Kidney-bone axis: Emerging paradigms in cross-talk between renal function and skeletal health

Abstract

The kidney-bone axis represents a complex endocrine network that extends beyond traditional mineral metabolism, with profound clinical implications in chronic kidney disease (CKD)-mineral and bone disorder. CKD affects approximately 700 million people worldwide, with 18%-32% developing osteoporosis and experiencing a 2.5-4-fold higher fracture risk compared with the general population. Fracture incidence increases from 15 to 46.3 per 1000 person-years across advancing CKD stages, with dialysis patients exhibiting hip fracture mortality rates 2.4 times higher than those in the general population. Secondary hyperparathyroidism affects 20%-80% of CKD patients depending on disease severity, yet traditional biomarkers such as parathyroid hormone and phosphate provide incomplete prognostic value. Emerging molecular pathways involving fibroblast growth factor-23 and its co-receptor klotho have unveiled novel bone-kidney endocrine mechanisms regulating phosphate homeostasis and bone turnover. Klotho deficiency and elevated fibroblast growth factor-23 levels appear early in CKD and may serve as biomarkers and therapeutic targets for both cardiovascular and renal disease progression. Integrating clinical, molecular, and translational approaches to understand the interactions between kidney and skeletal systems offers promising therapeutic strategies addressing both bone fragility and systemic complications, potentially transforming outcomes for patients with CKD-related bone disorders.

Key Words: Chronic kidney disease; Vitamin D; Renal failure; Osteoporosis; Cardiovascular disease

Core Tip: The kidney-bone axis represents a bidirectional endocrine network extending beyond mineral metabolism. Chronic kidney disease affects hundreds of millions worldwide, causing substantially elevated fracture risk and mortality. Traditional biomarkers provide incomplete prognostic value, necessitating novel approaches. The fibroblast growth factor-klotho pathway emerges as a critical mechanism regulating phosphate homeostasis, bone turnover, and cardiovascular complications, with alterations appearing early in disease progression. Understanding these integrated molecular pathways enables a paradigm shift from symptomatic management toward mechanism-based interventions, offering transformative potential for targeted therapies that simultaneously address skeletal fragility and systemic complications in chronic kidney disease-mineral and bone disorder.

INTRODUCTION

The management of bone fragility in patients with chronic kidney disease (CKD) remains one of the most complex and frequently underestimated challenges in nephrology. Historically, bone disease in CKD has been narrowly defines as “disturbances in calcium-phosphate metabolism”, a perspective that does not reflect the true complexity of the condition[1]. Bone health in CKD patients extends beyond simple mineral balance, resulting from a multifaceted interplay among skeletal remodeling, cardiovascular risk, endocrine signaling, nutritional status, and overall clinical frailty. The consequences of this dynamic interaction include increased risk of fractures, impaired quality of life, vascular calcification, and higher mortality[2,3].

The kidney-bone axis represents a fundamental regulatory network in human physiology, characterized by continuous bidirectional communication between these two organs. This interplay is mediated by classical hormones such as parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), α-klotho, calcitriol, and bone morphogenetic proteins, as well as skeletal-derived factors including sclerostin and receptor activator of nuclear factor κB ligand[4-6]. The kidney regulates daily calcium and phosphate handling through filtration and tubular reabsorption, while also producing calcitriol and klotho. Conversely, bone, traditionally viewed as a passive mineral reservoir, functions as an endocrine organ through the secretion of FGF23, sclerostin, and other signaling molecules. Together, kidney and bone maintain systemic mineral balance, regulate bone remodeling, and preserve vascular health[7-9].

Progressive loss of renal function in CKD leads to a growing disruption of the finely regulated systems governing mineral metabolism and endocrine signaling. The result is CKD-mineral and bone disorder (MBD), a systemic syndrome characterized by secondary hyperparathyroidism (sHPT), phosphate retention, altered bone turnover, impaired vitamin D metabolism, vascular calcification, and increased fracture risk[2,3,10,11]. sHPT develops early in the course of CKD, driven by phosphate retention, reduced calcitriol synthesis, and hypocalcemia. Over time, the parathyroid glands undergo hyperplasia and downregulate calcium- and vitamin D-sensing receptors, leading to persistently elevated PTH, cortical bone thinning, marrow fibrosis, and vascular calcification[2,3].

Recent evidence demonstrates a rapid, hormone-independent kidney-bone signaling axis that enables acute regulation of calcium homeostasis[12]. The dysregulation of FGF23 and Klotho is equally pivotal in the pathophysiology of CKD-MBD. FGF23 levels rise early in CKD as a compensatory response to phosphate overload. While initially protective, this elevation becomes maladaptive over time, suppressing calcitriol synthesis, perpetuating PTH elevation, and contributing to cardiovascular complications such as left ventricular hypertrophy[3,7,13]. In parallel, klotho deficiency exacerbates vascular calcification, accelerates systemic aging, and contributes to bone fragility[13]. CKD-associated bone disease is highly heterogeneous, ranging from high-turnover states driven by PTH excess to adynamic bone disease (ABD) induced by overaggressive PTH suppression with vitamin D analogues or calcimimetics[14]. Osteomalacia, though less frequent than before the introduction of aluminium-free phosphate binders, still occurs with severe vitamin D deficiency or aluminium exposure.

Recognition of the systemic implications of CKD-MBD has led to a paradigm shift in clinical practice. The 2017 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended, for the first time, the routine assessment of bone mineral density (BMD) in patients with CKD stages G3-5D who are at risk of fracture[7,8]. This marked a significant evolution in the field, positioning bone health as a central determinant of patient outcomes rather than a secondary concern (Figure 1).

Figure 1 The figure illustrates both physiological and pathological kidney related conditions which influence bone-mineral metabolism. The figure was created using BioRender (https://biorender.com). A: Under physiological conditions, increased phosphate stimulates the bone to secrete fibroblast growth factor (FGFR)-23, which binds to the FGFR1 receptor with the assistance of the co-receptor klotho. This functional complex is primarily expressed in the distal convoluted tubule and parathyroid glands, where it regulates calcium and phosphate homeostasis; B: In chronic kidney disease, reduced kidney function causes hyperphosphatemia, hypocalcemia, klotho deficiency, and reduced calcitriol production, preventing proper FGF23-receptor binding. These alterations lead to parathyroid hyperplasia and secondary hyperparathyroidism, resulting in vascular calcifications and renal osteodystrophy characterized by increased bone fragility. FGFR: Fibroblast growth factor; PTH: Parathyroid hormone; CKD: Chronic kidney disease.

This article provides an integrated overview of the kidney-bone axis, examining how renal dysfunction disrupts endocrine signaling, mineral homeostasis, and skeletal remodeling. We outline the major hormonal pathways and their clinical implications in CKD-MBD, addressing the diagnostic challenges of differentiating high- and low-turnover bone disease. Emerging biomarkers, advanced imaging modalities, and novel therapeutic strategies are critically evaluated. Finally, we contrast CKD-related bone disease with age-related osteoporosis to clarify their distinct pathophysiological mechanisms and clinical trajectories.

PATHOPHYSIOLOGICAL AND CLINICAL ALTERATIONS IN CKD-MBD

In early CKD, nephron loss triggers phosphate retention, activating compensatory mechanisms to maintain calcium-phosphate homeostasis. FGF23 and its co-receptor klotho emerge as the initial responders, promoting phosphaturia and preserving serum phosphate levels. As renal function progressively declines, however, these adaptive responses prove insufficient. The ensuing mineral dysregulation manifests as sHPT, hypocalcemia, and hyperphosphatemia. In advanced disease, these disturbances culminate in diverse skeletal and cardiovascular complications, including ABD, renal osteodystrophy, and vascular calcification. FGF-23 is a hormone produced primarily by osteocytes and osteoblasts, serving as a fundamental link between the skeletal system, kidneys and parathyroid glands in the pathophysiology of CKD-MBD. FGF-23 levels rise early in CKD well before changes in calcium, phosphate, or PTH and continue to increase as renal function declines due to enhanced synthesis and reduced renal clearance[15]. This early elevation has been demonstrated in multiple in vivo studies in both humans and animal models[16].

Once secreted, FGF-23 binds to its receptor complex comprising the FGF receptor and the klotho co-receptor in the kidney and parathyroid glands. This interaction reduces phosphate levels by inhibiting PTH secretion and suppressing the vitamin D active form calcitriol [1,25(OH)₂D] synthesis. In the kidney, FGF23 promotes phosphate excretion by downregulating sodium-phosphate co-transporters (NaPi-IIa and NaPi-IIc) in the proximal tubule. Simultaneously, it enhances calcium and sodium reabsorption in the distal tubule by upregulating the epithelial calcium channel TRPV5 and the sodium-chloride co- transporter[15].

Klotho is a transmembrane protein expressed predominantly in the kidney and, to a lesser extent, in other tissues such as the brain and parathyroid glands. It plays a central role in mineral metabolism. Klotho exists in two principal forms: A membrane-bound isoform that serves as an obligate co-receptor for FGF23 signaling through FGF receptors, and a soluble isoform generated by proteolytic cleavage of the extracellular domain and released into circulation[15].

In the kidney, klotho is localized mainly to the distal convoluted tubules, with lower expression in the proximal tubules and collecting ducts. Through its interaction with FGF-23, membrane bound klotho facilitates phosphate excretion by suppressing the expression of sodium-phosphate cotransporters, while simultaneously inhibiting calcitriol synthesis and enhancing its degradation[17].

Soluble klotho functions as a circulating hormone that contribute to renal calcium and phosphate handling and modulates the activity of 1-α hydroxylase, PTH, and FGF23. It also exerts vasculoprotective, antioxidative, and anti-fibrotic effects[18]. In the distal nephron, soluble klotho enhances calcium reabsorption by stabilizing TRPV5 channels, while in the renal tissue it attenuates fibrosis by inhibiting the transforming growth factor-β signalling pathway[19].

Klotho expression is markedly reduced in both acute and CKD[20], due not only to the loss of renal tissue but also to hyperphosphatemia and elevated levels of inflammatory cytokines and uremic toxins, which induce epigenetic silencing of the klotho gene through hypermethylation or histone deacetylation. The resulting klotho deficiency leads to FGF23 resistance, necessitating higher circulating FGF23 concentrations to maintain phosphate balance[21]. This maladaptive compensation perpetuates a vicious cycle of reduced calcitriol synthesis, sHPT, and vascular calcification. Moreover, klotho deficiency directly promotes renal fibrosis, tubular atrophy, and endothelial dysfunction, thereby accelerating CKD progression and amplifying systemic complications such as left ventricular hypertrophy and arterial stiffness[22].

In CKD, under the influence of FGF-23 and PTH, phosphate excretion is initially maintained through reduced tubular reabsorption. However, with progressive renal impairment, klotho deficiency limits FGF-23 activity at the proximal tubule, shifting the regulatory burden increasingly toward PTH as the GFR declines. Eventually, this compensatory mechanism becomes insufficient, and hyperphosphataemia develops despite markedly elevated levels of PTH and FGF-23[23]. CKD disrupts bone phosphate metabolism by promoting skeletal release while inhibiting matrix deposition, amplifying phosphate retention. This hyperphosphatemia induces osteogenic differentiation of vascular smooth muscle cells, precipitating vascular calcification[24]. Hyperphosphatemia also exerts several endocrine and molecular effects. It suppresses renal 1-α-hydroxylase activity, thereby reducing calcitriol synthesis; it stimulates PTH synthesis via calcium- and vitamin D-independent pathways within the parathyroid glands; and it enhances FGF-23 production by osteocytes and osteoblasts[25]. Hyperphosphatemia mediates skeletal toxicity through direct cellular effects: Phosphate excess inhibits osteoblast differentiation via intracellular signaling dysregulation and triggers osteocyte apoptosis through oxidative stress pathways. The resultant imbalance between impaired bone formation and sustained resorption yields ABD, marked by diminished turnover and heightened fracture susceptibility[26]. Vascular smooth muscle cells internalize phosphate, initiating osteogenic differentiation pathways that replace the compliant arterial matrix with ectopic mineralized tissue[27]. This process results in calcium deposition within the medial and intimal layers, driving the characteristic vascular complications of CKD, arterial stiffness, loss of vascular compliance, and increased pulse-wave velocity[28].

This hyperphosphatemia-driven mineral imbalance creates a self-reinforcing cycle: Impaired bone remodeling releases additional phosphate, which further promotes vascular calcification and accelerates cardiovascular events.

Hypocalcemia typically manifests during the advanced stages of CKD, when hormonal alterations regulating calcium homeostasis, including vitamin D, PTH, FGF23 and klotho, become increasingly pronounced[29]. Impaired calcitriol synthesis leads to reduced intestinal calcium absorption, resulting in a decline in serum calcium levels. This hypocalcemia stimulates PTH secretion, which temporarily restores calcium concentrations by enhancing bone resorption and increasing renal calcium reabsorption in the distal tubules. With advancing renal failure, this compensatory PTH elevation becomes maladaptive, producing sustained hyperparathyroidism, high-turnover bone disease, and progressive mineral dysregulation[30]. Beyond its skeletal consequences, chronic hypocalcemia exerts systemic effects, contributing to neuromuscular irritability, QT interval prolongation, and impaired cardiac contractility. Moreover, hypocalcemia also promotes the osteogenic transformation of vascular smooth muscle cells, thereby exacerbating vascular calcification[11]. Thus, hypocalcemia in CKD represents a critical pathophysiological milestone in the evolution of CKD-MBD, marking the transition from adaptive to maladaptive mineral homeostasis.

Vitamin D deficiency is one of the earliest metabolic disturbances observed in CKD. The kidney plays a central role in the conversion of 25-hydroxyvitamin D into its biologically active form, 1,25-dihydroxyvitamin D (calcitriol), via the enzyme 1α-hydroxylase[31]. As kidney function declines, the loss of 1α-hydroxylase activity leads to a progressive reduction in calcitriol synthesis, accompanied by increased FGF-23 and phosphate retention which further suppress calcitriol production[32]. Consequently, calcitriol deficiency reduces intestinal calcium absorption, predisposing to hypocalcemia. In combination with klotho deficiency and chronic inflammation, this also leads to vitamin D receptor impairment, rendering the parathyroid glands less responsive to calcitriol. The resulting dysregulation promotes excess PTH synthesis, driving sHPT and high-turnover bone disease[33]. Finally, multiple studies have demonstrated that calcitriol deficiency is associated with increased cardiovascular risk and altered immune function in both native and transplant CKD populations, underscoring the systemic consequences of disrupted vitamin D metabolism[34].

sHPT represents a hallmark complication of CKD-MBD arising from constellation of hormonal and mineral abnormalities characteristic of CKD. The progressive increase in PTH synthesis parallels the decline in renal function and results from a combination of interrelated disturbances, including phosphate retention, hypocalcemia, reduced calcitriol synthesis, and dysregulation of the FGF23-Klotho axis. As CKD advances, the parathyroid glands undergo structural and functional remodelling, characterized by diffuse or nodular hyperplasia and a progressive loss of sensitivity to feedback regulation by calcium, phosphate, and calcitriol[35]. Furthermore FGF-23, which under normal physiological conditions inhibits PTH secretion, loses its suppressive effect as klotho expression declines within parathyroid tissue, further amplifying PTH release[13]. The clinical consequences of sHPT include increased bone turnover, manifesting as accelerated bone remodeling, cortical bone thinning, and marrow fibrosis, all of which contribute to heightened fracture risk and reduced skeletal integrity[36]. Conversely, excessive bone resorption may promote hypercalcemia, thereby increasing the risk of vascular calcification and ectopic soft-tissue mineral deposition[37]. Beyond its skeletal effects, PTH exerts direct actions on the cardiovascular system. Chronic PTH elevation has been implicated in left ventricular hypertrophy, endothelial dysfunction, and arterial stiffness, processes that collectively drive the excess cardiovascular morbidity and mortality observed in CKD[38].

Tertiary hyperparathyroidism (tHPT) is characterized by semiautonomous, excessive secretion of PTH that persists despite correction of the original stimuli for sHPT. The most common cause of tHPT is long-standing CKD in which persistent hypocalcemia, hyperphosphatemia and calcitriol deficiency chronically stimulate PTH synthesis and parathyroid cell proliferation. During CKD, chronic injury to the epithelial cells of the distal convoluted and collecting tubules leads to impaired synthesis of TRPV5 calcium channels, reducing calcium reabsorption. Consequently, tubular dysfunction contributes to hypocalcemia due to decreased renal calcium reabsorption and hyperphosphatemia due to reduced phosphate excretion[39]. Hyperphosphatemia acts as direct stimulant on parathyroid chief cells, promoting nodular hyperplasia of the glands[40]. Over time, these morphological changes become irreversible, and the parathyroid glands develop autonomous function, secreting PTH independently of serum calcium regulation. Clinically, the tHPT manifests with features of excessive bone resorption and systemic calcium deposition. Typical manifestations include osteitis fibrosa cystica, bone cyst formation, nephrolithiasis, nephrocalcinosis, recurrent flank pain, anorexia, nausea, vomiting, conjunctival and corneal (band) calcifications, and muscle weakness.

Laboratory findings commonly show markedly elevated PTH, alkaline phosphatase and serum calcium levels, often accompanied by elevated phosphate. According to KDIGO CKD-MBD guidelines, a bone biopsy is recommended in patients with CKD stage 3a-5 to establish the type of renal osteodystrophy and guide appropriate therapy[8,41].

Current KDIGO and KDOQI CKD-MBD guidelines recommend conservative management for patients with biochemical parameters within the following ranges: Serum calcium between 8.4-10.2 mg/dL, serum phosphate between 2.5-4.6 mg/dL and PTH levels between 130-600 pg/mL. The cornerstone of medical therapy is the use of calcimimetics agents such as Cinacalcet and Etelcalcetide, which suppress PTH secretion by increasing the sensitivity of the calcium-sensing receptor on parathyroid cells. For patients with advanced CKD (stage 3a-5) presenting with severe hyperparathyroidism, refractory hypercalcemia, significant osteopenia or symptomatic disease, surgical intervention (parathyroidectomy) is indicated[8]. Surgical strategies include: Subtotal parathyroidectomy with bilateral cervical thymectomy; total parathyroidectomy with autotransplantation of parathyroid tissue and bilateral cervical thymectomy; total parathyroidectomy without autotransplantation, with bilateral cervical thymectomy; total parathyroidectomy without autotransplantation and without thymectomy parathyroidectomy[42].

BONE HEALTH IN CKD (RENAL OSTEODYSTROPHY)

Renal osteodystrophy is the term used to describe the bone component of CKD-MBD, encompassing all skeletal abnormalities resulting from altered mineral metabolism in CKD. The gold standard for diagnosis of renal osteodystrophy is represented by bone biopsy[43]. According to the KDIGO guidelines[8], renal osteodystrophy can be categorized into four main patterns.

High-turnover bone disease

This form is primarily driven by uncontrolled sHPT. PTH binds to its receptors on bone tissue (osteoblasts and osteocytes), promoting the differentiation and activation of osteoclasts, which enhance bone resorption[44]. The result in an increase of bone reabsorption, leading to accelerated bone remodeling with consequently negative bone balance and cortical thinning[45]. Furthermore, the compensatory increase in osteoblastic activity causes excess osteoid production with abnormal deposition of unmineralized bone matrix, directly contributing to skeletal fragility and increased fracture risk[46].

Low-turnover or ABD

ABD represents the low-turnover extreme of renal osteodystrophy, in which both bone formation and resorption are markedly reduced. Previously, aluminum intoxication was the main cause, as it suppressed the activity of osteoblasts and osteoclasts, leading to defective mineralization[47]. Nowadays, ABD is more commonly associated with PTH over-suppression, generally resulting from the aggressive use of vitamin D analogues, calcimimetics, or calcium-based phosphate binders which excessively suppress PTH secretion. In addition, additional predisposing factors include diabetes, aging and malnutrition-inflammation complex[48]. ABD is strongly associated with increased fracture risk, bone pain, and skeletal fragility but it also represents an independent risk factor for mortality in CKD[49].

Osteomalacia

This is a condition characterized by the deposition of unmineralized osteoid which delays the onset of mineral deposition[50]. The most prominent mechanism is deficiency of active vitamin D [calcitriol, 1,25(OH)₂D₃] due to impaired renal 1α-hydroxylase (CYP27B1) activity[51]. Chronic metabolic acidosis represents another critical contributing factor to osteomalacia in CKD. Metabolic acidosis develops as CKD impairs the kidney’s ability to excrete acid, and it contributes to bone demineralization through multiple mechanisms including direct dissolution of bone, stimulation of osteoclast-mediated bone resorption, and inhibition of osteoblast-mediated bone formation[52]. The net result is accumulation of unmineralized or hypomineralized osteoid matrix characteristic of osteomalacia, which frequently coexists with features of high-turnover bone disease and ABD as part of the broader spectrum of CKD-MBD[53].

Mixed uremic osteodystrophy

This entity combines features of both high and low turnover bone disease, displaying areas of increased resorption and poorly mineralized osteoid.

It is often present in the transitions between high and low PTH states. The heterogeneous nature of mixed uremic osteodystrophy poses particular therapeutic challenges, as treatment strategies must be carefully individualized to avoid exacerbating either the high or low turnover components of the disorder[54].

CLINICAL IMPLICATIONS AND DIAGNOSTIC CHALLENGES

Bone alterations are frequent complication in patient with CKD, and this phenomenon is more pronounced in end stage renal disease contributing significantly to patient morbidity and mortality[55]. In clinical practice, determining whether bone fragility reflects CKD-MBD, age-related osteoporosis, or their interaction remains problematic, hindering optimal treatment selection. Bone biopsy remains a useful diagnostic tool for differentiating between these entities, enabling the clinician to adopt the most appropriate therapeutic approach and to minimize the complications associated with CKD-related bone disease. Early identification of high-risk patients through integrated assessment of BMD, biochemical markers, and clinical risk factors is essential for implementing timely preventive interventions. A multidisciplinary approach involving nephrologists, endocrinologists, and bone specialists is crucial for optimizing fracture prevention and improving long-term outcomes in this vulnerable population.

Given the complex and heterogeneous skeletal alterations described above, dedicated imaging modalities are essential for characterizing bone quality and fracture risk in CKD.

ADVANCED IMAGING MODALITIES FOR SKELETAL ASSESSMENT IN CKD

While biochemical markers provide valuable insights, their inability to assess bone microarchitecture and strength in CKD has catalyzed advances in skeletal imaging[1]. Advanced imaging techniques non-invasively assess bone density, microarchitecture, and mineralization, offering critical insights into skeletal integrity. Their high reproducibility enables reliable longitudinal monitoring, establishing imaging as an indispensable tool in contemporary bone disease management. Plain radiography maintains universal availability and cost-effectiveness, and yet lacks the required sensitivity for early detection of bone alterations such as mineral loss. Furthermore, as a subjective evaluation, its interpretation is heavily operator-dependent. Nonetheless, plain film X-ray is useful in identifying progressive osseous abnormalities characteristically observed in advanced sHPT with prolonged CKD duration, including subperiosteal bone resorption, skeletal sclerosis, brown tumor formation, and ectopic soft tissue mineralization[56,57]; it remains highly effective in its primary role: The precise and rapid detection of fractures in case of acute symptoms, traumatic injury, or clinical suspicion of skeletal disruption.

CKD patients with compromised bone integrity may exhibit distinctive radiographic signatures following predictable anatomical patterns: Middle phalanges commonly display subperiosteal resorption along their radial margins, whereas sites of major tendon attachment, including the greater trochanter and ischial tuberosities, demonstrate subtendinous resorption[58,59]. Calvarial changes produce the characteristic “salt and pepper” skull pattern, while brown tumors emerge as well-defined osteolytic lesions with scalloped margins, preferentially involving axial and appendicular long bones, ribs, and pelvic structures[60]. Osteomalacia is associated with stress fractures, also known as Looser zones, presenting as thin radiolucent lines coursing perpendicular through cortical bone, representing incomplete fractures or pseudofractures at sites of repetitive mechanical stress[60]. Beyond the skeleton itself, plain radiography readily demonstrates the systemic complications of disordered mineral metabolism: Cartilaginous calcification (chondrocalcinosis), massive periarticular calcium deposits (tumoral calcinosis), and arterial wall calcifications affecting both peripheral vessels and the cardiovascular system[61].

Dual-energy X-ray absorptiometry (DXA) technology revolutionized clinical bone density assessment; since its introduction it has maintained its position as the predominant modality for skeletal health evaluation. The fundamental principle involves differential attenuation of two X-ray energy beams, conventionally operating at 30-50 keV and 70 keV, which enables computational separation of bone from overlying soft tissues. Routine scanning encompasses the lumbar vertebrae (L1-L4), proximal femur (including neck and trochanter), and distal forearm, generating areal bone density measurements expressed as g/cm²[62]. Interpretation relies on population standardized scoring systems. For postmenopausal women and men exceeding 50 years, T-scores quantify deviations from young adult peak bone mass, with values below -2.5 defining osteoporosis. Z-scores provide age-matched, sex-matched, and ethnicity-adjusted comparisons, serving as the appropriate metric for premenopausal women, younger men, and pediatric populations[63]. The technique offers compelling practical advantages: Negligible radiation burden (1-5 μSv), universal accessibility, efficient scanning protocols, and favorable cost profile.

CKD populations present unique challenges that compromise DXA accuracy. The fundamental limitation stems from projectional two-dimensional imaging, which calculates density across an area rather than true volumetric measurement. This methodology renders DXA vulnerable to multiple confounding influences highly prevalent among CKD patients: Vertebral osteophytes and facet arthropathy, extensive calcification of the abdominal aorta and iliac vasculature, and various spinal deformities may superimpose upon measurement regions. These artifacts typically inflate apparent bone density, potentially concealing genuine skeletal deterioration and dangerously underestimating fracture susceptibility[63].

Trabecular bone score emerged as a complementary analytical approach, extracting textural information from standard lumbar spine DXA acquisitions. This computational method evaluates spatial variation in gray-level intensities, yielding an indirect microarchitectural index independent of bone density[64].

Clinical guidelines regarding DXA utilization in CKD have undergone substantial revision. Initial 2009 KDIGO recommendations discouraged routine densitometry in CKD stages G3a-5D based on limited fracture prediction evidence[65]. Progressive research prompted the landmark 2017 guideline update, which recognized DXA's capability to forecast both ongoing bone loss, particularly affecting cortical-rich sites like the distal radius[65], and fracture events throughout advanced CKD stages[7]. Contemporary recommendations endorse bone density evaluation in CKD G3a-5D patients exhibiting mineral-bone disorder features or elevated fracture risk, specifically when measurements will directly influence treatment selection. This evolution reflects growing recognition of DXA’s clinical value despite its limitations[66,67].

Three-dimensional computed tomography (CT) imaging overcomes critical planar radiography constraints by enabling true volumetric density quantification. Two distinct CT-based approaches have gained prominence: Quantitative CT (QCT) for central skeleton assessment and high-resolution peripheral QCT (HR-pQCT) for extremity evaluation.

Central QCT employs axial spine or hip scanning with simultaneous calibration phantom imaging, enabling authentic volumetric BMD measurement in mg/cm³ and independent cortical-trabecular compartment analysis. The capacity to selectively evaluate trabecular bone, which exhibits preferential involvement in CKD-associated skeletal deterioration, represents a major advantage. Additionally, three-dimensional spatial resolution eliminates density inflation from vascular calcifications, degenerative spinal changes, and structural deformities including scoliosis[68]. The primary limitation involves substantially elevated radiation exposure (60-1500 μSv per examination), which constrains widespread routine application[63,69].

HR-pQCT utilizes specialized peripheral scanners for high-resolution distal radius and tibia imaging with dramatically reduced radiation delivery (3-5 μSv per site). This technology visualizes bone microarchitecture with exceptional detail, quantifying trabecular parameters (thickness, number, spacing, connectivity) alongside cortical metrics (thickness, porosity, volumetric density)[70]. These microstructural indices, completely inaccessible through conventional imaging, demonstrate strong correlations with mechanical bone strength and fracture vulnerability.

Validation research has established robust relationships between HR-pQCT-derived measurements and fracture history in postmenopausal and elderly male populations[71,72]. Type 2 diabetes with renal involvement exemplifies this phenomenon: Progressive cortical microarchitectural degradation and porosity undermine bone strength independent of maintained areal BMD[73]. This observation suggests microarchitectural evaluation could identify vulnerable patients overlooked by standard densitometry[74]. Moreover, being a low-dose technique, HR-pQCT could be the ideal technique for monitoring effects of medications over time. Nevertheless, HR-pQCT remains predominantly confined to research environments due to limited equipment availability, significant capital costs, peripheral site restriction, and absence of established diagnostic criteria for CKD cohorts[75].

Similar to DXA, dual energy CT (DECT) bases its specific operating mechanism on volumetric assessment with two different energy X-ray beams.

Regardless of the specific technology employed by manufacturers to obtain dual-energy datasets, DECT enables a voxel by voxel material decomposition by analysing the spectrum of attenuation of matter at different energies, that is influenced by the atomic number of its component[76].

This allows DECT scanners not only to assess material attenuation based on density (measured in Hounsfield units) like conventional multidetector scanners but also to quantify BMD directly and without use of calibration phantoms.

This technique carries all the advantages of a volumetric evaluation with superior morphological assessment of trabecular bone compared to biplanar imaging offered by DEXA and the ability to perform it phantom-less allows this analysis to be integrated into each DECT acquisition, also retrospectively, without additional radiation exposure and in a streamlined manner[77].

Several studies have investigated the potential of this technique with promising results: In their study, Piscone et al[78] compared different DECT basic material decomposition pairs to DEXA as an alternative for BMD assessment on a cohort of 41 patients undergoing both DEXA and DECT for oncologic follow-up, with strong and significant association between BMD measurement (Spearman’s ρ = 0.797). Gruenewald et al[79] tested the potential of DECT to predict the 2-year occurrence risk for osteoporosis-associated fractures and obtained high diagnostic accuracy (85.45% sensitivity and 89.19% specificity) using a density cut-off of 93.70 mg/cm³, with a strong association between DECT derived BMD and the occurrence of new fractures. Similar results were obtained by Reschke et al[77] on a cohort of 111 patients when testing the predictive power of DECT-derived BMD in a 2-year interval with the highest sensitivity (83%) and specificity (95%) for the prediction of osteoporotic fractures using an BMD 92 mg/cm³ obtained with ROC curve analysis.

Additionally, the material decomposition algorithms of DECT enables a more comprehensive evaluation of vertebral bone through the bone marrow fat fraction assessment that find application to the evaluation of osteoporosis and other metabolic disorders[80].

While these findings are promising, they currently represent preliminary data requiring validation in larger cohorts. Although DECT is not yet as widespread as conventional CT - being primarily used in research and high-volume institutions due to higher costs - it is expected that newer generation DECT technology will progressively replace conventional scanners over the next decade.

Magnetic resonance imaging (MRI) represents a radiation-free alternative for bone architecture evaluation, though implementation has been hampered by demanding acquisition protocols, restricted availability, and technical difficulties arising from mineralized bone's extremely abbreviated T2 relaxation characteristics. Conventional MRI sequences cannot directly image cortical bone, which produces signal void on standard imaging.

Technological advances have expanded MRI’s bone assessment capabilities. Sophisticated sequences, water-fat chemical shift imaging, quantitative susceptibility mapping, and magnetic resonance spectroscopy, permit quantification of marrow fat composition, lipid fraction, and tissue water content. The breakthrough development of ultrashort echo time (UTE) and zero echo time sequences have proven particularly significant, capturing transient signals from mineralized matrix and enabling direct bone visualization[81].

UTE-MRI permits quantification of water molecules bound within bone tissue and residing in cortical pores. Comparative investigations have revealed elevated bone water in osteoporotic individuals secondary to diminished mineralization and increased structural porosity, with measurements demonstrating negative correlations against BMD from DXA and HR-pQCT[82]. These indices may indicate compromised mechanical integrity, especially at fracture-susceptible anatomical regions including the proximal femur. In vivo research has shown cortical porosity quantification via UTE-MRI can differentiate fragility fracture patients from control subjects[83].

Despite these technological advancements, the clinical translation of MRI for fragility assessment is hindered by long scan times, limited availability, lower spatial resolution compared to CT techniques, dependence on specialized sequences, and absence of standardized protocols or widely accepted diagnostic thresholds.

Quantitative ultrasound (QUS) offers an appealing radiation-free, portable, and economical option for fracture risk evaluation. The methodology exploits ultrasound wave propagation through cortical bone, quantifying speed of sound and broadband ultrasound attenuation. These measurements provide indirect assessments of bone density, elastic properties, and structural organization[84].

Research has documented associations between diminished ultrasound velocity and elevated fracture probability across general populations and hemodialysis cohorts with hyperparathyroidism[85]. Typical assessment sites encompass the calcaneus, tibia, and finger phalanges, with heel measurements achieving the most extensive validation and clinical acceptance[84].

Notwithstanding its benefits, QUS encounters significant obstacles limiting widespread clinical integration. Considerable measurement inconsistency exists between anatomical locations and across different equipment manufacturers, impeding standardization efforts. Diagnostic thresholds and fracture prediction models remain insufficiently validated within CKD populations[86]. Furthermore, confounding factors including soft tissue composition, fluid retention, and operator-dependent technique can influence accuracy. Restricted availability of validated commercial systems has predominantly confined QUS to investigational rather than routine clinical applications.

Molecular imaging delivers distinctive capabilities for visualizing and quantifying bone cellular activity at the metabolic level. The most commonly employed tracer for bone scintigraphy is 99mTc-labelled diphosphonate. Bone scintigraphy is able to detect radiotracer accumulation in metabolically active bone, facilitating early recognition of osteoblastic dysfunction in osteoporosis and metabolic skeletal disorders[87]. The selective binding of the metabolic tracer allows the bone scan to easily identify lesions like rib pseudo fractures, that, not surprisingly, often go unrecognized on standard radiologic imaging.

Among investigated radiopharmaceuticals, ¹⁸F-sodium fluoride (NaF) positron emission tomography/CT has demonstrated greatest promise for metabolic bone evaluation[88]. Fluoride incorporation into hydroxyapatite occurs at active mineralization sites, with uptake magnitude directly reflecting osteoblastic function and regional turnover rates with strong correlation both with bone density in Hounsfield units and with DXA[89]. NaF exhibits superior imaging characteristics compared to conventional bone scintigraphy agents, rapid blood clearance, excellent target-to-background ratios, and minimal protein binding, enabling high-quality metabolic imaging[90].

A pivotal investigation in glucocorticoid-induced osteoporosis demonstrated NaF-PET’s exceptional sensitivity, detecting metabolic changes within three months of bisphosphonate initiation, considerably preceding densitometric changes by DXA[1,91]. These findings suggest potential utility for early therapeutic monitoring and treatment response evaluation.

However, NaF-PET application in CKD requires careful consideration. Disturbed phosphate regulation, compromised renal fluoride clearance, and abnormal bone turnover patterns characteristic of CKD-MBD may unpredictably alter tracer pharmacokinetics and skeletal uptake. Prospective validation in CKD-specific populations remains essential before clinical adoption. Additionally, practical limitations including substantial costs, restricted PET infrastructure, dependence on cyclotron facilities for tracer synthesis, and considerable radiation exposure (approximately 4-5 mSv) currently confine NaF-PET to specialized research centers.

HISTOPATHOLOGIC DIAGNOSIS: THE GOLD STANDARD APPROACH

Biomarkers and imaging, though widely used for bone health assessment in CKD, have limited capacity to accurately subtype renal osteodystrophy. In cases of diagnostic uncertainty or conflicting non-invasive findings, transiliac bone biopsy with histomorphometric evaluation remains the reference standard. This procedure permits direct measurement of the three fundamental bone histomorphometry parameters: Turnover (reflecting cellular remodeling activity), mineralization (representing osteoid maturation efficiency), and volume (quantifying trabecular bone mass). These measurements prove essential for discriminating among renal osteodystrophy (ROD) variants: High-turnover osteitis fibrosa cystica, low-turnover ABD, mineralization-deficient osteomalacia, and mixed uremic osteodystrophy. Such discrimination becomes particularly critical when considering antiresorptive or anabolic interventions, as therapeutic appropriateness depends fundamentally on underlying turnover status[92].

Despite unmatched diagnostic precision, bone biopsy sees minimal contemporary utilization due to its invasive character, necessity for specialized technical expertise, patient tolerability concerns, and scarce availability of facilities with histomorphometric capabilities. Addressing this diagnostic void, the European Renal Osteodystrophy initiative launched in 2016 to reinvigorate bone biopsy practice and advance ROD investigation[93]. This collaborative program seeks to delineate epidemiology, clinical impact, and therapeutic reversibility of distinct ROD forms through systematic specimen collection and analysis. Through standardized methodology promotion and multicenter cooperation, the initiative endeavors to enhance ROD understanding and ultimately optimize patient outcomes through precision diagnosis and pathophysiology-guided treatment strategies.

LIFESTYLE AND BONE FRAGILITY IN CKD: AN INTEGRATED APPROACH

Before initiating pharmacological therapy, lifestyle and non-pharmacological interventions play a decisive role in preserving skeletal health in CKD patients. Structured physical activity and regular exercise programs have been shown to improve functional capacity, BMD, muscle strength, and overall quality of life in both dialysis and post-transplant populations[1,4]. Resistance training specifically improves BMD and bone turnover markers while simultaneously attenuating sarcopenia and protein-energy wasting. Optimal nutrition is equally critical. Adequate intake of calcium, vitamin D, and magnesium supports skeletal health, while their deficiency, compounded by the malnutrition prevalent in CKD, accelerates bone fragility and fracture risk. Hypomagnesemia, whether from inadequate dietary intake or medication-induced losses, exemplifies how metabolic derangements synergistically compromise bone integrity, emphasizing the need for comprehensive nutritional monitoring[6].

Other lifestyle factors play a role in the management of bone health in individuals with CKD. Tobacco use and excessive alcohol intake are well-established contributors to the deterioration of both osteoporosis and CKD outcomes, and their cessation is strongly recommended[4]. Fall prevention strategies are particularly critical in patients undergoing dialysis, who are frail and at high risk of injury. Evidence-based interventions including muscle strengthening, balance training, and physiotherapy have been demonstrated to significantly reduce fracture incidence[1,4,6]. Thus, the optimization of lifestyle behaviours constitutes the cornerstone of a comprehensive, multifaceted approach to managing bone fragility in CKD.

Vitamin D dysregulation across the spectrum of CKD represents a central pathophysiological disturbance and serves as a main driver for sHPT and the complex cascade of mineral metabolic derangements that characterize CKD-MBD. The therapeutic approach for correcting vitamin D deficiency has evolved into a stage-dependent strategy that recognizes the progressive impairment of renal vitamin D metabolism while also accounting for the potential adverse effects associated with more aggressive interventions[51,94,95]. Initial management focuses on restoring vitamin D sufficiency through nutritional supplementation with cholecalciferol or ergocalciferol. These agents are effective in elevating circulating 25-hydroxyvitamin D concentrations and attenuating PTH hypersecretion, thereby contributing to the re-establishment of mineral homeostasis and improvement of bone turnover, particularly during the earlier stages of renal functional decline, when endogenous calcitriol synthesis remains partially preserved[94,96].

However, as CKD advances and renal capacity for calcitriol synthesis declines, the efficacy of nutritional vitamin D supplementation alone is often inadequate. This necessitates the consideration of alternative therapeutic options capable of delivering bioactive vitamin D metabolites more effectively, while minimizing the risks associated with direct calcitriol administration.

Extended-release calcifediol has emerged as an effective therapeutic bridge, addressing this clinical challenge by providing sustained, dose-dependent restoration of 25-hydroxyvitamin D concentrations and producing clinically meaningful PTH suppression[95]. This therapeutic effect is attributed to improved tissue bioavailability of vitamin D metabolites without the pronounced risk of hypercalcemia and hyperphosphatemia commonly associated with active vitamin D analogues. This pharmacological innovation is particularly valuable for patients with CKD stages G3-G4 and sHPT in the context of vitamin D insufficiency, offering superior mineral metabolic control compared to nutritional vitamin D alone, while maintaining a substantially improved safety profile relative to calcitriol or its analogues[32,97].

Active vitamin D analogues, such as calcitriol and paricalcitol, represent the most intensive tier of vitamin D-based therapeutic intervention. These agents are reserved primarily for patients with severe, progressive sHPT that is refractory to nutritional measures, particularly in the context of advanced CKD or established dialysis dependence[32]. While these agents effectively suppress PTH through direct vitamin D receptor activation, their use demands careful monitoring. Enhanced intestinal mineral absorption can induce hypercalcemia and hyperphosphatemia, potentially accelerating vascular calcification. Moreover, excessive PTH suppression may precipitate ABD by over suppressing bone remodeling[97]. ABD, characterized by pathologically reduced bone turnover and paradoxically increased fracture susceptibility despite apparent biochemical control, is a particularly insidious complication that underscores the delicate balance required when using these potent agents[98].

Contemporary vitamin D management in CKD reflect a stratified therapeutic framework that emphasizes safety while maximizing efficacy. This hierarchy begins with nutritional supplementation as the foundational strategy, incorporates extended-release calcifediol as an intermediate option for patients requiring enhanced vitamin D metabolite availability, and reserves active vitamin D analogues for highly selected cases where the anticipated benefits of aggressive PTH suppression outweigh the inherent risks of mineral and bone complications[99,100].

Hyperphosphatemia constitutes a central pathological feature of CKD-MBD. The propensity for phosphate retention emerges early in CKD as glomerular filtration progressively declines. However, compensatory reductions in tubular phosphate reabsorption typically preserve normophosphatemia until the estimated glomerular filtration rate falls below approximately 25-40 mL/minute/1.73 m²[101]. When overt hyperphosphatemia develops, it triggers a cascade of metabolic disturbances, including stimulation of PTH secretion, increased FGF23 production, reduced calcitriol synthesis, and accelerated of vascular calcification, all of which contribute to bone fragility and cardiovascular morbidity[48]. The clinical rationale for treating hyperphosphatemia is strongly supported by observational data. In hemodialysis patients, higher serum phosphate concentrations and elevated calcium-phosphate product has been consistently associated with increased mortality risk[102]. In non-dialysis CKD, a meta-analysis encompassing nearly 5000 patients revealed a 35% higher risk of death for each 1 mg/dL rise in serum phosphate[4]. Similarly, a recent systematic review further corroborated these findings, demonstrating that both calcium-phosphate imbalance and hyperphosphatemia are independently associated with cardiovascular events and mortality[103].

Current clinical guidelines underscore the importance of rigorous biochemical surveillance. KDIGO recommends regular monitoring of serum phosphate, calcium, PTH, and vitamin D metabolites once estimated glomerular filtration rate falls below 60 mL/minutes/1.73 m², with increasing frequency as kidney function declines. The KDOQI guidelines provide more specific thresholds: In non-dialysis CKD, dietary modification is advised when serum phosphate is ≥ 4.5 mg/dL, while phosphate binder therapy is reserved for persistent elevations exceeding 5.5 mg/dL[7]. The 2020 KDOQI nutrition update reaffirmed these targets, emphasizing individualized management to avoid malnutrition[104]. Dietary phosphorus restriction remains the cornerstone of hyperphosphatemia management. Recommendations typically limit phosphorus intake to 800-1000 mg/day, focusing on reducing processed foods and additives, which contain highly absorbable inorganic phosphate[105]. Phosphorus derived from plant sources, primarily in the form of phytates, exhibits lower bioavailability due to the absence of intestinal phytase in humans, rendering plant-based diets advantageous for phosphate control[106]. Dietary counselling should therefore highlight the differential bioavailability of phosphorus from animal proteins, plant sources, and industrial additives to optimize patient adherence[107].

In dialysis-dependent patients, optimizing treatment adequacy is critical. Conventional hemodialysis removes approximately 900 mg of phosphorus per session, which is often insufficient to maintain target levels. More intensive dialysis modalities, such as nocturnal or daily regimens, can significantly enhance phosphorus clearance and may reduce reliance on phosphate binders, although their feasibility remains limited[108].

Phosphate binders are indicated when dietary restriction measures and dialysis optimization fail to achieve adequate control. Non-calcium-containing binders such as sevelamer, lanthanum, ferric citrate, and sucroferric oxyhydroxide are generally preferred. A Cochrane review of 11 randomized trials involving 4622 patients reported lower all-cause mortality with non-calcium binders compared with calcium-based binders[109]. A separate meta-analysis confirmed the superiority of sevelamer, demonstrating reduced mortality and improved lipid profiles, although study heterogeneity across was high[110].

Calcium-containing binders, including calcium carbonate and calcium acetate, remain widely used but carry important risks. In CKD, total calcium intake including dietary and binder-derived sources often exceeds 2000 mg/day when binders are included, leading to positive calcium balance. Controlled metabolic studies have demonstrated that a significant fraction of ingested calcium is deposited in soft tissues rather than bone, thereby promoting vascular calcification[111]. For this reason, both KDIGO and KDOQI recommend limiting calcium-based binders and favouring non-calcium options whenever feasible[94,104].

Emerging therapies offer promising new avenues for phosphate control. Tenapanor, a selective inhibitor of the intestinal sodium/hydrogen exchanger 3, has demonstrated significant efficacy in phase 3 randomized trials, reducing serum phosphate by approximately 1.7-1.8 mg/dL in hemodialysis patient’s refractory to conventional therapy. However, diarrhoea remains a common adverse effect[102]. Despite these therapeutic advances, no randomized controlled trial has conclusively demonstrated that phosphate reduction directly improves survival outcomes. Nevertheless, the compelling pathophysiological rationale and consistent epidemiological evidence strongly support aggressive phosphate control as a central element of CKD-MBD management[112].

In summary, the management of hyperphosphatemia remains a cornerstone of CKD-MBD care, aimed at mitigating vascular calcification and preserving bone integrity. Treatment requires an individualized, stepwise approach, beginning with dietary modification, ensuring dialysis adequacy, and escalating to pharmacologic intervention with a preference for non-calcium binders. Although definitive randomized evidence linking phosphate reduction to improved survival is lacking, the cumulative body of evidence strongly supports proactive phosphate management as a critical component of nephrology practice.

sHPT is a major complication of CKD-MBD, arising from the synergistic effects of phosphate retention, decreased calcitriol synthesis, hypocalcemia, and parathyroid hyperplasia[8,113]. Persistent elevations of PTH promote high-turnover bone disease, increased skeletal fragility, and ectopic calcification, thereby exacerbating cardiovascular morbidity and mortality[30,114]. Epidemiological evidence consistently demonstrates a strong association between elevated PTH levels and increased risks of fracture and mortality, underscoring the need for proactive and targeted therapeutic intervention[115,116].

Calcimimetics act as positive allosteric modulators of the calcium-sensing receptor, which is predominantly expressed on parathyroid chief cells[117,118]. By increasing the receptor’s sensitivity to extracellular calcium, these agents suppress PTH synthesis and secretion, leading to reductions in serum calcium and phosphate. This pharmacological profile makes them particularly attractive in CKD, as they avoid the hypercalcemia and hyperphosphatemia commonly observed with vitamin D analogs[119]. Experimental data also suggest pleiotropic benefits, including improvements in bone histomorphometry and attenuation of vascular calcification[120,121].

Cinacalcet was the first calcimimetic approved for the treatment of sHPT in dialysis patients. Randomized controlled trials demonstrated significant reductions in PTH, serum calcium, and phosphate levels, along with a decreased need for parathyroidectomy[122]. Observational data from the Dialysis Outcomes and Practice Patterns Study registry further indicated lower mortality and fracture risk among elderly dialysis patients treated with cinacalcet[123]. The Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial, which enrolled over 3800 hemodialysis patients, did not meet its primary composite endpoint of reducing mortality and cardiovascular events in the intention-to-treat analysis, largely due to high dropout and crossover rates. However, subgroup analyses, particularly among patients aged ≥ 65 years, revealed consistent benefits in reducing cardiovascular events, fractures, and overall mortality[123]. Bone substudy findings also indicated improved skeletal outcomes, such as reduced fracture incidence and favourable changes in bone turnover markers[11].

Despite its efficacy, cinacalcet is associated with notable adverse effects, particularly hypocalcemia and gastrointestinal intolerance (e.g., nausea, vomiting), which may impair long-term adherence[117].

Etelcalcetide, a second-generation intravenous calcimimetic, offers an alternative administration route by being delivered post-dialysis, thereby improving adherence. Randomized clinical trials demonstrated that etelcalcetide was significantly more effective than placebo and non-inferior, or in some analyses superior to cinacalcet in achieving ≥ 30% reductions in PTH[124]. The average magnitude of PTH reduction with etelcalcetide averaged 50%-60% compared with baseline, compared with approximately 40% for cinacalcet[124]. Although hypocalcemia was more frequent, it was generally manageable through adjustments in vitamin D analogue therapy. Preliminary imaging and histological data also suggest improvements in trabecular BMD and microarchitecture at the lumbar spine and hip, which may translate into reduced skeletal fragility[94].

Beyond CKD-MBD, calcimimetics are also approved for the management of hypercalcemia associated with parathyroid carcinoma and for selected cases of primary hyperparathyroidism when surgery is contraindicated[94,117]. Off-label applications, including familial hypocalciuric hypercalcemia, have been reported in small case series, showing promising biochemical responses but insufficient evidence for routine use[94].

Traditional management of sHPT has relied on phosphate control, vitamin D analogs, and parathyroidectomy for refractory cases. Compared with vitamin D analogues, calcimimetics uniquely suppress PTH without increasing calcium-phosphate product. Compared with surgery, they offer an effective pharmacological option that can delay or reduce the need for parathyroidectomy, although not eliminate it entirely. Combination therapy with calcimimetics and vitamin D analogues is frequently employed to achieve optimal balance between PTH suppression and calcium-phosphate homeostasis[8,94,115].

According to KDIGO 2017 guidelines, calcimimetics are recommended, together with vitamin D analogues and phosphate binders, for dialysis patients with severe or refractory sHPT[8]. The KDOQI guidelines further emphasize individualized therapy, advocating calcimimetics use when hypercalcemia or hyperphosphatemia limit the administration of vitamin D agents[115]. Although definitive evidence of a survival benefit remains elusive, the consistent ability of calcimimetics to control PTH, reduce parathyroidectomy rates, and potentially mitigate fractures and vascular calcification supports their role as a cornerstone of advanced CKD-MBD management.

While calcimimetics represent a major advancement in sHPT management, their limitations - cost, adherence challenges, and adverse effects - must be acknowledged. In clinical practice, calcimimetics remain indispensable, particularly for patients with persistent sHPT, hypercalcemia, or contraindications to high-dose vitamin D analogues.

NEW FRONTIERS

Despite major advances in the characterization of CKD-MBD, several aspects remain uncertain. Current biochemical markers provide only partial insight into bone turnover: Diagnostic limitations are substantial: PTH shows high variability and poor histomorphometric correlation; FGF23 and klotho lack standardized assays and clinical cutoffs; DXA is confounded by vascular calcification; and bone biopsy, though definitive, is rarely performed. Therapeutic uncertainties parallel these diagnostic challenges: Fracture outcome data for specific interventions are limited, while optimal vitamin D analogue strategies, clinical significance of FGF23 reduction, and management of underdiagnosed low-turnover disease remain controversial. These gaps underscore the need for more refined biomarkers, better risk stratification tools, and studies that integrate biochemical, imaging, and histologic findings into cohesive clinical algorithms.

Pharmacological strategies for addressing bone fragility in CKD have expanded considerably in recent years, introducing both antiresorptive and anabolic treatment options.

Bisphosphonates remain first-line antiresorptive drug in the general population; however, their predominant renal elimination limits their use in advanced CKD. Although bisphosphonates can improve BMD and reduce vertebral fracture risk in patients with CKD stages 3-4, drug accumulation in dialysis raises concerns regarding the development of ABD[125].

Denosumab, a monoclonal antibody targeting receptor activator of nuclear factor kB ligand (receptor activator of nuclear factor κB ligand), is not renally cleared and can therefore be used in patients with advanced CKD and those on dialysis. Clinical trials have demonstrated significant improvements in BMD and reductions in both vertebral and non-vertebral fractures[126,127]. However, denosumab is associated with a substantial risk of post-dose hypocalcemia, particularly in dialysis patients, necessitating strict calcium and vitamin D monitoring[128].

Raloxifene, a selective estrogen receptor modulator, has shown potential in reducing vertebral fractures, although its effects on BMD remain less consistent[4].

Anabolic therapies are particularly promising in the low-turnover bone states frequently observed in advanced CKD. Teriparatide and abaloparatide stimulate osteoblast activity, increase BMD, and enhance bone formation markers. Although currently off-label for use in CKD, these therapies may offer benefit in carefully selected patients[129,130]. Romosozumab, a monoclonal antibody that inhibits sclerostin, further expands the therapeutic landscape, though clinical data in CKD population remain limited[48].

In kidney transplant recipients, long-term exposure to glucocorticoids and calcineurin inhibitors accelerates bone loss and increases fracture risk. Bone-protective strategies, including vitamin D repletion, bisphosphonate use in selected cases, and tailored physical activity regimens, are therefore essential components of post-transplant management[4,131,132].

Beyond pharmacological therapy, advances in laboratory diagnostics are reshaping the assessment and monitoring of bone health in CKD. Current PTH assays lack standardization, vitamin D immunoassays suffer from cross-reactivity, and FGF23 measurement remains largely confined to research settings. Liquid chromatography-mass spectrometry is emerging as the gold standard for vitamin D quantification, while bone turnover markers such as bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b show strong correlations with bone histomorphometry and may be integrated into routine clinical practice[133].

Pharmacovigilance remains essential within this delicate metabolic context. A recent case report described severe hypercalcemia in a stage 3 CKD patient receiving hydrochlorothiazide who initiated tirzepatide therapy, highlighting the vulnerability of the bone-kidney axis in the setting of polypharmacy and emerging treatments[134].

As we look toward the future of CKD-MBD management, it remains essential to learn from past challenges and refine our diagnostic precision, particularly in distinguishing CKD-related bone disease from age-related osteoporosis, a distinction that will become increasingly important in an aging population.

CKD-MBD, although distinct from age-related osteoporosis, shares some overlapping clinical features while arising from fundamentally different pathophysiological mechanisms. CKD-MBD encompasses a spectrum of bone abnormalities, collectively termed renal osteodystrophy, including high-turnover bone disease (e.g., osteitis fibrosa due to sHPT), low-turnover disease (ABD), and mixed forms. These are driven by disturbances in mineral metabolism (calcium, phosphate, PTH, vitamin D, FGF23) and are often accompanied by vascular calcification. CKD-MBD can manifest early in CKD progression, and bone fragility in CKD is not solely explained by BMD but also by compromised bone quality, including microarchitecture and mineralization defects[135-137].

Age-related osteoporosis is characterized by an imbalance favoring bone resorption over formation, primarily due to estrogen deficiency, cellular senescence, and intrinsic aging processes. It typically presents as low BMD and microarchitectural deterioration, leading to increased fracture risk in older adults. The pathogenesis is multifactorial, involving hormonal changes, increased oxidative stress, and impaired osteoblast function[138-140].

Diagnostic approaches differ: In osteoporosis, BMD assessment by DXA is central, while in CKD, BMD may underestimate fracture risk due to additional bone quality deficits. Bone biopsy is the gold standard for distinguishing renal osteodystrophy subtypes but is rarely performed; non-invasive methods (e.g., trabecular bone score, high-resolution imaging) are increasingly used[140-141].

Therapeutic strategies diverge: Osteoporosis is managed with antiresorptive and anabolic agents, lifestyle modification, and calcium/vitamin D supplementation. In CKD-MBD, treatment targets underlying mineral disturbances (e.g., phosphate binders, vitamin D analogs, calcimimetics), and anti-osteoporotic drugs are used cautiously, especially in advanced CKD, due to concerns about ABD and lack of robust efficacy/safety data[142].

In summary, CKD-related bone disease is a complex, multifactorial disorder involving both bone quantity and quality, distinct from the primarily age-driven pathogenesis of osteoporosis, though both increase fracture risk and share overlapping clinical features.

CONCLUSION

The management of bone fragility in CKD extends far beyond the correction of PTH or calcium levels. It requires an integrated, patient-centered approach encompassing lifestyle modifications, correction of vitamin deficiencies, phosphate control, and the judicious use of calcimimetics. The addition of antiresorptive or anabolic agents, and targeted post-transplant interventions further enriches the therapeutic arsenal, although their application must be carefully tailored to CKD stage and underlying bone turnover status.

Ongoing advancements in diagnostic technologies and biomarker development promise more precise evaluation of bone quality and turnover, while sustained pharmacovigilance will be crucial as novel agents enter nephrology practice. Ultimately, the kidney-bone axis should be regarded not merely as a secondary concern, but as a central determinant of systemic health. Its disruption contributes to fractures, vascular calcification, cardiovascular events, and reduced survival. Protecting this axis means preserving not only skeletal integrity but also quality of life and longevity for patients living with CKD.