A Case of Severe,Prolonged,Refractory Hypophosphatemia After Zoledronic Acid Administration

Introduction

The bisphosphonate zoledronic acid (ZA) is approved by the Food and Drug Administration (FDA) for the treatment of hypercalcemia of malignancy (HCM), along with multiple myeloma and metastatic bone lesions of solid tumors. ¹ Intravenous ZA is a recommended option for the treatment of HCM due to its ease of administration, efficacy in lowering calcium levels, and favorable safety profile. ^{2 –6} Although hypophosphatemia is not an uncommon adverse effect of ZA, we describe a case of extremely refractory and prolonged hypophosphatemia in a patient who received ZA for HCM. To the authors’ knowledge, this duration and severity of hypophosphatemia in response to ZA has not been reported in the literature.

Case

A 51-year-old Caucasian male with a medical history of hypertension, large B-cell lymphoma, chronic osteomyelitis, chronic pain syndrome, and chronic hypokalemia presented to the neuroscience intensive care unit (ICU) for fluctuating level of consciousness following a witnessed generalized tonic–clonic seizure. On the third day of his ICU stay, hematology was consulted regarding possible lymphoma recurrence and HCM. ZA 4 mg intravenously was administered as a single dose (day 0). On this day, the patient’s corrected serum calcium was 12.5 mg/dL (reference range 8.9-10.2 mg/dL) and the ionized calcium level was 6.45 mg/dL (reference range 4.80-5.70 mg/dL).

Just prior to ZA administration, the patient’s serum phosphorus was 3.6 mg/dL, within the reference range of 2.5 to 4.5 mg/dL. He had not required any phosphate replacement during his ICU stay up to that point. On day 3 after ZA, the first laboratory evidence of hypophosphatemia was noted at 2.1 mg/dL (see Table 1). No phosphate replacement was given. The following day (day 4), serum phosphorus level decreased to 1.8 mg/dL, for which a total of 6 packets of sodium/potassium phosphate was required (1 packet = 250 mg or 8.1 mmol phosphate for a total of 48.6 mmol). Despite this, on day 5, serum phosphorus level dropped to 0.9 mg/dL, for which the patient received both oral and intravenous phosphate replacement totaling about 60 mmol. Multiple, repeat daily doses of both intravenous and oral phosphate were required therein through day 33 after ZA when the patient died due to malignancy-related complications unrelated to hypophosphatemia. The doses of replacement phosphate administered via both oral and intravenous routes were highest in the first 2 weeks after ZA; between days 4 and 15, the average daily phosphate dose given was 77 mmol. Notably, this amount did not include phosphate sources in the patient’s tube feeds, which were changed from Osmolite 1.5 (Abbott Nutrition, IL, USA) to Promote (Abbott Nutrition, IL, USA) on day 7 for increased phosphate provision of 2016 mg/d (65.3 mmol) at goal feeds. Tube feeds were switched back to the lower phosphate Osmolite 1.5, which provided 1080 mg (35 mmol) phosphate at goal rate, on day 24 for unrelated reasons. Despite the high total daily dosing of phosphate from both replacement and dietary sources, serum phosphorus levels did not stabilize in the normal range for over 30 days after ZA, as he continued to require intermittent phosphate replacement but to a lesser degree than days 16 through 33.

OPEN IN VIEWER

Table 1.

Serum Phosphorus Values and Replacement Phosphate Doses.

Days After ZA Administration	Serum Phosphorus Range,a mg/dL	Ionized Calcium, mg/dLb	Enteral Phosphate Replacementc		Intravenous Phosphate Replacement, mmol	Total Daily Phosphate Replacement
			mg	mmol		mmol	mmol/kg
Day 0	3.6	6.45
Day 1	2.7-2.8	7.66
Day 2	2.6-3.1	6.01
Day 3	2.1	5.57
Day 4	1.8	4.89	1500	48.6		48.6	0.68
Day 5	0.9-1.8	4.45	500	16.2	45	61.2	0.85
Day 6	1.1-1.6	4.29	2500	81	45	126	1.75
Day 7	1.3-1.9	4.01	1000	32.4	45	77.4	1.08
Day 8	2.1	4.29	500	16.2	90	106.2	1.48
Day 9	1.3-2.1				60	60	0.83
Day 10	1.9-2.2				45	45	0.63
Day 11	1.3-2.2	4.89	1500	48.6	75	123.6	1.72
Day 12	2.3		2500	81	15	96	1.33
Day 13	2.3-3.2	5.05	2500	81	15	96	1.33
Day 14	2.7		2500	81		81	1.13
Day 15	3-3.5	5.01	1500	48.6		48.6	0.68
Day 16	2.6-2.9	4.69
Day 17	2.4-3.9	4.81			20	20	0.28
Day 18	2.9-4.4	4.81
Day 19	2-3	4.81			30	30	0.42
Day 20	2.9	4.49
Day 21	3.1-3.4	4.33
Day 22	2.2-2.5				15	15	0.21
Day 23	1.5-3	4.21	1000	32.4	30	62.4	0.87
Day 24	1.4-3.3	4.25			45	45	0.63
Day 25	2.1-2.3	4.77			35	35	0.49
Day 26	2.5	5.17
Day 27	2.9	5.09
Day 28	1.8	5.01			30	30	0.42
Day 29	1.4				30	30	0.42
Day 30
Day 31	1.6				45	45	0.63
Day 32		5.25
Day 33	2.1		1000	32.4		32.4	0.45

Abbreviation: ZA, zoledronic acid.

^aSerum phosphorus reference range 2.5 to 4.5 mg/dL.

^bSerum ionized calcium reference range 4.80 to 5.70 mg/dL.

^cOne sodium/potassium phosphate oral packet contains 250 mg or 8.1 mmol of phosphorus. This does not include dietary sources of phosphate.

Serum ionized calcium levels peaked on day 1 following ZA (7.66 mg/dL) and normalized at 5.57 mg/dL on day 3. No further laboratory occurrence of hypercalcemia was seen. Regarding other electrolyte abnormalities following ZA administration, the patient did exhibit persistent hypokalemia, and potassium requirements however remained stable and similar to that prior to ZA. The patient did not have laboratory evidence of hypomagnesemia.

Discussion

ZA is approved for the treatment of HCM when serum calcium levels exceed 12 mg/dL and for the use in patients with multiple myeloma and those with metastatic bone lesions of solid tumors. ¹ ZA has more potent effects on calcium and can cause a more profound hypocalcemic state than other bisphosphonates. ^{5 –9} As a class, bisphosphonates prevent calcium resorption into the bone, thus increasing calciuria. They also have direct inhibitory effects on osteoclast activity by causing apoptosis. ^{10 –13}

We conducted an extensive literature review via MEDLINE using the search terms “zoledronic acid,” “bisphosphonates,” “diphosphonates,” and “hypophosphatemia” and also searched the reference lists of articles.

Hypophosphatemia (serum phosphorus <2.5 mg/dL) has been reported in clinical trials of patients receiving ZA for HCM. ^9,14,15 Reports of the incidence of hypophosphatemia after ZA range from 3.5% to 51%. In an early dose finding study of ZA in HCM, 21% (7 of the 33 patients) developed transient hypophosphatemia. ⁹ Subsequently, 2 pivotal clinical studies to obtain FDA approval for HCM treatment reported an incidence of hypophosphatemia of just 3.5% (3 of the 86) in patients who received ZA 4 mg compared to 1% (1 of the 103) in patients who received pamidronate 90 mg. ¹⁴ A more recent clinical trial of ZA for the treatment of HCM found asymptomatic hypophosphatemia in 38% (10 of the 26) of the patients. ¹⁵ The manufacturer’s prescribing information cites an incidence of grade 3 hypophosphatemia (serum phosphorus level <2 mg/dL) of 51% (36 of the 70) and grade 4 hypophosphatemia (serum phosphorus <1 mg/dL) of 1% (1 of 70) in patients who received ZA for HCM compared to 33% (27/81) and 5% (5/81), respectively, in patients who received pamidronate for the same indication. ¹

To the authors’ knowledge, no case report or other publication has described this severity or duration of refractory hypophosphatemia following administration of ZA. Our patient experienced persistent hypophosphatemia despite high doses of both replacement and dietary phosphate for over 30 days following ZA. The daily range of the patient’s serum phosphorus values and the intravenous and enteral doses of phosphate administered are listed in Table 1. The first dose of phosphate was administered on day 4 following ZA, and the average daily replacement phosphate dose administered from days 4 through 15 via intravenous and enteral routes was 77 mmol. The patient’s hypophosphatemia and the need for replacement persisted through day 33 post-ZA, with serum phosphorus levels of <2 mg/dL measured on 12 of the 33 days and levels of <1.5 mg/dL on 7 of the 33 days.

Brown et al have studied adequate dosing for the treatment of hypophosphatemia in critically ill patients and recommend that severe hypophosphatemia (serum level <1.5 mg/dL) be treated with 0.64 mmol phosphorus/kg. ¹⁶ Repeat doses may sometimes be needed. With this guidance and the patient’s weight of 72 kg, the suggested intravenous dose to treat severe hypophosphatemia would be about 45 mmol. On days 4 through 15, the average daily dose of 77 mmol/d was equivalent to 1.1 mmol/kg. Despite this dosing, normophosphatemia was not achieved. Of note, this amount does not include that received from the patient’s tube feeds of Promote (given days 7-24), which provided up to 2016 mg/d (65.3 mmol), nearly triple the recommended daily allowance of phosphorus of 700 mg (22.6 mmol). ¹⁷ The daily parenteral requirement is 20 to 40 mmol. ¹⁸

It has been proposed that ZA-induced hypophosphatemia results from an increase in parathyroid hormone (PTH) in response to the abrupt reduction or normalization of serum calcium levels. ^19,20 Another suggested mechanism is the inhibition of bone resorption resulting in decreased release of phosphorus from the bone into the blood. ¹⁹ The effects of ZA on calcium level in HCM can be fully seen in 7 days, and the duration may last up to 40 days. ^15,21 It is thus reasonable to expect that hypophosphatemia associated with ZA may also be of prolonged duration.

Upon careful review, other factors attributable to this degree and timing of hypophosphatemia were not evident, other than vitamin D deficiency, which was present prior to ZA administration. Causes of hypophosphatemia are multifactorial and include (1) insufficient intake or impaired absorption, including malnutrition, vitamin D deficiency, chronic diarrhea, or use of phosphorus-binding antacids; (2) redistribution or intracellular shifting, as with increased insulin secretion in response to dextrose infusion or refeeding syndrome or with respiratory alkalosis; and (3) increased urinary excretion of phosphorus, which can result from hyperparathyroidism, osmotic diuresis, or renal tubular acidosis. ^20,22,23 The risk of hypophosphatemia and other electrolyte disturbances is also higher in critically ill patients who may have a number of reasons for deficiency or losses. ^16,23 We did not suspect that malabsorption (eg, bowel resection, bowel ischemia, diarrhea not present) nor refeeding syndrome was contributor in this case. The patient did not have recent weight loss and was not without nutrition for a prolonged amount of time. Additionally, other medications associated with hypophosphatemia (eg, diuretics, epinephrine, valproic acid, anticancer agents) ²⁰ were not given during this time frame. Insulin was administered intermittently but no more than 4 U aspart on any given day, and on most days, no insulin was given. The patient had neither renal impairment nor a remarkable acid/base disturbance. Serum PTH level was in fact low (12 pg/mL; reference range 15-65 pg/mL) prior to ZA administration. The patient had a low serum 25-hydroxy vitamin D level of 6.8 ng/mL (severe deficiency defined as <10 ng/mL), measured on laboratories prior to ZA administration, which may have increased the risk for the development of hypophosphatemia and its refractory nature after ZA administration. A single dose of ergocalciferol 50 000 U orally was given, but this was discontinued for concerns it could have worsened his hypercalcemia. Applying the Naranjo adverse drug reaction probability scale reveals a probability score of “possible.” ²⁴ It is difficult to strengthen the association via this tool with only a single dose of ZA administered.

Risks of severe hypophosphatemia include respiratory suppression and muscle weakness and cardiac abnormalities. The serum level at which signs and symptoms manifest is usually <1 mg/dL. ²³ Despite the patient’s severe hypophosphatemia, he did not exhibit overt clinical signs of deficiency, although it was difficult to determine given the patient was ventilated and sedated throughout the course.

This is the first case report to describe this degree of refractory hypophosphatemia following ZA administration. The following limitations are noteworthy. Our ability to ascertain a more definite causal relationship was limited by the patient’s concomitant vitamin D deficiency, which may have increased the propensity for the development of hypophosphatemia following ZA. Also, since our patient received only a single dose of ZA, we were unable to assess any effect of previous exposure, of repeated or reduced dosing, or of discontinuation of therapy on serum phosphorus levels, which would have strengthened the association of the adverse effect with the drug. Another limitation is the inability to quantify the exact contribution of dietary phosphate, given interruptions in tube feeding and limitations in charted tube feeding, although the contribution was likely substantial, given the patient’s good tolerance of tube feeding well before and after ZA administration. Strengths of this case study include the well-defined temporal relationship between ZA administration and hypophosphatemia, the ability to exclude documented risk factors for hypophosphatemia other than vitamin D deficiency, an established mechanism for hypophosphatemia and the prolonged duration of action of ZA on bone, and previous reports of hypophosphatemia with ZA use, albeit of lesser severity and shorter duration.

Currently, the American Society of Clinical Oncology and the International Society of Geriatric Oncology recommend routine monitoring with bisphosphonate use that includes broadly renal function and serum electrolyte monitoring. ^25,26 In patients with risk factors for hypophosphatemia, close monitoring of serum electrolytes, including phosphorus, is warranted after ZA administration.

Conclusion

Electrolyte abnormalities may occur after ZA administration. This report illustrates an unusual case of severe, refractory hypophosphatemia that occurred following ZA administration. The authors recommend inclusion of serum phosphorus with routine electrolyte monitoring following ZA in patients with risk factors for electrolyte deficiency or who are critically ill. Aggressive treatment of hypophosphatemia should be provided if indicated. In this case, phosphate administration to treat deficiency following ZA greatly exceeded expected doses otherwise needed for the treatment of uncomplicated severe hypophosphatemia.