bluuebunny/crossref_metadata_2025 huggingface dataset:
Premenopausal Osteoporosis & Perfluoroalkyl Substance Exposure; Is There a Link?
Authors: Vemula Bhavana , Olajide Omolola Bolaji
Published: May 2021

Introduction: Perfluoroalkyl substances (PFAS) like Perflouroctanoate (PFOA) and Perflurooctane sulfonate (PFOS) are ubiquitous environmental contaminants that have been in industrial use for many years. Many known adverse effects include malignancies, reproductive and thyroid dysfunction. However, there is limited literature regarding PFAS causing low bone density. We report a case of a premenopausal woman with a history of exposure to PFAS who was recently diagnosed with osteoporosis.

Clinical Case: A 36-year-old lady with a history of hypothyroidism, on levothyroxine, presented to the orthopedics clinic with complaints of sudden onset right foot pain with no trauma. She was found to have a fracture of her right second metatarsal bone. Notably, over a period of five years she had suffered multiple fractures including metatarsal, elbow and a wrist fracture, all with minimal or no trauma. She denied smoking, alcohol, chronic steroid or PPI use, history of malabsorption, celiac disease, kidney stones, malignancy or liver problems. Her menstrual cycles were regular; she was on oral contraceptives in the past for dysmenorrhea. She is on Vitamin D supplementation and consumes adequate dairy products daily. There is no family history of hip fracture or osteoporosis. Labs showed: Calcium 8.9mg/dl, Phosphorus 2.4mg/dl (2.5–4.5mg/dl), intact PTH was 92.7pg/ml (8-97pg/ml), 24-hour urine calcium was undetectable. Vitamin D was 56.6ng/ml (30-100ng/ml). CBC, TSH, FSH, liver & kidney functions were all normal. Anti-endomysial, anti-gliadin and anti-tissue trans glutaminase antibodies were all unremarkable. IgA level was 362mg/dl (8–352 mg/dl). DXA scan revealed the lowest Z-score (-3.1) in the lumbar spine. She reported a history of exposure to PFAS with a blood level of 22.3ng/ml for PFOA and 48.4ng/ml for PFOS in the year 2005. Plan is to initiate bisphosphonate therapy for the treatment of osteoporosis.

Discussion: PFAS are known endocrine disruptive agents that have been used widely in making a wide range of consumer products including nonstick and stain-resistant coatings of cookware, food containers. Recent studies suggest that serum PFAS concentrations were associated with lower bone density. There was a higher incidence of lower lumbar spine bone density in patients exposed to PFOS. PFOA is believed to compete with calcitriol at the same binding site on Vitamin D receptor resulting in changes in the osteoblasts thereby decreasing bone mineralization.

Conclusion: There needs to be increased awareness about the association of low bone density in patients exposed to PFAS. This is especially important in the evaluation of premenopausal osteoporosis.

References: 1. Environ Health Perspect. 2016 Jan;124 (1):81–7, 2. J Clin Endocrinol Metab 2014; 99(6) 2173–2180, 3. Sci Rep 2020 Oct 8;1091):16789
Primary Hyperparathyroidism From Ectopic Parathyroid Adenoma in a Patient With Bilateral Slipped Capital Femoral Epiphysis
Authors: Vitale Rebecca J , Shieh Hester , Modi Biren P , Gordon Rebecca J
Published: May 2021

Background: Primary hyperparathyroidism has been reported in 13 pediatric patients presenting with slipped capital femoral epiphysis (SCFE), but never in patients with ectopic parathyroid adenoma [1]. Case report: A 12-year-old boy with obesity (BMI 99th percentile) and autism spectrum disorder presented with a limp and was found to have bilateral SCFE. Calcium was elevated to 12.3 mg/dL (reference range 8.0–10.5) with phosphorus of 3.2 mg/dL (3.0–5.7), alkaline phosphatase 775 units/L (40–360), tubular reabsorption of phosphorus 89% (> 95%), 25OH-vitamin D 12.1 ng/mL (30–80), 1,25OH-vitamin D 246.6 pg/mL (19.9–79.3), and PTH 1191 pg/mL (10–65). He had significant neuropsychiatric agitation but denied constipation, polyuria, and other symptoms of hypercalcemia. He had in situ pinning of the SCFE bilaterally and was hyperhydrated with minimal improvement in his calcium level. Neck ultrasound revealed no parathyroid adenoma. He was discharged on cholecalciferol 1000 IU daily with plans for outpatient Tc-99m Sestamibi scintigraphy. Following discharge, he developed significant nausea, did not tolerate the cholecalciferol, and was non-weight bearing. Repeat labs and imaging 5 days later demonstrated calcium had risen to 16.7 mg/dL with phosphorus of 2.2 mg/dL. He was admitted and calcium improved transiently to less than 12 mg/dL with intranasal calcitonin therapy. Sestamibi and subsequent CT scan revealed a 2.7x1.6x1.9 cm ectopic parathyroid adenoma in the upper anterior mediastinum. He had thoracoscopic resection of the mass, which was revealed to be intrathymic, and PTH levels fell from 1613 pg/mL pre-operatively to 76 pg/mL 30 minutes post-resection. Post-operatively, he developed hungry bone syndrome with a calcium nadir of 7.6 mg/dL and phosphorus nadir of 1.6 mg/dL, which required oral calcium and calcitriol for 10 days. With normalization of his calcium, his neuropsychiatric symptoms improved. Pathology revealed a parathyroid adenoma. Conclusion: Primary hyperparathyroidism can be associated with SCFE and should be considered even in patients with traditional risk factors for SCFE, especially with bilateral disease. Pediatric patients with primary hyperparathyroidism and negative neck imaging should be further evaluated for ectopic parathyroid adenomas. References: 1. George, G.S., Raizada, N., Jabbar, P.K., Chellamma, J., Nair, A. Slipped Capital Femoral Epiphysis in Primary Hyperparathyroidism - Case Report with Literature Review. Indian J Endocrinol Metab. 2019 Jul-Aug;23(4):491–494.
Primary Hypoparathyroidism and Chronic Kidney Disease: Is It Always Related to Treatment?
Authors: Zlatanski Todor , Simon Nicole
Published: May 2021

Background: Anterior neck surgery is the leading cause of acquired hypoparathyroidism. Renal failure is the most common complication of treatment for hypoparathyroidism with active vitamin D and calcium supplements. However, the contribution of hypoparathyroidism to development of CKD in the absence of treatment is not well studied.

Clinical Case: A 70-year old woman was brought to ED after she was found on the floor at home. Medical history was significant only for a partial thyroidectomy over 20 years prior, without reported post-operative complications. She was not taking any medications. Pertinent physical findings included altered mental status, hand tremors, involuntary contractions of left arm, and ashen skin. Laboratory tests upon presentation were significant for profoundly low albumin-corrected calcium of 3.68 mg/dL (n 8.6–10.2 mg/dL); low PTH 9.9 pg/dL (n 15–65 pg/dL); elevated phosphorous 8.5 mg/dL (n 2.7–4.5 mg/dL), elevated BUN 36 mg/dL (n 8–22 mg/dL), creatinine 2.76 mg/dL (n 0.5–1.3 mg/dL) and elevated CK of 4787 U/L (n 10–225 U/L). EKG showed QT interval prolongation. Head CT revealed periventricular and basal ganglia calcifications. Renal US was normal. The patient was treated with IV and PO calcium acetate and active vitamin D with resolution of the symptoms while calcium level improved. Post hospital follow-ups were significant for persistent hyperphosphatemia, which gradually improved with calcium and non-calcium phosphate binders as well as active vitamin D. Although this patient presented with acute hypocalcemia, she had chronic hypoparathyroidism as evidenced by basal ganglia calcifications. In the absence of other medical conditions, including negative PTH antibodies, or treatment for chronic hypoparathyrodism, the most likely cause of the CKD was chronic hypoparathyroidism itself.

Conclusion: Post-surgical hypoparathyroidism may develop many years after surgery and can be asymptomatic. It is essential to diagnose this condition early to avoid late complications of the disease. The kidneys are particularly affected. Conventional treatment with calcium and vitamin D analogues is associated with ectopic mineralization and can lead to CKD. Untreated hypoparathyroidism on the other hand, can also lead to CKD, posing therapeutic challenges on finding the most appropriate and balanced treatment regimen in order to prevent further renal complications. Close monitoring and optimizing therapy plays critical role in preserving renal function of patients with hypoparathyroidism.
Recurrent Atraumatic Pelvic Fractures in a Patient With Cushing’s Disease - Is DEXA Scan Really Useful to Predict the Future Fracture Risk?
Authors: Shekhda Kalyan Mansukhbhai , Rathore Ali , Ojewuyi Taofeek , Ahlquist James
Published: May 2021

Background: Cushing’s disease may present with a variety of clinical features, including osteoporosis and fracture. Due to the inhibitory effects of cortisol on osteoblastic activity and enhancing effects on osteoclastic activity, these patients are more prone to have osteoporotic fractures. We report a case of ACTH dependent Cushing’s disease presenting with recurrent atraumatic pelvic fractures in a woman despite normal bone mineral density for her age. Clinical Case: A 56 year-old-woman was referred to the endocrinology department for suspected Cushing’s syndrome following a recent atraumatic fracture of right pubic ramus. She had a history of weight gain and easy fatigue. On examination, she had subtle changes suggestive of Cushing’s syndrome, including mild truncal obesity, minimal bruising and moon face. She had been taking hormone replacement therapy for 3 years for the post-menopausal symptoms. Her bone mineral density was normal for her age on a recent DEXA scan [femoral neck T score: -0.9, Z score: 0.1, lumbar spine (L1-L4) T score: -1.2, Z score: -0.1]. Her vitamin D, serum calcium and parathyroid hormone levels were normal. Her 24-hour urinary cortisol was 688 nmol/day (reference range: <200 nmol/day), low dose dexamethasone suppression cortisol 525 nmol/L (reference range: <50 nmol/day), ACTH 96 ng/L (reference range: <50 ng/L), indicating ACTH dependent Cushing syndrome. MRI pituitary showed 7 mm right sided hypoenhancing area suggestive of a pituitary microadenoma. CT neck, thorax, abdomen and pelvis did not show any source of ectopic ACTH secretion but did show generalised osteopenia, with old fractures of the ribs and left ilium. She was referred for trans-sphenoidal resection of pituitary tumour. While awaiting pituitary surgery she was treated with metyrapone: at this time she suffered a further atraumatic fracture of the left pubic ramus. Conclusion: Glucocorticoid excess predominantly affects trabecular bones (pelvis, ribs, lumbar spine) as compared to cortical bones. Due to micro-architectural changes, reduction in bone strength is disproportionately greater than would be expected from BMD measured by DEXA. Clinicians should be aware that recurrent fracture of trabecular bones may indicate Cushing’s disease even though other clinical features of cortisol excess are minimal or absent.
Severe Hypophosphatemia and Elevated FGF23 Level Following Zoledronic Acid Infusion
Authors: Betlachin Anna , Grock Shira , Ahmadi Sheila
Published: May 2021

Background: Severe hypophosphatemia may be seen following zoledronic acid infusion, however FGF23 elevation has not been previously reported.

Clinical Case: A 67-year-old man with Crohn’s disease status post remote ileocolonic resection, malnutrition (BMI 16.7), anemia, history of hypovitaminosis D, secondary hyperparathyroidism, and severe osteoporosis, was advised to present to the emergency room for hypocalcemia and hypophosphatemia after routine lab draw. His initial ionized calcium was 0.89 mmol/L (1.09–1.29 mmol/L) and phosphorus was 0.9 mg/dL (2.3–4.4 mg/dL), with a 25-hydroxyvitamin D level of 62 ng/mL (20–50 ng/mL), PTH of 132 pg/mL (11–51 pg/mL), and normal renal function. Hemoglobin was stable between 8–9 g/dL (13.5–17.1 g/dL). He endorsed ongoing fatigue, oral ulcers, and perioral numbness, which had been attributed to Humira infusion 2 months prior. He denied other paresthesias, carpopedal spasms, seizures, bone pain, or confusion. He reported receiving his second annual infusion of zoledronic acid 10 days prior in Turkey. He was started on high-dose oral calcium, calcitriol, and phosphate, which were continued on discharge 5 days later. Several days into his hospitalization, the patient spoke with his wife in Turkey who confirmed that his calcium and phosphorus were both within normal limits immediately prior to his infusion. A 1,25-hydroxyvitamin D level obtained during his workup was normal at 42.5 pg/mL (19.9–79.3 pg/mL), however an FGF23 level, which returned 2 weeks later, was elevated at 287 RU/mL (<=180 RU/mL). Dotatate PET to rule out oncogenic osteomalacia was negative. One month later, after normalization of calcium and phosphorus levels, repeat PTH and FGF23 levels were both within normal limits.

Conclusion: This case demonstrates that a transient increase in FGF23 levels may accompany and exacerbate hypophosphatemia following zoledronic acid infusion. The mechanism for this elevation is unclear, though we speculate that in the setting of acute hypocalcemia and hypophosphatemia due to zoledronic acid infusion, secondary hyperparathyroidism may upregulate FGF23 production, which further decreases phosphorus levels. If this scenario is accurate, the transient FGF23 elevation seen is not pathologic, but physiologic. Indeed, in the patient above, calcium and phosphorus repletion lead to normalization of both PTH and FGF23.
Severe Osteomalacia and Fractures Secondary to Vitamin D Deficiency
Authors: Mathew Justin , Berger David , Tabatabaie Vafa
Published: May 2021

Background: Vitamin D deficiency is a common entity among the elderly. Low vitamin D levels can lead to poor bone mineralization, in addition to elevations in PTH levels with resultant increases in bone turnover. However, severe Vitamin D deficiency causing osteomalacia has become uncommon in the United States due to increased screening and treatment. Vitamin D supplementation is a mainstay of therapy for osteoporosis, yet its effect on bone density is generally thought to be modest. We present here an extreme case of vitamin D deficiency leading to severe secondary hyperparathyroidism and bone demineralization, with excellent response to supplementation.

Clinical Case: Patient was a 73-year-old woman with hypertension who presented to the ER with acute on chronic back and lower extremity pain. She had these pains for about a year, but they had worsened over the last 4 days. She had been homebound for the past 1–2 years due to severe pain while ambulating, reported a five-inch loss of height and 50 pounds weight loss, and maintained a vegan diet. She had not had medical care in 15 years. Imaging studies demonstrated a displaced left femoral neck fracture, a nondisplaced right femoral neck fracture, multilevel thoracolumbar compression fractures, and a nondisplaced right scapular fracture. Blood tests revealed normal renal function, calcium 8.6mg/dL (nl 8.5–10.5), phosphorus 2.6mg/dL (nl 2.5–4.5), and alkaline phosphatase 2,821U/L (nl 45–164). Secondary osteoporosis workup was negative for hypercalciuria or multiple myeloma, but was notable for a PTH level of 2,190 pg/mL (nl 10–65) and 25-OH Vitamin D level of <5ng/mL (nl >30). C-telopeptide was measured at 3,346 pg/mL (nl <1000) and osteocalcin >300ng/mL (nl 8–32). DEXA scan showed T-scores of -4.2 at the lumbar spine and -6.8 at the distal forearm. She was started on high-dose vitamin D supplementation, with serum Vitamin D level rising to 42.1ng/mL after 6 months of treatment. This corresponded to a decrease in PTH to 141.1pg/mL and alkaline phosphatase to 375U/L. Repeat DEXA two years later showed 52.8% increase in bone mineral density at the lumbar spine, and 27.1% increase at the forearm. The patient’s body pains have significantly improved and she is now ambulatory again.

Conclusions: Vitamin D deficiency is an uncommon cause of severe bone demineralization in the United States. However, in certain high-risk populations, it can present with debilitating osteomalacia and numerous pathologic fractures. Even in cases of osteoporosis with severe PTH elevation, Vitamin D deficiency must be ruled out as a potential secondary etiology, as it can be easily treated with potentially dramatic response.
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

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

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

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>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

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<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

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

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

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 < + 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

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 < 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.
Type 1 Familial Hypocalciuric Hypercalcemia Caused by p.M74L Variant in the Calcium Sensing Receptor (CASR) Gene
Authors: Antony McAnto , Maliakal Alvin , Burdette Jameson , Verma Vipin , Kant Ravi
Published: May 2021

Background: Familial hypocalciuric hypercalcemia (FHH) is a rare cause of hypercalcemia caused by inactivating mutations in specific regions of chromosome 3 and 19. Most cases are due to inactivating mutations in the Calcium sensing receptor (CASR) which is encoded by the gene located on the long arm of chromosome 3 (3q 21.1). FHH is characterized by hypercalcemia, an inappropriately normal to elevated serum PTH level, hypocalciuria, and a family history of hypercalcemia. Several mutations in the CASR gene have been described in literature. However, the p.M74L variant in the CASR gene has an extremely low frequency of occurrence in population databases such as the genome aggregation database (gnomAD)1.

Clinical Case: A 67 years old woman with a past medical history of hypertension, dyslipidemia, type 2 diabetes mellitus, and chronic kidney disease presented for an evaluation of a long standing history of hypercalcemia. Patient reported non-specific symptoms including chronic fatigue and arthralgias. She denied a history of renal stone or chronic use of lithium. She distinctly recalled that her mother and maternal grandmother had high blood calcium levels. Review of old records showed an elevated corrected calcium level of 11.3 mg/dl, which was elevated since at least October 2013 (no medical records prior to October 2013 were available) which persisted to-date. Patient underwent work-up which revealed a high corrected serum calcium of 10.4 (8.6–10.0mg/dl), high serum PTH of 101 (15–65 pg/ml), an extremely low 24hr urine calcium of <9.2 (100–300 mg/24hr) with corresponding urine volume of 1150 cc and urine creatinine of 1392 (740–1570 mg/24hr), low 25-OH vitamin D of 20.6 (30–100 ng/ml), and a low eGFR of 47 ml/m/1.73. SPECT parathyroid gland was negative. FHH was suspected and subsequent CASR gene analysis panel showed a heterogenous DNA sequence change at nucleotide position c.220 in exon 3 of the CASR gene (c.220A>C). This nucleotide change results in an amino acid change from methionine (M) to leucine (L) at position 74 in the CASR protein (p.M74L).

Conclusion: We report a case of a p.M74L variant in the CASR gene which is an extremely uncommon mutation in the CASR gene1. Our case supports the current limited evidence that p.M74L variant in the CASR gene can cause FHH.

References: 1) Genome Aggregation Database: https://gnomad.broadinstitute.org/
Chronic Stimulation of Arcuate Kiss1 Neurons Decreases Bone Mass in Female Mice
Authors: Rodriguez Ruben , Herber Candice B , Krause William C , Ingraham Holly A
Published: May 2021

Loss of peripheral estrogen in postmenopausal women is often associated with decreased physical activity and loss of bone mass, leading to an increased risk of metabolic diseases, osteoporosis, and skeletal fragility. While it is well-established that loss of peripheral estrogen signaling results in bone loss, we previously found that eliminating central estrogen signaling paradoxically results in an unexpected massive increase in bone mass only in female mice. Specifically, deletion of estrogen receptor alpha (ERα) signaling in kisspeptin 1 (Kiss1) expressing neurons of the arcuate nucleus (ARCKiss1) increases bone mass at the expense of reproduction in female mice. Currently, the mechanisms and the neurocircuits that modulate these unexpected responses are unknown. Here, to begin addressing these questions, we asked if changing the neuronal output of ARCKiss1 neurons using chemogenetic manipulation of ARCKiss1 neurons might also alter bone mass and locomotion in female mice. To do this, we delivered stimulatory (AAV2-hM3Dq-mCherry) designer receptors exclusively activated by designer drugs (DREADDs) to the ARC of wild type and Kiss1-Cre+ (Kiss1-CrehM3q-DREADDs) female mice and asked if chronic activation of ARCKiss1 neurons might alter bone mass as analyzed by standard ex-vivo µCT imaging. Clozapine N-oxide (CNO) was delivered for 22 days (0.1 mg/mL). We also leveraged the ANY-Maze system to assess home cage activity over an extensive 96-hour period. Acute activation of ARCKiss1 tended to decrease home cage activity by nearly 40% in Kiss1-CrehM3q-DREADDs mice during the dark period compared to WT females. Interestingly, chronic activation of ARCKiss1 neurons significantly lowered trabecular bone volume by nearly 30%. Current studies are underway to ask if inhibiting ARCKiss1 neurons results in increased bone mass. Our findings collectively suggest that the neuronal activity of ARCKiss1 neurons is sufficient to shift energy allocation away from locomotion and bone-building to maximize reproductive capacity. We speculate that the widely used SERM in breast cancer treatment, Tamoxifen, might exert its bone sparing effect by silencing ARCKiss1 neurons.
Comparative Transcriptomic Profiling Revealed Distinctive Patterns in Differentially Expressed Genes Related to Clinicopathologic Features of Parathyroid Carcinoma and Adenoma
Authors: Hong Namki , Lee Seunghyun , Kim Kyoungjin , Jeong Jong Joo , Kim Sang Kyum , Jo Se-Young , Kim Sangwoo , Rhee Yumie
Published: May 2021

Parathyroid carcinoma is a rare malignancy which remains as a clinical unmet need lacking effective therapeutic intervention. (1) In this study, we compared mutational profile of parathyroid carcinoma, adenoma, and normal parathyroid tissue using RNA-Seq based transcriptomics analysis and whole exome sequencing. A total of 40 parathyroid specimens [parathyroid carcinoma (n=8), adenoma (n=24), and normal tissue incidentally obtained from thyroidectomy for various reasons (n=8)] from 39 individuals (women n=34, 87%; mean age 51 year) were analyzed. Compared to adenoma and normal parathyroid groups, parathyroid carcinoma group had younger age (carcinoma 35 ± 12 vs. other 56 ± 16 year, p=0.001) and higher serum parathyroid hormone (PTH; 231 [145–474] vs. 114 [88–196] vs. 34 [29–41] pg/mL, p=0.001) prior to surgery. CDC73 mutation was found in 7 of 8 carcinoma specimens, which harbored germline mutation in 6 of them. Among top feature gene mutations for classifying adenoma and carcinoma, carcinoma-specific genes showed high specificity, whereas adenoma-related key features were largely overlapped with normal tissues. Transcriptional profiling revealed 546 carcinoma-specific differentially expressed genes (DEGs), 135 adenoma-specific DEGs, and 323 common DEGs. Hierarchical clustering with 546 carcinoma-specific DEGs detected four clusters with distinctive clinicopathologic characteristics (cluster 1 [n=12]: 7 normal tissues and 5 adenomas; cluster 2 and 3 [n=22]: all adenomas except one normal tissue; cluster 4 [n=9]: all parathyroid carcinomas except one adenoma). Carcinoma-specific DEGs include upregulation of GRIN2A, LYPD1, and SOX2 and downregulation of ENTPPL, MYO3B, and PIK3C2G. Gene ontology enrichment revealed that these DEGs were mainly involved in the binding of cell adhesion molecule, actin, and Rho GTPase, and extracellular matrix structural constituent. Two adenoma clusters significantly differed in urinary calcium excretion level (403 [312–488] vs. 205 [150–327], p=0.037) without significant differences in median PTH (102 [86–138] vs. 125 [92–229] pg/mL) and calcium level (11.1 ± 1.0 vs. 11.0 ± 0.9 mg/dL; P>0.05 for all). In summary, parathyroid carcinoma had distinctive transcriptional profiles which might improve the early detection of parathyroid carcinoma. Parathyroid adenomas were clustered into two groups with regard to urinary calcium excretion level based on transcriptional profiles, which merits further investigation. Reference: (1) Pandya C et al., JCI Insight. 2017 Mar 23; 2(6): e92061. Sources of Research Support: This study was supported by Severance Hospital Research Fund for Clinical Excellence (SHRC C-2019-0032; C-2020-0035).