INTRODUCTION — Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder that occurs in patients with progressive chronic kidney disease (CKD). Abnormalities in bone morphology, collectively called renal osteodystrophy, are an important component of CKD-MBD. The bone abnormalities resulting from loss of kidney function render CKD patients vulnerable to fractures.  

This topic reviews the evaluation of renal osteodystrophy and the indications for bone biopsy among CKD patients with CKD-MBD.

An overview of CKD-MBD is provided elsewhere. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

The treatment of secondary hyperparathyroidism is discussed elsewhere. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult dialysis patients".)

Other related topics are presented at length elsewhere:

●Postmenopausal osteoporosis (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Overview of the management of osteoporosis in postmenopausal women" and "Bisphosphonate therapy for the treatment of osteoporosis".)

●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".)

DEFINITION AND SUBTYPES OF RENAL OSTEODYSTROPHY — Renal osteodystrophy refers to specific changes in bone morphology associated with chronic kidney disease (CKD) [1]. It is part of the syndrome of chronic kidney disease-mineral and bone disorder (CKD-MBD). CKD-MBD was defined in 2006 by Kidney Disease: Improving Global Outcomes (KDIGO) to describe a systemic disorder that incorporates multiple abnormalities including but not limited to bone pathology [1]. Other components of CKD-MBD include laboratory abnormalities (calcium, phosphorus, fibroblast growth factor 23 [FGF23], vitamin D, and parathyroid hormone [PTH]) and extraskeletal calcification. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Introduction and definitions'.)

There are four subtypes of renal osteodystrophy:

●Osteitis fibrosa cystica – Osteitis fibrosa cystica is functionally characterized by high bone turnover due to persistently high PTH. There is a marked increase in the number and activity of osteoblasts (ie, bone-forming cells) and osteoclasts (bone-reabsorbing cells) and an increase in osteoid (unmineralized bone). The decrease in mineralization is believed to be relative to the marked increase in bone turnover. High turnover can contribute to hyperphosphatemia, increased cortical porosity and long bone fracture, anemia due to marrow fibrosis, and tendon rupture due to increased bone resorption at sites of tendon insertions.

●Adynamic bone disease – Adynamic bone disease is characterized by low bone turnover with reductions in both osteoblast and osteoclast activity. Low bone turnover is usually due to excessive suppression of the parathyroid glands by medication (ie, calcitriol or calcium-containing phosphate binders), but resistance to the bone stimulatory effects of PTH may contribute [2,3]. (See "Adynamic bone disease associated with chronic kidney disease".)

●Osteomalacia – Osteomalacia is primarily characterized by decreased mineralization, causing an increase in unmineralized osteoid [4,5]. Among end-stage kidney disease (ESKD) patients, osteomalacia used to be primarily caused by aluminum deposition in bone. Osteomalacia is considered uncommon in ESKD patients since aluminum-based phosphate binders were abandoned and stringent guidelines were established to minimize aluminum in dialysate water [6-9]. (See "Aluminum toxicity in chronic kidney disease", section on 'Sources of aluminum'.)

●Mixed uremic osteodystrophy – Mixed uremic osteodystrophy (MUO) is a term used to describe bone biopsy findings of both high bone turnover and a disproportionate decrease in mineralization resulting in increased osteoid. As in osteitis fibrosa cystica, the high bone turnover is mediated by increases in both osteoblast and osteoclast activity. In contrast to osteitis fibrosa cystica, the marked decrease in mineralization suggests a concomitant mineralization defect. A precise etiology and clinical correlate to MUO are not known.

DIAGNOSIS OF RENAL OSTEODYSTROPHY AND IDENTIFICATION OF SUBTYPES — A definitive diagnosis of renal osteodystrophy and the identification of histologic subtype are made by bone biopsy [1,10]. A bone biopsy, performed after tetracycline labeling, is the gold standard for assessing the bone remodeling, mineralization, and structure. A bone biopsy is indicated if the knowledge of the type of renal osteodystrophy will impact treatment decisions. (See 'Indications' below.)

However, bone biopsies are rarely performed because there is insufficient expertise in their interpretation at most academic centers [11]. For most patients, we rely on serum biomarkers and, occasionally, imaging tests to diagnose the most likely subtype of renal osteodystrophy. (See 'Noninvasive evaluation' below.)

Noninvasive evaluation — A variety of noninvasive tests are used for the evaluation of patients suspected of having renal osteodystrophy. These tests include serum calcium, phosphorous, parathyroid hormone (PTH), and alkaline phosphatase (total or bone-specific) levels and, occasionally, imaging studies. None of these tests, singly or in combination, are completely accurate for the identification of low- normal- or high-turnover bone disease in individual patients [12,13].

Laboratory tests — We use circulating PTH concentrations to predict the risk of high-turnover disease (ie, osteitis fibrosa cystica or mixed uremic osteodystrophy [MUO]) or low-turnover disease (ie, adynamic bone disease). We use multiple PTH values and trends over time rather than a single measurement to predict risk, although this has not been shown to improve accuracy [12].

PTH levels are the best noninvasive option for assessment of bone turnover. In a study utilizing stored serum and biopsy data of 492 dialysis patients, PTH was able to discriminate low from non-low and high from non-high-turnover bone disease with an area under the receiver operating curve of between 0.7 and 0.8 [14]. Low and high PTH were defined by Kidney Disease: Improving Global Outcomes (KDIGO) practice guidelines for treatment [12].

We use the following parameters to define the risk for specific subtypes of renal osteodystrophy [15]:

●PTH <100 pg/mL suggests adynamic bone disease and a decreased risk of osteitis fibrosa cystica and or MUO.

●PTH >450 pg/mL suggests osteitis fibrosa cystica and/or MUO.

●Intermediate 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 or increased turnover or even reduced turnover.

Total and bone-specific alkaline phosphatase are measures of osteoblastic activity [14]. In the study cited above that correlated stored serum and biopsy data of 492 dialysis patients, bone-specific alkaline phosphatase performed equally well to PTH in discriminating low from non-low and high from non-high-turnover bone disease but did not add to the ability of PTH to discriminate in this study (table 1) [14].

We do not use biochemical markers, including serum C-telopeptide of type I collagen (CTX) [16-19].

Imaging — We do not perform routine radiographic screening for bone disease in patients with end-stage kidney disease (ESKD). Radiographic findings are less sensitive for diagnosis than PTH levels and do not establish the type of bone disease.

Imaging may be done for patients with unexplained bone pain or fractures. 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.

Radiographs may also reveal soft tissue calcification, particularly including the vasculature, although we do not screen chronic kidney disease (CKD) patients for vascular calcification. (See "Vascular calcification in chronic kidney disease".)

Bone density measurement — We agree with the 2017 KDIGO guidelines that selected CKD patients who have evidence of chronic kidney disease-mineral and bone disease (CKD-MBD) and/or risk factors for osteoporosis should be assessed by bone mineral density (BMD) measurement if results will inform treatment [12]. This issue is discussed elsewhere. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Assessment of fracture risk'.)

Bone biopsy — Bone biopsy is the gold standard for diagnosing renal osteodystrophy and identifying the specific type. (See 'Definition and subtypes of renal osteodystrophy' above.)

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 [12].

Because the availability of expertise in performing and interpreting bone biopsies varies among centers, there are different thresholds for doing the test. Biopsies may be performed in the following circumstances:

●Among ESKD patients who are undergoing parathyroidectomy because of persistent symptoms of hyperparathyroidism, but who have an indeterminate PTH level (ie, <450 pg/mL). The reason for the biopsy is to confirm the presence of PTH-mediated high-turnover bone disease (providing that a confirmed diagnosis would alter treatment decisions). (See 'Laboratory tests' above and "Refractory hyperparathyroidism and indications for parathyroidectomy in adult dialysis patients", section on 'Symptomatic patients'.)

●Among patients with unexplained bone pain or fractures (ie, with minimal or no trauma). (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult dialysis patients".)

●When there is a suspicion of osteomalacia, generally based on history of aluminum exposure. This is uncommon today. (See "Aluminum toxicity in chronic kidney disease".)

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

●We do not routinely perform a biopsy in patients who are to undergo bisphosphonate therapy, unless the diagnosis of osteoporosis is uncertain or there is a progressive decrease in BMD despite standard therapy. The use of bisphosphonates in patients with CKD is discussed elsewhere. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Antiresorptive agents'.)

In one survey, the common reasons for bone biopsy included diagnosis of a low-impact fracture, presence of unexplained bone pain, hypercalcemia or radiologic abnormality, and to confirm heavy or rare metal toxicity. In addition, it was also pursued prior to parathyroidectomy (to confirm high bone turnover) or prior to initiation of antiresorptive drugs (to exclude low bone turnover) [20].

Technique of bone biopsy — Bone biopsy is typically obtained from the iliac crest after the administration of two different time-spaced tetracycline markers [21]. 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.

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. (See 'Pathologic diagnoses' below.)

Pathologic diagnoses — The results of a bone biopsy will typically give a specific diagnosis that reflects the predominant subtypes of renal osteodystrophy based upon characteristic histologic findings.

To help clarify the interpretation of the bone biopsy, the turnover, mineralization, and volume (TMV) classification system was developed by the 2006 National Kidney Foundation (NKF) working group on renal osteodystrophy [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 theoretical and descriptive, but does not provide information about the cause of the bone disease or the risk of fracture.

Following is a brief description of bone histopathology diagnoses and treatment implications in ESKD:

●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 to replace resorbed bone. Quantitative bone histomorphometry performed on bone biopsies provides an assessment of osteoblast-mediated bone formation and mineralization of extracellular matrix (ie, osteoid), the degree of osteoclast-mediated bone resorption, structure of trabecular and cortical bone, toxic metal accumulation, and the condition of the bone marrow space.

Normal bone osteoid appears red-brown with the Goldner-Masson (trichrome) stain, and mineralized bone appears blue under light microscopy (picture 1). The osteoid appears orange, and the mineralized bone is green when the section is viewed under fluorescent light. The luminescent tetracycline bands within bone represent active mineralized bone formation 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).

●Osteitis fibrosa cystica – Osteitis fibrosa cystica is histologically characterized by marrow fibrosis, woven osteoid, increased number and activity of osteoblasts, expansion of osteoid surfaces, and numerous osteoclasts and resorptive surfaces (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. Pharmacologic or surgical interventions to reduce PTH should be undertaken for patients with osteitis fibrosa cystica. (See "Management of secondary hyperparathyroidism in adult dialysis patients".)

●Mixed uremic osteodystrophy – MUO resembles osteitis fibrosa on light microscopy, except that there is a greater degree of osteoid accumulation (picture 3). 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 decreased mineralization lag time. Pharmacologic or surgical interventions to reduce PTH should be undertaken. Patients should be evaluated for factors contributing to impaired mineralization, such as vitamin D deficiency, hypocalcemia, hypophosphatemia, metabolic acidosis, and exposure to heavy metals. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

●Osteomalacia – Osteomalacia is characterized by a marked increase in the fraction of bone exhibiting wide osteoid seams and by the absence of osteoblasts or erosive surfaces (picture 4). Examination under fluorescent light reveals little or no tetracycline deposition.

Osteomalacia may be accompanied by extensive aluminum deposition on bone surfaces. Aluminum can be detected histologically with a Villanueva-prestained section stained with aurintricarboxylic acid (picture 5). The osteoid is light blue, and the mineralized bone is white. Aluminum stains as a red band at the osteoid-bone interface. Patients should be evaluated for factors contributing to impaired mineralization, such as vitamin D deficiency, hypocalcemia, hypophosphatemia, metabolic acidosis, and exposure to heavy metals. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

●Adynamic bone disease – Adynamic bone disease is characterized by reductions in osteoblast and osteoclast number and activity resulting in low bone formation and resorption [13,22]. There is a reduction in osteoblast and osteoclast number and activity. These defects are manifested histologically by thin osteoid seams that display no active mineralization, inactive-appearing osteoblasts, and decreases in osteoclast number and bone resorptive surfaces (picture 6). Management of adynamic bone disease is presented elsewhere. (See "Adynamic bone disease associated with chronic kidney disease", section on 'Experimental therapies' and "Adynamic bone disease associated with chronic kidney disease", section on 'Treatment'.)

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

●Renal osteodystrophy refers to specific changes in bone morphology associated with chronic kidney disease (CKD). Subtypes of renal osteodystrophy include osteitis fibrosa cystica, adynamic bone disease, osteomalacia, and mixed uremic osteodystrophy (MUO). Each form of renal bone disease is associated with characteristic histologic findings. (See 'Definition and subtypes of renal osteodystrophy' above and 'Pathologic diagnoses' above.)

●The definitive diagnosis of renal osteodystrophy is made by bone biopsy. However, bone biopsy is not widely performed, because there is insufficient expertise in its interpretation at most academic centers. In most patients, we use the intact parathyroid hormone (PTH) to identify the most likely subtype of renal osteodystrophy. PTH remains the best noninvasive test available for the assessment of bone turnover. (See 'Noninvasive evaluation' above.)

●Bone biopsy is generally indicated if knowledge of the type of renal osteodystrophy will affect treatment decisions, although the threshold for biopsy varies markedly among centers. Biopsies may be performed among end-stage kidney disease (ESKD) in the following circumstances:

•Among ESKD patients who are undergoing parathyroidectomy because of persistent symptoms of hyperparathyroidism but who have an indeterminate PTH level (ie, <450 pg/mL).

•Among patients with unexplained bone pain or fractures (ie, with minimal or no trauma).

•When there is a suspicion of osteomalacia, generally based on history of aluminum exposure.

•To confirm the diagnosis of adynamic bone disease in patients with bone pain and persistent serum PTH levels <100 pg/mL, despite withdrawal of calcitriol or other vitamin D analogs. (See 'Indications' above.)