Erin McNerny

Bone Quality in Chronic Kidney Disease: Definitions and Diagnostics

Purpose of ReviewIn this paper, we review the epidemiology, diagnosis, and pathogenesis of fractures and renal osteodystrophy.Recent FindingsThe role of bone quality in the pathogenesis of fracture susceptibility in chronic kidney disease (CKD) is beginning to be elucidated. Bone quality refers to bone material properties, such as cortical and trabecular microarchitecture, mineralization, turnover, microdamage, and collagen content and structure. Recent data has added to our understanding of the effects of CKD on alterations to bone quality, emerging data on the role of abnormal collagen structure on bone strength, the potential of non-invasive methods to inform our knowledge of bone quality, and how we can use these methods to inform strategies that protect against bone loss and fractures. However, more prospective data is required.SummaryCKD is associated with abnormal bone quality and strength which results in high fracture incidence.

Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate.

Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.

Assessing the inter- and intra-animal variability of in vivo OsteoProbe skeletal measures in untreated dogs

The OsteoProbe is a second-generation reference point indentation (RPI) device without a reference probe that is designed to simplify RPI testing for clinical use. Successful clinical implementation of the OsteoProbe would benefit from a better understanding of how its output, bone material strength index (BMSi), relates to the material properties of bone and under what conditions it reliably correlates with fracture risk. Large animal models have the potential to help fill this knowledge gap, as cadaveric studies are retrospective and limited by incomplete patient histories (including the potential use of bone matrix altering drugs such as bisphosphonates). The goal of this study was to assess the intra and inter-animal variability of OsteoProbe measures in untreated beagle dogs (n = 12), and to evaluate this variability in comparison to traditional mechanical testing. OsteoProbe measurements were performed in vivo on the left tibia of each dog and repeated 6 months later on the day of sacrifice. Within-animal variation of BMSi (CV of 5–10 indents) averaged 8.9 and 9.0% at the first and second timepoints, respectively. In contrast, inter-animal variation of BMSi increased from 5.3% to 9.1%. The group variation of BMSi was on par with that of traditional 3-point mechanical testing; inter-animal variation was 10% for ultimate force, 13% for stiffness, and 12% for total work as measured on the femur. There was no significant change in mean BMSi after 6 months, but the individual change with time across the 12 dogs was highly variable, ranging from − 12.4% to + 21.7% (mean 1.6%, SD 10.6%). No significant correlations were found between in vivo tibia BMSi and femur mechanical properties measured by ex vivo 3-pt bending, but this may be a limitation of sample size or the tests being performed on different bones. No relationship was found between BMSi and tissue mineral density, but a strong positive correlation was found between BMSi and tibia cortical thickness (ρ = 0.706, p = 0.010). This report shows that while the OsteoProbe device has inter-individual variability quite similar to that of traditional mechanical testing, the longitudinal changes show high levels of heterogeneity across subjects. We further highlight the need for standardization in post-testing data processing and further study of the relationships between OsteoProbe and traditional mechanical testing.

Response to Comments on "True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo".

We appreciate the kind words offered by Drs Farr, Amin, and Khosla about our recent review article on reference point indentation (RPI). Their comments, for the most part, echoed thosewe posed in the article, including 1) the need for newways to characterize patients at risk for fracture and 2) that RPI “may have” clinical utility. However, the authors believe our review “missed the forest for the trees” because, in their opinion, the main practical question is whether BMSi is clinically useful. Dr Farr and colleagues have shown that BMSi differs in patients with type 2 diabetes mellitus (T2DM) compared with nondiabetic controls. In their opinion, regardless of what BMSi is measuring, this result “suggests it may have potential clinical utility in identifying patients with T2DM for fragility fractures.” We acknowledge that they may be right, but we feel that basic information is needed regarding the relationship to traditional mechanical properties. Despite what is stated in their letter, there are no published data demonstrating that BMSi measures bone material properties. Dr Farr and colleagues reference the work of Bridges and colleagues, who tested calibration materials (not bone) with OsteoProbe and a Rockwell Hardness tester and found the two were correlated. This provides no insight into bone and is actually confounded by the manufacturer’s statement that the “impact force does change depending on the material being tested.” Thus, in these tests, the machine likely was indenting with variable force across the three materials. It remains unclear, at least to us, the degree to which OsteoProbe indentation forces vary in bone, a heterogeneous composite material. This information is critical because if the forces differ across bones of various properties, the resultant data would be practically meaningless with respect to a mechanical measure. A related reason for suggested caution is that without data showing that BMSi reflects some aspect of bone mechanical properties, the fact that it is lower is challenging to interpret. Is a lower BMSi always bad? How low a BMSi warrants concern? Is there any relation of BMSi change to change in fracture risk? If we don’t know these things, then making clinical decisions based on a change in BMSi seems like a slippery slope. We acknowledge that these questions are difficult to answer. Thus, the more plausible way to translate the OsteoProbe and BMSi to the clinic would be to understand what it is actually measuring. Drs Farr, Amin, and Khosla are at the forefront of trying to develop new approaches to assess fracture risk. If progress is going to be made, they are going to be a major part of it. Our hope is that by working together to truly understand the “trees,” we can push the field forward and make the “forest” a reality. As it stands, the forest canopy has gaps too large to bridge.

Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model.

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1–2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.