Denosumab is novel agent used to treat osteoporosis and prevent fractures associated with malignancies. Not much literature exists on use of this agent in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. A recent article in the American Journal of Kidney Diseases presents a case report of severe hypocalcemia after using this agent in a dialysis patient. Dr. Brendan McCormick (BM) discusses this report with eAJKD Blog Editor Kenar Jhaveri (eAJKD).
eAJKD: Can you discuss briefly what denosumab is and where it is currently being used?
BM: Denosumab is an anti-resorptive drug that increases bone mineral density by decoupling osteoclastic from osteoblastic activity, analogous to the action of bisphosphonates. The mechanism of action is entirely different from bisphosphonates. Denosumab is a monoclonal antibody directed against receptor activator of NF-κB (RANK) ligand. Binding of RANK ligand to the RANK receptor normally results in activation of osteoclasts, and thus inactivating the RANK ligand with denosumab prevents osteoclast activation, and decouples osteoclastic and osteoblastic activity favoring net bone formation.
There are two approved indications for denosumab. The first is in the treatment of post menopausal osteoporosis. A large randomized controlled trial demonstrated an increase in BMD and decrease in fracture risk in this population. It has also been shown to reduce skeletal-related events such as pain and fractures in patients with breast and prostate cancer metastatic to bone. Denosumab is not excreted via the kidneys, and it has been shown conclusively that denosumab does not seem to accumulate in kidney failure. It has been promoted as safe to use in CKD based on this fact and the experience in a relatively small number of patients with CKD stages 3 and 4 enrolled in these RCTs.
eAJKD: Briefly discuss your case, and what makes it unique?
BM: Other than an abstract presented by Block and colleagues at the 2010 National Kidney Foundation’s Spring Clinical Meetings, there are no reports of the use of denosumab in patients with CKD stage 5. Even though pharmacokinetics suggest that denosumab may be safe, our experience with three hemodialysis patients suggest that there is a risk of severe hypocalcemia with this compound. We hypothesize that this is a pharmacodynamic phenomenon, that is to say that patients with renal osteodystrophy are much more prone to hypocalcemia when osteoclastic function is down-regulated by denosumab.
This is an important observation as many dialysis patients have osteopenia or osteoporosis, and there is often an inclination to treat this finding, especially by non-nephrologists. Denosumab is easily administered by subcutaneous injection, and is rapidly gaining in popularity as a treatment due to ease of administration. We feel that our case is important to disseminate as a cautionary tale of the risks associated with this compound when used in patients with CKD stage 5. We highlight the fact that there is no data suggesting that denosumab is either safe or effective in treating osteoporosis in CKD stage 5.
eAJKD: The FREEDOM trial excluded patients with advanced CKD and ESRD. What do you think the effect would be of such an agent on CKD stage 5 and ESRD patients when used for osteoporosis?
BM: The effect of denosumab on bone mineral density in patients with CKD stage 5 may well be to increase the bone mineral density, but this does not necessarily mean that the fracture risk or vascular disease risk is reduced. There is a very weak link between BMD scores and fracture risk in dialysis populations, and it is well described that a large portion of CKD stage 5 patients have low turnover bone disease. In this population, further reducing bone turnover with antiresorptive agents such as denosumab (or bisphosphonates for that matter) would likely aggravate the situation and may actually increase risk of fracture and increase vascular calcification. On the other hand, those with high turnover bone disease (osteitis fibrosa cystica) could see some improvement in their bone histology with denosumab, though the associated hypocalcemia would likely further increase their PTH levels. Those with high turnover bone disease may also be the most susceptible to severe hypocalcemia with denosumab as these patients are much more dependent on osteoclastic activity to maintain their serum calcium since low vitamin D levels cannot up-regulate gut absorption of calcium.
eAJKD: This agent, under the brand name as Xgeva, is used to treat cancer associated hypercalcemia (specifically in prostate and breast cancer patients). Studies showed no adverse effects on patients with CKD and acute kidney injury. Any comments on that?
BM: Xgeva is approved to prevent skeletal-related events such as pain and fractures in patients with cancer that has metastasized to bone. It has not been studied among those with bony metastases and CKD stage 5, a population with renal osteodystrophy. To my knowledge, Xgeva is not FDA approved for treatment of malignant hypercalcemia, though there is a recent case report in the Annals of Internal Medicine that shows a marked drop in serum calcium and improvement of acute kidney injury in a patient with myeloma-related hypercalcemia. Malignant hypercalcemia is in large part related to increased secretion of RAND ligand induced by production of cytokines by tumor cells. Denosumab use is quite logical from a pathophysiologic perspective. Those with acute kidney injury should not experience the same severe hypocalcemia as those with CKD stage 5 as they do not have renal osteodystrophy and are not dependent on upregulation of osteoclasts by RAND activation to maintain serum calcium.
eAJKD: What bone biopsy changes would you anticipate in a patient with advanced CKD or ESRD who receives this agent?
BM: I think much would depend on the baseline bone histology. The concern is that adynamic bone disease could either be induced or aggravated by denosumab. In this situation, bone biopsy finding would show inactive osteoblasts with a reduced number of osteoclasts and thin osteoid surfaces with very little or no active mineralization.