bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypocalcemia in Setting of Malignancy of Unknown Origin: A Case Report
Authors: Fung Russell K , Jurado-Flores Marilu Margarita
Published: May 2021

Background: Hypercalcemia is a common finding well-recognized in up to 30% of cases of malignancy, associated with poor prognosis and advanced disease state. Hypocalcemia, while uncommon, can also be found in cases of malignancy facilitated by its own unique mechanism and etiologies. We present a case of severe hypocalcemia in the setting of malignancy of unknown origin.

Clinical Case: 72-year-old female with a history of metastatic carcinoma of unknown origin, followed actively by Oncology, presented acutely with shortness of breath, chest pain, stiff hands and clenched fist. Patient had reported a 20 lbs weight loss over three months with a “knot” in the epigastric area affecting appetite and interfering with eating. Prior CT showed diffuse adenopathy with diffuse permeative bone destruction highly suspicious for malignancy. Follow up PET-CT showed mixed lytic lesion and sclerotic changes throughout the entire skeleton from the skull to mid thighs compatible with osseous metastatic. Initial tests show severe hypocalcemia with appropriately PTH elevation and normal vitamin D25 (calcium 5.5 mg/dL, albumin 3.9 g/dL, phosphorus (PO4) 2.3 mg/dL, magnesium (Mg) 1.5 mg/dL, PTH 243 pg/mL, vitamin D25 31.44 ng/mL). Further workup shows normal creatinine levels (0.88 mmol/L) and elevated alkaline phosphatase (1140 IU/L). Physical exam revealed bilaterally clenched fist and positive Chvostek sign. After two doses of 2 grams calcium gluconate, calcium had improved up to 7.2 mg/dL (corrected 7.76 mg/dL, albumin 3.3 g/dL) with plans to replete Mg and PO4. Patient was started on Calcium-Vitamin-D 500-200 mg-units (Oscal) two tabs trice daily. However, calcium continues to drop the next day with levels at 5.7 mg/dL (corrected 6.42 mg/dL, albumin 3.1 g/dL). A calcium infusion of 10 grams was then given over 16 hours. Calcitriol 0.25 mg twice daily was started. 24-hour urine study showed low calcium excretion (<0.8 mg/dL), normal Mg excretion (6.5 mg/dL) with an adequate creatinine collected (0.6 grams) showing no deficiencies in kidney resorption. Prior to discharge, patient’s calcium had stabilized (corrected 8.2 mg/dL, albumin 3.4 g/dL) and her associated symptoms had resolved. She was discharged on Oscal 2 tabs 4 times daily and Calcitriol 1 mcg twice daily.

Conclusion: Given these biochemical results and imaging evidence of bone metastases, this case highlights the uncommon findings of hypocalcemia in the setting of malignancy. With the combination of low 24-hour urine calcium, elevated PTH, normal vitamin D25, low PO4, normal kidney function and increased alkaline phosphatase, these findings most likely indicate hypocalcemia secondary to osteoblastic bone metastasis, resulting from deposition of calcium in osteoblastic lesions.

References: Schattner A, Dubin I, Huber R, Gelber M. Hypocalcaemia of malignancy. Neth J Med. 2016 Jul;74(6):231–9. PMID: 27571720
In Search of a Missing Adenoma
Authors: Tavdy Tammy , Mahali Lakshmi P
Published: May 2021

Background:

The most common cause of primary hyperparathyroidism (PHPT) is overproduction of PTH by a parathyroid gland adenoma. While definitive therapy is parathyroidectomy, 4% of patients develop persistent PHPT - a sustained hypercalcemic state that is detected within six months of parathyroidectomy. A missed parathyroid adenoma is the most common cause of persistent PHPT, and accurately locating these glands presents a diagnostic challenge. We describe a rare case of persistent PHPT due to a missed mediastinal parathyroid adenoma.

Case:

A 54-year-old woman with a history of PHPT presented with abdominal pain, nausea, and decreased oral intake. She underwent parathyroidectomy six months ago with reimplantation of one parathyroid gland into the right sternocleidomastoid muscle (SCM). She was now hypercalcemic to 13.9 mg/dL (8.5–10.5) with intact PTH 1273 pg/mL (15.0–65.0), vitamin D 25-OH 31.4 ng/mL (>30.0), and normal PTHrP. She was not taking calcium, and other causes of hyperparathyroidism were excluded. Sestamibi scintigraphy localized only to the right SCM, and the initial impression was recurrent HPT due to the previously implanted gland. Follow-up CT neck with and without contrast failed to localize any regrowth in the SCM, but did reveal a 1.4 cm mediastinal soft tissue mass, suspicious for an ectopic parathyroid adenoma. She subsequently underwent video-assisted thoracoscopic excision, and pathology was consistent with ectopic hypercellular parathyroid tissue. Post-operatively, her PTH down-trended and calcium normalized.

Conclusion:

This case describes a small yet biochemically aggressive mediastinal adenoma causing persistent PHPT. While sestamibi scans have ~90% sensitivity for localization of ectopic adenomas, they can fail to identify a small culprit lesion in 12% of patients, whereas CT imaging with and without contrast has increased sensitivity for adenomas <2 cm. Thus, diagnosing persistent PHPT requires sestamibi scan in combination with other imaging modalities for accurate diagnosis of missed adenomas.
Paget ‘s Disease: Not So Typical for Atypical Femur Fracture
Authors: Mittal Ashima , Gordon Murray B
Published: May 2021

Introduction: Atypical femur fractures (AFF) are reported in patients taking prolonged bisphosphonate therapy, but Paget’s disease (PD) has been rarely reported as a cause of AFF. Case: 71-year-old female with past medical history of right hip osteoarthritis, seizure disorder, hypertension, and Hashimoto’s thyroiditis presented with persistent right hip pain. There was no history of trauma or fall. She had otosclerosis with bilateral hearing loss and bilateral stapedectomies. Her medications were primidone, levothyroxine, lisinopril-hydrochlorothiazide, and vitamin D. She did not smoke tobacco or drink alcohol. She had elevated serum alkaline phosphatase of 300 U/L (35–104). The X-ray of the skull was negative for any cortical thickening. CT of right femur revealed cortical thickening and coarsening of trabeculae of the proximal right femur consistent with PD and incomplete atypical subtrochanteric proximal fracture. Urine NTx 303 BCE/mM Cr (<89). Bone scan showed uptake in the R proximal femur, L distal tibia, and L3-L4 vertebral bodies suspicious of PD. DXA showed osteopenia. She was given zoledronic acid 5 mg IV. Discussion: PD leads to an increased incidence of fractures particularly of the lower extremities with most fractures transverse in nature. Non-union is not uncommon1. Stress fractures in PD are caused by disorganized bone remodeling due to excessive breakdown and formation of bone. Our patient met the major criteria for AFF as per the ASBMR 2010 task force report but there was no exposure to bisphosphonates2. The ASBMR task force recommended that bisphosphonates should be discontinued

in patients with bisphosphonate-associated AFF due to their severely suppressed bone turnover status. On the other hand, the AFF in patients with PD may heal in response to bisphosphonate treatment. References: 1. Singer FR. Bone Quality in Paget’s Disease of Bone. Curr Osteoporos Rep. 2016;14(2):39–42. DOI:10.1007/s11914-016-0303-62. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA et.al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010; 25:2267–2294.
Post-Traumatic Heterotopic Ossification With Incidental Hyperparathyroidism
Authors: Wootton Elizabeth , Balcerek Matthew , Lazarus Syndia , Duncan Emma L
Published: May 2021

Background: Heterotopic ossification (HO) is a rare disease characterised by abnormal bone growth in non-osseous tissues, causing pain, immobility and impaired quality of life. Although still being elucidated, the underlying pathophysiology may relate to local macrophage-driven inflammation in response to trauma1.

Case: A 35-year-old man involved in a motor vehicle accident (MVA) fractured over twenty bones (multiple vertebrae, ribs and complex open book pelvic fracture with shattered left acetabulum) with extensive soft tissue injuries requiring multiple surgeries. Past medical history included a renal calculus three years earlier. His serum corrected calcium on admission was elevated at 2.87mmol/L (2.10-2.60mmol/L). Peri-operative fluid over-resuscitation necessitated boluses of intravenous furosemide, and serum calcium transiently normalised before rapidly incrementing and peaking at 3.04 mmol/L. Serum parathyroid hormone post-operatively was inappropriately high at 9.4pmol/L (1.0–7.0pmol/L) and 25-hydroxyvitamin D low at 24nmol/L (50-150nmol/L). Oral vitamin D replacement was commenced and he received intravenous pamidronate (3x60mg infusions) which briefly restored normocalcaemia. Neck ultrasound and sestamibi scintigraphy demonstrated a left parathyroid adenoma, and he underwent parathyroidectomy. Histology revealed a single parathyroid adenoma. He has been normocalcaemic since surgery. Despite excellent overall recovery, mobility at the left hip remained restricted in all planes of movement. He could not perform simple activities such as putting on his shoe. Plain radiographs showed HO lateral to the left acetabulum, femoral head and neck, with bony bridging to the left ilium on computed tomography. Bone turnover markers (BTMs) measured eleven months post-MVA (and pamidronate) were elevated, with CTX of 750ng/L (100-600ng/L) and P1NP of 207ug/L (15-80ug/L). BTMs gradually reduced over time, plateauing two years post-MVA (CTX 480ng/L and P1NP 103ug/L). Surgery with pre-operative radiotherapy to remove the left hip HO is now planned.

Discussion: This man had multiple recognised risk factors for HO, including male sex, trauma followed by immobilisation and pelvic fracture. His hyperparathyroidism may have predisposed HO development through excess calcium-phosphate product promoting soft tissue calcification. Bisphosphonates may also increase the risk2. Elevated BTMs have been demonstrated in the early phase of HO; further research may elucidate whether BTMs can guide timing of surgical intervention relative to the pathophysiological processes driving HO.

References:

1 Meyers C et al. Heterotopic Ossification: A Comprehensive Review. JBMR Plus 2019, 3: e10172

2 Genêt F et al. Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle 2015. J Pathol. 236(2):229–40
Prednisone-Responsive Hypercalcemia in a Patient With IgG4 Disease and Elevated Serum PTHrP Levels
Authors: Cohen Melissa , Sanchez Julienne , Toft Daniel Joseph , Eisenberg Yuval , Kukreja Subhash C
Published: May 2021

Background: Ninety percent of hypercalcemia cases are related to either primary hyperparathyroidism or malignancy (1). This case presents one of the atypical etiologies of hypercalcemia.

Clinical Case: A 53-year-old man with past medical history of nephrectomy was admitted for acute respiratory distress syndrome secondary to SARS-CoV-2. Hospital stay was complicated by septic shock and acute kidney injury requiring hemodialysis. Three months post hospital admission, the patient developed non-parathyroid (PTH) mediated hypercalcemia. Lab work results showed elevated serum calcium of 12.7 mg/dl (8.6–10.6), ionized calcium 6.8 mg/dl (4.2–5.4), albumin 2.6 g/dl (3.4–5.4), serum creatinine of 3.5 mg/dl (0.5–1.5), eGFR of 18.4 ml/min, and a PTH of 4 pg/ml (12–88). Liver profile - total bilirubin of 10.5 mg/dl (0–1.2), direct bilirubin of 5.9 mg/dl (0–0.2), GGTP 2055 U/L (6–60), alkaline phosphatase of 936 u/L (40–125), bone fractionated alkaline phosphatase 216 u/L (0–55), 25-OH Vitamin D of 11 ng/nl (20–80), 1,25 OH vitamin D of <5 pg/ml (19–79), TSH of 3.56 mciu/mL (0.35–4.0), CPK of 20 u/L (21–232) and a normal SPEP and immune-electrophoresisTreatment for hypercalcemia was initiated with calcitonin and oral steroids (prednisone 40mg/day for 4 days, 20mg/day for 1 day, and 10mg/day for 2 days), resulting in normalization of serum calcium. Patient received tube feedings that contained 2192 mcg retinol activity equivalents of vitamin A daily, which is associated with vitamin A intoxication in the presence of renal insufficiency. Vitamin A returned 0.78 mg/L (0.3–1.2). Serum Parathyroid hormone-related peptide (PTHrP) was elevated at 12.4 pmol/L (0.0–2.0). There was no obvious malignancy on various imaging studies. A magnetic resonance cholangiopancreatography (MRCP) showed biliary stricturing suggestive of primary sclerosing cholangitis (PSC), however, liver biopsy was not consistent with PSC. Serum IgG4 level was found to be elevated to 142 mg/dl (range: 1–123) which raised suspicion for autoimmune cholangiopathy.

Discussion: Patient presented with non-PTH mediated hypercalcemia with low serum 1,25 OHD levels and elevated serum PTHrP level. Although most cases of elevated PTHrP associated with hypercalcemia are due to solid tumors, increased PTHrP levels have been seen in hypercalcemic patients with hematological malignancies and rare benign causes such as pneumonia (5). Association of elevated hypercalcemia with elevated IgG4 levels and PTHrP levels has not been previously reported. MRCP findings and abnormal morphology detailed in liver biopsy are suggestive of IgG4-related disease (IgG4RD) (3). The responsiveness in hypercalcemia to prednisone also supports this diagnosis. IgG4RD is associated with multi-organ autoimmune involvement. This case report highlights another complication of IgG4RD (i.e. hypercalcemia) associated with elevated PTHrP levels.
Rare Case of Severe Hypocalcemia Due to PTH Resistance Related to Diet Pill
Authors: Katkar Rujuta Baban , Madam Narasa
Published: May 2021

Introduction: The production of parathyroid hormone (PTH) is essential for calcium the maintenance of normal mineral metabolism. Parathyroid cells have cell-surface calciumsensing receptors, even small changes in extracellular Ca induce rapid changes in PTH secretion. Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We present rare case of severe hypocalcemia due to PTH resistance caused by hypomagnesemia related to diet pill. Case Report: 61 year old Hispanic obese female with chronic gastritis on omeprazole 20 mg daily, no other significant past medical and surgical history, not taking any prescribed medications presents to ED with complaints of tingling and numbness around the mouth, abdominal cramps, chest pain, shortness of breath and anxiety. On arrival calcium was found to be 6.0mg/dl(8.2–10.2mg/dl) with ionized calcium of 0.60mmol/l(1.13-1.32mmol/l) and EGFR>90ml/min, Albumin-4.0g/l, Magnesium-1.1mg/dl(1.6–2.3mg/dl), Phosphorus-6.1mg/dl(2.4–4.5mg/dl),rest of the electrolytes were normal. Patient was given IV calcium gluconate 2g and magnesium which helped improving her symptoms. PTH was 1700pg/ml(23-73pg/ml), low Vitamin D 25-hydroxy 20ng/dl(30-100ng/dl). Urinary calcium was <1mg/dl(2.0–17.5mg/dl). Vitamin D1,25- dihydroxy 34pg/ml(18-78pg/ml), PTH-like peptide levels 0.6pmol/l(<4.2pmol/l). EKG was normal no QT interval changes. For 4 weekspatient was taking weight loss medication was given to her by her brother called nucific-bio-x4. Patient had lost 4 pounds while taking the medication and had suppression of appetite. Physical features of pseudohypoparathyroidism were not seen. Patient had poor dietary intake of calcium, denied taking vitamin D supplements. Patient was given calcium acetate 2001 mg TID with meals, calcitriol 0.5mcg daily and calcium gluconate 2g IV intermittently was given. That improved her calcium levels to 6.8mg/dl with ionized calcium-0.90mmol/l. Magnesium was replaced IV and discharged on magnesium oxide 400mg BID to maintain magnesium the normal range. The patient was given loading dose of ergocalciferol 50,000 IUfor 8 weeks. At the time of discharge repeat PTH levels were 1600 pg/ml and calcium levels were 8.2mg/dl. 3D CT of the neck did not parathyroid mass. After discharge patient continued on oral calcium and magnesium to maintain calcium levels between 8.4–10.2mg/dl. After discharge calcium levels were 8.6mg/dl, vitamin D 25-hydroxy levels were 32ng/dl and maintenance dose of vitamin D3 2000 IU daily also continued. Nucific-bio-x4 pill was discontinued. Conclusion: In conclusion, severe life threatening hypocalcemia can occur with unsupervised weight lossmedications due to malabsorption of magnesium in patient with likely mutation in magnesium receptors causing PTH resistance. Vitamin D deficiency worsens hypocalcemia resulting into secondary hyperparathyroidism.
Severe Hypocalcemia and Vitamin D Deficiency in Adolescence - A Case Series
Authors: Rothstein Rachel , Allen Natalie
Published: May 2021

Background: Hypocalcemia due to vitamin D (vit D) deficiency is uncommon among adolescents in the US. Only 3% to 6% of those ages 12- to 19-years-old have a vit D level <12 ng/ml.1 We present three cases of severe hypocalcemia secondary to vit D deficiency in non-obese adolescents with restricted diets and limited sun exposure.

Clinical Cases: A 14-year-old Ethiopian male with history of absence seizures presented with bloody stool. Incidentally, labs revealed: Ca 5.6 (8.4–10.2) mg/dL, iCal 0.71 (1.2–1.38) mmol/L, PTH 295.1 (10.0–65.0) pg/mL, 25(OH)D <4 (20–100) ng/mL, Mg 1.9 (1.7–2.2) mg/dL, PO4 3.8 (2.5–4.5) mg/dL. He endorsed weight loss and knee pain, but denied paresthesias, tetany and seizures. He was a vegetarian and had minimal sun exposure. EKG and femur X-ray were unremarkable. He was started on IV calcium gluconate initially. Oral calcium carbonate and cholecalciferol were started on days three and four. He was discharged on day ten with iCal 0.84 on oral calcium carbonate and calcitriol.

A 16-year-old male with history of autism, ADHD and bipolar disorder presented with a seizure. Labs revealed: Ca 5.7, iCal 0.62, PTH 372, 25(OH)D <4, Mg 1.9, PO4 3.5. Exam showed tetany, carpopedal spasms and positive Trousseau and Chvostek signs. EKG revealed prolonged QTc of 480 (<450) ms. He had a restricted diet and minimal sun exposure. His mother described his gait as “waddling” for the past two years. X-ray revealed bilateral femoral head fractures and evidence of rickets. He underwent bilateral surgical repair. He was started on IV calcium gluconate initially. Oral calcium carbonate and cholecalciferol were started on days two and four. He was discharged on day 14 with iCal 1.01 on oral calcium carbonate and cholecalciferol.

A 16-year-old male with history of severe food allergies and restricted diet presented with a seizure. He visited urgent care three months prior for perioral tingling, muscle cramps and chest pain. He started a multivitamin for “low Ca” and “prolonged QTc.” The ED labs revealed: Ca 4.8, PTH 414.8, 25(OH)D 11, Mg 1.9, PO4 5.0, Alk Phos 539 (44–147) IU/L. Exam showed upper extremity twitching and QTc was 543 ms. He received 2 g calcium gluconate IV, then began oral calcium carbonate and cholecalciferol and continued supplementation following discharge on day six.

Conclusions: Vit D deficiency among adolescents is re-emerging, likely due to decreasing sun exposure, unbalanced diets and increasing obesity.2 Adolescents with restricted diets due to allergy or behavioral disorders may be at higher risk of vit D deficiency. Increased screening of high-risk adolescents may lead to early identification of cases.

References: 1) Palacios, C., et al. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2013;144PA;138-145 2) Antonucci, R., et al. Vitamin D deficiency in childhood: old lessons and current challenges. J Pediatr Endocrinol Metab. 2018;31(3);247–260.
Short-Term Treatment With Teriparatide Restores Independent Ambulation in a Patient With Glucocorticoid-Induced Osteonecrosis of the Knees and Ankles
Authors: Chen Xin , Mimoto Mizuho
Published: May 2021

Teriparatide is a well-established treatment for osteoporosis. It is emerging as a promising treatment for osteonecrosis of the jaw and may be superior to alendronate for treating glucocorticoid-induced osteonecrosis of the femoral head and reduce collapse progression. However, few studies have investigated its efficacy in treating steroid-induced osteonecrosis affecting other sites such as the knee and ankle. Osteonecrosis treatment at these sites in early stages is limited to protected weight bearing and pain management. Surgical management is required for advanced stages. This case describes an unusual presentation of steroid-induced osteonecrosis in the bilateral lower extremities and illustrates the potential benefit of teriparatide as an alternative to surgery in managing this debilitating condition. A 25-year-old male with a history of a heart transplant for viral myocarditis was admitted to the hospital for severe bilateral lower extremity pain. His post-transplant course was complicated by giant cell myocarditis, treated with a prednisone taper from 80 mg to 7.5 mg daily over the course of one year. MRI showed diffuse osteonecrosis in the distal femora, medial femoral condyles, bilateral proximal tibias, left distal tibia, and bilateral ankles. A bone density test showed only mildly low bone mass with Z-scores of -0.8 at the right femur, -1.3 at the left femur and -1.3 at the lumbar spine. Due to progressive osteonecrosis on imaging and a decline in functional status over the next two months, following a discussion of risks, benefits and alternatives, he was started on daily teriparatide injections. Prior to therapy, he was using a walker and had difficulty ambulating more than a few feet. Within a month of teriparatide initiation, he reported improvement in both pain and mobility, and was able to walk independently into clinic. MRI two months later demonstrated no new lesions and significant improvement in previously necrotic areas. Our case highlights the importance of considering osteonecrosis at atypical locations in patients on chronic glucocorticoid therapy. It also demonstrates a promising role for teriparatide in treating steroid-induced osteonecrosis atypical sites and without concurrent osteoporosis.
Successful Parathyroidectomy May Not Resolve Hypercalciuria in Patients With Primary Hyperparathyroidism
Authors: Izkhakov Neriy , Prasad Heranmaye , Vernetti Nicholas John , Nakhle Samer
Published: May 2021

Background: Hypercalciuria, with twenty-four-hour urinary calcium of >400 mg/day, is one of the indications for parathyroidectomy in patients with primary hyperparathyroidism. We report five cases where hypercalciuria is not resolved following a successful parathyroidectomy (normalization of serum calcium) in such patients. Here resolution of hypercalciuria is defined as twenty-four-hour urinary calcium of less than 200 mg/day. Clinical Case: This is a case series of five patients who remained hypercalciuric at 6 to 19 months after successful parathyroidectomy. Pre-parathyroidectomy, average PTH was 95 pg/dL (Min 69 pg/dL, Max 120 pg/dL), average serum calcium was 11.0 mg/dL (min 10.3 mg/dL, max 12.0 mg/dL), and average twenty-four-hour urinary calcium was 455 mg/day (min 386 mg/day, max 551 mg/day). Calcium levels were corrected to normal range post-parathyroidectomy and remained in normal range. However, hypercalciuria did not resolve. Post-parathyroidectomy, average PTH was 44 pg/dL (min 25 pg/dL, max 69 pg/dL), average serum calcium was 9.6 mg/dL (min 9.3 mg/dL, max 9.8 mg/dL), and average twenty-four-hour urinary calcium was 284 mg/day (min 201 mg/day, max 376 mg/day). Two patients who had history of nephrolithiasis prior to parathyroidectomy continued to develop nephrolithiasis at six and sixteen months after successful parathyroidectomy. Conclusions: This case series showed that hypercalciuria may not resolve following a successful parathyroidectomy in patients with primary hyperparathyroidism and elevated twenty-four-hour urinary calcium at 6 to 19 months after surgery. Further observations to evaluate long term effects of parathyroidectomy on hypercalciuria is needed.
The Importance of Interpreting Urine Calcium:Creatinine Ratio in PHPT Within Ethnic Context
Authors: Abdel-Malek Mariana , Zaman Shamaila , Tharakan George , Mills Edouard G , Buckley Adam John , Todd Jeannie , Behary Preeshila , Cox Jeremy Philip , Comninos Alexander N
Published: May 2021

A 56-year-old Afro-Caribbean lady was found to have incidental hypercalcaemia on routine GP investigations. Tiredness was the only elicitable hypercalcaemic symptom and aside from early menopause at age 40, she had no significant past medical or family history. Examination was unremarkable. Blood results showed a raised adjusted calcium 2.68mmol/L (2.2–2.6), normal phosphate 1.06mmol/L (0.80–1.50), raised parathyroid hormone (PTH) 14.1pmol/L (1.6–7.2) and low 25-hydroxyvitamin D 28.1nmol/L (70–150).

She had osteopaenia of the femora and left radius on DEXA scan but no nephrocalcinosis on renal ultrasound. On initial investigation, her urinary calcium output was low at 1.55mmol/day resulting in a 24h calcium:creatinine ratio (UCCR) of 0.0065. Although suggestive of Familial Hypocalciuric Hypercalcaemia (FHH), her notable Vitamin D deficiency was considered to contribute to the observed hypocalciuria. After Vitamin D repletion, a repeat UCCR improved to 0.012, however, remained in the indeterminate range. No known pathogenic variant was identified on genetic analysis for FHH.

Her PTH and Calcium levels remained persistently high within 9.7–17.1pmol/L and 2.65-2.82mmol/L respectively, suggestive of Primary Hyperparathyroidism (PHPT) given the end organ damage and negative genetic studies. Based on her symptom of fatigue, osteopaenia at a young age and hypercalcaemia, localisation studies were arranged which showed no definitive evidence of a parathyroid adenoma and explorative surgery was planned.

The negative genetic testing, PTH level 17.1pmol/L, osteopaenia, low-normal magnesium and phosphate level collectively support a diagnosis of PHPT in this case, despite a low UCCR which however is observed in some PHPT patients. Indeed, a lower UCCR ratio has been reported in the healthy Afro-Carribean population across all age groups, as well as in Afro-Carribean patients with PHPT [1]. The underlying mechanism for this is yet to be determined but may be due to increased renal sensitivity to PTH or altered activity of the tubular calcium reabsorptive pathways. One can further speculate regarding an evolutionary reason behind a protective homeostatic system favouring renal calcium reabsorption over excretion in this frequently vitamin D deficient population.

Clinical practice relies heavily on the use of UCCR in aiding the biochemical differentiation of PHPT and FHH. However, as this case highlights, its use can be misleading in Afro-Carribean patients and therefore should be interpreted within an ethnic context.

References: Taha W., Singh N., Flack J. M., Abou-Samra A. B. Low urine calcium excretion in African American patients with Primary Hyperparathyroidism. Endocr Pract. 2011; 17: 867–872
Vitamin D Supplements: Over-the-Counter Accessibility... It Is Safe?
Authors: Figueroa-Cruz Alegyari , Villarrubia-Ocasio Lisselle M , Madera-Marin Luis N , Ortiz-Torres Yineli , Vazquez-Roura Francis , Garcia-Mateo Jose M
Published: May 2021

Calcium is the fifth most abundant element in earth and human body. It has multiple functions within our system such bone mineralization, neuromuscular excitability regulation, hemostasis, membrane transport, release of hormones and neurotransmitters, among others. For duodenal absorption of calcium, we need vitamin D, reason for which supplementation of both components is important to maintain adequate calcium homeostasis. However, it is entirely beneficial or can be harmful? As we know everything in excess has its consequences, as we describe below.

72 y/o male is brought to the ED after relative find him lethargic, she reports noticing generalized weakness that has been progressing over weeks, prominent in upper extremities with associated increased in urinary frequency. Patient past medical history is relevant for CAD, hypothyroidism, dyslipidemia, and DMT2. On physical examination patient is found hypoactive, but arousable to verbal stimuli, without distress, focal neurologic deficit, thyromegaly nor lymphadenopathy. Presents with Ca+: 18.8mg/dL (n:8.0–10.5mg/dL), that could explain patient clinical presentation for which workup for hypercalcemia is done finding PTH suppress: 14.57pg/mL (n:15-65pg/mL). Patient now with non-PTH related hypercalcemia is further evaluated and found with negative UPEP and SPEP ruling out multiple myeloma and PTH-rp <2.0pmol/L (negative). While etiology of severe hypercalcemia is being study, patient complications of it are being managed such as AKI stage 3 as he presents with Cr: 3.85mg/dL, BUN: 62.5, CrCl:18ml/min and GFR: 15ml/min. Aggressive IV hydration and bisphosphonate therapy failed to decrease calcium and renal function continues worsens, for which hemodialysis is required for calcium clearance. Patient then found with vitamin D25-OH levels: 210.4ng/mL (n:30-100ng/mL), upon questioning he reports taking multivitamins and supplements equivalent for a daily ingestion of 50,700IU of Vitamin D3 and 334mg of calcium carbonate. Patient calcium levels normalize after dialysis but develops renal failure for which he has to be discharged on permanent hemodialysis.

Although prevalence is unknown, hypercalcemia due to vitamin D intoxication is relatively uncommon in comparison to hyperparathyroidism and malignancy. An exact dose intake that leads to intoxication has not yet being stablished but supplementation besides dosage is also dependent on duration of therapy. This case has a lot to teach us, starting with detrimental effects of hypercalcemia, follow by the consequences of lack of counseling and close follow-up of patient over-the-counter supplementation. As physicians we should inquire more about OTC medications and supplements our patients are taking not only for intoxication concerns, but also for drugs interactions. Counseling must be the cornerstone of our practice to avoid life changing consequences as in this case.
In Vitro Effect of CCL11 on Myogenic Differentiation and Its Relevance With Sarcopenia Parameters in Older Adults
Authors: Park So Jeong , Kim Da Ae , Lee Jin Young , Kim Beom-Jun
Published: May 2021

Background: The C-C motif chemokine ligand 11 (CCL11) has been receiving attention as a potential pro-aging factor and thus may be also involved in muscle metabolism and sarcopenia, a key component of aging phenotypes. To clarify this possibility, we investigated the effects of CCL11 on in vitro muscle biology and clinical relevance with sarcopenia parameters in older adults. Methods: Primary mouse myoblasts and C2C12 cells were used for experimental research. Blood samples were collected from 79 participants who underwent a functional assessment, and CCL11 level was measured using a quantikine ELISA kit. Sarcopenia was diagnosed using the Asian-specific cut-off points. Results: CCL11 treatment stimulated the differentiation of both primary myoblasts and C2C12 cells into mature myotubes, and consistently increased the expression of myogenic differentiation markers, such as myosin heavy chain and myogenin. Among C-C chemokine receptors (CCRs), CCR5, not CCR2 and CCR3, was predominantly expressed in muscle cells, and CCR5 inhibitor blocked CCL11-stimulated myogenesis. In a clinical study, after adjustment for sex, age, and body mass index, serum CCL11 level was not significantly different according to the status of sarcopenia, low muscle mass, low muscle strength, and low physical performance, and was not associated with any of skeletal muscle index, grip strength, gait speed, time to complete 5 chair stands, and short physical performance battery score. Conclusions: Contrary to expectations, CCL11 showed the beneficial effects on muscle metabolism at least in vitro system. However, the role of CCL11 on muscle health in humans was not evident, suggesting that circulating CCL11 level may not be a useful biomarker for sarcopenia risk assessment in older adults.
Oleanolic Acid Modulates 25-Hydroxyvitamin D3 1-alpha-hydroxylase in Osteoblasts and Human Mesenchymal Stem Cells
Authors: Yu Wen-Xuan , Poon Christina Chui-Wa , Lee Wayne Yuk-Wai , Wong Man-Sau
Published: May 2021

Objectives: 25-Hydroxyvitamin D3 1-alpha-hydroxylase (CYP27B1) catalyzes the hydroxylation of 25-hydroxyvitamin D3 (25(OH)D3) to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), the bioactive form of vitamin D3. Our previous studies suggested that oleanolic acid (OA), a pentacyclic triterpenoid presents in many food and herbs, can improve circulating 1,25(OH)2D3 in ovariectomized (OVX) mice and increase CYP27B1 expression in human renal proximal tubular cells (HKC-8). However, the role of OA in regulating CYP27B1 in bone is far from clear. The present study is designed to study the effects of OA on CYP27B1 expressions and 1,25(OH)2D3 production in bone cells. Methods: The mRNA and protein expressions of CYP27B1, as well as bone metabolism markers were determined in osteoblast-like UMR-106 cells in response to treatments of parathyroid hormone (PTH) (10–7 M) or OA (10–9 - 10–5 M) for 24 hours. By using excessive 25(OH)D3 (10–6 M) as substrate, cellular production of 1,25(OH)2D3 was measured to determine CYP27B1 activity. To mimic the physiological condition, human mesenchymal stem cells (hMSCs) were pre-treated with 25(OH)D3 (10–7 M) for 12 hours, followed by OA treatment (10–9 - 10–6 M) for another 24 hours, the osteogenic effects of OA on alkaline phosphatase (ALP) activity and CYP27B1 expression were evaluated. Results: PTH (10–7 M, p<0.001) and OA (10–9 M, p<0.05) significantly upregulated mRNA and protein expressions of CYP27B1 in UMR-106 cells. 4-hour treatments of PTH (10–7 M) and OA (10–9 M) also stimulated the 1,25(OH)2D3 production by 46.02 % (p<0.001) and 17.60 % (p<0.01), respectively. Moreover, the mRNA expressions of ALP and osteocalcin (OCN) involved in osteoblast differentiation, were upregulated in response to PTH and OA in UMR-106 cells (p<0.05). The protein expression of CYP27B1 was upregulated by treatment with OA in hMSCs supplemented with 25(OH)D3 (10–8 M, p<0.05 vs. supplement alone). Furthermore, OA (10–8 M) potentiated the effects of 25(OH)D3 on osteogenesis in hMSCs by enhancing ALP activity by 47.77 % (p<0.01). Conclusions: Our results indicated that the bone anabolic effects of OA are associated with its actions to improve local bioactivation of vitamin D3 in osteoblasts and hMSCs, suggesting the involvement of paracrine or autocrine activities of 1,25(OH)2D3 in mediating the actions of OA in bone. Funding Sources: This work is supported by research studentship of Wen-Xuan Yu, The Hong Kong Polytechnic University.
The Effect of Dietary Vitamin D3 Level on Bone Osteometry and Mechanical Properties in Young Rats
Authors: Muszyński Siemowit , Świątkiewicz Małgorzata , Szymczyk Beata , Oczkowicz Maria , Furgał-Dzierżuk Iwona
Published: May 2021

Recent knowledge indicates that vitamin D3 not only regulates the calcium-phosphate metabolism, but also as a hormone with steroidal features, has significant remedial-homeostatic ability and has a pleiotropic function in the body. Medical observations confirm the beneficial effect of elevated levels of vitamin D3 in the prevention or alleviation of the course of many diseases of the cancer and autoimmune basis, diabetes and coronary diseases. The deficiencies of this vitamin in children, adolescents and young women are observed, causing the rickets or bone fragility. As the increasingly limited role of obtaining vitamin D3 from the sun exposure, supplementation of food sources becomes particularly important. The aim of the study was to evaluate the effect of the increased dietary vitamin D3 level on health status using rats as the model animals. The experiment was carried out on 36 weaned rat Wistar, half female and male, 5–6 weeks old. Animals were divided into 3 groups. All rats obtained ad libitum the same feed mixture but differed in the vitamin D3 level (0, 1000 or 5000 IU/kg). Bone length and weight, cross-section area and wall thickness were measured, cortical index was calculated. The mechanical properties were determined using the 3-point bending test performed on a universal testing machine (Zwick Z010). The supports were placed at 40% of the total bone length and the measuring head loaded bone samples with a constant speed of 10 mm/min until fracture. The bone mineral density was determined using the dual-energy X-ray absorptiometry (DEXA) method on a DiscoveryWHologic X-ray densitometer. We observed that, the vitamin D3 presence in feed did not significantly affect the bone geometrical traits in young rats. The vitamin D3 supplementation, regardless its level, increased the bone mineral density by 8–12% (P<0.05) and some mechanical properties were improved (P<0.05) in comparison to group without vitamin D3 supplementation. Also, the femur bone of rats supplemented with vitamin D3 characterised by the higher share force (11–14%), work needed for destruction (24–55%), ultimate strain, ultimate stress (5–7%). The bone elastic strength was the highest in group III, receiving the vitamin D3 in amount excessing the standard requirement of rats. Summerizing it can be concluded, contrary to the assumptions, we did not confirmed the significant effect of increased vitamin D3 level in feed on MBD and most of the mechanical traits. However, the maximal elastic strenght was the highest in group receiving 5000 IU/kg of vitamin D3, which reflects the highest elastic strength of midshaft cortical bone under reversible deformation and the maximum stress which a bone can withstand before fracture, but the difference was not statistically confirmed.
The Role of Thyroid Hormone 3,3 ‘, 5 - Triiodothyronine (T3) in the Expression of Osteocalcin and Lipocalin 2 (LCN2) in Osteoblasts
Authors: de Camargo Andrade Amanda Fantini , Pinto Thaís Silva , Feltran Geórgia Silva , Ferretti Renato , Zambuzzi Willian Fernando
Published: May 2021

Introduction: The thyroid hormone 3,3 ‘, 5 - triiodothyronine (T3) has an important role in bone physiology and metabolism, stimulating osteodifferentiation and bone homeostasis. Although there is this evidence, little is known about the synergistic events of T3 together with the endocrine role of other players that interfere with osteoblast metabolism, such as Lipocalin 2 (LCN2) and its hypothalamic-located MCR4 receptor. It is also known that LCN2 interferes at a physiological level with the parameters of food intake. Objective: To evaluate the role of the thyroid hormone 3,3 ‘, 5 - Triiodothyronine (T3) in the control of the expression of both Osteocalcin (OCN) and Lipocalin 2 (LCN2) in osteoblasts. Materials and Methods:. In order to understand the molecular and physiological mechanisms about that probable synergism, the experiments were as follows: Mouse pre-osteoblasts were challenged with T3 hormone treatments in three levels (1nM; 1.5nM; 2.0nM) and different times (0h; 24h; 72h). The samples were collected to perform gene expression of the main osteodifferentiation markers (RUNX2, OTX, BSP), matrix remodeling (MMPs, TIMPs, BMPII) and zymography assay for analysis of metalloproteinase activities (MMPs). Results and Discussion: Preliminarily, it was founded a synergism between the hormone T3 and LCN2 expression in osteoblasts, occurring the modulation of the marker genes of differentiation, extracellular matrix and hormonal synthesis. The T3 hormone acts in the modulation of RUNX2, OTX, BMP2, favoring osteodifferentiation and the remodeling of the matrix, probably activating the TIMP1-MMP9 and TIMP2-MMP2 complexes, mainly in hyperthyroid conditions. In addition, we note a direct influence of T3 on the both expression of both Osteocalcin (OCN) and Lipocalin 2 (LCN2). Final Considerations: Our preliminary data indicates that the hormone T3 acts on the metabolism of osteoblasts through the modulation of LCN2 and BMPII. These molecular findings need to be confronted with further analyzes in vivo for more conclusive physiological conclusions.
A Hospitalist-Led Fracture Liaison Service Improves Care of Hip Fracture Patients
Authors: Drabkin Anne , Rothman Micol Sara , Audrey Goold , Robin Yasui , Diana Mancini
Published: May 2021

Background: Osteoporosis care traditionally falls to outpatient primary care providers despite the fact that over 300,000 elderly patients are hospitalized yearly with hip fractures in the United States. Internal medicine hospitalists are often involved in the co-management of their care on surgical teams and are skillful in osteoporosis recognition and management. Objective: A hospitalist-led Fracture Liaison Service (FLS) was established to provide improved care of hospitalized patients with hip fractures. Methods: A retrospective evaluation of inpatient and post-discharge management of patients admitted with low-impact hip fractures was performed before (8/17-2/18) and after (8/19 - 2/20) launch of the hospitalist Fracture Liaison Service (H-FLS). Results: Eighty-nine patients were admitted with a hip fracture in post-launch period compared to 73 admitted prior. 74% vs 11% of eligible patients (based on adequate renal function and vitamin D stores) were discharged with anti-osteoporosis medications (p<0.001), 82% vs 38% were discharged with vitamin D/calcium supplements (p<0.001), 22% vs 5% underwent a DXA scan after discharge (p<0.05) and 65% vs 0% were referred to outpatient osteoporosis-specific care at discharge (p<0.001). Conclusion: A hospitalist-led FLS is a unique approach to osteoporosis care that significantly improved quality metrics for elderly patients with osteoporotic hip fractures including initiation of anti-osteoporosis medication and bone density imaging. Outpatient follow-up data are needed to evaluate adherence to this initial management over time.
Clinical Risk Factors for Osteoporotic Fractures in Men With Non-Metastatic Prostate Cancer on Androgen Deprivation Therapy With or Without Anti-Osteoporosis Treatment
Authors: Sonnabend Hajerah , Pulipati Vishnu Priya , Baim Sanford , Beck Todd , Simmons J Alan , Ritz Ethan M
Published: May 2021

Introduction: Androgen deprivation therapy (ADT) decreases bone mineral density and increases osteoporotic fracture (OsteoFx) risk.

Hypothesis: To assess OsteoFx clinical risk factors (CRF) most predictive of future OsteoFx among men with prostate cancer on ADT.

Methods: 4370 electronic medical records were reviewed of adult men with prostate cancer on cancer therapy +/- anti-osteoporosis therapy (Anti-OsteoRx) from 2011–2019. Cancer therapy included ADT (anti-androgens, GnRH agonists & antagonists, orchiectomy) and supplemental cancer therapy (SupplRx) (prostatectomy, brachytherapy, radiation, immunotherapy, and chemotherapy). Anti-OsteoRx included bisphosphonates, denosumab, and parathyroid hormone analogs. Patients with other cancers within 5 years of initial visit, metastasis, and traumatic fractures were excluded. Retrospective analysis was done to determine baseline characteristics, type and duration of ADT, Anti-OsteoRx, SupplRx, and osteoporosis CRF.

Results: 615 men on ADT +/- SupplRx +/- Anti-OsteoRx were included in the study. 10.08% had OsteoFx irrespective of SupplRx or Anti-OsteoRx. Comparing the OsteoFx group to the non-fracture group, the following CRF were found to be statistically significant (p <0.05): age at prostate cancer diagnosis (75.10 +/- 11.80 vs 71.59 +/- 9.80 y), diabetes mellitus (DM) (33.9 vs 19%), pre-existing comorbidities affecting bone (PreCo) (41.9 vs 24.8%), steroid use (11.3 vs 4.0%), and anti-convulsant and proton-pump inhibitor (med) use (45.2 vs 26.8%).

9.89% of 374 men on ADT only without (wo) Anti-OsteoRx fractured. Statistically significant CRF for OsteoFx were age (76.86 +/- 10.55 vs 73.02 +/- 10.06 y), DM (40.5 vs 19.6%), PreCo (45.9 vs. 26.4%), and med use (48.6 vs. 25.5%).

In the following subgroups there were no statistically significant difference in CRF:•7.64% of 170 men on ADT + SupplRx wo Anti-OsteoRx •19.23% of 52 men on ADT only + Anti-OsteoRx •10.52% of 19 men on ADT + SupplRx + Anti-OsteoRx

To increase statistical power, patients on ADT +/- SupplRx were assessed:•Among 71 men on ADT +/- SupplRx + Anti-OsteoRx, there were no statistically significant differences in CRF•Among the 544 men on ADT +/- SupplRx wo Anti-OsteoRx, significant CRF for OsteoFx were age (75.16 + 11.70 vs 71.37 + 9.85 y), DM (38 vs 19.4%), PreCo (38 vs 24.1%), steroid use (12 vs 3.8%), and med use (48 vs 24.3%)

Discussion:

Men with prostate cancer requiring ADT have a higher incidence of osteoporosis defined by DXA prior to initiating ADT compared to age-matched cohorts (Hussain et al). Our study revealed ADT with CRF is associated with OsteoFx irrespective of SupplRx or Anti-OsteoRx. Limitations include inability to evaluate efficacy of Anti-OsteoRx due to insufficient power.

Conclusion: OsteoFx risk assessment utilizing CRF, FRAX, DXA with timely intervention may prevent OsteoFx in these high-risk patients.
Fracture Rates in Men With Non-Metastatic Prostate Cancer on Androgen Deprivation Therapy With or Without Anti-Osteoporosis Treatment
Authors: Sonnabend Hajerah , Pulipati Vishnu Priya , Baim Sanford , Beck Todd , Ritz Ethan M , Simmons J Alan
Published: May 2021

Introduction: Androgen deprivation therapy (ADT) decreases bone mineral density and increases osteoporotic fracture (OsteoFx) risk. Hypothesis: To assess OsteoFx incidence most predictive of future OsteoFx among men with prostate cancer on ADT. Methods: 4370 electronic medical records were reviewed of adult men with prostate cancer on cancer therapy +/- anti-osteoporotic therapy (Anti-OsteoRx) from 2011–2019. Cancer therapy included ADT (anti-androgens, GnRH agonists & antagonists, orchiectomy) and supplemental cancer therapy (SupplRx) (prostatectomy, brachytherapy, radiation, immunotherapy, and chemotherapy). Anti-OsteoRx included bisphosphonates, denosumab, and parathyroid hormone analogs. Patients with other cancers within 5 years of initial visit, metastasis or traumatic fractures were excluded. Retrospective analysis was done to determine baseline characteristics, type and duration of ADT, Anti-OsteoRx, SupplRx, and OsteoFx incidence. Results: Fracture rate subgroups: • ADT only - Anti-OsteoRx 37/ 374 fractured (9.89%) • ADT only + Anti-OsteoRx 10/52 fractured (19.23%) • ADT + SupplRx + Anti-OsteoRx 2/19 fractured (10.53%) • ADT + SupplRx + Anti-OsteoRx 13/170 fractured (7.65%) Comparing fracture rates between subgroups: • Comparing ADT only +/- Anti-OsteoRx, statistical significance was observed with higher fracture rate in patients taking Anti-OsteoRx (19.23% vs. 9.89%, p < 0.044) • Comparing ADT + SupplRx +/- Anti-OsteoRx, no significant difference in fracture rates due to small number of fractures Comparing combined subgroups: • ADT +/- SupplRx + Anti-OsteoRx 12/71 (16.9%) fractured • ADT +/- SupplRx - Anti-OsteoRx 50/544 (9.19%) fractured • Statistically significant between groups fracture rates was observed (p= 0.042) in patients treated with Anti-OsteoRX. Discussion: Patients receiving Anti-OsteoRx, regardless of their prostate cancer therapies, had higher rates of fractures (16.9 vs. 9.19%, p= 0.042) due to their being selected for therapy based on greater clinical risks. The Anti-OsteoRx group had a higher percentage of glucocorticoid listed as a historical medication (26.8 vs.15.3% vs, p= 0.023), glucocorticoids administered (50.7 vs. 30.3% p=0.001), and anticonvulsants and proton-pump inhibitor use (45.1 vs. 26.5%, p= 0.002). Conclusion: Higher fracture rates were observed in patients on Anti-OsteoRx that could be related to their being selected for treatment based on risk factors known to be associated with osteoporosis. Limited Anti-OsteoRx use in our study is possibly related to lack of standardized guidelines for prevention of osteoporotic fractures in prostate cancer patients. OsteoFx risk assessment utilizing CRF, DXA, and FRAX may prevent fractures in these high-risk patients. Further long-term prospective studies to address these unresolved queries are warranted.