David B. Burr

Basic biomechanical measurements of bone: A tutorial

Although bone densitometry is often used as a surrogate to evaluate bone fragility, direct biomechanical testing of bone undoubtedly provides more information about mechanical integrity. Like any other specialized field, biomechanics contains its own techniques and vocabulary. This article serves as a guide to biomechanical principles and testing techniques for bone specimens.

Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task Force of the American Society for Bone and Mineral Research

ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person‐years. However, long‐term use may be associated with higher risk (∼100 per 100,000 person‐years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research Running Title: Atypical Femoral Fractures Task Force Report

Reports linking long‐term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross‐linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long‐term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management.

Bone remodeling in response to in vivo fatigue microdamage

It has been suggested that osteonal remodeling is triggered by bone microdamage. The validity of this theory rests on the assumption that loading within the physiological range will produce substantial microdamage with relatively few load cycles. The object of the first experiment was to determine threshold values required to consistently produce fatigue microdamage in vivo. The left forelimb of five groups of dogs, characterized by different strain levels and different numbers of load cycles, were loaded in three point bending. The number of microscopic fields which contained some microdamage was calculated as a percentage of the total number of fields. This experiment indicated that loads producing strains as low as 1500 microstrain on the radius and 1400 microstrain on the ulna for 10,000 cycles will produce significant bone microdamage. A second experiment was performed to verify this threshold and to determine whether microcracks are associated with the initiation of bone remodeling. Procedures in this experiment were the same as those in the first, except that all dogs were loaded in such a way as to produce strains on the radius of 1500 microstrain for 10,000 cycles, and the dogs were sacrificed 1-4 days after loading. The loaded limb demonstrated significantly more microdamage than the control limb (p = 0.03). Moreover, we observed 44 times as many microcracks in association with resorption spaces as expected by chance alone. These data support the hypothesis that fatigue microdamage is a significant factor in the initiation of intracortical bone remodeling.

Suppressed Bone Turnover by Bisphosphonates Increases Microdamage Accumulation and Reduces Some Biomechanical Properties in Dog Rib

It has been hypothesized that suppression of bone remodeling allows microdamage to accumulate, leading to increased bone fragility. This study evaluated the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties of cortical bone in the dog rib. Thirty‐six female beagles, 1–2 years old, were divided into three groups. The control group (CNT) was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right ninth rib was assigned to cortical histomorphometry or microdamage analysis. The left ninth rib was tested to failure in three‐point bending. Total cross‐sectional bone area was significantly increased in both RIS and ALN compared with CNT, whereas cortical area did not differ significantly among groups. One‐year treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS, 53%; ALN, 68%) without impairment of mineralization and significantly increased microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT. Although bone strength and stiffness were not significantly affected by the treatments, bone toughness declined significantly in ALN (20%). Regression analysis showed a significant nonlinear relationship between suppressed intracortical bone remodeling and microdamage accumulation as well as a significant linear relationship between microdamage accumulation and reduced toughness. This study showed that suppression of bone turnover by high doses of bisphosphonates is associated with microdamage accumulation and reduced some mechanical properties of bone.

Bone Microdamage and Skeletal Fragility in Osteoporotic and Stress Fractures

The accumulation of bone microdamage has been proposed as one factor that contributes to increased skeletal fragility with age and that may increase the risk for fracture in older women. This paper reviews the current status and understanding of microdamage physiology and its importance to skeletal fragility. Several questions are addressed: Does microdamage exist in vivo in bone? If it does, does it impair bone quality? Does microdamage accumulate with age, and is the accumulation of damage with age sufficient to cause a fracture? The nature of the damage repair mechanism is reviewed, and it is proposed that osteoporotic fracture may be a consequence of a positive feedback between damage accumulation and the increased remodeling space associated with repair.

In vivo measurement of human tibial strains during vigorous activity

Our understanding of mechanical controls on bone remodeling comes from studies of animals with surgically implanted strain gages, but in vivo strain measurements have been made in a single human only once. That study showed that strains in the human tibia during walking and running are well below the fracture threshold. However, strains have never been monitored in vivo during vigorous activity in people, even though prolonged strenuous activity may be responsible for the occurrence of stress fractures. We hypothesized that strains > 3000 microstrain could be produced on the human tibial midshaft during vigorous activity. Strains were measured on the tibiae of two subjects via implanted strain gauges under conditions similar to those experienced by Israeli infantry recruits. Principal compressive and shear strains were greatest for uphill and downhill zigzag running, reaching nearly 2000 microstrain in some cases, about three times higher than recorded during walking. Strain rates were highest during sprinting and downhill running, reaching 0.050/sec. These results show that strain is maintained below 2000 microstrain even under conditions of strenuous activity. Strain rates are higher than previously recorded in human studies, but well within the range reported for running animals.

Increased intracortical remodeling following fatigue damage.

We previously demonstrated that microcracks occurred in common with resorption spaces more often than expected by chance, and proposed that fatigue damage initiates remodeling events. However, it was possible that cracks accumulated at sites of preexisting resorption spaces and did not initiate new remodeling. The goal of this work was to determine whether osteonal remodeling follows the accumulation of microcracks, as expected if microcracks are responsible for initiation of bone remodeling, or if it precedes microdamage accumulation. A three-point bending load was applied to the left limb of 13 dogs for 10,000 cycles at 2 Hz with 2500 microstrain on the cranial radial surface. The right limb was loaded in the same manner eight days later, and the dogs sacrificed immediately after the second loading episode. A nonloaded groups (n = 7) was used as an external control. Radii were strained en bloc for microdamage; parameters related to bone resorption, microdamage accumulation, and the association of damage and resorption were collected. The data demonstrate a significant increase in new remodeling events subsequent to the generation of microdamage. This temporal relationship between microcracks and resorption spaces is inconsistent with the hypothesis that cracks localize at sites of preexisting resorption spaces. This demonstrates that bone remodeling occurs preferentially in fatigue-damaged regions, and supports a direct cause and effect relationship between the initiation of microdamage in bone and its repair.

Stiffness of compact bone: effects of porosity and density

Stiffness of compact bone is found to be highly and nonlinearly dependent on its porosity, its complement, bone volume fraction and apparent density. Elastic modulus decreases as a power (0.55) of increasing porosity and increases both as a power of increasing bone tissue volume (10.92) and increasing apparent density (7.4). These data indicate that small changes in the amount or density of compact bone tissue exert a more pronounced influence on its stiffness than would similar changes in trabecular bone.