bluuebunny/crossref_metadata_2025 huggingface dataset:
Fix That PHEX Loss
Authors: Sunny Sonie Sarah
Published: May 2021

Phosphorous has a critical role in multiple biological functions in the body, such as skeletal mineralization, and an imbalance of this can lead to several musculoskeletal disorders. An important regulator of renal phosphate excretion is fibroblast growth factor 23 (FGF23) which is produced by osteocytes and osteoblasts themselves thus providing a mechanism for the skeletal system to influence its own mineralization needs. PHEX is a gene that regulates FGF23 secretion therefore a loss-of-function mutation in this gene would result in elevated circulating FGF23 and phosphate depletion. This mutation has been identified as a cause for X-linked hypophosphatemia (XLH). Treatment of XLH has been limited and mainly involved phosphorous replacement in combination with 1,25(OH) vitamin D. Antiresorptive osteoporosis treatment can exacerbate the skeletal mineralization process. Here we present a patient with multiple fractures who was on denosumab treatment for presumed osteoporosis before being found to have PHEX mutation. The patient is a 64 year-old female with past medical history of bilateral hip replacement and recurrent femur fractures who was seen in clinic in 2014 due to recurrent fractures and diagnosis of osteoporosis since early 2000s. She had only tried alendronate up until that point. Due to the recurrent fractures she was switched to denosumab therapy while workup was underway for secondary causes. She was found to have low phosphorous levels and elevated FGF23 therefore genetic counseling was pursued and was recommended to check for PHEX mutation. The testing came back positive for loss-of-function mutation in PHEX, and by that point she had received 3 doses of denosumab therapy. She suffered another femoral fracture which was determined to be an atypical fracture, and therefore denosumab treatment was stopped and she was continued on phosphorous replacement as well as 1,25(OH) vitamin D replacement. Most recently her phosphorous levels have been controlled with therapy, and there is current discussion underway to try burosumab, an antibody to FGF23. During evaluation for osteoporosis, it is important to consider phosphorous roles in skeletal mineralization. If recurrent fractures are seen in a patient with low phosphorous levels, especially while they are on conventional antiresorptive osteoporosis medications, genetic testing for PHEX mutations should be considered as well as safely stopping antiresorptive medications.
Genetic Testing in a Patient With Suspected Hyperparathyroidism- Jaw Tumor Syndrome (HPT-JT)
Authors: Kazi Fatima M , Sadiq Sobia
Published: May 2021

Introduction: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disorder characterized by parathyroid tumors in association with fibro-osseous jaw tumors, uterine tumors and renal lesions. We present a case of suspected HPT-JT. Clinical Case: A 50-year-old female with suspected HPT-JT was referred for treatment of osteoporosis. Patient was initially diagnosed with osteosarcoma in 1980 at age 10, and underwent resection with leg amputation and chemotherapy. Around 1995, she was found to have primary hyperparathyroidism secondary to a parathyroid adenoma and underwent one gland parathyroidectomy. At age 30, she was then found to have multiple uterine tumors requiring hysterectomy. In 2017, she underwent CT abdomen for suspected appendicitis, which revealed multiple renal cysts and hepatic hemangiomas. In 2019, patient was found to have recurrent parathyroid adenoma and underwent revision parathyroidectomy. Pathology revealed hypercellular parathyroid gland consistent with adenoma. Based on constellation of symptoms, HPT-JS was suspected. Patient was referred to genetic counselor. Detailed family history revealed multiple family members affected by malignancies including melanoma, breast cancer, prostate cancer, liver cancer and two cousins with suspected MEN1. She underwent testing for hereditary hyperparathyroidism and melanoma including CDC73 gene. All genetic testing was surprisingly unrevealing. Discussion: CDC73 gene (also known as HRPT2 gene) is responsible for the pathogenesis of HPT-JT. While HPT-JT itself is a rare condition, 60% of patients affected by it, harbor the HRPT2 gene mutation. About 10–15% of these individuals are affected by parathyroid carcinoma. HRPT2 mutated parathyroid adenomas also seem to have some malignant potential. The autosomal dominant inheritance of HPT-JT makes gene testing important since it has implications for other family members and carries weight in clinical management of genetic carriers. Therefore patients with extensive personal or family history of malignancy should be followed closely. Endocrinologists should have a low threshold to refer such patients for genetic counseling and testing. However genetic testing also has its limitations and can only explain 50–75% of cases of HPT-JT syndrome. Hence, even though our patient has a negative genetic screen, the possibility of HPT-JT is not complete ruled out.
Hypercalcemia Due to Immobilization
Authors: Ahamed Irshad , Jauhar Niyati
Published: May 2021

Background: Hypercalcemia associated with immobilization is an infrequent diagnosis. It is usually associated with prolonged immobility due to traumatic brain injury or spinal cord injuries. It results from rapid bone turnover. Diagnosis requires workup to rule out other causes of hypercalcemia. Keywords: Hypercalcemia; immobilizationCASE REPORT: We report a case of a 49 year old woman with severe traumatic brain injury and paraplegia following an electric-scooter accident. She had an extended stay in hospital and was noted to be hypercalcemic after six months’ in-patient. Laboratory investigations showed increased calcium level at 3.34 mmol/l (ref. 2.15–2.50 mmol/l) with diminished parathyroid hormone (PTH) level of 0.2 pmol/l (ref. 1.6–6.9 pmol/l), low 25-hydroxyvitamin D at 26.7 ug/l (toxicity >100 ug/l) and low 1,25-dihydroxyvitamin D at 13 pg/l (ref. 18–78 pg/l) with increased 24-H urinary calcium at 11.74 mmol/day (ref. 2.50 – 7.50 mmol/day). There was no clinical or biochemical evidence of other endocrinopathies such as hyperthyroidism or adrenal insufficiency. There was also no underlying malignancy to explain the hypercalcemia. In the context of recent prolonged immobility, a diagnosis of immobilisation hypercalcemia (IH) was made. The pathophysiology of IH is unclear. It is said that muscle activity transmits signal for bone formation through osteocytes and with immobility, mechanical stimulation is reduced, causing unopposed resorption. Another cause may be increased acidic environment due to low blood flow which impairs bone mineralization. There is also increased osteoclastic resorption, leading to loss of calcium from bones and hypercalciuria. Hypercalcemia occurs when calcium efflux from bone exceeds renal calcium excretion. For our patient, hydration therapy was initiated with no improvement in calcium. SC calcitonin was added and IV pamidronate given. Two weeks after treatment serum calcium improved to 2.38 mmol/L and remained normal on subsequent monitoring. Conclusion: IH is a known but uncommonly recognized complication in immobile patients. If not treated properly patients may develop typical complications of hypercalcemia including dehydration, confusion and renal impairment. Mobilization by using weight bearing exercises where possible is a cornerstone of long term management. In conclusion, our case serves as an important reminder of this differential and illustrates the management of IH.
Hypercalcemia in a Patient Treated With Abaloparatide
Authors: Sherpa Chheki , Shrestha Bishow Chandra , Nallala Deepika , Gabriely Ilan
Published: May 2021

Introduction: The antifracture efficacy of newer agents like PTHrP analogues is promising but knowledge about the mechanism of action and safety profile is needed in order to use these agents effectively. The reported incidence of hypercalcemia defined as albumin-adjusted serum calcium ≥10.7mg/dL was 3.4% in Abaloparitide. Case Presentation: A 59 year-old female with past medical history significant for diabetes mellitus type 2, hypothyroidism, necrotizing autoimmune myositis, osteoporosis and renal stones presented with complaints of generalized body aches and pains with swelling and redness of the left leg. The patient was diagnosed with osteoporosis based on atraumatic L4 compressive injury involving superior end plate. Her only DXA scan was 8 years ago which showed osteopenia, with the lowest T score of -1.2 at lumbar spine. Subsequent evaluation with DXA scan was unable to be performed due to physical disabilities. She was intolerant to oral bisphosphonates and was started on abaloparatide subcutaneous injections 2 weeks prior to her current admission. Her physical examination was positive for obesity, proximal muscle weakness and bilateral leg edema with bruises and left leg erythema. Laboratory findings showed hypercalcemia with corrected calcium levels of 12.48 mg/dl, suppressed intact PTH 4 pg/ml. Evaluations for secondary causes of hypercalcemia were negative. Her last dose of abaloparatide injection was the morning prior to her presentation to the emergency room. The patient was treated with IV fluids and her calcium level improved within 24 hours with normalization of intact PTH level in 72hrs. Abaloparatide injection was suspended on admission. Hypercalcemia with suppressed PTH was most likely secondary to abaloparatide given the timing of the hypercalcemia after the injection and resolution of hypercalcemia and normalization of PTH. Conclusions: Abaloparatide is a peptide that selectively binds to the RG conformation of the parathyroid hormone type 1 receptor. Abaloparatide is increasingly used following the results from the ACTIVE and ACTIVExtend trials which demonstrate significant increase in bone mineral density and risk reduction of vertebral, nonvertebral, clinical, and major osteoporotic fractures. Hypercalcemia was reported as a side effect, but there is no guidance on further evaluation or management of these patients. The incidence of hypercalcemia defined as albumin-adjusted serum calcium ≥10.7mg/dL is 3.4 % and risk is increased in patients with renal impairment. As in our case, transient hypercalcemia and PTH suppression may be associated with abaloparatide. Efficacy of abaloparatide and impact on bone density with delay or interrupted treatment are not available. Further studies are needed to guide monitoring and treatment of clinically symptomatic transient hypercalcemia in patients taking abaloparatide.
Hypercalcemia in Disseminated Coccidioidomycosis
Authors: Ryu Christina , Kirkeby Kjersti Meyer
Published: May 2021

Introduction: Hypercalcemia is associated with various granulomatous diseases, most commonly sarcoidosis and tuberculosis, less frequently fungal disease. We present a rare case of hypercalcemia associated with disseminated coccidioidomycosis.

Clinical Case: A 44-year-old man with ESRD s/p DDRT on immunosuppression presented with fever and cough. His physical exam was significant for tender scattered cutaneous nodules. His labs revealed non-PTH mediated hypercalcemia: calcium 12 mg/dL (normal 8.5–10.1 mg/dL), albumin 2.2 g/dL (normal 3.6–5.1 g/dL) and PTH 41 pg/mL (normal 14–72 pg/mL). Further hypercalcemia work-up was unremarkable: PTHrP 16 pg/mL (normal 14–27 pg/mL); 25-hydroxyvitamin D 33 ng/mL (normal 30–100 ng/mL); 1,25-hydroxyvitamin D 62 pg/mL (normal 20–79 pg/mL); serum electrophoresis was indeterminate; and immunofixation did not detect monoclonal proteins. His highest calcium level was 12.8 mg/dL with albumin 1.9 g/dL. He underwent additional tests that explained his presentation: sputum culture grew Coccidioides immitis; CT scan showed miliary pulmonary nodules, and bilateral deep cervical and mediastinal lymph node enlargement; lumbar puncture revealed elevated protein and cell counts; and a biopsy of a nodule on his thigh revealed Coccidioides immitis. He was treated with amphotericin for disseminated coccidioidomycosis with pulmonary, cutaneous and possible CSF involvement. He received IV fluids, furosemide and pamidronate for treatment of hypercalcemia. Based on his presentation, evaluation and complete resolution without recurrence of hypercalcemia after treatment of disseminated coccidioidomycosis, the most likely cause of hypercalcemia was disseminated coccidioidomycosis.

Hypercalcemia is associated with various granulomatous diseases. It is a rare complication of disseminated coccidioidomycosis that is important to recognize as Coccidioides is endemic in the United States. The pathology of the disease is pyogenic granuloma. In contrast to sarcoidosis, our case and previous case studies of hypercalcemia in coccidioidomycosis did not show an elevation of 1,25 dihydroxyvitamin D. Various potential inducers have been implicated including PTHrP, lipopolysaccharide, prostaglandin E, interleukin 1 and transforming growth factor β. It has been demonstrated that granulomas produce PTHrP; however, not all patients with granulomas develop hypercalcemia. One theory is that hypercalcemia may be a sequelae in cases with a greater number and extent of lesions making PTHrP as seen in disseminated disease.

Conclusion: Hypercalcemia is a rare complication of disseminated coccidioidomycosis that is important to recognize as coccidioidomycosis is endemic in the United States. The mechanism of hypercalcemia is poorly understood; in contrast to other granulomatous disease, it appears to be unrelated to 1,25-hydroxyvitamin D.
Hypercalcemia: A Metabolic Complication of an AIDS-Defining Illness
Authors: Bennett Dorothy E , Riachy Ruba , Blanton Lucas S , Belalcazar L Maria
Published: May 2021

Background: Hypercalcemia may result from the activation of macrophages in granulomatous diseases with increased production of 1,25 dihydroxyvitamin D/calcitriol. Its occurrence in patients with human immunodeficiency virus-1 (HIV-1) infection may be atypical and signal major changes in immune status. We report on a patient with acquired immunodeficiency syndrome (AIDS) presenting with new-onset hypercalcemia after months of treatment for mycobacterium avium complex (MAC) infection and normal calcitriol levels. Clinical Case: A 37-year-old man on treatment for HIV-1 and disseminated MAC infection presented to the hospital 6 months after initial diagnosis with worsening headache, cough, and abdominal pain. On arrival he was afebrile and without palpable lymphadenopathy. He was found to have a high serum calcium (13.4 mg/dL, n 8.6–10.6 mg/dL) and acute kidney injury (AKI) (creatinine 4 mg/dL, n 0.6–1.25 mg/dL). His CD4 count had increased from 24 at time of diagnosis to 162 cells/μL (n 410–1,590 cells/μL); his HIV viral load was undetectable. Workup for hypercalcemia revealed an elevated phosphorus (5.2 mg/dL, n 2.5–5.0 mg/dL), low 25-OH vitamin D level (<13 ng/mL, n 25–80 ng/dL), low PTH (4.8 pg/mL, n 12–88 pg/mL), and calcitriol level of 31.4 pg/mL, n 19.9–73.3 pg/mL). Additional tests, including serum electrophoresis, thyroid stimulating hormone, and parathyroid hormone-related peptide levels, were unremarkable. The patient was diagnosed with hypercalcemia secondary to dysregulated calcitriol production in the setting of disseminated MAC and possible immune reconstitution. Hypercalcemia resolved with hydration and prednisone 20 mg daily. Patient was discharged with an 8-day prednisone taper, but readmitted to the hospital 3 weeks later with recurrent hypercalcemia (13.8 mg/dL) and AKI. Urine calcium was found to be elevated (484 mg/24 hours, n100-300 mg/24 hours) and repeat calcitriol was 53.6 pg/ml. Patient was restarted on prednisone 40 mg daily with normalization of calcium within 5 days (calcium 10.3 mg/dL). Conclusion: Hypercalcemia due to increased calcitriol production in the setting of MAC infection, an AIDS-defining illness, may occur months after initiation of effective antibiotic and antiviral therapy and could represent a manifestation of immune reconstitution. The deleterious effects of excess calcitriol may be present even in patients with chronic vitamin D deficiency and a calcitriol level that inappropriately remains within the normal range.
Hyperparathyroidism-Jaw Tumor Syndrome in a Patient With Colon Cancer: A Case Report
Authors: Alexandre Maria Inês , Marçalo José , Gomes Ana , Domingues Rita , Silva Ana Luisa , Bugalho Maria Joao
Published: May 2021

Background: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disease, caused by mutations in the CDC73 gene, characterized by parathyroid tumors in association with fibro-osseous lesions of the mandible or maxilla. The occurrence of renal cysts or tumors, uterine and thyroid tumors has been reported. The association with other neoplastic lesions has been described, but its meaning and frequency are not well established. Clinical Case: A 48-year-old Roma woman was admitted to our hospital due to severe abdominal pain and constipation. She had a past history of kidney stones with several episodes of acute renal colic and had been recently diagnosed with colon cancer. Her family history was positive for colon cancer. Disease staging suggested the presence of liver metastases and multiple lytic lesions of the axial skeleton, pelvis and femurs. Laboratory investigation disclosed high calcium levels (15 mg/dL) and cancer associated hypercalcemia was suspected. However, PTH was markedly elevated (2979 pg/mL), in favor of a parathormone dependent cause. Further imaging procedures showed a heterogeneous mass, posterior to the right thyroid lobe and bone lesions on the left mandible, likely to correspond to brown tumors. Once the hypercalcemia was controlled, she was submitted to parathyroidectomy and right thyroid lobectomy plus sigmoidectomy and liver biopsy. The histology revealed an atypical parathyroid adenoma with 3,5 cm and papillary thyroid cancer with 1,2 cm, as well as colon adenocarcinoma metastatic to the liver. Postoperatively, the patient developed a hungry bone syndrome needing adequate treatment. Two months after surgery, the patient initiated chemotherapy for colon cancer. Screening for germline mutations in the CDC73 gene (formerly HRPT2) was positive for a deletion (c.765_766delTG/p.Val256LysX10). Conclusions: Hypercalcemia in a patient with malignant disease may be independent of malignancy. In the patient presented herein her past history of kidney stones and the involvement of the mandible were highly suggestive of HPT-JT. Missing the diagnosis would negatively impact in the patient′s prognosis and in the management of her family. Further clinical and genetic studies are ongoing trying to clarify whether the patient has two inherited conditions or a phenotype of HPT-JT including colon cancer.
Hypervitaminosis A: A Rare Cause of Hypercalcemia
Authors: Patel Chandani , Anbari Raghda Al , Lomonaco Mayra Romina
Published: May 2021

Introduction: Hypercalcemia is a rather common clinical problem and a majority of cases are found to be secondary to primary hyperparathyroidism and malignancy. A rare cause of hypercalcemia is associated with high levels of vitamin A and thought to be secondary to the effect of vitamin A on bone to stimulate osteoclastic resorption or inhibit osteoblastic formation. Clinical Case: A 54 year-old male with a past medical history of CKD stage 3 secondary to medullary sponge kidney presented for hypercalcemia. He complained of chronic constipation, joint pain, mood changes and recurrent kidney stones. Reported multivitamin use (including 1000mcg of vitamin A) for years but was discontinued one year prior to visit. Lab work showed calcium of 11.5 mg/dL (8.7–10.2mg/dL), albumin 4.9 g/dL (3.8–4.9g/dL), elevated 24h urine calcium, eGFR 40 mL/min/1.73, parathyroid hormone 5 pg/mL (15-65pg/mL,) normal 1,25-OH vit D and 25-OH vit D, PTHrP <2.0 pmol/L, serum protein electrophoresis unremarkable. His vitamin A level was elevated to 103 ug/dL (20.1–62.0ug/dL). CT chest showed no findings concerning for sarcoidosis. Bone density scan showed normal bone mineral density. Patient diagnosed with hypercalcemia secondary to elevated vitamin A levels. Current limited literature shows stopping the vitamin A supplement will normalize vitamin A levels and correct the hypercalcemia. This patient had discontinued his multivitamin 1 year prior and vitamin A remained elevated, thought to be due to his poor kidney function. Treatment was targeted at improving his hypercalcemia and reducing his symptoms. He was prescribed a one-week course of prednisone 40 mg daily. His calcium level improved to 10.5 mg/dL. Prednisone was reduced to 20 mg daily with normalization of calcium to 10.3 mg/dL (8.7–10.2mg/dL). Conclusion: Hypercalcemia is a rare but known complication of vitamin D toxicity. The liver, kidney and adrenal glands store vitamin A and it is excreted in the urine. Liver and kidney disease pose higher risk of vitamin A toxicity. We present a unique case of Hypercalcemia secondary to elevated vitamin A levels in a patient with moderate chronic kidney disease who was not taking excessive amounts of vitamin A and whose calcium and vitamin A did not normalize once vitamin A supplements were discontinued. The CKD 3 may have reduced vitamin A clearance and increased its toxicity. Hypercalcemia is not the only concern regarding vitamin A toxicity, the increasing use of dietary supplements and over the counter medications may pose significant risks for osteoporosis and bone fractures. A high clinical suspicion and thorough workup to exclude other causes of hypercalcemia is warranted to diagnose hypervitaminosis A as the etiology. Steroids can reduce gastrointestinal absorption of calcium, however, its role in vitamin A toxicity remains unclear. Further research is needed to investigate the appropriate treatment for these patients.
Hypocalcemia in a 15 Year Old With New Onset Type 2 Diabetes Mellitus
Authors: Becerril Romero Carlos C , Aguirre Rebecca Schneider , Imel Erik Allen , DiMeglio Linda A , Gohil Anisha
Published: May 2021

Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia.

Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec (<440 msec)], prompting transfer to the intensive care unit for telemetry, intravenous calcium gluconate, and regular calcium monitoring. Treatment was commenced with cholecalciferol 2000 international units daily and oral calcium carbonate (50 mg elemental calcium/kg/day) in divided doses for presumed Vitamin D deficiency. After several intravenous calcium gluconate doses over 24 hours, the patient’s QTc and ionized calcium normalized. At discharge, calcium was 8.5 mg/dL. He was discharged on the above regimen of calcium and cholecalciferol, and basal and bolus insulin. After discharge, laboratory results returned indicating negative diabetes autoantibodies (GAD 65, Insulin, IA-2) and 25-OH Vitamin D <10 ng/mL (30 - 100ng/mL). Two days after discharge, calcium was 7.3 mg/dL. Two weeks later, labs were: 25-OH Vitamin D 11.3 ng/mL, PTH 10.4 pg/mL, and calcium 9.6 mg/dL.

Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.
Iatrogenic Hypocalcemia With Treatment of Milk-Alkali Syndrome
Authors: Parikh Sharan D , Bhat Geetha K
Published: May 2021

Hypercalcemia is common disorder with the most likely etiology being primary hyperparathyroidism in the outpatient setting and malignancy in the hospitalized. With emergence of proton pump inhibitors and histamine blockers, milk-alkali syndrome has become a rarity. We report a unique case of hypercalcemia secondary to milk-alkali syndrome overtreated with bisphosphate therapy resulting in hypocalcemia.

A 77-year-old woman with a past medical history of hypertension, gastroesophageal reflux disease presented with slurring of speech for 2 days with nausea and vomiting. Labs showed a calcium of 15.4 mg/dL, with an albumin of 4.0 g/dL. Other pertinent labs showed an ionized calcium of greater than 7.3 mg/dL, pH of 7.49, PTH of 15 pg/mL, PTHrP of 9 pg/mL, vitamin D 25-OH of 16 ng/mL, TSH of 2.16 IU/mL and acute kidney injury. Patient was started on intravenous fluids and given both calcitonin and pamidronate on presentation by the admitting team. When seen in consultation, history revealed that patient was consuming more than eight calcium carbonate antacid tablets daily and was also on hydrochlorothiazide. The calcium level decreased to 8.7 mg/dL within 48 hours. There was a concern for potential hypocalcemia due to pamidronate. Patient was advised to restart calcium carbonate 500 mg twice daily upon discharge with close follow up. However, supplementation was not started and repeat calcium was 6.7 mg/dL twelve days later. The calcium normalized within a week after starting temporary calcium supplementation.

A now rare cause of hypercalcemia, milk-alkali syndrome is often overlooked in the differential diagnosis resulting in overtreatment and potentially dangerous hypocalcemia. Emergent management of intravenous hydration and bisphosphonate therapy is often immediately given by clinicians. Bisphosphonate therapy is not immediately effective and demonstrates calcium lowering effects by the second to fourth day. However, patients with milk-alkali syndrome generally improve with intravenous hydration and cessation of the causative agent. This case demonstrates the importance of obtaining a proper history with a complete list of medications and over the counter supplementations prior to treatment.
Lung Transplantation in a Patient With Osteogenesis Imperfecta and Osteoporosis
Authors: Fan Lena , Benvenuto Luke J , Nolan Margaret , DiMango Angela , Shane Elizabeth , Glorieux Francis H , Rubin Mishaela Ruth
Published: May 2021

Background:

Osteogenesis imperfecta (OI) and transplantation (TP) are independently associated with fractures. Yet reports regarding the skeletal effects of organ TP in OI are limited. We report the early skeletal outcomes in an OI patient with osteoporosis who underwent lung TP.

Clinical Case: A 35-year-old man with moderate/severe OI and severe bronchiectasis was admitted for progressive respiratory failure and expedited lung TP evaluation. OI was diagnosed at age 10 after sustaining a hairline coccyx fracture when falling off a stool; scoliosis was diagnosed at age 14; additional fractures included ankle (18 y), toes (28 y) and rib (34 y). He had dentogenesis imperfecta, but no hearing loss, easy bruising or OI family history. Bronchiectasis also began at age 10 and progressed, with multiple drug resistant infections and glucocorticoid (GC) treatments. At admission, he was on 6L oxygen and bed-bound from dyspnea. Notably, he had been rejected twice for TP because of his bone disease. Admission medications included calcium, D3, famotidine, inhaled fluticasone, tobramycin, and tiotropium bromide. His exam was notable for height 5’5”, BMI 16.5 kg/m2, kyphoscoliosis, blue sclera and joint laxity. Labs were notable for (mg/dl): serum calcium 9.4, magnesium 2.4, phosphate 4.4; albumin 4.2 g/dl, alkaline phosphatase 75 U/L, 25(OH)D 34 ng/ml, sCTX 535 pg/ml, urinary calcium 370 mg/24 hr. DXA showed T-scores of -4.7 (lumbar spine), -3.3 (femoral neck), -3.2 (total hip), -2.6 (1/3 radius). Endocrinology was consulted about the skeletal risk of lung transplantation.

Discussion and Follow-up:The patient’s manifestations of OI increased the risk of adverse skeletal outcomes. His high CTX suggested increased bone resorption, often seen with OI; bone formation was not directly measured but in OI is frequently reduced. Notably, his bronchiectasis was likely related to the OI: in addition to restrictive lung disease in OI, the abnormal type 1 collagen likely alters alveolar structure and elasticity. His risk for post-TP fractures was high given that the expected post-TP bone loss would likely be exacerbated by high dose GCs further increasing bone resorption and reducing presumed low bone formation. Nevertheless, because he had never sustained a major fracture even without OI treatment, the decision was made to proceed. He received zoledronate (ZOL) 5 mg IV and underwent an uncomplicated double lung transplant; initial high dose GCs were tapered to prednisone 10 mg/d. Three months later, he has steadily rising lung function, excellent functional status, and is working full time. A current sCTX of 73 pg/ml suggests that bone loss is not increased. Admittedly, the patient remains within the early high-risk fracture window. Yet this case is the first report to our knowledge which suggests that lung TP in an OI patient treated with ZOL did not lead to fracture in the early post-TP period.
Maxillary Brown Tumor as a Rare Complication of Hyperparathyroidism
Authors: Castellano Janet Colón , Ortega Nydia Ivette Burgos , Cordero Nicole Hernandez , Borrero Walter Morales , Nieves Yadiel Rivera , Santini Alberto Javier Grana , Canales Nicolle , Vick Margarita Ramirez , Santiago Milliette Alvarado , Rodriguez Loida Alejandra Gonzalez , Feliciano-Emanuelli Melba
Published: May 2021

Secondary hyperparathyroidism is a common complication of end stage renal disease (ESRD). The inherent impaired phosphorus and calcium metabolism result in altered bone metabolism, which rarely may manifest as osteitis fibrosa cystica with approximately 2% presenting as brown tumors. Brown tumors are areas of excessive bone resorption replaced by giant cells and fibrovascular tissue. Maxillofacial brown tumors are rare and result in increased patient morbidity due to associated nasal bleeding, diffuse pain and focal deformities. Nonetheless, these tumors are treatable and may regress following reduced parathyroid hormone (PTH) levels. Case of a 64-years-old Hispanic male with history of ESRD on hemodialysis for more than 20 years, secondary hyperparathyroidism with fragility fractures of femur status post parathyroidectomy on years 1999 and 2010, coronary artery disease and hypertension, who was consulted to our service for evaluation of a bleeding nasal septum mass suspected of a brown tumor. The patient presented to the emergency room with a massive spontaneous nasal bleeding which was subsequently controlled and evaluated by imaging. Maxillofacial CT scan without contrast showed an expansile soft tissue mass at the right maxillary sinus measuring 3.4 x 3.5 x 3.7 cm with innumerable, similar lesions distributed throughout the cranial, cervical and visualized portions of the shoulder girdle bones. Biochemical evaluation was remarkable for PTH levels 1,229 pg/ml (nl, 18.5 – 88.0 pg/ml), corrected serum calcium 9.0 mg/dl (nl, 8.3 – 10.6 mg/dl), alkaline phosphate levels 391 U/L (nl, 46 – 116 U/L), serum phosphoros 5.5 mg/dl (nl, 2.5 – 4.5 mg/dl), calciferol levels 32.2 ng/ml (nl, 30 – 100 ng/ml) and an estimated glomerular filtration rate at 21 ml/min/1.73 m2 (nl, > 60 ml/min/1.73 m2). An excisional tissue biopsy showed osteoclastic-like multinucleated cells consistent with a brown tumor. These findings are consistent with secondary hyperparathyroidism complicated with osteitis fibrosa cystica. Following histologic diagnosis, a 99mTc-Sestamibi parathyroid scan showed two focal lesions of increased radiotracer uptake in the lower poles of the thyroid confirming parathyroid hyperplasia. Patient’s medical therapy was optimized by increasing cinacalcet dose and adding calcitriol, while continuing Sevelamer. Serum calcium, PTH, and phosphorous levels were closely monitored. Finally, patient was referred for parathyroidectomy. Patients with ESRD are at high risk of developing secondary hyperparathyroidism. Even with prior parathyroidectomy, these patients can develop disease recurrence. Early recognition and management of secondary hyperparathyroidism is crucial to decrease disease complications such as Brown tumors.
Neuroendocrine Tumor Associated Severe Hypercalcemia of Pregnancy
Authors: Deshmukh Shilpa , Coyne Christopher
Published: May 2021

Background: Literature of pregnancy associated neuroendocrine tumors is limited. We report an unusual case of severe hypercalcemia of pregnancy secondary to a neuroendocrine tumor. Clinical Case: A 43-year-old lady presented to our center in her 28th week of pregnancy with complaints of worsening nausea and epigastric pain over few days. She had developed gestational diabetes at 24 weeks for which she was taking insulin. On examination she was tachycardic, mildly confused with a distended abdomen. Serum chemistries revealed serum calcium of 15.9 mg/dL, elevated PTHrP of 64 pg/mL and low PTH of 2 pg/mL consistent with PTHrP mediated hypercalcemia. She had low 25-OH- vitamin D (15 ng/mL) with normal 1–25- OH vitamin D. An abdominal ultrasound showed a solid, heterogenous, soft tissue mass interposed between the left kidney and spleen measuring 11 x 9 x 12 cm. This was confirmed on Abdominal MRI, which also showed multiple large hepatic metastasis. Tumor biopsy with pathology confirmed well differentiated neuroendocrine tumor of gastric or pancreatic origin. Her hypercalcemia was initially treated with infusions of IV normal saline, furosemide diuresis, calcitonin 200 units SC 12 hourly and a single dose of dexamethasone 10 mg IV. Calcitonin and diuresis were discontinued after 5 days once calcium improved to 10 mg/dL. Oncology deferred treatment of the tumor until she had delivered. Patient was discharged with serum calcium of 10.7 mg/dL and counselled for plenty of oral hydration. She was readmitted with nausea, vomiting and serum calcium level of 15.1 mg/dL at 32 weeks gestation. She was again treated with a similar regimen of IV saline and furosemide along with calcitonin 480 units SC 12 hourly and prednisone 10 mg daily, but calcium levels remained high (13.6 mg/dL) despite aggressive treatment. Labor was induced at 33 weeks and she delivered a healthy boy through an uncomplicated vaginal delivery. Remarkably, her serum calcium normalized on day two post-partum and remained so throughout. Her serum calcium remains normal at 2 months post-partum (10.3 mg/dL, PTHrP 36 pg/mL, PTH 7 pg/mL) despite the presence of unresected tumor. She is planned to undergo surgical resection of the tumor and hepatic metastatic lesions. Conclusion: Clinicians must be aware that severe hypercalcemia may be the presenting manifestation of neuroendocrine tumors in pregnancy. In this case, we hypothesize a potential placental contribution to her elevated PThrP given resolution of hypercalcemia post-delivery. However, persistent elevated PThrP post-partum may also be physiologic or related to the abdominal tumor. A placental histopathological could be performed due to logistic reasons.
Rebound-Associated Vertebral Fractures Two Months After a Missed Dose of Denosumab
Authors: Caseja Ahl Jeffrey , Abdullah Najwa , Nakhle Samer
Published: May 2021

Introduction:

Denosumab, an anti-resorptive medication approved for treatment of osteoporosis, increases bone mineral density and reduces fracture risk. Discontinuation of treatment is associated with bone turnover rebound and reduced bone mineral density. We report a case of a woman without prior history of fragility fractures who presented with multiple spontaneous vertebral fractures two months after a missed dose of Denosumab, which is earlier than current available literature.

Clinical Case: A 54-year old female was diagnosed with osteoporosis at the age of 50 with a DXA revealing T-scores of LS -2.9 SD, LFN -0.6 SD, TH -0.5 SD. Ten-year probability of MOF evaluated by FRAX was 6%. Work-up for secondary causes of osteoporosis during the time was unremarkable. She was started on Denosumab 60 mg every 6 months from July 2016 to July 2019, receiving a total of 5 injections. She had missed her dose of Denosumab in January 2020. Two months after the missed dose, she presented to a local hospital with complaints of chest and epigastric pain. A CTA was performed as part of evaluation which was unremarkable aside from an incidental finding of thoracic compression fractures. An MRI of the spine was subsequently done which showed a recent-appearing moderate to severe wedge compression fracture and edema of the T7 and T6 vertebral bodies, and of the upper two-thirds of the T4.

A biological and radiological work-up to exclude other causes of osteoporosis to explain the patient’s vertebral fractures was performed. The patient did not have renal failure, vitamin D deficiency, hyperthyroidism, primary hyperparathyroidism, Cushing’s disease, hypophosphatemia, multiple myeloma, Celiac disease, diabetes mellitus, or prior glucocorticoid treatment. During the time of treatment and discontinuation of Denosumab, the patient was on adequate supplementation of calcium and Vitamin D. The patient’s vertebral fractures were treated with kyphoplasty. To treat osteoporosis and prevent further risk of fractures, she was started on an anabolic agent Abaloparatide.

Conclusion: This case demonstrates rebound vertebral fractures occurring very shortly after discontinuing Denosumab in a relatively young woman with low probability of major osteoporotic fracture. Further investigation must be done to determine pathophysiological process involved of vertebral fractures and treatment regimen after sudden discontinuation of Denosumab.
Severe Hypercalcemia as Rare Manifestation of Acute Lymphoblastic Leukemia in Adolescent
Authors: Fatya Atikah Isna , Annisa Firda , Tahapary Dicky L , Purnamasari Dyah , Yunir Em , Harbuwono Dante Saksono
Published: May 2021

Background: Hypercalcemia is a rare manifestation of acute lymphoblastic leukemia (ALL). Several studies reported that severe hypercalcemia is very uncommon in pediatric ALL, but there is no report regarding ALL in adolescence and young adult (AYA) which comprises distinct entity with diverse prognosis.

Clinical Case: A 18-year-old male presented with prolonged fever, general weakness, fatigue, pale and decrease of body weight for 3 months. He also complained visual disturbances which progressively worsened for 1 month. On admission, systemic examination showed that he was alert, had tachycardia, proptosis of both eyes and splenomegaly. There was neither lymphadenopathy nor thyroid/parathyroid abnormality. Initial laboratory investigation revealed pancytopenia (hemoglobin of 6.8 g/dl, hematocrit of 19.1%, white blood cell count of 3.8 x 109/L with platelets of 58 x 109/L and no blast). There was severe hypercalcemia of 18 mg/dL, hypomagnesemia 1.14 mg/dL, with normal phosphorus level. His serum creatinine level slightly increased to 1.3 mg/dL with filtration rate of 79 ml/min/1.73 m2. Bone marrow evaluation showed blast cells infiltration, consistent with ALL type L3. Leukemia phenotyping revealed B cell-lineage with aberrant exp CD5. CT scan orbita and brain showed bilateral retrobulbar mass and diffuse lytic lesion in skeletal bones due to leukemic cells infiltration. Patient was treated with supplemental oxygen, hydration targeting natriuresis, loop diuretic and steroid. The serum calcium level remained high, thus bisphosphonate was given. There was progressive decline of serum calcium level after therapy. The patient is then prepared to start chemotherapy.

Discussion: Hypercalcemia is associated with both PTH or PTH-independent mechanism, including malignancy. It complicates 5–20% of malignancy, but only 0.6–4.8% reported in leukemia. Hypercalcemia in malignancy may present due to: (1) direct invasion of cancer cells to bone and (2) secretion of humoral PTH-related peptide (PTHrP) which mimics PTH. Severe hypercalcemia without inadequate treatment is fatal. Initial treatment of hypercalcemia includes hydration, loop diuretic, calcitonin and bisphosphonate targeting decline of serum calcium level of 3–9 mg/dL in 24–48 hours. The main treatment of leukemia-related hypercalcemia is chemotherapy. Several cases of pediatric ALL reported normocalcemia after starting induction phase of chemotherapy and exerted good prognosis.

Conclusion: Hypercalcemia should be investigated in leukemia patients and vice versa. The main aim of therapy is to normalize the serum calcium level and treat underlying causes. In adolescent ALL, adequate treatment of hypercalcemia helps achieving better outcome.
Single Dose of Denosumab Effective for Management of Bisphosphonate-Refractory Hypercalcemia of Malignancy Related to Non-Small Cell Lung Cancer
Authors: Dinh Kathryn , Narla Radhika Rao
Published: May 2021

Background: First line therapy for hypercalcemia of malignancy (HCM) includes cancer directed treatment and bisphosphonate therapy. Denosumab is effective in bisphosphonate-refractory HCM (BR-HCM), approved for treatment with dosing schedule at 1, 8, 15, and 29 days and then monthly.

Clinical Case: We present the case of a 64 year-old man with Stage IIIA squamous cell lung carcinoma diagnosed 5/2019 with corrected serum calcium (CSC) of 11.2 mg/dL (8.4–10.2) at presentation. Prior to treatment, he developed symptomatic CSC 14.0 mg/dL, treated with IV pamidronate 90mg and IV fluids (IVF) 6/28/2019 with improvement to CSC 9.7 mg/dL. Hypercalcemia recurred 8/2019 while undergoing radiation therapy with CSC 14.7 mg/dL, phosphorus 2.5 mg/dL (2.7–4.5), PTH 7 pg/mL (15–65), PTHrP 2.2 pmol/L (<2.0), 25-OH vitamin D 30.16 ng/mL (30–100), and 1,25-OH2 vitamin D 98.7 pg/mL (19.9–79.3). He was treated with IVF and 4mg zoledronic acid (ZA) on 8/20 and 8/29/2019. CSC normalized 9/30/2019 and he subsequently received three cycles of pembrolizumab 11/25/2019 to 1/6/2020, discontinued for associated pneumonitis He again developed HCM 6/5/2020 with CSC 12.6 mg/dL. He was treated with ZA 4mg on 6/16 and 6/29/2020 with persistent, symptomatic hypercalcemia to 13.7 mg/dL 7/9/2020 with ongoing confusion, constipation, and lethargy. Endocrinology was consulted 7/9/2020 and initiated IVF, calcitonin SQ 4U/kg q12h for 48 hours, and prednisone 30mg daily for 5 days. Chemotherapy was initiated 7/14/2020. CSC remained stable <11.5 mg/dL until 8/3/2020 with recurrent calcium to 13.0 mg/dL despite cancer-directed therapy. He was then given 120mg SQ denosumab on 8/7/2020. CSC improved to 10.6 mg/dL on 8/11/2020 and has remained <11 mg/dL at 70 days after a single dose of denosumab.

Conclusion: Denosumab was approved for BR-HCM with a complex treatment schedule based on a single-arm study of 33 patients, of whom 39% had treatment-related adverse events.1 We present a case of successful management of BR-HCM with a single dose of 120mg denosumab with CSC <11.5 mg/dL at day 4 after treatment and persistent control of calcium at day 70 without further treatment. Further investigation is warranted to determine the most effective treatment schedule of denosumab for BR-HCM to reduce adverse events including hypocalcemia and overtreatment.

References:

1. Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014 Sep;99(9):3144–52
An Observational Study to Assess the Safety and Efficacy on Quality of Life and Patient Satisfaction With Raloxifene/Cholecalciferol Combination Therapy in Postmenopausal Women Requiring Prevention or Treatment for Osteoporosis
Authors: Chung Yoon-Sok , Lee Dong-Yun
Published: May 2021

Background: Preventing bone loss is an important concern for women during post-menopausal period. Menopause significantly speeds bone loss and increases the risk for osteoporosis. The aim of this study was to investigate the effectiveness on quality of life (QOL), patient satisfaction in postmenopausal women receiving raloxifene/cholecalciferol combination therapy. In addition, we analyzed adverse events to assess the safety profile of this drug. Methods: This study is a multicenter, prospective, non-interventional observational study of women receiving raloxifene/cholecalciferol (raloxifene 60 mg + cholecalciferol 800 IU, Rabone D®, Hanmi Pharma, South Korea) combination therapy to treat or prevent postmenopausal osteoporosis. Data have been collected from patients receiving routine clinical practice at 99 hospitals (local clinics and general hospitals) in South Korea. Patients were followed for more than 6 months to evaluate changes in, and QOL (EQ-5D-5L), patient satisfaction with efficacy and convenience (questionnaire), and safety. This study has been approved by Institutional Review Board and is in compliance with clinical research ethics regulations. Results: A total of 3,907 subjects with an average age of 67.68 ± 9.34 (Mean ± SD) were enrolled from November 2017 to July 2020. QOL was significantly improved from 0.77 ± 0.15 to 0.80 ± 0.12, 0.82 ± 0.11 (3 months, 6 months, respectively) after raloxifene/cholecalciferol therapy (p<0.001). Compared to prior drug regimens of all types (bisphosphonates, bisphosphonates with vitamin D, selective estrogen receptor modulators, etc.), QOL after raloxifene/cholecalciferol treatment was significantly improved (p<0.001). Patient satisfaction of efficacy was significantly increased from 37.25% to 67.70% over 6 months (p<0.0001), and patient satisfaction of convenience was significantly increased from 42.75% to 74.07% (p<0.0001). Serious adverse drug reaction (ADR) did not occur. Hot flush as ADR occurred in 12 subjects (0.30%), lower than Caucasian but similar with previous reports in Asians. Conclusion: In postmenopausal women, combination therapy with raloxifene/cholecalciferol significantly improved quality of life, and patient satisfaction with no serious adverse events. This drug regimen has been proven to be suitable therapy for postmenopausal women with osteoporosis in a real-world clinical setting.

References: Kim et al., Expert Opin Drug Safety 2019; 18: 1001–8. Takeuchi et al., Menopause 2015; 22: 1134–7. Xu et al., Osteoporos Int 2011; 22: 559–65.