The Use of Time-Lapse High-Resolution Peripheral Quantitative Computed Tomography for Noninvasive Bone Turnover and Bone Quality Assessment in CKD

CKD is a global health problem affecting approximately 10% of the population. CKD-associated osteoporosis, as defined by the recent Kidney Disease Improving Global Outcomes guidelines, is a complex and multifactorial skeletal disorder.¹ Patients with CKD-associated osteoporosis exhibit an advanced aging skeletal phenotype; they have two-fold to six-fold higher hip fracture risk compared with age-matched and sex-matched individuals without CKD, and these fractures are associated with four-fold to six-fold higher mortality.² CKD-associated osteoporosis is largely characterized by abnormalities in bone mass, mineralization, and turnover. Histologically, patients with CKD often present with extreme high or low turnover. Although both subtypes may result in net bone loss and increased bone fragility, they are managed with different bone-targeted therapeutic strategies. Specifically, patients with low turnover may benefit from strategies to increase turnover, such as decreasing vitamin D and calcium intake in the setting of parathyroid hormone oversuppression or initiating an anabolic agent (e.g., teriparatide). By contrast, patients with high turnover may benefit from strategies to suppress turnover, such as lowering parathyroid hormone levels by initiating activated vitamin D, calcimimetics, dietary phosphate control, phosphate binders, or antiresorptive treatments (e.g., bisphosphonates).¹ In addition, patients with CKD can experience changes in turnover with disease progression or concurrent treatment. Thus, knowledge of turnover before and during treatment may be critical for optimizing clinical management of CKD-associated osteoporosis by monitoring treatment efficacy and informing therapeutic strategies.

An important roadblock to the management of CKD-associated osteoporosis is the inability to obtain accurate turnover assessments. The gold standard turnover assessment is tetracycline double-labeled iliac crest bone biopsy with quantitative histomorphometry, which is the only technique that quantitatively and mechanistically assesses bone tissue–level and cellular-level features that may be impaired in CKD. However, bone biopsy with histomorphometry is invasive, expensive, and requires highly specialized expertise. This procedure is available at very few centers worldwide and is rarely performed repeatedly in the same individual in clinical practice to monitor response to treatment. Consequently, despite broad recognition of its clinical value among nephrologists and ongoing efforts to promote its wider implementation, the procedure is rarely performed clinically for managing CKD-associated osteoporosis.³ As such, many patients with CKD receive either no treatment or treatment that is not optimized for their individual turnover subtype.

Noninvasive assessments offer alternative approaches for bone turnover evaluation. Circulating bone turnover markers are well-established in the general population⁴; however, their use in CKD is controversial. Some bone turnover markers are cleared by the kidney and accumulate with declining kidney function, independent of turnover status. Although Kidney Disease Improving Global Outcomes, the International Federation of Clinical Chemistry and Laboratory Medicine, and the International Osteoporosis Foundation recommend a systematic incorporation of non–kidney-cleared bone turnover markers in CKD, their clinical implementation and effectiveness on predicting patient-relevant outcomes, including bone loss and fracture, remain unestablished.^1,4 Furthermore, studies to date have shown low positive predictive values, making their interpretation to guide patient-specific clinical decision making challenging. ¹⁸F-sodium fluoride positron emission tomography is an advanced imaging modality that has shown promise in classifying bone turnover subtypes⁵; however, its clinical application is limited by high radiation exposure and the need for specialized expertise. Similarly, ^44/42Ca ratio is an emerging noninvasive approach for turnover assessment; however, it has not been validated against gold standard bone biopsy with histomorphometry.⁶ Taken together, an accessible and reliable tool for assessing and monitoring bone turnover remains an unmet clinical need for managing CKD-associated osteoporosis.

Time-lapse high-resolution peripheral quantitative computed tomography (HR-pQCT) is a novel application of HR-pQCT that may hold promise to fill this clinical need. HR-pQCT is a low-radiation dose imaging modality (approximately 2–5 μSv; approximately 1/2–1/5 spine dual-energy X-ray absorptiometry scan) that provides the highest in vivo resolution for evaluating 3D bone microarchitecture (Figure 1A). Time-lapse HR-pQCT is an extension of standard HR-pQCT analysis capable of directly evaluating volumetric temporospatial bone formation and resorption. By registering sequential images taken at two or more time points in the same individual, the same bone volume can be evaluated at both time points. As such, bone present only in the follow-up image is considered bone gain, whereas bone present only in the baseline is considered bone loss. When the time-lapse duration between the baseline and follow-up images does not exceed a full remodeling cycle of a single basic multicellular unit (approximately 4–6 months), the bone gain/loss can be interpreted as turnover that may reflect the level of remodeling activity and help classify turnover status (Figure 1, B and C). Time-lapse HR-pQCT has the potential to combine the strengths of bone biopsy with histomorphometry and bone turnover markers, providing a noninvasive approach capable of repeatedly assessing bone turnover and quality metrics in CKD over time, which has not been offered by any prior noninvasive approaches.

Figure 1.

Schematics of HR-pQCT imaging and time-lapse HR-pQCT pipeline, with its comparison with the gold standard turnover assessment. (A) HR-pQCT scans of the tibia highlighting the cortical deterioration with CKD. Representative time-lapse HR-pQCT (B) pipeline and (C) baseline and follow-up distal tibial scans with the time-lapse overlay visualizing bone formation and resorption evaluated over a 2-month period. (D) Time-lapse HR-pQCT volumetric trabecular bone formation data based on nine patients with kidney failure agreeing with previously reported bone formation data in other kidney failure cohorts measured by bone biopsy with quantitative histomorphometry. HR-pQCT, high-resolution peripheral quantitative computed tomography.

Time-lapse HR-pQCT has been evaluated in primary osteoporosis,⁷ and our recent work has demonstrated its capability in turnover assessment in CKD.⁸ We developed and optimized a pipeline for mapping bone formation and resorption using time-lapse HR-pQCT in patients with kidney failure (n=9), established its precision, and verified its capability to assess turnover in these patients. The work demonstrates that time-lapse HR-pQCT can reliably evaluate turnover in patients with kidney failure over a 2-month period, which is generally equivalent to or shorter than the total time required for clinical tetracycline double-labeled bone biopsy with histomorphometry. We also showed that time-lapse HR-pQCT is capable of monitoring changes in turnover over time. Furthermore, time-lapse HR-pQCT accurately describes the rapid cortical bone loss well-documented for patients with CKD/kidney failure.⁹ Excitingly, time-lapse HR-pQCT captures bone turnover metrics in line with the ranges of turnover data reported by previous studies using bone biopsy with histomorphometry in patients with kidney failure (Figure 1D). As the pilot study did not incorporate a blood draw, we were unable to compare time-lapse HR-pQCT turnover metrics with biochemical markers. Furthermore, the accuracy of time-lapse HR-pQCT requires validation against gold standard bone biopsy with histomorphometry in large and diverse cohorts, especially across stages of CKD. Nevertheless, our pilot data suggest that time-lapse HR-pQCT is capable of noninvasively informing bone turnover status and bone quality with CKD-associated osteoporosis.

Our primary goal is to provide a noninvasive measure of bone turnover for patients with CKD. Currently, a major limitation of HR-pQCT is that it is not US Food and Drug Administration approved or available at many centers; however, this time-lapse HR-pQCT pipeline should readily transfer to other high-resolution clinical imaging modalities. One such emerging technology is photon-counting CT (PCCT), a US Food and Drug Administration–approved low-radiation dose modality that offers a similar resolution to HR-pQCT (approximately 100 μm). In addition, PCCT has demonstrated accuracy in bone microarchitecture and strength evaluation comparable with HR-pQCT.¹⁰ Although further development and optimization are required to adapt the time-lapse pipeline to PCCT, the increasing clinical availability of PCCT scanners should allow for its widespread application in the near future.

In conclusion, patients with CKD-associated osteoporosis often experience high-risk bone abnormalities in bone turnover and bone quality. Limitations of the current clinical bone turnover assessment in CKD, including bone biopsy with quantitative histomorphometry and circulating bone turnover markers, highlight the unmet need for alternative noninvasive approaches that are reliable and available. Upon further validation, time-lapse HR-pQCT has the potential to fulfill this need with its capability to not only assess but also monitor both bone turnover and bone quality metrics over time for CKD bone care.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F381.

Author Contributions

Conceptualization: Joachim H. Ix, Galateia Kazakia, Thomas L. Nickolas, Isidro B. Salusky, Minhao Zhou.

Data curation: Minhao Zhou.

Formal analysis: Isabel Yu, Minhao Zhou.

Funding acquisition: Joachim H. Ix, Galateia Kazakia, Thomas L. Nickolas, Minhao Zhou.

Investigation: Galateia Kazakia, Minhao Zhou.

Methodology: Galateia Kazakia, Isabel Yu, Minhao Zhou.

Project administration: Galateia Kazakia.

Resources: Galateia Kazakia.

Supervision: Galateia Kazakia.

Visualization: Minhao Zhou.

Writing – original draft: Minhao Zhou.

Writing – review & editing: Joachim H. Ix, Galateia Kazakia, Thomas L. Nickolas, Isidro B. Salusky, Minhao Zhou.

Funding

G. Kazakia: National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR084815, P30 AR075055) and Center for Scientific Review (S10 OD021803). M. Zhou: School of Medicine, University of California, San Francisco Dept of Radiology and Biomedical Imaging Seed Grant (MRBSDG2412).