Suppression of Remodeling and Bone Fragility

“The primary purpose of remodeling of bone is to maintain its load-bearing capacity. This is accomplished both by preventing the adverse effects of excessive age at the microscopic and submicroscopic levels, and by repairing damage after it occurs.” —Parfitt AM, 1996.⁽¹⁾

A statement like Parfitt's is included in most introductions to the physiology of bone. A corollary of this statement is that suppression of bone remodeling, by increasing tissue age and preventing damage repair, has the potential to compromise the load-bearing capacity of bone. The possibility that long-term suppression of remodeling might promote bone fragility has been a concern since the introduction of antiresorptive therapies, confirmed to some degree by the discovery of atypical femoral fractures in patients with a history of treatment with antiresorptive agents.^{(2, 3)} In this issue, Haider and colleagues⁽⁴⁾ address one aspect of this possibility by examining the ability of bone tissue to resist cyclic loading after 1 year of antiresorptive treatment.

To understand how suppression of bone remodeling might make bone more fragile, it is useful to remember that there are multiple pathways in which bone tissue may break. Most reports focus on bone strength, which is a mechanical property defined as mechanical failure of bone after a single loading event. However, there are other ways in which bone may break that are characterized by distinct mechanical properties, including fracture toughness and fatigue strength (see Hernandez and van der Meulen⁽⁵⁾ for an introduction to these other failure modes). Mechanical failure under fatigue loading, in particular, has been proposed as a contributor to atypical femoral fracture.^{(3, 5)} Fatigue failure occurs through the accumulation of microscopic damage over many loading cycles at magnitudes well below bone strength and is measured as the number of cycles to failure. Suppression of bone remodeling is thought to reduce the number of cycles to failure of bone by preventing remodeling-based repair of microscopic damage, thereby allowing more rapid accumulation of tissue damage.^{(2, 5)}

Prior work in animals support the idea that long-term antiresorptive treatment increases the accumulation of microscopic tissue damage in bone,⁽⁶⁾ but direct measurement of fatigue failure after prolonged suppression of bone remodeling has been limited because of technical challenges.^{(7, 8)} Most notably, measuring fatigue failure requires 4 to 5 times more specimens than are needed to measure strength. Additionally, the accumulation of microscopic damage in bone is influenced by Haversian canals and cement lines; hence, more expensive animal models that display Haversian remodeling are needed to provide mechanical insights relevant to human tissue.

Haider and colleagues address these challenges by examining a non-human primate with Haversian remodeling (cynomolgus monkeys) submitted to suppression of remodeling for 1 year.⁽⁴⁾ Importantly, the study included a sample size (n = 240 beams of cortical bone) sufficient to detect differences in fatigue failure among study groups. They report that, on average, the number of cycles to failure of cortical bone is 4 times greater in animals receiving antiresorptive treatment compared with controls (shift to the right in the regression lines in Fig. 3). This finding is the opposite of what would be expected if suppression of remodeling promotes fatigue failure. Cortical bone from animals treated with antiresorptives showed reduced cortical porosity that led to an associated increase in material stiffness (Young's modulus). After accounting for differences in Young's modulus, there were no detectable differences in fatigue life among groups (Supplemental Fig. S1), suggesting that the observed differences in fatigue life were explained by the reduction in cortical porosity caused by suppression of remodeling.

Although useful, the findings by Haider and colleagues do not completely rule out the possibility that suppression of remodeling could promote bone fragility in humans. First, the study was limited to examination of fatigue failure and did not assess another key failure mode: fracture toughness (not to be confused with “toughness” measured in a monotonic test).⁽⁵⁾ Fracture toughness describes the ability of a material to resist rapid growth of a crack at the location of a stress concentration such as a hole, rapid change in material properties, or a preexisting crack. Bone has many naturally occurring stress concentrations such as Haversian canals, cement lines, and resorption cavities.⁽⁵⁾ Fracture toughness has been shown to be impaired in bone tissue from humans receiving bisphosphonates,⁽⁹⁾ and fracture patterns observed in atypical femoral fracture are consistent with mechanical failure due to impaired fracture toughness.⁽⁵⁾ Fracture toughness and fatigue life are distinct mechanical properties, and the presence of a robust fatigue life does not preclude the possibility of reduced fracture toughness.

Additionally, tissue age, defined as the length of time the tissue has been present in the body, is thought to influence fatigue life of bone. Tissue age in the Haider study was limited by the age of the cynomolgus monkeys (9–14 years). In humans, regions of interstitial bone tissue formed during adolescence are still present in individuals over 60 years of age (tissue age 40+ years) and are more likely to accumulate microscopic cracks after cyclic loading.^{(10, 11)} Increased fragility of interstitial bone in humans is thought to be caused by changes in chemical composition of bone matrix that accumulate in tissue after decades in the body and may therefore not be present in cynomolgus monkeys. Without the presence of regions of bone matrix with excessive tissue age that rapidly accumulate microscopic damage, the biomechanical effects of suppression of remodeling may be muted.

Despite these limitations, Haider and colleagues overcome substantial technical challenges to provide a key piece of long-sought evidence regarding the effects of suppression of remodeling on mechanical failure of cortical bone. Their finding that fatigue life is not impaired by suppression of bone remodeling is unexpected and highlights the importance of modes of mechanical failure that are not dominated by strength.

Conflicts of Interest

The author has nothing to disclose.

Author Contributions

Christopher J. Hernandez: Conceptualization; writing – original draft; writing – review and editing.