bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypophosphatasia Misdiagnosed as Osteoporosis in a Young Girl
Authors: Tsang Tiffany , Raghuwanshi Maya P
Published: May 2021

Introduction: Hypophosphatasia (HPP) is a rare inherited disease of mineral metabolism characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNALP), which causes an inability to liberate inorganic phosphate for hydroxyapatite crystal propagation as well as toxic accumulation of inorganic pyrophosphate, pyridoxal-5’-phosphate and urinary phosphoethanolamine. It has a prevalence of 1/100,000 to 1/900,000, although milder forms have an estimated prevalence of 1/6,370. Variable mutations in TNALP cause clinical expressions ranging from a severe perinatal form, which is often fatal after birth from pulmonary complications, to an infantile form, which can cause vitamin B6-responsive seizures, to an asymptomatic adult form.

Case: A 27-year-old, ventilator-dependent female with osteoporosis, hypothyroidism, cerebral palsy with previous spinal fusion, seizure disorder and nephrocalcinosis presented with surgical site infection from a right femur ORIF she underwent a month ago. She had a history of microfractures and low-impact fractures of both femurs requiring several surgeries. Osteoporosis was diagnosed at age 5 and she had been on Fosamax ever since. She did not meet any developmental milestones as a baby and never reached menarche. Various diagnoses by multiple specialists did not fully explain her clinical presentation. Her medications included alendronate 5 mg, calcium carbonate 600 mg, ergocalciferol 400 U and levothyroxine 50 mcg. Physical exam showed poor dentition, a misshapen skull and bowed legs with contractures of her extremities. Her labs revealed Ca 9.1 mg/dL (8.4–10.2 mg/dL), albumin 3.2 gm/dL (3.5–5.2 gm/dL), phosphorus 5.1 mg/dL (2.5–4.5 mg/dL), alkaline phosphatase 32 U/L (35–105 U/L), PTH 28 pg/mL (15–65 pg/mL), vitamin D 33.5 ng/mL (30–100 ng/mL), C-telopeptide 509 pg/mL (34–635 pg/mL). A right knee X-Ray reported diffusely gracile and demineralized bones with muscular atrophy. She recently transitioned care from a pediatric endocrinologist to an adult endocrinologist, who tested her positive for heterozygous ALPL pathogenic variant hypophosphatasia and was considering her for asfotase alfa enzyme replacement therapy.

Discussion: Our patient had infantile HPP, but due to misdiagnosis as osteoporosis, she was inappropriately treated with a bisphosphate for over 20 years. Treatment of HPP had been supportive until the approval of asfotase alfa (Strensiq) in October 2015. It is a bone-targeted human recombinant enzyme replacement therapy approved for infantile- and juvenile-onset HPP and has been shown to decrease mortality from 73% to 16% at age 5. With improvement in life-sustaining technology, more HPP patients are able to survive into adulthood. Awareness of the complex and polymorphic presentation of HPP by adult endocrinologists is paramount for accurate diagnosis, thus avoiding inappropriate treatments.
Paraneoplastic Hypercalcemia as the Initial Presenting Sign of Metastatic Renal Cell Carcinoma
Authors: Gaballa Salem , Malkhasian Armen
Published: May 2021

Introduction: Malignant hypercalcemia can occur in patients with renal cell carcinoma as part of a paraneoplastic syndrome. The suggested mechanisms of malignant hypercalcemia include overproduction of parathyroid hormone-related peptide (PTHrP), interleukin-6 (IL-6), prostaglandins, and tumor necrosis factor-alpha (TNF-α). This report describes an unusual case of paraneoplastic hypercalcemia as the initial manifestation of metastatic renal cell carcinoma (RCC). Case presentation: A 44-year-old Caucasian male with no past medical history who presented to his PCP complaining of unintentional weight loss of 25 lbs, increasing fatigue, occasional right flank pain, and nausea. His family history is significant for multiple myeloma of his mother. The physical exam was unremarkable. Labs were remarkable for serum calcium of 11.5 mg/dL, Albumin of 4.5 g/dL, intact parathyroid hormone (PTH) of 9 pg/mL, undetectable PTHrP, 25 hydroxy VitD of 26.4 ng/mL, and 1, 25 hydroxy VitD of 18 pg/mL. Serum and urine protein electrophoresis and PSA were unremarkable. CXR revealed the right lower lobe noncalcified nodule of 15×11×7 mm. CT abdomen/Pelvis revealed a right renal mass of 13×14×12 cm without lymphadenopathy or local metastasis. The patient was referred to a medical oncologist and further workup including PET/CT scan that demonstrated increased uptake in right lung nodule of SUV 6, right renal mass uptake of SUV 72, and MRI brain without metastasis. The patient treated with right total nephrectomy that revealed a sarcomatoid renal cell carcinoma. Right lung nodule biopsy revealed a clear cell renal carcinoma. The patient further treated with two cycles of Gemcitabine/oxaliplatin and four cycles of nivolumab/ipilimumab. A repeated PET/CT scan showed a complete resolution of a right lung nodule. Repeated labs were unremarkable, including serum calcium of 8.7 mg/dL. Discussion: Hypercalcemia is a frequent occurrence in patients with RCC, but it is an unusual presenting symptom. The initial evaluation should focus on whether the hypercalcemia is parathyroid-dependent or medication-related. Basic laboratory investigations for hypercalcemia include PTH, PTHrP, and 1, 25(OH)2D. Bone-resorbing cytokines may be present in those patients in which the cause of the hypercalcemia is unclear. In our case, we could not determine the specific cytokine that caused hypercalcemia, as IL-6 and TNF-α were unavailable. If laboratory tests are unavailable, bone scan, CT scan, or PET-CT should be considered to evaluate for lytic bone lesions or underlying malignancy. Evaluation for carcinoma should be persistently pursued in a patient who has symptoms suggestive of paraneoplastic hypercalcemia. Finally, symptomatic malignant hypercalcemia can be treated with IV fluids and bisphosphonates. Approximately 50% of patients who undergo nephrectomy and/or tumor debulking will revert to normocalcemia.
Profound Hypocalcemia Following Thyroidectomy for Graves’ Disease
Authors: New Ru H , Hare Matthew J L , MacKay Diana , Kasireddy Vidya , Ellis Elna , Thomas Mahiban E , Chitturi Sridhar
Published: May 2021

Introduction: While transient parathyroid insufficiency is not an uncommon complication of thyroidectomy, severe and prolonged hypocalcemia attributed to a combination of post-surgical hypoparathyroidism, hungry bone syndrome (HBS) and hypovitaminosis D is unusual.

Clinical Case: A 17-year-old female from a remote community in Australia with Graves’ disease, complicated by exophthalmos and atrial flutter, underwent total thyroidectomy due to challenges with medication adherence leading to persistent thyrotoxicosis. FT4 was >150 pmol/L (normal 10–20 pmol/L) almost two years after diagnosis. Pre-operatively, she received Lugol’s iodine, carbimazole and beta-blockade. The operation was uncomplicated and three parathyroid glands were preserved. Within six hours of thyroidectomy, she developed symptomatic hypocalcemia with corrected calcium 1.9 mmol/L (7.6 mg/dL) (normal 2.2–2.65 mmol/L). PTH level was 0.8 pmol/L (normal 1.4–9.0 pmol/L). Magnesium and phosphate levels were initially normal but hyperphosphatemia developed the following day. 25-OH vitamin D was low (29 nmol/L, normal 50–150 nmol/L) and was corrected with high dose cholecalciferol.

Despite use of continuous intravenous calcium gluconate in addition to oral calcium carbonate, as well as both intravenous and oral calcitriol and magnesium, urinary calcium excretion remained undetectable. Teriparatide 20 mcg BD was commenced on post-operative day 14 with no demonstrable improvement in serum calcium. Less than 48 hours after cessation of parenteral calcium on day 18 post-operation, corrected calcium and ionised calcium declined to 1.47 mmol/L (5.9 mg/dL) and 0.46 mmol/L (normal 1.15–1.33 mmol/L) respectively, prompting recommencement of calcium infusion.

Her remarkably high requirement for calcium replacement with negligible urinary calcium excretion for at least one month in spite of parenteral calcium infusion for a total of three weeks’ duration is highly suggestive of HBS which became evident due to post-surgical hypoparathyroidism. She had elevated ALP (618 U/L, normal 35–140 U/L) and increased bone resorption marker (N-telopeptide/creatinine 262 nmol BCE/mmol, normal <100 nmol BCE/mmol), with osteopenia at lumbar spine (Z-score -1.7) and femur (Z-score -1.3). Additionally, vitamin D deficiency is likely to have contributed to the severity of hypocalcemia.

60 days after surgery, she was still requiring calcium carbonate 2500 mg QID (4 g/day elemental calcium) and calcitriol 1 mcg TDS. Her phosphate level had normalised and ALP gradually declined to 241 U/L.

Clinical Lesson: This case highlights the importance of attaining euthyroid status as early as possible pre-operatively to allow near-complete reversal of thyrotoxicosis-induced osteodystrophy, as indicated by normalisation of serum ALP, and ensuring vitamin D levels are replete prior to thyroidectomy for Graves’ disease.
Radiotherapy-Associated Pelvic Insufficiency Fracture Treated by Romosozumab: Course of L1 and L5 Vertebral Body CT Attenuation
Authors: Adly Hussein , Ing Steven
Published: May 2021

Background: Radiotherapy is a risk factor for osteoporosis and insufficiency fractures via osteoblast apoptosis and vascular injury. PTH analogs teriparatide and abaloparatide are contraindicated in patients with prior exposure to radiotherapy crossing bone due to the increased risk of osteosarcoma. Patients with radiotherapy-associated fractures or osteoporosis were eligible only for antiresorptive agents until romosozumab was recently FDA-approved. Current International Society for Clinical Densitometry (ISCD) guidelines include assessment of “opportunistic CT” as a surrogate for DXA scan using L1 vertebral body attenuation: >150 Hounsfield units (HU) is normal and <100 HU signifies osteoporosis.

Clinical Case: A 60 year old female patient with history of endometrial cancer diagnosed at age of 57 and treated with hysterectomy and bilateral salpingo-oophorectomy, chemotherapy, then pelvic radiotherapy, was referred to endocrinology for pelvic insufficiency fractures evaluation. Two years after completing chemoradiotherapy, she complained of right groin and low back pain with difficulty walking. MRI pelvis showed bilateral sacral ala and right pubic ramus insufficiency fractures. She had normal serum mineral concentration, 25-OH vitamin D sufficiency, normal PTH, eGFR, liver function tests and 24-hour urine calcium excretion. Screening for celiac disease and multiple myeloma was negative. DXA scan BMD T-score showed osteoporosis, -3.0 at the right femoral neck. L1-L4 T-score was +0.4 but unreliable due to presence of degenerative changes. Four months after onset of pain, patient started romosozumab 210mg SQ monthly for a total of 12 doses, after which she started oral alendronate. Pain essentially resolved within 6 months of romosozumab therapy. C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were obtained at baseline, 3 and 12 months after romosozumab initiation. CTX was 362, 247 and 258 pg/mL (reference range, >49 years: not established), and P1NP was 82, 178 and 62 mcg/L (reference range, 20 - 108), respectively. Attenuation of L1 and L5 vertebral body was measured using CT abdomen and pelvis scans before and 5 months after radiotherapy, and before and after completion of romosozumab therapy. L1 attenuation measured 161, 132, 127 and 179 HU, and L5 measured 150, 46, 50 and 86 HU, respectively.

Conclusion: Pelvic radiotherapy was associated with a decline in L1 CT attenuation and even greater magnitude of decrease at L5. Romosozumab was associated with clinical improvement, restoration of L1 CT attenuation and diminishment of regain at L5. Although L5 attenuation has not been previously assessed for osteoporosis, this site may be of predictive value in patients who receive pelvic radiotherapy.
Rebound Hypercalcemia After Denosumab Therapy in a Child With Cherubism
Authors: Litao Melissa Kaori S , Murthy Deepa Badrinath , Klein Jason
Published: May 2021

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>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 <3 pg/mL (N: 24–86), 25-OH vitamin D 32 ng/mL (N: >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

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

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 <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

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

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 > 80%) ratifying for renal phosphate wasting, normal iPTH level, and elevated serum FGF-23 level of 460 (normal < 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

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

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

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 <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 <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

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.
Bone Markers Are Diminished in Offspring of Long-Lived Families Compared With Matched Controls, but Respond Equally to T3 and rhTSH
Authors: Zutinic Anna , Roelfsema Ferdinand , van Heemst Diana
Published: May 2021

Objective: We explored the effects of T3 and rhTSH administration on bone turnover in subjects of the Leiden Longevity Study. Design: Twenty-six subjects (13 offspring and 13 matched controls), mean age 68 y, underwent a rhTSH (0.1 mg i.m) and a T3 challenge (100 µg orally) with an interval of at least 3 m. Bone markers were measured at baseline and hereafter once daily for 3–4 days. Outcome Measures: Bone markers and changes after T3 and rhTSH. The influence of sex, group and time, and relations with incremental changes in TSH, fT4 and T3. Results: CTX (bone resorption) was lower in offspring than controls (mean ± SEM), 0.324±0.026 vs 0.443±0.036 ng/mL, P= 0.02. P1NP (bone formation) was also lower in offspring than in controls (40.3±2.2 vs 59.0± 4.7 ng/mL, P=0.004). No sex differences were found. In offspring, CTX but not P1NP was positively related to TSH and fT4 (R=0.48, P=0.001 and R=0.55, P=0.005). In controls, CTX was negatively related to TSH (R=-0.50, P=0.009), while P1NP was positively related with fT4 (R=0.52, P=0.006). TSH administration increased bone resorption and formation (P<0.0001 and 0.005, respectively). CTX was maximal at 48 h, increasing from 0.415±0.032 to 0.470 ±0.037 ng/mL, P=0.001. P1NP increased from 51.1±4.09 to a maximum of 56.2±3.9 ng/mL at 24 h (P=0.005). T3 also increased bone resorption (P=0.049) and formation (P=0.001). CTX increased from 0.386±0.034 to 0.410± 0.041 ng/mL, P=0.05, and P1NP from 48.9± 4.3 to 55.5±4.2 ng/mL, P=0.007), with maximal values at 48 h. Offspring and controls had similar responses and sex had generally no statistical impact. Significant linear regressions were found between the incremental changes of CTX and TSH at 24 h (R=0.44, P=0.003), but not later. Here, significant linear relation were found for the incremental fT4 and CTX (R=0.60, P=0.001 at 48 h, and R=0.49, P=0.013 at 72 h). For P1NP such relations were not present (R values between from 0.002 to 0.14). T3 changes did not correlate with bone markers at any time point. Conclusion: This study demonstrates that bone turnover is diminished in members of long-lived families where bone resorption was positively related to serum TSH and fT4. Nevertheless, the responses to TSH (and fT4) and T3 were similar in offspring and controls. Interestingly, the maximal effect of TSH increment on bone resorption preceded that of fT4, suggesting that TSH may have an independent stimulatory effect on bone resorption. At physiological TSH concentrations such stimulatory effect on bone resorption may be postulated in offspring, along with many other factors, e.g PTH, vitamin D, GH, sex hormones and cytokines.
In a Clinical Trial There Was No Effect of Vitamin D on Physical Performance in Either Black or White Women
Authors: Smith Lynette M , Gallagher J C
Published: May 2021

Introduction: The effect of vitamin D supplementation on physical performance is controversial. Longitudinal cohort studies show very low levels of serum 25OHD (< 15- 20ng/ml) are associated with lower physical performance. There are few clinical trials of the effect of vitamin D on physical performance and results are mixed. Design: 163 white and 110 black independent living women entered a 12-month double blind randomized dose ranging study of daily vitamin D,400,800,1600,2400,3200,4,000,4800IU or placebo together with calcium supplement as needed for a total intake of 1200mg and mean diet vitamin D of 114 IU. Inclusion criteria: total serum 25OHD ≤ 20ng/ml (Diasorin RIA); no known disease or drugs affecting calcium or bone metabolism. Physical performance tests were performed at baseline and end as described in the Short physical performance battery (SPPB) that included Balance, Timed walk, Chair rising test. Additional tests included Timed up and Go, Grip strength and Balance (Biodex). Fall history was recorded at baseline and at 3-monthly visits. Serum 25OHD was measured by Diasorin RIA and LCMS, Free 25OHD was measured by Elisa (Future Diagnostics). Changes in physical performance and fallers were analyzed by dose groups and by quintiles of total and free serum 25OHD. This was a secondary analysis using Intent to treat strategy. Chi square and ANOVA determined association between dose, quintiles and tests. Results: Mean age 66.2 years (SD 7.3, range 57–87), mean BMI 30.3 kg/m2 (SD 5.9). Compliance, measured every 3 months, was 94% for vitamin D and 91% calcium. 147 White and 89 Black women completed study. There was significant better performance in physical performance in women < age 70 years compared to > age 70 years. Black women performed better with all tests except grip strength after adjustment for age and BMI. When the absolute change in test performance was examined according to serum total or free 25OHD quintiles there was no correlation between serum levels of 25OHD and change in any physical performance test except for an improvement in chair rising test in younger Black women. Conclusions: There is no significant effect of vitamin D on physical performance in either black or white women. In a previous analysis we found a significant U-shaped response in fall incidence in the serum 25OHD range 30-40ng/ml but in this analysis there is no correlation between physical performance of fallers versus non- fallers
Low Testosterone in Males May Warrant Liver Health Assessment and Intervention
Authors: DelConte Anthony , Bruno Benjamin J , Kim Kilyoung , Vangara Kiran , Papangkorn Kongnara , Chidambaram Nachiappan , Patel Mahesh
Published: May 2021

Low testosterone (T) is a serum marker of hypogonadism. Reportedly, diabetes mellitus, cardiovascular disease, peripheral artery disease, hypertension, hyperlipidemia, depression, obesity, metabolic syndrome, sleep apnea, chronic obstructive pulmonary disease (COPD), and opioid dependency, are associated with low testosterone. However, the association of chronic liver disease with low T is underappreciated. In one study, ~75% of biopsy confirmed Nonalcoholic Steatohepatitis (NASH) male patients had T levels of <372 ng/dL. A study with patients receiving androgen deprivation therapy (ADT), with no pre-therapy evidence of liver disease, increased liver disease risk relative to no ADT suggesting low T can adversely affect liver health. However, prevalence of compromised liver health in hypogonadal males, and any beneficial effects of T therapy intervention on liver health are unclear. The objective of this investigation was to evaluate prevalence of liver disease in hypogonadal males, and to assess for potential beneficial effects of LPCN 1144, a novel oral T therapy candidate, on liver health of hypogonadal males. Investigation was performed through clinical studies in hypogonadal males, and a pre-clinical study. Clinical studies: (1) a one-year treatment, open label, active control, randomized study (NCT02081300); (2) a four-month treatment, open label, single arm study (NCT03868059); a 12-week study in a high-fat-diet (HFD) induced steatohepatitis and hepatic fibrosis rabbit model. 39% of hypogonadal males (N=210) tested had the elevated key liver injury marker (ALT>30 U/L). LPCN 1144 intervention for 52 weeks in hypogonadal males with elevated ALT levels at baseline resulted in mean decrease about 15%. Moreover, abnormal ALT, AST, ALP, and GGT were normalized in 52%, 50%, 67%, 32% of patients, respectively. In the 4-month study, fatty (>5%) liver disease was present in about 66% of a cohort of hypogonadal males (N=32), more than double the reported rate in the general population (25%). Post LPCN 1144 treatment, the proportion of fatty liver-free subjects increased by 94%. HFD induced substantial suppression of T levels in rabbits accompanied with histologically evidenced hepatic steatosis, inflammation, ballooning, and fibrosis. Upon 12 weeks of LPCN 1144 treatment in conjunction with HFD, histological ballooning, inflammation and fibrosis scores were improved. Importantly, relatively to control, % of hepatic fibrosis in the tissues were significantly reduced with LPCN 1144 treatment. In conclusion, compromised liver health is prevalent in hypogonadal males and may warrant a periodic assessment. Pre-clinical and clinical results with oral T therapy suggest potential beneficial effects on liver health in hypogonadal males. An ongoing study in biopsy-confirmed NASH male patients is expected to shed more light on the potential benefits of LPCN 1144.
Mild Autonomous Cortisol Secretion in Primary Aldosteronism Enhances Renal and Hemorrhagic Cerebrovascular Complications
Authors: Matsuba Ren , Katabami Takuyuki , Kurihara Isao , Ichijo Takamasa , Takeda Yoshiyu , Tsuiki Mika , Wada Norio , Ogawa Yoshihiro , Sone Masakatsu , Inagaki Nobuya , Yoshimoto Takanobu , Kobayashi Hiroki , Tanabe Akiyo , Naruse Mitsuhide ,   JPAS JRAS, study group
Published: May 2021

Background: It is well known that primary aldosteronism (PA) is often associated with renal dysfunction and cardiovascular events (CVEs). However, the synergic effect of mild autonomous cortisol secretion (MACS) on the co-morbidities among PA has not been clarified yet. Thus, we retrospectively assessed whether the presence of MACS in PA patients with adrenal tumor, which may have MACS, to enhance the risk of the complications using a large Japanese multicenter database.

Methods: We enrolled patients with both confirmed PA and obvious adrenal tumor (diameter > 1 cm) on computed tomography. The subtype of PA was diagnosed based on the results of adrenal venous sampling with ACTH stimulation. A total of 575 study subjects were stratified into two groups according to 1-mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS group (N=174, 30.2%) and non-MACS group (N=401, 69.8%). Decreased estimated glomerular filtration rate (eGFR) was defined as <60 ml/min per 1.73m2.

Results: The percentage of unilateral PA between the MACS and non-MACS group was equivalent (50.0% vs. 48.1%). Prevalence of decreased eGFR in the MACS group was higher than in the non-MACS group [odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.20–3.04, P=0.006]. Conversely, prevalence of MACS was higher in patients with decreased eGFR than those without decreased eGFR (42.7% vs 28.0%, P=0.008). Proteinuria was deteriorated with the increase in post-DST serum cortisol concentration as well as the basal plasma aldosterone concentration (PAC) (P=0.028 and P<0.001, respectively), although PAC but not the presence of MACS was selected as an independent factor related with decreased eGFR. Prevalence of cerebral hemorrhage in the MACS group was higher than the non-MACS group. (OR 5.35, 95%CI 1.83–15.6, P=0.002). We found that MACS was the only significant factor which increased the odds of developing cerebral hemorrhage (OR 9.13, 95%CI 2.15–38.90, P=0.003). Prevalence of other CVEs between the two groups was similar. Regardless of the PA subtype, complication rate of decreased eGFR and cerebral bleeding in the MACS group were significantly or tend to be higher than non-MACS group.

Conclusion: Our date strongly suggested that co-secretion of cortisol in PA directly and/or indirectly increase renal and cerebrovascular comorbidities. Given that MACS is common in PA, endocrinological testing with DST is recommended in PA patients, especially those with adrenal tumor on imaging. (Supported by Research Grants of AMED:JP17ek0109122, JP20ek0109352; National Center for Global Health and Medicine:27–1402, 30–1008), and Ministry of Health, Labour, and Welfare, Japan (046).