Clinical Utility of Bone Turnover Markers in Chronic Kidney Disease

Article information

J Bone Metab. 2024;31(4):264-278

Publication date (electronic) : 2024 November 30

doi : https://doi.org/10.11005/jbm.24.789

Praopilad Srisuwarn^1,2, Richard Eastell¹, Syazrah Salam^1,3

¹Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK

²Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

³Metabolic Bone Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

Corresponding author: Richard Eastell, Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Medical School, EU38, Beech Hill Road, Sheffield S10 2RX, UK, Tel: +44-114-215-9667, E-mail: r.eastell@sheffield.ac.uk

Received 2024 August 8; Revised 2024 September 6; Accepted 2024 September 9.

Abstract

GRAPHICAL ABSTRACT

INTRODUCTION

Chronic kidney disease (CKD) is characterized by kidney damage or a decline in glomerular filtration rate (GFR). As CKD progresses, patients often develop mineral and bone disorders (CKD-MBD), which can begin as early as CKD G2 and become nearly universal in dialysis patients (CKD G5D).[1] This complication includes three main aspects: (1) abnormal calcium-phosphate metabolism and related regulatory hormones, including parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D₃ (1,25[OH]₂D₃), fibroblast growth factor 23 (FGF23) and klotho; (2) vascular and soft tissue calcification; and (3) bone abnormalities (renal osteodystrophy [ROD]).[2]

Bone fragility in CKD results from a combination of premature aging, hypogonadism, and CKD-related bone abnormalities.[3] This interplay of low bone mass, detrimental bone microarchitecture and poor bone quality significantly increases the fracture risk in CKD patients compared to the general population, twice as high in CKD G3 and up to four times higher in CKD G5D.[4] Within one year of sustaining a fracture, patients with CKD G5D face a seven-fold higher risk of sustaining a new fracture and a four-fold higher risk of death compared to those without a fracture.[5,6] Despite this high risk, there are still no licensed treatments for fracture prevention in this population.

Understanding the underlying pathophysiology and disease phenotypes is crucial in managing ROD. ROD encompasses several subtypes, including hyperparathyroidism-related bone disease (which can present as either a mild form or a severe form known as osteitis fibrosa cystica), mixed uremic osteodystrophy, osteomalacia, and adynamic bone disease. Bone histomorphometry, after double-tetracycline labeling, is considered the gold standard test for classifying ROD subtypes. This classification is based on TMV characteristics: T for turnover (bone formation and resorption rates), M for mineralization, and V for volume (Table 1). While bone volume is not required to classify ROD subtypes, it serves as an indicator of the duration and severity of the disease.[2] However, this labour-intensive procedure and analysis can take months and is often limited by the availability of equipment, specialists and high costs. Additionally, patients may be reluctant to undergo this painful procedure.[7]

Table 1

Renal osteodystrophy subtypes and turnover, mineralization, and volume characteristics

To overcome these diagnostic challenges, the CKD-MBD clinical practice guideline published by the Kidney Disease Improving Global Outcomes (KDIGO) suggests using serum PTH and bone-specific alkaline phosphatase (bone ALP) to predict underlying bone turnover phenotype in ROD.[8] Additionally, the ease of obtaining serum samples allows for multiple assessments to monitor disease progression.

In this narrative review, we summarise the current scientific evidence on bone turnover markers (BTMs) in the diagnosis, prediction of fractures and following the treatment of pre-dialysis and dialysis CKD. Our primary literature search was conducted using Ovid MEDLINE, with the last search performed in April 2024. The search terms included “bone turnover marker*”, “BTM”, and “bone adj2 biomarker*”, combined with “kidney”, “renal”, or “nephro”. The search was limited to human studies and articles published in English.

Additionally, we conducted manual snowball searches by reviewing reference lists and tracking prominent authors and major journals in the fields of bone and renal disease to identify further relevant articles. After an initial screening based on titles and abstracts, the selected articles were thoroughly examined in full text for inclusion in this review.

PTH

PTH is the principal regulatory hormone for calcium, secreted in its active form (1-84) PTH before being cleaved by the liver into amino-(N-) and carboxy-(C-) terminal fragments, which are excreted through the kidneys. PTH exerts its primary function by binding to PTH1 receptors (PTH1R) in kidneys and bones, resulting in: (1) kidney effects: inhibits calciuria, stimulates phosphaturia and promotes production of 1,25(OH)₂D₃; and (2) bone effects: stimulates bone resorption by activating the remodeling/modeling process, directly affecting osteoblast differentiation, preventing osteoblasts apoptosis, inhibiting sclerostin expression in osteocyte and indirectly stimulating osteoclasts through increased receptor activator of nuclear factor-κB ligand synthesis from osteocyte.[9,10]

Secondary hyperparathyroidism (SHPT) occurs in nearly 50% of CKD patients with an estimated GFR (eGFR) <40 mL/min/1.73 m² and worsens as CKD progresses.[1] This is due to continuous stimulation from reduced 1,25(OH)₂D₃, hyperphosphatemia, and downregulation of its regulated receptors such as vitamin D receptor, FGF23 receptors and calcium-sensing receptors (CaSR).[1,11] Although PTH is known for its effects on bone remodeling, serum PTH levels in CKD may not reflect bone activity accurately due to measurement issues and variations in PTH responsiveness.

1. PTH assay

CKD serum contains a mixture of PTH fragments that progressively accumulate as eGFR falls below 20 mL/min/1.73 m².[12] These fragments, along with post-transcriptional modifications of PTH can interfere with PTH function and measurement.[12]

The development of immunoassays has mitigated cross-reaction issues to some extent. The widely used 2nd generation assay, known as intact PTH (iPTH), improves upon the 1st generation by using two different antibodies: one against the C-terminus and another against the N-terminus (1-34) (Fig. 1). Although this method improves specificity for (1-84) PTH, it still cross-reacts with N-terminal truncated PTH fragments, believed to be the 7-84 fragment.[13] However, mass spectrometry has challenged this, suggesting other interfering fragments such as 34-84 or 34-77.[12]

Fig. 1

Circulating parathyroid hormone (PTH) molecular forms and three generations of PTH assay. iPTH, intact parathyroid hormone.

The 3rd generation assay, known as whole PTH, targets the N-terminus (1-4), presumably capturing only (1-84) PTH. Measured concentrations are usually 30% to 50% lower than iPTH.[13,14] However, this assay can cross-react with amino-PTH (PTH with phosphorylation at serine 17) and may, in rare cases, cause higher whole PTH concentrations than iPTH.[15,16] Due to unclear evidence supporting whole PTH over iPTH in predicting bone turnover, KDIGO 2017 continues to recommend the 2nd generation PTH assay in clinical practice.[8,14]

Oxidized forms of PTH, which cause partial or complete loss of function, are proposed to form in CKD and cross-react with PTH assays.[17] However, current assays do not show additional benefits in differentiating bone turnover compared to whole PTH and even question their existence due to undetectability by mass spectrometry.[12,18,19]

Another issue with iPTH and whole PTH assays is high inter-assay variability.[13] This could restrict result comparison across assays and hampers defining diagnostic cut points for disease. The recent publication proposes using LC-MS to standardize 2nd and 3rd generation PTH by regression equation, potentially harmonizing PTH measurement in the future.[19]

2. PTH responsiveness

Increasing serum PTH in CKD partly compensates for the skeletal system hyporesponsiveness to normalize serum calcium and bone turnover rate.[20,21] This condition is attributed to multiple mechanisms such as altered function or expression of PTH1R and CaSR.[22] Additionally, the variation of parathyroid responsiveness is influenced by race, primary renal disease, comorbidities, mineral metabolism and treatment.[23] For example, African American and Japanese populations tend to have a higher degree of resistance than Caucasian populations.[24,25] This could explain the broad range of diagnostic cut points when applying PTH as a diagnostic test, in particular discriminating low from non-low turnover ROD, as shown in Table 2.

Table 2

Diagnostic accuracy for parathyroid hormone and bone turnover markers in diagnosing low vs. non-low bone turnover renal osteodystrophy in chronic kidney disease 4–5D in the last decade

BTM

BTMs are biochemical substances released from bone cells or the bone matrix, mainly as by-products of collagen type I during bone formation or resorption, enabling the assessment of whole skeletal bone activity. BTMs can be broadly categorized into two groups: (1) bone formation markers including N-procollagen type N-terminal propeptide of type I collagen (P1NP), bone ALP and osteocalcin; and (2) bone resorption markers, including tartrate-resistant acid phosphatase 5b (TRAP5b), C-terminal telopeptide (CTX), and urinary N-terminal telopeptide (NTX).[26]

CTX and total P1NP are recommended markers for monitoring treatment and predicting fractures in osteoporosis patients.[27] However, CTX is cleared by the kidney, limiting its use in CKD.[26] Total P1NP measures monomeric and trimeric forms of P1NP, with the former accumulating in GFR <45 mL/min/1.73 m², making trimeric P1NP (intact P1NP assay) more appropriate for CKD.[28] Additionally, bone ALP and TRAP5b are not affected by kidney clearance, making them good markers for studying ROD in CKD.[29]

1. BTMs and the diagnosis of ROD

The distribution of bone turnover subtypes changes as CKD progresses. A biopsy study of 56 patients in CKD G3-G4 showed that about 35% had low turnover ROD, with high bone turnover increasing from 4% in CKD G3 to 36% in CKD G4.[30] In dialysis patients, there has been a shift towards a higher prevalence of low bone turnover, partly due to changes in clinical practice over the last decade.[31] While mineralization defects have become rare, they still occur in up to 40% of the population in areas with high aluminum toxicity.[32]

PTH is widely available and commonly used to manage CKD patients. KDIGO suggests maintaining PTH levels at 2 to 9 times the upper normal limit (UNL) for the assay in CKD G5D, based on epidemiological data showing the lowest mortality rate.[33] However, this range is not necessarily a target for optimizing bone health, as a high proportion of patients within this target still have abnormal bone turnover ROD.[14]

For diagnostic purposes, iPTH is still a reasonable tool for distinguishing between high and non-high bone turnover ROD, with levels around 4 to 5 times above the UNL showing area under the curves (AUCs) of moderate accuracy (0.7–0.8).[14,34–36] Conversely, iPTH shows inconsistent performance in distinguishing low from non-low bone turnover ROD, with one study reporting AUCs of poor accuracy (0.56) with a cut point of 2.3 times above the UNL. [14,34–36] This variability can be attributed to differences in PTH responsiveness and assay noise.

BTMs have gained interest as alternative diagnostic tools. Recent studies on the diagnostic accuracy of BTMs and PTH in CKD are summarised in Table 2 and 3. For both low and high bone turnover, bone ALP and intact P1NP show promise, with AUCs ranging from 0.7–0.8 across various CKD populations. For example, Salam et al.[34] proposed a cut point of bone ALP <20 IU/L by IDS assay (equivalent to <30 IU/L by Quidel assay) with a negative predictive value at 96% to rule out low bone turnover ROD in CKD G4-5D.

Table 3

Diagnostic accuracy for parathyroid hormone and bone turnover markers in diagnosing high vs. non-high bone turnover renal osteodystrophy in chronic kidney disease 4–5D in the last decade

In cases of suspected mineralization defects, such as underlying renal tubulopathy affecting serum calcium and phosphate, and untreated renal tubular acidosis, a bone biopsy remains necessary to confirm the diagnosis.[37] Elevated bone ALP and ALP levels can indicate bone mineralization defects. PTH can also increase in response to low calcitriol, irrespective of bone turnover status. Patients with aluminum toxicity can be symptomatic, including bone pain, pruritus, higher phosphate levels, and lower PTH compared to non-aluminum toxicity groups.[38] In regions without aluminum toxicity, dialysis patients with mineralization defects tend to have longer dialysis duration, increased bone ALP and increased PTH compared to unaffected groups with low/normal calcium and vitamin D levels.

CHOOSING OSTEOPOROSIS AGENTS

When managing osteoporosis and fragility fractures in CKD G4-G5D, understanding disease pathophysiology is crucial. After controlling biochemical abnormalities (including serum PTH, calcium, and phosphate), osteoporosis medications should be tailored to the bone turnover phenotype, e.g., anti-resorptive agents for high bone turnover ROD and anabolic agents for low bone turnover ROD. Antiresorptive agents should be avoided in patients with low bone turnover phenotype due to concerns about further suppressing pre-existing low bone remodeling, which may not improve bone strength and could induce adynamic bone and worsen vascular calcification.[49,50]

To navigate treatment, most clinical studies still employ conventional approaches using bone biopsy or serum PTH to diagnose bone turnover phenotype. BTMs are under-used despite growing evidence supporting their use as alternative diagnostic tests, highlighting the need for more clinical studies to fill this evidence gap.

Teriparatide could improve bone mineral density (BMD) in patients with low bone turnover ROD diagnosed either by biopsy or extremely low PTH <60 pg/mL.[51–53] Malluche et al.[31] used BTMs, including serum PTH, whole PTH to C-terminal PTH fragment ratio, and serum TRAP5b, to categorise high and non-high bone turnover ROD; then randomly assigned non-high bone turnover ROD patients to teriparatide or a control placebo group. The significant BMD improvement in non-high bone turnover ROD without safety concerns of increasing coronary artery calcium (CAC) scores supports treatment guided by BTMs and broadens teriparatide usage in this group.

Bisphosphonates and denosumab are commonly prescribed for high bone turnover ROD, diagnosed through bone biopsy or extremely high PTH. In cases of PTH >500 pg/mL, a combination of high-dose calcitriol with pamidronate or denosumab can control PTH and improve BMD. [54,55] Notably, in some practices, anti-resorptive agents are initiated only if PTH is well-controlled to the range of 60 to 240 pg/mL, a level that may raise concerns about low bone turnover phenotype. However, treatment with either alendronate or denosumab in this group for one year can improve BMD without significantly increasing CAC scores, challenging current practice patterns for CKD patients. [56,57]

TREATMENT OPTIONS

International guidelines suggest treating osteoporosis and fragility fractures in CKD G1-G3 without CKD-MBD features similarly to the general population, based on subgroup analyses from large-randomised controlled trials. [8,58–62] However, CKD G3b group has a much smaller sample size, which might call into question the studies’ power to confirm fracture prevention efficacy in this subgroup.

As patients progress to CKD G4-G5D or develop CKD-MBD, treatment becomes more complicated and challenging due to the lack of strong evidence from large fracture outcome trials. Most available data rely on small studies using BMD endpoints.[63] Additionally, the effects of various co-interventions such as calcium, vitamin D, calcitriol, calcimimetics, or treatment initiation criteria should be considered, as they can affect treatment outcomes.[53–55,64]

While improving BMD could serve as a surrogate marker for fracture risk, changes in lumbar spine (LS) BMD assessed by dual energy X-ray absorptiometry (DXA) in the anteroposterior view can be interfered with by accelerated abdominal aortic calcification. This raises questions about whether the observed changes in LS BMD are genuine, especially if the medication solely improves LS BMD. However, this interference has been challenged by a recent study demonstrating a negligible effect of a calcified aorta on BMD results, even in heavily calcified abdominal aortas. [65]

Monitoring BTMs during treatment in CKD could help in understanding treatment responsiveness which may be different from the general population. Rapid changes in BTMs enable early treatment adjustment, quicker than BMD or fracture outcomes which could take years. Conversely, serum PTH is less useful in this situation, as changes are in response to fluctuations in serum calcium due to medication.

The following section will focus on the effects of osteoporosis medication in CKD G4-G5D and how BTM patterns change in response to each drug.

CASE VIGNETTE

A 45-year-old man with type 1 diabetes mellitus and CKD G4 (eGFR 18 mL/min/1.73 m²) resulting from diabetic nephropathy was referred to the metabolic bone clinic following a wrist fracture. He sustained a wrist fracture a year ago after a fall from standing height. A DXA scan performed six months post-fracture showed osteoporosis, with T-scores of −2.8 at the total hip and −2.9 at the LS. Laboratory results one-year post-fracture revealed normal adjusted calcium levels (9.4 mg/dL), controlled phosphate levels (4.6 mg/dL), low vitamin D levels (13 ng/mL), and elevated PTH levels (110 pg/mL, 1.7 times the UNL). What is the next appropriate management?

CASE DISCUSSION

This patient is at high risk of sustaining further fractures, particularly within two years of the initial fracture. While anti-osteoporotic treatments can effectively reduce fracture risk in the general population, managing patients with CKD requires a more tailored approach due to varying disease phenotypes. Therefore, a multidisciplinary team approach is recommended for complex cases like this.

Understanding the patient’s bone turnover phenotype is crucial for selecting the appropriate fracture prevention treatment. In this case, the combination of type 1 diabetes mellitus and CKD G4 may suggest a low bone turnover phenotype; however, the elevated PTH might indicate a high turnover state. This elevation could also be a compensatory response to vitamin D deficiency rather than an indicator of increased bone turnover. Furthermore, the patient’s lab results suggest the possibility of early-stage osteomalacia, characterized by low vitamin D, elevated PTH, and normal serum calcium and phosphate levels.

BTMs can provide additional insights into the patient’s bone turnover phenotype. In this case, these markers, measured one-year post-fracture, revealed elevated total P1NP (269 ng/mL) and bone ALP (40 IU/L, measured using the Quidel/MicroVue assay). The timing of these measurements is optimal, as BTMs typically return to baseline levels one year after a fracture. Assessing these markers too soon post-fracture can be misleading due to temporary elevations related to bone healing.[79]

According to Salam et al.[34], a total P1NP level greater than 125 ng/mL suggests non-low bone turnover ROD, although P1NP may not be entirely reliable in CKD due to the accumulation of monomeric P1NP. Similarly, an elevated bone ALP level greater than 30 IU/L also suggests non-low bone turnover ROD, as supported by a study from Sprague et al.[14] (Table 2). However, the interpretation is complicated by the patient’s low vitamin D levels, as elevated bone ALP could also indicate osteomalacia, which would typically require confirmation via bone biopsy.

To avoid a bone biopsy, the initial recommendation is to supplement vitamin D to achieve levels above 30 ng/mL. Once vitamin D levels are normalized, it is advisable to reassess bone ALP. If bone ALP remains persistently above 30 IU/L, this would support a diagnosis of non-low bone turnover ROD. If non-low bone turnover is confirmed, treatment with denosumab may be beneficial. To reduce the risk of hypocalcemia, denosumab should be administered along with calcium and vitamin D. Serum calcium levels should be monitored weekly, especially during the first four weeks, to minimize this risk.

CONCLUSION

BTMs are a valuable alternative tool for diagnosing bone turnover subtypes in ROD and guiding treatment when bone biopsies are not feasible. They provide insights into the patient’s bone metabolism, allowing for tailored and effective treatment strategies. Additionally, BTMs can help to monitor treatment response and adjust therapies accordingly. Overall, integrating BTMs into clinical practice can enhance the management of osteoporosis and fragility fractures in CKD patients.

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