A modified method for reducing renal injury in zoledronic Acid treatment of hypercalcemia and adverse skeletal events.

AIMS: In this paper, we have reported a previously undescribed risk factor of deterioration of renal function in zoledronic acid treatment of skeletal metastasis - high serum calcium level. Based on this consideration, a modified method of treatment of hypercalcemia (HCM) with zoledronic acid is suggested in this paper.
MATERIAL AND METHODS: Bone scan findings of 1090 cancer patients were analyzed, of which 26 had intense renal parenchymal uptake as a result of HCM or bone metastases. Subsequently, a total of 56 bone metastases patients with zoledronic acid treatment were divided into three groups: HCM group who were pre-treated to normal serum calcium level (13 patients), HCM group (19 patients), and normal serum calcium group (24 patients).
RESULTS: More patients with intense renal parenchymal uptake were hyperglycemic, statistically significantly (18/26 versus 19/1064, P = 2.1, E-78). No more patients with intense renal parenchymal uptake were associated with bone metastases (14/26 versus 438/1064, P = 0.20). Subsequently, more HCM patients receiving zoledronic acid treatment showed renal injury compared to patients with normal serum calcium level (5/15 versus 2/24, P < 0.05) and HCM patients with pre-treatment to normal serum calcium level (5/15 versus 1/17, P < 0.05).
CONCLUSIONS: Intense renal parenchymal uptake of bisphosphonates is closely related to HCM rather than to bone metastases in cancer patients. The serum calcium should be measured and reduced to normal level before zoledronic acid is used in managements of adverse skeletal events in order to decrease the risk of renal injury.

INTRODUCTION

Bone metastases cause skeletal-related events (SREs), including bone pain, pathological fractures, spinal cord compression, and hypercalcemia (HCM), which are the result of the resorption of mineralized bone by osteoclasts.[12] Bisphosphonates have been used extensively in the treatment of HCM and in the prevention or palliation of skeletal complications associated with osteolytic lesions in various kinds of solid tumors.[34] Zoledronic acid is a highly potent bisphosphonate that has shown superior efficacy in the treatment of HCM as compared with pamidronate, the current standard treatment.[56] Recently, it has been reported that zoledronic acid offers greater convenience and is as effective and well-tolerated as pamidronate in the treatment of bone metastases from breast cancer, multiple myeloma, prostate cancer, and lung cancer.[789101112]

Administration of bisphosphonates for bone metastases of cancer carries a certain risk of deterioration of renal function,[131415] but the pathogenesis is still poorly understood. In patients who have pre-existing chronic kidney disease, the administration of bisphosphonates should be carried out with caution to avoid its deleterious effect on kidney function. Renal function monitoring guidelines have been introduced to reduce the incidence of this serious adverse event, and serum creatinine level measurement has been suggested as the important parameter to avoid renal toxicity when zoledronic acid is administered.[16171819] On the other hand, several authors have reported results of renal imaging obtained occasionally during bone scanning with 99mTc-polyphosphate and 99mTc-pyrophosphate. After 4 h of the intravenous infusion of 99mTc-labeled methylene diphosphonate (MDP), about 50% of the chemical is excreted in the urine. Therefore, renal, urinary tract, and bladder abnormalities are often detected on bone images. There was no significant difference between the various 99mTc phosphate compounds.[2021]

There is in fact a close link between HCM and renal toxicity. Acute renal failure (ARF) can cause HCM. When ARF causes HCM, it starts with excess levels of phosphorous that trap calcium in soft tissues. As renal function improves, lowering the phosphorous levels, the excess calcium is released into the body. HCM that results from excessive bone resorption is one of the causes of ARF. Kidney failure is produced by lesions on the renal tubular epithelium, which alters the ability to concentrate urine and, sometimes, causes epithelial cell necrosis and obstruction of the tubules. This can then lead to stasis and calcium deposits in tissues, especially in those with an alkaline medium, such as kidneys. There is an improvement of renal function as serum calcium levels decreases.[22] Diphosphonate and pyrophosphate are structurally similar with zoledronic acid and pamidronate, since they all belong to bisphosphonate compounds with similar bio-distribution. Associations of high renal activity on bone scintigrams with HCM have also been recognized. It is reasonable to consider that more calcium will accumulate in renal tube and more 99mTc-labeled MDP would combine and deposit in kidney, resulting in more renal toxicity in the condition of HCM. In this paper, we have reported a previously undescribed risk factor of deterioration of renal function in zoledronic acid treatment of skeletal metastasis – high serum calcium level – and have reported a modified method to treat HCM with zoledronic acid.

MATERIALS AND METHODS

Bone scan findings

Patients with histologically proven primary cancer and suspected of bone metastases were referred to the Department of Nuclear Medicine, Tianjin Cancer Hospital and Tianjin Union Medicine Center, Tianjin, China, from January 2011 to July 2011. The bone scans were obtained 3-4 h after infusion of 20 mCi of 99mTc-Sn-MDP. The patients were asked to drink water and then to void prior to scanning. The levels of serum calcium were recorded within 1 month of the scintigrams. A total of 1090 patients satisfied the criteria, including 493 cases of breast cancer, 356 cases of lung cancer, 39 cases of kidney cancer, 23 cases of prostate cancer, 21 cases of nasopharyngeal, 20 cases of colorectal cancer, 18 cases of lymphoma, 14 cases of esophageal cancer, 14 cases of gastric cancer, 11 cases of myeloma, and 81 cases of other cancers, and 26 cases with intense renal parenchymal uptake were concerned especially.

Method of zoledronic acid treatment

Each patient received an intravenous (IV) infusion of zoledronic acid 4 mg over 15 min every month for 6 doses. Delays of administration were required for notable changes in serum creatinine (SCr) level [Table 1]. For patients with a notable increase in SCr, the next dose was withheld until the SCr level returned to within 10% of the baseline SCr level.

Table 1

Definition of notable SCr level increases

Modified method of hypercalcemia treatment

Each patient with HCM due to bone metastases received hydration adjusted to maintain the urine output at more than 2 l/24 h, and intravenous infusion of calcitonin 10 mg on the first, second, and third day, respectively. In the cases of edema and changes of heart function, diuretics were used. When the serum calcium level decreased after the 3 days of pre-treatment, compared to the routine methods including the simultaneous administration of saline, calcitonin, and zoledronic acid treatment, the patient received an infusion of zoledronic acid 4 mg over 15 min every month for 6 doses [Table 2].

Table 2

Modified methods of malignant hypercalcemia treatment

Clinical studies of zoledronic acid treatment

A total of 56 patients with bone metastases were studied, including 21 cases of breast cancer, 16 of lung cancer, 4 of colorectal cancer, 3 of prostate cancer, 2 each of kidney, myeloma, and lymphoma, and 6 of other cancers. They were divided into three groups: Group A—13 patients with HCM received zoledronic acid treatment by the modified method suggested in Table 1; Group B—19 patients with HCM received zoledronic acid treatment by the routine methods; Group C—24 patients without HCM received zoledronic acid treatment by routine method.

RESULTS

Renal uptake of 99mTc-Sn-MDP

A total of 1090 patients satisfied the criteria, and 26 cases with intense renal parenchymal uptake were identified [Figures 1–4].

Figure 1

Appearances of the kidney on bone scintigraphy. Bone scintigraphy in a breast cancer patient with normal bone scan and normal renal parenchymal uptake

Figure 4

Appearances of the kidney on bone scintigraphy. Bone scintigraphy in a malignant lymphoma patient with bone metastases scan and intense renal parenchymal uptake

Appearances of the kidney on bone scintigraphy. Bone scintigraphy in a breast cancer patient with bone metastases scan and normal renal parenchymal uptake

Appearances of the kidney on bone scintigraphy. Bone scintigraphy in a lung cancer patient with normal bone scan and intense renal parenchymal uptake

Of the 26 patients with intense parenchymal uptake, 18 were HCM and 8 had normal calcium levels (normal range: 2.10-2.70 mmol/1). Of the 1064 patients without parenchymal uptake, 19 were HCM and 1023 had normal calcium levels. More patients with intense renal parenchymal uptake were HCM, statistically significantly (18/26 vs. 19/1064, P = 2.1, E-78) [Table 3].

Table 3

Renal uptake of 99mTc-Sn–diphosphonate and hypercalcemia

There was an apparent association between raised serum calcium and intensity of renal parenchymal uptake of MDP. This seemed to occur most often in patients with carcinoma who had bone metastases, but it was not true by our data [Table 4] as, of 26 patients with intense parenchymal uptake, 14 had bone metastases and 12 had normal bone scanning, and, of 1064 patients without parenchymal uptake, 438 had bone metastases and 1064 had normal bone scanning. No more patients with intense renal parenchymal uptake were associated with bone metastases (14/26 vs. 438/1064, P = 0.20) [Table 4].

Table 4

Renal uptake of 99mTc-Sn-diphosphonate and bone metastases

Zoledronic acid treatment

After pre-treatment with hydration, calcitonin, and diuretics, the serum calcium level of all 19 patients decreased, except for two. These two patients belonged to group B. The rate of renal injury appearance in three groups were 1/17, 5/15, and 2/24, respectively, after receiving an infusion of zoledronic acid 4 mg over 15 min every month for 6 doses. More HCM patients receiving zoledronic acid treatment showed renal injury as compared to patients with normal serum calcium level (5/15 vs. 2/24, P < 0.05) and HCM patients with pre-treatment to normal serum calcium level (5/15 vs. 1/17, P < 0.05) [Table 5].

Table 5

Results of zoledronic acid treatment

DISCUSSION

Since bisphosphates are calcium chelating agents, they precipitate calcium in the circumstances of solution state, such as blood circulation or urine in the renal tube. Their combination is according to the formula: [Ca2+] × [PO43−] =K ([Ca2+] is calcium concentration; [PO43−] is phosphate concentration; K is precipitation constant). If the serum concentration of either calcium (in HCM) or phosphate (in zoledronic acid infusion) is increased, more precipitation form. If the clearing of the precipitation is much slower than that of free bisphosphate, it accumulates in the renal tube. As the result, renal injury occurs.[2324]

Zoledronic acid 4 mg given as a 5-min infusion had been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which could progress to renal failure. The incidence of renal toxicity and renal failure had been shown to be reduced when zoledronic acid 4 mg was given as a 15-min infusion. Zoledronic acid should be administered over no less than 15 min.

More patients with intense renal parenchymal uptake were HCM, statistically significantly (18/26 vs. 19/1064, P = 2.1E-78). On the other hand, patients with known bone metastases did not exhibit more tendency of high renal activity and had normal distribution of MDP (14/26 vs. 438/1064, P = 0.20). An association between HCM and high accumulation of bisphosphate in kidney has been demonstrated in this paper. It was indicated that the presence of metastases alone was not the factor that was associated with intense renal parenchymal uptake and that it is only when HCM occurs in association with carcinoma and bone metastases that the intense renal uptake occurs. Neither serum calcium level or bone scintigrams was routine test in this retrospective study. It was not easy to find the patients with both tests. The calcium levels were drawn up to 1 month away from the test. It was a long time for metastatic patients and might have missed some patients that also had HCM. This was potentially a confounding factor for the results in this study. Certain types of cancers may have the impact on the apparent correlation between renal disease and HCM. Multiple myeloma (MM) is one of the most typical ones, which should be mentioned, although there are few cases in our study. MM is a clonal B-cell disease of slowly proliferating plasma cells, accompanied by monoclonal protein production and lytic bone lesions. It is well known that free light chains play a crucial role in causing such renal damage. HCM is produced in patients with MM due to the increased bone resorption caused by osteoclasts activation, especially due to the hyperactivity of the RANK/RANKL receptor. HCM can produce calcium salt deposits in tissues, especially those with an alkaline medium, such as kidneys.[25]

Increased uptake of another bone radiopharmaceutical (99mTc-HEDP) in ischemic rabbit kidneys has been demonstrated.[2021] The calcium concentration in these ischemic kidneys was at least six times greater than normal and the uptake of HEDP was significantly greater than in normal kidneys. It would, however, seem that the high uptake of HEDP was related to the high calcium content in the ischemic kidneys. A possible explanation is that there may be high tissue calcium in the kidneys of hypercalcemic patients that could account for the high uptake of 99mTc-MDP. Bossuyt suggested that increased uptake in kidneys is due to nephrocalcinosis in the hypercalcemic patients.[26]

Although bisphosphonates are commonly used to treat established HCM, they have also been given to prevent the other SREs in patients with metastatic cancer to bone. The bisphosphonates are nonhydrolyzable analogs of inorganic pyrophosphate that adsorb to the surface of bone hydroxyapatite and inhibit calcium release by interfering with osteoclasts-mediated bone resorption.[272829]

Routine therapy of HCM includes simultaneous administration of saline, calcitonin, and bisphosphonate.[30] As our results showed there may be high tissue calcium in the kidneys in hypercalcemic patients, which may result in an increased risk of renal toxicity. Our modified method for treatment of HCM with zoledronic acid is that the blood calcium is reduced to normal level with saline and/or calcitonin and zoledronic acid is used subsequently. It has been demonstrated that saline and calcitonin can reduce calcium concentration rapidly, but sustained shorter efficiency duration. In contrast, zoledronic acid is a more potent agent for management of HCM due to excessive bone resorption. More HCM patients receiving zoledronic acid treatment showed renal injury as compared to patients with normal serum calcium level (5/15 vs. 2/24, P < 0.05) and HCM patients with pre-treatment to normal serum calcium level (5/15 vs. 1/17, P < 0.05).

We conclude that HCM should be considered as an increased risk of renal toxicity observed on HCM treatment with zoledronic acid and suggest that the serum calcium should be measured and reduced to normal level before zoledronic acid would be used in the management of adverse skeletal events.