Novel Biomarkers, Diagnostic Approaches for Subtyping Bone Turnover, Improving Patient Outcomes

In an interview with Pharmacy Times, Thomas Nickolas, MD, nephrologist and associate professor of medicine at Columbia University, discusses novel biomarkers for bone turnover and their potential role in improving the precision and accuracy of subtyping renal osteodystrophy. He also notes that pharmacists should be aware of the impact of medications, such as vitamin D receptor analogs, which can suppress bone turnover. Nickolas will be presenting at the panel “Novel Circulating and Noncirculating Biomarkers as Tools to Identify Renal Osteodystrophy Subgroups” during ASN Kidney Week in Philadelphia, Pennsylvania (November 2, 2023, to November 5, 2023).

Pharmacy Times: The session introduces the concept of novel circulating and noncirculating biomarkers of bone turnover. Can you describe what these novel biomarkers are, how they differ from traditional markers, and their potential role in improving the precision and accuracy of renal osteodystrophy (ROD) subtyping?

Thomas Nickolas: Bone strength is defined as a combination of both bone quantity—or bone density—and bone quality, and the density of that bone, we can measure with DEXA scanning or other 3D-scanning techniques that are based on CAT scan imaging. Bone quality has to do with material properties of bone, and that has to do with things like bone turnover, mineralization, collagen content, mineralization rates, and crystal structure. And the current biomarkers of bone turnover really only assess 1 aspect of bone strength—the bone turnover aspect—whereas novel diagnostic markers or ROD are now going into the space where they're becoming better biomarkers of overall bone strength, in particular bone quality. And if we have a better biomarker of bone quality—which includes turnover, in addition to the other aspects of bone quality—we hope that we will be able to better identify the type of ROD and then use that biomarker to develop therapeutics that have more clinical efficacy.

Pharmacy Times: Traditional diagnostic approaches, including biomarkers of bone turnover, are mentioned as tools for subtyping ROD. Can you outline these traditional diagnostic methods and explain how they have been used to categorize ROD during chronic kidney disease (CKD) and after kidney transplantation?

Nickolas: Sure, so the current methodologies, or non-invasive methodologies, that we use to define bone turnover, are what we call bone turnover markers. And these are protein-based biomarkers that are secreted by the cells that form bones—so osteoblasts—or they're secreted by cells that destroy bone—the osteoclasts—or they're secreted from osteoclast activity, such as collagen breakdown products. So, these bone turnover markers give us a dynamic assessment of what the bone cells are doing, and currently they can be used—based on the clinical trials to date—to assess whether patients have low or high bone turnover based on the level of the biomarker.

There are biomarkers that seem to perform better than others. Based on their level of kidney clearance, some of these biomarkers are cleared by the kidney and the preference right now is to use the biomarkers that are not cleared by the kidney, which include the osteoblast markers, bone-specific alkaline phosphatase, multimeric P1NP, and the osteoclast markers, or the resorption marker, TRAP 5b. And the clinical data that we have to date shows that in comparison, or using gold standard bone biopsy as a marker of bone turnover, that we can achieve AUCs of about 0.8 for the differentiation of low versus non-low and high versus non-high bone turnover.

Pharmacy Times: Can you provide some insights into the potential applications of these novel biomarkers and precision medicine approaches for ROD? How can health care professionals, specifically pharmacists, effectively incorporate these tools into their practice to improve patient care and outcomes?

Nickolas: First, I want to state that in terms of the biomarker development process, the novel diagnostic tools are still in early phases of development, and we're still in the identification and early validation phases. They're not ready for clinical use. But in terms of the novel diagnostic markers, our hope is that these will be shown to be better markers or biomarkers of overall bone quality, and when they're used, they can be used not just for the diagnosis of ROD subtype, not just in terms of the bone turnover, but also in other aspects of bone quality that may be impaired in these patients, and then they can be used for disease monitoring. So, when we do apply therapeutics to the patients, that they we can use them to assess treatment efficacy and also to predict the degree of efficacy of that treatment.

So, I think what pharmacists need to know is that nephrologists give a number of medications that do alter bone turnover and that if they're given for the inappropriate type of turnover, that they may provoke damage to the skeleton into the vasculature. And currently, let's say we do get medications like vitamin D receptor analogues to suppress parathyroid hormone production, but if we over suppress bone turnover, then that may be harmful to the patient. So, for pharmacists, it may be helpful to ask their prescribing clinicians if they've assessed at least bone-specific alkaline phosphatase to ensure that they haven't over suppress bone turnover in the patients who are on vitamin D receptor analogs.

Pharmacy Times: Are there any recent advancements or breakthroughs in the field of renal osteodystrophy and biomarker discovery that have the potential to revolutionize our understanding and management of this condition?

Nickolas: I think some really interesting breakthroughs that that have come around recently are 2, and it's the use of novel imaging technologies to assess bone quality and turnover. So, whether it's PET CT imaging or serial imaging using high-resolution peripheral quantitative computed tomography, I think that those are very interesting novel breakthroughs.

Another very novel approach to assessing this question in CKD patients is the use of microRNA analysis and also transcriptomics. One interesting thing about microRNAs and transcriptomics is that these clue us in better into the underlying pathogenesis of ROD, and they also are potentially not just disease monitoring tools, but also potentially druggable targets. So, we can use, let's say microRNAs that are associated with different types of ROD, we can manage them and treat them that will both affect the disease and then we can use those same microRNAs to monitor therapy similar to what we do for lipids with cardiovascular risk or even albuminuria with CKD progression.