Optimization of Antiosteoporotic Therapy in Patients with Liver Fibrosis

The purpose of the study: to investigate the effect of zolendronic acid on bone mineral density in patients with osteoporosis and fibrotic changes of the liver due to steatohepatitis. Materials and methods. We examined 28 female patients with a mean age of 55.3±4.7 years with decreased bone mineral density, nonalcoholic steatohepatosis and liver fibrosis. All studied patients were in menopause duration of 7.8±3.5 years. For inclusion in the study, all patients were excluded from the presence of comorbidities. The degree of liver fibrosis was determined on the basis of 2D shear wave elastometry by transcutaneous access by the method of shear wave in the SWE mode. The study included patients with liver fibrosis F1 - F3 on METAVIR. Determination of bone mineral density was performed using an X-ray densitometer DEXXUM T by dual energy absorption. Results and discussion. The initial level of liver tissue stiffness in the studied patients was 8.52±1.12 kPa, which corresponded to the stage of fibrosis F2 - F3 according to METAVIR. Isolated decrease in lumbar spine mineral density was diagnosed in 20 patients, 8 patients had a combination of decreased spinal mineral density with decreased femoral mineral density, mean T vertebral T-test was -2.25±0.2, mean femoral neck T-test was -1, 9±0.3. In order to maintain and restore bone mineral density, these patients were advised to minimize the factors that contribute to bone loss, mainly by stopping alcohol and smoking. Patients were advised to exercise as much as possible under the supervision of a rehabilitologist, especially to do exercises aimed at improving the mechanics of the spine. One year after administration of 5 mg zolendronic acid intravenously and daily intake of 1500 mg calcium and 800 IU vitamin D the level of liver tissue stiffness in the studied patients was 7.69±1.14 kPa, which corresponded to the stage of fibrosis F2 - F3 according to METAVIR and not due to a moderate decrease in indicators, there was no statistically significant difference. Isolated decrease in lumbar spine mineral density was diagnosed in 19 patients, in 9 patients there was a combination of decrease in spinal mineral density with decrease in femur mineral density, the average criterion of T vertebrae was 1.1±0.3 (p=0.032), the average criterion of T femoral neck -0.9±0.3 (p=0.029). The study of the level of alaline transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyltranspeptidase did not reveal any abnormalities. After administration of zolendronic acid in 7 patients there was an increase in temperature to febrile levels within 2-3 days. None of the patients showed signs of bone fractures of any localization during the observation period. Conclusion. Thus, the administration of zolendronic acid to patients with decreased bone mineral density on the background of fibrous changes in liver tissue due to steatohepatitis is safe and highly effective

Bisphosphonate Therapy in the Management of Symptomatic Melorheostosis of Tibia

Introduction: Melorheostosis is a rare sclerosing bone disease characterized by linear hyperostotic bone dysplasia with its radiological appearance as melting candle wax dripping by its side. It usually affects long bones, especially the lower limb. The exact cause of the disease has not been clearly explained though many theories are available. It is insidious in onset and symptoms being pain, deformity, and joint stiffness. Although there is no definitive treatment, the administration of bisphosphonates dramatically reduces pain and improves the patient clinically. Case Report: We described a case of a 28-year-old female who presented with a history of pain and swelling in her left leg for the past 2 years. The onset of complaints was insidious. On physical examination, there was tender swelling over the shaft of the tibia with irregular borders. Knee and ankle range of movements were normal. Radiographs showed hyperostosis of the proximal two-thirds of the tibia of the left leg with a flowing candle wax appearance. The patient was treated with a single dose of intravenous zolendronic acid and physical therapy. The patient had dramatic alleviation of pain without the need for any further treatment till 1 year follow-up. Conclusion: Although there is no specific treatment available for this disease, the intravenous infusion of zolendronic acid has dramatically improved the patient clinically. Keywords: Melorheostosis, flowing candle wax, bisphosphonates, zolendronic acid.

Osteonecrosis of the jaw in metastatic renal cell carcinoma (mRCC) patients treated with zolendronic acid and denosumab: An observational retrospective multicenter trial.

299 Background: Bone is one of the most common site of metastasis occurring in 30% of metastatic renal cell carcinoma (mRCC) patients (pts)3,4. Skeletal metastases from mRCC are usually osteolytic and associated to high rate of morbidity and complication through skeletal related events (SRE). Bone-targeted therapies (BTT) such as zolendronic acid (ZOL AC) and denosumab (Dmab), shown to decrease the time-to-first and subsequent SREs12. Osteonecrosis of the jaw (ONJ) is a rare but potentially serious adverse event associated with BTT. It occurs in 1-2% of pts treated with BTT and in 10-17% of mRCC pts treated with ZOL AC or Dmab. Vascular endothelial growth factor-Tyrosine kinase inhibitors (VEGF-TKI) represent the backbone treatment for mRCC. Nevertheless, it is unclear whether the association of DMAB and ZOL AC to VEGF-TKITTagents could be associated to higher incidence of ONJ. Methods: We retrospectively collected data, from 2 Italian referring centers for mRCC, about 74 pts with bone metastases from mRCC who received, concurrently or sequentially to VEGF-TKI or immune-oncology (IO), AC ZOL and DMAB from January 2013 to January 2020. All pts provided informed consent for inclusion in the study. Results: All pts received VEGF-TKI as first line treatment. 17 pts received AC ZOL whereas 57 received DMAB. All pts received odontological consultation and orthopantomography before start BTT. The median time of Dmab and AC ZOL exposure was 11.6 months. ONJ occurred in 10/74 pts (7.4%): 6/10 pts were on first line treatment and 4/10 on second line. Treatments administered at the time of ONJ diagnosis were nivolumab (1/10), cabozantinib (2/10), sorafenib (1/10), sorafenib (1/10), sunitinib (4/10) and one pts was off therapy. Conclusions: In this real-life Italian population, treatment with BTT in mRCC pts treated with VEGF-TKI inhibitors and IO is associated to higher incidence of ONJ compared to previous report of pts treated with BTT for bone metastasis and lower compared to previous reports in mRCC. Despite the retrospective collection, we provided one of the largest sample of pts treated concurrently with VEGF-TKI or IO and BTT. Physicians should be careful in the use of BTT combined with other treatments in mRCC pts.

MON-908 Carcinoid Causing Catastrophic Calcemia

Intro: Carcinoid tumors are rare, slow growing, indolent neuroendocrine tumors typically originating from enterochromaffin in the gastrointestinal tract and bronchopulmonary tree1. While often found to be secreting serotonin, many different secretory products have been described2. We present the case of a patient with refractory hypercalcemia due to a carcinoid tumor producing parathyroid hormone related peptide (PTHrP). Case: A 65-year-old male was found to have hypercalcemia of 14.7 mg/dL after presenting for nausea and vomiting. He was treated with Zolendronic acid and intravenous (IV) fluids as initial work-up revealed an appropriately suppressed parathyroid hormone level, no monoclonal spike, and a PTHrP that was dramatically elevated. He refused further work-up initially but was admitted two months later for persistent severe hypercalcemia. Computed tomography imaging showed innumerable liver lesions. Histologic analysis of the largest liver lesion was consistent with carcinoid tumor. For the next two years, he was managed outpatient with Pamidronate, Denosumab, and Sandostatin, along with two liver embolizations. Control of serum calcium levels became more difficult and he had multiple hospitalizations for symptomatic hypercalcemia until chemotherapy, Sunitinib, was initiated. Calcium levels normalized for one year after starting Sunitinib prior to onset of suspected medication-induced pancreatitis. He was switched to Everolimus but did not respond to that and was readmitted mere weeks later for symptomatic hypercalcemia and a combination of Folinic acid, Fluorouracil, and Oxaliplatin (Folfox) was started. He continued to get frequent bisphosphonates and IV fluids along with Folfox but several months later he stopped responding to all medical options. His calcium level climbed to 19.9mg/dL and he underwent a technically complicated surgical procedure in which significant tumor burden was removed from his liver. Since surgery, the patient has remained normocalcemic without additional medical therapy. Discussion: Carcinoid tumors are uncommon with reported incidence of 40 per one million people2. PTHrP is most commonly produced by squamous cell lung cancer, renal cell cancer, gynecologic cancers, and lymphoma3. Carcinoid tumors producing PTHrP with resultant hypercalcemia is rare with a few cases reported in literature4. Our patient had a complex treatment course including IV fluids, anti-resorptive agents, somatostatin analogs, liver embolization, chemotherapeutic agents, and eventual surgical debulking. Surgical intervention is not commonly required for carcinoid tumors5. This patient had a rare tumor, producing an uncommon hormone, and required extensive treatment. This case shows the importance of a multidisciplinary approach in patients with hypercalcemia secondary to carcinoid tumors but refractory to traditional therapy.

SAT-153 PTHrP Mediated Hypercalcemia

PTHrp mediated hypercalcemia Introduction: PTHrp is a normal gene product, which helps tooth eruption and mammary gland development. However, PTHrp production in an adult is mostly related to solid tumor malignancy. The homology of PTHrp to PTH from the 1st to 13th amino acids decided the similar mechanism of acting at PTH-1 receptor on increasing bone resorption and calcium reabsorption at the distal renal tubule. Lung cancer is known to secrete PTHrp and PTHrp secreting hepatic cellular carcinoma (HCC) is exceedingly rare. It’s only been documented in case reports. Two cases of PTHrp secreting atypical HCC are included in this case report. Case presentation: 67 year old with history of alcohol abuse with 17.8 x 8.8 cm mass in the left hepatic lobe presented with acute encephalopathy and calcium of 14.4 mg/dl. Patient was treated with zolendronic acid 4mg, IV fluid and calcitonin. Patient has a PTH level of 7 pg/ml and PTHrp level of 335 pg/ml. Bone turnover marker Beta crosslaps of 1595 pg/ml. 25-hydroxy vitD of 25 ng/ml and 1,25 dihydroxy vitD of 42 pg/ml. Liver biopsy demonstrated moderately differentiated hepatocellular carcinoma. The undifferentiated portion was positive with CD56, CAM 5.2 suggestive of neuroendocrine differentiation and epithelial lineage. Patient had negative metastatic bone scan and no pathologic fractures. Second case is a 63 year old male with NASH cirrhosis was admitted for hypercalcemia of 13.2 mg/dl. Patient was found to have metastatic atypical hepatocellular carcinoma and L4 vertebral lesion. PTHrp was 30 pg/ml and PTH 14 pg/ml. Bone turnover marker Beta crosslaps of 405 pg/ml. 25-hydroxy vitD of 48 ng/ml and 1,25 dihydroxy vitD of 9 pg/ml. Patient expired prior to biopsy. Discussion: 4 cases of similar HCC were found in the literature. The treatment approach was resection of tumor, chemo or ablation. Hypercalcemia is controlled with reduction of the tumor burden and rarely by zolendronic acid alone. Both of presented cases were too advanced for surgery or chemo treatment. When tumor was not amendable for treatment, the hypercalcemia was not controllable long term. A small size study in japan administering 10mg alendronate via hepatic artery rather than IV route for patients with HCC showed enhancement of the apoptosis of HCC in addition to controlling hypercalcemia. An animal study on anti-PTHrp monoclonal murine antibody showed improved mortality of PTHrp producing pancreatic carcinoma (FA-6) in transplanted nude mice. Conclusion: Most of the patients with PTHrp mediated hypercalcemia have advance cancer that is not amendable for surgery or chemotherapy. A non-invasive treatment approach other than alendronate should be investigated to control PTHrp mediated hypercalcemia.

SAT-359 Hypercalcemia - Is This Sarcoidosis, Hyperparathyroidism, or Both?

Hypercalcemia (HC) is a common clinical problem. Among all causes of HC, primary hyperparathyroidism (HPT) and malignancy are the most common, accounting for >90 % of cases. We present a case of HC in a patient attributed to long-standing history of Sarcoidosis (SC) and later found to also have HPT with Parathyroid Adenoma (PA) and Vitamin D Deficiency. A 64-year-old female presented to the emergency room for social needs. She had not received medical care for the past 10 years and had known history of SC, previously treated with prednisone and methotrexate. She also noted a long-standing history of elevated calcium (Ca) up to 11 mg/dL. She was fasting for the past 1 month for spiritual reasons and was not taking any medications or supplements. Initial labs were significant for Ca of 13.2 mg/dL, Albumin 4.4 g/dL, ionized Ca 1.43 mmol/L. Creatinine was 1.1. EKG revealed T-wave inversions in V1, 2, 3. She received IV fluids and Ca improved to 11 mg/dL. HC was attributed to known history of SC. However further evaluation revealed parathyroid hormone (PTH) level high at 156 pg/mL, 25-OH Vit D level low at 8.5 ng/mL with normal 1,25 hydroxy Vit D levels at 46 pg/mL. Parathyroid sestamibi scan revealed a left parathyroid adenoma. Surgery was deferred because patient was asymptomatic and did not meet criteria for parathyroidectomy. On discharge, Ca levels remained stable and she was started on Ergocalciferol 50,000 units weekly. HC can be either parathyroid mediated, non-parathyroid mediated, or due to medications. In primary HPT, the elevated PTH levels cause increased bone resorption through activated osteoclasts and increased intestinal Ca absorption. Malignancies involving solid tumors and leukemias can lead to HC through osteolysis and osteoclasts or PTH-related peptide. Thiazide diuretics increase renal Ca absorption that lead to mild HC which can be reversed when the medication is discontinued. Other endocrine disorders that can lead to HC include thyrotoxicosis-induced bone resorption, adrenal insufficiency and pheochromocytoma. Management of hypercalcemia depends upon the level of Ca. Mild HC (Ca < 12mg/dL) is usually asymptomatic and improves with hydration. Asymptomatic or mildly symptomatic patients with chronic moderate HC (Ca 12-14 mg/dL) may not require immediate treatment. Severe HC (Ca >14mg/dL) is treated with IV hydration with normal saline (NS), calcitonin and zolendronic acid. Administration of calcitonin and NS results in substantial reduction in Ca within 12-48 hours. Although, HC was initially attributed to SC, primary HPT and low 25-OH Vit D levels also contributed to HC in this patient. Thus, it is important to evaluate patients with known HC from sarcoid for other etiologies.

MON-335 Bisphosphonate and Denosumab Refractory Hypercalcemia of Malignancy: What Else Is at Play?

Hypercalcemia of Malignancy has been historically responsive to anti-resorptive agents. However, when multiple mechanisms contribute, it may be difficult to treat with one modality. This case highlights the importance of the work up in treatment of hypercalcemia in a low PTH state. A 44 yo M with h/o high grade metastatic spindle cell neoplasm with skeletal metastasis was admitted with hypercalcemia. He reported some constipation prior to presentation, however denied confusion. His vital signs were notable for HR of 86 bpm and BP of 112/75 mmHg. Labs at admission were remarkable for an uncorrected Ca of 16.1 (8.8-10.3 ng/mL), a phosphorus (Phos) level of 3.3 mg/dL (2.5-4.5 mg/dL), a PTH level of 11 pg/mL (15-65 pg/mL), PTHrP level of 134 pg/mL (14-27 pg/mL), a 25 OH vit D level of 11 ng/mL (30-100 ng/mL), and a BUN/Cr and GFR of 34/2.38 (8-22 mg/dL/0.5-1.3 mg/dL) and 32 ml/min/m2. He was given intranasal calcitonin and ergocalciferol, then received 2mg IV of zolendronic acid, which reduced the patient’s Ca level to a nadir of 6.6 ng/mL in 5 days. On the next admission serum Ca was elevated to 15.7 ng/dL, which did not respond to zolendronic acid. Given that patient’s Ca was refractory to zolendronic acid, denosumab was given but had no response. He then underwent surgery for cord compression and was given dexamethasone (dex) 4mg IV Q6h post-op. His Ca responded quickly to dex, with a nadir to 9.2 ng/dL, however his Ca became elevated after cessation. Given response to dex, vit D 1,25 OH level was sent and was elevated at 94 pg/mL (18-72 pg/mL). In addition, given his inappropriately normal Phos level in the setting of low PTH, FGF23 was sent and came back elevated at 473 RU/mL (<180 RU/mL). This was likely due to increased bone turnover and release of FGF23. He was discharged with a Ca level of 12.5 ng/mL, however was found to have an elevated Ca to 14.9 ng/mL on presentation to clinic. Given concern that Vit D 1,25 OH, PTHrP and direct bony involvement were all contributing to his hypercalcemia, patient was started on IVF and dex IV. His calcium responded 11.5 ng/mL and was then transitioned to PO dexamethasone and plaquenil. The most likely explanation for this phenomenon is malignancy induced cytokine/PAMP release, which stimulates 1-alpha hydroxylase in tumor macrophages to convert 25 OH D to 1,25 OH D. This was supported by his elevated 1,25 OH D level and a decreased 25 OH D, which suggests that 25 OH D was used as substrate by activated macrophages. This case highlights the importance of ancillary work up of hypercalcemia when a patient’s calcium is refractory to standard anti-resorptive therapy. Moreover, it shows the need for a systematic approach when treating hypercalcemia.

Systemic Mastocytosis and Essential Thrombocythemia: Case Report and Literature Overview

Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.

Bisphosphonate Combination Therapy in the Management of Postchemotherapy Avascular Necrosis of the Femoral Head in Adolescents and Young Adults: A Retrospective Study From India

Purpose With improved survival after chemotherapy for acute lymphoblastic leukemia (ALL), it is imperative to maintain good quality of life as part of the management of post-therapy adverse effects. Avascular necrosis of the femoral head (AVNFH) is one such adverse effect. A need exists for a therapy that ameliorates discomfort, provides a productive life, is cost effective, and is joint preservative. We conducted the current study to evaluate the response to bisphosphonate in the nonsurgical management of AVNFH in adolescents and young adults (AYA) who receive treatment for ALL. Materials and Methods This is a retrospective study of 20 AYA patients—34 affected hips—who received zolendronic acid 5 mg intravenously each year along with oral alendronate 70 mg weekly for 3 years. Clinical evaluation was performed by using the Visual Analog Scale and the Harris Hip Score. Radiographs were used to classify the Ficat-Arlet stage, monitor radiologic collapse, and evaluate the rate of progression. Results Pain relief with a drop in the Visual Analog Scale score was observed at a mean duration of 5.2 weeks (range, 3 weeks to 11 weeks) after the start of therapy. Radiologic progression by one grade was observed in 12 hips (35.3%), and only one hip (2.94%) showed progression by two grades. At a mean follow-up of 50.3 months, 31 affected hips (91.1%) had a satisfactory clinical outcome and had not required any surgical intervention. The proportion of hips that required total hip arthroplasty were 0%, 5%, and 22.2% in Ficat-Arlet stage I, II, and III, respectively. Conclusion The combination of intravenous zolendronic acid and oral alendronate provides a pragmatic solution for the management of AVNFH after therapy for ALL in AYA patients. This therapy is safe, effective, and well tolerated.

Severe Hypocalcemia and Hypomagnesemia with Denosumab in Advanced Chronic Kidney Disease: Case Report and Literature Review

Background. Denosumab has become the preferred agent over zolendronic acid to help prevent skeletal-related events in patients with metastatic bone disease and multiple myeloma because it is approved for use in those with kidney dysfunction. However, denosumab has been linked to cases of hypocalcemia, particularly in those with advanced kidney disease. Case Presentation. We present the case of a patient with metastatic prostate cancer and chronic kidney disease due to obstructive nephropathy who developed severe hypocalcemia and hypomagnesemia after denosumab injection, which required intensive care unit admission, aggressive calcium supplementation, and hemodialysis assistance. We reviewed the evidence behind the safety profile of denosumab in chronic kidney disease, and we also looked at additional factors that may precipitate severe hypocalcemia with denosumab in advanced kidney disease. Conclusion. We believe that denosumab should be avoided in advanced chronic kidney disease due to the potential life-threatening, severe hypocalcemia that has been observed.