2020 Volume 67 Issue 1 Pages 31-35
We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.
DENOSUMAB is a human monoclonal antibody that prevents adhesion between a receptor activator of nuclear factor κB (RANK) and RANK ligand. It inhibits recruitment and differentiation of osteoclasts. Denosumab is used to treat osteoporosis and reduce the number of skeletal-related events in patients with solid tumors (e.g. breast or prostate cancer) or bone metastases [1]. Few cases of hypercalcemia after discontinuation of denosumab have been reported [2-6].
Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone involved in maintaining phosphate homeostasis. FGF-23 increases urinary phosphate excretion and decreases intestinal phosphorous absorption by suppressing the synthesis of 1,25-dihydroxyvitamin D3 [7], leading to hypophosphatemia. Hypophosphatemic patients diagnosed with tumor-induced osteomalacia or several inherited hypophosphatemic disorders show high plasma levels of FGF-23 [7].
Here, we report a case of hypercalcemia following discontinuation of denosumab with markedly elevated levels of circulating FGF-23.
At age 42, the patient underwent right mastectomy for breast cancer, and received the aromatase inhibitor letrozole (2.5 mg/day). She had joined a clinical trial (20060359 study) and therefore had received subcutaneous denosumab (120 mg every month for the first 6 months, followed by 120 mg every 3 months for the next 4.5 years) until 6 months before her hospitalization. At age 46, bilateral oophorectomy was performed due to ovarian cysts. In total, 3,600 mg of denosumab was administered over 5 years to prevent bone metastasis. Several months after the final dose of denosumab, the patient developed thirst, appetite loss, and bilateral ankle pain. She was referred to our hospital 6 months after the last injection of denosumab because of hypercalcemia. On examination, height was 163 cm and weight was 39 kg. Temperature was 36.6°C, blood pressure was 97/52 mmHg, and heart rate was 107 beats per minute. She had diffuse goiter and was diagnosed with Graves’ disease. Laboratory investigation showed hypercalcemia, elevated fractional excretion of calcium, normal estimated glomerular filtration rate, and decreased plasma levels of 1,25-dihydroxyvitamin D3 (Table 1). Urinary phosphorus excretion was high, but plasma levels of phosphorus and intact PTH were within normal limits. Further investigation revealed that plasma levels of FGF-23 were extremely high (4,000 pg/mL, reference range: 10–50). Serum levels of tartrate-resistant acid phosphatase 5b (TRACP-5b) and urinary levels of N-terminal cross-linked telopeptide of type I collagen (NTX) were both elevated (Table 1). Bone scintigraphy revealed markedly increased uptake 1 month after admission (Fig. 1A, 1B), suggesting progression of severe bone resorption. Although plasma levels of intact PTH were not suppressed, technetium-99 methoxyisobutylisonitrile scintigraphy and computed tomography showed no PTH-secreting tumors. Radiological investigations did not show recurrence of breast cancer or bone metastasis. The patient was treated with thiamazole and potassium iodine for hyperthyroidism, discontinuation of the aromatase inhibitor that was suspected of causing hypercalcemia, saline infusion, and calcitonin. The hyperthyroidism improved, but the hypercalcemia persisted for one month (Fig. 2). Administration of zoledronic acid improved the hypercalcemia and decreased the urinary excretion of calcium (Fig. 2). Five months after treatment, abnormal uptake on bone scintigraphy was decreased (Fig. 1C) and ankle pain had resolved. Although hypocalcemia developed transiently after the administration of zoledronic acid, serum calcium concentrations were maintained within normal limits for the next 2 years.
| Laboratory Test | Values | Reference range |
|---|---|---|
| Serum | ||
| Albumin (g/dL) | 3.8 | 3.8–5.2 |
| Corrected calcium (mmol/L) | 3.59 | 2.10–2.54 |
| Phosphorus (mmol/L) | 1.29 | 0.97–1.52 |
| Intact PTH (pg/mL) | 23 | 10–65 |
| PTHrP (pmol/L) | <1.0 | <1.0 |
| 25-hydroxyvitamin D (ng/mL) | 29 | 20–50 |
| 1,25-dihydroxyvitamin D (pg/mL) | 6 | 18–78 |
| FGF-23 (pg/mL) | 4,000 | 10–50 |
| BAP (μg/L) | 18.6 | 3.8–22.6 |
| TRACP-5b (mU/dL) | 724 | 120–420 |
| Free T3 (pg/mL) | >30.0 | 1.71–3.71 |
| Free T4 (ng/dL) | 3.85 | 0.70–1.48 |
| TSH (μIU/mL) | <0.01 | 0.35–4.94 |
| TRAb (%) | 87.2 | <15 |
| LH (mIU/mL) | 45.8 | 7.7–58.5 |
| FSH (mIU/mL) | 61.4 | <157.8 |
| Estradiol (pg/mL) | <10 | <47 |
| eGFR (mL/min/1.73 m2) | 66 | >90 |
| 24-h urine | ||
| Urine volume (mL/day) | 3,800 | <3,000 |
| %TRP (%) | 66 | 81–90 |
| FECa (%) | 6.6 | 2–4 |
| NTX (nmol BCE/mmol creatinine) | 510 | 14.3–89.0 |
Abbreviations: BAP, bone alkaline phosphatase; BCE, bone collagen equivalent; eGFR, estimated glomerular filtration rate; FECa, fractional excretion of calcium; FGF-23, fibroblast growth factor 23; NTX, N-telopeptide of type I collagen; TRAb, TSH receptor antibody; TRACP-5b, tartrate-resistant acid phosphatase 5b; %TRP, percentage tubular reabsorption of phosphate.
Bone scintigraphy before and after zoledronic acid treatment. (A) On admission. (B) One month after admission. (C) Five months after zoledronic acid treatment.
Clinical course
*: measured on day 359 after zoledronic acid administration
Abbreviations: FECa, fractional excretion of calcium; FGF-23, fibroblast growth factor 23; S, serum; U, urine
We described a patient with hypercalcemia and markedly elevated levels of circulating FGF-23 following discontinuation of denosumab. Hyperthyroidism, aromatase inhibitor therapy, a PTH-producing tumor, and discontinuation of denosumab treatment were considered as possible causes of the hypercalcemia in this case. Hypercalcemia due to hyperthyroidism is induced by the activation of bone resorption, and is ameliorated by normalization of thyroid function [8]. Letrozole, an aromatase inhibitor, increases bone resorption and leads to hypercalcemia [9]. In our case, hypercalcemia lasted for 1 month despite normalization of hyperthyroidism and discontinuation of letrozole. Intact PTH was not suppressed during the hypercalcemic period, but no PTH-producing tumor was detected by radiological investigations. We could not exclude an occult PTH-producing tumor, but the chronic and massive phosphorus load induced by bone resorption might have stimulated PTH secretion. To date, five cases of hypercalcemia after discontinuation of denosumab have been reported [2-6] (Table 2). Four of five cases were in pediatric patients; our patient was the second case in an adult (Table 2). Underlying diseases were variable, and serum levels of calcium were remarkably high (median, 1.22 mmol/L higher than upper normal limit). Hypercalcemia occurred at 7 weeks to 6 months (median, 4.5 months) after the last denosumab dose. Pediatric cases had shorter duration of denosumab administration than adult cases (2 to 24 months and 5 to 10 years, respectively). All patients had elevated bone resorption markers and bisphosphonate administration was effective. Recurrence of hypercalcemia was reported in pediatric but not adult patients. Circulating FGF-23 was slightly high in Patient 1 (95.5 pg/mL) [2] but extremely high in our patient (4,000 pg/mL).
| Case | Age/Sex | Underlying disease |
S-Calcium (mmol/L) |
FGF-23 (pg/mL) |
Duration of denosumab administration | Total dose of denosumab | Time to onset of hypercalcemia after cessation of denosumab | Time to relapse of hypercalcemia after initial treatment | Reference |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 9/M | FD MAS |
4.50 (2.10–2.60) |
95.5 (20–50) |
7 M | 8.25 mg/kg | 2 M | N/A | [2] |
| 2 | 8/F | JPD | *4.07 (2.15–2.45) |
N/A | 2 M | 1 mg/kg | 7 W | N/A | [3] |
| 3 | 14/F | GCTB | *4.13 (2.18–2.70) |
N/A | 24 M | 3,240 mg | 5 M | 5–10 M | [4] |
| 4 | 10/F | GCTB | 3.80 (2.22–2.72) |
N/A | 14 M | 1,440 mg | 4 M | 5 W | [5] |
| 5 | 77/F | Osteoporosis | 3.10 (2.20–2.55) |
N/A | 10 Y | 1,200 mg | 5 M | N/A | [6] |
| Present case | 47/F | Graves’ disease Breast cancer |
3.59 (2.10–2.54) |
4,000 (10–50) |
5 Y | 3,600 mg | 6 M | N/A |
*: calculated with 1 mg/dL as 0.25 mmol/L
Abbreviations: FD, fibrous dysplasia; FGF-23, fibroblast growth factor 23; GCTB, giant cell tumor of bone; JPD, juvenile Paget’s disease; M, months; MAS, McCune-Albright syndrome; N/A, not available; S, serum; W, weeks; Y, years
FGF-23 is predominately produced by osteocytes and acts as a phosphaturic hormone in maintaining phosphate homeostasis. High plasma levels of FGF-23 are useful for diagnosing hypophosphatemia in patients with tumor-induced osteomalacia or several inherited hypophosphatemic disorders such as X-linked hypophosphatemia and fibrous dysplasia [7]. In patients with chronic kidney disease (CKD), circulating FGF-23 levels are elevated to maintain normal phosphorus balance by increasing urinary phosphate excretion. Plasma levels of FGF-23 starts to increase in early stages of CKD and increase up to 1,000-fold of the upper limit of the normal range in end-stage renal disease [10]. In healthy adults with normal renal function, continuous but not acute high-phosphorus diets lead to FGF-23 elevation without changes in serum phosphate levels [11], suggesting that FGF-23 is secreted when there is a continuously high phosphorus load. In our patient, abnormal uptake on bone scintigraphy and high levels of TRACP-5b and NTX suggested that the increased blood phosphorus load was due to bone resorption after discontinuation of denosumab, particularly since the PTH level was normal and there was no excess phosphorus absorption from the intestine. High plasma levels of FGF-23 might be induced by chronic and massive bone resorption lasting over 1 month or by an unknown mechanism whereby osteocytes produce FGF-23 after discontinuation of denosumab. Normophosphatemia and normal renal function in this case led us to hypothesize that the high phosphorus load led to FGF-23 secretion, which increased phosphorus excretion into the urine. Reduction of bone resorption with zoledronic acid ameliorated ankle pain, abnormal uptake on bone scintigraphy, and high levels of circulating FGF-23.
In conclusion, the present patient showed hypercalcemia and high levels of FGF-23 due to abnormal bone resorption after discontinuation of denosumab. To the best of our knowledge, this is the first report showing high levels of FGF-23 induced by bone resorption in a patient without renal phosphorus wasting disorders or CKD. Precise mechanisms underlying the elevation of circulating FGF-23 levels have not been determined, the present case provides novel insights on FGF-23 in patients with severe bone resorption. More attention should be paid to hypercalcemia 6 months after the discontinuation of long-term denosumab treatment. FGF-23 might be a biomarker of massive bone resorption triggered by discontinuation of long-term denosumab treatment.
T. U. and H. Y. wrote the case report. C. K., T. Y., and M. N. contributed to the clinical management of this patient.
The authors have nothing to disclose.
