Bone Metabolism Research Articles

6683 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)

Abstract Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None. Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022. Presentation: 6/1/2024

9275 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)

Abstract Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None. Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022. Presentation: 6/1/2024

7793 Bone Mineral Density, Turnover And Bone Microarchitecture Alterations With Dapagliflozin In Post-menopausal Women With Type 2 Diabetes Mellitus: An Open-Label, Parallel-Arm, Randomized, Controlled Study

Abstract Disclosure: S.K. Bhadada: None. L. Das: None. M. Baruah: None. V. Singla: None. V. Dhiman: None. S. Ram: None. S. Sharma: None. N. Sachdeva: None. P. Dutta: None. Introduction: Evidence is limited and there is no consensus about the effects of SGLT2i on bone metabolism. The objective of the current study was to assess changes in bone mineral density (BMD), turnover markers (BTMs), and microarchitecture with the use of dapagliflozin in type 2 diabetes mellitus (T2DM). Methods: Post-menopausal women (<65 years) with T2DM (both menopause and T2DM duration > 5 years and HbA1c 7-11%) were randomly allocated (1:1) to receive either add-on dapagliflozin with standard-of-care or standard-of-care alone for T2DM management. Those with osteoporosis, on anti—osteoporotic medication, chronic glucocorticoids (>3 months), thiazolidinediones, phenytoin, tamoxifen, estrogen, eGFR<30ml/min/1.73m2, contraindication/past usage of SGLT2i, or with known endocrinopathy were excluded. Patients were made Vitamin D sufficient [25(OH)D > 30ng/ml] with oral cholecalciferol (60K daily for 1 week), if deficient. BMD (DXA, Hologic), BTMs (P1NP, CTX) and microarchitecture were assessed at baseline, 6 and 12 months. Results: A total of 131 patients were screened, of which 101 were randomized (50 dapagliflozin, 51 non-dapagliflozin). The mean age (± SD) in the dapagliflozin group was 58.1 ± 5.8 years, diabetes duration was 9.4 ± 5.2 years and HbA1c was 8.5 ± 1.7%. Baseline clinico-biochemical, areal BMD, volumetric BMD, trabecular structural (number, thickness, separation) and cortical structural (thickness and porosity) parameters were comparable between both groups. Only cortical pore diameter (Ct.Po.Dm) (±SD) at radius (0.199 ± 0.04 vs 0.180 ± 0.03, p =0.01) and tibia (0.256 ± 0.04 vs 0.226 ± 0.03, p =0.001) were higher in the dapagliflozin than the non-dapagliflozin group. At 6 months, BMD at lumbar spine (LS), hip, femoral neck (FN), and distal radius and BTMs were comparable between the dapagliflozin (n=38) and the non-dapagliflozin (n=39) groups. However, there was significantly higher trabecular thickness (Tb.Th) (0.230 ± 0.02 vs 0.218 ± 0.01, p=0.003), cortical thickness (Co.Th) (1.104 ± 0.2 vs 0.998 ± 0.2, p=0.04), intra-cortical porosity (Ct.Po) (0.008 ± 0.005 vs 0.005 ± 0.003, p= 0.020) and Ct.Po.Dm (0.192 ± 0.03 vs 0.169 ± 0.02, p=0.003), all at radius in the dapagliflozin group. At 12 months follow-up, BMD (g/cm2) at all 4 sites were again comparable between the dapagliflozin (n=36) and non-dapagliflozin (n=36) groups. Serum CTX (pg/ml) (388.8 ± 191.5 vs 327.4 ± 140.8, p = 0.06), and P1NP (ng/ml) (38.8 ± 16.3 vs 32.5 ± 16.3, p = 0.12) were non-significantly higher with dapagliflozin use. Among microarchitecture parameters, only Ct.Po.Dm at the radius (0.189 ± 0.03 vs 0.169 ± 0.03, p= 0.025) and tibia (0.251 ± 0.05 vs 0.228 ± 0.03, p= 0.030) remained significantly higher in the dapagliflozin group. Conclusion: Dapagliflozin has no long-term detrimental effects on BMD, BTMs or bone microarchitecture after 1 year of treatment in postmenopausal women with T2DM. Presentation: 6/1/2024

8693 Dexamethasone Increases Bone Mass In Mice

Abstract Disclosure: F. Sultana: None. M.L. Temple: None. S. Kim: None. V. Ryu: None. F. Korkmaz: None. A. Gumerova: None. P. Georgii: None. U. Cheliadinova: None. D. Vasilyeva: None. V. Laurencin: None. R. Witztum: None. O. Barak: None. L. Cullen: None. A.R. Pallapati: None. S. Rojekar: None. J. Gimenez Roig: None. D. Lizneva: None. W. Zhou: None. T. Yuen: None. M. Zaidi: None. Severe osteoporosis and bone fractures are strongly associated with long-term or recurring glucocorticoid use in people. Steroids have traditionally been used as an anti-inflammatory and immunosuppressive agent, and while their use has been widely implicated in causing bone loss by suppressing osteoblastic bone formation, recent data have consistently shown mixed results in mice. It is also important to stress that dexamethasone (DEX) in particular has been used for over three decades in cell cultures to stimulate osteoblast formation. We therefore posit that mechanisms other than direct steroid effects on osteoblasts contribute to bone loss, and that, at least physiologically, steroids stimulate (rather than inhibit) bone formation. Here, we have aimed to clarify the effects of DEX on bone metabolism. We first studied the effects of low and high doses of DEX (1 mg/kg and 10 mg/kg), given daily as intraperitoneal injections to 8-week-old C57BL/6 mice. Micro-CT showed that DEX markedly increased bone microarchitecture, including the bone volume fraction, connectivity density, and trabecular number, while decreasing trabecular spacing in femoral epiphyses compared with vehicle-injected controls. Serum levels of adrenocorticotropic hormone (ACTH) and corticosterone did not change following DEX. These findings suggest that both low and high DEX doses are anabolic to the skeleton. Reaffirming these data, we found that adrenalectomy (with salt replacement) caused a significant decline in bone mineral density. Likewise, Tpit-/- mice, in which ACTH and corticosterone are both reduced, display reduced bone microarchitectural parameters, together with low mineralizing surface and bone formation rates on dynamic histomorphometry, impaired osteoblast formation in Cfu-f cultures, and lowered expression of the osteoblastogenesis genes Bmp2, Ibsp, Runx2 and Sp7. Finally, deleting the glucocorticoid receptor (Gr) specifically in osteoclasts in Acp5-Cre;Grfl/fl mice had no effect on microarchitectural parameters at the spine or proximal tibial metaphysis. However, and importantly, absent GR in the osteoclast, DEX increased bone mass significantly, suggesting that its notable anabolic action was mediated by the osteoblast. Our findings challenge the longstanding premise that steroids directly impact the osteoblast to cause bone loss, and that other mechanisms, such as reduced ACTH levels and/or central effects of DEX, may play a key role. Presentation: 6/1/2024

7138 Testosterone Modulation of Muscle Transcriptome Profile During Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism

Abstract Disclosure: V. Viola: None. T. Samanta: None. M. Duremdes Nava: None. A. Celli: None. R.C. Villareal: None. N.H. Nguyen: None. G. Colleluori: None. Y. Barnouin: None. N. Napoli: None. C. Qualls: None. B.A. Kaipparettu: None. D.T. Villareal: None. Background: We reported that testosterone replacement added to lifestyle therapy can mitigate weight loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism (Barnouin et al., J Clin Endocrinol Metab, 2021). Objective: To investigate the molecular mechanisms underlying the mitigation of muscle and BMD loss in response to testosterone replacement therapy during intensive lifestyle intervention in this at-risk population. Materials and Methods: Among the 83 older (≥ 65 y) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently <300 ng/dl) associated with frailty (PPT score ≤ 31) who were randomized into 26-week lifestyle therapy plus testosterone (LT+Test) or placebo (LT+Pbo), 38 underwent serial muscle biopsies for the muscle transcriptomics substudy. Results: Despite a similar 9% weight loss, lean body mass and thigh muscle volume decreased less in LT+Test than LT+Pbo (both -2% vs -4%, respectively; p=0.04). Hip BMD was preserved in LT+Test compared with LT+Pbo (0.4% vs -1.1%; p=0.03). Muscle strength increased similarly in LT+Test and LT+Pbo (23% vs 24%; p=0.95). Total testosterone increased more in LT+Test than LT+Pbo (133% vs 32%; p=0.01). Based on Next Generation Sequencing, of the 39,160 and 39,115 genes detected in LT+Test and LT+Pbo, respectively, 151 genes were differentially expressed (DEGs) in LT+Test and 114 in LT+Pbo group. Gene Ontology enrichment analyses revealed that in the LT+Test group, just four muscle-related terms (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated, and one term (muscle system process) was upregulated while in the LT+Pbo, nine terms related to muscle (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy), and one term related to bone (bone mineralization involved in bone maturation) were downregulated. Notably, muscle system process was upregulated in the LT+Test but downregulated in the LT+Pbo. The RT-PCR analyses showed that LT+Test resulted in a higher expression of MYOD1 (p=0.02) and WNT4 (p= 0.08), key genes involved in muscle and bone metabolism, respectively, compared to LT+Pbo. Furthermore, we observed significantly higher mRNA expression of MYBPH (p=0.01), SCN3B (p=0.02), and DSC2 (p=0.01), genes involved in the muscle system process, in response to LT+Test compared to LT+Pbo. Conclusion: The addition of testosterone replacement to lifestyle therapy mitigates the weight loss-induced reduction of muscle mass and BMD via countering the weight loss-induced downregulation of genes involved in muscle and bone anabolism. Presentation: 6/2/2024

7588 Coexistent Toxic Nodular Goiter And Primary Hyperparathyroidism (PHPT), A Combo With Diagnostic And Management Implications

Abstract Disclosure: D. Dave: None. A. Bhan: None. S.D. Rao: None. About 17-84% of patients with PHPT have concomitant thyroid disorders, but the prevalence of coexistent hyperthyroidism in PHPT varies 9-14 %. A vast majority had Graves’ disease with only 3 cases of toxic multinodular goiter (MNG) and PHPT reported in the literature as of 2022 ([1]). We present a rare case of coexistent toxic MNG and PHPT. Case Description: A 68y woman presented with recent 23 kg unintended weight loss and palpitations, but no other symptoms. Denied having kidney stones or fractures. On examination she had fine tremors of hands, MNG without exophthalmos. An ultrasound showed multinodular MNG with cystic lesions. A diagnosis of toxic MNG was made. Laboratory results were: TSH (<0.01 uIU/mL), free T4 1,68 ng/dL (normal: 0.61-1.44 ng/ml), high serum Ca (11.0 - 11.4 mg/dl) over 4y, but PTH was unavailable prior to the visit when it was 107 pg/ml and 89 pg/ml after 3 months of antithyroid therapy. Despite clinical and biochemical euthyroidism after 3 months, serum Ca and PTH levels remained high (11.4 mg/dl and 89 pg/ml respectively). Because she had pulmonary embolism a few years ago, we deferred parathyroidectomy until complete remission of hyperthyroidism. Discussion: Hypercalcemia is the biochemical hallmark of PHPT but can occur in 2-10% of patients with hyperthyroidism alone but only 1% of those will have coexistent PHPT. When these two conditions coexist, hypercalcemia is moderate to severe, and an occasional patient may present with hypercalcemic crisis (2). Prior to the availability of PTH assays, it was a challenge to diagnose coexistent PHPT. Hypercalcemia in hyperthyroidism responds to propranolol but not in PHPT, although the response is variable (3). With the availability of sensitive PTH assays, this maneuver is not necessary. In most cases, current PTH assays distinguish hypercalcemia of hyperthyroidism with suppressed PTH from coexistent PHPT in whom PTH level is non-suppressed or elevated. Monitoring serum Ca and PTH levels during therapy of hyperthyroidism would be useful as normalization of serum Ca and PTH has occasionally been reported (4). In our patient, serum Ca and PTH levels remained high with 3-months of methimazole and atenolol. The impact of both conditions on bone and mineral metabolism are profound, with fractures and kidney stones. Since kidney stones are uncommon in hyperthyroidism, presence of kidney stone in a hyperthyroid hypercalcemic patient should alert the possibility of PHPT. Similarly, significant decrease in bone density in such patient also raises the possibility of PHPT. Prompt diagnosis and appropriate treatment of both conditions is necessary to avoid irreversible complications.

8410 Lipid modification enhances the calcemic and bone building effects of injected PTH(1-14) and PTH(1-11) fragment peptides in mice

Abstract Disclosure: J. Höppner: None. H. Noda: None. A. Khatri: None. H. Jüppner: None. T.J. Gardella: None. PTH analogs with improved actions in vivo are of interest as potential treatment options for bone and mineral ion diseases such as hypoparathyroidism and osteoporosis. The efficacies in vivo of conventional PTH peptides are generally limited by rapid rates of clearance from the circulation (t1/2 = ∼ 5-30 minutes) and relatively short-dwell times on the receptor (PTH1R). This is especially true for small fragment analogs, such as M (modified)-PTH(1-14), and M-PTH(1-11), which have only been shown to be active in vitro. We explored whether PTH fragment peptide efficacy in vivo could be enhanced by addition of a lipid chain (e.g., a C15 palmitoyl chain (palm)) to either the peptide C-terminus or to the side chain of the amino acid residue at position 11 or 13. The C-tail lipid modifications were specifically designed to promote binding to serum albumin, and hence extend circulation half-life, while the lipid chains at sidechains of residue positions 11 and 13 were designed, based on structural models, to anchor the ligand to the receptor in situ -- i.e. by projection of the acyl chain between two adjacent transmembrane helices and into the surrounding plasma membrane -- to thereby extend receptor dwell time. Assessment of cAMP signaling potencies in HEK293/hPTH1R/glosensor cells revealed that both types of lipid modifications can preserve agonist potency, and that the lipid extensions at position 11 or 13 can indeed prolong receptor dwell times, as shown by extended durations of cAMP signaling after initial binding of Palm 11 or 13-modified M-PTH(1-14) and M-PTH(1-11) peptide fragment. Single subcutaneous injection of either Palm-13-M-PTH(1-14) or Palm-11-M-PTH(1-11) into mice resulted in prolonged increases in blood serum calcium levels, while 14 days of daily injection resulted in profound increases in bone mass, as measured by uCT, and marked increases in blood levels of the bone turnover markers CTX1 and P1NP, whereas non-lipidated M-PTH(1-14) control peptides were inactive in vivo. Peptide lipidation thus holds promise as a strategy to employ in the design of new PTH analogs with improved efficacies in vivo. Presentation: 6/1/2024

9379 From Diagnosis To Treatment: A Comprehensive Approach To Pregnancy-Related Osteoporosis With Teriparatide

Abstract Disclosure: C. Hubers: None. M. Renzu: None. V. Mehta: None. A. Manzoor Qazi: None. A.M. Satei: None. D.K. Yerasuri: None. Introduction: Pregnancy and lactation related osteoporosis (PLO) is a rare but serious condition with significant consequences for maternal and fetal health. Teriparatide's efficacy in treating this condition is promising, particularly given concerns about bisphosphonate use in this population. Clinical Case: A 26-year-old white female sought evaluation for concerns arising after her first pregnancy. Following delivery via Cesarean section, she experienced acute back pain, instability while walking and frequent falls. A subsequent bone scan showed superior end plate fractures of T9, T11, T12, and L1, while an MRI of the lumbosacral spine showed mild acute to subacute compression deformities involving the superior endplates of the L2-L5 vertebral bodies. Despite having Factor V Leiden disease, her medical history is unremarkable for significant chronic conditions or comorbidities affecting bone health. Bone density scans revealed a Z-score of -2.4 in the lumbar spine and -1.6 in the total hip, with a femoral neck Z-score of -1.3. Her lumbar spine T-score was reported as -2.8, reflecting significant bone mineral density (BMD) loss with a BMI of 20.67. She underwent thorough testing to rule out other potential contributory conditions, such as celiac disease and hemochromatosis, but was eventually diagnosed with PLO. Treatment was initiated with teriparatide, administered as a daily 20 µg subcutaneous injection. The patient demonstrated an excellent response, with marked improvements in pain and enhanced ability to perform daily activities. After treatment with teriparatide, the patient’s c-telopeptide also improved. Discussion: PLO is a very rare manifestation of osteoporosis, mainly affecting women with lower BMI and advanced age. The etiology involves hormonal changes, increased calcium demands during pregnancy and lactation, and decreased BMD. Our patient's history and clinical course highlight a compelling instance of PLO, likely attributed to decreased estrogen exposure secondary to amenorrhea and breastfeeding, resulting in increased bone turnover. While bisphosphonates are often recommended for PLO, concerns about safety in pregnant and lactating women underscore the need for alternative treatments like teriparatide. Potential effects on gestational age, neonatal birth weight, and neonatal calcium levels have been observed in newborns with maternal exposure to bisphosphonates. Teriparatide is a synthetic form of parathyroid hormone that works primarily by stimulating osteoblast activity, leading to increased bone formation and BMD. It also enhances calcium and phosphate absorption in the kidneys and intestines, further contributing to its bone-building effects. Our patient's response to teriparatide emphasizes its potential as a safer option in managing PLO, warranting further research to establish comprehensive management guidelines. Presentation: 6/3/2024

6564 A Case of Severe Hypercalcemia in Carney's Complex

Abstract Disclosure: J. Chippior: None. M. Rayan: None. L. Wright: None. L.S. Kirschner: Grant Recipient; Self; Medpace, Sparrow, Corcept Therapeutics, Corcept, Spruce, CinCor, Crinetics, Adrenas. S.W. Ing: Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Amgen Inc, Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Bridge Bio. Carney complex is a rare syndrome with fewer than 750 reported cases, characterized by lentigniosis, myxomas, and the occurrence of both endocrine and non-endocrine tumors. An inactivating mutation PRKAR1A, which encodes for the type 1A regulatory subunit of Protein kinase A, is responsible for over 70% of familial cases and 37% of sporadic cases. A 31-year-old female with a history of Carney complex, Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD), facial lentigines, spinal Schwannomas, and recent ischemic stroke secondary to embolization of a cardiac atrial myxoma, was transferred to our medical center for hyperemesis and severe hypercalcemia. Albumin-corrected serum calcium measured 15.4 mg/dL (8.6-10.5 mg/dL), ionized calcium 7.8 mg/dL (4.6-5.3 mg/dL) associated with suppressed PTH, normal PTH-related protein, and elevated bone turnover markers, C-telopeptide 4,273 pg/ml (150-635) and Procollagen Type 1 N-terminal Propeptide 222 mcg/L (19-83). Evaluation for etiology of hypercalcemia revealed elevated 1,25 dihydroxy vitamin D at 107.0 pg/ml (20-79) and elevated interleukin-6 at 11 pg/ml (<6.4). IL-6 is expressed by cardiac myxomas. Serum angiotensin-converting enzyme level was 50 U/L (16-85) and infectious workup was negative for potential granulomatous causes of elevated calcitriol (including testing for tuberculosis, histoplasma, blastomyces, bartonella, and coccidioides). CT angiogram of the abdomen and pelvis (completed in preparation of atrial myxoma resection) revealed ground-glass opacities in bilateral posterior lung fields and multiple pulmonary nodules, with the largest measuring 8 mm. After treatment with aggressive intravenous fluid resuscitation, intramuscular calcitonin, and intravenous zoledronic acid, corrected calcium normalized to 9.4 mg/dL at discharge. Urinary cortisol was 6.2 mcg per 24-hr (3.5-45), for which she started hydrocortisone 20 mg daily to treat suspected adrenal insufficiency as excess cortisol secretion in PPNAD may be episodic. Thus remission of hypercortisolism may have unmasked an underlying hypercalcemia, and adrenal insufficiency itself may have contributed to this finding. She had excision of left atrial myxoma and has continued to exhibit normal calcium levels on steroid replacement therapy. Repeat chest CT to further characterize these pulmonary findings is planned. This case illustrates a unique constellation of endocrine features associated with severe hypercalcemia in Carney complex. Presentation: 6/1/2024

7686 A Case Of A 66-Year-Old Male With Systemic Macrocytosis Complicated By Osteoporosis

Abstract Disclosure: J.M. Gri: None. M. Hillhouse: None. P. madhavan: None. Background: Osteoporosis in men is underestimated and warrants investigation for secondary causes of osteoporosis. Systemic mastocytosis is a rare secondary cause of osteoporosis. Clinical Case: This is a 66-year-old male with a past medical history of severe persistent asthma, eczema, hypertension, GERD with esophagitis, basal cell carcinoma, and systemic mastocytosis (diagnosed in 2010). Family history was significant for lung cancer in both of his parents. Patient was first noted to have hyperpigmented skin lesions on his legs, trunk and upper extremities in the early 1990s. The spots were biopsied and he was diagnosed with urticaria pigmentosa in 1998. Due to persistent symptoms of facial flushing and soft stool, he was referred to Hematology and was started on antihistamines. He later underwent a bone marrow biopsy in 2010 which showed multifocal mast cell aggregates but normal trilineage hematopoiesis. He endorsed back pain shortly after his diagnosis and a DXA scan was completed. The DXA scan showed osteopenia of the spine T score of -1.8, BMD 0.999 mg/mm3 and normal bone density in bilateral hips. He had no history of fractures. He was started on alendronate and remained on the medication from 2012 to 2015. It was stopped due to intolerable symptoms of acid reflux and he required proton pump inhibitors. DXA scan in 2017 showed normal bone density of the hips and osteopenia of the lumbar spine (T score -1.2). DXA scan in 2022 showed a decrease in spine BMD by 6% (T score -1.8) from 2017 to 2022 but unchanged from 2010. Hip bone mineral density was normal but decreased by 10% since 2010 and by 6% since 2017. Labs obtained in May 2022 showed normal serum electrophoresis, normal urine calcium and creatinine ratio, calcium and vitamin D level and urine NTX of 41 nM BCE/mM (21-83) and bone specific alkaline phosphatase level of 31.5 U/L (15-41.3). After discussion with the patient, conservative management with calcium, vitamin D and exercise has been implemented along with close follow up. Should the patient’s bone turnover markers increase or fracture risk increase, additional antiresorptive therapy will be initiated. Conclusion: This case study highlights the importance of screening for osteoporosis in patients with systemic macrocytosis. As this patient was diagnosed with osteopenia at age 53, this case also emphasizes the importance of early screening in both women and men with this rare condition. Presentation: 6/3/2024

8079 PPI Breaks a Leg! An Unusual Case of Atypical Femur Fracture

Abstract Disclosure: M. Sedghian: None. M. Flanagan: None. D. Pinkhasova: None. K. Selk: None. G. Moloney: None. Background: Atypical femur fractures (AFF) occur along the shaft of the femur extending from the subtrochanteric region proximally to the distal femoral metaphysis. These fractures have an increased incidence in patients taking bisphosphonates and denosumab for osteoporosis and develop as stress reactions in the lateral cortex of the femoral shaft (beaking). However, few cases that meet the characteristics of these fractures have occurred in patients who have never used antiresorptive drugs. We present a case with a history of long-term proton pump inhibitor (PPI) use and possible association with AFF. Clinical Case: The patient is a 68-year-old female with a past medical history of hypothyroidism who presented to the emergency department (ED) after an atraumatic femur fracture and consequently ground level fall. The patient reported experiencing a distinctive cracking sound in her femur while leaning over to wash her feet, resulting in a fall that prompted her to seek immediate care in the ED. Upon initial evaluation, radiographic imaging was significant for displaced left mid-femoral diaphyseal fracture and right femur lateral cortex thickening consistent with AFF. Labs were consistent with elevated PTH to 100.7 [18.4-80.1], Vit D2 1,25 (OH)2 <8 pg/mL, Vit D 25OH 34 ng/ml [30-100], and Calcium level of 9.5. Upon further history taking, the patient stated that she has been taking PPIs intermittently for more than 10 years. She denied a history of bisphosphonate and denosumab exposure, non-Hodgkin's lymphoma, rheumatoid arthritis, and COL1A2 variant mutations as main predisposing factors for atypical femur fractures. She had potential steroid exposure for less than a year before hospitalization as she was on "adrenal complex" from her functional medicine provider. The patient underwent open reduction and internal fixation of the left femur with placement of intramedullary nail and prophylactic fixation with placement of intramedullary nail of the right femur as there was radiographic evidence of beaking. Discussion/Conclusion: Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. Overall, PPIs are positively associated with elevated fracture risk in multiple studies. Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, decreasing bone turnover, impairing calcium absorption, and altering homocysteine levels through impairment of folate and vitamin B12 absorption.This case supports a potential association between long-term PPI use and atypical femur fractures. There have been other case reports that also highlight this potential risk of PPI use. This shows the importance of more comprehensive research on this topic as the number of patients on long-term PPIs is growing in outpatient settings. Presentation: 6/2/2024

12520 Preliminary Findings From An Ongoing Open-label Phase 2 Study Demonstrate That The Calcilytic Encaleret Can Improve The Relationship Between Blood And Urinary Calcium In Individuals With Post-surgical Hypoparathyroidism

Abstract Disclosure: I.R. Hartley: Research Investigator; Self; Calcilytix Therapeutics, Inc. R.I. Gafni: Research Investigator; Self; Calcilytix Therapeutics, Inc. K.L. Roszko: Research Investigator; Self; Calcilytix Therapeutics, Inc. X. Li: None. E.A. Ferguson: Research Investigator; Self; Calcilytix Therapeutics, Inc. C.A. Moore: Research Investigator; Self; Calcilytix Therapeutics, Inc. K.A. Pozo: Research Investigator; Self; Calcilytix Therapeutics, Inc. K.T. Ampuero: Research Investigator; Self; Calcilytix Therapeutics, Inc. A.V. Sridhar: Employee; Self; Calcilytix Therapeutics, Inc. A.S. Mathew: Employee; Self; Calcilytix Therapeutics, Inc. M. Roberts: Employee; Self; Calcilytix Therapeutics, Inc. S.H. Adler: Employee; Self; Calcilytix Therapeutics, Inc. E.F. Nemeth: Consulting Fee; Self; Calcilytix Therapeutics, Inc. M.T. Collins: Research Investigator; Self; Calcilytix Therapeutics, Inc. Parathyroid hormone (PTH) and the calcium-sensing receptor (CaSR) are the primary regulators of blood and urinary calcium. The independent contributions of PTH and the CaSR on renal calcium handling are not well understood, largely due to their intertwined physiology. In individuals with functioning parathyroid tissue, calcilytics (negative modulators of the CaSR) increase PTH secretion and decrease urinary calcium excretion, leading to increased blood calcium levels. We hypothesized that calcilytic administration to individuals with post-surgical hypoparathyroidism (PSH) may reveal the PTH-independent effects of CaSR modulation on renal calcium handling and clarify the potential therapeutic role of calcilytics in PSH. Four women (26-69y) with PSH enrolled in an ongoing, open-label, phase 2, proof-of-principle study of encaleret, an oral investigational calcilytic (NCT05735015). Encaleret 162 mg was administered every 12 hours for up to 10 doses. Calcitriol was discontinued one day prior to the first dose of encaleret. All participants received calcium supplementation initially. To maintain eucalcemia, 1 participant discontinued calcium supplementation and 3 required re-initiation of low-dose calcitriol (0.25 mcg daily). Results are presented as mean (range) of fasting baseline pre-dose levels compared to fasting levels 12 hours after the last dose of encaleret. Fractional excretion of calcium (FECa), a measure of renal calcium handling that quantifies the relationship between blood and urinary calcium, decreased by 52% (34-78). Albumin-corrected blood calcium increased from 8.4 mg/dL (range 8.1-8.6; nl 8.4-10.2) to 9.3 (8.6-10.7). Urinary calcium excretion decreased from 348 mg/day (range 204-501; nl <250) to 169 (76-350), with normalization in 3 participants and a 30% decrease in the fourth. Baseline PTH of 7.4 pg/mL (range 4.6-10.1; nl 15-65) transiently increased 30 minutes after the first dose to 13.0 (4.5-18.1), then returned to near baseline levels. Bone turnover markers were normal and did not change on encaleret. There were no serious adverse events reported. The only treatment-related adverse events (AEs) were mild hypercalcemia causing headache in 1 participant. Her blood calcium levels continued to be mildly elevated for 60 hours after the last dose of encaleret even after calcium and calcitriol supplementation was discontinued. Despite elevated blood calcium, her 24-hour urine calcium remained <200 mg/day. Encaleret reduced FECa in the first four participants with PSH, improving the relationship between blood and urinary calcium. These preliminary results from this Phase 2 study support continued evaluation of encaleret as an orally administered therapy for the treatment of patients with PSH. Presentation: 6/1/2024

6820 Assessing The Efficacy And Safety Of Setrusumab For Osteogenesis Imperfecta: Updated Phase 2 Data From The Phase 2/3 Orbit Study

Abstract Disclosure: G.S. Gottesman: Advisory Board Member; Self; Ultragenyx, Kyowa Kirin, Inc. Consulting Fee; Self; Ultragenyx. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Ultragenyx. T.O. Carpenter: Advisory Board Member; Self; Ultragenyx. Consulting Fee; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. M. Wallace: Advisory Board Member; Self; Ultragenyx. Consulting Fee; Self; Novosteo. P. Smith: Grant Recipient; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. E.A. Imel: Consulting Fee; Self; Ultragenyx. Grant Recipient; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. H. Wang: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. H.M. Byers: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. S. Krolczyk: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. E.M. Lewiecki: Consulting Fee; Self; Amgen Inc, Radius Health, Inc. Grant Recipient; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Research Investigator; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Speaker; Self; Amgen Inc, Kyowa Kirin, Inc. Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and low bone mass with no universally accepted treatment. Setrusumab is a fully human anti-sclerostin monoclonal antibody that improved bone mineral density (BMD), bone strength, and bone turnover markers in adults with OI (ASTEROID; NCT03118570). In the ongoing Phase 2/3 Orbit study (NCT05125809), Phase 2 evaluated the efficacy and safety of setrusumab in pediatric and young-adult cohorts with OI based on PK/PD, safety, and BMD data, to determine the dosing strategy for the Phase 3 portion. Subjects with OI Types I, III, or IV, ages 5 to <26 years, were randomized 1:1 to receive 20 or 40 mg/kg setrusumab intravenously monthly. Six-month data as of August 2023 are presented. Twenty-four subjects (50% female, 75% <18 years of age) with OI Type I (n=17/24, 71%) or III/IV (n=7/24, 29%) were enrolled and randomized to receive 20 mg/kg (n=14/24) or 40 mg/kg (n=10/24) of setrusumab. The mean (SD) baseline-corrected area under the effect curve (AUEC) for serum P1NP in the 20 mg/kg setrusumab group was 4153 (4407) µg/(L*day) over month one of treatment, and 5256 (5521) µg/(L*day) in the 40 mg/kg group. Mean (SE) change from baseline in lumbar spine BMD in the 20 mg/kg group was 9.1% (1.8%) and 12.8% (2.5%) at M3 and M6, respectively (all p<0.05 vs baseline) and 9.3% (2.4%) and 16.1% (3.9%) in the 40 mg/kg group (M6 p<0.05 vs baseline). Mean (SE) baseline BMD Z-score in the 20 mg/kg group of 2.1 (0.8) improved by 0.6 (0.8) at M3 and 0.9 (0.8) at M6, and improved from 1.1 (0.4) at baseline by 0.5 (0.4) and 0.9 (0.4) at M3 and M6, respectively, in the 40 mg/kg group (all p<0.05 vs baseline). The median annualized fracture rate (excluding fingers, toes, face, and skull) was reduced significantly from 0.7 to 0 (p=0.042) after setrusumab initiation (calculated reduction of 67%). No new radiographically confirmed fractures excluding fingers, toes, face, and skull were reported in 20/24 (83%) subjects after starting setrusumab, while only 4/24 (17%) reported fractures (precipitating events: one subject: slipped on ice, stubbed toe, one subject each: fell off of tricycle, bending over in bed, tripped and fell). Setrusumab treatment resulted in no unexpected adverse events. Treatment-related adverse events included infusion-related reaction (7/24, 29%), headache (3/24, 13%) infusion site pain, bone pain, and upper respiratory tract infection (each 1/24, 4%). In Orbit Phase 2, we observed significant improvements from baseline in lumbar spine BMD at M3 and M6 at both 20 and 40 mg/kg doses, with no marked differences between dose groups. Fracture rates significantly decreased with setrusumab initiation, with 83% of subjects reporting no new fractures. Presentation: 6/1/2024

6986 Efficacy and Safety of Weekly Liquid Alendronate Sodium Trihydrate in Korean Postmenopausal Women with Osteoporosis: A 12-Month, Multi-Center, Randomized Trial

Abstract Disclosure: Y. Rhee: None. S. Ahn: None. N. Hong: None. D. Seo: None. S. Hong: None. Background: Although alendronate is the most prescribed oral bisphosphonate for osteoporosis treatment, it can lead to gastrointestinal problems, impacting treatment compliance and efficacy. This study aimed to assess the efficacy and safety of once-weekly alendronate sodium trihydrate (ALN-S), an oral solution, compared to once-weekly alendronate sodium (ALN-T), an oral tablet, in Korean postmenopausal women with osteoporosis. Methods: Conducted as a 12-month, multi-center, prospective, randomized, open-labeled, parallel trial at two hospitals in Korea, 170 postmenopausal women were randomized to ALN-S (N=85) or ALN-T (N=85). Bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total hip (TH) was measured at baseline and after 12 months. Bone turnover markers, including C-telopeptide (CTX) and procollagen type 1 amino-terminal propeptide (P1NP), were assessed at baseline, 6 months, and 12 months. The primary outcome was the percentage change in LS BMD, evaluated for non-inferiority. Results: After 12 months, both ALN-S and ALN-T groups exhibited a significant increase in LS, FN, and TH BMD, with no significant intergroup differences (ALN-S: LS 5.0 ± 0.6%, FN 1.8 ± 0.6%, TH 2.2 ± 0.5%; ALN-T: LS 5.2 ± 0.6%, FN 1.6 ± 0.6%, TH 1.8 ± 0.5%). ALN-S was found to be non-inferior to ALN-T for BMD change at LS (treatment difference: -0.22%, 95% CI: -1.84 to 1.40%), excluding the predefined non-inferiority margin of -2.29%. Changes in both CTX and P1NP over time did not significantly differ between the groups. There was no significant difference in the frequency of adverse events between the groups. Conclusion: Weekly liquid alendronate sodium trihydrate demonstrated non-inferiority to weekly tablet alendronate sodium in increasing LS BMD in Korean postmenopausal women with osteoporosis. Presentation: 6/2/2024

6714 Bone And Radiologic Findings In Congenital Generalized Lipodystrophy: A Systematic Review

Abstract Disclosure: R.M. Tuska: None. M. Brush: None. A.A. Livinski: None. R.J. Brown: None. Congenital Generalized Lipodystrophy (CGL) is characterized by a near-total loss of subcutaneous adipose tissue, leading to severe metabolic and systemic comorbidities. CGL is most commonly caused by mutations in AGPAT2 (CGL1) and BSCL2 (CGL2) genes. Skeletal abnormalities such as diffuse sclerosis, lytic bone lesions, and high bone mineral density (BMD) have been recognized in many patients with CGL, but the radiologic and clinical features of these bone phenotypes remain ill-defined. The aim of this systematic review was to evaluate the bone manifestations and radiologic findings associated with CGL1 and CGL2. We searched 6 databases: CINAHL Plus, Embase, Global Index Medicus (WHO), PubMed, Scopus, and Web of Science: Core. We screened articles utilizing a dual reviewer process in Covidence. Included publications reported primary bone and radiologic findings in patients with CGL1 or CGL2. Exclusions comprised publications without full text, duplicate publications, those lacking bone measures, and review articles. Two reviewers extracted data using RedCap and assessed risk of bias. 270 records were screened and 37 records reporting 179 cases of CGL were included for data extraction. Among the 79 patients assessed for bone cysts, 49 (62%) exhibited lytic appearing lesions. Of these 49, 14 (29%) patients presented with symptomatic lesions, primarily manifesting as bone pain at the lesion site (n=6), or pathologic fracture at the lesion site (n=9). Bone biopsy (n=7) revealed thin trabeculae and extensive vascular proliferation at the lesion site. Bone marrow biopsies (n=2) and imaging (n=20) revealed normal hematopoietic marrow with a marked reduction in marrow fat. 12 patients underwent serial bone imaging revealing diffuse osteosclerosis and the absence of lytic lesions in early childhood. During adolescence, lytic lesions appeared and progressed throughout the proximal and distal ends of the long bones in the appendicular skeleton sparing the axial skeleton. Markers of bone turnover were within normal limits except for sclerostin, which was elevated in a cohort of 11 patients. High BMD (n= 65), advanced skeletal maturation (n= 49), diffuse osteosclerosis (n=30), scoliosis (n=8), pseudo-osteopoikilosis (n=6), coxa valga (n=5), enlarged epiphyses (n=7), and coarse trabeculae (n=8) were also reported. While leptin replacement therapy improved metabolic parameters in many patients, it did not reverse the high bone mineral density or significantly alter markers of bone turnover. Individuals with CGL exhibit a spectrum of skeletal abnormalities including lytic-appearing lesions, osteosclerosis, high bone mineral density, advanced skeletal maturation, and pseudo-osteopoikilosis. Further long-term follow-up is needed to comprehensively assess the progression of these lesions over the life course and to elucidate the mechanisms contributing to their development. Presentation: 6/2/2024

6871 Hungry Bone Syndrome After Parathyroidectomy in End-Stage Kidney Disease: A Case Report Analysis

Abstract Disclosure: R. Rani: None. C. Mullarkey-desapio: None. Introduction: Hungry Bone Syndrome (HBS) is a rare yet severe complication following parathyroidectomy, characterized by pronounced hypocalcemia subsequent to a rapid decline in parathyroid hormone (PTH) levels. Renal hyperparathyroidism (RHPT) carries a heightened risk of HBS compared to primary hyperparathyroidism (PHPT), with prevalence varying from 15% to 25% in PHPT to as high as 75-92% in RHPT. This elevated risk in RHPT is attributed to chronically elevated PTH levels, both in terms of duration and intensity as compared to PHPT. Preoperative predictors for HBS occurrence and severity include younger age, larger gland size, lower preoperative calcium levels, elevated bone turnover markers, and the magnitude of PTH elevation. Case Report: We present a case of a 36-year-old female with End-Stage Renal Disease (ESRD) requiring dialysis, complicated by renal osteodystrophy and a radial fracture, unresponsive to medical therapy, who was admitted for parathyroidectomy. Preoperative labs revealed calcium at 8.3 mg/dL, phosphate at 4.1 mg/dL, alkaline phosphatase (ALP) at 797 IU/L, and an extremely elevated parathyroid hormone (PTH) level at 4139 pg/ml. Within 24 hours of parathyroidectomy (three and a half glands were removed, the largest weighing 0.7gm), her PTH levels declined to the 130s, accompanied by symptomatic hypocalcemia (calcium 6.5mg/dL). Initial management involved intravenous calcium gluconate and subsequent high-dose oral calcium (up to 10-16gm daily) with Calcitriol 1 mcg twice daily. Despite repletion, her calcium levels remained low on postoperative day 4 (calcium 6.8mg/dL, phosphate 1.9 mg/dL, magnesium 1.7mg/dL) with PTH at 131 pg/ml, confirming Hungry Bone Syndrome. After seven days of aggressive intravenous and oral calcium supplementation with high-dose Calcitriol, she was discharged with a calcium level of 8.9mg/dL. Discussion: Management of HBS following renal hyperparathyroidism surgery presents significant challenges due to associated comorbidities and other electrolyte abnormalities, with limited literature providing guidance on prevention and management. Our case demonstrated that early suspicion and aggressive management improved patient outcomes. Suspecting HBS in high-risk individuals and initiating interventions pre and post-surgery, including pre-treatment with calcitriol, bisphosphonates, and early aggressive intravenous calcium supplementation post-surgery, could potentially reduce morbidity and length of hospital stay. Presentation: 6/1/2024

5071 Impact of Estrogen Replacement Therapy on Bone Health in a Novel Non-human Primate Model of Postmenopausal Women Living with HIV

Abstract Disclosure: K. Sauter: None. D.L. Takahashi: None. G. Webb: None. H. Hofmeister: None. O. Varlamov: None. J. Sacha: None. P. Kievit: None. Current antiretroviral therapy (ART) regimens have rendered HIV a manageable chronic condition rather than a fatal disease, with people who initiate ART soon after infection achieving nearly normal life expectancy. As a consequence of increased survival, more women living with HIV (WLWH) will now undergo menopause and be subject to a disease burden that reflects age along with adverse skeletal consequences of postmenopausal estrogen deficiency. In addition to known bone loss and increased fracture risk in postmenopausal women, ART also causes decreased bone mineral density. Therefore ART-suppressed WLWH may have a compounded detrimental effect on bone due to long-term ART treatment combined with menopause that may be attenuated with estrogen replacement. Eleven rhesus macaques were infected intravenously with SIVmac239M and received ART two weeks post-infection (PI). All animals were ovariectomized (OVX) at 35 weeks PI and received estrogen implants (n=6) or cholesterol implants (n=5). Weekly blood samples were collected and animals were monitored longitudinally for body composition including bone mineral content (BMC) via dual x-ray absorptiometry (DEXA). Infection with SIV caused a significant decrease, -8.2%, in pelvis BMC after 14 days of peak viremia with SIV. These changes were not observed in the BMC of spine or extremities. BMC remained suppressed by ∼7% for an additional 25 weeks PI during ART treatment. Measurement of circulating bone turnover markers (BTMs), osteocalcin and C-terminal telopeptide of type 1 collagen (CTX), decreased post infection without significant improvement after ART suppression. Induction of menopause via OVX and loss of estrogen induced a drastic increase in BTMs with a much larger increase in CTX, indicating potential global bone loss due to OVX. Post-implant, the control animals’ pelvis BMC continued to decrease to -20.9% and pelvis BMD to -9.3% indicating that OVX further exacerbated the effect of SIV and ART. However, animals that received estrogen implants demonstrated marked improvement in both measures to greater than baseline. SIV and subsequent long-term ART negatively impact pelvic BMC and BMD and this effect is compounded by menopause in our model of post-menopausal WLWH. However, estrogen replacement post-menopause may attenuate these detrimental bone effects despite long-term ART treatment. Presentation: 6/1/2024

7949 Unraveling a Unique Presentation of Paget’s Disease of Bone

Abstract Disclosure: S. Puri: None. L. Bovee: None. R. Narla: None. Background: Paget's Disease of Bone (PDB) is a disorder characterized by rapid bone destruction and repair, which results in distortion of bone architecture. PDB occurs most commonly in adults over 55 and of European descent. PDB presents with both lytic and sclerotic lesions, predominantly in the axial skeleton. Serum alkaline phosphatase (ALP) levels and bone turnover markers (BTMs) are typically elevated in PDB. Clinical Case: A 53-year-old African-American woman with a history of breast cancer, PTSD, depression, and obesity (BMI 37) presented with worsening back pain over the past six months. Her pain would start at the center of her back and radiate to her left lower extremity. She endorsed rapid weight loss and night sweats and had lumbar bony tenderness on exam, prompting a spinal MRI. Spinal MRI was significant for diffuse sclerosis of the L3 vertebral body only. The radiology report provided a broad differential for this finding, including metastases, lymphoma, infection, PDB, and hemangioma. Due to progression of the patient’s back pain and concern for possible malignancy, a whole-body SPECT was completed which showed isolated tracer uptake into the L3 vertebral body extending into the pedicles and spinous process. Similar findings were noted on bone scans dating back to 2001. Per the radiology report, the presence of sclerosis with minimal expansion is most suggestive of PDB. Endocrinology was consulted for guidance on treatment and surveillance imaging for this patient. The endocrinology team discussed the case with radiology, who confirmed that the patient’s imaging findings had classic features of PDB. Bone specific ALP (B-ALP) and procollagen type 1 amino-terminal propeptide (P1NP) as bone turnover markers (BTMs) were within normal limits. A DEXA scan is pending to evaluate for concurrent osteoporosis. Clinical Lessons: PDB was favored as the most likely diagnosis primarily due to the sclerotic appearance of the patient’s vertebral lesion on imaging, radicular symptoms, and exam finding of bony point tenderness. Other diagnoses, such as metastatic disease, were considered and were thought to be unlikely given that the vertebral lesion is monostotic and stable. This case highlights the necessity of carefully evaluating radiographic findings and clinical history in the diagnosis of PDB. In this case, the patient was from a demographic group unlikely to have PDB and, unexpectedly, did not have elevated BTMs. It is important to consider PDB on the differential diagnosis in cases such as this because PDB can present in myriad ways and in a variety of patient populations. Presentation: 6/2/2024

6483 Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma: A Rare Skeletal Dysplasia/Sarcoma Syndrome

Abstract Disclosure: A. Grover: None. C.R. Ferreira: None. R.I. Gafni: None. S. Jumani: None. M.T. Collins: None. K.L. Roszko: None. I.R. Hartley: None. Introduction: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is a rare autosomal dominant syndrome associated with pathologic fractures, myopathy, premature hair graying, and aggressive osteosarcomas. DMS-MFH has been linked to genetic variants in the methylthioadenosine phosphorylase (MTAP) gene, which encodes an enzyme in the methionine salvage and polyamine synthesis pathway. This pathway is implicated in other skeletal fragility disorders, such as Snyder-Robinson syndrome, suggesting a still undefined role of this pathway in bone biology. We describe a kindred with DMS-MFH and identify diagnostic challenges. Case: A 53-year-old perimenopausal woman presented with four fragility fractures over one year. Relevant history included premature hair graying, esophageal strictures, and nephrolithiasis. The patient’s bone formation markers were slightly elevated; bone resorption markers were within reference range. Her only osteoporosis risk factor was perimenopausal status. Bone series showed a diffuse heterogeneous appearance of the long bones with a mixed lytic/sclerotic appearance. DEXA scan revealed osteopenia. Family history was significant for 2 sons with aggressive osteosarcomas diagnosed in their late teens; one died at age 20. The other son is currently 39-years-old with recurrent osteosarcomas in three different limbs. The family also has a multigenerational history of severe bone fragility, muscle weakness, and premature hair graying. The patient, her living son, and his father underwent genome sequencing that identified a variant in MTAP (c.885A>G; p.(R295=)) in the patient and son. This variant was previously reported in three other families with DMS-MFH and has been shown to alter splicing. Notably, commercial genetic testing did not report this as a relevant variant, and diagnosis required independent analysis of the raw sequence data. Based on these findings, the patient and her son were diagnosed with DMS-MFH. Given the bone fragility with elevated bone turnover markers we treated the patient with yearly zoledronic acid infusions with no subsequent fractures. Surveillance for osteosarcoma is also being performed with annual whole-body MRI. Conclusion: DMS-MFH has been reported in only five families to date. The sixth family described here has clinical characteristics similar to the other kindreds. Due to high risk of aggressive osteosarcoma, timely diagnosis is imperative to decrease morbidity and mortality. Commercial genome sequencing may miss this diagnosis, so targeted genetic testing should be pursued. As more cases are identified, characterization of affected families may enhance our understanding of the natural history of the disease and guide surveillance and treatment strategies. Presentation: 6/2/2024

8749 Skeletal effects among pre and postmenopausal women with hypoparathyroidism (HypoPT); data from the Canadian National Hypoparathyroidism Registry (CNHR)

Abstract Disclosure: H. AbuAlrob: None. S. Hussein: None. H. Afifi: None. D.S. Ali: None. A. Almoulia: None. D. Bole: None. M. Braga: None. P. Chandra: None. A. Cheng: None. R. Cheung: None. J.E. Young: None. J. Hetal: None. S. Khan: None. T.S. Khan: None. J. Malhem: None. H. Malik: None. S. Mehmood: None. A. Millar: None. E. Morgante: None. F. Naveed: None. H. Niazi: None. T.L. Paul: None. A. Prebtani: None. Z. Punthakee: None. J.A. Shaban: None. R. Shah: None. M. Shrayyef: None. M. Shaikh: None. C. Tagra: None. S.R. Teschke: None. I.T. Tauqir: None. S. Van Uum: None. W. Robert: None. M. Ovize: Employee; Self; Amolyt. A.A. Khan: Research Investigator; Self; Amolyt, Ascend Therapeutics (A Besins Healthcare company), Takeda. Introduction: the CNHR registry was established in 2014 with the objectives of identifying the etiology, presentation, natural history and current treatment of hypoPT[1]. Methods: 101 patients with hypoPT were included in this prospective study. Patients completed baseline assessments including 3 site bone mineral density (BMD), trabecular bone score (TBS), fracture risk assessments, and bone biomarkers. Baseline data is presented. Results: A total of 101 participants were enrolled, 83 (82%) were female, and 18 (18%) were male. There were 35 (42%) premenopausal females and 48 (58%) postmenopausal females (PMF). Only PMF were on antiresorptive therapy. Seven (7/8) were on bisphosphonate therapy (i.e., alendronate), and 3 females were on denosumab. Among premenopausal females the average corrected calcium (Ca) was 2.03 mmol/L (SD=0.26), calcium phosphate product (Ca PO4) was 2.75 (SD=0.62), and the eGFR 94.63 mL/min (SD=18.08). The average bone turnover markers among premenopausal women for the Telopeptide-C (CTX) was 242.4 ng/L (SD=209.4) (CTX within the reference range (WRR) 136-689 ng/L) while the Propeptide 1 Collagen (P1NP) was 37.6 ug/L (SD=39.2) (P1NP WRR 19-83 ug/L). Among PMF, the average corrected Ca was 2.22 mmol/L (SD=0.18), Ca PO4 was 2.14 (SD=0.17), and the eGFR 73.9 mL/min (SD=23.0). The average bone turnover markers among PMF for CTX was 346.1 ng/L (SD=488.4) (WRR 177-1015 ng/L) while P1NP was 47.1 ug/L (SD=33.1) (WRR 16-98 ug/L). Among premenopausal women (n=35), the mean total hip Z-score was 0.87 (SD=1.29), L1-L4 Z-score 0.98 (SD=1.19), FN Z-score 0.59(SD=1.17), and 1/3R Z-score -0.04 (SD=0.77). Among PMF (n=48) the mean total hip T-score was -0.20 (SD=1.65), L1-L4 T-score -0.24 (SD=1.88), FN T-score -0.43(SD=1.59), and 1/3R T-score -0.94(SD=1.23).TBS scores in premenopausal women were normal (TBS=1.41 (SD=0.10)) however the TBS was partially degraded among PMF (TBS= 1.28(SD=0.15)). Fracture data has previously been reported3. Conclusion: The effects of hypoPT on bone strength needs further study2. Our data suggests that bone quality maybe impaired in PMF with hypoPT as noted by the presence of degraded TBS scores and the presence of fragility fracture in this population. Reference 1.Khan AA et al Canadian national hypoparathyroidism registry: an overview of hypoparathyroidism in Canada. Endocrine 2021. 2.Khan AA et al JBMR 2022 Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop3.Hussein S et al. Skeletal effects of hypoparathyroidism (HypoPT); data from the Canadian National Hypoparathyroidism Registry (CNHR). Available here: https://amolytpharma.com/wp-content/uploads/2023/10/ASBMR-CNHR_FINAL.pdf Presentation: 6/2/2024