bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical Tumor Marker Status and Its Role in Treatment Response in Patients Who Received High-Specific-Activity I-131 MIBG in Advanced Pheochromocytoma and Paraganglioma (PPGL): Results From a Pivotal Phase 2 Clinical Trial
Authors: Jimenez Camilo , Chin Bennett B , Noto Richard A , Noto Richard B , Dillon Joseph S , Solnes Lilja , DiPippo Vincent A , Stambler Nancy , Pryma Daniel A
Published: May 2021

Background: High-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG; AZEDRA®) has been approved for the treatment of adult and pediatric patients (pts) 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. We have previously presented data showing improved biomarker responses in pts treated with HSA I-131 MIBG. Here we report the impact of biomarker status on the study primary endpoint and objective tumor response. Methods: Pts with iobenguane-avid PPGL who were ineligible for surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive medication regimen were treated. Pts received up to two therapeutic doses, each at ~18.5 GBq (or 296 MBq/kg for pts ≤62.5 kg), administered ~90 days apart. Biomarkers were analyzed at baseline and over a 12-month efficacy period. Confirmed biochemical responses (at least ≥ 50% decrease in abnormal tumor marker value for all hypersecreted biomarkers) required subsequent responses to be identical to or better compared with the previous assessment. The primary endpoint was clinical benefit, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) for ≥6 months beginning during the efficacy period. The secondary endpoint, confirmed objective tumor response by RECIST, was also evaluated. Results: 68 pts received at least one therapeutic dose of HSA I-131 MIBG. For all pts with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN) (n=60), a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006; Fisher exact P = 0.012). For pts with norepinephrine only-hypersecreting tumors (n=31), a correlation coefficient of 0.47 (P = 0.008; Fisher exact P = 0.015) was observed. The overall biomarker response also correlated with objective tumor response (n=55) yielding a correlation coefficient of 0.36 (P = 0.007; Fisher exact P = 0.012) for all pts with hypersecreted biomarkers. Pts who were not biochemical hypersecretors for any biomarker (n=6) had only one responder for the primary endpoint and no objective tumor responses. Conclusions: The biomarker data from this study establish a moderate but statistically significant correlation between biomarker response following treatment with HSA I-131 MIBG and objective tumor response and durable reduction of antihypertensive therapy. This correlation was improved with norepinephrine only-hypersecreting tumors in pts with unresectable, locally advanced or metastatic PPGL.
A Case of Hypocalcemia Secondary to Infection With SARS-CoV-2 Virus
Authors: Khan Abdul Mannan , Lightell James , Majors Corey
Published: May 2021

Background: A Case of Hypocalcemia Secondary to Infection with SARS-CoV-2 Virus.

Clinical Case: A 40 year-old obese male presented to the emergency department with a five day history of nausea, vomiting, shortness of breath, and nonproductive cough. Symptoms progressed culminating in a single episode of pre-syncope leading to his seeking medical care. Positive testing for the presence of SARS-CoV-2 as well as findings from computed tomography of the patient’s chest led to a diagnosis of COVID-19 and the patient’s admission to a COVID-19 ward, where treatment with dexamethasone, doxycycline, and 2 L oxygen via nasal cannula began. Blood testing on admission revealed profound hypocalcemia (6.2 mg/dL total and 3.5 mg/dL ionized) as well as newly diagnosed diabetes mellitus type 2 (T2DM) (HbA1c 13.0% on admission). Further electrolyte disturbances noted were consistent with his history of vomiting and untreated T2DM. Thyroid stimulating hormone and thyroxine levels showed primary hypothyroidism, but the patient’s parathyroid hormone level (16.5 pg/mL) was inappropriately normal. No other causes for hypocalcemia were identified. The patient’s hypocalcemia was treated with intravenous calcium gluconate and rose consistently through day six of hospitalization. Calcium fell sharply between day six and seven (7.6 mg/dL to 7.3 mg/dL) coinciding with worsening respiratory symptoms and requiring a doubling of oxygen dose from 2 to 4 L with subsequent improvement in hypocalcemia once underlying pulmonary function improved. Discussion: SARS-CoV-2 infection presenting with hypocalcemia has been well documented without definitive explanation [1]. Further, while the precise mechanism of SARS-CoV-2 virion export is unclear, the patient’s worsening hypocalcemia, respiratory symptoms, and concurrent presumable increased viral load suggests this is caused by a calcium-dependent exocytotic process [2]. 1: Marazuela, M., Giustina, A. & Puig-Domingo, M. Endocrine and metabolic aspects of the COVID-19 pandemic. Rev Endocr Metab Disord 21, 495–507 (2020). https://link.springer.com/article/10.1007/s11154-020-09569-22: Fehr A.R., Perlman S. (2015) Coronaviruses: An Overview of Their Replication and Pathogenesis. In: Maier H., Bickerton E., Britton P. (eds) Coronaviruses. Methods in Molecular Biology, vol 1282. Humana Press, New York, NY. https://link.springer.com/protocol/10.1007%2F978-1-4939-2438-7_1.
A Case of Teriparatide Use in Nonunion Atypical Ulnar Fracture
Authors: Tun Yin Nwe , Russell Yan , Guber Helena Abby
Published: May 2021

Background: Atypical upper limb fracture is a rare complication of bisphosphonate use. The management of nonunion fractures is challenging, especially in patients who are not surgical candidates. Teriparatide, a novel anabolic drug for osteoporosis has been increasingly used off-label for treatment of nonunion fractures and bisphosphonate related atypical fractures of the lower extremity. The proposed mechanism of healing is by enhancement of callus formation and mechanical strength. Clinical Case: A 72 year-old woman with a history of bilateral lower extremity paralysis and bilateral upper extremity paresis, who mobilized short distances with Canadian crutches, had been treated for 15 years with alendronate, for osteopenia associated with multiple risk factors for osteoporosis. 11 months before referral, and a month after alendronate was discontinued, she sustained a muscle-spasm induced fracture of the mid-shaft of the right ulna. She was treated nonoperatively due to chronic osteomyelitis with recurrent bacteremia from a prior non-healing left ulnar fracture (with internal fixation). Bone density of the right forearm had been normal. Since the right ulna break was transverse with minimal comminution, located in the diaphysis, occurred after trivial force and exhibited delayed healing, it was thought to be an atypical fracture secondary to bisphosphonates. She was initiated on cyclical teriparatide injection 20 mcg subcutaneously daily, with 2 months on and 2 weeks off. In one year, patient responded with dramatic radiographic improvement by forming a large callus with almost complete healing of the fracture. Conclusion: Mid-forearm atypical fracture from long-term bisphosphonate use is rare and is at risk for nonunion. The management of atypical upper limb nonunion fracture in nonoperative patients is not well established. Case reports exist of patients with atypical upper limb fracture who are either treated conservatively, or surgically with fixation/bone grafting +/- teriparatide. Our case showed that teriparatide, when used cyclically, exerted positive osteogenic effect and improved healing of the nonunion of an atypical fracture of forearm in a patient who continued weight bearing activity on her only functional limb.
A Challenging Case of Phosphaturic Mesenchymal Tumor With Primary Hyperparathyroidism
Authors: Salim Michael , Barengolts Elena
Published: May 2021

Background: Localization of tumor-induced osteomalacia (TIO) is often challenging. Primary hyperparathyroidism (HPT) following curative surgery for TIO is rarely reported. Clinical Case: A 49-year-old man presented with fragility rib fractures, generalized bone pain, and muscle weakness worsening over the past 3 years. Rheumatologic workup was negative. Initial tests showed elevated levels of parathyroid hormone (PTH) 114.1 pg/mL (14–72 pg/mL) and alkaline phosphatase (ALP) 283 IU/L (44–174 IU/L), reduced levels of 25(OH)D 16 ng/mL (30–100 ng/mL), 1,25(OH)2D 9 pg/mL (18–72 pg/mL), and phosphorus 1.6 mg/dL (2.5–4.9 mg/dL), calcium levels of 9.2 mg/dL (8.5–10.1 mg/dL), and eGFR 58 mL/min/1.73 m2. A sestamibi scan showed normal parathyroid uptake. The diagnosis was secondary HPT due to chronic kidney disease and vitamin D deficiency. The patient was treated with D3 and phosphate. During a 2-year follow-up, the patient reported improvement of pain and weakness with no additional fractures. Further investigations showed persistent hypophosphatemia with elevated urinary fractional phosphate excretion (44%, ref. <20%), indicating renal phosphate wasting. Fibroblast Growth Factor 23 (FGF23) was high, 291 RU/mL (0–180 RU/mL). DXA results were consistent with osteopenia. TIO was suspected. At a 3-year follow-up, investigations included three whole-body 18F-FDG PET-CT scans revealing several areas suspicious for tumor presence. However, multiple MRIs were inconclusive. Laboratory tests showed persistent hypophosphatemia (despite D3 and phosphate treatment), elevated FGF23 (1330 RU/mL) and PTH (274.4 pg/mL), and normal calcium, 25(OH)D, and 1,25(OH)2D. The patient subsequently underwent 68Ga DOTATATE PET-CT, which revealed a somatostatin receptor-positive lesion involving the left upper lobe of the lung. The mass was resected without complications. Histopathology was compatible with a phosphaturic mesenchymal tumor. At a 6-month postoperative follow-up, the patient reported dramatically improved symptoms with decreased weakness and pain, normal phosphate, calcium, ALP, and FGF23 (160 RU/mL) levels, while DXA results were significantly improved. Phosphorus supplementation was discontinued. At follow-up 3 years post-surgery, the patient had slowly rising PTH (126.3 pg/mL) and calcium (10.1–10.6 mg/dL) levels with normal phosphate, 25(OH)D, and FGF23 (174 RU/mL) levels. A diagnosis of primary HPT was made. Further evaluation was deemed unnecessary since the patient did not meet the criteria for surgical treatment. The development of primary HPT was considered mechanistically related to long-standing hypophosphatemia and hypovitaminosis D stimulating PTH production. Conclusion: This case report highlights the pitfalls contributing to delayed diagnosis of TIO and alerts clinicians to the potential development of primary HPT after curative surgery for TIO.
Autosomal Dominant Hypocalcemia Due to a GNA11 Variant: The First Case in Japan
Authors: Yamauchi Ichiro , Ueda Yohei , Sugawa Taku , Hakata Takuro , Fujita Haruka , Okamoto Kentaro , Ohno Youichi , Fujii Toshihito , Taura Daisuke , Inagaki Nobuya
Published: May 2021

Background: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia due to hypoparathyroidism. ADH type 1 is caused by gain-of-function variants in CASR gene coding the calcium-sensing receptor. Recently, ADH type 2 caused by gain-of-function variants in GNA11 gene coding G-protein subunit α11 has been recognized.

Case: A 32-year-old female patient visited our hospital because she suffered from hyperhidrosis, exertional dyspnea, and palpitations. She had a past medical history of paroxysmal kinesigenic dyskinesia confirmed by genetic analysis of PRRT2. Although her sister has unspecified epilepsy, no members of her kindred have episodes of tetany. Her height was 155.7 cm and weight was 64.1 kg. She had goiter with tremor and tachycardia and was diagnosed as Graves’ disease (fT3 >32.55 pg/mL, fT4 >7.77 ng/dL, TSH <0.005 µIU/mL, and TRAb 36.9 IU/L). Thiamazole therapy ameliorated her hyperthyroidism, while serum calcium level was low (7.5 mg/dL) and serum phosphate level was slight high (5.1 mg/dL). Hypoparathyroidism was confirmed because intact-PTH was relatively low (20 pg/mL) under the hypocalcemia. Her episode of tetany that she could not sit on her heels from childhood and her basal ganglia calcification in head CT scan suggest the long disease duration. Germline whole exome sequence detected a rare variant in GNA11 gene; c.1023C>A resulted in p.Phe341Leu. There were no relevant pathogenic variants in other candidate genes such as CASR, PTH, and GCM2. Treatment with 2 µg/day of alfacalcidol and 1200 mg/day of calcium aspartate could not normalize serum calcium level (7.0 mg/dL) and serum phosphate level (5.3 mg/dL) even after 1 year.

Conclusions: The pathogenicity of the variant, p.Phe341Leu, in GNA11 gene was previously confirmed [1]. ADH type 2 is extremely rare as our literature review found only four previous reports; 17 patients in 5 families [1–4]. Phenotypes of the present case are mild and skeletal growth is normal. Meanwhile, we are having difficulty in management of her hypocalcemia, even though Graves’ disease might affect her bone metabolism. Optimal therapy for ADH type 2 needs further investigation.

References: [1] Nesbit et al. Mutations Affecting G-protein Subunit α11 in Hypercalcemia and Hypocalcemia. N Engl J Med. 2013; 368: 2476–2486. [2] Li et al. Autosomal Dominant Hypoparathyroidism Caused by Germline Mutation in GNA11: Phenotypic and Molecular Characterization. J Clin Endocrinol Metab. 2014; 99: 1774–83. [3] Piret et al. Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2). J Bone Miner Res. 2016; 31: 1207–14. [4] Tenhola et al. Impaired Growth and Intracranial Calcifications in Autosomal Dominant Hypocalcemia Caused by a GNA11 Mutation. Eur J Endocrinol. 2016; 175: 211–8.
Denosumab Induced Severe Hypocalcemia in a Patient With Metastatic Prostate Cancer
Authors: Naher Kamrun , Thrupthi Komandur , Samsuddoha Kazi , Galiveeti Sneha , Leung Vivien
Published: May 2021

Background: Denosumab can lead to severe hypocalcemia in patients with underlying risk factors such as vitamin D deficiency, low PTH, hypomagnesemia, and CKD. Denosumab is a monoclonal antibody against RANKL, reducing the activity of osteoclasts and thus reducing the release of calcium in the bloodstream causing hypocalcemia. Hypocalcemia can range from mild to severe symptoms requiring prolonged hospitalization. Medications such as zoledronic acid and Denosumab are known to reduce the occurrence of Skeletal related events (pathological fracture, spinal cord compression, and radiation to bone). For metastatic prostate cancer, about 90% can develop bone metastasis with significant morbidity and mortality [1]. Our patient presented with severe hypocalcemia after denosumab use without any above risk factors. Clinical Case: A 66-year-old male with a medical history of Prostate cancer with Metastasis to chest and bone presented to ER with syncope. Patient-reported poor oral intake, nausea, and vomiting for the last few days. In the ER, the patient was found afebrile, bp 116/76, HR 92, saturating 100% on room air. On examination, the patient was found lethargic, malnourished, foley in place due to chronic urinary retention. The abdomen was soft and non-tender. Laboratory findings were significant for Hb 9.1, Na 133, K3.6, bicarb 21, total calcium (Ca) 4.2, ionized Ca 0.63 and corrected Ca 5.4, magnesium 1.6, phosphorus 2.1, albumin 3.3, ALT 218, AST 229, ALP 1607. Lipase 82, Total bilirubin 1.5, direct bilirubin 0.8. Spot Urinary Ca 0.7, Vitamin D 25 OH 36.9, serum PTH 225 pg/mL. Serum cortisol AM 20.9, BUN 16, and serum Creatinine 1.0. The patient was started on 11g calcium gluconate in 1L dextrose @ 50c/hr and calcitriol 0.25mcg twice daily. Serum Ca level was monitored every 6 hours and reached 6.7. Later was started on Ca carbonate 1250 TID with meals. Finally, after electrolyte correction, the patient clinically improved and was discharged with the plan to follow Calcium at the outpatient clinic. On review of previous labs at the oncology clinic, the patient received Denosumab at his oncologist’s clinic 10 days before this hospital admission, last Ca level from 6 months ago 8.6, the patient was not any vitamin D or Ca supplement. Conclusion: Many case reports have been published on severe hypocalcemia after denosumab usage. Several patients had underlying risk factors such as vitamin D deficiency, osteoblastic lesion, and AKI leading to an additional cause of hypocalcemia. We emphasize careful monitoring of serum Ca levels particularly in the first few weeks of treatment even without significant risk factors for hypocalcemia. References: [1] Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ. . Hum Pathol. 2000 May; 31(5):578–83
Hypercalcemia With Non Suppressed Parathyroid Hormone in a Young Female- A Rare Case of Calcium Sensing Receptor Gene Related Familial Hypocalciuric Hypercalcemia-1
Authors: Shanaz Fazeena , Bachman Kristine Kay
Published: May 2021

Background: Familial Hypocalciuric Hypercalcemia (FHH) is a rare disorder, associated with hypercalcemia and hypocalciuria and inherited in an autosomal dominant manner. Its true prevalence is unknown, and is estimated to be around 1 in 78,000 as compared to primary hyperparathyroidism (PHPT) which is around 1 in 1000. There are 3 mutations known to cause FHH. FHH-1 is caused by inactivating mutation in the calcium sensing receptor (CaSR) gene. Mutations associated with FHH-2 and FHH-3 are GNA11 and AP2S1 respectively. Case Presentation: 38-year-old female presented to endocrinology, for evaluation of hypercalcemia (10.8 mg/dL, with normal albumin). She was not on any calcium supplements or any other medications which can cause hypercalcemia. She did not have any prior fracture or nephrolithiasis or renal insufficiency. Her father reported to have hypercalcemia; no further evaluations of her father were available. Examination revealed an obese female with no skeletal or dental or other physical abnormalities. Laboratory evaluations: PTH= 37 pg/ml (15–65), 25 OH vitamin=D-30 pg/ml, Mg=2 mg/dL (1.5–2.6), phosphorus=3.1 mg/dl (2.5–4.8), 24 hour urine calcium=0.151 g/24 hours-with 24 hour urine calcium clearance of 0.008. Therefore, evaluations were highly suggestive of FHH. Subsequently, she had genetic evaluation which confirmed heterozygous CaSR mutation, confirming FHH-1. Her mother had genetic testing and was not found to have the mutation. So, it was concluded that the patient likely inherited the gene from her father, who also had hypercalcemia. She is being monitored clinically and with serial laboratory evaluations to monitor her calcium levels. Discussion: CaSR is expressed in parathyroid glands and kidneys which plays a key role in calcium regulation. CaSR inactivating mutation (seen in FHH-1) leads to hypocalciuria and hypercalcemia. 24 hour urine calcium clearance (urine Ca x serum Cr/ serum Ca x urine Cr) of <0.01 is highly suggestive of FHH. Furthermore, higher concentration of calcium is required to suppress PTH release leading to high or nonsuppressed PTH. This finding can mislead towards the diagnosis of PHPT and unnecessary parathyroid surgery, if the diagnosis of FHH is missed. FHH is usually a benign disorder; subtotal parathyroidectomy does not cure the disease. FHH, rarely can cause atypical complications such as pancreatitis and total parathyroidectomy may be indicated to prevent further episodes of pancreatitis. Conclusions: This is a rare case presentation of hypercalcemia due to CaSR inactivating mutation related FHH. FHH and PHPT are competing diagnoses, when a patient presents with hypercalcemia and has nonsuppressed PTH. FHH is rare, however needs to be suspected in a young patient with family history of hypercalcemia, to avoid misdiagnosis of PHPT and unnecessary surgical intervention.
Osteitis Fibrosa Cystica: An Unusual but Still Prevalent Manifestation of Uncontrolled Secondary Hyperparathyroidism
Authors: Luzuriaga Maria Gracia , Diez-Cardona Elsie , Lagari-Libhaber Violet S
Published: May 2021

Background: Osteitis fibrosa cystica is an uncommon complication of untreated secondary hyperparathyroidism in patients with end-stage renal disease. The characteristic bony lesions that are seen in this condition very rarely can regress after medical treatment or parathyroidectomy. Clinical Case: A 65-year-old male with PMH of Systemic Lupus Erythematous (SLE) resulting in End-Stage Renal Disease (ESRD) on peritoneal dialysis (PD) and HTN, presented to his primary care physician for evaluation of a painful, enlarging lesion in his left forearm. The patient reported no history of trauma and denied having systemic symptoms. An X-Ray of his left forearm showed a lytic lesion within the proximal neck of the ulna, with erosion of the adjacent cortex. CT of the forearm showed a very vascular soft tissue mass causing significant erosive changes of the anterior cortex in the proximal ulna. Due to the characteristics of the lesion, an underlying malignancy was suspected as a possible diagnosis. The patient had a whole-body PET CT which showed multiple scattered hypermetabolic lytic osseous lesions throughout the axial and appendicular skeleton, including a large left proximal ulnar lesion. The patient had a bone biopsy from the lesion in his left ulna which showed a giant cell proliferation in a background of fibrosis and hemosiderin, suggestive of Osteitis Fibrosa Cystica (brown tumor of hyperparathyroidism). His laboratory workup around the time of the symptoms showed a normal serum calcium (9 mg/dl), associated with a high serum phosphorus (6.2 mg/dl), low vitamin D (20 ng/ml), and an elevated PTH (900 pg/ml). The patient was started on Cinacalcet, an increased dose of phosphate binders, as well as Calcitriol and the lesions and pain disappeared. Follow up lab work showed a normal Vitamin D (34 mg/dl), normal Phosphorus (4 mg/dl), and a PTH of 199 mg/dl, with a normal serum Calcium. A surveillance PET was performed 6 months after the initial one when the lesions clinically had disappeared and it showed again the presence of the bony lesions described prior, including the one in the left ulna, but with decreased FDG uptake, as well as new lesions in the spine. To date, the patient is asymptomatic and has not noted any new painful lesions. Conclusions: Osteitis fibrosa cystica remains a rare manifestation of secondary hyperparathyroidism, which may lead to an initial impression of malignancy. This patient exhibited clinical resolution of the painful symptoms associated with osteitis fibrosa cystica following medical management, though the lytic lesions involving the axial and appendicular skeleton persisted on surveillance imaging. This case serves as a reminder of the severe manifestations of a skeletal disease that has become rare given advances in early detection of and appropriate medical management of hyperparathyroidism.
Prolonged Hypercalcemia After Recovery From Severe Rhabdomyolysis and Acute Renal Failure
Authors: Mody Tanvisha , Mullally Jamie
Published: May 2021

Introduction: Rhabdomyolysis is characterized by elevated creatine kinase, electrolyte abnormalities and acute renal failure. After the initial hypocalcemic phase, serum calcium levels can normalize or become significantly elevated during the recovery phase. We report a case of persistent hypercalcemia during the recovery phase of rhabdomyolysis-induced acute renal failure. Case Description: A 26-year old woman with Cornelia de Lange syndrome initially presented with septic shock, complicated by severe rhabdomyolysis and acute renal failure requiring hemodialysis. On admission, creatine kinase level was >30,500 U/L [29–168], BUN 95 mg/dL [6–22], Creatinine 3.39 mg/dL [0.57–1.11], and Corrected Calcium 7.1 mg/dL [8.6–10.2]. Approximately 1 month after admission, the patient developed hypercalcemia with corrected calcium values ranging from 10.4 to 14.5 mg/dL with PTH 10.5 pg/mL [8.7–77.1] and 1,25-Dihydroxyvitamin D and 25-OH Vitamin D levels <8.0 pg/dL [18–78] and 21.20 ng/mL [30–80], respectively. Her renal function improved and dialysis was discontinued seven weeks after initial presentation, although her GFR remained impaired (22 mL/min/BSA). She remained hypercalcemic and was treated with intermittent doses of Calcitonin when the level rose above 12.0 mg/dL. Spot urinary calcium to creatinine ratio was low at 0.13. Improvement in her calcium was seen with a level of 10.8 mg/dL eleven weeks after she was initially noted to be hypercalcemic and she was able to be discharged. Two weeks after discharge, an outpatient calcium improved further to 10.4 mg/dL.

Discussion: Rhabdomyolysis is a clinical syndrome that results from severe muscle damage with release of the breakdown products from injured muscle cells leading to acute renal failure and electrolyte abnormalities. The initial hypocalcemic phase is due to entry of calcium into damaged myocytes and deposition of calcium salts in damaged muscle. After recovery, most patients have normalization of calcium levels. However, in up to one-third of patients, a rebound hypercalcemia can ensue. The proposed mechanism is massive muscle calcium release during renal recovery. In the cases reported, the hypercalcemia phase resolves by an average of 8 days with the longest reported recovery being 3.5 months. We report a case of prolonged hypercalcemia in the setting of continued renal impairment. It appears that the patient’s low GFR impaired urinary calcium excretion resulting in persistent hypercalcemia which eventually resolved over time with some improvement in renal function. Other case reports have described treatment with IV fluids, Calcitonin, Pamidronate and hemodialysis, although the efficacy of these interventions is unclear. Rhabdomyolysis is an under-recognized cause of hypercalcemia. Our case highlights the potential for prolonged hypercalcemia after recovery from rhabdomyolysis in the setting of renal impairment.
Prolonged Hypocalcemia After a Single Dose of Denosumab in Chronic Kidney Disease
Authors: Puar Akshan , Saeed Zeb Ijaz
Published: May 2021

Introduction: Denosumab, a monoclonal antibody that inhibits RANK L (receptor activator nuclear factor-kappa beta ligand), is one of the few medications that can be used to treat osteoporosis in patients with chronic kidney disease (CKD). However, its use is associated with a much higher incidence of hypocalcemia in this patient population. What remains unclear is the duration of hypocalcemia after denosumab use. We describe a case of prolonged hypocalcemia of 9 months in a patient with CKD after a single dose of denosumab.

Case: A 64-year-old Caucasian man with a history of bilateral lung transplant for interstitial pulmonary fibrosis and CKD Stage IV was referred to the Endocrinology clinic for evaluation of steroid-induced osteoporosis. Bone density scan was consistent with osteoporosis with the lowest T-score of -2.8 at the left femoral neck, which showed a 25.3% decline from a previous one two years prior. His labs upon initial visit: 25 hydroxy Vitamin D: 36.5 ng/mL (30–100), 1, 25 hydroxy vitamin D 32 pg/ml (19.9–79.3), corrected Serum Calcium 8.9 mg/dL (8.5–10.5), Serum Cr 4.38 mg/dL (0.6–1.4), PTH 157 pg/mL (10–65), Serum Alkaline Phosphatase 61 Units/L (25–125), Urine NTX 39 nM BCE/mM creatinine (21–83). After discussing risks and benefits, he was given a dose of subcutaneous denosumab 60 mg. He had been started on Calcium/Vitamin D (600 mg/400 IU BID) prior to receiving his dose. Keeping in mind the increased risk of hypocalcemia given his history of CKD, his corrected serum calcium was checked one week later, and it was 6.5 mg/dL. The patient was asymptomatic. However, given the severity of his hypocalcemia, he was started on calcitriol 0.25 mcg oral BID and calcium carbonate 1200 mg daily. He did show mild improvement in three days to a corrected calcium of 7.0 mg/dL. His calcitriol was briefly increased to 0.5 mcg BID and calcium carbonate was increased to 1800 mg daily. The regimen was weaned to calcitriol 0.25 mcg daily and previous calcium/Vitamin D dosing later that month. Thereafter, his labs were monitored regularly and there were several unsuccessful attempts made to decrease the calcitriol/calcium carbonate. Given persistent hypocalcemia, other bloodwork including a bone specific alkaline phosphatase and celiac screen were checked which were unremarkable. Finally, nine months after his denosumab dose, calcitriol was discontinued safely. Serum calcium levels have remained stable thereafter. Given prolonged hypocalcemia, it was decided not to administer another dose of denosumab.

Conclusion: Patients with CKD who receive denosumab are not only at risk for developing severe, but also prolonged hypocalcemia. Therefore, it is imperative to monitor serum calcium levels, not only immediately after receiving a dose, but serially.
The Unusual Suspect: Hypocalcemia in Preeclampsia After Magnesium Infusion
Authors: Abdulhadi Basma , Agarwal Monica
Published: May 2021

Background: Magnesium plays a vital role in calcium homeostasis. Magnesium sulfate is used in obstetric populations for the management of preeclampsia and eclampsia. Hypocalcemia secondary to iatrogenic hypermagnesemia is an uncommon complication. We report a case of symptomatic hypocalcemia due to hypermagnesemia. Clinical Case: A 26-year-old female with type 1 diabetes at 33 weeks gestation was admitted for preeclampsia. She had severe hypertension and proteinuria, and the decision to induce labor was made. She was started on a magnesium sulfate drip and remained on the drip for 33 hours. Magnesium levels peaked at 7.5 mg/dL (1.7–2.5 mg/dL). The magnesium drip was suspended after delivery. She complained of mild tingling and numbness in her hands, feet, and perioral area. Shortly after delivery, she had a pre-syncopal event. The laboratory evaluation revealed a calcium of 5.9 mg/dL (8.4–10.4) with an albumin of 2.2 g/dL (3.7–5.5), magnesium of 4.2 mg/dL, phosphorus 2.2 mg/dL (2.3–4.6) and GFR above 60 mL/min/1.73m2 . Spot urine calcium to creatinine ratio was 0.17 mg/dL. The 25-hydroxy vitamin D level was low at 12 ng/mL (20–100). The parathyroid hormone (PTH) level was inappropriately normal at 21.7 pg/mL (12–88). She had no history of hypocalcemia, and calcium level obtained six months before the presentation was normal. She received one calcium gluconate infusion, was then started on a continuous calcium gluconate infusion for symptomatic hypocalcemia. She also received oral supplementation of calcium and vitamin D. The calcium levels normalized within 24 hours as the hypermagnesemia resolved from the discontinuation of the magnesium drip. The subsequent PTH level was 38.8 pg/mL. She was discharged on vitamin D supplements. She had no recurrence of hypocalcemia. Conclusion: Our case highlights the effect of magnesium infusion on the parathyroid gland leading to profound symptomatic hypocalcemia. Magnesium plays an essential role in the secretion of PTH. Transient hypoparathyroidism can occur due to hypomagnesemia and hypermagnesemia (tocolytic therapy). In hypomagnesemia, the parathyroid gland secretes insufficient PTH, and the renal and skeletal response to PTH is reduced. In hypermagnesemia, the magnesium activates the extracellular calcium-sensing receptor, subsequently causing inhibition of the parathyroid gland. Amelioration of hypermagnesemia leads to the normalization of parathyroid function. Health care providers should be aware of this phenomenon, especially in the obstetric population receiving magnesium infusion. The monitoring of calcium levels may be necessary for this patient population. The laboratory testing should include magnesium in the evaluation of hypocalcemia. References:

1. Shoback, D. (2008). Hypoparathyroidism. New England Journal of Medicine, 359(4), 391–403.
Unusual Case of Pelvic Osteomyelitis Revealing Osteoporosis
Authors: Farooqi Iqra N , Sharma Anupa
Published: May 2021

Pelvic osteomyelitis is an uncommon and challenging condition to treat. Pressure ulcers, spinal injuries, contiguous sources of tracking infections, pelvic surgical procedures, traumatic injuries and open fractures all serve as nidi for developing pelvic osteomyelitis. We present a case of pelvic osteomyelitis suspected to be caused by insufficiency fractures due to osteoporosis in an anorexic adult.51 year old postmenopausal Caucasian female with undiagnosed anorexia presented to the hospital for severe right-sided pelvic pain and nausea. She denied fevers, vomiting, trauma, surgical procedures, history of pelvic infections, abnormal vaginal discharge, travel, prolonged steroid therapy. She disclosed a strict vegetarian diet, excessive daily exercise, low dairy intake and over 100lb intentional weight loss over the past 30 years. She reported normal menses, used oral contraceptives between ages of 25 to 30, and reached menopause at 49 years. For many years, she denied medical care including age-appropriate cancer screenings. She is employed in academia and denies tobacco, alcohol or drug use. On admission, height 153cm and weight 43kg, BMI 16.7kg/m2. Examination was notable for frail body habitus, moderate RLQ and pelvic tenderness, prominent PSIS and SI joints with decreased RLE range of motion. Laboratory results showed calcium 9.5mg/dL (n 8.6–10.4), phosphorus 4.1mg/dL (2.5–4.5), ALP 181IU/L (45–115), PTH 23pg/dL (n 9–76), Vitamin D 35ng/dL (n 25–80), 24-hour urinary calcium 285mg/24h (n 50–400). Abdominopelvic CT scan showed chronic right pubic ramus and bilateral sacral insufficiency fractures confirmed on MRI with septic arthritis of the pubic symphysis, osteomyelitis of pubic bodies and intramuscular abscess extending to the right adductor muscle. Wound culture was positive for Streptococcus viridans and pelvic bone biopsy showed degenerative changes. The patient completed IV Ceftriaxone therapy and underwent DXA scan confirming osteoporosis (T-scores:-3.8 lumbar spine L1-L4, -3.6 left femoral neck, -3.3 right femoral neck). Alendronate 10mg daily and calcium citrate-vitamin D 1000mg-800IU twice daily was prescribed. Diagnostic workup for secondary causes of severe osteoporosis was unremarkable except for hypercalciuria, for which calcium supplement was held with a plan to repeat in the future. Concern for her cachectic appearance and severity of her illness also elicited a dietician referral. Pelvic osteomyelitis and septic arthritis are seldom found without inciting insults. We report an atypical cause of presumed anorexia induced osteoporosis resulting in pelvic osteomyelitis. Untreated osteoporosis may lead to fracture, resulting in inflammation and predisposing patients to infections. Thus, early recognition and evaluation of osteoporosis in patients at high risk for fracture, such as patients with anorexia, is critical for prevention.
Global Wnt Inhibition With a Porcupine Inhibitor Decreases Established Trabecular Bone in a Mouse Model of Fibrous Dysplasia
Authors: Lung Hsuan , Moody Tania , Wentworth Kelly , Kang Misun , Ho Sunita , Hsiao Edward
Published: May 2021

Background: G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including bone development and remodeling. Fibrous dysplasia (FD) is a common skeletal dysplasia caused by increased Gs-GPCR signaling and characterized by fibrotic expansile bone lesions. FD has no effective medical treatments. Our prior studies used the ColI(2.3)+/Rs1+ mouse model where osteoblastic-cell Gs signaling induced a dramatic FD-like phenotype and increased Wnt signaling, which we hypothesized is a major driver of the phenotype. Furthermore, we previously showed that blocking Rs1 expression could reverse the abnormal bone phenotype, providing proof-of-concept for finding therapies for FD.

Methods: Long bone stromal cells from wildtype and ColI(2.3)+/Rs1+ 9-week-old male mice were analyzed by single-cell RNAseq to identify potential cellular sources of Wnt ligands. We compared these findings with global inhibition of Wnt activity by oral administration of the porcupine inhibitor LGK974 to ColI(2.3)+/Rs1+ mice. These mice were analyzed by histology and micro-computed tomography (micro-CT).

Results: Control and ColI(2.3)+/Rs1+ bones showed similar scRNAseq results, except for a large expansion of osteoblastic lineage cells and increased differential expression (DE) genes in this cluster. Expression of Gi-GPCRs was increased, potentially as compensation for the strong Gs-GPCR pathway activation induced by Rs1 expression. We also found increased GH/IGF1 pathway activation in the osteoblastic cluster, and expression of multiple Wnt ligands within multiple cell clusters. We also identified a cell population unique to the ColI(2.3)+/Rs1+ FD-like bone lesions. Broad Wnt production inhibition of porcupine by LGK974 induced dose-dependent resorption of the abnormal FD bone shown by decreased bone volume and trabecular thickness; however, the fibrocellular infiltrate in the ColI(2.3)+/Rs1+ mice was still present.

Conclusions: FD-like bones of ColI(2.3)+/Rs1+ mice showed broad activation of Wnt signaling in multiple cell types, suggesting both cell autonomous and non-cell autonomous activity. Broad Wnt inhibition decreased established FD-like trabecular bone, but the fibrocellular infiltrate did not fully reverse. These results suggest distinct roles of Gs-GPCR and Wnt signaling in FD pathogenesis.
Bone Mineral Density Assessment Following Radiotherapy Related Insufficiency Fractures (RRIFs) of the Pelvis
Authors: Grigoriadou Victoria Chatzimavridou , Higham Claire Emily
Published: May 2021

Background: Pelvic radiotherapy causes symptomatic Radiotherapy Related Insufficiency Fractures (RRIFs) in around 20% of patients. Pathophysiology and predisposing factors for RRIFs are not well understood. Some studies have determined low BMD/osteoporosis to be a risk factor but only a few utilised DXA assessment of BMD at baseline prior to radiotherapy or at the time of RRIF development. Primary or secondary interventions to prevent/treat RRIFs have not been assessed. Methods: Retrospective analysis of patients (n=44; 42F; median age 65.5yrs [IQR 55, 73]) who underwent a DXA (Hologic) scan (Lumbar Spine (LS) (L1-4), Total Hip (TH), Femoral neck (FN) and Trabecular Bone Score (TBS)) following a diagnosis of pelvic RRIF between 2010–2019 at a tertiary referral cancer centre in the UK. Patient characteristics and treatment history were assessed. Osteoporosis (T-score <-2.5), osteopenia (T-score <-1 >-2.5) and normal BMD (T-score >-1) were defined as per WHO classification. Results: Cancer diagnoses; cervical (n=17), endometrial (n=9), vaginal (n=6), anal (n=6), other (n=6). Cancer treatments; chemotherapy (n=36), surgery (n=22), brachytherapy (n=26). Conventional risk factors for osteoporosis; previous fragility fracture (n=9, one on bisphosphonate prior to RRIF), smoking (n=7), glucocorticoid use (n=4), parental hip fracture (n=3), alcohol excess (n=3) and hypogonadism (n=2 and 8 on HRT). Median BMI = 25.4 [22.8, 28.5] kg/m2. Median interval between initiation of radiotherapy and RRIF was 9.8 [7.1, 19.3] months and between RRIF and DXA 3.5 [2, 8] months. At the time of the RRIF, 5 had normal BMD, 20 had osteopenia and 16 osteoporosis. Three patients were <40yrs at time of DXA (lowest Z-score -2 at LS in n=1). Median T-scores in LS, FN and TH were -1.8 [-2.8, -0.98], -1.65 [-2.4, -1.18] and -1.25 [-1.68, -0.5] respectively; N=24 had all Z-scores ≥-1. Median TBS T-score was -2.65 [-3.48, -2]. Median 10-yr hip fracture risk (FRAX HF) was 1.8% [0.7–4.1], major osteoporotic fracture risk (FRAX MO) was 8.9% [5.2- 13] (if RRIF included as FRAX risk factor: 2.9% [1–5] and 15% [8.7- 20] respectively). FRAX HF was ≥ 3% in n=14 and FRAX MO ≥ 20% in n=6 (accounting for RRIF: n= 20 and 12 respectively). Most patients therefore fell below the intervention threshold. Pelvic radiotherapy dose was negatively associated with LS BMD (p=0.0228). Body mass index was positively correlated with LS BMD (p=0.002). Discussion: Most patients did not have osteoporosis at the time of RRIF and overall had low fragility fracture risk as defined by FRAX. RRIFs can also occur with normal hip and spine BMD. Low BMD at the spine was however associated with higher pelvic radiotherapy dose. The mechanism of RRIFs is likely different to osteoporotic fragility fractures and whilst low BMD is a probable risk factor, further studies are required to fully understand their pathophysiology and how fracture risk should be best assessed in these patients.
Temporal Trends in Prescribing of Bone-Directed Therapies in the United States, 2009–2020
Authors: Cromer Sara , D’Silva Kristin M , Yu Elaine Wei-Yin , Landon Joan , Desai Rishi , Kim Seoyoung C
Published: May 2021

Multiple new osteoporosis therapies, including some with novel mechanisms of action, have been introduced in the past decade. However, little is known about temporal trends in prescribing these new medications. Using claims data from the Clinformatics Data Mart (Optum, Inc.), we determined the number of enrolled individuals over age 50 who were prescribed any osteoporosis medication during each quarter between January 1, 2009 and March 31, 2020. Of all individuals receiving therapy, we then calculated the percent receiving each medication. In subgroup analyses, we limited the population to (1) only those with ICD codes for osteoporosis in the current or previous three quarters and without codes for active malignancy during the current or previous quarter, and (2) only those with ICD codes from an oncology provider for active malignancy likely to metastasize to bone during the current or previous quarter. In the all-user cohort, a total of 15.48 million unique prescription or medication administration claims from 1.46 million unique individuals during the study period were analyzed. Of these, 89% were women and 71% over the age of 65, with a mean age of 69. Alendronate was the most common medication used, representing >50% of all treated individuals, and its use increased over time. Percent of users receiving zoledronic acid doubled during this period but remained <5%. Use of other bisphosphonates declined steadily. By comparison, after its approval in 2010, denosumab use increased rapidly, reaching 10% of users in 2015 and 15% of users in 2018. Percent of individuals treated with raloxifene declined after 2013. Use of teriparatide, abaloparatide, and romosozumab remained less than 2% throughout the study period. Trends in the osteoporosis cohort paralleled those in the all-user cohort. In the malignancy cohort, alendronate and zoledronic acid were each used in approximately 30% of individuals at the onset of the study, and both declined over the decade. By contrast, denosumab use rapidly increased after introduction and surpassed use of either bisphosphonate by 2013. Denosumab use continued to increase over time and reached approximately 50% of all bone-directed medication use in the malignancy cohort. Use of other medications, mainly alternate bisphosphonates, was low and declined throughout the study period. In a privately insured cohort between 2009–2020, denosumab use increased significantly in both osteoporosis and malignancy populations, outpacing gains in use of other agents, despite guidelines suggesting that either bisphosphonates or denosumab could be considered first-line therapy for osteoporosis.
Clinical Burden and Practice Patterns in Patients With Chronic Hypoparathyroidism in the United States (US): A Claims Data Analysis Using Diagnosis-Based Criteria
Authors: Sharma Dolly , Deering Kathleen L , Loustau Patrick , Culler Michael D , Allas Soraya , Weiss Blandine , Mitchell Deborah M , Astolfi Danette , Mannstadt Michael
Published: May 2021

Objectives: Significant knowledge gaps exist regarding the comorbidities, treatment and lab testing patterns of patients with chronic hypoparathyroidism (cHP). This study describes a large cohort of patients with cHP identified using a diagnosis-based criteria from a claims database.

Methods: This retrospective cohort study was conducted using a large (130 million individuals) claims database (HealthVerity Closed Payer Claim Medical and Pharmacy databases: Private Source 20) from Oct 2014 to Dec 2019. Eligible patients had ≥2 diagnosis claims of HP (ICD9/10 codes: E20.0, E20.8, E20.9, 252.1) that were 6–15 months apart, a prescription claim for either active vitamin D, calcium, PTH or thyroid replacement therapy between the first qualifying HP claim and within 30 days of the second HP claim, and continuous enrollment for one year before the index date (the date of the first of two qualifying HP diagnosis claims) and ≥16 months after. Patients were followed up to two years after the index date. Patient characteristics, comorbidities, lab testing and treatment patterns were descriptively analyzed.

Results: Out of 43,640 patients with a diagnosis claim for HP, 4,118 patients met the eligibility criteria. The mean age of the cohort was 56.5 years + 18.6 (SD), and 76.4% were females, similar to data from other large cohort studies. The most common comorbidities during the 1-year follow-up were hypertension (56.0%), hypocalcemia (38.7%), cancer (30.5%, of which 24% were thyroid cancers), diabetes (29.4%), chronic pulmonary disease (24.1%), cardiac arrhythmias (17.4%), CKD stage 3–5 (17.0%), osteoporosis (9.6%) and neuropsychiatric disorders, including depressive disorders (22.0%), anxiety (21.6%), and sleep-wake disorders (18.4%). During the 1-year follow up, commonly monitored lab tests included serum calcium (89.9%), eGFR/creatinine (85.7%), 25-hydroxy vitamin D (61.1%), and intact PTH (43.9%). Remarkably, serum phosphorous (36.3%), serum magnesium (35.4%), and 24h-urine calcium (10.5%) were much less often monitored. In addition, BMD was measured in 10.9% patients. Also during the 1-year follow-up, 67.1% of patients had a prescription claim for thyroid replacement therapy, 60.5% for calcitriol, 15.7% for ergocalciferol, and 3.4 % for PTH.

Conclusion: Findings from this study highlight the high comorbidity burden in cHP patients which aligns with the monitoring patterns. Kidney function appears to be a key concern and may be important when considering therapeutic intervention. The comorbidities and practice patterns observed in this study are consistent with the results obtained using a surgery-based approach to identify cHP patients in the same claims database. Future studies will also examine the economic burden of cHP.