Evaluation of renal osteodystrophy

INTRODUCTION — Renal osteodystrophy collectively constitutes a group of abnormalities in bone morphology or histology that are an important component of mineral bone disorders among patients with chronic kidney disease (CKD-MBD). The bone abnormalities resulting from loss of kidney function render patients with CKD vulnerable to fractures.

This topic reviews the evaluation of renal osteodystrophy with noninvasive tests and with a bone biopsy, when indicated.

Other related topics are discussed in detail elsewhere:

●An overview of CKD-MBD (see "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)")

●Treatment of secondary hyperparathyroidism (see "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis")

●CKD and osteoporosis (see "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation" and "Osteoporosis in patients with chronic kidney disease: Management")

●Bone disease after kidney transplantation (see "Kidney transplantation in adults: Bone disease after kidney transplantation")

OVERVIEW OF NORMAL BONE — Bone is a dynamic tissue that is constantly undergoing remodeling in response to changes in hormones and environmental factors. Osteocytes, embedded in bone, are the master regulators of bone and mineral homeostasis. Also present in the bone are osteoclasts, which resorb bone, and osteoblasts, which generate a mineralizable extracellular matrix (ie, osteoid) to replace resorbed bone.

The purpose of obtaining a bone biopsy is to determine the underlying bone pathology and its cause. Quantitative bone histomorphometry performed on bone biopsies provides an assessment of osteoblast-mediated bone formation and mineralization of extracellular matrix, the degree of osteoclast-mediated bone resorption, structure of trabecular and cortical bone, toxic metal accumulation, and the condition of the bone marrow space. With bone histomorphometry using the Goldner-Masson (trichrome) stain under light microscopy, normal bone osteoid appears red-brown and mineralized bone appears blue (picture 1). Under fluorescent light, the osteoid appears orange and the mineralized bone appears green. The luminescent tetracycline bands represent the formation of active mineralized bone beneath the osteoid surface.

The osteoid is lamellar, present on a modest amount of the bone surface (<25 percent), and covered with mature osteoblasts (approximately 40 percent). Bone resorption is minimal (<7 percent), and osteoclasts are present on a small percentage of the bone surface (<2 percent).

SUBTYPES OF RENAL OSTEODYSTROPHY — Renal osteodystrophy refers to specific changes in bone histology associated with chronic kidney disease (CKD) [1,2]. It is an important component of chronic kidney disease-mineral and bone disorder (CKD-MBD). (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Introduction and definitions'.)

Traditionally, four main subtypes of renal osteodystrophy are recognized: osteitis fibrosa cystica, adynamic bone disease, osteomalacia, and mixed uremic osteodystrophy. These subtypes represent changes in bone turnover (or remodeling), mineralization, and volume, which comprise the more recent TMV classification (see 'TMV classification' below). The pathologic features of these four subtypes are presented below.

Osteitis fibrosa cystica — Osteitis fibrosa cystica (OFC) is functionally characterized by high bone turnover (ie, high bone formation and resorption), typically caused by elevated circulating parathyroid hormone (PTH) levels.

There is a marked increase in the number and activity of osteoblasts and osteoclasts and an increase in woven osteoid and marrow fibrosis (picture 2). The woven osteoid represents disordered collagen that contrasts with the parallel collagen strands observed in normal bone. Distinct tetracycline labels cover the majority of bone surfaces, indicating accelerated bone formation and the absence of a mineralization defect. The decrease in mineralization is believed to be relative to the marked increase in bone turnover.

Adynamic bone disease — Adynamic bone disease (ABD) is characterized by low bone turnover (ie, low bone formation and resorption) due to reductions in both osteoblast and osteoclast activity [3,4]. Low bone turnover is usually due to excessive suppression of the parathyroid glands by medication (eg, calcitriol or calcium-containing phosphate binders) or parathyroidectomy, but resistance to the bone stimulatory effects of PTH may contribute [5,6]. Low turnover is observed in a substantial subset of patients following successful kidney transplantation.

These defects are manifested histologically by thin osteoid seams that display no active mineralization, inactive-appearing osteoblasts, and fewer osteoclasts and bone resorptive surfaces (picture 3). (See "Adynamic bone disease associated with chronic kidney disease".)

Osteomalacia — Osteomalacia (OM) is characterized by reduced mineralization with increased unmineralized osteoid in conjunction with a prolonged mineralization lag time [7,8]. OM can be associated with either low or high bone turnover. Among patients with end-stage kidney disease (ESKD), low-turnover OM was previously attributed to aluminum deposition in bone. With the elimination of aluminium-based phosphate binders and introduction of stringent guidelines to minimize aluminum in dialysate water, OM has become uncommon in patients with ESKD [9-12]. However, other factors that impair mineralization, such as vitamin D deficiency and hypocalcemia (both typically associated with elevated PTH and high bone turnover), as well as hypophosphatemia, metabolic acidosis, and exposure to heavy metals, can also cause OM.

Histologically, OM is characterized by a marked increase in the volume of osteoid, an increase in the fraction of wide osteoid seams (picture 4), and delayed mineralization of bone protein. Examination under fluorescent light reveals little or no tetracycline deposition, suggesting low mineralization of bone. Aluminum can be detected histologically by staining a Villanueva-prestained section with aurintricarboxylic acid (picture 5). (See "Aluminum toxicity in chronic kidney disease", section on 'Sources of aluminum'.)

Mixed uremic osteodystrophy — Mixed uremic osteodystrophy (MUO) is a disorder with combined features of OFC and OM. The disease is characterized by high bone turnover and abnormal mineralization as seen with osteomalacia. As in OFC, the high bone turnover of MUO is mediated by increases in both osteoblast and osteoclast activity. A precise etiology and clinical correlate to MUO are not known. However, because MUO has features of both OFC and OM, elevated PTH, and/or factors contributing to impaired mineralization, such as vitamin D deficiency, hypocalcemia, hypophosphatemia, metabolic acidosis, and exposure to heavy metals could potentially result in MUO.

MUO resembles OFC on light microscopy, except that there is a greater degree of osteoid accumulation, similar to that seen in OM (picture 6). Fluorescent microscopy shows impaired mineralization, as evidenced by diffuse tetracycline deposition and the absence of tetracycline in some bone-forming surfaces. There is also a prolonged mineralization lag time, which is the histologic hallmark of OM.

TMV classification — As an alternative to the traditional renal osteodystrophy subtype diagnostic classification, the turnover, mineralization, and volume (TMV) classification system was developed by the 2006 National Kidney Foundation working group on renal osteodystrophy to help clarify the interpretation of the bone biopsy and inform treatment decisions [1]. The TMV system employs three key histologic descriptors [1]:

●Turnover, which may be low, normal, or high

●Mineralization, which may be normal or abnormal

●Volume, which may be low, normal, or high

This classification is largely descriptive but provides less information than contained in the traditional histologic classifications described above. As an example, the TMV classification in OFC will differ for trabecular and cortical bone; where the TMV will be high turnover, accelerated mineralization, and high bone volume in trabecular bone, in cortical bone it will be high remodeling of the haversian system, increased endosteal mineralization rates, and lower cortical bone density due to increased cortical porosity. In the TMV classification for MUO, the mineralization rate as measured by tetracycline labeling would be impaired. The TMV system does not include quantification of the degree of peritrabecular fibrosis. OM in the TMV system would be coded as T, either high or low depending on the etiology, M would be impaired or decreased, and V would be variable depending on whether mineralized bone volume or total bone volume is being reported. For ABD, T is invariably low, M is low to absent (ie, very little presence of tetracycline labeling of bone surfaces), and V of trabecular bone is low, consistent with osteopenia.

In addition, the TMV system does not provide information about the cause of the bone disease or the risk of fracture. The report must be interpreted in the context of the patient, their medications, and their biochemical profile. As an example, a patient with OM might have abnormalities in serum phosphorus that need to be aggressively managed, may have vitamin D deficiency, or may need to be assessed for overexposure to heavy metals or iron. The term bone volume does not distinguish between trabecular bone loss from increased cortical porosity.

CLINICAL FEATURES — Patients with renal osteodystrophy frequently are asymptomatic until they develop a fracture although some patients may develop bone pain, tendon rupture, muscle weakness, and, in growing children, growth retardation and skeletal deformities. There are no clinical features that clearly distinguish the various types of renal osteodystrophy, although patellar tendon rupture and leontiasis ossea point to secondary hyperparathyroidism.

Characteristic radiographic findings of osteitis fibrosa cystica include subperiosteal resorption and new bone formation, particularly at the radial aspect of the middle phalanges. Resorptive loss of bone may be also observed at the terminal phalanges, distal ends of the clavicles, and in the skull [13]. However, no skeletal imaging method can differentiate among renal osteodystrophy subtypes. Routine imaging with dual x-ray absorptiometry (DXA) to evaluate for renal osteodystrophy is not commonly performed but may be useful in identifying clinically important osteoporosis and fracture risk. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation".)

Noninvasive bone turnover markers (such as intact parathyroid hormone [iPTH], bone-specific alkaline phosphatase [BSAP], intact procollagen type I N-terminal propeptide [PINP], and tartrate-resistant acid phosphatase isoform 5b [TRAP5b]), when used in combination, have improved accuracy in distinguishing high and low turnover bone disease in chronic kidney disease [14].

The gold standard diagnostic method for identifying the type of renal osteodystrophy is tetracycline double-labeled iliac crest bone biopsy. (See 'Initial noninvasive testing for all patients' below and 'Bone biopsy for selected patients' below.)

EVALUATION

When to suspect renal osteodystrophy — Renal osteodystrophy should be suspected in all patients with advanced (ie, stages 3 to 5) chronic kidney disease (CKD). The prevalence of renal osteodystrophy increases as CKD stage and its associated metabolic derangements worsen [15,16]. Thus, by the time patients reach end-stage kidney disease (ESKD), most will have some form of metabolic bone disease [15].

Initial noninvasive testing for all patients — The evaluation and diagnosis of renal osteodystrophy are important for identifying and properly managing bone disease among patients with CKD, who have a significantly higher fracture risk compared with age- and sex-matched individuals without CKD [17-25]. In patients with CKD, it is also important to distinguish renal osteodystrophy from osteoporosis, as management of these conditions is different. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Fracture risk in chronic kidney disease'.)

A definitive diagnosis of renal osteodystrophy and the identification of histologic subtype are established by bone biopsy [1,26]. However, bone biopsies are rarely performed because there is insufficient expertise in their performance and interpretation at most academic centers [27].

For most patients, we and most other clinicians use serum intact parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BSAP) levels as surrogate markers to distinguish among various types of renal osteodystrophy. However, these markers have limited sensitivity and specificity to correctly classify bone disease in an individual patient with CKD [28,29]. Some authors also use serum C-telopeptide of type I collagen (CTX) levels, which have also been shown to correlate well with bone turnover [16]. We do not routinely obtain bone imaging studies (eg, radiography, dual-energy x-ray absorptiometry [DXA]), as these tests do not reliably distinguish among the various types of renal bone lesions, although they may help identify the overall severity of the metabolic bone disorder. This approach is consistent with the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines [2]. (See "Bone physiology and biochemical markers of bone turnover".)

We use multiple values of PTH and bone turnover markers (BSAP and CTX) and trends over time rather than a single measurement since bone remodelling takes three or more months to achieve a steady state after changes in PTH. Serial measurements, however, have not been shown to improve accuracy. There is no uniform agreement about how frequently these biomarkers should be monitored. We generally monitor laboratory values with a schedule that is largely consistent with the KDIGO Clinical Practice Guidelines [2]:

●Intact PTH – As there is marked variability in different PTH assays, the same assay should be used for repeat measurements [2].

•Stage G3 – Measurements are based upon the baseline level and CKD progression

•Stage G4 – Measurements at least every 6 to 12 months

•Stage G5 – Measurements at least every 3 to 6 months

●BSAP – This is measured for patients with CKD stages G4 and G5 every 12 months, or more frequently when PTH is elevated.

●CTX – If used, this is measured for patients with CKD stages G4 and G5 once at baseline and then every 12 months.

If therapy is initiated to correct serum abnormalities or to treat renal osteodystrophy, the guidelines recommend that laboratory evaluation should be performed more frequently to ensure a response to therapy or to identify the need to adjust therapy [2]:

We use the following values for intact PTH, BSAP, and CTX to define the risk for specific subtypes of renal osteodystrophy. PTH, which measures parathyroid gland function and therefore the severity of secondary hyperparathyroidism, is an indirect marker of bone turnover that correlates with bone turnover markers. BSA, which is produced by osteoblasts, is a marker of osteoblastic activity. CTX is used as a marker of osteoclastic activity. The value of individual biochemical measurements in predicting bone histologic changes is relatively low, but values that are markedly elevated and/or that are progressively increasing with time are used in the diagnosis and treatment of bone disease in patients with CKD, as described below [29-33]:

●Among patients on dialysis, a persistently low intact PTH (ie, <100 pg/mL) suggests the diagnosis of adynamic bone disease (ABD) and a decreased risk of osteitis fibrosa cystica (OFC) and/or mixed uremic osteodystrophy (MUO).

●Among patients not on dialysis, an intact PTH that is persistently <100 pg/mL may not reflect ABD, especially if serum calcium and phosphorus concentrations are within the normal range. Among such patients, ABD is suggested by a PTH concentration that was initially high and progressively decreases to less than the upper limit of normal for the PTH assay (generally 65 pg/mL) in the setting of treatment with active vitamin D analogs.

●Among patients on or not on dialysis, intact PTH levels >450 pg/mL suggest the diagnosis of OFC and/or MUO. Patients with intact PTH levels >500 pg/mL are unlikely to have ABD [34].

●Among patients on or not on dialysis, intermediate intact PTH levels between 100 and 450 pg/mL are not useful to predict the type of renal osteodystrophy. Intermediate values may be associated with normal, high, or low turnover. In patients who have intermediate intact PTH concentrations and either symptoms of bone pain or unexplained hypercalcemia or hypophosphatemia, we assess the serum BSAP level. A high BSAP level (≥20 ng/mL) virtually excludes the diagnosis of ABD, particularly if the PTH is >200 pg/mL [35], and suggests OFC or osteomalacia (OM); very high BSAP levels may suggest a diagnosis of OM [15]. By contrast, a low or borderline BSAP with a low serum PTH is consistent with, but does not establish, a diagnosis of ABD.

Bone biopsy for selected patients — A bone biopsy, performed after tetracycline labeling, is the gold standard for assessing the bone remodeling, mineralization, and structure. However, due to limited availability of expertise for the performance of bone biopsies and interpretation of histomorphometry, these are reserved for a selected group of patients.

Indications — Controversy exists over the exact indications for bone biopsy. We agree with the KDIGO 2017 guidelines that a bone biopsy is indicated if knowledge of the type of renal osteodystrophy will affect treatment decisions [28].

Clinical scenarios in which results from a bone biopsy may impact treatment decisions include the following:

●Patients with unexplained bone pain or fractures (ie, with minimal or no trauma).

●Patients with unexplained, refractory hypercalcemia, to rule out the presence of multiple myeloma or granulomatous diseases, such as sarcoidosis, tuberculosis, or coccidiomycosis. This is generally a rare indication for a bone biopsy, and a bone marrow biopsy may be performed as an alternative. (See "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia" and "Hypercalcemia in granulomatous diseases" and "Hypercalcemia of malignancy: Mechanisms".)

●Patients with suspicion of osteomalacia, based upon a history of aluminum exposure or other risk factors (eg, vitamin D deficiency, hypocalcemia, hypophosphatemia, metabolic acidosis). (See "Aluminum toxicity in chronic kidney disease".)

●Patients who have an atypical response to standard therapies for elevated PTH, to rule out atypical or unexpected bone pathology. As an example, in a patient who develops fractures after treatment, we would consider a bone biopsy to clarify whether ABD or OM is present.

●Patients with ESKD who are planning to undergo parathyroidectomy because of bone-related symptoms (eg, bone pain and/or fractures) but who have an indeterminate PTH level (ie, <800 pg/mL). The reason for the biopsy is to confirm the presence of PTH-mediated, high-turnover bone disease (provided that a confirmed diagnosis would alter treatment decisions). (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis", section on 'Symptomatic patients'.)

●Patients with bone pain and persistent serum intact PTH levels <100 pg/mL despite withdrawal of calcitriol or other vitamin D analogs, to confirm the diagnosis of adynamic bone disease. (See "Adynamic bone disease associated with chronic kidney disease", section on 'Clinical features'.)

●Patients in whom an inconsistency in biochemical parameters precludes a definitive interpretation (eg, levels of serum intact PTH are high, but BSAP levels are low).

We do not routinely perform a bone biopsy in patients who are going to receive bisphosphonate therapy, unless a diagnosis of low-turnover or adynamic bone disease cannot be excluded with noninvasive testing. The use of bisphosphonates in patients with CKD is discussed elsewhere. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Antiresorptive agents'.)

Procedure — Bone biopsy is typically obtained from the iliac crest after the administration of two different time-spaced tetracycline markers [36]. The tetracycline markers bind to hydroxyapatite and emit fluorescence, which allows identification of bone. The rate of bone formation is determined by identifying the new bone formed in the time interval between the administration of different tetracycline labels.

A typical labeling schedule requires two three-day periods of tetracycline labeling, separated by 21 days. The second labeling period must be completed two days before the biopsy. As an example, we typically administer tetracycline 250 mg three times daily on days 23 to 25 before biopsy, followed by demeclocycline 300 mg three times daily on days 2 to 4 before biopsy.

Our preferred approach is to obtain a transcortical sample with an 8 mm trocar. However, emerging data suggest that a small 3.5 mm core obtained with a Jamshidi bone biopsy trephine likely provides equivalent information on dynamic and mineralization parameters [37]. The biopsy procedure can be performed under local anesthesia although moderate sedation is recommended to maximize patient comfort. Standard precautions for bleeding risk should be followed, and preoperative antibiotics are typically provided only to patients with a dialysis access or who are receiving immunosuppressive medications.

The bone specimen is stained with Goldner-Masson trichrome for differentiation of mineralized lamellar bone and nonmineralized osteoid and Villanueva stain for tetracycline fluorescence. At the discretion of the pathologist, in consultation with the referring clinician, the sample may also be stained for aluminum (using aurintricarboxylic acid), depending on indications or history or on other observed histologic features. As an example, staining for aluminum may be performed in a patient with a significant clinical history of aluminum exposure or if prominent findings of osteomalacia are observed by the pathologist.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease-mineral and bone disorder".)

SUMMARY AND RECOMMENDATIONS

●Overview – Renal osteodystrophy collectively constitutes a group of abnormalities in bone morphology or histology that are an important component of mineral bone disorders among patients with chronic kidney disease (CKD-MBD). The bone abnormalities resulting from loss of kidney function render patients with CKD vulnerable to fractures.

●Subtypes of renal osteodystrophy – Traditionally, four main subtypes of renal osteodystrophy are recognized:

•Osteitis fibrosa cystica – Osteitis fibrosa cystica (OFC) is functionally characterized by high bone turnover (ie, high bone formation and resorption), typically caused by elevated circulating parathyroid hormone (PTH) levels. (See 'Osteitis fibrosa cystica' above.)

•Adynamic bone disease – Adynamic bone disease (ABD) is characterized by low bone turnover (ie, low bone formation and resorption) due to reductions in both osteoblast and osteoclast activity (picture 3). (See 'Adynamic bone disease' above.)

•Osteomalacia – Osteomalacia (OM) is characterized by reduced mineralization with increased unmineralized osteoid in conjunction with a prolonged mineralization lag time (picture 4). OM can be associated with either low or high bone turnover. (See 'Osteomalacia' above.)

•Mixed uremic osteodystrophy – Mixed uremic osteodystrophy (MUO) is a disorder with combined features of OFC and OM. The disease is characterized by high bone turnover and abnormal mineralization as seen with osteomalacia. (See 'Mixed uremic osteodystrophy' above.)

●TMV classification – The turnover, mineralization, and volume (TMV) system classifies renal osteodystrophy based on bone turnover, mineralization, and volume as assessed by bone biopsy and histomorphometry. (See 'TMV classification' above.)

●Clinical features – Patients with renal osteodystrophy frequently are asymptomatic until they develop a fracture although some patients may develop bone pain, tendon rupture, muscle weakness, and, in growing children, growth retardation and skeletal deformities. There are no clinical features that clearly distinguish the various types of renal osteodystrophy. Characteristic radiographic findings of osteitis fibrosa cystica include subperiosteal resorption and new bone formation, particularly at the radial aspect of the middle phalanges. Resorptive loss of bone may be also observed at the terminal phalanges, distal ends of the clavicles, and in the skull. However, no skeletal imaging method can differentiate among renal osteodystrophy subtypes. (See 'Clinical features' above.)

●Evaluation – Renal osteodystrophy should be suspected in all patients with advanced (ie, stages 3 to 5) CKD. A definitive diagnosis of renal osteodystrophy and the identification of histologic subtype are established by bone biopsy. However, bone biopsies are rarely performed because there is insufficient expertise in their performance and interpretation at most academic centers. For most patients, we and most other clinicians use serum intact parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BSAP) levels as surrogate markers to distinguish among various types of renal osteodystrophy. However, these markers have limited sensitivity and specificity to correctly classify bone disease in an individual patient with CKD. (See 'Evaluation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Berkoben, MD, who contributed to earlier versions of this topic review.