Year : 2009 | Volume
: 20 | Issue : 1 | Page : 12--19
Role of bone biopsy in renal osteodystrophy
Wisam Al Badr, Kevin J Martin
Division of Nephrology, Saint Louis University, Saint Louis, Missouri, USA
Wisam Al Badr
Division of Nephrology, Saint Louis University, 3635 Vista Ave, St. Louis, MO 63110
Renal osteodystrophy (ROD), the abnormal bone histology that occurs in the context of kidney disease, is a disease spectrum and not a uniform progressive bone disease. It is an important component of the broad disturbances of bone and mineral metabolism associated with chronic kidney disease (CKD). There are multiple pathogenetic factors which contribute to the histological abnormalities seen on bone biopsy. The patients with ROD are rarely symptomatic in the early stages of CKD. It is also noteworthy that the clinical manifestations are usually preceded by biochemical changes that are insidious and subtle. This makes it difficult for the clinician to suspect the presence of bone and mineral metabolism abnormalities without direct testing. The serum calcium, phosphorus, and alkaline phosphatase levels are usually normal until late in the course of CKD. The main screening test for abnormal bone and mineral metabolism is the measurement of parathyroid hormone which is also somewhat delayed. The clinical signs and symptoms are also challenging to interpret because of their slow and non-specific nature which may include vague, ill-defined, bone aches and pains, and muscle weakness. The gold standard for diagnosis of ROD is bone biopsy with mineralized bone histology after double tetracycline labeling, iron staining and aluminum staining. The currently used histomorphometric descriptions of bone histology are not well integrated clinically and a new nomenclature that is clinically more relevant and useful has been proposed. Additional studies are required to define the spectrum of ROD in the current therapeutic era, and to find clinically useful non-invasive biomarkers to improve the treatment and monitoring of the abnormal bone in the setting of CKD.
|How to cite this article:|
Al Badr W, Martin KJ. Role of bone biopsy in renal osteodystrophy.Saudi J Kidney Dis Transpl 2009;20:12-19
|How to cite this URL:|
Al Badr W, Martin KJ. Role of bone biopsy in renal osteodystrophy. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Dec 2 ];20:12-19
Available from: https://www.sjkdt.org/text.asp?2009/20/1/12/44701
The histologic bone abnormalities that occur in association with kidney disease have beenknown since the late 1800's and became further defined in the late 1960's, with the recognition that abnormal mineralization could occur in addition to the presence of osteitis fibrosa cystica. The work of Ritz et al in 1973 distinguished the entity "mixed uremic osteodystrophy", wherein a mixture of fibro-osteoclastic and defective mineralization features occurred at the same time in the majority of cases. 
Renal osteodystrophy (ROD) is the generic term used to describe the histologic abnormalities of bone in the setting of chronic kidney disease (CKD). As described by Malluche and Faugere in 1986, ROD occurs almost universally in all CKD stage 5 patients.  The clinical correlation of the bone histologic findings is poor. Malluche and Faugere have proposed a new nomenclature to better describe ROD in more clinical terms in Kidney Disease Improving Global Outcomes (KDIGO) position statement in 2006 and may provide a guide to therapy [Figure 1A] and [Figure 1B]. 
How is the bone histology of renal osteodystrophy different in the last two decades?
The earliest reports have shown hyperparathyroid bone disease to be the predominant form of ROD.  Osteomalacia (OM) developed mainly as a consequence of aluminum-intoxication,  but can also be seen in some cases of vitamin D deficiency and in the presence of metabolic acidosis.  In 1993, Sherrard et al assessed the bone histology in 259 chronic dialysis patients and demonstrated that aluminum related bone disease is much less common than previously described. A different pattern of bone lesions is seen in patients on peritoneal dialysis (PD) than hemodialysis (HD), with low turnover disorders comprising 66% of the lesions seen in PD and high turnover lesions accounting for 62% of the bone histologic findings in HD.  A later report by Couttenye et al noted in 103 HD patients that adynamic bone disease was present in 38 (37%) of the patients.  Others have confirmed the changing patterns of ROD in recent years.
In the pre-dialysis population, Ingham et al in 1973 reported on forty six patients after an elective iliac crest biopsy regardless of the presence of skeletal symptoms. Quantitative studies showed osteosclerosis in 10 patients, and OM (alone or in combination with other lesions) in 14 and osteitis fibrosa (alone or in combination with other lesions) in 29.  Two Spanish studies reported an increased prevalence of adynamic bone disease in end-stage renal disease patients, not yet on dialysis, of 32 and 48%, respectively. , In a recent Asian study by Shin et al, 58 pre-dialysis patients were evaluated with bone histology. The authors noted that 91.4% of the patients showed ROD before the start of dialytic therapy. Mild osteitis fibrosa was observed in 36.2%, severe osteitis fibrosa in 8.6%, mixed lesions in 12.1%, osteomalacia in 10.3%, adynamic bone disease in 24.1%, and normal bone in 8.6% of the patients.  In 2003, Spasovski et al, reported, in an unselected group of pre-dialysis patients, that 62% of the cases already presented with an abnormal bone histology. Adynamic bone disease was apparent in 23% of the cases, 12% of patients fulfilled the criteria of OM and mixed osteodystrophy was diagnosed in 18% of the subjects. 
Thus, there are widely different incidences of the various histological patterns of ROD reported by many investigators. The differences in the spectrum of ROD reported can, at least in part, be explained by differences in criteria for patient recruitment (selected vs unselected populations), cohort size, genetic and dietary factors, different ethnic groups, referral rates and use and nature of concomitant therapy e.g., phosphate binding agents and vitamin D sterols. 
What are the available non-invasive markers available to diagnose ROD?
While bone histology is the gold standard for accurate assessment of the state of the bone, the search for biochemical markers has been ongoing for a number of years. Measurement of parathyroid hormone (PTH) has been widely used since PTH is a major regulator of bone turnover and skeletal cellular activity.  Intact PTH is the principal surrogate biochemical marker for diagnosis of bone turnover. While such assays have been extremely valuable, especially when serial measurements are used, it is now known that these assays also measure a large N-terminally truncated PTH fragments such as PTH 7-84 that can lead to widely different results by the many different assay kits that are available [Figure 2]. The considerable variability of the different commercially available intact PTH assays makes biochemical data interpretation even more confusing for the clinical nephrologists and makes practice guidelines for desirable target ranges difficult. While the extremes of PTH (very low or very high values) values generally correlate with bone turnover, in patients with intermediate PTH levels (approximately 100-400 pg/ mL) the correlation is relatively poor. 
Other biochemical markers have been evaluated including: total alkaline phosphatase, bone-specific alkaline phosphatase, pro-collagen type I C-terminal extension peptide (PICP), and osteocalcin, all of which reflect bone formation. On the other hand, tartrate resistant acid phosphatase type 5b (TRAP-5b), Type I collagen cross-linked telopeptide (ICTP), and osteoprotogerin (OPG) are biochemical indicators of bone resorption. These markers may provide useful information about bone turnover, but none appear to provide sufficient correlation to the clinical state of ROD [Table 1] ,
There is no role for the use of DEXA in the assessment of bone turnover. It can provide information on overall bone mineral content/ density, but not how that mineral is arranged. In the setting of CKD, measurements of bone mineral content do not give any indication of abnormalities in the cellular components of bone, and so they cannot be used for classification of various forms of ROD (e.g., high turnover and low turnover disease). Theoretically, if bone mineral content is progressively decreasing, the skeleton is undergoing demineralization, and thus presents a problem that ultimately will need to be addressed. Much of the current data on the use of bone mineral density relates to fracture risk in osteoporosis. No such data are available for the fracture risk in patients with ROD. Similarly, there is a lack of data to support the use of DEXA in CKD stages 2 to 4, since interpretation of results may be complicated by menopausal status, testosterone levels, or other concurrent therapy such as corticosteroids. 
At the present time there are no reliable biomarkers or non-invasive radiologic techniques available to evaluate ROD.
What are the therapeutic implications gained after a bone biopsy?
Identification and therapy of ROD continues. Until a decade ago, most patients presented with secondary hyperparathyroidism while currently, adynamic bone has become the most common lesion within the dialysis population. The relevance of such a clinical distinction is extremely important since low bone turnover requires a reduction in therapy aimed at suppression of PTH using calcium-based phosphate binders and vitamin D sterols. On the other hand, the formation of disorganized woven bone due to hyperparathyroidism requires further PTH suppression.
In the last two decades, vitamin D analogs have been introduced that suppress the activity of the parathyroid glands while minimizing the toxicities that may result from increased intestinal absorption of calcium and phosphorus produced by the native hormone, calcitriol. The influence of these sterols, 19-nor-1,25(OH) 2 D 2 (paricalcitol), 1,α(OH)D2(doxercalciferol), 22-oxacalcitrol (maxacalcitol), and hexafluoro 1,25 (OH) 2 D 3 (falecalcitriol) on the histology of bone is not well documented at the present time. ,,, Differences in these vitamin D analogues on ROD have not been adequately addressed. The effect of the vitamin D analogues on the reduction in PTH measurements may be an oversimplification and the independent influences of vitamin D sterols on bone needs to be considered.  Further studies in this regard are indicated.
Calcimimetic agents are a novel class of drugs, have been designed to target the calcium recaptor in the parathyroid glands, thereby providing the means of controlling hyperparathyroidism independent of other approaches. Clinical studies appear to show efficacy in the control of hyperparathyroidism.  The effects of this therapy on bone are presented in a recent prospective, double-blind, placebo-controlled trial which assessed the effects of cinacalcet on bone histology. The study demonstrated significant correlations between improvements in serum markers of bone metabolism and bone turnover rates determined by bone biopsy during cinacalcet treatment. The results were limited by the use of vitamin D sterols and baseline bone biopsy heterogeneity which will limit date interpretation. 
Should we do bone biopsies to diagnose renal osteodystrophy?
Bone biopsy is the "gold standard" in patients with CKD. Traditionally, five major histopathologic patterns are described: osteitis fibrosa, mild lesion, osteomalacia, mixed uremic osteodystrophy, and adynamic bone disease. Others propose a three pattern nomenclature of bone biopsy interpretation which provide important information on precisely the type of renal bone disease affecting the patients:
predominant hyperparathyroid bone disease;low-turnover uremic osteodystrophy, encompassing osteomalacia and adynamic renal bone disease; andmixed uremic osteodystrophy, consisting of mild to moderate hyperparathyroid bone disease and defective mineralization. 
As mentioned above, Malluche and MonierFaugere have proposed a new nomenclature with the three headings: bone turnover, bone balance and bone mineralization; this may help the clinician to guide therapy.
What are the clinical indications for bone biopsy?
Trueba et al, summarized the potential clinical indications for bone biopsy in CKD patients.  They include the following: a) patients with persistent and unexplained hypercalcemia who are not responding to medical management with a low to intermediate iPTH level, b) patients who have continuous and unexplained elevated phosphorus, with no evidence of dietary noncompliance, who may have significant bone resorption despite only moderately elevated serum PTH levels, c) cases of unexplained bone pain and fractures which could be a presentation of any histological form of ROD and, d) although now rare, suspected aluminum-related bone disease, particularly in developing countries, where aluminum-based medication is still used in the treatment of hyperphosphatemia. Bone biopsy is also useful in patients with osteoporosis, osteomalacia, osteogenesis imperfecta, Paget's disease, b2-microglobulin amyloidosis, gonadal deficiency, osteopenia, post-transplant osteoporosis, and other metabolic bone diseases. 
Why not biopsy more often?
There are several reasons for the lack of enthusiasm among clinicians to do bone biopsies more frequently. Some of the common reasons include:
the invasiveness of the procedure;the lack of technical training;the potential for painthe cost associated with the procedure;the lack of specialized centers with the expertise to interpret bone samples;the time delays between performing the biopsy and pathologic reports;the analysis of a single site and type of bone; andage, sex, race, and geographic area may be important in determining the normal ranges for the parameters measured, and appropriate normal ranges need to be developed and expanded using standardized techniques. ,
What are the bone biopsy techniques available?
Investigators use one of two techniques to obtain the bone sample; either a transiliac approach or vertical biopsy.  The first step that determines the quality of the sample is the double labeling technique. Currently, labeling is done with antibiotics from the tetracycline family because they are nontoxic, bind to actively forming bone surfaces, and have spontaneous fluorescence.  Additionally, tetracycline provides information on mineralization rate and bone formation when the bone histology is assessed. The administration of the first label of tetracycline for two days is followed by a free interval period that varies from eight to 15 days. Two to four days after the free interval period, a second course of antibiotics is given. The bone biopsy is then performed four to six days after the last uptake of tetracycline. This recommended time delay allows the tetracycline to be slightly buried within mineralized osteoid, which helps prevent antibiotics from leaching out of the bone into the fixative solution. 
The physician should extract bone samples without major physical force. The iliac crest offers the best site for sample collection. Available bone biopsy instruments are classified as manual trochars  or electric drills.  Generally, bone samples of 0.4 to 0.5 cm in diameter and 2.5 to 3.5 cm in length (taken vertically from the anterior iliac crest) or 0.5-0.8 cm in diameter and 1.5 to 2 cm in length (taken trans iliac) are determined to be sufficient for qualitative and quantitative bone histology [Figure 3]. 
The bone is then embedded in plastic, sectioned, stained, and analyzed using quantitative histomorphometry, a technique that requires considerable expertise and is only available in a few centers in the world. 
What are the anticipated complications of bone biopsy?
Complications as a result of bone biopsies include hematoma, neuropathy, wound infection, and pain but in general the procedure is well tolerated.
Bone biopsy remains the gold standard in the diagnosis of ROD which continues to be a complication of CKD and is associated with morbidity and poor quality of life. There are different types of ROD and the patient can dynamically shift between these types. An accurate diagnosis may lead to changes in therapy. The need remains for expertise in bone histomorphologic diagnosis which requires a highly specialized training in bone histology. The limitation of the available biochemical surrogate parameters is an important reason why the bone biopsy remains the "gold standard" for diagnosis of ROD. The search for a more accurate and reliable non-invasive technique is still an area of interest to many researchers. The current use of newer vitamin D analogs such as paricalcitol and novel compounds such as the calcimimetics which provide additional therapeutic approaches for the control of hyperparathyroidism may alter the expression of ROD.
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