Novel Insights from Clinical Practice / Case Report Horm Res Paediatr DOI: 10.1159/000510625
Received: March 3, 2020 Accepted: August 3, 2020 Published online: September 30, 2020
Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism Elizaveta Mamedova a Anna Kolodkina b Evgeny V. Vasilyev b Vasiliy Petrov b Zhanna Belaya a Anatoly Tiulpakov b
aDepartment bDepartment
of Neuroendocrinology and Bone Diseases, Endocrinology Research Centre, Moscow, Russia; and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russia
Established Facts • Primary hyperparathyroidism is rare in children, and it is usually symptomatic at presentation. • Denosumab has been used off-label in children with osteogenesis imperfecta, aneurysmal bone cysts, fibrous dysplasia, and several other disorders.
Novel Insights • Denosumab has demonstrated a good safety profile and efficacy in lowering serum calcium in a pediatric patient with primary hyperparathyroidism and a hypercalcemic crisis.
Abstract Introduction: Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. Case Presentation: A 16-year-old fe-
[email protected] www.karger.com/hrp
© 2020 S. Karger AG, Basel
male was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15–2.55), parathyroid hormone 2,151 pg/ mL (15–65), and phosphate 1.07 mmol/L (1.45–1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient’s condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological exami-
Anatoly Tiulpakov Department of Inherited Endocrine Disorders, Endocrinology Research Centre Dmitriya Ulianova Street, 11 Moscow 117036 (Russian Federation) genes @ endocrincentr.ru
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Keywords Denosumab · Primary hyperparathyroidism · Children · CDC73 · Hypercalcemia · Hypercalcemic crisis
© 2020 S. Karger AG, Basel
Introduction
Primary hyperparathyroidism (PHPT) is rare in children [1, 2]. In contrast to adult patients, the majority of pediatric patients with PHPT (up to 95%) are symptomatic, with high prevalence of skeletal involvement (9– 89%), kidney stones (25–50%), hypercalcemic crises (9– 50%), and unspecific symptoms (abdominal pain, arterial hypertension, fatigue, etc.) [1, 2]. PHPT in children may be sporadic (65–70%) or familial (27–31%) [1]. The latter could be a part of several familial syndromes, including multiple endocrine neoplasia types 1, 2A, and 4; hyperparathyroidism-jaw tumor syndrome; familial hypocalciuric hypercalcemia types 1–3; and familial isolated hyperparathyroidism [3]. Denosumab, a human monoclonal antibody of the receptor activator of nuclear factor kappa-B ligand (RANKL), is approved for the treatment of osteoporosis in adults at a dose of 60 mg subcutaneously every 6 months and for the treatment of skeletal metastases, giant-cell tumors, and hypercalcemia of malignancy at a dose of 120 mg subcutaneously every 4 weeks [4]. According to the literature, denosumab has been used offlabel in adults with PHPT for the treatment of hypercalcemia prior to a parathyroidectomy [5, 6], long-term management of parathyroid carcinoma-mediated hypercalcemia [7–9], and medical treatment of osteoporosis in PHPT [10]. It has been used off-label in children with several skeletal diseases, for example, osteogenesis imperfecta [11–13], fibrous dysplasia [14], aneurysmal bone cysts [15–18], giant-cell tumors [19], Paget’s disease of bone [20], glucocorticoid-induced osteoporosis in Duchenne muscular dystrophy [21], osteoradionecrosis [22], cherubism [18, 23], as well as for hypercalcemia reduction after bone-marrow transplantation in osteopetrosis [24] and in squamous cell carcinoma [25]. To our knowledge, only 1 case of denosumab usage in a child with severe PHPT due to a parathyroid carcinoma and ineffectiveness of bisphosphonates has been reported to date [26]. 2
Horm Res Paediatr DOI: 10.1159/000510625
Methods Blood Analysis The patient had fasting 8–9:00 a.m. serum samples taken to obtain routine biochemistry and hormonal status (parathyroid hormone [PTH]). Routine biochemistry was performed on Architect 8000 (Abbott, Chicago, IL, USA). Serum samples of PTH were assayed by electrochemiluminescence (ECLIA) Cobas 6000 Module e601 Roche (reference range 15–65). DNA Analysis Genomic DNA was extracted from peripheral leukocytes and homogenized fresh frozen tumor tissue using PureLink® Genomic DNA Mini Kits (Thermo Scientific, Waltham, MA, USA). A custom Ion AmpliseqTM panel (Ion Torrent, Thermo Scientific, Waltham, MA, USA) targeting 9 genes associated with familial forms of PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, and CDKN2D) was used for DNA library preparation. Sequencing was performed using the Personal Genome Machine (PGM) semiconductor sequencer (Ion Torrent, Thermo Scientific, Waltham, MA, USA). Bioinformatics analysis was carried out using Torrent Suite 4.2.1 (Thermo Scientific, Waltham, MA, USA) and ANNOVAR ver. 2018Apr16 software packages [27]. The results of the NGS were confirmed by Sanger sequencing using the Genetic Analyzer 3130 sequencer (Life Technologies, Carlsbad, CA, USA). A description of the sequence variants was given in accordance with the recommendations of Human Genome Variation Society [28]. Case Report A 16-year-old girl was initially referred to our care for the treatment of established PHPT. The patient was from a nonconsanguineous family, at birth her weight was 2.4 kg and length 47 cm. The family history was suggestive of PHPT; the maternal grandmother had neck surgery and developed kidney stones later in life. Five months before admission, the patient reported progressive pain in the right thigh, with gradual limp development. Two months before admission, a closed pathologic intertrochanteric fracture of the right hip with displacement occurred. The patient was hospitalized in a secondary care center, where she underwent skeletal traction with subsequent plaster cast. The plain radiographs showed a bone cyst in the upper third of the right femur and multiple bone lytic lesions in the pelvis, skull, right humerus, and ribs. During hospitalization, a spontaneous fracture of the upper third of the right humerus occurred. The biochemical test showed severe hypercalcemia: serum total calcium 3.93 mmol/L (2.15–2.55) and serum ionized calcium 2 mmol/L (1.03–1.29), with marked elevation of PTH 2,207 pg/mL (15–65), which confirmed the diagnosis of PHPT. At admission, the patient suffered from nausea, vomiting, polyuria, polydipsia, pruritus, and extensive weight loss. She was immobilized due to the hip fracture, which did not allow measurement of her height and weight. On examination, her blood pressure was 120/80 mm Hg, her heart rate was 110 beats per min, and her temperature was 36.7°C. She developed cachexia with severe loss of adipose tissue and skeletal muscle. Her laboratory data are presented in Table 1. Neck ultrasound revealed a tumor of the right inferior parathyroid gland 1.8 × 1.5 × 1.2 cm, confirmed by (99 m) Tc-sestamibi single photon emission tomography combined with X-ray
Mamedova/Kolodkina/Vasilyev/Petrov/ Belaya/Tiulpakov
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nation revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. Conclusion: Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.
mmol/L
4.50 4.30 4.10 3.90 3.70 3.50 3.30 3.10 2.90 2.70 2.50 2.30 2.10 1.90 1.70 1.50 1.30 1.10 0.90 0.70 0.50
3.93
Calcium
4.17
3.30
3.30
2.93
2.57
2.81 2.70 2.87 2.80 2.79 2.79
2.87 2.89
2.93
2.25
1.3
–12 d –5 d
1.07 0.95
0
0.79
12 h 24 h
0.74 0.62 2d
5d
0.73 0.78
6d
7d
0.65 8d
0.81
9d
Phosphate
12 d 14 d 16 d 19 d
1.99
1.88 1.71
0.78 0.82
0.66 0.72 0.55 0.68
Time
2.43
2.36
0.69
+1 d +2 d +5 d +9 d +14 d +19 d
Fig. 1. Changes in serum calcium and phosphate levels after denosumab injection and saline infusion (thin arrow) and after surgery (thick arrow). X axis, time after denosumab injection and after surgery; h, hours; d, days; 0, the day of admission; Y axis, concentration, mmol/L.
Denosumab in a Pediatric Patient with Primary Hyperparathyroidism
Table 1. The patient’s laboratory data
Parameters
Results
Reference range
Serum total calcium, mmol/L Serum ionized calcium, mmol/L Creatinine, μmol/L PTH, pg/mL Phosphate, mmol/L Serum total protein, g/L Glucose, mmol/L Aspartate aminotransferase, IU/L Alanine aminotransferase, IU/L Hemoglobin, g/L Hematocrit, % White blood cell count, per mm3 Red blood cell count, per mm3
4.17 2.14 56.2 2,151 1.07 59 3.61 35 15 86 27.3 10,340 3,090,000
Red blood cell sedimentation rate, mm/h Platelet count, per mm3
43 535,000
2.15–2.55 1.03–1.29 27–62 15–65 1.45–1.78 60–80 3.1–6.1 15–60 7–35 115–150 35–46 4,500–9,500 3,800,000– 5,200,000 2–15 152,000– 372,000
PTH, parathyroid hormone.
(Fig. 1) which was corrected only with high doses of alfacalcidol (up to 4.5 μg/per day) and calcium supplements (up to 4,500 mg/ per day). Hypophosphatemia persisted after surgery, requiring phosphate supplementation (280 mg/per day). In addition, the patient’s mother showed elevated serum calcium (2.7 mmol/L, reference range, 2.15–2.55) and upper-normal
Horm Res Paediatr DOI: 10.1159/000510625
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computed tomography. Abdominal ultrasound showed no kidney stones. Saline infusion of 500 mL was administered the day before admission, and on admission, saline infusion was increased to 2.5 L/24 h. Taking into account the critical condition of the patient, the decision was made to administer denosumab alongside with saline infusion to acutely lower serum calcium, based on the authors’ personal observations of its ability to significantly lower serum calcium in adults with severe PHPT. Moreover, bisphosphonates remain in bone tissue for years, and the authors felt it was preferable to avoid this potential exposure in a young female patient, given uncertainty about the effects of bisphosphonates on future childbearing. Informed consent from the patient’s mother and the patient was obtained, and after that denosumab 60 mg was injected subcutaneously. The treatment resulted in a rapid lowering of serum calcium (Fig. 1), which was accompanied by a significant clinical improvement of the patient’s condition. No side effects (except for the decline in the calcium level) were recorded. Two days after denosumab injection, saline infusion was replaced by increased water intake (1.5–2 L/24 h). Targeted NGS revealed a heterozygous variant in exon 2 of CDC73 gene NM_024529: С.176С>Т (p.Ser59Phe), which was previously described as a cause of familial hyperparathyroidism [29]. Twenty-two days after admission, the patient underwent a right hemithyroidectomy and excision of the right inferior parathyroid gland with the tumor. Histologic examination revealed a parathyroid adenoma. Genetic testing of the tumor sample showed an additional variation in exon 2 of CDC73 gene NM_024529: c.162C>G (p.Tyr54*), which was in trans with the С.176С>Т substitution. Immediately after surgery, PTH fell to 227.6 pg/mL, and it was 6.75 pg/mL the following day. Severe hypocalcemia developed
Discussion
This is a clinical description of successful denosumab administration for severe hypercalcemia treatment in a 16-year-old girl with PHPT. Subcutaneous administration of denosumab was effective at decreasing serum calcium level from 4.17 to 2.57 mmol/L within 24 h. This led to a significant improvement in the child’s condition, which further improved every day until the surgery. Taking into account the family history and significant clinical improvement after denosumab administration, the surgery was postponed until DNA analysis results were obtained. In children, PHPT can be part of familial syndromes, which can influence the extent of surgical intervention (e.g., subtotal/total parathyroidectomy in multiple endocrine neoplasia type 1) [3]. Severe PHPT is suspicious for parathyroid carcinoma, which in turn may be part of hyperparathyroidism-jaw tumor syndrome [3]. The molecular diagnosis was consistent with hyperparathyroidism-jaw tumor syndrome; however, histologic examination revealed benign parathyroid adenoma. This case illustrates that denosumab can be used offlabel in children with PHPT and severe hypercalcemia to lower serum calcium before a parathyroidectomy. In the report by Lenherr-Taube et al. [26], it was shown that denosumab was effective in normalizing serum calcium though it occurred after the usage of intravenous fluids, calcitonin, and pamidronate. In our case, it was decided to administer simultaneously both saline infusion and denosumab on admission and not to monitor serum calcium on saline infusion alone based on the severity of clinical symptoms and the level of serum calcium. Though saline infusion remains one of the firstline treatments in severe hypercalcemia, it is used mainly to restore euvolemia and per se cannot significantly lower serum calcium (on average, 0.6 mmol/L) [30, 31]. In the aforementioned reports of denosumab use in PHPT, aggressive saline hydration alone was not effective in significantly lowering serum calcium [5, 6, 26]. In PHPT, the use of denosumab is justified by its mechanism of action on hypercalcemia. PTH receptor signaling activation in osteoblasts and osteocytes increases the RANKL/osteoprotegerin ratio, increasing both osteoclast recruitment and osteoclast activity and 4
Horm Res Paediatr DOI: 10.1159/000510625
thereby stimulating bone resorption [32]. Rapid and severe bone resorption causes hypercalcemia. Denosumab blocks this leading mechanism of bone resorption in PHPT and therefore decreases calcium levels. PTH may be involved in fat tissue and skeletal muscle loss in cachexia [33]. Nevertheless, cachexia in this patient may not be explained by hypercalcemia only. RANKL inhibition has improved muscle strength in experimental study and may be beneficial in humans [34–36]. Despite the absence of clinical trials, it seems reasonable that the decrease in the extremely high calcium level and consequently the improvement of the patient’s condition may have contributed to a more favorable postoperative prognosis. The dosage of denosumab remains a question for discussion. Denosumab can be administered according to the patient’s weight, age, and the level of serum calcium. The dose and regimen of administration of denosumab in children with other disorders varied between the studies, and there are no guidelines regarding this topic. Hypocalcemia and hypophosphatemia can occur after a parathyroidectomy in severe PHPT due to the development of “hungry bone” syndrome [37]. Nevertheless, prolonged hypocalcemia was not reported in adult patients who were treated with denosumab prior to surgery and subsequently received calcitriol and calcium [5, 6]; however, it was seen in a pediatric patient with a parathyroid carcinoma [26]. It is possible that children may require higher doses of vitamin D and calcium, but further investigations are needed. In conclusion, subcutaneous denosumab 60 mg was beneficial in reducing calcium levels and improving clinical symptoms in a 16-year-old girl with familial PHPT, multiple fractures, and cachexia. Statement of Ethics The research was conducted in accordance with the ethical standards. Informed consent was obtained from the patient and the patients’ mother to perform genetic testing and to publish her data. Written informed consent was obtained from the patient and the patients’ mother to perform denosumab injection. Genetic testing was approved by the ethics committee of the Endocrinology Research Center.
Conflict of Interest Statement The authors have no conflicts of interest to declare.
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PTH (49.5 pg/mL, reference range, 15–65). Sanger sequencing of exon 2 of the CDC73 gene revealed the same germline p.Ser59Phe variant in her mother’s blood sample.
Funding Sources
Author Contributions
This work was supported by Alfa-Endo Program of Charities Aid Foundation (CAF) Russia and by the state assignment “Hereditary tumor syndromes and multiple endocrine neoplasias: personalization of diagnosis and treatment, risk prediction, identification of nuclear families” (state registration number #AAAAA18-118051590057-2).
Elizaveta Mamedova: literature search and writing of the article; Anna Kolodkina: the patient’s attending physician; Evgeny Vasilyev: NGS, Sanger sequencing, and data analysis; Vasily Petrov: NGS and data analysis; Zhanna Belaya: final editing of the article; Anatoly Tiulpakov: data analysis and final editing of the article.
References
Denosumab in a Pediatric Patient with Primary Hyperparathyroidism
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Received: March 3, 2020 Accepted: August 3, 2020 Published online: September 30, 2020
Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism Elizaveta Mamedova a Anna Kolodkina b Evgeny V. Vasilyev b Vasiliy Petrov b Zhanna Belaya a Anatoly Tiulpakov b
aDepartment bDepartment
of Neuroendocrinology and Bone Diseases, Endocrinology Research Centre, Moscow, Russia; and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russia
Established Facts • Primary hyperparathyroidism is rare in children, and it is usually symptomatic at presentation. • Denosumab has been used off-label in children with osteogenesis imperfecta, aneurysmal bone cysts, fibrous dysplasia, and several other disorders.
Novel Insights • Denosumab has demonstrated a good safety profile and efficacy in lowering serum calcium in a pediatric patient with primary hyperparathyroidism and a hypercalcemic crisis.
Abstract Introduction: Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. Case Presentation: A 16-year-old fe-
[email protected] www.karger.com/hrp
© 2020 S. Karger AG, Basel
male was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15–2.55), parathyroid hormone 2,151 pg/ mL (15–65), and phosphate 1.07 mmol/L (1.45–1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient’s condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological exami-
Anatoly Tiulpakov Department of Inherited Endocrine Disorders, Endocrinology Research Centre Dmitriya Ulianova Street, 11 Moscow 117036 (Russian Federation) genes @ endocrincentr.ru
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Keywords Denosumab · Primary hyperparathyroidism · Children · CDC73 · Hypercalcemia · Hypercalcemic crisis
© 2020 S. Karger AG, Basel
Introduction
Primary hyperparathyroidism (PHPT) is rare in children [1, 2]. In contrast to adult patients, the majority of pediatric patients with PHPT (up to 95%) are symptomatic, with high prevalence of skeletal involvement (9– 89%), kidney stones (25–50%), hypercalcemic crises (9– 50%), and unspecific symptoms (abdominal pain, arterial hypertension, fatigue, etc.) [1, 2]. PHPT in children may be sporadic (65–70%) or familial (27–31%) [1]. The latter could be a part of several familial syndromes, including multiple endocrine neoplasia types 1, 2A, and 4; hyperparathyroidism-jaw tumor syndrome; familial hypocalciuric hypercalcemia types 1–3; and familial isolated hyperparathyroidism [3]. Denosumab, a human monoclonal antibody of the receptor activator of nuclear factor kappa-B ligand (RANKL), is approved for the treatment of osteoporosis in adults at a dose of 60 mg subcutaneously every 6 months and for the treatment of skeletal metastases, giant-cell tumors, and hypercalcemia of malignancy at a dose of 120 mg subcutaneously every 4 weeks [4]. According to the literature, denosumab has been used offlabel in adults with PHPT for the treatment of hypercalcemia prior to a parathyroidectomy [5, 6], long-term management of parathyroid carcinoma-mediated hypercalcemia [7–9], and medical treatment of osteoporosis in PHPT [10]. It has been used off-label in children with several skeletal diseases, for example, osteogenesis imperfecta [11–13], fibrous dysplasia [14], aneurysmal bone cysts [15–18], giant-cell tumors [19], Paget’s disease of bone [20], glucocorticoid-induced osteoporosis in Duchenne muscular dystrophy [21], osteoradionecrosis [22], cherubism [18, 23], as well as for hypercalcemia reduction after bone-marrow transplantation in osteopetrosis [24] and in squamous cell carcinoma [25]. To our knowledge, only 1 case of denosumab usage in a child with severe PHPT due to a parathyroid carcinoma and ineffectiveness of bisphosphonates has been reported to date [26]. 2
Horm Res Paediatr DOI: 10.1159/000510625
Methods Blood Analysis The patient had fasting 8–9:00 a.m. serum samples taken to obtain routine biochemistry and hormonal status (parathyroid hormone [PTH]). Routine biochemistry was performed on Architect 8000 (Abbott, Chicago, IL, USA). Serum samples of PTH were assayed by electrochemiluminescence (ECLIA) Cobas 6000 Module e601 Roche (reference range 15–65). DNA Analysis Genomic DNA was extracted from peripheral leukocytes and homogenized fresh frozen tumor tissue using PureLink® Genomic DNA Mini Kits (Thermo Scientific, Waltham, MA, USA). A custom Ion AmpliseqTM panel (Ion Torrent, Thermo Scientific, Waltham, MA, USA) targeting 9 genes associated with familial forms of PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, and CDKN2D) was used for DNA library preparation. Sequencing was performed using the Personal Genome Machine (PGM) semiconductor sequencer (Ion Torrent, Thermo Scientific, Waltham, MA, USA). Bioinformatics analysis was carried out using Torrent Suite 4.2.1 (Thermo Scientific, Waltham, MA, USA) and ANNOVAR ver. 2018Apr16 software packages [27]. The results of the NGS were confirmed by Sanger sequencing using the Genetic Analyzer 3130 sequencer (Life Technologies, Carlsbad, CA, USA). A description of the sequence variants was given in accordance with the recommendations of Human Genome Variation Society [28]. Case Report A 16-year-old girl was initially referred to our care for the treatment of established PHPT. The patient was from a nonconsanguineous family, at birth her weight was 2.4 kg and length 47 cm. The family history was suggestive of PHPT; the maternal grandmother had neck surgery and developed kidney stones later in life. Five months before admission, the patient reported progressive pain in the right thigh, with gradual limp development. Two months before admission, a closed pathologic intertrochanteric fracture of the right hip with displacement occurred. The patient was hospitalized in a secondary care center, where she underwent skeletal traction with subsequent plaster cast. The plain radiographs showed a bone cyst in the upper third of the right femur and multiple bone lytic lesions in the pelvis, skull, right humerus, and ribs. During hospitalization, a spontaneous fracture of the upper third of the right humerus occurred. The biochemical test showed severe hypercalcemia: serum total calcium 3.93 mmol/L (2.15–2.55) and serum ionized calcium 2 mmol/L (1.03–1.29), with marked elevation of PTH 2,207 pg/mL (15–65), which confirmed the diagnosis of PHPT. At admission, the patient suffered from nausea, vomiting, polyuria, polydipsia, pruritus, and extensive weight loss. She was immobilized due to the hip fracture, which did not allow measurement of her height and weight. On examination, her blood pressure was 120/80 mm Hg, her heart rate was 110 beats per min, and her temperature was 36.7°C. She developed cachexia with severe loss of adipose tissue and skeletal muscle. Her laboratory data are presented in Table 1. Neck ultrasound revealed a tumor of the right inferior parathyroid gland 1.8 × 1.5 × 1.2 cm, confirmed by (99 m) Tc-sestamibi single photon emission tomography combined with X-ray
Mamedova/Kolodkina/Vasilyev/Petrov/ Belaya/Tiulpakov
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nation revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. Conclusion: Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.
mmol/L
4.50 4.30 4.10 3.90 3.70 3.50 3.30 3.10 2.90 2.70 2.50 2.30 2.10 1.90 1.70 1.50 1.30 1.10 0.90 0.70 0.50
3.93
Calcium
4.17
3.30
3.30
2.93
2.57
2.81 2.70 2.87 2.80 2.79 2.79
2.87 2.89
2.93
2.25
1.3
–12 d –5 d
1.07 0.95
0
0.79
12 h 24 h
0.74 0.62 2d
5d
0.73 0.78
6d
7d
0.65 8d
0.81
9d
Phosphate
12 d 14 d 16 d 19 d
1.99
1.88 1.71
0.78 0.82
0.66 0.72 0.55 0.68
Time
2.43
2.36
0.69
+1 d +2 d +5 d +9 d +14 d +19 d
Fig. 1. Changes in serum calcium and phosphate levels after denosumab injection and saline infusion (thin arrow) and after surgery (thick arrow). X axis, time after denosumab injection and after surgery; h, hours; d, days; 0, the day of admission; Y axis, concentration, mmol/L.
Denosumab in a Pediatric Patient with Primary Hyperparathyroidism
Table 1. The patient’s laboratory data
Parameters
Results
Reference range
Serum total calcium, mmol/L Serum ionized calcium, mmol/L Creatinine, μmol/L PTH, pg/mL Phosphate, mmol/L Serum total protein, g/L Glucose, mmol/L Aspartate aminotransferase, IU/L Alanine aminotransferase, IU/L Hemoglobin, g/L Hematocrit, % White blood cell count, per mm3 Red blood cell count, per mm3
4.17 2.14 56.2 2,151 1.07 59 3.61 35 15 86 27.3 10,340 3,090,000
Red blood cell sedimentation rate, mm/h Platelet count, per mm3
43 535,000
2.15–2.55 1.03–1.29 27–62 15–65 1.45–1.78 60–80 3.1–6.1 15–60 7–35 115–150 35–46 4,500–9,500 3,800,000– 5,200,000 2–15 152,000– 372,000
PTH, parathyroid hormone.
(Fig. 1) which was corrected only with high doses of alfacalcidol (up to 4.5 μg/per day) and calcium supplements (up to 4,500 mg/ per day). Hypophosphatemia persisted after surgery, requiring phosphate supplementation (280 mg/per day). In addition, the patient’s mother showed elevated serum calcium (2.7 mmol/L, reference range, 2.15–2.55) and upper-normal
Horm Res Paediatr DOI: 10.1159/000510625
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computed tomography. Abdominal ultrasound showed no kidney stones. Saline infusion of 500 mL was administered the day before admission, and on admission, saline infusion was increased to 2.5 L/24 h. Taking into account the critical condition of the patient, the decision was made to administer denosumab alongside with saline infusion to acutely lower serum calcium, based on the authors’ personal observations of its ability to significantly lower serum calcium in adults with severe PHPT. Moreover, bisphosphonates remain in bone tissue for years, and the authors felt it was preferable to avoid this potential exposure in a young female patient, given uncertainty about the effects of bisphosphonates on future childbearing. Informed consent from the patient’s mother and the patient was obtained, and after that denosumab 60 mg was injected subcutaneously. The treatment resulted in a rapid lowering of serum calcium (Fig. 1), which was accompanied by a significant clinical improvement of the patient’s condition. No side effects (except for the decline in the calcium level) were recorded. Two days after denosumab injection, saline infusion was replaced by increased water intake (1.5–2 L/24 h). Targeted NGS revealed a heterozygous variant in exon 2 of CDC73 gene NM_024529: С.176С>Т (p.Ser59Phe), which was previously described as a cause of familial hyperparathyroidism [29]. Twenty-two days after admission, the patient underwent a right hemithyroidectomy and excision of the right inferior parathyroid gland with the tumor. Histologic examination revealed a parathyroid adenoma. Genetic testing of the tumor sample showed an additional variation in exon 2 of CDC73 gene NM_024529: c.162C>G (p.Tyr54*), which was in trans with the С.176С>Т substitution. Immediately after surgery, PTH fell to 227.6 pg/mL, and it was 6.75 pg/mL the following day. Severe hypocalcemia developed
Discussion
This is a clinical description of successful denosumab administration for severe hypercalcemia treatment in a 16-year-old girl with PHPT. Subcutaneous administration of denosumab was effective at decreasing serum calcium level from 4.17 to 2.57 mmol/L within 24 h. This led to a significant improvement in the child’s condition, which further improved every day until the surgery. Taking into account the family history and significant clinical improvement after denosumab administration, the surgery was postponed until DNA analysis results were obtained. In children, PHPT can be part of familial syndromes, which can influence the extent of surgical intervention (e.g., subtotal/total parathyroidectomy in multiple endocrine neoplasia type 1) [3]. Severe PHPT is suspicious for parathyroid carcinoma, which in turn may be part of hyperparathyroidism-jaw tumor syndrome [3]. The molecular diagnosis was consistent with hyperparathyroidism-jaw tumor syndrome; however, histologic examination revealed benign parathyroid adenoma. This case illustrates that denosumab can be used offlabel in children with PHPT and severe hypercalcemia to lower serum calcium before a parathyroidectomy. In the report by Lenherr-Taube et al. [26], it was shown that denosumab was effective in normalizing serum calcium though it occurred after the usage of intravenous fluids, calcitonin, and pamidronate. In our case, it was decided to administer simultaneously both saline infusion and denosumab on admission and not to monitor serum calcium on saline infusion alone based on the severity of clinical symptoms and the level of serum calcium. Though saline infusion remains one of the firstline treatments in severe hypercalcemia, it is used mainly to restore euvolemia and per se cannot significantly lower serum calcium (on average, 0.6 mmol/L) [30, 31]. In the aforementioned reports of denosumab use in PHPT, aggressive saline hydration alone was not effective in significantly lowering serum calcium [5, 6, 26]. In PHPT, the use of denosumab is justified by its mechanism of action on hypercalcemia. PTH receptor signaling activation in osteoblasts and osteocytes increases the RANKL/osteoprotegerin ratio, increasing both osteoclast recruitment and osteoclast activity and 4
Horm Res Paediatr DOI: 10.1159/000510625
thereby stimulating bone resorption [32]. Rapid and severe bone resorption causes hypercalcemia. Denosumab blocks this leading mechanism of bone resorption in PHPT and therefore decreases calcium levels. PTH may be involved in fat tissue and skeletal muscle loss in cachexia [33]. Nevertheless, cachexia in this patient may not be explained by hypercalcemia only. RANKL inhibition has improved muscle strength in experimental study and may be beneficial in humans [34–36]. Despite the absence of clinical trials, it seems reasonable that the decrease in the extremely high calcium level and consequently the improvement of the patient’s condition may have contributed to a more favorable postoperative prognosis. The dosage of denosumab remains a question for discussion. Denosumab can be administered according to the patient’s weight, age, and the level of serum calcium. The dose and regimen of administration of denosumab in children with other disorders varied between the studies, and there are no guidelines regarding this topic. Hypocalcemia and hypophosphatemia can occur after a parathyroidectomy in severe PHPT due to the development of “hungry bone” syndrome [37]. Nevertheless, prolonged hypocalcemia was not reported in adult patients who were treated with denosumab prior to surgery and subsequently received calcitriol and calcium [5, 6]; however, it was seen in a pediatric patient with a parathyroid carcinoma [26]. It is possible that children may require higher doses of vitamin D and calcium, but further investigations are needed. In conclusion, subcutaneous denosumab 60 mg was beneficial in reducing calcium levels and improving clinical symptoms in a 16-year-old girl with familial PHPT, multiple fractures, and cachexia. Statement of Ethics The research was conducted in accordance with the ethical standards. Informed consent was obtained from the patient and the patients’ mother to perform genetic testing and to publish her data. Written informed consent was obtained from the patient and the patients’ mother to perform denosumab injection. Genetic testing was approved by the ethics committee of the Endocrinology Research Center.
Conflict of Interest Statement The authors have no conflicts of interest to declare.
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PTH (49.5 pg/mL, reference range, 15–65). Sanger sequencing of exon 2 of the CDC73 gene revealed the same germline p.Ser59Phe variant in her mother’s blood sample.
Funding Sources
Author Contributions
This work was supported by Alfa-Endo Program of Charities Aid Foundation (CAF) Russia and by the state assignment “Hereditary tumor syndromes and multiple endocrine neoplasias: personalization of diagnosis and treatment, risk prediction, identification of nuclear families” (state registration number #AAAAA18-118051590057-2).
Elizaveta Mamedova: literature search and writing of the article; Anna Kolodkina: the patient’s attending physician; Evgeny Vasilyev: NGS, Sanger sequencing, and data analysis; Vasily Petrov: NGS and data analysis; Zhanna Belaya: final editing of the article; Anatoly Tiulpakov: data analysis and final editing of the article.
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Denosumab in a Pediatric Patient with Primary Hyperparathyroidism
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