bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rebound Hypercalcemia After Denosumab Therapy in a Child With Cherubism
Authors: Litao Melissa Kaori S , Murthy Deepa Badrinath , Klein Jason 
Published: May 2021

Abstract
Background: Cherubism, caused by autosomal dominant mutations in the SH3BP2 gene, is characterized by increased bone resorption with development of bilateral fibro-osseous lesions limited to the maxilla and mandible. The SH3BP2 gene is thought to be involved in osteoclastogenesis. Affected children, while usually asymptomatic at birth, typically present at 2–5 years of age with cheek and jaw swelling with upward tilting of eyes due to expansion of fibrous tissues. Bone resorption and proliferation of lesions continues until puberty after which spontaneous regression occurs. RANKL is a cytokine expressed on the surface of osteoclast precursors and is responsible for inducing osteoclast differentiation. Denosumab is an anti-RANKL monoclonal antibody which prevents osteoclast maturation. However, it has a short half-life, and effects on bone turnover have been found to be rapidly reversible after drug discontinuation. The rebound increased bone turnover can lead to severe hypercalcemia.
Clinical Case: A 4 year old boy with cherubism (c.1253C&gt;G pathogenic variant in SH3BP2), after failing a 10-month trial of tacrolimus, was placed on monthly denosumab (2 mg/kg) for a total of 10 doses. During denosumab therapy, he received calcium and vitamin D to prevent hypocalcemia; these were stopped once denosumab was discontinued. He presented to the hospital 4 months after the final denosumab dose with polyuria, polydipsia, fatigue, nausea and abdominal pain. Work-up revealed serum Ca 15.3 mg/dL (N: 8.4–10.2), PTH &lt;3 pg/mL (N: 24–86), 25-OH vitamin D 32 ng/mL (N: &gt;19 ng/mL), 1,25-dihydroxyvitamin D 6.7 pg/mL (N: 19.9–79.3), and urine Ca/Cr 0.48. Renal ultrasound showed normal kidneys with a small amount of layering debris in the bladder. During hospitalization, he received IV fluids, 1 dose of furosemide, 3 doses of calcitonin, 24 hours of hydrocortisone, and a single 0.5 mg/kg dose of pamidronate. He was discharged 48 hours after the bisphosphonate with serum Ca 9.5 mg/dL. He returned with serum Ca 13.5 mg/dL 9 days after the pamidronate and was readmitted. He again received 4 doses of calcitonin and 1 dose of pamidronate (0.5 mg/kg). Calcium levels improved to 9.5 mg/dL at discharge but rose to 11.6 mg/dL a week later. He received a 0.05 mg/kg dose of zoledronate outpatient, with improvement in serum Ca to 10.1 mg/dL. A week later, he twisted his ankle, resulting in transverse impacted buckle fractures of his left distal tibia and fibula; no lytic or sclerotic lesions were noted on x-ray. His leg was immobilized by Orthopedics. Calcium levels remained within range (9.9 mg/dL) 7 months after the zoledronate. Conclusion: Rebound hypercalcemia can occur months after denosumab withdrawal, indicating the need for close monitoring of calcium levels in patients who receive this drug. The hypercalcemia appears to respond best to bisphosphonates, with a more sustained response to zoledrenate compared to pamidronate.
Response of Severe Osteomalacia to High Dose Vitamin D3 Replacement in a Patient With Ulcerative Colitis and Liver Transplantation on Immunosuppressive Therapy
Authors: Azmath Misbah , Mirza Faryal Sardar 
Published: May 2021

Abstract
Background: Bone disease is common in inflammatory bowel disease (IBD), more frequently in Crohn’s disease than ulcerative colitis (UC). We present the case of a patient with prior history of ulcerative colitis with severe 25 OH vitamin D deficiency and metabolic bone disease. Case: 67 year old male with h/o ulcerative colitis, colon cancer s/p proctocolectomy and ileostomy, chemo-radiation, h/o primary sclerosing cholangitis (PSC) and orthotopic liver transplantation (OLT) 20 years prior presented with presented with severe muscle aches, severe limitation in mobility and severe vitamin D deficiency. He had been on chronic prednisone and tacrolimus, mycophenolate. Three years after OLT, he had fragility fractures at different times in both hips requiring hip arthroplasty. Labs were significant for persistently elevated alkaline phosphatase (ALP) up to 1569 U/L for last 10 years, bone specific ALP at 423.6 mcg/L, Calcium 9 mg/dl, phosphorus 2 mg/dl, 25 OH vitamin D was 4 ng/ml, 1, 25-hydroxy vitamin D (25-OHD) was 34 ng/ml, PTH was 189 pg/ml, urine calcium/creatinine ratio was 50 mg/g and urine NTX at 223 nM BCE/mM. Celiac screen was negative and tacrolimus levels were within normal range. Patient had extensive workup by gastroenterology for elevated ALP including three liver biopsies which were unrevealing. A bone scan showed increased uptake in thoracic region and metaphyses of large joints. A diagnosis of osteomalacia and secondary hyperparathyroidism was made and he was started on high dose vitamin D gradually increased to 8000 units thrice a day. Within few weeks, he noted marked improvement in mobility, bone pain and need for pain medications. In few months, BSAP decreased to 144.9 mcg/l, NTX and PTH also improved. 25 OH has also increased slightly to 13. He continues on high dose vitamin D and 1200mg of calcium daily. Discussion: Our patient likely had severe osteomalacia due to prolonged vitamin D deficiency, caused by multiple etiologies. Firstly, poor absorption in UC might lower 25-OHD levels. Secondly CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D, this could result in enhanced vitamin D metabolism, which would explain persistently low vitamin D level despite replacement with such high doses. The significant improvement in his symptoms with supplementation resulting in increased mobility despite not having a normal vitamin D level suggest other pleiotropic effects of vitamin D on muscle and bone as well. Additionally effects of liver transplantation on vitamin D metabolism need to be explored further.
Silicone Induced Severe Hypercalcemia
Authors: K Jayathilaka Dhammi K , Gnanapragasam Helen Prathiba , Batra Manav 
Published: May 2021

Abstract
Background: Silicone injections are becoming increasingly prevalent for cosmetic enhancement in the transgender population. We report a case of silicone-induced hypercalcemia to highlight the process of extra-renal production of 1,25-hydroxy (OH) vitamin D (calcitriol) and discuss the approaches in managing this rare entity.
Clinical Case: A 51-year-old African American transgender female with a past medical history of human immunodeficiency virus (HIV) on antiretroviral therapy with undetectable viral load presented with right flank pain, nausea, and vomiting for one day. On examination, nodules were palpated in both breasts, left lateral hip, and the gluteal area had hyperpigmentation from silicone injections ten years ago. Calcium was elevated at 15.2 mg/dL (8.5–10.5) with albumin 3.8 g/dL (3.5–5), ionized calcium 7.4 mg/dL (4.64–5.28), phosphate 4.5 mg/dL (2.5–4.8) and creatinine of 3.2 mg/dL (0.4–1.4). Imaging revealed right ureteral calculi with hydronephrosis requiring stent placement.
PTH was suppressed &lt;5 pg/ml (12–72) and PTHrP were negative. Vitamin D 25 (OH) of 28 ng/mL (30–100) with elevated 1, 25 OH2 D3 144 pg/ml (19–79) and ACE 141 units/L (12–60) were suggestive of a granulomatous process. CT chest and abdomen without contrast did not show any hilar, mediastinal, or abdominal lymphadenopathy to suggest sarcoidosis or lymphoma, but numerous bilateral calcified masses were noted within the breasts consistent with silicone injections. Serum and urine electrophoresis were consistent with monoclonal gammopathy of undetermined significance. Patient deferred further evaluation (PET-CT and skin biopsy for granulomatous changes) as an outpatient.
Calcium improved in 4 days to 10.5 mg/dL with intravenous hydration, calcitonin 260 units, IV furosemide 20 mg, and pamidronate of 60 mg. Despite a repeat dose of Pamidronate 60 mg a week later her calcium was rising again to 11.1 mg/dL. Plastic surgery evaluation concluded that due to extensive implants, surgery would be very disfiguring and challenging. She was reluctant to start prednisone as it may affect healing after surgery and the need for antibiotic prophylaxis for HIV, but she later agreed. Prednisone 20 mg daily was started for granulomatous disease and Calcium improved to 10.3 mg/dL.
Conclusion/Clinical Lesson: Silicone Induced hypercalcemia is a rare entity with diagnostic and treatment dilemmas. Based on the few reported cases, silicone induced severe hypercalcemia is managed with IV hydration, denosumab, or zoledronic acid. However, glucocorticoids may maintain normocalcemia like in other granulomatous diseases. Removal of silicone implants may improve hypercalcemia, but it is challenging given the extent of implants, disfigurement, and possible disseminated disease and may not be curative. These aspects need to be considered in evaluating and management.
Spontaneous Resolution of Primary Hyperparathyroidism Following COVID-19 Infection
Authors: Siddiqui Mahwash F , Maalouf Naim 
Published: May 2021

Abstract
Background: Spontaneous resolution of primary hyperparathyroidism (PHPT) is extremely rare, and has previously been reported exclusively in the setting of apoplexy (auto-infarction) of a large parathyroid adenoma outgrowing its blood supply. We report an unusual case of spontaneous PHPT resolution after Covid-19 infection. Clinical Case: A 38-year-old Hispanic woman was seen in clinic for evaluation of hypercalcemia first noted on routine bloodwork in 2018. She had a history of nephrolithiasis (1 episode) but no other symptom associated with hypercalcemia. She was not on medications associated with hypercalcemia, and had no family history of Ca disorder. Serum biochemistry was notable for hypercalcemia (Ca: 10.9, 10.5, and 10.8 mg/dL, nl 8.4–10.2), normal albumin and Cr, elevated PTH (106 and 70 pg/mL, nl 15–65), with low phosphate (2.3 mg/dL, nl 2.4–4.5) and 25-OH-Vit. D (14 ng/mL, nl 20–80). 24-hr urinary studies showed elevated urine Ca (285 and 375 mg/day, nl 100–250), with urine Cr of 1.3 and 1.5 g/day, respectively. Findings of hypercalcemia, hypercalciuria, and elevated serum PTH, led to the diagnosis of PHPT. Neck ultrasound and sestamibi scan of the parathyroids with SPECT-CT did not localize any abnormal parathyroid gland. A month after PHPT diagnosis, and prior to surgical evaluation, patient presented with a 9-day history of fever, cough, and shortness of breath. She tested positive for Covid-19 infection by SARS-CoV-2 PCR on nasal swab, and was quarantined at home with symptomatic treatment. No glucocorticoids were given. Serum Ca was normal (9.5 mg/dL) at the time of Covid-19 diagnosis. All Covid-19 symptoms subsided 14 days after onset. Repeat labs 1 and 3 months after Covid-19 infection showed persistently normal serum Ca (10.0 and 9.8 mg/dL), with low then normal PTH (13 and 43 pg/mL), compatible with spontaneous resolution of PHPT. Patient denied any neck discomfort before, during, or after Covid-19 infection. Spontaneous resolution of PHPT is rare and follows apoplexy of a large parathyroid adenoma. In our patient, imaging failed to localize a large parathyroid adenoma, making it less likely that resolution of her PHPT was caused by apoplexy. Resolution of PHPT temporally coincided with Covid-19 infection, although the link between the two conditions is unclear at this time. Hypothesized mechanisms include an imbalance in the normal PTH-Ca axis caused by SARS-CoV-2 mediated release of inflammatory cytokines (e.g. interferon, previously reported to lower serum calcium), or development of antibodies against the parathyroid or CaSR. RNA and protein expression of ACE2, the SARS-CoV-2 cell receptor gene, is not detected in normal parathyroid tissue. Conclusion: To our knowledge, this is the first reported case of spontaneous resolution of PHPT after Covid-19 infection. Further studies are needed to understand the frequency of this occurrence, and the underlying mechanism.
Sternal Phosphaturic Mesenchymal Tumor-Induced Osteomalacia, Diagnosis and Management: A Case Report
Authors: Adeyemo Mopelola Adetola , Guo Aili 
Published: May 2021

Abstract
Background: Tumor induced osteomalacia (TIO) is a rare paraneoplastic disorder in which overproduction of fibroblast growth factor-23 (FGF-23) by mesenchymal tumor results in decreased renal phosphorus reabsorption and low to inappropriately normal 1,25-dihydroxyvitamin D, leading to hypophosphatemia and osteomalacia. Patients often present with bone pain, fractures, muscle weakness, and progressive decline in mobility. Due to the nonspecific nature of presenting symptoms of TIO diagnosis is often delayed. Clinical Case: A 55-year-old male presented with complaints of chest pain, shortness of breath, and generalized weakness following a ground level fall. Patient also reported a 10-year history of osteoarthritis with chronic back pain and 1-year history of generalized weakness, resulting in significant decline in functional status. On work-up, the initial CT scan of chest revealed multiple fractures including ribs, manubrium, scapula, and pubic rami. Subsequent biochemical evaluation was remarkable for hypophosphatemia to low of 1.3 mg/dL (2.4 - 5.0 mg/dL), low of 1,25-dihydroxyvitamin D of 13.1 pg/ml (19.9 - 79.3 pg/mL), reduced tubular phosphate reabsorption rate of 28% (normal &gt; 80%) ratifying for renal phosphate wasting, normal iPTH level, and elevated serum FGF-23 level of 460 (normal &lt; 180). Then, localization imaging for TIO was performed. After PET/CT scan showing increased uptake at the sternal area suggestive of lytic metastasis, subsequent CT angiogram of the chest identified mottled, irregular, mildly expansile appearance of the sternal manubrium. Sternal biopsy revealed phosphaturic mesenchymal tumor with positive FGF 23 mRNA expression. Surgical resection was delayed due to poor functional status and concurrent discovery of an EBV-positive nasopharyngeal carcinoma. Prior to surgery patient was treated with phosphorus and calcitriol supplements. Post-operatively serum phosphorus and FGF-23 levels were normalized. Patient also improved clinically. Patients treatment course was complicated by secondary hyperparathyroidism; however, this improved following surgery. Conclusion: Diagnosis of TIO can be delayed due to its nonspecific symptoms. Thus, in patients with chronic bone pain, muscle weakness, and atraumatic fractures, TIO should be kept on the differential and these patients should undergo thorough biochemical and imaging evaluation. Tumor localization could be challenging. Patients should be managed with supplements of active vitamin D and phosphorus with goal to normalize phosphorus level to prevent further bone demineralization prior to surgery. However, surgical intervention remains the mainstay of management as this is curative of TIO.
Follicle-Stimulating Hormone Does Not Impact RANKL-Induced Osteoclastogenesis
Authors: Zhou Ziyue , Gambino Luisina Ongaro , Bernard Daniel J 
Published: May 2021

Abstract
Postmenopausal osteoporosis has been attributed to decreased estradiol levels. In the hypothalamic-pituitary-gonadal axis, estradiol synthesis is stimulated by follicle-stimulating hormone (FSH). FSH is secreted from the anterior pituitary gland and estradiol feeds back to the hypothalamus and pituitary to suppress FSH production. In postmenopausal women, the loss of estradiol (and inhibin) negative feedback leads to elevated serum FSH levels. It was recently proposed that this increase in FSH also contributes to postmenopausal osteoporosis by stimulating differentiation and activation of bone-resorbing osteoclast cells. Our objectives were to determine whether FSH has direct actions on osteoclast differentiation in vitro and, if so, its mechanism(s) of action. First, a murine leukemic monocyte/macrophage cell line, RAW264.7, was differentiated into osteoclasts by treatment with receptor activator of nuclear factor kappa-B ligand (RANKL, 50 ng/mL) for seven days. As expected, we observed the appearance of osteoclasts, characterized as tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. RANKL also induced expression of established osteoclast differentiation markers, including Trap, cathepsin K (Ctsk), and matrix metalloproteinase-9 (Mmp9). The mRNA expression of FSH receptor (Fshr), however, was low to undetectable both before and after osteoclast differentiation. Co-treatment of RAW264.7 cells with FSH (35, 70 and 140 IU/L) and RANKL did not further impact the expression of Rank, Trap, Ctsk, Mmp-9, or Fshr. Second, primary murine monocytes were differentiated into osteoclasts by treatment with RANKL (50 ng/mL) and macrophage colony-stimulating factor (M-CSF, 25 ng/mL) for five days. FSH co-treatment (70 and 140 IU/L) had no impact on the expression of osteoclast markers, and Fshr expression was low to undetectable both before and after osteoclast differentiation, consistent with the results from RAW264.7 cells. In conclusion, in our hands, FSH does not impact RANKL-induced osteoclast differentiation in immortalized or primary murine monocytes.
Inflammatory Cytokine TNF-a Controls Mesenchymal Stem Fate by Regulating JMJD3 Expression
Authors: Ramadoss Sivakumar 
Published: May 2021

Abstract
Introduction: Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can differentiate in to osteoblast, adipocytes and chondrocytes. Lineage specification of MSC is governed by various systemic hormones, systemic and local growth factors and cytokines. TNF-α is an inflammatory cytokine produced at the site of tissue injuries and known to regulates MSC migration and differentiation. However, its role on lineage specification and differentiation of MSCs remain complex and elusive. In this study we explored the same utilizing human bone marrow and adipocyte derived MSCs. Experimental Methods: Human MSCs derived from bone marrow and adipocytes were differentiated in to osteoblast and adipocytes in the presence or absence of TNF-α. Expressions of osteoblast and adipocyte differentiation markers were assessed by qRT-PCR. The key epigenetic factor of lineage specification JMJD3 was depleted in MSCs utilizing lentiviral ShRNA. Results: TNF-α promoted the osteoblastic and inhibited the adipogenic differentiation of MSC as assessed by Alizarin and oil red O staining, respectively. Consistently, while inducing the key osteogenic factors, TNF- α repressed the adipogenic markers in MSCs. Mechanistically, TNF-α regulates MSC fate by inducing lysine-specific demethylase JMJD3/KDM6B, which is a key epigenetic factor that determines mesenchymal stem cell lineage specification. ShRNA mediated knockdown of JMD3 in MSCs inhibited TNF- α mediated activation and inhibition of osteogenic and adipogenic differentiation, respectively. Conclusion: Our study uncovers the novel mechanisms of TNF-α mediated MSC lineage commitment and differentiation and thus highlight JMJD3 as mediator of TNF-α actions in MSCs.
Osteoporosis Care After Hip Fracture: A Regional Healthcare System Experience
Authors: Thonn Ethan , Ruanpeng Darin 
Published: May 2021

Abstract
Background: Pharmacologic treatment is recommended to reduce risk of future fractures and possibly reduce mortality in patients with hip fracture. We investigated osteoporosis care after hip fracture at a regional comprehensive healthcare system to identify rates of pharmacologic treatment after hip fracture and barriers to treatment. Methods: We identified all patients admitted with a low impact hip fracture between 1/2017-12/2018. Follow-up clinical data was collected for a minimum of 16 months after hip fracture. Results: 208 patients were admitted with low impact hip fractures: 130 (62%) were female, mean age was 79.6 (SD 12.6), 24 (12%) were nursing home resident, and 117 (56%) had BMI &lt;25 kg/m2. At the time of the fracture, 80% had polypharmacy, 42% used mobility aide, 24% had known osteoporosis, 22% had dementia/cognitive impairment, 20% has history of cancer, 20% had history of stroke, 19% had diabetes and 2% were on dialysis. Two hundred (96%) underwent surgery. Forty-three (20%) had vitamin D level checked, of this, 20 (46%) had level &lt;30 ng/mL. Prior to admission prescription of vitamin D was 53% and calcium was 36%. Discharge prescription of vitamin D was 64% and calcium was 50%. Prior to fracture, 18/208 (9%) were prescribed osteoporosis medication and at 1 year following fracture, 26/192 (14%) were prescribed osteoporosis medication (11 new, 15 continuation of medication). For follow up, 114/192 (59%) were seen in orthopedics clinic, 61 (32%) in primary care clinic, 2 (1%) in endocrinology clinic and 99 (52%) in other clinics. Sixteen (8%) patients died during the hospitalization for hip fracture and 47 (22%) died within 1 year. Conclusions: Osteoporosis treatment after hip fracture is suboptimal and a model of care is needed to close this care gap.
A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study
Authors: Allas Soraya , Ovize Michel , Culler Michael D , Geraul Clarisse , van de Wetering Jeroen , Mannstadt Michael 
Published: May 2021

Abstract
Hypoparathyroidism is a rare disease characterized by a deficiency in parathyroid hormone (PTH) that results in hypocalcemia and hyperphosphatemia. Current treatment approaches, including high dose oral calcium and active vitamin D, as well as recombinant human PTH (1–84), do not provide adequate or consistent control of either serum calcium or clinical symptoms over a full 24-hour period. AZP-3601 is a novel 36 amino-acid PTH analog that has been designed to potently bind to the R0 conformation of the PTH1 receptor, which results in prolonged signaling responses in vitro and prolonged calcemic responses in animals despite having a short circulating half-life. A Phase 1 double-blind, placebo-controlled, single and multiple ascending dose study is being conducted to evaluate the safety, tolerability and pharmacodynamics of AZP-3601 in healthy adults. Here we report data from the first cohorts of the single ascending dose portion of the study. Sequential cohorts of 4 (cohort 1) to 8 (cohort 2 to 4) healthy male subjects aged 18–60 years, with a body mass index of 19–28 kg/m2, were assigned to receive 5, 10, 20 or 40μg of AZP-3601 or placebo at a ratio of 3:1. The study drug was administered in the morning by subcutaneous injection in the abdominal wall and was well tolerated with no remarkable adverse events. As compared with placebo controls, AZP-3601 treatment produced a clear, dose-dependent increase in mean albumin-adjusted serum calcium values from baseline. The normal physiological diurnal variation of albumin-adjusted serum calcium was gradually attenuated with 5 and 10μg AZP-3601, and was completely eliminated with 20μg. With the dose of 40μg AZP-3601, mean albumin-adjusted serum calcium values were significantly increased but stayed within normal laboratory range and remained elevated through at least 24 hours post-administration. We observed a dose-dependent decrease in mean endogenous serum PTH that was significantly correlated with the concomitant increase in mean serum calcium. These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours following a single administration.