Intravenous Bisphosphonates Research Articles

Role of intravenous zoledronic acid in management of giant cell tumor of bone- A prospective, randomized, clinical, radiological and electron microscopic analysis

BackgroundThe primary treatment of Giant cell tumor of bone is surgical management. Bisphosphonates are antiresorptive drugs which inhibit osteoclast mediated bone resorption and shown to have inhibitory effect on various tumors. The present study aims to establish clinical, ultrastructural and radiological response of intravenous zoledronic acid on giant cell tumor of bone. MethodologyDesign - Prospective randomized controlled study. A group of 30 patients of GCT bone were randomized into two equal groups. Patients in control group did not receive any adjuvant therapy before surgery. Patients in bisphosphonate group received three doses of intravenous zoledronic acid at four weeks interval prior to definitive surgery. The evaluation was done based on size of swelling, VAS score, plain radiograph, MRI and histopathological and Transmission electron microscopic examination findings. ResultsSignificant reduction in VAS score (from mean 5.33 to 1.8), increased mineralization particularly at periphery of lesion in plain radiograph, statistically significant increase in mean apoptotic index, P value < 0.0001 (mean 41.46 in bisphosphonate group and 6.06 in control group) was noted in bisphosphonate group. No significant change in tumor volume is noted in MRI. No significant side effects were noted. DiscussionOne distinctive feature of pathogenesis of GCT bone is osteoclastogenesis which causes extensive bone destruction. Use of intravenous Zoledronic acid counteracts this bone destruction. Further, possible antiangiogenic effect of intravenous bisphosphonates inhibits tumor growth and provides symptomatic improvement. ConclusionIV Zoledronic acid alleviates pain, produce sclerosis and induce apoptosis hence decrease the rate of tumor progression and decrease the rate of local bone destruction, hence they are useful adjuvant to surgery in GCT.

MEDICATION RELATED OSTEONECROSIS OF THE JAW CO-EXISTENT WITH OTHER LESIONS

<h3>Background</h3> Medication related osteonecrosis of the jaw (MRONJ) is a severe adverse drug reaction, consisting of progressive bone destruction in the maxillofacial region. Although its pathophysiology is not completely understood, 2 pharmacologic agents can cause MRONJ: antiresorptive agents, such as bisphosphonates (BP) and denosumab; and antiangiogenic agents. The diagnosis and staging of MRONJ is based on clinical and radiographic findings. <h3>Discussion/Conclusions</h3> We present 2 cases of MRONJ overlapped with 2 different lesions in the mandible. The first case is of a 63-year-old female patient undergoing intravenous bisphosphonate therapy for multiple myeloma. Cone beam computed tomography (CBCT) showed an ill-defined osteolytic lesion in the right ramus with diffuse sclerosis. The case was confirmed as multiple myeloma overlapping with MRONJ. The second case is of a 74-year-old female patient with a history of MRONJ in the right retromolar area 9 years ago, and managed with surgery as well as extraction of teeth #31 in 2012, which resulted in complete healing. The patient presented last month with pain in tooth #30, for which endodontic treatment was planned. However, CBCT showed a periapical lesion around the tooth, with severe sclerosis and a sequestrum in the adjacent area of previous MRONJ lesion. Endodontic treatment was accomplished, and surgical debridement of the necrotic bone and adjacent area was planned. MRONJ can coexist with other lesions, including malignant neoplasms and periapical pathoses. Overlapping of these lesions with MRONJ might lead to misdiagnosis and inadequate management. Correlation of medical history, clinical findings, and careful radiographic interpretation can lead to the appropriate diagnosis and management of patients with these lesions.

Treatment Effects of Bisphosphonates and Denosumab on Survival and Refracture from Real-World Data of Hip-Fractured Patients.

We examined differences in patients' survival after hip fracture (HF) and risk for subsequent HF among patients treated with oral and intravenous bisphosphonates (oBPs, iBPs), denosumab (DMAB), and patients without therapy. We used data from all patients in Austria aged ≥ 50 who sustained a HF between 2012 and 2017 and were followed for a subsequent HF and all-cause mortality until 2017. Antiosteoporotic treatment-naïve patients, who were incident users of BPs and DMAB, were eligible for propensity score matching 1:1 to obtain comparable user groups. We applied competing risk approach and calculated cumulative incidence functions and subdistribution-hazards for refracture. Cox regression models were applied for mortality risk. A total of 54,145 hip-fractured patients were observed (1919 oBPs; 1870 iBPs; 555 DMAB users; and 42,795 untreated patients were included in the matched sets) and followed up for a median (interquartile range) of 22.6months (26.2). Patients treated with antiresorptive medications had significantly longer survival time than patients without treatment. Receiving treatment significantly decreased a hazard of dying only for women by 17% for iBPs (HR 0.83, 95% CI 0.71-0.98, p = 0.023). For DMAB and oBPs, the results were not statistically significant. Higher risk of a subsequent HF was observed in women on DMAB (SHR 1.77, 95% CI 1.08-2.91) and on iBP (SHR 1.81, 95% CI 1.35-2.41), and in men on oBPs (SHR 2.89, 95% CI 1.58-5.30). Patients who were treated with antiresorptive medications after HF had longer survival than patients without treatment, highlighting the importance of initiation of antiresorptive treatment after HF.

Prevalence and risk factors of medication-related osteonecrosis of the jaw in osteoporotic and breast cancer patients: a cross-sectional study.

Medication-related osteonecrosis of the jaw (MRONJ) has been reported as a side effect of bisphosphonate (BP). The aim of this study was to identify the prevalence of MRONJ in women taking BP for osteoporosis and for metastatic breast cancer and correlate it with risk factors and biochemical markers of bone metabolism. Patients taking oral or intravenous BP with osteoporosis (G1; n = 153; median 72.8years) and with metastatic breast cancer (G2; n = 134; median 58.2years) had their hospital charts reviewed, were submitted to dental inspection, and answered a health questionnaire. Fasting blood samples were randomly collected from both groups to measure osteocalcin, carboxy-terminal cross-linking telopeptide of type I collagen, intact parathyroid hormone and procollagen type 1 amino-terminal propeptide (P1NP), 25 hydroxyvitamin D (25OHD), creatinine, and total calcium. G1 was older (p = 0.001) and had more cases of diabetes (p = 0.043). P1NP was higher (p = 0.022) and 25OHD lower (p = 0.004) in G2 compared with G1. MRONJ was not found in the G1, whereas 4 cases (3%) were detected in G2. Positive risk factors for MRONJ were number of BP doses and number of visits to the dentist and dental extractions. The biochemical parameters, however, could not identify those who developed MRONJ. The prevalence of MRONJ was 3% in women with metastatic breast cancer receiving BP. No cases were identified in women receiving oral BP chronically for osteoporosis. P1NP was higher in women with metastatic breast cancer, even during treatment with antiresorptives, but could not differentiate those with MRONJ.

The Ketogenic Diet and Its Effect on Bone Mineral Density: A Retrospective Observational Cohort Study.

During long-term follow-up of children treated with the ketogenic diet therapy (KDT) have an increased incidence of bone fractures. However, the exact contribution of KDT to a decreased bone mineral density (BMD) remains unclear. This study aimed to evaluate (changes in) BMD in children treated with KDT and to evaluate whether intravenous bisphosphonate therapy may be effective. In this retrospective, observational cohort study, all children treated with KDT from 2010 until 2018 at the Radboudumc Amalia Children's hospital were included. Patients who were on KDT for more than 6 months and who had at least two dual-energy X-ray (DXA)-scans were eligible for inclusion for longitudinal analysis. Z-scores of DXA-scans were compared over the course of time. In 34 out of 68 patients, one or more lumbar DXA-scans were performed, with a mean lumbar Z-score of -1.32 ± 1.74. Of these 68 patients, 8.8% got a fracture during KDT, and also 8.8% got kidney stones. In 20 patients, more than one DXA-scan was performed. A statistically not significant decrease in BMD (0.22 Z-score/year) was found. However, there was an increase in BMD in the five patients treated with intravenous bisphosphonate therapy. This was statistically significant in comparison to the nonbisphosphonate treated group (p = 0.034). Children on KDT have low normal BMD which may decrease further during KDT. For this reason monitoring of BMD is crucial, as is monitoring of kidney stones and hypercalciuria. Intravenous bisphosphonate therapy may have a positive effect, when other therapies have failed.

Results of Rodding and Impact on Ambulation and Refracture in Osteogenesis Imperfecta: Study of 21 Children

Introduction:Delay in presentation and surgical intervention is quite usual in osteogenesis imperfecta (OI) because of various local and cultural beliefs. The purpose of this study is to review the results of 21 children who had intramedullary rodding and its effect on ambulation and refracture.Methods:We reviewed 21 children with a clinical diagnosis of OI. The mean age of children at presentation was 8.74 years (3–21 years). All children had recurrent fractures of long bones. Twenty eight femurs and 21 tibiae were stabilized with intramedullary rodding. Ambulatory status was assessed by the Hoffers and Bullock's (H and B) grading, and muscle power was recorded using the Medical Research Council, U. K., grade. Ten children had received intravenous bisphosphonates preoperatively. Postoperatively, the children were assessed for ambulatory status, pain, and ability for independent self-care.Results:The mean followup period was 34 months (24–48 months). Rush rods were used in 20 femurs, the Fassier–Duval (FD) rods in 6 femurs, and in two cases, with narrow intramedullary canals, Kirshner (K) wires were used. For the tibiae, 15 children received rush rods and in 6 cases, an FD rod was used. The mean time to fracture union was 8 weeks (6–12 weeks). Before surgery, 13 children were in H and B Grade 4 (wheel-chair independent or carried by parents usually in a developing country), four were able to ambulate with a walking aid (H and B Grade 3b), and four children were able to walk about in the house without aids (H & B Grade 2). After the rodding procedure, the ambulatoty status improved in 11 (50%) children. Seven children (33%) became household physiologic walkers (H & B Grade 3b), three achieved independent ambulation with orthosis (H & B Grade 1b), and one child with mild OI could walk unaided (H & B Grade 1a). No child had deterioration in ambulatory status. Only two children had refractures at the distal end of the rod due to continual growth of bones.Conclusions:Intramedullary rodding treatment for recurrent fractures in children with OI improves their mobility potential. It also and prevents repeated cast application, disuse wasting, and osteopenia which can lead to deterioration in the quality of the long bones.

Intravenous bisphosphonate treatment in severe infantile hypercalcemia associated with Williams Syndrome

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Osteogenesis Imperfecta: Skeletal Outcomes After Bisphosphonate Discontinuation at Final Height.

Intravenous cyclical bisphosphonates are widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Bisphosphonates are often discontinued when growth is completed, but subsequent skeletal changes have not been studied in detail. We assessed 31 patients (22 females) with OI who had started intravenous bisphosphonates (either pamidronate or zoledronic acid) before 13 years of age, were treated for at least 2 years (range 4.7-15.7 years), and discontinued treatment after completion of growth, when their age ranged from 13.4 to 20.0 years (mean 16.4 years). At 4 years after treatment discontinuation, lumbar spine areal bone mineral density (BMD) had increased by 4% (p < 0.05). Peripheral quantitative computed tomography of the radius showed a decrease in trabecular volumetric BMD at the distal metaphysis of 19% but an increase in cortical volumetric BMD of 4% (p < 0.05 for both). None of the patients sustained a new vertebral compression fracture during follow-up. The proportion of patients with new long-bone fractures was higher in the 2 years before treatment discontinuation than in the last 2 years of follow-up (42% and 16%, respectively; p < 0.05). © 2019 American Society for Bone and Mineral Research.

Detection of Atypical Femur Fractures

The 2019 International Society for Clinical Densitometry (ISCD) Position Development Conference Task Force for monitoring with dual-energy X-ray absorptiometry (DXA) identified detection of atypical femur fractures (AFFs) as an important topic and established this working group to answer key questions in this area. The authors conducted a systematic review of the literature and deliberated on proposed ISCD positions, which were then reviewed by an external expert panel and vetted at the 2019 ISCD Position Development Conference in Kuala Lumpur on March 23, 2019. This paper summarizes the final ISCD positions and the rationale for supporting these positions. Default-length femur imaging or extended-length femur imaging as well as full-length femur imaging (FFI), both single-energy and dual-energy scans, by DXA can detect abnormalities in the spectrum of AFF. It is important to visually inspect all DXA scans of the hip and femur, and report on findings of focal periosteal and endosteal thickening at the lateral cortex (grade: Good, A, W). FFI is the preferred DXA scan mode for detecting abnormalities in the spectrum of AFF. The FFI report should state the absence or presence of abnormalities in the spectrum of AFF. If focal thickening is present on the lateral cortex, the report should state whether a lucent line is seen (grade: Fair, C, W). The ISCD recommends considering the use of bilateral FFI in patients who are currently or have been in the past year on potent antiresorptive therapy (ie, oral or intravenous bisphosphonate or subcutaneous denosumab therapy) for a cumulative period of 3 or more years, especially those on long-term glucocorticoid therapy (grade: Fair, B, W). More research is needed to determine the role of repeat testing and the optimal time interval for follow-up DXA scans, whether an automated measuring tool would perform better than visual inspection, whether FFI would change patient management and outcomes, and the cost-effectiveness of FFI.

Management of osteoporosis in the Middle East and North Africa: a survey of physicians' perceptions and practices.

The 2011 IOF Middle East Osteoporosis Audit highlighted major care gaps in osteoporosis care in the Middle East and North Africa (MENA) region. We investigated osteoporosis management practice patterns in this region. We mailed an electronic survey to a convenience sample of physicians, explaining the study rationale and methods. It gathered information on physicians' profiles, availability and utilization of resources, risk assessment, and management. Five hundred seventy-three responses were obtained from the United Arab Emirates (UAE, 36%), Saudi Arabia (KSA, 25%), Lebanon (14%), and others (25%). Endocrinology was the single most represented specialty. Sixty percent of participants had access to densitometers, but treating physicians were not in charge of densitometry reading. Screening for vitamin D deficiency and secondary contributors to osteoporosis was frequently implemented. Although two-thirds of professionals were aware of FRAX®, only 42% used it, either because of lack of know how or of a country specific calculator. Almost all (96.0%) had access to oral and 68.9% to intravenous bisphosphonates, and over half to teriparatide (46.4%) and denosumab (45.0%). Most participants (92%) were aware of concerns regarding side effects of bisphosphonates, and this changed the management in the majority (73%). Important barriers to osteoporosis care were lack of osteoporosis awareness among physicians, patients, and cost of treatment. This first look at physicians' practice patterns on the diagnosis and treatment of osteoporosis in the MENA region underscores the pressing need for an official call for action, at all levels, to address this large care gap.

Long-term control of Paget’s disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a “real world” setting

Bisphosphonates are the mainstay of the treatment of Paget’s disease of bone (PDB). Clinical practice guidelines recommend treatment with intravenous zoledronic acid or high-dose oral nitrogen bisphosphonates (N-BPs). We present our long-term experience treating PDB patients with lower than recommended oral doses of N-BPs, equivalent to once-weekly doses used for treating osteoporosis. PDB patients were seen, between 1990 and 2015 at the endocrine clinic of an academic medical center. Diagnosis was established according to accepted criteria. Patients were initially treated with alendronate 70 mg/week or risedronate 35 mg/week. Whenever the initial dose failed to produce remission, the dosage was increased to twice a week the respective dose. Patients were followed for a mean of 11.9 years (range: 1.7–24.8). Out of 96 treatment courses with N-BPs, 89% were with alendronate and 11% with risedronate. Remission was achieved in 84% of the courses with alendronate 70 mg/week. 90% of those who did not achieve remission subsequently responded to 140 mg/week. Out of the 8 treatment courses with risedronate 35 mg/week, 87% achieved remission, and the 2 patients who did not achieve remission subsequently responded to 70 mg/week. The median duration of remissions following 3-4 months courses of alendronate 70 mg/week or risedronate 35 mg/week was 8.8 months (IQR: 5.5, 14.8). In a large proportion of “real world” PDB patients, remission can be achieved with once-weekly, “osteoporosis doses” of alendronate or risedronate.

Racial differences in intravenous bisphosphonate utilization among older patients with multiple myeloma.

e18165 Background: Intravenous bisphosphonates (IV BP) reduce the risk of skeletal-related events in patients with multiple myeloma (MM). However, data describing racial differences in utilization of IV BP in non-clinical trial settings is limited. In this study, we evaluated population-level IV BP utilization and factors associated with initiation and discontinuation of IV BP therapy. Methods: We conducted a retrospective cohort study of patients aged 65 years or older diagnosed with first primary MM between 2001 and 2011. Patients were identified using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database and followed through December 2013. Patients were required to have Medicare Parts A and B coverage and patients with end-stage renal disease were excluded. Treatment with anti-MM therapy (chemotherapy and/or proteasome inhibitors) were treated as time-dependent variables. We analyzed cumulative incidences of IV BP initiation from the diagnosis of MM for all patients and separately time to discontinuation from IV BP initiation. In multivariable Fine and Grey models accounting for competing risks, we estimated subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) for initiation and discontinuation. Results: 14,231 eligible patients had a mean [median] age of 76.8 [76] years and 51.8% were male. During a median follow-up of 23.1 months, 53.7% of patients received at least one intravenous bisphosphonate (IV BP) administration. IV BP initiation, duration and treatment frequency differed between racial groups. Among white patients, 64.4% of IV BP were administered every 4 weeks, compared to 59.3% in African Americans, 62.7% in Hispanic, and 64% in Asians. In multivariable models, Black patients experienced a significant delay in IV BP initiation (SHR 0.75, 95%CI 0.70-0.80) and were more likely to have early discontinuation (SHR 1.08, 95%CI 1.00-1.17). Conclusions: Despite recommended therapy with IV BP for MM patients, approximately half of older patients did not receive the therapy, with a significant lag experienced among racial minority groups. Efforts to improve uptake of IV BP and continued management of therapy in minority groups are needed. [Table: see text]

Adherence and cumulative bisphosphonate dose in relation to risk of skeletal-related events among older patients with multiple myeloma.

e18250 Background: Adjuvant intravenous bisphosphonates (IV BP) reduce the risk of skeletal-related events (SRE) in patients with multiple myeloma (MM). We examined the effects of bisphosphonate utilization patterns (adherence, cumulative dose and frequency) on risk of SRE. Methods: Patients aged 65 years or older and diagnosed with first primary MM between 2001 and 2011 were identified using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Patients receiving at least one dose of IV BP after MM diagnosis were identified and 5-year SRE-free survival was estimated using the Kaplan-Meier method stratified by demographic groups and compared with the log rank test. Cox proportional hazards models were fit to determine the association between IV BP utilization patterns and SRE after propensity score matching. We investigated the outcome of multiple recurrent SRE using the approach of Andersen-Gill, and estimated subdistribution hazard ratios (SHR) and 95% confidence intervals for risk of first SRE, accounting for death as competing risk. Results: The final cohort included 9176 MM patients with a median age of 76 years. The adjusted 5-year competing-risk SRE model showed a 48% reduction in risk of SRE (95% CI 0.49-0.55) with use of IV BP. In multivariable analyses taking into account competing risks, greater adherence to IV BP, higher cumulative IV BP dose and more frequent administration were all associated with a statistically significant reduction in SRE risks (See Table). Conclusions: Use of IV BP in patients with MM was associated with significant reduction in SRE risk over the 5-year period after MM diagnosis. The effectiveness of IV BP therapy was greater with increasing cumulative dose, adherence to and greater frequency of IV BP administration. [Table: see text]

De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis.

Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA's in patients with bone metastases from breast cancer. We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014-March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI). From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88-1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15-1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation. These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.

Pharmacogenomics of osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.

SAT-505 A Rare Case of Teriparatide Induced Persistent Hypercalcemia

INTRODUCTION Teriparatide is a recombinant endogenous parathyroid hormone. It is an anabolic medication which is FDA approved for treating Osteoporosis in postmenopausal women, men with primary or hypogonadal osteoporosis and Glucocorticoid-induced osteoporosis. Transient hypercalcemia with Teriparatide is reported in 1-3% of patients, 4-6 hours after the dose administration and lasts for 24 hours. It is thought to be through the increased renal production of 1,25-dihydroxy vitamin D, increased intestinal calcium absorption and inhibition of renal calcium excretion. We report a case of persistent hypercalcemia with Teriparatide use. CASE REPORT: A 74-year-old Caucasian female presented to the hospital with mental status changes, generalized bone pain, weight loss, and poor oral intake. Her past medical history includes Rheumatoid arthritis, Sjogren syndrome, osteoporosis with compression fractures and osteoarthritis of multiple joints. Patient’s medications include Prednisone 5 mg daily, calcitonin nasal spray, vitamin D and calcium supplements. She had previously failed bisphosphonate therapy for osteoporosis. She developed new compression fracture of L4 vertebra while being treated with Denosumab. Hence Teriparatide was started 4 months prior and she received the last dose 3 days prior to the presentation On presentation, she was noted to have severe hypercalcemia with total calcium of 17.3 mg/dL, ionized calcium of 9.4 mg/dL, albumin of 3.2 g/dL and a suppressed PTH of 3ng/L. Laboratory workup including renal function, phosphorus level, 25-hydroxyvitamin D level, 1,25-dihydroxy vitamin D, Parathyroid hormone-related peptide, Thyroid stimulating hormone, serum, and urine protein electrophoresis was unremarkable. CT scan of the neck, chest, abdomen, and pelvis showed no mass lesions or lymphadenopathy. An extensive evaluation failed to identify other causes of hypercalcemia except for immobilization. She was treated as a new onset Non-PTH dependent severe Hypercalcemia case. The patient had multiple admissions with recurrent hypercalcemia since then despite discontinuation of Teriparatide. Her calcium level normalized transiently with Intravenous fluids, an Intravenous bisphosphonate, and calcitonin. However, such treatment failed to maintain normal calcium level for more than 3-4 weeks.DISCUSSION Recurrent severe hypercalcemia with Teriparatide use is rarely reported. Although immobilization can precipitate hypercalcemia, immobilization is rarely a sole etiology of severe hypercalcemia. Our case report suggests that severe recurrent hypercalcemia can be associated with teriparatide use especially in the setting of immobilization. As far as we are aware, this is the fourth reported case of persistent hypercalcemia with Teriparatide use. This case highlights the importance of monitoring calcium levels periodically when Teriparatide is used.

SAT-LB052 Intravenous Bisphosphonate Therapy in Children with Spinal Muscular Atrophy

Introduction: Children with Spinal Muscular Atrophy (SMA) are at high risk for poor bone health with 50% of the most severely affected patients reporting at least one fragility fracture prior to age 10 years. Intravenous bisphosphonate (IV BP) has been used for treatment of disuse osteoporosis, primarily in children with cerebral palsy or muscular dystrophy. Our group has previously demonstrated that children with secondary osteoporosis are at increased risk for developing acute adverse events following IV BP but the safety and efficacy of IV BP in SMA population have not been studied. Objective: To evaluate safety profile and the efficacy of IV BP for treatment of concerns for osteoporosis in children with SMA. Methods: We retrospectively reviewed IV BP use in children with SMA at a tertiary pediatric center from 2010 to 2018. Demographic data, fractures history, laboratory indices, and bone mineral density (BMD) by DXA were obtained from electronic medical record and are presented in this case series. Results: Eight children (50% female; 75% SMA type I, 25% SMA type II) were included in this study. The median age of first IV BP infusion was 6.7 years (range 2.3 - 19.0 years). Six had long bone fractures (total of 15) prior to IV BP treatment; two of these fractures were healing fractures discovered 1 month after IV BP started. Two patients were treated based on declining BMD. Patients received a total of 39 infusions (54% pamidronate, 46% zoledronic acid). All received their first IV BP in an inpatient setting due to need for monitoring of respiratory support (BiPAP). Acute phase reactions occurred following 38% (3/8) and 3% (1/31) of initial and subsequent infusions, respectively. All were considered mild and no adverse respiratory events were noted. Hypocalcemia was observed following 5% of infusions (2/37). Hypophosphatemia was common (73%, 27/37) but rarely required intravenous replacement. There was no significant change in BMD at 1 year pre- and post-IV BP treatment among four who had DXA scans for comparison. In 32.7 patient years of follow up, two patients (25%) had total of 3 subsequent fractures, including an occurrence of atypical femur fracture which was observed in one patient 3 years after initiation of IV BP. Conclusion: Although the acute adverse events from IV BP therapy were generally mild, caution needs to be taken given the occurrence of an atypical femur fracture in this population. More follow up is needed to determine the efficacy of therapy in maintaining BMD and preventing further fracture in patients with disuse osteoporosis secondary to SMA. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SUN-513 Parathyromatosis: A Case of Stubborn Hypercalcemia Treated with Denosumab

Background: Parathyromatosis is a rare cause of recurrent or persistent hyperparathyroidism (HPT). Two proposed pathogenic mechanisms involve spillage and seeding of parathyroid tissue during parathyroid surgery and hyperplasia of embryologic rests of parathyroid tissue. Treatment of parathyromatosis remains a challenge as neither surgical nor pharmacological treatment has been successful in controlling the deleterious consequences of long-standing untreated HPT. We present a case of persistent parathyromatosis successfully treated with denosumab. Clinical Case: A 78 year old female with a history parathyromatosis was admitted to our teaching hospital with anorexia and acute renal failure after a cinacalcet dose increase. She had persistent hyperparathyroidism despite 7 operations including a right hemithyroidectomy and mediastinal split. Complications from her persistent hypercalcemia have included recurrent nephrolithiasis requiring 13 lithotripsies and osteoporosis treated with multiple doses of intravenous bisphosphonate over 26 years. She had known remnant parathyroid tissue within the neck and refused further surgeries, her most recent medical regimen included cinacalcet 180 mg/day and vitamin D analogues. Labs on admission included a serum calcium of 11.0 mg/dl (8.6 - 10.2 mg/dl), ionized calcium of 5.3 mg/dL (normal 4.8 - 5.2 mg/dL), PTH of 230.8 ng/l (normal 15.0 - 65.0 pg/mL), 250H-vitamin D of 39 ng/mL (normal 30 - 60 ng/mL), serum creatinine of 4.05 mg/dL (normal 0.51 - 0.95 mg/dL) and a 24-hour urine calcium of 242 mg (normal 100 - 240 mg/24hr). Imaging studies included a renal ultrasound (US) that showed bilateral nephrolithiasis without hydronephrosis, a parathyroid US and a technetium Tc 99m-sestamibi scan that showed known remnant parathyroid tissue within the thyroid bed. Because of her modest response to lower doses of cinacalcet and failure to tolerate higher doses; inability to use bisphosphonates due to ARF, denosumab at a dose of 60 mg was initiated. The use of denosumab in combination with a lower dose of cinacalcet resulted in successful control of hypercalcemia. Conclusion: Parathyromatosis remains a rare etiology of recurrent or persistent HPT. Successful treatment and control of parathyromatosis remains a challenge. Surgery remains the mainstay of therapy, but attempts at surgical cure are commonly unsuccessful, and medical therapy with calcimimetics and bisphosphonates appear to be of limited value. The addition of Denosumab, a monoclonal receptor activator of nuclear factor κB ligand (RANKL) antibody proved to be effective and appears to be a safe alternative for the management of refractory hypercalcemia.

SAT-524 Re-hospitalization And Mortality Outcome Following Atypical Femur Fracture

INTRODUCTION: Older women with proximal femur (hip) fractures have high morbidity and mortality; over 10% are re-hospitalized within 30 days of discharge and the overall mortality at 1 year is 20-25%. Outcomes differ for women with atypical femur fractures (AFF), although published findings have shown conflicting results. One study found a greater risk of death in patients with AFF (median survival 9 months) compared to non-AFF diaphyseal femur fractures, although AFF cases also had greater comorbidity burden (JCD 19:359-67, 2016). A second study found that mortality was much lower for patients with AFF compared to non-AFF diaphyseal fractures, with no deaths in the first year following fracture (JBMR 31:491-497, 2015). This study further examines morbidity and mortality in women who experienced an AFF, focusing on rehospitalization and all-cause mortality outcome in comparison to proximal femur fractures. METHODS: This retrospective cohort study used post-fracture outcome data from 112 women (age 67.1 ± 8.4, 63% Asian, 26% white, 11% all others) who experienced an AFF after initiating oral bisphosphonate therapy in 2002-2014. Exclusion criteria included use of intravenous bisphosphonates, teriparatide, denosumab, skeletal disorders, or advanced chronic kidney disease. Women were followed up to 1 year after the initial AFF event to determine rehospitalization outcome within 30 and 90 days of discharge. Mortality was examined at 6 months and 1 year after AFF, and results were compared to published findings for typical femur fractures occurring in the same healthcare setting. RESULTS: Among 112 women who had an AFF during 2002-2015, 38% were age 65-74 years and 22% age 75-84 years; none were age 85 and older. This contrasts with previous findings in older women with hip fracture where more than one-third were age 85 and older, the age subgroup with highest mortality (over 30%). Six women with AFF were re-hospitalized within 30 days (5.4%) and 10 within 90 days (8.9%), with principal indications for rehospitalization within 30 days relating to infection (3/6) and cardiac arrhythmia (2/6). Six-month and one-year mortality were extremely low at 0.9% overall, and by age group: 2% among age <65 years, 0% among women age 65-74 years and 0% among women age 75-84 years. These results contrast with much higher one-year mortality previously reported for women age 65-74 years (14%) and 75-84 years (18%) who experienced a proximal femur fracture within the same health plan setting. DISCUSSION: Women with AFF appear to have substantially different survival outcomes compared to women with typical femur (hip) fracture, consistent with findings reported in other studies. Whether these differences are primarily related to health status and physical function, or the relationship of chronic disease and (typical) fracture risk, should be further examined.

SUN-508 Intravenous Bisphosphonates Induced Renal Injury with Nephrotic Range Proteinuria in a Patient with Severe Hypercalcemia Secondary to Parathyroid Carcinoma

Background: Bisphosphonates is a known therapeutic option for PTH dependent hypercalcemia. We report a patient who developed nephrotic range proteinuria after treatment with Bisphosphonates for severe hypercalcemia in parathyroid carcinoma (PTHCa). Clinical Case: A 43 year old male with PTHCa presented with corrected serum calcium (Sr Ca) of 16.1 [8.5-10.5 mg/dl] and iPTH of 1116 [6.0-65.0 pg/mL]. He had undergone two surgeries for the parathyroid mass 7 years prior to presentation at another hospital and was lost to follow up for 5 years. At admission he was treated with IV fluids, calcitonin and IV Pamidronate [IVP] 90mg with improvement in calcium within 1-2 day. Imaging showed a 1.7cm mediastinal mass. Subsequently he had frequent hospitalizations due to recurrence of hypercalcemia. He was started on cinacalcet and was unable to tolerate it due to severe nausea. Hence, he received almost weekly bisphosphonate infusions, 6 doses of IVP and 2 doses of IV zoledronic acid (ZA) in 3 months. He then underwent surgery to removal the mediastinal mass which was lymphoid tissue only. He had persistent high iPTH (1206 pg/ml) and Sr Ca 17.4 mg/dl. He received 3 cycles of chemotherapy with transient improvement in Sr Ca, with subsequent recurrence of hypercalcemia. As there was no structural disease noted on imaging, he was treated medically. During the subsequent 6 month after surgery, patient received further 8 doses of IVP 90mg and 3 doses of IV ZA 4mg. Repeat imaging 4 months later, showed a new mediastinal mass, 2.6 cm invading trachea for which he had another surgery. Post-surgery, iPTH was low (84.6 pg/ml) and he developed hypocalcemia. However, hypercalcemia recurred and he was noted to have proteinuria with progressive worsening serum creatinine from baseline 1.3 [0.6-1.4 mg/dl] to 4.1 mg/dl. This was seen after 14 doses of IVP 90mg and 5 doses of ZA over a period of 9 months. 24-hour urine protein was 12gm/24hr. Workup for proteinuria including Hepatitis panel, HIV, RPR, ANA, C3/C4, SPEP were unremarkable. Renal US showed markedly echogenic kidneys suggesting medical renal disease. Patient declined renal biopsy. Bisphosphonate induced focal segmental glomerulosclerosis [FSGS] with nephrotic range proteinuria was diagnosed after exclusion of other etiologies. Conclusion: In experimental models, bisphosphonates especially Pamidronate has shown to cause kidney injury in a dose-dependent pattern. It is a rare complication with very few cases reported in the literature and most of them in breast cancer patients. We are reporting the same in a patient with PTHCa. Multiple mechanisms have been proposed to cause nephrotic range proteinuria including collapsing FSGS, mitochondrial apoptosis in podocytes and/or proximal tubular cells by IVP and ATN by ZA. In patients requiring large and frequent dose of bisphosphonates monitoring for proteinuria may help in early detection.