bluuebunny/crossref_metadata_2025_split huggingface dataset:
THU434 A Case Of An Atypical Femur Fracture Managed Medically With Teriparatide
Authors: Rupani Sawan V , Kotwal Anupam , Graeff-Armas Laura 
Published: October 2023

Abstract
Disclosure: S.V. Rupani: None. A. Kotwal: None. L. Graeff-Armas: None.
Atypical femur fractures (AFFs) are atraumatic or low-trauma femur fractures located in the sub-trochanteric region or femoral shaft. AFFs represent around 0.5% of all femur fractures. The increased use of bisphosphonates has led to a rise in the incidence of AFFs as it has emerged as a potential complication. While the mechanism of bisphosphonate-related AFFs has yet to be elucidated, one proposed mechanism is that bisphosphonates can cause over-suppression of bone turnover. If over-suppression is a contributing factor, then hypothetically, anabolic therapy can help heal existing fractures and prevent impending fractures by reversing over-suppression. Numerous animal models have demonstrated that parathyroid hormone and teriparatide enhance fracture healing. However, clinical trials and meta-analyses on the effects of teriparatide in fracture healing have been equivocal. There have been both retrospective and prospective studies, along with anecdotal reports demonstrating the benefits of teriparatide in healing in AFFs. However, there have been no randomized controlled trials assessing the efficacy of teriparatide in AFFs. Based on this limited evidence, the American Society for Bone and Mineral Research recommends considering teriparatide in patients who have failed conservative therapy. We present a case of an incomplete AFF in the setting of short-term bisphosphonate use that was managed with teriparatide in addition to conservative measures. Our patient presented with a complete right AFF treated surgically and an incomplete left AFF that we managed medically with teriparatide. Repeat left femur imaging six months after starting teriparatide therapy showed interval callus formation consistent with a healed fracture. Right femur imaging also showed a healing proximal femoral shaft fracture status post intramedullary fixation. She completed twenty-five months of teriparatide therapy and did not sustain any interval fractures. Repeat imaging one year after completion of teriparatide therapy continued to show a stable healed left AFF, along with a healed right AFF. She is currently more than two years post-completion of teriparatide and has remained fracture free. This case highlights the role that teriparatide may have as an option for medical management in incomplete AFFs and to accelerate healing in complete AFFs that have been managed surgically. Furthermore, with therapeutic options for osteoporosis management limited in the post-AFF setting, teriparatide helps increase bone mineral density and reduce future fracture risk. Randomized controlled trials are needed to draw definite conclusions on the efficacy of teriparatide in managing AFFs. However, this is difficult given the rare occurrence of AFFs. Therefore, case reports like ours offer insight into when teriparatide may be helpful in managing AFFs.
Presentation: Thursday, June 15, 2023
THU438 A Case Of Pregnancy Associated Osteoporosis
Authors: Maradana Sandhya , Iqbal Fizzah , Safran Marjorie 
Published: October 2023

Abstract
Disclosure: S. Maradana: None. F. Iqbal: None. M. Safran: None.
Background: Pregnancy associated osteoporosis (PAO) is a rare form of osteoporosis that is seen in late pregnancy and early post-partum period. Hip and vertebral body are most involved in PAO. Common clinical manifestation is back pain, and many patients suffer from vertebral fractures and kyphosis causing great physiologic burden and negative impact on quality of life. We report a case of PAO with good response to teriparatide. Clinical case: A 27-year-old female with no significant past medical history presented with severe acute back pain two months after delivery of her second child, whilst still breast feeding. Imaging studies demonstrated acute compression fractures of T12, L1, L2 and L3 vertebrae. She had regular monthly menstrual cycles prior to pregnancy with no previous history of fractures. Her pre pregnancy weight was 135 lbs and she had been physically active, while caring for her older son. Family history is notable for osteoporosis in multiple paternal aunts and maternal grandmother with no family history of fractures. There were no other identifiable risk factors. Evaluation for secondary causes of osteoporosis showed 25-OH vitamin D levels of 23 ng/mL (NL 30-100 ng/mL), TSH 1.72 uIU/mL (NL 0.28-3.8 uIU/mL), PTH 19 pg/mL (NL 14-64 pg/mL), calcium 9.7 mg/dL (NL 8.7-10.7 mg/dL), phosphorus 4 mg/dL (NL 2.5-4.5 mg/dL), tryptase 4 mcg/L (NL &lt;11 mcg/L), alkaline phosphatase 111 U/L (NL 30-115 U/L) and 24-hour urine calcium 168 mg (NL 100-300 mg). Urine immune electrophoresis and serum immunofixation did not show any evidence of monoclonal gammopathy. DEXA scan showed low BMD with Z-score of −4.4 SD in lumbar spine -3.1 in femoral neck. She was diagnosed with PAO. She stopped breast feeding after the diagnosis. As the bone mineral density was very low, she was started on teriparatide along with calcium and vitamin D supplementation. One year after treatment initiation, her DEXA scan showed improved bone mineral density with Z-score of −3.5 in lumbar spine and −1.9 in femoral neck. Her osteoporosis is currently being managed with teriparatide with plan to continue for a total duration of 24 months. Conclusion: PAO is under-recognized and under-reported, with limited available evidence on the management. Spontaneous improvement in BMD is known to occur in 6-12 months after pregnancy and lactation have been completed, although, the addition of anti-resorptive treatment in this setting may result in superior BMD gain compared with calcium and vitamin D supplementation alone. Use of teriparatide has shown to have significant increase in BMD and help with pain relief in PAO. Teriparatide has helped with improving the BMD in our patient. Nevertheless, controlled trials are lacking, and the optimal timing of teriparatide use in these women remains uncertain.
Presentation: Thursday, June 15, 2023
THU441 Teriparatide As Treatment For Severe Osteoporosis In Lung Transplant Recipients
Authors: Muir Christopher Alan , Raven Lisa Mary , Goodall Louise , Center Jacqueline R 
Published: October 2023

Abstract
Disclosure: C.A. Muir: None. L.M. Raven: None. L. Goodall: None. J.R. Center: None.
Background: Lung transplantation (LTx) is a life-saving treatment for end-stage pulmonary disease. With improvements in immunosuppression, LTx survival continues to improve with current 5-year survival rates of over 70%. Consequently, management of long-term transplant-related complications is increasingly important. Osteoporosis is one such complication, with the incidence of osteoporosis and osteoporotic fracture highest in LTx patients compared to other solid organ transplant recipients. Despite high fracture rates, including in patients treated with anti-resorptive medications, no data has been published using anabolic treatments for the management of osteoporosis in LTx recipients. Study design: Clinical case series. We present clinical, biochemical and bone mineral density data for four patients with severe osteoporosis post LTx treated with teriparatide. Results: Four LTx patients were treated with teriparatide 20 mcg daily for 18 months. Prednisone dose ranged between 5-10 mg daily throughout the treatment period. All patients had been previously treated for osteoporosis using zolendronate (last dose 12-24 months prior to teriparatide initiation). Bone turnover was monitored repeatedly during treatment in two patients. Following completion of teriparatide treatment, all patients received consolidation treatment with zolendronate (3 patients) or denosumab (1 patient). Bone density was measured prior and within 6-12 months after completion of teriparatide. All four patients experienced an increase in bone density at the spine (median 13%; range 2-14%) and total proximal femur (median 8%, range 6-10%) related to teriparatide treatment. No adverse effects were observed. Conclusion: Given that severe osteoporosis is highly prevalent in LTx patients and that fractures often continue to occur after treatment with anti-resorptive medication, teriparatide should be further studied as an alternative treatment in this clinical setting. Our experience in four patients suggest it is safe and effective.
Presentation: Thursday, June 15, 2023
THU453 Chronic Headaches As A Presentation For Monostotic Craniofacial Fibrous Dysplasia: A Case Study
Authors: Dyer Barbara , Bhattacharya Rajib Kumar 
Published: October 2023

Abstract
Disclosure: B. Dyer: None. R.K. Bhattacharya: None.
Background: Monostotic craniofacial fibrous dysplasia (CFFD) is often asymptomatic and is found incidentally on imaging. Previous reports described cases in which CFFD diagnosis was preceded by chronic headaches, but there remains a lack of clinical association between these diagnoses. Clinical Case: Patient is a 22-year-old female with a long history of chronic headaches who presented to the emergency department two days after a motor vehicle accident with complaints of headache, blurred vision, nausea, and dizziness. CT revealed an incidental sclerotic mass in the left frontal region measuring 7.9x7.3x3.7cm extending inferiorly into the left ethmoid sinus. At her primary care follow-up, she reported a pounding, left-sided headache in addition to balance issues, dizziness, nausea, and blurry vision. Workup was significant for vitamin D level of 11.2ng/mL (n = 30-100ng/mL), alkaline phosphate of 106U/L (n = 35-104U/L), and calcium of 9.1mg/dL (n = 8.6-10.3mg/dL). MRI was significant for a heterogeneous, hypointense expansile calvarial lesion within the left frontal and left sphenoid bones. The patient was diagnosed with CFFD based on radiologic findings. The patient was advised against surgical intervention due to her disease’s large, invasive nature. The patient was seen by neurology for recurrent headaches and was subsequently started on topiramate with partial symptom relief. Endocrinologist management included confirmation of monostotic CFFD by bone scan. Biopsy was deferred due to the low likelihood of malignant transformation, and bisphosphonate treatment was initiated. She was subsequently started on 5000 IU per day of vitamin D to normalize the vitamin D level before the initiation of bisphosphonate treatment for her pain. She received 5mg intravenous infusion of zoledronic treatment. At follow-up, the patient states she had significant improvement in all symptoms. Conclusion: Pain from FD can be debilitating and often increases in severity as the patient ages, though pain is not strongly correlated to presentation or disease burden. The mechanism by which CFFD produces pain is not fully elucidated. The unique innervation of bone and the creation of new sensory nerve fibers during inflammatory states may contribute. Additionally, excess IL-6 during inflammatory states may also play a role in pain production due to lesion expansion from osteoclast activation, cystic formation within the lesion, and hormonal reactivity of the lesion. Bisphosphonates are believed to inhibit IL-6 production, reducing osteoclastic activity and leading to symptomatic pain relief. In the case presented, the patient’s chronic headaches improved significantly following combination therapy with migraine abortive medication and bisphosphonate therapy. Early recognition and multidisciplinary treatment are key in the long-term management of CFFD pain.
Presentation: Thursday, June 15, 2023
THU463 Etiology Of Hypophosphatemia In A Patient With Co-existing Mesenchymal Tumor And Fibrous Dysplasia
Authors: Patil Madhuri , Wangsiricharoen Sintawat , Lazar Alexander , Guise Theresa Ann 
Published: October 2023

Abstract
Disclosure: M. Patil: None. S. Wangsiricharoen: None. A. Lazar: None. T.A. Guise: None.
Tumor induced osteomalacia (TIO) is a rare paraneoplastic phenomenon. Fibroblast growth factor-23 (FGF23) secretion from phosphaturic mesenchymal tumor (PMT) is implicated as the cause for hypophosphatemia and osteomalacia. Other rare conditions associated with dysregulated FGF23 production include fibrous dysplasia (FD). Coexistence of two unusual conditions which could increase FGF23 concentrations is rare. We report a case of PMT causing TIO in a patient with evidence of FD. A 79-year-old male was evaluated for worsening rib and right flank pain of more than one year duration. He also complained of generalized muscle weakness. His total alkaline phosphatase (ALP) levels were noted to be increased for many years. Computed tomography (CT) showed scattered sclerosis within ribs, and lytic lesions with cortical bone destruction in right iliac bone (4.3 x1.5 cm) and L4 vertebra. Biopsy of the right iliac lesion revealed findings compatible with PMT. Positron Emission Tomography (PET) showed fluorodeoxyglucose (FDG) avid lesion of the right anterior iliac wing, diffuse osteomalacia, insufficiency fractures of the ribs, as well as FDG avid lesions in left supra-acetabular area and in L4 vertebral body concerning for metastatic disease. Laboratory evaluation revealed ALP 306 (40-129 U/L), bone specific ALP 99 (0-20 mcg/L), phosphorus 1.5 (2.5-4.5 mg/dL), 25-(OH)-vitamin D 27 (30- 100 ng/mL), 24 hour urinary phosphorus 0.6 (0.4-1.3 g/24 hr), PTH 51.3 (15-65 pg/mL), FGF23 303 (&lt;180 RU/mL), Calcium 10.3 (8.4-10.2 mg/dL), albumin 4.4 (3.5- 5.2 gm/dL), C-terminal telopeptide of type 1 collagen (CTX) 1611 (10-854 pg/mL). CT-guided cryoablation of the right iliac lesion was performed. Also, biopsy and cryoablation of the left supra-acetabular lesion was performed; pathology showed fibrous dysplasia (FD). Mutation analysis confirmed a mutation in exon 8 of GNAS gene. Post ablation, FGF23 dropped to 102 RU/mL and phosphorus increased to 3.0 mg/dL. The patient had significant improvement in bone pain and weakness. The patient with classic features of TIO improved with simultaneous cryoablation of both the PMT as well as the FD lesions. The unusual feature of the case is co-existence of PMT and FD. Malignant transformation of FD lesions is a rare complication. We confirmed that the PMT did not have GNAS mutation and is unlikely to arise from FD. And FGF23 in situ hybridization was strongly positive in the PMT and negative in the FD, ruling out FD as a contributor to patient’s hypophosphatemia. We plan to perform DOTATATE scan to differentiate PMT from FD in the L4 lesion. This is a unique case of coexistence of two separate conditions, both of which could secrete intact FGF23. Our studies suggest that PMT is the only etiology of hypophosphatemia and TIO.
Presentation: Thursday, June 15, 2023
OR03-05 Cinacalcet Acts As A Spatially Biased Allosteric Modulator To Enhance CaSR Signaling From Endosomal Membranes
Authors: Wyatt Rachael , Gorvin Caroline M 
Published: October 2023

Abstract
Disclosure: R. Wyatt: None. C.M. Gorvin: None.
The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis by activating Gαq/11 and Gαi/o signaling to regulate parathyroid hormone (PTH) release. CaSR can also continue signaling once internalised (known as sustained signaling) to elicit responses that are distinct from those at the plasma membrane. Loss-of-function mutations of CaSR cause familial hypocalciuric hypercalcemia type 1 (FHH1), while Arg15 mutations in the adaptor protein-2 σ-subunit (AP2σ) cause FHH3, by impairing CaSR internalisation and disrupting sustained signaling. However, the sustained signaling pathway has been incompletely defined and the effects of allosteric modulators on the process are unknown. Here we examined CaSR membrane trafficking and G protein activation in different endomembrane compartments using bystander BRET and HILO advanced imaging in HEK293 cells. This showed that internalised CaSR is targeted to Rab5-positive early endosomes and Rab4-positive early-to-recycling membranes, and not to degradation pathways as previously hypothesised. CaSR exclusively recruits active Gq/11 to early endosome membranes to drive sustained signals that produce distinct transcriptional profiles than those from plasma membranes. We next mutated a C-terminal region within CaSR predicted to form a dileucine endocytic motif that interacts with AP2σ. NanoBiT assays confirmed that the CaSR-dileucine mutant disrupted interactions between CaSR and AP2σ to the same magnitude as AP2σ-Arg15 mutations. Moreover, this CaSR-dileucine mutant impaired CaSR internalisation and reduced Gq/11 sustained signals from Rab5 and Rab4 endosomes to similar levels to those observed in cells expressing the FHH3-associated AP2σ-Arg15 mutant. Gi/o and G12/13 responses from plasma membranes were not affected by the CaSR-dileucine mutant. Finally, we assessed whether the CaSR positive allosteric modulator, cinacalcet, affects sustained signalling. When exposed to cinacalcet CaSR significantly increased the recruitment of active Gq/11 to early endosomes, resulting in a significant increase in signaling, while signals from the plasma membrane were not different to vehicle-treated cells. In summary, we have demonstrated that CaSR is targeted to an early-to-recycling endosomal pathway, which could explain how CaSR responds rapidly to fluctutations in serum calcium to maintain calcium homeostasis. Moreover, we have defined the endocytic motif within the CaSR required for sustained signaling and shown that cinacalcet is a spatially-biased allosteric modulator of the CaSR that preferentially enhances signaling from endosomal membranes. Thus, FHH3-associated AP2σ mutations, CaSR dileucine mutants and cinacalcet can be used as tools to better understand CaSR spatiotemporal signaling and define its physiological significance.
Presentation: Thursday, June 15, 2023
SAT177 Molecular Analysis Of AMBRA1 As A Candidate Tumor Suppressor In Sporadic Parathyroid Adenomas
Authors: Chinwo Stephanie , Costa Jessica , Arnold Andrew , Bellizzi Justin 
Published: October 2023

Abstract
Disclosure: S. Chinwo: None. J. Costa: None. A. Arnold: None. J. Bellizzi: None.
Primary hyperparathyroidism is a common endocrine disorder that is most often caused by a sporadic single-gland parathyroid adenoma. Currently, the only known and experimentally validated oncoprotein for parathyroid adenomas is cyclin D1. The overexpression of cyclin D1 protein has been reported in 20-40% of cases and about 8 percent of cases harbor a DNA rearrangement involving the cyclin D1 (CCND1) locus. Otherwise, the molecular mechanisms underlying this cyclin D1 overexpression have yet to be identified. Here, we explored a potential parathyroid tumorigenic mechanism that could increase cyclin D1 stability through a defect in the AMBRA1 E3 ligase adaptor, a molecule responsible for its degradation. Evidence that AMBRA1 may be a tumor suppressor gene includes the accumulation of cyclin D with hyperproliferation in AMBRA1-deficient cells, the context-dependent growth of tumors in Ambra1-deficient mice, and the finding that low levels of AMBRA1 correlated with poor clinical outcomes in The Cancer Genome Atlas. Therefore, we proceeded to examine AMBRA1 for evidence of tumor suppressor-type inactivation within a cohort of 98 typical parathyroid adenomas. Genomic DNA samples from these tumors were subjected to PCR-amplification of all 18 coding exons of AMBRA1, followed by Sanger sequencing. Sequences were analyzed by comparison to the normal reference sequence: ENST00000683756.1, seeking to assess any observed intragenic or splice-site variants as potential or likely loss-of-function mutations. Thus far, with 97 percent of the coding region for this 1298-amino acid protein fully sequenced, we have identified an inactivating mutation in 1 of the 98 tumors (1%): c.126G&gt;A in exon 2, resulting in an early stop codon p.Trp42*. Sequencing the patient’s matched germline DNA confirmed the mutation was somatic and showed loss of heterozygosity. We also identified likely-nonpathogenic variants in 5 parathyroid adenomas: missense variant c.3385G&gt;T (p.Ala1129Ser), 3’ UTR variants c.*576A&gt;T and c.*491T&gt;C and synonymous variants c.579C&gt;T and c.2776C&gt;T, each in a single tumor. 4 of 5 were found as germline variants in the normal population and the one missense scored benign by in silico criteria. To conclude, our observations suggest that AMBRA1 may function as a classical tumor suppressor gene in sporadic parathyroid adenomas at very low frequency. Further study may include protein expression analysis of AMBRA1 to investigate influences on gene expression. To further elucidate the mechanisms behind cyclin D1 overexpression in parathyroid adenomas, other molecules that participate in its degradation should be explored as potential tumor suppressors.
Presentation: Saturday, June 17, 2023
SAT195 A Curious Case Of Severe Reversible PTH-mediated Hypercalcemia Of Pregnancy
Authors: Albanese Isabella , Nicolas Nathalie , Sipen Wing Simon , Mitmaker Elliot , Vautour Line 
Published: October 2023

Abstract
Disclosure: I. Albanese: None. N. Nicolas: None. S.S. Wing: Grant Recipient; Self; Pfizer Global R&D. Other; Self; Almac Discovery (Independent Contractor). E. Mitmaker: None. L. Vautour: None.
Background: Primary hyperparathyroidism is rarely diagnosed in pregnancy as symptoms may overlap with those of pregnancy and biochemical diagnosis may be masked by physiologic changes in calcium homeostasis. Hyperparathyroidism in pregnancy is associated with increased maternal and fetal complications. While mild disease is treated conservatively, moderate to severe disease is generally treated surgically in the second trimester. Safe pharmacotherapy options are limited in pregnancy. Case: A 35-year-old woman G3P1 at 10 weeks presented to our institution with polyuria, bone pain and weakness with labs demonstrating severe hypercalcemia (Calcium total: 3.82mmol/L (normal: 2.12-2.62); PTHi: 12pmol/L (normal: 1.5-9.3)). PTHrP was suppressed. She had a prior history of PTH-mediated hypercalcemia in her first pregnancy. She previously underwent three exploratory surgeries in which only three parathyroid glands were found and removed. The hyperparathyroidism and hypercalcemia persisted post-operatively thus she also required intravenous fluids, calcitonin and cinacalcet. The pregnancy was otherwise uncomplicated. Post-partum, she developed hypoparathyroidism and hypocalcemia. Throughout this current pregnancy, multiple imaging modalities were used (ultrasound, MRI and parathyroid sestamibi), none of which were unable to localize any hyperfunctioning parathyroid tissue. Thus, management was limited to medical therapy. Despite aggressive hydration, calcitonin and cinacalcet, total calcium and PTH levels consistently rose reaching peaks of 4.06mmol/L and 45.4pmol/L, respectively. Given hypercalcemia severity and associated neurological symptoms, she was also given bisphosphonates (pamidronate 60mg and zoledronic acid 4mg). She underwent C-section at 25+3 weeks due to fetal decelerations and placental insufficiency. She again developed hypoparathyroidism and hypocalcemia 1-week post-partum. Genetic testing was negative for any causes of hyperparathyroidism. Discussion: This is a unique case of severe PTH-mediated hypercalcemia in that the exact mechanism is unknown but appears to be pregnancy-mediated and reversible such that it only occurs in pregnancy with subsequent hypoparathyroidism post-partum. Investigations to better elucidate the mechanism of this are ongoing.
Presentation: Saturday, June 17, 2023