Renal Complications from Bisphosphonate Treatment
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REVIEW CURRENT OPINION Renal complications from bisphosphonate treatment Raimund Hirschberg Purpose of review More than 10 years ago evidence emerged that bisphosphonate therapy especially in malignant bone diseases is associated with renal complications. The nature of renal injury from bisphosphonates has become clearer in recent years. Recent findings Pamidronate can rarely cause (collapsing) focal segmental glomerular sclerosis with the nephrotic syndrome and renal insufficiency. This renal complication has also been observed with other bisphosphonates but only in isolated cases. Other types of renal injury include transient but self-limited rises in creatinine, and, very rarely, acute tubular necrosis causing acute renal failure. The frequency of the latter two complications appears to follow the potency of different bisphosphonates. Although thus far no tubular transport for bisphosphonates has been identified (renal excretion appears to be only by glomerular ultrafiltration), the occurrence of tubular cell injury gives rise for the possibility that these cells can take up bisphosphonates. In patients receiving bisphosphonates monitoring of serum creatinine before and after intravenous (i.v.) dosing or periodically with oral bisphosphonates is advised. Summary Renal complications with bisphosphonates are rare but creatinine monitoring, especially with i.v. bisphosphonates is strongly advised. The mechanisms by which bisphosphonates can cause renal insufficiency are still elusive and opportunities for research include the discovery of potential mechanisms of tubular cell uptake of bisphosphonates. Keywords acute kidney injury, nephrotic syndrome, renal handling of bisphosphonates INTRODUCTION cause apoptosis (Table 1) [1]. Nitrogenic bisphosph- Bisphosphonates are chemically related to pyro- onates have additional actions once internalized phosphate but contain a carbon with two side into osteoclasts (Table 1). These latter compounds chains. The phosphonate group provides affinity inhibit the mevalonic acid pathway by inhibiting to bone and binding to hydroxyapatite. In most farnesyldiphosphate synthase and, hence, reduce bisphosphonates, one of the side chains is an OH protein farnesylation and geranyl-geranylation. (except clodronate) and the second side chain is These posttranslational protein modifications are more variable between different bisphosphonates important for the normal function of some cellular [1]. proteins and the lack of these modifications inhibits osteoclast function and also causes apoptosis [1]. It is thought that osteoclasts are the only cells that MECHANISMS OF ACTIONS OF take up bisphosphonates. However, there is a mod- BISPHOSPHONATES erate amount of evidence that other cells including After i.v. administration or after oral ingestion and perhaps tubular cells may take up bisphosphonates, uptake into the blood stream bisphosphonates are rapidly taken up by bone minerals to which they Los Angeles Biomedical Research Institute at Harbor-UCLA Medical bind with high affinity. Hydroxyapatite-bound Center, Torrance, California, USA bisphosphonates are then slowly taken up by osteo- Correspondence to Raimund Hirschberg, Los Angeles Biomedical clasts by endocytosis. Nonnitrogen bisphospho- Research Institute at Harbor-UCLA Medical Center; 1124 West Carson nates, that is, those that do not contain nitrogen Street, Torrance, CA 90502, USA. Tel: +1310 222 3891; e-mail: (N) in the R2-side chain act primarily by intra- [email protected] cellular incorporation into nonhydrolysable ATP- Curr Opin Support Palliat Care 2012, 6:342–347 analogues, which inhibit osteoclast function and DOI:10.1097/SPC.0b013e328356062e www.supportiveandpalliativecare.com Volume 6 Number 3 September 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Renal complications from bisphosphonate treatment Hirschberg Bone-bound bisphosphonates become active KEY POINTS when resolved from the bone matrix and endocy- Bisphosphonates can cause the nephrotic syndrome but tosed by osteoclasts. These cells express electrogenic this is a very rare complication. Proton-(V-)-ATPase in the bone exposed membrane and secrete protons (and ClÀ through Cl-channels) In randomized controlled trials in bone lesions from as well as cathepsin K into the neighboring bone. The solid tumors or multiple myeloma, the incidence of acidification (pH 5) dissolves minerals and cath- renal insufficiency was only moderately greater with zoledronic acid compared with placebo epsin digests the organic bone matrix. During this or pamidronate. process, bisphosphonates are endocytosed and exert intracellular effects that reduce osteoclast activity. Renal complications appear to be more common in Bisphosphonates are clinically used to treat patients with baseline renal diseases or renal hypercalcemia of malignancy, for the treatment of insufficiency. It is recommended that bisphosphonates are avoided when the estimated creatinine clearance Paget’s disease and to prevent skeletal-related- less than 30–35 ml/min. events (SREs) in malignant bone disease (multiple myeloma and bone metastases from solid cancers) The mechanisms of renal injury by bisphosphonates and in osteoporosis. In the latter setting, bisphosph- remain elusive but there may be some uptake by renal onates have been shown to increase bone mineral epithelial cells albeit the transport mechanisms are not known. If uptake into cells does occur it is possible that density (BMD). In osteoporosis, bisphosphonates cell injury results from the same mode of action of may be given for long periods of time and side bisphosphonates in osteoclasts. effects and complications are perhaps more likely to develop. On the contrary, treatment regimen of There is insufficient data to recommend any dosing of some bisphosphonates with long-dosing intervals intravenous (i.v.) bisphosphonates in chronic hemodialysis patients and use of bisphosphonates in up to 1 year are efficacious and reduce drug exposure patients is not recommended by regulatory agencies. to other organs such as kidney [2,3]. Another One consideration might be to use one-half of the approach to minimize exposure to bisphosphonates normal dose followed by a hemodialysis session is based on biomarker-directed dosing, using urinary 12–24 h later. levels of N-telopeptide of collagen type I (NTx) or procollagen 1 c-terminal extension peptide (P1NP) to direct dosing and dosing intervals [4,5]. Such too. This finding could explain renal cell injury approaches may help to reduce complications of by bisphosphonates. bisphosphonate therapy. One of the most serious The efficiency of bisphosphonates to reduce complications of treatments with bisphosphonates bone reabsorption appears to reside in their avidity may be renal toxicity. to bind to bone mineral as well as their intracellular activity in osteoclasts. As a rule, nitrogenic bisphosphonates are more efficacious compared HANDLING OF BISPHOSPHONATES BY with nonnitrogenic bisphosphonates. Bisphospho- THE KIDNEY nates that are ‘buried’ in bone mineral are believed Oral bisphosphonates are poorly absorbed by to be inactive for long periods (many months to few the gastro-intestinal tract (3%) and nitrogenic years). This situation has clinical importance as it bisphosphonates tend to have even lower absorption allows for long dosing intervals of monthly (ibandr- rates after oral administration [6]. After i.v. admin- onate) to annually (zoledronic acid) in some indica- istration bisphosphonates are largely and quickly tions. However, there is a slow ‘leak’ of bone taken up by bone but the proportion of bone-bound bisphosphonates back into the blood stream during drug varies more so between patients than between interdosing intervals. bone diseases and individual bisphosphonates. For example the bone retention for zoledronic acid in patients with bone metastases ranged between Table 1. Nonnitrogenic and nitrogenic 25% and 93% [7]. Bisphosphonates that are not bisphosphonates taken up in bone are rapidly excreted by the kidney Nonnitrogenic bisphosphonates Nitrogenic bisphosphonates in their unchanged, native form. Thus, the vari- Etidronate Pamidronate ation in the proportion of a fixed administered dose Clodronate Alendronate that is rapidly taken up by bone defines renal Tiludronate Risedronate exposure to the drug and, as a result, may help to Ibandronate define patients at greater risk for renal toxicity. Zoledronic Acid As indicated earlier, nonnitrogenous bispho- sphonates are metabolized to ATP-analogues in 1751-4258 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.supportiveandpalliativecare.com 343 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Bone and haematological problems osteoclasts, which are part of their mode of action. nephrotic syndrome and (collapsing) focal segmen- Nitrogenic bisphosphonates are not recognized by tal glomerular sclerosis (FSGS); acute kidney injury metabolizing enzymes or transporters: Bisphospho- (AKI) with acute renal failure and tubular necrosis; nates that are not taken up in bone are rapidly ‘creeping creatinine’, that is, slowly progressing or excreted in urine after glomerular ultrafiltration nonprogressing renal insufficiency. More common in their native, un-metabolized form. There is no is a transient rise in serum creatinine with sub- evidence for active tubular secretory transport in sequent return to baseline. humans albeit this has been shown