bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe Refractory Hypocalcemia After Administering Zoledronic Acid for Osteoporotic Fracture in Primary Hyperparathyroidism That Is Complicated Into Hungry Bone Syndrome: A Case Report
Authors: Alhamdan Ali Saleh , Douba Najah Younes , Aljamaan Abdulaziz , Alghamdi Abdulrahman Aidh , Alhammad Zahrah Abbas , Alanazi Khalid 
Published: May 2021

Abstract
Zoledronic acid is a very effective (IV) amino bisphosphonate which is indicated in osteoporosis, hypercalcemia of malignancy, multiple myeloma, Paget’s disease, and bone metastases from solid tumors. Bisphosphonate inhibits bone resorption through actions on osteoclast activity resulting in increasing bone density. Unfortunately, there are side effects associated with zoledronic acid one of those is mild to moderate hypocalcemia. Hungry Bone Syndrome (HBS) is defined as a severe drop in calcium levels less than 2.1 mmol/L and/or prolonged hypocalcemia for more than 4 days post parathyroidectomy. Most seen in patients’ who have secondary hyperparathyroidism compared to primary hyperparathyroidism. The sudden drop of parathyroid (PTH) levels post parathyroid resection after a prolonged duration of high PTH levels causes net calcium to move into the bone, this is the most proposed hypothesis. The authors report a case of a 32 years old female known case of severe osteoporosis presented to the emergency department complaining of left hip pain after a short height fall admitted as a case of pathological fracture. Furthermore, upon admission was vitally stable although on examination the patient had left side hip pain and tenderness otherwise unremarkable. Initial lab investigation showed a calcium level of 2.57 mmol/L and PTH level 37 pmol/L otherwise electrolytes and full blood count were unremarkable. Radiological investigations were done, and an X-ray has shown a left hip fracture where the patient underwent an operating room for fixation. In addition, a 99mTc-HDP bone scan revealed hyperparathyroidism and brown tumor. 99m Tc SESTA-MIBI whole body scan suggested metabolic bone disease. Furthermore, the parathyroid showed suggested typical parathyroid adenoma below and lateral to the lower pole of the left thyroid lobe. The ultrasound of the thyroid showing a well-defined hypoechoic nodule 2.5x1.15 cm with significant hypervascularity is seen, which is most likely to be enlarged left parathyroid gland. Thus, diagnosis of primary hyperparathyroidism has been reached with parathyroid adenoma which was resected during a hospital stay. The patient received pre-op zoledronic acid as a treatment for osteoporosis prior to the hip operation. After the parathyroid adenoma resection, the patient had a sudden drop of PTH and developed hypocalcemia which was 1.1 mmol/L. Thus, the complication of post operated parathyroid adenoma of HBS diagnosis has been made. Interestingly the patient needed to increase the length of stay of the hospital due to refractory hypocalcemia where the patient has been receiving IV calcium and vitamin D supplementation which hadn’t improved until a month of IV calcium gluconate. Although, the patient didn’t develop any signs or symptoms of hypocalcemia.
Sporadic Pseudohypoparathyroidism 1B in Monozygotic Twins: Insights Into the Pathogenesis of Methylation Defects
Authors: Keidai Yamato , Iwasaki Yorihiro , Iwasaki Kanako , Honjo Sachiko , Bastepe Murat , Hamasaki Akihiro 
Published: May 2021

Abstract
Background: Pseudohypoparathyroidism (PHP) 1B is an imprinting disorder characterized by renal resistance to parathyroid hormone (PTH) without Albright Hereditary Osteodystrophy (AHO). PHP1B is associated with methylation defects at the GNAS differentially methylated regions (DMRs). In sporadic cases with PHP1B, the mechanistic basis of methylation defects remains to be solved, except in rare cases with uniparental disomy of chromosome 20. In addition, to date, monozygotic twin cases with sporadic PHP1B have not been reported.
Clinical Case: The patients were 26-year-old Japanese female monozygotic twins. They had been born to nonconsanguineous parents after an uneventful pregnancy. Both twins had common biochemical features, including hypocalcemia, hyperphosphatemia, elevated PTH levels, and impaired urinary excretion of phosphorus and cAMP in response to teriparatide. They showed no signs of AHO. The serum calcium levels of their parents and brother were within the normal range, and family history was unremarkable. Based on these findings, the twins were diagnosed with PHP1B. Targeted bisulfite sequencing of the GNAS DMRs in all family members revealed almost complete gain-of-methylation at the NESP55 DMR, and loss-of-methylation at the AS, XL, and A/B DMRs in the twins, but not in other family members. Except for the GNAS locus, we did not find clear methylation defects in other imprinted genome loci in the twins. Methylation defects at the GNAS locus were further confirmed by methylation-sensitive restriction enzyme-qPCR. Whole-genome sequencing of the twins showed no pathogenic variants in the GNAS exons encoding the Gs alpha subunit. No large deletions or insertions were found at the STX16 locus or in the region from AS exon 5 to XL. Based on the SNP genotyping results, large paternal isodisomies in the GNAS DMRs were unlikely. Collectively, these results suggested that the twins had concordant methylation defects that are seen in the sporadic form of PHP1b. We speculate that an early developmental event before the twin splitting is responsible for the abnormal methylation of the GNAS DMRs.
Conclusion: We report, for the first time, monozygotic twins with sporadic PHP1B who were phenotypically and epigenetically concordant. Our comprehensive molecular genetic analyses have thus far ruled out the previously described genetic defects underlying PHP1B. The current findings provide new insights into the mechanistic basis of the GNAS methylation defects in sporadic PHP1B.
Successful Early Treatment of Severe Neonatal Hyperparathyroidism With Cinacalcet
Authors: Thakkar Keya , Romero Christopher Joseph , Rapaport Robert 
Published: May 2021

Abstract
Introduction: Neonatal severe hyperaparathyroidism (NSHPT) can cause significant bone disease early in life and prompt treatment is therefore necessary. Cinacalcet is a calcimimetic primarily used in adult patients with hypercalcemia to treat secondary hyperparathyroidism, but has only been trialed in neonates with NSHPT. Successful treatment appears to be dependent on the mutation leading to hypercalcemia. We describe a neonate born with severe hypercalcemia and a suspected mutation of the calcium sensing receptor (CaSR) who received successful early treatment with cinacalcet and decrease in calcium levels.
Case Report: A full-term baby girl was found to have rapid breathing at 2.5 hours of life requiring CPAP. A chest x-ray demonstrated bone demineralization with rib fractures. Lab evaluation demonstrated hypercalcemia (total calcium = 12 mg/dl) with an inappropriately elevated PTH level of 386 pg/mL, hypophosphatemia (3.3 mg/dL), normal magnesium (2.0 mg/dL), a normal urine calcium to creatinine ratio of 0.26 and calcium to creatinine clearance ratio of 0.05 and a slightly low vitamin D-25 of 28.8 ng/mL.
The father had a history of asymptomatic hypercalcemia without a diagnosis. Paternal genetic testing identified a heterozygous pathogenic CASR defect: c. 554G&gt;A (p.Arg185Gln). This has been described in patients with NSHPT.
The patient was initially treated with IV fluids and Lasix, but calcium levels did not decrease. Cinacalcet therapy was given on day of life 10. Patient had a decreased PTH to 231 pg/ mL after one day. After 26 days of treatment, patient’s PTH level decreased to 63 pg/mL. Patient was weaned off of CPAP and was discharged home.
Discussion: Cinacalcet, a calcimimetic that works at the level of the CASR, was able to successfully and significantly decrease PTH levels in a neonate patient with NSHPT. Treatment options are limited in patients with this condition and we believe prompt treatment with this therapy facilitated patient’s discharge. The patient’s osteopenia secondary to the NSHPT and subsequent rib fractures resulted in a prolonged requirement of CPAP. Early recognition and treatment, even prior to results of genetic testing, prevented further fractures. We demonstrate the potential benefit of calcimimetics in a case of NSHPT where conventional treatment was ineffective. More importantly, we anticipate improvement in osteopenia and any future comorbidities secondary to this condition. Continued success with this treatment is yet to be evaluated.
Successful Medical Management of a Non-Localising Case of Tumour-Induced Osteomalacia
Authors: Shan Hoong Caroline Wei , Mok Shao Feng 
Published: May 2021

Abstract
Introduction: TIO is a rare paraneoplastic syndrome characterised by renal phosphate wasting due to fibroblast growth factor-23 (FGF23) over-secretion from a phosphaturic mesenchymal tumour (PMT). While surgery is potentially curative, localisation is often challenging.
Clinical Case: A 53 year old lady presented with recurrent fragility fractures in the spine (T10-L1, L4, S1-2), right femoral neck fracture and pelvic fractures at the bilateral superior and inferior pubic rami, associated with a 2 year onset of lower limb pain and proximal myopathy. Power was 2/5 proximally, rendering her progressively chairbound. She had no family history of fragility fractures. Biochemistry revealed hypophosphatemia of 0.48 mmol/l (NR 0.86–1.45 mmol/l), normal adjusted calcium of 2.32 mmol/l (NR 2.15–2.55 mmol/l), hyperphosphaturia (TmP/GFR 0.39 mmol/l, NR 0.88–1.42 mmol/l), mildly insufficient 25(OH)D level of 25 μg/l, inappropriately suppressed 1,25(OH)2D at 13 pg/ml (NR 18–78 pg/ml) and raised FGF23 at 484 RU/ml (NR&lt;180 RU/ml). Localisation of the PMT was unsuccessful, despite multiple investigations including 68-Gallium-DOTANOC PET-CT, bilateral lower limb MRI for non-specific inguinal lymph nodes and various ultrasonographic evaluation of soft tissue lesions including biopsy of a benign breast tumour. Surgical removal of the breast papilloma did not affect FGF23 levels. In the absence of any suspicious lesion, selective venous sampling was not performed due to uncertain utility. She was treated medically, requiring 16mmol oral phosphate, 1000 IU cholecalciferol and 0.5mcg calcitriol daily, with a view to perform interval DOTA-peptide scan. Despite an increase in FGF23 to 760 RU/ml over 29 months, phosphate level was maintained in the low-normal range and alkaline phosphatase, as a marker of disease activity, normalised from 370 U/l to 92 U/l (NR 40-130U/l). Development of secondary hyperparathyroidism improved with uptitration of calcitriol. There was no hypercalciuria on monitoring of urinary calcium. Symptoms of generalised body pain resolved, and her bone mineral density (BMD) improved over 47 months of medical therapy. Power improved to 4/5, and she was able to ambulate with assistance. BMD at the femoral neck, total hip and lumbar spine increased by 68.2%, 44.6% and 65.2% respectively.
Conclusion: This is a challenging case of TIO which has failed to localise despite best efforts. One must consider FGF23-independent and dependent causes of osteomalacia when patients present with severe frailty and hypophosphatemia as substantial morbidity results from delayed diagnosis and treatment. TIO-related PMTs can be difficult to localise, even with a combination of functional and anatomical imaging. With medical therapy, bone mineralisation and symptoms can improve significantly. Patients need to be monitored for complications of long-term phosphate and calcitriol replacement.
Transient Osteoporosis
Authors: Poku Caroline A , Camacho Pauline M , Ilyas Zubair 
Published: May 2021

Abstract
Background: Transient osteoporosis is an uncommon and self-limited clinical syndrome characterized by acute joint pain with evidence of bone marrow edema on MRI. It predominantly affects healthy middle-aged men or women in the third trimester of pregnancy. The hips, knee, foot and ankle are affected in decreasing order of frequency. Pathophysiology is unknown but multiple etiologies such as ischemia, neurogenic compression or impaired venous return have been proposed. Classically, it is unilateral and bilateral in only 20%-40% of cases. It has been reported to periodically involve different joints over time with one report showing the progression to regional migratory osteoporosis in at least 20% of patients. There are no specific biomarkers to aid with diagnosis, MRI shows diffuse bone marrow edema sometimes associated with joint effusion with infrequent subchondral microfractures. Other etiologies to consider for bone marrow edema include osteomyelitis, avascular necrosis, trauma, tumors and inflammatory arthropathy. Transient osteoporosis can be self- limiting however, bisphosphonate use has been associated with shortened recovery time. In our patient given lack of access to his previous records to review and ascertain his previous diagnosis, his diagnosis of record was transient osteoporosis rather than regional migratory osteoporosis. Clinical Case: A 47 yo male presented to clinic with complaint of left ankle pain. Pain initially noted when he tripped and fell one year ago. Initial x-rays did not reveal any fractures. He was unable to weight bear due to pain although he had full range of motion at the ankle with a normal neurological and vascular exam of the foot. Due to persistence of pain, an MRI was done which showed cutaneous edema around the medial and lateral aspects of the ankle, trace tibiotalar joint effusion, marrow edema in the distal tibia and navicular with no acute fracture or definite evidence of avascular necrosis. On further questioning he reported a previous history of hip pain at age 32 and 41 with no preceding trauma. X-rays were negative for fracture and MRI showed marrow edema. Symptoms resolved after a few weeks with possible treatment with Alendronate. With the current presentation biochemical work up including Vitamin D, PTH, 24-hour urine calcium, electrolytes, phosphorus and alkaline phosphatase was unremarkable. Given the marrow edema reported on MRI, absence of fracture, osteochondral lesion or recent trauma transient osteoporosis was diagnosed. Given the duration of symptoms he was treated with Reclast 5mg IV once and reported 80% improvement in ankle pain during follow up 4 weeks later.
Conclusion: It is important to identify transient osteoporosis and regional migratory osteoporosis to prevent unnecessary medical or surgical therapy.
Treatment of Polyostotic Fibrous Dysplasia With Intravenous Ibandronate
Authors: Kazi Fatima M , Meah Farah 
Published: May 2021

Abstract
Introduction: Fibrous Dysplasia (FD) is proliferation of fibrous tissue within the bone marrow causing osteolytic lesions and pathologic fractures. Polyostotic FD in combination with a thigh myxoma is consistent with Mazabraud syndrome (MS). Bisphosphonates have shown promise in treatment and prevention of progression of FD. Clinical Case: A 34-year-old male with an unremarkable family history developed left thigh pain shortly after Whipple’s procedure for pancreatic cancer in 2017. Imaging revealed a 9cm left thigh mass and multiple femoral and pelvic intramedullary lesions compatible with FD. The thigh mass was removed and final pathology revealed an intramuscular myxoma with +GNAS mutation. Given clinical picture, genetics raised concern for MS and recommended endocrinology consultation. Patient reported chronic pain in chest, abdomen, back and multiple joints requiring spinal stimulator placement. Labs displayed subclinical hyperthyroidism and thyroid uptake scan revealed a right toxic MNG. Hence ablation was performed. Labs also displayed elevated alkaline phosphatase (ALP) bone isoenzyme of 103 IU/L (RR 0–72). Thoracic X-ray revealed chronic endplate vertebral compression fracture with no history of trauma and normal DEXA scan. NM bone scan was consistent with FD in skull, humerus, scapula, ribs, pelvis, femur and tibia. Given chronic pain at multiple sites and compression fractures, therapy with IV Zoledronic acid was given after Vitamin D was repleted. Within several hours, patient developed acute phase reaction (APR) with severe bone pain requiring hospitalization. ALP levels normalized within 1 year of therapy. 1.5 years post therapy, patient experienced a grand mal seizure. MRI brain revealed multifocal abnormal bone marrow within the calvarium, facial bones and skull base. Labs again displayed elevated ALP but new hypophosphatemia and an elevated serum FGF23. Given progression of skeletal disease as indicated by elevated FGF23, additional off-label injectable treatment options were reviewed and patient agreed to Ibandronate. Discussion: Majority of evidence for bisphosphanate treatment in FD is derived from observational studies, which report variable symptomatic improvement despite improvement of bone turnover markers. Oral anti-resorptives are commonly used but were not an option for our patient given history of Barrett’s esophagus and Whipple’s surgery. Pamidronate was first used in the treatment of FD with variable success rates. Denosumab is also being considered as a therapeutic option in FD however there are insufficient case reports to outline safety profile. Zoledronic acid is commonly used however our patient developed APR to the first dose and refused retrial. Given progression of disease, treatment was recommended. Therefore a milder anti-resorptive such as Ibandronate was considered which warrants further investigation in the treatment of FD.
Tumor Induced Osteomalacia - Long Term Medical Treatment When Surgery Is Risky
Authors: Levy Shiri , Honasoge Mahalakshmi , Mann Yasmeen 
Published: May 2021

Abstract
Introduction: Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness and fractures caused by production of a phosphaturic factor by rare mesenchymal bone or soft tissue tumors that causes isolated renal phosphate loss and osteomalacia. Low phosphate (iP), high bone alkaline phosphatase (BAP), and normal or low 125 dihydroxy D, are salient biochemical findings. Fibroblast derived growth factor (FGF 23) may be high or inappropriately normal. Gallium-68 Dotatate (DoT) imaging has become the imaging method of choice. Long term medical management may be required when removal of the tumor is risky or not feasable. Case Report: 65 yr old woman with carcinoid tumor of the right lung and a bony lesion in the T3 vertebral body diagnosed with TIO. She was initially screened for osteoporosis after traumatic rib fractures. Bone scan and SPECT-CT revealed numerous foci of increased uptake. She had elevated alkaline phosphatase 186 IU/L (0–140) and PTH 83 pg/ml (15–65) with a low phosphate 1.5 mg/dl (2.5–4.5), along with normal FGF23 level 102 RU/ml Ref Range &lt; + 180 RU/ml. DoT and PET CT imaging for TIO evaluation showed a foci of increased uptake right lower lobe of her lung, and “osseous metastatic disease” in the right scapula, vertebral body, iliac, and pubic ramus. Sclerosis of T3 vertebral body was noted in the area of intense Gallium Dotatate uptake. Transbronchial excision of the lesion showed a well differentiated neuroendocrine carcinoma. Chromogranin A and 24 hour urine for 5HIAA were normal. She responded well to medical therapy with oral phosphate, calcium and calcitriol. Follow up, DoT and FDG PET showed persistent intense uptake in the sclerotic lesion on T3 vertebral body, while the rest of the hot spots resolved. Sclerotic T3 lesion is likely the primary lesion that is responsible for the TIO. Neuroendocrine tumor of the lung may be a mere association. Biopsy of the T3 lesion was not feasible and excision was considered risky to the patient.
Discussion: Our case illustrates that awareness is the key to early diagnosis of TIO. FGF 23 in some TIO cases may be inappropriately normal in commercial assays and even in research labs. Measurement of fibronectin 1 (FN1) and FGF receptor 1 fusion gene which is noted in up to 60% of tumors are not commercially available. While DoT and PET CT are imaging modality of choice, CT and MRI may be useful to define the anatomy of the lesion. Long term medical management may be necessary when removal of primary lesion is not possible or risky. Most tumors are benign while some may prove to be malignant.
Tumor Induced Osteomalacia in Patients With Metastatic Prostate Cancer: Case Report and Literature Review
Authors: Khadilkar Arjun , Tarasova Valentina , Zhang Jingsong , Hallanger-Johnson Julie E 
Published: May 2021

Abstract
Background:Tumor induced osteomalacia (TIO), driven by elevated levels of fibroblast growth factor (FGF23), has been associated with progressive aggressive prostate cancer. FGF23, expressed by osteocytes, plays an important role in tumorigenesis through cell proliferation, chemotaxis, and angiogenesis. FGF23 regulates phosphate homeostasis through feedback loops between the kidney and bone. We present a case report of a patient with TIO and advanced prostate cancer (PC) and review previously published data.
Clinical Case: A 63-year old male with castrate-resistant PC with bone metastases presented with symptoms of profound fatigue, memory loss, and brain fog. Laboratory studies demonstrated severe hypophosphatemia (phosphorus 0.8 mg/dL, normal 2.5–4.5 mg/dL), mild hypocalcemia, secondary hyperparathyroidism, normal 25 hydroxy-vitamin D and 1,25-dihydroxy vitamin D. After treatment with IV and oral replacement, phosphorus improved to 2.2 mg/dL. Urinary phosphorous was elevated at 2105 mg/24 hours (normal 400–1300 mg/24 hours) and FGF23 545 RU/mL (normal &lt; 180 RU/mL). His PC treatment regimen extended over 10 years with multiple systemic, radiation, and targeted ablation therapies. He was also on denosumab every 3 months for metastatic bone disease, but it was discontinued due to hypophosphatemia. He is now treated with calcium carbonate-vitamin D 1000 mg-250 IU twice daily, calcitriol 1.5 mcg/daily, Phospha Neutral 250mg 2 tablets four times daily, and abiraterone acetate. His hypophosphatemia, hypocalcemia and secondary hyperparathyroidism has resolved with this regimen. To our knowledge there are 17 cases of TIO in metastatic PC are reported to date. Majority of the patients have similar clinical presentation. Treatment of metastatic PC, as well as calcitriol, phosphorus replacement, octreotide, and cinacalcet were described.
Conclusions: FGF23 plays an important role in metastatic prostate cancer progression. TIO is a rare entity in patients with metastatic PC, however mild cases are underdiagnosed due to its nonspecific symptoms and lack of routine screening. The FGF pathway represents a new target for prostate cancer treatment and clinical trials targeting FGF23 pathway in PC are needed for further drug development. Also, the efficacy of burosumab, a novel monoclonal antibody directed against human FGF23 in treatment of hypophosphatemia in metastatic PC requires further investigation.