Rethinking Osteoporosis in Chronic Kidney Disease: Breaking Norms, Saving Bones (Part 1)

Chronic Kidney Disease—Mineral Bone Disease (CKD-MBD) encompasses a spectrum of skeletal, vascular, and mineral metabolism abnormalities, including alterations in calcium, phosphorus, parathyroid hormone (PTH), and vitamin D metabolism. These disturbances affect bone quality, contributing to a 4- 6-fold higher risk of fractures compared to the general population, representing a substantial burden of preventable morbidity and mortality (1).

As a nephrologist, my training has traditionally emphasized the evaluation and management of CKD-MBD by monitoring and treating abnormalities in calcium, phosphorus, parathyroid hormone (PTH), and vitamin D levels, often at the expense of recognizing and treating osteoporosis in patients with advanced CKD and ESRD (Figure 1).

Figure 1. Factors contributing to decreased bone strength in patients with CKD/ESRD (green arrows indicate activation and red arrows indicate inhibition)

This emphasis is understandable, given the diagnostic complexity of differentiating bone quality changes in CKD-MBD from bone quantity aberrations in osteoporosis and concerns about the inability of DEXA scans to differentiate osteoporosis from skeletal manifestations in CKD-MBD reliably (Figure 2). As a result, many of us have adopted a conservative stance, often avoiding DEXA scans altogether in this population. However, the historical emphasis on CKD-MBD has overshadowed the fact that CKD-MBD and osteoporosis coexist, with osteoporosis being estimated to be two-fold more prevalent in CKD 3-5 and four-fold more prevalent in ESRD patients compared to the general population (2).

Figure 2. Determinants of bone strength in CKD/ESRD patients (adapted and modified from J. Evaluating Osteoporosis in Chronic Kidney Disease: Both Bone Quantity and Quality Matter. J. Clin. Med. 2024, 13 (4), 1010)

The 2017 update to the KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline marks a significant shift in our understanding of osteoporosis in CKD. Unlike the 2009 guidelines, which discouraged routine DEXA scan testing in CKD stages 3a and beyond, including ESRD, the updated recommendations now suggest DEXA scans to assess fracture risk if results will impact treatment decisions (3). This reversal was driven by compelling new evidence from four prospective cohort studies demonstrating that DEXA bone marrow density (BMD) measurements do indeed predict fractures across the spectrum of CKD severity, including ESRD patients. These studies found associations between BMD and fracture risk comparable to those seen in patients without kidney disease, challenging long-standing assumptions about bone assessment in this population (4).

 As our understanding of bone disease in CKD and ESRD advances, it is increasingly important to integrate the CKD-MBD and osteoporosis frameworks to provide comprehensive skeletal care. This includes using DEXA scans in appropriate CKD/ESRD patients (h/o fragility fractures, steroid use, post-transplant,  post menopausal women, and men >50 years), alongside evaluating parathyroid hormone (PTH) levels and abnormalities in calcium, phosphate, and vitamin D metabolism to assess bone health (5). However, treating osteoporosis in CKD/ESRD patients requires accurate assessment of bone turnover to distinguish high from low bone turnover states and have the ability to monitor turnover status periodically for proper management and treatment decisions. Bone biopsy for histomorphometric analysis of turnover, mineralization, and volume (TMV classification) is considered the gold standard to evaluate bone strength, but it is time-intensive, lacks easy availability, and is invasive (Figure 3).

Figure 3. Various manifestations of renal osteodystrophy based on histomorphometry analysis on bone biopsy (adapted and modified from July 2006 Kidney International 69(11):1945-53)

DOI:10.1038/sj.ki.5000414

Traditionally, intact parathyroid hormone (PTH) has been used as a surrogate biomarker for bone turnover assessment, with patients with iPTH < 2X the upper limit of normal defined as having low bone turnover (adynamic bone disease) and > 9X the upper limit of normal as having high bone turnover(osteitis fibrosa cystica). However, studies have shown a poor correlation between PTH levels and actual bone biopsy findings in the vast majority of patients whose iPTH levels fall between 2 and 9 times the upper limit of normal (6). PTH levels can overlap among patients with different types of renal osteodystrophy  (e.g., adynamic bone disease, osteomalacia, or mixed lesions), making it difficult to distinguish the underlying pathology. Besides, PTH levels are affected by factors unrelated to bone turnover, such as vitamin D status, calcium/phosphate balance, and assay variability, all of which limit its use in isolation as a bone turnover marker (7). To address this gap, incorporating other bone turnover markers into clinical evaluation may help distinguish high-turnover (osteitis fibrosa) from low-turnover (adynamic bone disease) states, guide targeted treatment strategies, and minimize the risk of inappropriate therapies (8).

Bone turnover markers (BTMs) are biochemical byproducts released by osteoblasts and osteoclasts during bone remodeling, offering insight into skeletal metabolism (Figure 4). Bone formation is driven by osteoblasts, whose activity is reflected by markers such as bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), and procollagen type I N-terminal propeptide (P1NP). Conversely, bone resorption by osteoclasts leads to the release of degradation products like the N- and C-telopeptides of type I collagen (NTX and CTX), as well as the enzyme tartrate-resistant acid phosphatase type 5b (TRAP-5b).

Figure 4. Bone Turnover Markers in patients with (only highlighted) and without (all listed) CKD/ESRD.

In osteoporosis, CTX and total P1NP are widely recommended for monitoring treatment response and assessing fracture risk (9). However, their utility is limited in chronic kidney disease (CKD) patients. CTX is renally cleared, and its accumulation in CKD diminishes its reliability. Similarly, total P1NP includes smaller fragments that accumulate in CKD, potentially leading to overestimation of bone formation. In contrast, the intact P1NP assay provides a more accurate assessment, as it is less affected by renal dysfunction. Importantly, bone ALP and TRAP-5b are not cleared by the kidneys, making them reliable markers for evaluating bone turnover in patients with CKD and end-stage renal disease (ESRD). In these populations, relying on kidney-independent BTMs is critical for accurately differentiating high-turnover bone disease (osteitis fibrosa) from low-turnover states (adynamic bone disease), guiding appropriate therapeutic decisions (6).

As our understanding of CKD-mineral and bone disorder (CKD-MBD) advances, the selective use of BTMs based on clearance pathways and assay specificity becomes essential for precision in diagnosis and management. Integrating DEXA scans, biochemical markers, and bone turnover assessments into CKD/ESRD skeletal care allows a more precise and individualized treatment approach. Given the complexities of CKD-MBD and osteoporosis, this expanded framework ensures that therapeutic decisions are based not only on bone density but also on bone quality and turnover dynamics, optimizing fracture prevention and long-term bone health.

References:

1. Kattah, A. G.; Titan, S. M.; Wermers, R. A. The Challenge of Fractures in Patients with Chronic Kidney Disease. Endocr. Pract. 2025, 31 (4), 511–520.

2. Nitta, K.; Yajima, A.; Tsuchiya, K. Management of Osteoporosis in Chronic Kidney Disease. Intern. Med. 2017, 56 (24), 3271–3276.

3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. Suppl. (2011) 2017, 7 (1), 1–59.

4. Lloret, M. J.; Fusaro, M.; Jørgensen, H. S.; Haarhaus, M.; Gifre, L.; Alfieri, C. M.; Massó, E.; D’Marco, L.; Evenepoel, P.; Bover, J. Evaluating Osteoporosis in Chronic Kidney Disease: Both Bone Quantity and Quality Matter. J. Clin. Med. 2024, 13 (4), 1010.

5. Hsu, C.-Y.; Chen, L.-R.; Chen, K.-H. Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review. Int. J. Mol. Sci. 2020, 21 (18), 6846.

6. Khairallah, P.; Nickolas, T. L. Updates in CKD-Associated Osteoporosis. Curr. Osteoporos. Rep. 2018, 16 (6), 712–723.

7. Ginsberg, C.; Ix, J. H. Diagnosis and Management of Osteoporosis in Advanced Kidney Disease: A Review. Am. J. Kidney Dis. 2022, 79 (3), 427–436.

8. Srisuwarn, P.; Eastell, R.; Salam, S. Clinical Utility of Bone Turnover Markers in Chronic Kidney Disease. J. Bone Metab. 2024, 31 (4), 264–278.

9. Joint consensus highlights the role of bone turnover markers in osteoporosis diagnosis and management. https://www.osteoporosis.foundation/news/joint-consensus-highlights-role-bone-turnover-markers-osteoporosis-diagnosis-and-management (accessed 2025-05-18).