is often mentioned as a material property of bone tissue that influences fracture risk but is distinct from strength ^(7-12). Here we discuss three distinct tissue material properties that describe mechanical failure of bone: tissue strength, fracture toughness and fatigue strength. The goal of this perspective article is to explain the differences among these three tissue material properties, the physical situations in which each is relevant and how consideration of material properties other than strength is necessary for further advancements in fracture prevention.

II. Strength, Fracture Toughness and Fatigue: Distinct But Related Material Properties

In colloquial use, the “strength” of an object or material indicates the ability to resist loads without failure. Many scientific articles examining bone use the term “strength” in this colloquial manner, meaning resistance to mechanical failure. The ability of an object to resist mechanical failure is due to a combination of object size and the properties of the material from which the object is made. Material properties can greatly influence how an object breaks: A glass bottle breaks in a much more dramatic way than a plastic one. The failure of the axle of an automobile after years of regular use can hardly be attributed to insufficient strength because the axle carried loads for years prior to failure. Recognizing that mechanical failure can occur through different mechanisms, engineers long ago realized that the colloquial use of the term “strength” does not adequately describe mechanical failure of a material. Instead the engineering community has developed a list of distinct material properties that describe how well a material resists mechanical failure under different conditions (Table 1). Here we define and contrast three tissue material properties that describe mechanical failure of bone: strength, fracture toughness and fatigue strength¹.

Table 1.

A list of material properties describing mechanical failure is shown along with conceptual definitions and common materials.

Material Property	Technical Definition	Conceptual Definition	Common Materials
Strength	Maximum mechanical stress	Greatest load that can be applied at once	High: Metals Low: Plastics
Fracture Toughness	Ability to resist unstable crack growth	Likelihood that the material will shatter when it breaks	High: Soft Plastics Low: Glass
Fatigue Strength	Number of cyclic loads that can be experienced before failure	Failure from damage accumulation over thousands to millions of loading cycles	High: Fiber Composites Low: Ceramics

Material strength is the maximum load carrying capacity of the material and is measured independent of object size and shape. Metals such as stainless steel are an example of a high strength material and plastics are common low strength materials. Strength is the most commonly referenced material property of bone, because the term is widely used colloquially, and because strength is relatively easy to measure experimentally. Strength describes failure under a single load, and is therefore most directly related to clinical fracture during a single event such as a fall. Of the three failure properties discussed here, material strength appears to be the most closely correlated with bone mineral density (as measured by quantitative computed tomography) ^(14,15).

Fracture toughness describes the ability of a material submitted to loads to resist rapid growth of a crack originating at a stress concentration. Stress concentrations (also known as stress risers) are regions in an object where stress increases greatly due to holes, sharp edges, rapid changes in material properties or a pre-existing crack. A material with low fracture toughness often shatters when breaking due to the rapid growth of a relatively straight crack. Glass and ceramics are common materials with low fracture toughness. Plastics, like the polyethylene used to make Falcon tubes and syringes, have relatively high fracture toughness; they do not shatter when loaded to failure at room temperature even when stress concentrations are present. Fracture toughness is relevant to the skeleton because bone tissue has a number of naturally occurring stress concentrations including Haversian canals, cement lines and microscopic cracks that accumulate over time ^(16-19). Fracture toughness, which describes the stress intensity at the tip of a crack that leads to rapid unstable crack growth during a single load is often confused with the material property “modulus of toughness” or “toughness” that is the energy absorbed at the tissue level prior to failure. While toughness provides some information distinct from strength, the measure is an indirect description of failure caused by rapid crack growth.

Fatigue is failure of a material following many cycles of loading at magnitudes well below the material strength (i.e. failure does not occur from one loading event). The failure of a car axle described above is a fatigue failure since the axle experienced millions of cycles of modest loads before mechanical failure. Fatigue failure occurs as a result of the initiation and propagation of many microscopic or sub-microscopic cracks that initiate at naturally forming stress concentrations or flaws within the material. Fiber composites (such as fiberglass) have high fatigue strength due to complex interactions between fibers, the matrix between them and damage accumulation. Ceramics tend to have lower fatigue strengths because once a microscopic crack initiates, few components of the microstructure inhibit damage propagation. In bone, fatigue failure is most commonly referenced in discussions of stress fractures called fatigue fractures, which are the result of an excessive number of large magnitude cyclic loads on otherwise normal bone tissue ⁽²⁰⁾. A less commonly discussed type of stress fracture is the insufficiency fracture, which is the result of normal cyclic loading on weakened bone ^(20-22) and represents a common form of fragility fracture.

The three mechanical failure properties we have discussed are often misinterpreted as having independent contributions to fracture risk, with strength being the most influential (Figure 1, left). However, all three material properties describe different processes leading to the same final result – rupture of bonds at the atomic scale – and for this reason the three failure properties are often correlated with one another. The correlations between these three properties has led some investigators to refer to them interchangeably, but it is useful to understand how the measures are distinct and how they are related. The contributions of the three mechanical properties are more accurately illustrated in a Venn diagram (Figure 1, right). The circles within the diagram indicate the information regarding mechanical failure that is provided by each material property. For example, a measure of strength provides information that can only be gained by measuring strength, but is also influenced to a small degree by the fracture toughness and fatigue strength of the material. The physical reasons for overlap in these three material properties are a topic of great interest to materials scientists (see ⁽¹³⁾), but are beyond the scope of the current discussion.

Figure 1.

The contributions to whole bone fracture by tissue material properties are illustrated with circles. (Left) A common misperception is that tissue material strength, fracture toughness and fatigue strength are independent and that tissue strength is much more important. (Right) In reality the three material properties have interdependencies that are represented by the overlap in the figures. For example, a measure of tissue material strength is influenced by fracture toughness and fatigue strength (the regions overlapping with other circles).

III. Strength, Fracture Toughness and Fatigue have Differential Effects on Clinical Fracture

When a load bearing structure such as a bridge or aircraft undergoes mechanical failure, structural engineers perform a failure analysis to understand the mechanism. By considering the physical forces at the time of failure and the morphology of the broken part one can identify the failure process and determine if failure was dominated by insufficient material strength, fracture toughness or fatigue strength. Only by identifying the influential failure mode can the most appropriate intervention be applied to prevent subsequent failures.

An examination of the loads associated with fragility fracture can also provide insight into the dominant failure mode. The failure mechanism is evident from high loads associated with a traumatic event such as an automobile accident, but fragility fractures, by definition involve lower magnitude loads. A fragility fracture may occur following a single large load such as a fall, but many fractures occur without a single memorable loading event and therefore must be the result of multiple loads that do not exceed bone tissue strength. Large loads such as those incurred by a fall from standing height may occur once per year or more in some elderly populations ^(23-25). Moderate magnitude loads such as lifting a child or stumbling off a curb without falling may happen more frequently or even a few times per week. Low magnitude loads such as those caused during locomotion and other activities of daily living occur many times each day.

Recognizing that fragility fractures are not all caused by the same loading conditions, we propose that the physical causes of fracture can be divided into a series of mechanistic pathways, analogous to molecular mechanisms describing cell signaling. We describe fragility fractures using three mechanistic pathways with distinct loading histories (Figure 2A). As we discussed in Section II, material properties that describe failure are also associated with loading histories, and a specific material property is closely aligned with each mechanistic pathway. Common osteoporosis-related fragility fractures do not all occur through the same mechanistic pathways (see hypothesized distribution in Figure 2B). Wrist fractures, for example, are almost always associated with a single large overload such as a fall ⁽²⁶⁾. Vertebral fractures can be associated with a single loading event, but as many as 60% of vertebral fragility fractures occur spontaneously or are detected incidentally ⁽²⁷⁾, suggesting that many vertebral fractures occur following damage accumulation from multiple loading cycles ^(28,29). Up to 90% of hip fractures are associated with a fall ⁽²⁹⁾, suggesting that the fracture usually occurs after a single overload, although the possibility remains that some hip fractures occur due to a combination of a fall and accumulated tissue damage from previous activity (including previous falls that did not result in fracture). The association between these mechanistic pathways to failure and tissue mechanical properties suggest that alterations in tissue mechanical properties may have differential effects on common clinical fractures (Table 2).

Figure 2.

There are multiple mechanistic pathways to mechanical failure of bone. (A) Fracture may occur as a result of a single large load, a single modest load applied in the presence of pre-existing tissue damage or as a result of many cycles of loading and associated damage accumulation. Each of these mechanistic pathways to mechanical failure are dominated by a different bone tissue material property (strength, fracture toughness or fatigue strength). (B) Hypothetical representations of the relative importance of each mechanistic pathway to common osteoporosis-related fracture are shown with darkened regions. Wrist fractures occur predominately as a result of a single large load. Vertebral fractures occur predominately due to cyclic loading and less often due to a single large overload. Hip fractures are almost always associated with a single loading event but may also be associated with damage accumulation from prior overloads.

Table 2.

Hypothesized relative contribution of each material property to clinical fractures.

Clinical Fracture	Dominant Tissue Material Property
Wrist Fracture	Strength
Hip Fracture	Strength, Fracture Toughness
Vertebral Fracture	Fatigue, Strength
Atypical Femoral Fractures	Fatigue, Fracture Toughness, Strength
Insufficiency Fractures	Fatigue Strength

The differences among the three mechanistic pathways have relevance to evaluation of fracture risk. The primary assay of fracture risk is BMD, which encompasses bone size and density. Measures of bone density at the tissue level (apparent density, ash density, volumetric BMD) are strongly correlated with bone tissue strength ^(14,15,30), but do not appear to be strongly correlated with fracture toughness or fatigue ^(31-33). We propose that increases in fracture risk that are not explained by BMD often reflect alterations in fracture toughness or fatigue strength leading to failure through mechanistic pathways other than a single overload. Atypical femoral fractures associated with long-term antiresorptive treatment are an extreme example of how a change in tissue material properties alters the mechanistic pathway to fracture. Atypical femoral fractures occur in bone that is relatively dense, which would suggest high whole bone strength. Atypical femoral fractures often occur following pain associated with accumulation of tissue damage. Additionally, atypical femoral fractures occur rapidly with a fracture plane involving transverse growth of a single crack – a process that is more consistent with insufficient fracture toughness than insufficient bone tissue strength ^(7,34). Hence, atypical femoral fractures occur through a mechanistic pathway more consistent with damage accumulation and rapid crack growth following a modest load. Although the local bone remodeling response can contribute to atypical femoral fracture pathogenesis ⁽⁹⁾, the physical mechanisms of atypical femoral fracture are consistent with impaired tissue fatigue strength and/or fracture toughness.

IV. Understanding Strength is not Enough

Recognizing the differences in tissue material failure properties and their associated mechanistic pathways to failure has the potential to lead to improvements in our understanding of the effects of chronic conditions on fracture risk and the development of new intervention strategies.

Chronic conditions that result in increases in fracture risk beyond what are expected by BMD are often attributed to alterations in tissue material properties. Although assessment of bone tissue failure properties in vivo could directly diagnose bone tissue fragility, any such approach is unlikely to become a routine clinical screening method. Instead, understanding the correlations between chronic conditions, bone tissue constituents and bone tissue mechanical properties are more likely. Characteristics of bone tissue such as degree of mineralization and other matrix properties have been shown to alter bone stiffness or strength, but fracture toughness or fatigue strength are rarely examined. Indeed, many animal studies examine the effect of a chronic clinical condition or interruption of a novel biological pathway on bone density/microarchitecture, but mechanical testing of bone tissue is either not included or examined only at the whole bone level to evaluate strength. While these studies have contributed to our understanding of bone strength, fracture is not always a result of insufficient strength and a condition may greatly alter fracture toughness or fatigue strength. In such cases, biomechanical studies limited to bone density and strength will often incorrectly conclude that the condition being studied does not affect bone failure properties. More studies relating bone tissue constituents or clinical conditions to fracture toughness and fatigue are needed. While all three failure properties do not need to be measured in every biomechanical study, thoughtful consideration of the associated changes in bone tissue constituents will help to identify the failure property that is most appropriate to examine experimentally. Simply measuring strength without an underlying rationale is unlikely to address contributors to fracture risk beyond what has already been established.

The recognition that some mechanistic pathways to failure involve multiple loads over time has the potential to lead to new intervention strategies. A fracture that develops over time (weeks to months) could be detected before overt failure, raising the possibility that a treatment/intervention can be applied to prevent clinical fracture. Engineers have long used early detection to prevent catastrophic failure of durable structures such as buildings and aircraft. Using what is known as a “damage-tolerant” approach, nondestructive inspections of a structure are performed and an assessment of the need for intervention/repairs is made ⁽¹³⁾. The idea that developing fractures could be detected and interrupted in bone has received little attention, but is the concept behind prophylactic intramedullary nailing for patients with emergent atypical femoral fractures ^(7,35). Recent findings suggest that it may be possible to detect fractures before they reach completion. Incipient fractures appear in magnetic resonance images as a radiologic finding known as a bone marrow lesion or bone marrow edema ^{(21,22,36,37)}. A bone marrow lesion can precede overt fracture ⁽³⁸⁾, but not all bone marrow lesions/edemas progress to fracture ^(39-41). Further complicating the situation, we know little about the underlying pathophysiology of a bone marrow lesion, and bone marrow lesions are also associated with a number of other clinical conditions ^(36,42), suggesting their use as a diagnostic indicator may be challenging. However, the idea that an impending fracture could be detected and arrested with treatment has broad application, especially if our hypothesis is true that BMD is less indicative of fractures that develop over time.

Over the last 20 years the primary strategy to address fragility fractures and assessment of fracture risk has been based on a single mechanistic pathway to failure: fractures caused by a single load such as a fall and insufficient bone strength. This approach has allowed effective assessment of fracture risk using BMD and enabled the development of pharmacologic treatments that reduce fracture risk by 50%. Further reductions in fracture risk will require improvements in diagnosis and treatment. Advances in diagnosis of fracture risk will require addressing fractures that occur through mechanistic pathways to fracture that occur over time and/or impairment of bone tissue fracture toughness or fatigue strength.