Dose Of Zoledronic Acid Research Articles

8802 A Rare Case Of Symptomatic Hypercalcemia In A Patient With Untreated Chronic Tophaceous Gout

Abstract Disclosure: S. Avula: None. A. Kumar: None. Z.J. Anderson: None. A. Chauhan: None. L.T. LaFave: None. Background: Hypercalcemia is a medical condition with abnormally high serum calcium levels. There are numerous mechanisms for the development of hypercalcemia, but gout is not well documented.Hypercalcemia attributed to Tophaceous gout is a rare phenomenon that is not well studied. Here we report a case of symptomatic hypercalcemia in a patient with a history of untreated tophaceous gout, leading to hypercalcemia and osteolytic lesions. Clinical Case: The patient is a 52-year-old male with a medical history of hypertension, rheumatoid arthritis, and tophaceous gout who immigrated from Tanzania. He presented with two weeks of abdominal pain that acutely worsened the morning of his presentation. He reported a 16-year history of tophaceous gout, for which he had been treated with allopurinol without success. On physical examination polyarticular subcutaneous nodules were present in the bilateral upper and lower extremities, primarily over the joints. There were similar lesions on the buttocks. Initial laboratory evaluation included a complete blood count which was notable for a hemoglobin of 10.3 g/dL (13.1 - 17.5 g/dL). His albumin was normal at 4 g/dl. (3.8 - 5.1 g/dl). Serum calcium was elevated at 12.9 mg/dL (8.8-10.0 mg/dL), with a serum ionized calcium level of 6.52 mg/dL(4.40-5.20 mg/dL). PTH was low at 15.8 pg/mL (16.0 - 65.0 pg/mL), and PTHrP was 2.9 pg/ml (<4.5 pg/ml). Uric acid level on admission was elevated to 11.4 mg/dL (3.4 - 7.0 mg/dL). 1-25 dihydroxy vitamin D elevated at 93.2 pg/mL (19.9 - 79.3 pg/mL). Computed tomography (CT) with intravenous contrast of the chest, abdomen, and pelvis was notable for axillary, pelvic, and inguinal lymphadenopathy concerning for lymphoproliferative or neoplastic processes. Biopsy of right inguinal node biopsy showed benign-appearing lymphoid tissue. Additional findings included multiple lobulated calcified hyperdense foci throughout the subcutaneous and muscular tissues of the buttocks with resorptive changes of the axial skeleton. Spectral CT reconstruction determined these to be uric acid deposits. Radiographs of his extremities were consistent with advanced gouty arthropathy. Infectious work-up was negative. Patient was given 3 liters of 0.9% sodium chloride. He received four doses of Calcitonin (4 units/kg) followed by one dose of Zoledronic acid 5 mg I.V. He was treated with Febuxostat, solumedrol and Azathioprine for his tophaceous gouty arthritis. Conclusion: Hypercalcemia is a commonly encountered yet a very important clinical condition. Parathyroid and malignant etiologies of hypercalcemia account for approximately 90% of cases of hypercalcemia. Gout as the inciting factor for developing hypercalcemia is a rarely documented phenomenon. This case highlights hypercalcemia as an unusual yet severe manifestation of untreated chronic gout and demonstrates the need for additional studies and reviews. Presentation: 6/2/2024

Efficacy of a single 5mg zoledronic acid infusion in preventing bone loss and fracture in postmenopausal women with breast cancer.

Chemotherapy-induced bone loss (CTIBL) is common among breast cancer patients, requiring comprehensive assessment and intervention. Zoledronic acid, a strong inhibitor of bone resorption, is effective in CTIBL management, though information on dosing and intervals, particularly the efficacy of the 5mg annual dose for osteoporosis in breast cancer patients, is limited. In this 12-month prospective observational study, 85 breast cancer patients were divided into three groups: 17 received no treatment, 17 received tamoxifen, and 51 received anastrozole or letrozole (AI). Post-surgery, patients were administered a single 5mg dose of zoledronic acid and monitored over 12months for changes in bone mineral density (BMD), fracture rates, and biochemical markers. Initially, the AI group was the oldest, averaging 59.1 ± 8.7years. At baseline, no significant differences in variables, except age, were observed. After 12months, BMD increased in all groups following a single zoledronic acid dose, with the smallest increase in the AI group at the lumbar spine: no treatment (2.4% ± 6.1%), tamoxifen (2.6% ± 3.4%), AI (0.6% ± 14.5%) (p = 0.778). CTx and P1NP levels were consistently suppressed up to 12months post-treatment, with smaller reductions in the AI group. There were no significant differences in fracture or bone metastasis rates among groups. A single infusion of 5mg zoledronic acid was effective in increasing bone density in breast cancer patients. However, AI-treated patients showed less improvement in vertebral bone mineral density and biochemical markers. Further long-term studies with larger cohorts are needed.

Severity of acute phase reaction in children receiving the first dose of zoledronic acid and the impact of the underlying condition: a cross-sectional study

IntroductionZoledronic acid (ZA), used for treatment of children with osteoporosis, can cause acute phase reaction (APR) following the first infusion. Many institutions have a policy to admit and monitor all...

Posterior scleritis following a single infusion of zoledronate for osteoporosis: A case report and literature review

Key Clinical MessageThe most frequently reported adverse reaction to zoledronic acid is an acute phase reaction resembling influenza. While rarer adverse events such as osteonecrosis of the jaw and atypical femoral fractures have gained significant recognition, the ocular adverse effects, particularly scleritis, are not yet fully comprehended. Here, we present the case of a 75‐year‐old female patient with osteoporosis who developed bilateral redness and intense eye pain 48 h after receiving a 5 mg intravenous dose of zoledronic acid. Clinical presentation suggested bilateral conjunctivitis, but treatment with levofloxacin eye drops and acyclovir ophthalmic gel exacerbated the symptoms over 2 days, predominantly affecting the left eye. Ocular ultrasonography revealed thickening of the left eyeball wall with a “T” sign, while an orbital CT scan showed increased thickness of the left sclera. Treatment with methylprednisolone 80 mg intravenous infusion twice daily led to gradual symptom improvement and eventual resolution of inflammation. This report, based on a review of relevant literature, investigates the treatment and outcomes of zoledronic acid‐induced scleritis, emphasizing the importance for clinicians to promptly identify and manage this rare and serious ocular adverse reaction.

Intermittent dosing of zoledronic acid based on bone turnover marker assessment reduces vertebral and non-vertebral fractures

Intermittent dosing of zoledronic acid based on bone turnover marker assessment reduces vertebral and non-vertebral fractures

Abstract PO1-12-10: Zoledronic acid to prevent rebound fractures after stopping adjuvant denosumab: a randomized controlled sub-study of the ABCSG-18 trial

Abstract Introduction ABCSG-18 trial showed that 60mg denosumab subcutaneously every 6 months halves fracture risk in postmenopausal patients with early breast cancer, who are treated with adjuvant aromatase inhibitors. However, it has been reported that stopping denosumab may lead to overactivation of osteoclasts resulting in so called rebound vertebral fractures. As shown previously, zoledronic acid (ZA), when given to patients of the ABCSG-18 trial after stopping denosumab prevents a high bone turnover state that can occur in some patients. Here we report the impact of a single ZA dose on bone mineral density (BMD) and fractures after stopping denosumab. Methods ABCSG-18 trial patients, who had received adjuvant denosumab were re-randomized to receive a single dose of ZA 5mg i.v. or not, 8 months +- 4 weeks after their last denosumab dose. DXA scans, lateral spine X-rays and bone turnover markers (CTX and osteocalcin) were assessed at baseline and at 6, 12 and 18 months thereafter. New clinical fractures were assessed until 18 months after randomization. Results 50 patients were randomized to either ZA (24pts) or control (26pts). All patients of the ZA arm and 25 out of 26 patients of the control arm had received 7 doses of denosumab within the ABCSG 18 trial before re-randomization. Baseline bone health factors were well balanced between the 2 arms: Baseline BMD did not differ between the two arms with regard to femoral neck (ZA: 0.817 g/cm2; SOC: 0.816g/cm2), total hip (ZA: 0.918g/cm2; SOC: 0.921g/cm2) and lumbar spine (ZA: 1.128 g/cm2; SOC 1.142 g/cm2), respectively. Relative changes in BMD differed significantly between both arms for femoral neck after 12 months (ZA: 0.5%; control: -4.98%, p 0.004) and for total hip after 6 months (ZA: -0.73%; control: -4.61%, p< 0.001) and after 12 months (ZA: -0.13%; control: -5.62%; p< 0.001). There was a trend towards a greater decline in BMD at lumbar spine after 6 months in the control arm versus the ZA arm (-3.35% vs 0.67%, p=0.052). After randomization, 3 asymptomatic fractures (lumbar vertebral and thoracic vertebral in one patient and thoracic vertebral in a second patient) occurred in the ZA arm, whereas 2 clinical fractures (one radius fracture and one lumbar vertebral fracture) occurred in the SOC arm. Conclusion A single dose of Zoledronic acid prevents high bone turnover state resulting in loss of BMD in some patients after stopping denosumab. ZA may therefore be offered to breast cancer patients with aromatase inhibitor after stopping denosumab. Citation Format: Georg Pfeiler, Christian F. Singer, Dominik Hlauschek, Manfreda Diether, Ferdinand Haslbauer, Paul Sevelda, Kristin Köck, Karl Tamussino, Arno C. Reichenauer, Florian Fitzal, Dietmar Heck, Richard Greil, Claudia Pasterk, Sonja Heibl, Walter Herz, Marija Balic, Daniel Egle, Lidija Sölkner, Michael Gnant. Zoledronic acid to prevent rebound fractures after stopping adjuvant denosumab: a randomized controlled sub-study of the ABCSG-18 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-10.

Abstract 6722: A CD33 antigen targeted Gamma Delta T-cell engager in combination with zoledronate promotes Vg9Vd2+ T cell proliferation and cytotoxicity against acute myeloid leukemia

Abstract Vγ9Vδ2+ T cell (GDT) targeted immunotherapy is of interest to harness its MHC-independent cytotoxic potential to promote anti-tumor immunity. However, it remains unclear whether GDT (1-5% of total T cells) are present at sufficient numbers to be therapeutically relevant. Accumulation of intracellular phosphoantigens promotes heterodimerization of butyrophilin (BTN) 2A1 and BTN3A1 on the cell surface, leading to TCR-mediated activation of GDT. To date, clinical trials in cancer patients have failed to demonstrate monotherapy activity using a variety of GDT activating agents, including aminobisphosphonates such as zoledronic acid (ZA), Vδ2+ targeted T cell engagers and BTN3A1 targeted antibodies. These data leave fundamental questions regarding the therapeutic potential of GDT unanswered, including whether they are present in sufficient numbers, whether the agents in question are providing adequate GDT activation, and whether GDT are being directed to tumor cell targets. The studies herein were thus designed to further understand the role of phosphoantigens, butyrophilins and antigen presenting cells (APCs) in activating GDT. Specifically, APC mediated GDT activation was studied in an in vitro co-culture system in the presence and absence of ZA or a CD33-directed GDT engager incorporating a heterodimer of BTN2A1 and BTN3A1 to dissect the contribution of phosphoantigens, butyrophilins and other costimulatory molecules on GDT proliferation and activation. To this end, while BTN2A1/3A1-Fc-CD33scFv treatment alone in T and monocyte-derived dendritic cell (mDC) co-cultures or in unfractionated PBMCs increased the frequency of GDT by 2 to 10-fold after 7-12 days, the combination with low dose ZA (0.5 to 2 μM) synergistically increased GDT proliferation by 40 to 100-fold. These results indicate that GDT proliferation relies both on the abundance of BTN2A1/3A1 heterodimers and other costimulatory signals activated by ZA. Synergistic effects of ZA and BTN2A1/3A1-Fc-CD33scFv in GDT proliferation was similarly observed in human PBMC-engrafted NSG-IL-15tg mice 12 days after treatment. Importantly, the addition of BTN2A1/3A1-Fc-CD33scFv to T (or PBMC) and CD33+ AML co-cultures enhanced both GDT proliferation and anti-leukemic activity while sparing healthy CD33+ immune cells. Collectively, these results demonstrate that GDT proliferation and effector function is dependent both upon the abundance of butyrophilin heterodimers, and other cell surface molecules which are modulated by intracellular phosphoantigen accumulation. Citation Format: Anne Y. Lai, Chunyan Wang, Dana C. Baiu, Kelsey Smith, Arpita Patel, Kinsley Evans, Noah Murr, Derek Franklin, Mahmud Hussain, Joseph Pate, Nathan Oien, Vishruti Makani, Abhinav Shukla, Keith Wilson, George Fromm, Taylor H. Schreiber, Jenny E. Gumperz, Suresh De Silva. A CD33 antigen targeted Gamma Delta T-cell engager in combination with zoledronate promotes Vg9Vd2+ T cell proliferation and cytotoxicity against acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6722.

Costs to Medicare of Nonrecommended Bone-Modifying Agent Use for Castration-Sensitive Prostate Cancer.

Bone-modifying agents (BMAs) do not prevent skeletal-related events among patients with castration-sensitive prostate cancer (CSPC), but many patients receive BMAs unnecessarily. The costs to Medicare from overuse have not been assessed. We used linked SEER-Medicare data 2011-2015 to measure the frequency and number of doses of zoledronic acid (ZA) and denosumab received during CSPC (between diagnosis and initiation of metastatic, castration resistant prostate cancer therapy). We estimated excess BMA among patients who received BMA therapy for CSPC and did not have an indication for osteoporosis fracture prevention. We used the Medicare fee schedule for drug prices and peer-reviewed sources to estimate adverse event frequencies and costs. Median CSPC duration was 387 days (IQR, 253-573), during which time 42% of patients received ≥one dose of denosumab (mean doses, 7) and 18% received ≥one dose of ZA (mean doses, 7). Thirty-eight percent of those receiving denosumab and 47% of those receiving ZA had a history of osteoporosis, osteopenia, spine or hip fracture, or hypercalcemia. The estimated, annual excess BMA cost to Medicare was $44,105,041 in US dollars (USD), composed of $43,303,078 USD and $45,512 USD in drug costs for denosumab and ZA, respectively, and $682,865 USD and $75,585 USD in adverse event costs, respectively. In one-way sensitivity analysis, the estimate was most sensitive to denosumab dosing frequency (estimate range, $28,469,237 USD-$98,830,351 USD) and duration of CSPC (estimate range, $36,823,311 USD-$99,015,908 USD). BMA overuse in CSPC incurs substantial cost to Medicare, largely because of denosumab drug costs. Excess costs may be reduced by greater adherence to guideline-concordant BMA use.

Depressive Disorder in Primary Hyperparathyroidism and Effects of Surgery in Elderly Patients: Case Series

Background: Patients with primary hyperparathyroidism (PHPT) often present nonspecific symptoms such as major depressive disorder and psychosis. Calcium plays a role in the pathogenesis of psychiatric symptoms by determining changes in monoamine metabolism in the central nervous system, thereby modifying neurotransmission and resulting in mood and cognitive alterations. Case series: This report presents a case series of 3 patients; 70-year-old, 78 year- old and 94 year-old women with PHPT and severe depression symptoms and its response to parathyroidectomy. The patients were a poor historian. Results of preoperative laboratory tests showed an increased serum calcium level (11.15mg/dL, 10.9 mg/dL and 11.4 mg/dL- reference range 8.4-10.2 mg/dL). A repeat serum calcium test confirmed hypercalcemia with concurrent elevated intact parathyroid hormone level. Two patients were undergone at parathyroidectomy. A 94 year-old patient refuse surgical approach and was efficacy treated with a single dose of zoledronic acid. Therefore, the patients underwent parathyroidectomy two months after procedure had a clinical improvement on depressive symptoms. There was any recurrent laryngeal nerve injury or recurrent PHTP. Conclusion: The presence of a long-standing depressive disorder unresponsive to medical therapy may suggest an organic disorder such as chronic hypercalcemia which may be secondary to PHPT. Surgical intervention in these selected cases can assist medical therapy in the improvement of depressive symptoms.

Cost to Medicare from bone modifying agent overuse in castration-sensitive prostate cancer.

12 Background: Bone modifying agents (BMAs) prevent skeletal related events among patients with castration-resistant prostate cancer (mCRPC) and bone metastasis, but not among patients with castration sensitive prostate cancer (CSPC). However, approximately 1/3 of Medicare patients with CSPC receive BMAs unnecessarily, and the costs to Medicare resulting from this overuse have not been assessed. Methods: We used linked SEER registry and Medicare claims data for persons diagnosed with stage IV prostate adenocarcinoma during 2011-2015, identified those who subsequently received a cancer therapy used exclusively for mCRPC, and measured 1) the number of doses of zoledronic acid and denosumab received between diagnosis and initiation of mCRPC therapy and 2) presence of patient comorbidities which may warrant BMA therapy for fragility fracture prevention (eg., osteoporosis, osteopenia). We estimated excess BMA costs to Medicare by assessing the proportion of patients who received BMA therapy during their CSPC interval and did NOT have an indication for fragility fracture prevention, using the Medicare fee schedule for drug prices. We estimated adverse event costs using event frequency and costs estimates drawn from the peer-reviewed literature. The modeled outcome was the cost to Medicare from excess BMA use for the cohort of patients diagnosed with stage IV prostate cancer each calendar year. We conducted one-way sensitivity analysis for each model input by using the highest and lowest estimates available from peer-reviewed sources, monthly vs. every-three-month dosing frequencies for both drugs, and by +/-20% for all other inputs. Results: The median time from diagnosis to initiation of CRPC therapy was 387 days (IQR 253,573), during which time 42% received >=1 dose of denosumab (mean doses = 7) and 18% received >=1 dose of zoledronic acid (mean doses = 7). The estimated, annual excess BMA cost to Medicare was $45,392,377, comprised of $43,303,078 and $45,512 in drug costs for denosumab and zoledronic acid, respectively, and $1,625,869 and $419,917 in adverse event costs, respectively. The estimate was most sensitive to denosumab administration schedule (monthly vs. every-three-month) [estimate range: $29,487,144 - $101,060,692] and the duration of CSPC [estimate range: $37,853,180 - $101,754,921]. Conclusions: BMA overuse in CSPC incurs substantial cost to Medicare, largely due to denosumab drug costs. Our sensitivity analyses suggest we may overestimate costs if denosumab dosing frequency is now lower than during our observation period (eg., if more providers now use 3-month dosing), and we may underestimate costs if patients now experience CSPC for a longer duration (a plausible consequence from the introduction of ARSi therapy for CSPC in the post-LATITUDE era). Avoidable costs and toxicity may be reduced by greater adherence to guideline-concordant use of BMAs.

SAT251 A Tale Of Two Calcium Disorders: Hypercalcemia In Pregnancy

Abstract Disclosure: M. Stezzi: None. C. Hayes: None. M. Misiura: None. E. Skutnik: None. G.A. Perilli: None. S. Koshy: None. Introduction: Hypercalcemia in pregnancy is a rare event that can be difficult to diagnose given nonspecific presentation of symptoms and distinguishing it from typical symptoms of pregnancy. Primary hyperparathyroidism is the leading cause of hypercalcemia in pregnancy. Management presents a challenge as drug treatment and surgery options are limited. We present two cases of the uncommon non PTH mediated hypercalcemia in pregnancy. Case 1: A 31-year-old pregnant female G1P0 with no past medical history presented at 38 weeks from her obstetrician’s office for elevated blood pressures. She was admitted for preeclampsia without severe features. On initial labs, corrected calcium level was elevated 14.6 mg/dl (8.5-10.1). Her PTH was appropriately suppressed at <6.3 pg/mL. The patient’s PTHrP was slightly elevated at 3.6 pmol/L (0.0-3.4). She was treated with calcitonin. Due to her preeclampsia, labor was induced with subsequent cesarian section. The day after, the corrected calcium level markedly improved to 8.7 mg/dL. Her hypercalcemia was secondary to the humoral response of pregnancy caused by PTHrP produced by the placenta. Case 2: A 38-year-old pregnant female G3P1011 with a past medical history of hypertension presented at 35 weeks and 6 days after getting an MRI for back pain which showed evidence of metastases and a burst fracture of the T9 vertebra. A left breast mass was palpable on exam. On arrival, labs showed a corrected calcium 12.5 mg/dL. Further work up revealed appropriately suppressed PTH <6.3 pg/mL and PTHrP elevated at 29 pmol/L (0.0-3.4). Corrected calcium peaked at 14.5 mg/dL. Cesarian section was performed. Treatment was initiated with four doses of calcitonin and a dose of zoledronic acid. After two days of treatment, corrected calcium was 12.2 mg/dL. Corrected calcium measured 9.3 mg/dL at discharge. Biopsy revealed invasive ductal cell carcinoma. She was also found to have diffuse bone metastasis to the spine and liver. Her hypercalcemia was secondary to invasive ductal cell carcinoma with metastasis. Discussion: Hypercalcemia in pregnancy is difficult to diagnose and treat due to nonspecific maternal symptoms and changes in homeostasis of calcium and vitamin D. Management is difficult as medications used in hypercalcemia outside of pregnancy may be contraindicated. Calcitonin has been used safely in pregnancy. Bisphosphonates are used for life threatening cases of hypercalcemia due lack of long-term data on fetal effects. Short term effects of bisphosphonates are transient neonatal hypocalcemia and low birth weight. Denosumab is not used in pregnancy. Cinacalcet is used in primary hyperparathyroidism. Cinacalcet has been safely used in pregnancy in animal studies. In conclusion, hypercalcemia in pregnancy requires prompt diagnosis and treatment with the mainstay acceptable therapies for non PTH mediated hypercalcemia being intravenous fluids and calcitonin. Presentation: Saturday, June 17, 2023

FRI693 Pthrp Mediated Hypercalcemia In A Patient With Recurrent Hepatocellular Carcinoma

Abstract Disclosure: D. Bondarenko: None. M. Ahmad: None. M. Mack: None. P. Ucciferro: None. Background: Humoral hypercalcemia is seen in 30 percent of cancer patients, most commonly driven by parathyroid hormone related peptide (PTHrP) production, osteolytic cytokine production, and 1,25-OH vitamin D production. The most common malignancies associated with PTHrP mediated hypercalcemia are squamous cell carcinomas and breast cancer. Less often hepatocellular cancer presents with hypercalcemia. We describe the case of a patient presenting with hepatocellular carcinoma presenting with recurrent episodes of severe hypercalcemia due to excessive PTHrP production. Clinical Case: The patient was a 68-year-old male with a past medical history of recurrent hepatocellular carcinoma with liver transplant in the past and type 2 diabetes mellitus who presented to the emergency department (ED) for one day of altered mental status. The patient was noted to be extremely agitated and confused by his home health aide and EMS was called. In the ED the patient’s vital signs were as follows: blood pressure of 196/80 mmHg, heart rate of 82 beats per minute, respiratory rate of 18 breaths per minute and temperature of 36.6 degrees Celsius. Initial lab work showed: calcium 13.5 mg/dL, albumin 4.2 g/dL, ionized calcium of 1.63 mmol/L, creatinine 0.99 mg/dL (baseline 0.5 mg/dL), glucose of 438 mg/dL, bicarbonate 23 mmol/L, anion gap 19, and beta hydroxybutyrate 51 mg/dL. Hypercalcemia workup revealed a suppressed PTH of 5 pg/mL (normal 11-67 pg), normal 25-OH vitamin D 43.6 ng/ml (normal 30-100 ng/ml), normal 1,25-OH vitamin D 38 pg/ml (normal 18-72 pg/ml), and elevated PTHrp 36 pg/ml (normal 11-20 pg/ml). The patient was started on aggressive IV fluid resuscitation with normal saline, administered a one-time dose of zoledronic acid and administered a three-day course of calcitonin. For his significant hyperglycemia the patient was started on an insulin infusion and was eventually transitioned to his home basal bolus insulin regimen. On discharge, the patient was scheduled with his oncologist to begin denosumab as an outpatient; however, he chose a palliative approach due to the terminal nature of his disease and recurrent hospitalizations for hypercalcemia. Conclusion: Hypercalcemia of malignancy is common in many different carcinomas with squamous cell cancer, renal cell cancer, breast cancer and multiple myeloma being commonly associated with this phenomenon. Reports of hepatocellular carcinoma associated with hypercalcemia are less common and occur in only 4-8 % of cases. With this case report, we hope to highlight PTHrP as a potential mechanism of humoral hypercalcemia in patients with hepatocellular carcinoma and propose denosumab as a possible treatment for patients with refractory hypercalcemia of malignancy. Presentation: Friday, June 16, 2023

THU432 Severe Osteoporosis Associated With A Novel Plastin 3 (PLS3) Mutation

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. S.M. Gandhi: None. E.S. Nylen: None. Early Onset Osteoporosis (EOOP) affects children and young adults and can be caused by endocrinopathies, chronic medical conditions, nutritional deficiencies, and/or genetic mutations. The most common inherited cause is osteogenesis imperfecta(OI), and a rare variant linked to OI includes a defect in the X chromosomal gene encoding Plastin 3 (PLS3). In our case, a 34-year-old male was referred for severe osteoporosis. He had been diagnosed with osteopenia at age 21. At age 24, imaging revealed multiple vertebral compression fractures and DXA scan confirmed severe osteoporosis. He required L3-L5 kyphoplasty and started on oral bisphosphonates for presumed OI despite negative gene mutation (i.e., COL1A1/COL1A2). He continued treatment for only 2 years. 8 years later, he had persistent osteoporosis (DXA L2-4 Z-score -3.6, LFN Z-score -3.2). He had no evidence of kyphosis or scoliosis and no extraskeletal manifestations such as blue-grey sclera or any dysmorphic features. The workup was negative for secondary causes of EOOP and he denied a family history of osteoporosis. Labs showed normal 24-hour urine calcium, bone markers, and bone Alkaline Phosphatase. Karyotyping showed normal XY and gene analysis was again negative for OI. He started treatment with intravenous Zoledronic acid, however, had a 2-year gap between doses initially causing BMD to drop by 6.5% in L2-L4 (Z -4.1) and by 5.7% in LFN (Z -3.1). Subsequently, he received a total of 5 doses of Zoledronic acid to date and had no further fractures. DXA significantly improved by 10.4% in L2-4 (Z -2.6), and 16.3% in LFN (Z -2.0). Repeated expanded gene testing showed a novel PLS3 hemizygous mutation (deletion at site C.234_237+10del of Exon 3). This case demonstrates a novel PLS3 mutation variant to be a plausible cause of adulthood EOOP which was responsive to bisphosphonate treatment. PLS3 is an F-actin binding and bundling protein involved in cytoskeletal remodeling and may have roles in calcium homeostasis, cell migration, endocytosis, DNA repair, and membrane trafficking. Currently, less than 30 loss of function variants of PLS3 have been identified and all lead to severe osteoporosis- particularly in children. However, our patient’s known onset of bone loss occurred much later- in his twenties and he had no evidence of extra-skeletal manifestations. The cause for such late presentation is unclear but may be attributed to this specific variant of PLS3. This case highlights that PLS3 mutation should be on the differential for EOOP even in early adulthood. Our patient’s BMD has markedly improved with bisphosphonates and he sustained no further fractures after starting therapy. Timely diagnosis and earlier detection will allow for appropriate genetic counseling, earlier screening, and treatment of affected family members. Presentation: Thursday, June 15, 2023

THU445 Complicated Course And Management After Denosumab Discontinuation: A Case Report

Abstract Disclosure: I. Arora: None. L. Ceglia: None. Background: Discontinuation of denosumab (DMAb) can lead to rapid bone loss and sometimes multiple vertebral fractures (VFx). Here we present such a case and related challenges in management. Case: A 56-year-old perimenopausal female presented for management of osteoporosis (OP) complicated by multiple VFx following a missed dose of DMAb in 8/2020. Past bone health history was notable for treatment with alendronate for approximately 11 years as a premenopausal woman. During a drug “holiday” in 2015, she was found to have a decline in bone mineral density (BMD). She was advised to start treatment with DMAb in 8/2016. She was adherent to DMAb injections for 4 years but missed a dose in 8/2020 due to the COVID-19 pandemic. In 1/2021, she developed back pain with no trauma and was diagnosed with VFx of T7, T10 and T12. She underwent vertebroplasty of all 3 vertebrae by 2/2021. DMAb was resumed in 2/2021 and 8/2021. Labs were only notable for hypercalciuria for which hydrochlorothiazide (HCTZ) was initiated. In 11/2021 she presented with new symptomatic VFx of T5, T9 and T11. In 12/2021 (3 weeks post 3 new VFx), serum fasting C-telopeptide (CTX) was 79 pg/mL. Teriparatide or abaloparatide were avoided due to hypercalciuria and potential BMD losses with this transition. Thus in 1/2022, she started romosozumab (ROMO) in an attempt to prevent new VFx. CTX was initially 78 pg/mL and rose rapidly over 3 months to 325 pg/mL with new back pain in 4/2022. No new VFx were detected; however, ROMO was discontinued due to the rise in CTX level. In 5/2022, she received a dose of zoledronic acid (ZOL). It suppressed CTX from 325 to 131 pg/mL by 6/2022. She received another 2 doses of ZOL in 8/2022 and 11/2022 due to rebound rises in CTX. Of note, as she reported ongoing menopausal complaints, transdermal low-dose estradiol therapy was started in 11/2022. She has not had a new VFx in more than 1 year. Hypercalciuria persisted throughout 2022 requiring rising doses of (HCTZ). DXA in 12/2022 was stable vs. 12/2021 without evidence of significant BMD loss. Discussion: This case not only highlights the known risk for multiple VFx in a patient discontinuing long-term DMAb treatment (4 years), but also the risks for such VFx complications in women of younger age during menopausal transition and a history of vertebroplasty. In addition, this report does not support transitioning from long-term DMAb to ROMO in order to prevent a rapid increase in the bone resorption marker, CTX. Rather, treatment with ZOL every 12 weeks based on frequent CTX monitoring successfully maintained BMD stable following long-term DMAb discontinuation. Presentation: Thursday, June 15, 2023

SAT245 Hips Don’t Lie: A Case Of Peri-Prosthetic Pseudotumor Leading To Hypercalcemia After Total Hip Replacement.

Abstract Disclosure: F. Sotomayor: None. H. Whitlatch: None. Background: Peri-prosthetic pseudotumors are well described, yet rare complications of total hip replacement. They can present as destructive or granulomatous lesions. We present the first documented case of 1,25 vitamin D-mediated severe hypercalcemia caused by a periprosthetic granuloma. Case: A 62-year-old man with a history of osteoporosis, ankylosing spondylitis presented with hypercalcemia (calcium 12.2 mg/dL) on routine laboratory testing. He had a history of bilateral cement hip arthroplasty in 1981 followed by multiple bilateral revisions - three revisions of left hip arthroplasty, one revision of right hip arthropasty. Biochemical evaluation included PTH 5 pg/mL (8 - 54 pg/mL), PTHrP 2.7 pmol/L (0.0 - 2.3 pmol/L), vitamin D-25 59 ng/mL (20-80 ng/mL), a negative Quantiferon TB Gold, and normal serum protein electrophoresis. 1,25 Vitamin D was elevated at 280.5 pg/mL (19.9-79.3 pg/mL). During investigation of 1,25 vitamin D-mediated hypercalcemia, he received a dose of zoledronic acid with transient improvement in hypercalcemia. ACE was negative and CT chest and abdomen was without evidence of granulomatous disease. A whole-body PET scan showed increased metabolic activity surrounding the right femoral and acetabular components with a broad zone of osteolysis in the proximal femur and increased metabolic activity surrounding the left greater trochanter. These findings were concerning for inflammatory granuloma formation. He was prescribed prednisone 30 mg daily with rapid normalization of serum calcium. Prednisone was gradually tapered to 10 mg daily with maintenance of normocalcemia. Discussion: Pseudotumors are an uncommon complication of total hip arthroplasty. These are described as non-infectious and non-neoplastic adverse soft tissue reactions to implants. They manifest as destructive or granulomatous periprosthetic lesion. They cause osteolysis, erosions, pathological fractures, and dislocations. Their formation is due to foreign body reaction to polyethylene, methylmethacrylate, cement or metal adjacent to the joint implant. Associated inflammation leads to macrophage activation, prostaglandin release, and osteolysis. Histologically, they are characterized by the presence of macrophages, extensive coagulation necrosis, lymphocytes, eosinophilic infiltration and granulomatous reaction. While non-malignant, they can cause extensive bony destruction and may require complex revision surgery. To date, this is the first reported case of hypercalcemia due to excess 1,25 vitamin D caused by a periprosthetic granuloma. Conclusion: Hypercalcemia is a well-described complication of granulomatous diseases, including sarcoidosis, mycobacterium infection, and lymphoma. In patients with a history of arthroplasty, we recommend adding peri-prosthetic pseudotumors to the differential diagnosis of 1,25 vitamin D mediated hypercalcemia. Presentation: Saturday, June 17, 2023

SAT253 A Rare Case Of Osteolytic Hypercalcemia Of Malignancy In Acute Myeloid Leukemia

Abstract Disclosure: S. Elahi: None. S. Baim: None. Introduction: Acute myeloid leukemia (AML) and other leukemias do not commonly induce hypercalcemia of malignancy (HCM). Limited previous reports of AML-related HCM have largely attributed cases to inflammatory-cytokine-mediated osteoclast activation, with rare reports of calcitriol-mediated HCM and ectopic parathyroid hormone (PTH) production. We describe an unusual case of AML-induced HCM caused by direct leukemic bone invasion, which responded to bisphosphonate therapy. Case Presentation: A 59-year-old female presented with spontaneous bruising and severe leukocytosis concerning for AML. The diagnosis was confirmed by flow cytometry and bone marrow biopsy. Imaging did not reveal any gross destructive bone lesions, but showed soft tissue nodules in the lumbar region which biopsy revealed to be myeloid sarcoma. Prior to initiation of chemotherapy, the patient developed severe hypercalcemia that was treated with aggressive intravenous hydration and zoledronic acid. Intrathecal chemotherapy and high-dose glucocorticoid therapy were initiated thereafter with normalization of serum calcium levels. PTH levels were suppressed. Calcitriol and PTHrP were below normal and undetectable, respectively. Bone turnover markers (C-telopeptide and bone-specific alkaline phosphatase) were significantly elevated prior to administration of zoledronic acid and normalized post-therapy. Calcium levels did not rebound after several interruptions in chemotherapy. Bone marrow biopsy showed focal areas of erosion in trabecular bone consistent with diffuse microscopic osteolytic disease. The patient developed bisphosphonate-induced hypocalcemia following treatment with zoledronic acid, which normalized with treatment with oral calcium carbonate. Discussion: Hypercalcemia of malignancy is a very unusual consequence of AML. No currently-published reports of this phenomenon have described biopsy-proven diffuse microscopic bone erosion associated with AML. We attribute our patient’s severe HCM to large-scale focal bone erosion by AML, independent of and/or associated with concurrent bone resorption mediated by inflammatory cytokines. A single dose of zoledronic acid, a potent suppressor of bone remodeling, achieved long term control of calcium for our patient despite interruption of chemotherapy. Bisphosphonate therapy should be considered an early treatment of HCM in patients with AML due to several potential mechanisms that result in direct calcium release from the skeleton. Presentation: Saturday, June 17, 2023

THU443 Acute Iridocyclitis Associated With Intravenous Zoledronic Acid

Abstract Disclosure: A.R. Ankireddypalli: None. S.D. Sibley: None. Introduction: Bisphosphonates are widely used for osteoporosis. Intravenous (IV) zoledronic acid (ZA) is frequently prescribed in cases of oral bisphosphonate intolerance or noncompliance. Well known immediate ZA side effects include flu-like symptoms such as nausea, myalgias and fever. Here we report a case of a rare side effect of acute anterior uveitis following initial ZA dosing. CASE: A 71-year-old female was diagnosed with osteoporosis; DEXA scan had lowest T score of -2.6 at the lumbar spine. Vitamin D level was 10 ng/mL. She received calcium and vitamin D supplementation. Two months later vitamin D level was 31 ng/mL. ZA was recommended due to difficulty with adherence to oral bisphosphonate. Five days after infusion she presented to our emergency department (ED) with progressive symptoms of bilateral eye itching, redness, excessive tearing, blurry vision, photosensitivity, floaters, pain and headaches that had begun 1 day post infusion. She’d had 2 prior outside ED visits for these symptoms and received polymyxin B and later ofloxacin eye drops which did not relieve them. She denied fever, chills, arthralgias and myalgia. She denied any prior known autoimmune disorder or prior history of eye symptoms. On examination she was afebrile and had bilateral conjunctival injection, excess tearing and watery discharge. She was discharged with olopatadine eye drops and cetirizine, diagnosed with allergic conjunctivitis, and referred to ophthalmology. On ophthalmic exam 7 days after her infusion, visual acuity was 20/60 in the right eye, and 20/60 in the left eye. Intraocular pressure was 12 mmHg in the right eye and 16 mmHg in the left eye. Slit lamp eye exam showed diffuse conjunctival injection of the right eye, mild corneal endothelial folds, and flare with cells in anterior chamber and synechiae posterior to the iris. Right acute iridocyclitis was diagnosed, she received prednisolone eye drops and cyclopentolate eye drops. Symptoms improved in 1 week with almost complete resolution after 3 weeks of therapy. She has not had a recurrence of these symptoms; she has declined future treatment with ZA. Conclusion: ZA-associated ocular inflammation is a rare but serious side effect. This adverse effect has been hypothesized to be associated with increased levels of pro-inflammatory cytokines including Interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha. As with other acute phase reactions to ZA, it does not appear that ocular inflammation tends to recur with subsequent ZA. Optimizing vitamin D levels prior to treatment may help to prevent this condition. There is some evidence for higher rates of acute phase reaction in patients with lower levels of vitamin D but this patient’s vitamin D status was adequate at the time of treatment. Clinicians should be aware of the rare occurrence of post-ZA ocular inflammation. Early recognition and prompt treatment are essential. Presentation: Thursday, June 15, 2023

Optimization of the dosage regimen of zoledronic acid with a kinetic-pharmacodynamic model and exposure-response analysis.

Purpose: In order to support the dose optimization of zoledronic acid, the kinetic-pharmacodynamic model and exposure-response analysis were used to describe the changes in bone mineral density in different doses of zoledronic acid and establish the relationship between dose and acute phase reaction. Methods: Data were extracted from literature in accessible public databases. The kinetic-pharmacodynamic model was developed based on the above data using the NONMEM package to estimate parameters describing the relationship between the dose of zoledronic acid and bone mineral density. Exposure-response analysis was developed to establish the relationship between dose and acute phase reaction. Model evaluation was performed using goodness-of-fit, coefficient of variation (CV%). And sensitivity analyses were performed to assess the necessity of related parameters. Then the established model was used to simulate the changes of bone mineral density under different administration regimens, and the literature data was verified. Results: The kinetic-pharmacodynamic model successfully described zoledronic acid dose and change of bone mineral density in osteoporosis patients, with coefficient of variation of most less than 71.5%. The exposure-response analysis showed the incidence of acute phase reaction is dose-dependent. The bone mineral density was simulated based on the developed kinetic-pharmacodynamic model. And the simulated change of bone mineral density and the incidence of acute phase reaction could be helpful to propose a dosage regimen. Conclusion: Overall, the kinetic-pharmacodynamic model described changes of bone mineral density in different doses of zoledronic acid in vivo. And, the model and the exposure-response analysis also showed to provide the assessment of dose-response relationship for zoledronic acid.

Effects of low dose bisphosphonates treatment on the mandibular bone in rats with and without mini-implants application: an experimental model

Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a pathological condition observed in patients underwent oral surgical procedures during bisphosphonates treatment. Although several studies have focused on the BRONJ, the exact pathophysiological pathways remain still unclear. In this study we aimed to observe the effects of the low-dose bisphosphonates administration on mandibular bone of rats with and without mini-implants application. For this study we used 28 male Wistar rats, divided in in two groups: 1) control group, treated with saline solution (n = 14 rats); 2) ZA group, treated with low dose zoledronic acid (n=14 rats). After 6 weeks of treatment, the half of each group underwent mini-implant application. All rats were sacrificed and their mandibles were analyzed by light microscopy and scanning electron microscopy (SEM). Our data have shown a healthy bone tissue of control group both with and without mini-implant application. In the treated group empty osteocyte lacunae have been observed and they slightly increase in rats with mini-implant application. Although that, no bone exposition has been observed. By that, during low dose zoledronic acid treatment we can observe the presence of empty osteocytes lacunae, also called “primary lesion”, that not seem to be sufficient alone to determine osteonecrosis of the jaw spontaneously or even after mini-implant application.

Hypocalcemia in Children with Osteogenesis Imperfecta Treated with Intravenous Zoledronic Acid

Background: Bisphosphonates (Pamidronate and Zoledronic acid) mainly used for the treatment of childhood osteoporosis such as osteogenesis imperfecta have been associated with adverse effects ranging from acute phase response, hypocalcemia, musculoskeletal pain and up to serious side effects such as osteonecrosis of the jaw. In this report, we describe the prevalence of hypocalcemia among Saudi children treated with Zoledronic acid. Method: The biochemical profile of 13 Saudi children with osteogenesis imperfecta treated with Zoledronic acid was reviewed. The bone profile including calcium and phosphorus levels were monitored before and 4-24 hours after Zoledronic acid administration. The annual total Zoledronic acid dose was 0.1 mg/kg/year. Results: Post therapy, 46% of the treated children had mild hypocalcemia and 15% had mild hypophosphatemia. None of the children had hypocalcemic or hypophosphatemic signs or symptoms. No reports of seizure or tetany or muscle spasm. Conclusion: Hypocalcemia associated with Zoledronic acid administration is common, however mild. Close monitoring and calcium supplementation might be needed.