Special issues in renal osteodystrophy, ROD : Survey Results

by Vincent Brandenburg and Thilo Krüger

 

Comments to the NDT-educational online survey upon adynamic bone disease and post-transplant bone disease.
By Vincent Brandenburg, MD & Thilo Krüger, MD, University Hospital of the RWTH Aachen, Aachen, Germany.
Vincent.Brandenburg@post.rwth-aachen.de

Overall, about 450 colleagues participated in this online survey. Within the following section, we will give some comments and background information regarding some selected Q&A of the present “renal osteodystrophy” survey.

INTRODUCTION

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KNOWLEDGE SURVEY

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The survey started with three “knowledge” questions. We would like to comment on these questions since there seem to be some uncertainties in the field. The diagnosis of “ADYNAMIC BONE DISEASE (ABD)” is most accurately based on “histomorphometry” analyses from specimen obtained by bone biopsies – most often performed at the iliac crest. There is no non-invasive diagnostic method that can diagnose ABD as accurately as bone biopsy can do. X-ray and bone densitometry are not helpful in the diagnosis. Bone markers such as bone alkaline phosphatase can help estimate bone metabolism, but they are not able to replace histomorphometry. Some clinicians use bone markers for non-invasive longitudinal monitoring. However, also this approach has not been tested sufficiently in (biopsy-) controlled studies. So overall, bone biopsy and histomorphometry are the gold-standard in establishing the diagnosis of any subtype of ROD and maybe especially of ABD. The answers indicate that some uncertainties exist over how ABD can be exactly diagnosed in histomorphometry. Indeed, iron staining is not helpful. Osteomalacia and ABD both belong to the low-turnover subtypes of ROD. The major difference is the magnitude of unmineralized bone tissue in both forms: While a large amount of unmineralized bone = osteoid belongs to the definition of osteomalacia, ABD is characterized by low amounts of osteoid. For a comprehensive and detailed review of ABD (aetiology, clinical importance, and potential therapy) please refer to: V. Brandenburg, J, Floege: Adynamic bone disease – bone and beyond. NDTplus (2008) 3:133-147. (Read the article: http://ckj.oxfordjournals.org/content/1/3/135.full?sid=c26e6cfe-11ca-4889-b0b2-5a665b2aa7f0 )
So briefly summarizing the diagnosis of ABD includes the following histomorphometry findings: minimal or absent fibrosis, low osteoid accumulation and low bone turnover (as e.g. assessed via bone formation rate).

 

PRACTICE PATTERN SURVEY

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There are no biopsy data available clarifying this issue. Therefore, the exact point during CKD development, in other words the degree of GFR decline at which ABD becomes a relevant problem is unknown. However, we agree with the majority of answers indicating that ABD develops before ESRD already in the pre-dialysis setting. That can be safely concluded from biopsy studies in pre-dialysis patients showing ABD in a large proportion of patients (Torres A et al. Kindney Int 1995; 47:1434-1442)

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The answers to this question are inhomogeneous. Several large biopsy-biobank-databases indicate that depending on comorbidities and especially co-therapies (aluminium, vitamin D usage, degree of PTH-control etc.) the prevalence is most presumably changing over time. According to large cohort studies from Lexington (Malluche HH et al. Nephrol Dial Transplant 2004; 19(Suppl) i9-i13) there is an increase in prevalence.

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From all we know the prevalence of ABD at any given institution is presumably higher. However, many patients with ABD might be clinically asymptomatic and bone biopsies are virtually never performed on a systematic screening basis. Therefore, the percentage of patients with overt ABD might actually be the tip of the iceberg. At this point, it is important to mention that ABD may well be present already in patients whose PTH levels are within current guideline target ranges.

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The possible answers to this question represent the entire variety of potential consequences of ABD. Therefore, there is no “right or wrong”. There is a generally accepted fear that ABD might particularly impair mineral metabolism and therefore predispose to vascular disease. However, final proof for this theory is pending.

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The distribution of answers reflects the well known reality that bone biopsy is not a frequent diagnostic procedure in nephrology. It is currently unknown if more frequent biopsies would change our therapeutic approach to ROD. However, adynamic bone is suspected based on biochemical parameters, mainly parathyroid hormone (PTH) and bone alkaline phosphatase, but it needs to be proven using a bone biopsy, where a low or zero bone formation rate and a reduction or absence of osteoblasts and osteoclasts should be found.

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As already discussed, not all currently applied bone markers can replace bone histomorphometry regarding accuracy in diagnosing ABD. Therefore, bone biopsy (if possible, combined with previous tetracycline labelling) is still the gold standard in the diagnosis of ABD. We are quite surprised about the high proportion of answers pointing towards a role of radiological examinations – e.g. bone densitometry or plain X-ray. Actually, there is no role for these diagnostic tools in establishing the diagnosis of ABD. In contrast, low bone density or osteopenia can indeed also occur in high-turnover bone disease such as hyperparathyroid bone disease or may just reflect underlying (postmenopausal) osteoporosis in patients with CKD / ESRD. Therefore, we do not recommend establishing the diagnosis of ROD solely based on bone density or presence or absence of osteopenia. Both X-ray and densitometry cannot discriminate between high-turnover versus low-turnover.

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Establishing the answer to this question is one of the major unsolved therapy issues in ROD. The clinical management of adynamic bone has important limitations and currently does not allow to take many active measures. Treatment is mainly based on the prevention of risk factors known to induce PTH over-suppression, such as aluminium and calcium load and very high doses of vitamin D receptor activators. There is only very limited data available pointing towards positive effects of reducing calcium-containing phosphate binders and introducing non-calcium containing phosphate binders to patients with proven ABD. However, reduction of calcium burden is presumably the most widely applied treatment strategy in these patients.

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Whether there is any effective treatment against ABD remains speculative. Again, the majority of colleagues favour usage of calcium-free phosphate binders. Indeed, we recommend such an approach. Teriparatide (1-34 PTH) as a bone-stimulating agent is interesting. However, such an approach needs to undergo randomized controlled trial investigation.

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Posttransplant bone disease (PTD) is associated with accelerated bone loss, increased fracture risk and also with increased morbidity in renal transplant recipients. The answers indicate that bone densitometry and monitoring of bone biomarkers are often part of the monitoring program. However, about a third of answers indicate that transplant centers have not established a SOP regarding monitoring and surveillance of PTD. It is a matter of debate as to whether such a SOP including e.g. pre- and pot-transplant densitometry improves outcome in renal transplant recipients.

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The participating colleagues favour an individualized approach for PTD. Such an individualized approach was nicely described by Mainra and Elder in 2010 (Clin J Am Soc Nephrol. 2010; 5(1):117-24): The authors described a therapy algorithm that incorporated BMD, prevalent vertebral fractures, biomarkers of bone turnover, and risk factor assessment. According to the algorithm results the patients received bisphosphonates or calcitriol with cholecalciferol treatment as background therapy in all patients. Before such a treatment algorithm can be incorporated in general guidelines, however, its efficacy and safety must be confirmed in additional controlled trials. However, we recommend such an approach rather than therapeutic neglect.

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The most comprehensively investigated substances are bisphosphonates and calcitriol in the setting of PTD. Calcidiol and calcium supplementation may be regarded as background therapy. It is currently not clear if one of the substances is superior to the other in terms of hard endpoint reduction (e.g. fracture incidence). The current KDIGO guidelines on chronic kidney disease–mineral and bone disorder suggest both bisphosphonates and calcitriol as therapies for the prevention of bone loss in kidney transplant recipients with stable renal function and low BMD. Please also refer to a recent commentary on that issue: V. Brandenburg and J. Floege in Nat Rev Nephrol (2013); 9, 5–6.

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Many of the answers agree that bisphosphonate application may influence bone metabolism. Concerns about the use of bis­phosphonates are justified, particularly given the unresolved issues of renal safety, the unknown effects on fracture rates, and the potential exacerbation or induction of adynamic bone disease. The efficacy and long-term effects of bisphosphonate therapy in addition to calcitriol for stabili­zation of BMD following kidney transplan­tation have not yet been determined. In our opinion, bisphosphonate therapy should be limited to patients who have a particularly high fracture risk (for example, those with a history of fractures, those who are receiving high-dose steroids and those who have low overall bone mass) and, ideally, adynamic bone disease should be excluded via bone biopsy prior to the administration of bis­phosphonate therapy in kidney transplant recipients. Therefore, we recommend limiting application of bisphosphonates to those patients with the highest fracture risk, stable transplant function and preserved bone metabolism (similar to Mainra & Elder (2010); Clin. J. Am. Soc. Nephrol. 5, 117–124 . There is well-substantiated data available showing that both calcitriol and bisphosphonates reduce accelerated bone loss within the first year after renal transplantation compared to placebo.