ResearchPad - bone-disease-from-bench-to-bedside https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SUN-333 Burosumab Improves Bone Density in Patients with X-Linked Hypophosphatemia]]> https://www.researchpad.co/article/elastic_article_8794 Background: X-linked hypophosphatemia (XLH) causes rickets in children and osteomalacia in adults due to lifelong renal phosphate wasting that is mediated by high circulating levels of FGF-23. Burosumab, is a recently approved fully human monoclonal antibody that blocks FGF23, thereby correcting the renal phosphate leak, improving mineral metabolism and reducing osteomalacia by 50-75% in adults [1]. Whether this results in measurable changes in skeletal mass and microarchitecture is unclear. Objective: We examined the impact of burosumab on regional bone mineral density (BMD) and trabecular bone scores (TBS) in study subjects involved in two phase III clinical trials of burosumab.

Methods: In these trails subjects received burosumab 1 mg/kg every 4 weeks. Some patients received placebo for the first 6 months of one trial so we considered their month 6 data as their baseline. Most of the patients had been treated at some point in the past with calcitriol and phosphorus. DXA and TBS were obtained at baseline and then after 6, 12 and 18-24 months of drug treatment. Paired t-tests and ANOVA were performed to assess changes in L-spine BMD, Total Hip BMD and TBS.

Results: 25 subjects with XLH (mean age 38.9 years, 56% female) were enrolled in these studies. Paired data were available in 23 subjects at 6 months, 15 subjects at 12 months and 18 subjects at 18-24 months. Compared to baseline, there were significant increases in L-spine BMD at all time points by paired analysis: 6 months (+6.0%, p=<0.0001), 12 months (+6.95%, p=<0.0001), 18-24 months (+6.13%, p=0.0005). Although there was no significant difference in total hip BMD at 6 months when compared to baseline, there were significant increases at 12 months (+6.72%, p=0.0005) and a further increase at 18-24 months (+10.02%, p=0.0029). When all available subjects were analyzed by one-way ANOVA, there was a significant effect of time of treatment on these regional BMD measurements. There was no change in trabecular bone score over the course of treatment.

Conclusion: Treatment with burosumab is associated with a marked improvement in BMD, particularly in the hip. Since the hip is a frequent site of fracture in XLH, the effect of burosumab at this site is of considerable clinical relevance. The lack of an effect on TBS may relate to the fact that this measurement is much less sensitive to therapeutic interventions than BMD assessed by DXA.

References:

[1] JBMR. 2019. https://doi.org/10.1002/jbmr.3843.

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<![CDATA[SUN-334 Real-World Clinical Profiles of Adults with Hypophosphatasia (HPP) from the Global HPP Registry]]> https://www.researchpad.co/article/elastic_article_8757 Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by low activity of tissue non-specific alkaline phosphatase (TNSALP). HPP in adults has a heterogeneous clinical presentation, often with multiple musculoskeletal and systemic manifestations, which can lead to misdiagnosis and substantial delays in diagnosis. To better understand the most common clinical profile of adults with HPP, data from 270 adults with confirmed HPP diagnosis (≥18 year of age, low ALP and/or ALPL mutation) in the Global HPP Registry were analyzed. Most were women (75.2%) with a median age at enrollment into the registry of 50 years and a median ALP activity of 25 U/L (normal range: 40-150 U/L). Based on medical history, pain (74.8%), mostly described as chronic bone pain or generalized body pain, was the leading symptom reported. Dental manifestations, such as early loss of primary teeth, were reported in 60.4% of adults. Skeletal manifestations, such as recurrent and poorly healing fractures or pseudofractures, were observed in 47.8% of adults. A substantial proportion also reported fatigue (35.2%) and muscle weakness (26.3%). Of the adults who had quality of life data available, median (range) of SF-36v2 Physical Component Score was 42.4 (17.9, 63.3; n=203; population norm=50) and pain interference on the BPI-SF was 3.5 (0, 9.5; n=196; 0=does not interfere; 10=completely interferes). Most adults with available data (n=212) reported some disability on the HAQ-DI (66%). Of these 270 adults, 77 were treated with enzyme replacement therapy (asfotase alfa) while 193 had never received treatment. Demographics and baseline ALP activity were similar between ever and never treated adults. Treated patients had a higher occurrence of pain, dental issues, recurrent and poorly healing fractures or pseudofractures, fatigue, and muscle weakness compared with untreated patients. Generally, treated adults reported poorer quality of life before treatment initiation compared with untreated adults, though data were limited in treated adults. Of the patients treated, 61.0% had pediatric-onset HPP which likely reflects the indication for asfotase alfa in most countries; 29.9% had unknown onset. 57.5% of untreated adults had adult-onset HPP, 24.3% had pediatric-onset, and 18.1% has unknown onset. Pain, dental issues, fatigue, recurrent and poorly healing fractures or pseudofractures, and muscle weakness were the most frequently reported symptoms in both adults with pediatric- or adult-onset HPP. These results establish real-world clinical profiles of adults with HPP, both untreated and before treatment start. Similarities in clinical profiles between adults with pediatric-onset and adult-onset HPP suggest that the age at onset itself is of limited clinical utility; current clinical status and the degree of disability are likely more meaningful in making treatment decisions.

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<![CDATA[SUN-363 Hypophosphatemia Gene Panel Sponsored Program: A High Yield Of Molecular Diagnoses from Clinically Confirmed XLH and Suspected XLH/ Genetic Hypophosphatemia]]> https://www.researchpad.co/article/elastic_article_8667 X-linked hypophosphatemia (XLH), an X-linked dominant disorder caused by a pathogenic change (variant) in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. XLH is one of multiple etiologies of hypophosphatemia; depending on genetic cause, management may differ. The program provides a no-cost test to confirm a clinical XLH diagnosis or to aid diagnosis of suspected XLH or other genetic hypophosphatemia.

Methods Program eligibility criteria: >/=1y old and either clinical XLH diagnosis (confirmatory) or suspicion of XLH/ genetic hypophosphatemia (suspected) as evidenced by 2 or more clinical signs/ symptoms. The next generation sequencing gene panel includes 13 genes: ALPL, CLCN5, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, PHEX, SLC34A3 and VDR. Copy number variant (CNV) detection was performed.

Results 317 unrelated probands have been tested as of October 2, 2019. Of 158 XLH confirmatory samples received, 143 (90.5%) had a PHEX variant: 14 (9.8%) were variants of uncertain significance (VUS) and 129 (90.2%) were either pathogenic or likely pathogenic (P/LP) XLH molecular diagnoses. Of the 15 patients (9.5%) where no PHEX variant was found, one had a P variant in FGF23 (autosomal dominant hypophosphatemic rickets molecular diagnosis) and another had P and LP variants in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2 molecular diagnosis). Of 159 suspected samples, 101 (63.5%) had a PHEX variant: 14 (13.9%) were variants of uncertain significance (VUS) and 87 (86.1%) were P/LP (XLH molecular diagnoses). No PHEX variant was found for 58 (36.5%) of suspected samples; however, 5 of these had other findings: a dominant-negative heterozygous P variant for ALPL was detected in 3 samples (3 hypophosphatasia, HPP, molecular diagnoses); a fourth carried two P variants in ALPL; a fifth had a LP variant and a VUS in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2). Of 121 unique P/LP PHEX variants detected, 59 were deletions duplications or insertions. A complex rearrangement and an Alu-mediated insertion were detected in the full cohort. To date, additional family member testing was performed for 10 probands with original VUS: in 4 cases the VUS was reclassified to P/LP; 2 were reclassified to P/LP due to more clinical info, highlighting the value of family testing and clinical info to resolve VUS. RNA analyses to resolve VUS and unidentified variants may further improve molecular diagnoses of genetic hypophosphatemia. Program results demonstrate a high diagnostic yield for confirmatory and suspected XLH/ genetic hypophosphatemia.

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<![CDATA[SUN-352 The Effects of Acute Hyponatremia on Bone Remodeling Markers in Patients with Subarachnoid Hemorrhage]]> https://www.researchpad.co/article/elastic_article_8636 Animal data and cross-sectional human studies have established that chronic hyponatremia predisposes to osteoporosis; the effects of acute hyponatremia on bone remodeling are unknown. Serum markers of bone remodeling (total procollagen type 1 amino-terminal propeptide (P1NP), bone specific alkaline phosphatase (bone ALP), N-mid-osteocalcin (OCI) and C-terminal teleopeptides of type I collagen (CTX-1)) were assessed in a cohort of patients admitted with subarachnoid hemorrhage (SAH), who were prospectively studied over seven days. The ratio of P1NP:CTX-1 was calculated to report a bone formation index.

Twenty-two patients (13 women), median (IQR) age 53 (47, 62) years were recruited. Patients who developed post-SAH ACTH deficiency and those treated with glucocorticoids, or continuous enteral feeding were excluded. All patients were eunatremic on initial assessment. Eight patients developed acute hyponatremia, median nadir plasma sodium concentration (pNa) 131 (128, 132) mmol/L, and 14 remained eunatremic, nadir pNa 136 (133, 137) mmol/L. The groups were matched for age, 25-hydroxy Vitamin D, PTH, WFSS and Fischer scores. Serum cortisol concentration was greater in the hyponatremic group, 571 (504, 671) nmol/L, than the eunatremic group, 449 (400, 501) nmol/L, p=0.008. Bone remodeling markers and bone formation index (P1NP:CTX-1 ratio) were similar in the two groups at baseline.

There was a significant rise in CTX-1 in both hyponatremic patients, +0.15 (0.09, 0.37) μg/l, p = 0.009, and patients who remained eunatremic, +0.11 (-0.02, 0.23) μg/l, p = 0.04, with no significant difference between the groups. There was, however, a significant fall in P1NP:CTX-1 ratio in patients with acute hyponatremia, p = 0.02, but no significant change in eunatraemic patients, with significant between group difference, p = 0.02.

Changes in P1NP and OCI correlated positively with nadir pNa; r = 0.43, p = 0.04 and r = 0.61, p = 0.001 respectively. In addition, there was a positive correlation between change in P1NP:CTX-1 ratio and nadir pNa, r = 0.43, p = 0.04. There was no correlation between change in OCI or CTX-1 and nadir pNa. Serum cortisol was strongly negatively correlated with change in P1NP (r = -0.64, p = 0.001) but not with change in other bone remodeling markers.

Acute hyponatremia following SAH is associated with a fall in bone formation index; physiological hypercortisolemia may contribute to this. Further analysis with larger numbers will help us determine whether hyponatremia is an independent risk factor.

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<![CDATA[SUN-LB68 Advanced Glycation Endproducts Are Associated With Worse Bone Material Strength in Older Adults With and Without Type 2 Diabetes]]> https://www.researchpad.co/article/elastic_article_6943 Patients with Type 2 Diabetes (T2D) are at increased fracture risk despite having relatively normal or even increased BMD by DXA. The critical aspect of bone quality deterioration in T2D patients could explain this clinically important discrepancy. Material composition is a component of bone quality that has emerged as a potential factor contributing to fragility fractures in T2D patients. However, there is sparse evidence regarding whether T2D patients have decreased bone material properties compared with non-diabetic controls. We hypothesized that increased production of advanced glycation endproducts (AGEs) has an important role in reducing bone material strength in patients with and without diabetes. Thus, we used the OsteoProbe®, a bone microindentation device that provides an index of cortical bone material properties (Bone Material Strength index – BMSi) in men with T2D age ≥ 50 yrs or postmenopausal women with T2D and nondiabetic controls. We also utilized a non-invasive measure of skin AGEs (AGE Reader®) to evaluate AGEs accumulation through skin autofluorescence. Linear regression models were used to assess group differences with and without adjusting for age, Body Mass Index (BMI), and sex. Relationships between variables were assessed using adjusted Pearson correlations. A total of 152 T2D patients (mean age 68.5 ±7.6 yrs.; 59.2% men; HbA1C=7.7 ±1.0%; mean diabetes duration 15.5 yrs.) and 105 non-diabetic controls (mean age 67.2±8.8 yrs.; 41.0% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was no difference in BMSi between T2DM and control subjects: unadjusted (p= 0.636); adjusted (p= 0.695). However, skin AGEs were negatively correlated with BMSi (r= -0.23, p <0.001). In subgroup analyses, skin AGEs were also negatively associated with BMSi in both T2DM (r= -0.23, p=0.004) and control (r= -0.21, p=0.033) subjects. In conclusion, these findings demonstrate that a higher burden of AGEs is associated with worse bone quality. Our findings may explain the conflicting findings regarding reductions in BMSi in T2D because only T2D patients with a high level of AGEs accumulation have impaired BMSi. Moreover, the association of skin AGEs with BMSi in non-diabetic subjects emphasizes the important role of AGEs in decreasing bone quality and potentially contributing to fracture risk. Collectively, our data indicate that non-invasive skin AGEs measurement could be used as a tool to evaluate bone quality in patients with T2D as well as in the non-diabetic population.

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<![CDATA[SUN-366 Neonatal Severe Hyperparathyroidism: Extreme Hypercalcemia as a Robust Marker for Homozygous Dosage of Pathogenic CASR Variants]]> https://www.researchpad.co/article/elastic_article_6888 Context: Neonatal severe hyperparathyroidism (NSHPT) is a rare and life-threatening emergency. It includes generalized hyperparathyroid bone disease and respiratory distress from combinations among a narrowed thorax, rib fractures, hypotonia, and biochemical disturbances. Successful therapy is compatible with long life and a healthy prognosis. However, neuromotor retardation may persist after otherwise successful therapy. The time and amplitude of hypercalcemia likely correlate with irreversible neuromotor retardation; thus, early intervention seems critical in many cases. NSHPT is usually caused by homozygous or heterozygous pathogenic variant(s) of the CASR; a heterozygous variant of this gene is also the usual cause of familial hypocalciuric hypercalcemia (FHH or FHH1). Homozygotes and heterozygotes with NSHPT are often not distinguished in the current literature. In theory, their management should differ. Optimum treatment in homozygotes is early total parathyroidectomy with induction of postoperative hypoparathyroidism. Optimal management of heterozygotes is more complex. It consists in temporizing measures and varies from careful observation without surgery, to bisphosphonates and/or calcimimetics, and to subtotal parathyroidectomy. The heterozygotes can then develop into healthy babies with asymptomatic FHH1.

Evidence Acquisition: Each case met strict criteria for “severe” and neonatal disease. We analyzed the core biochemical parameters of the maximal serum calcium and maximal PTH. To compare different immunoassays, PTH was analyzed as a ratio (thus without units) of the raw data divided by the upper limit of its normal range. Each case also required information about the allelic dosage of the pathogenic or likely pathogenic CASR variant(s).

Evidence Synthesis: There were 36 cases with homozygous pathogenic CASR variants and 21 cases with heterozygous pathogenic or likely pathogenic variants. Maximal serum calcium was far higher in homozygotes 5.8 +/- 1.5 versus 3.2 +/- 0.2 (P<.001) (normal 2.2–2.6 mM). Maximal serum PTH as a ratio was also far higher in homozygotes 17 +/- 12 versus 8 +/- 9 (P=.003) (normal ratio 0.3–1.0). We defined extreme hypercalcemia empirically as any calcium value above 4.5 mM. No heterozygote had a maximal calcium above 3.7 mM; however, 30 of 36 (81%) of the homozygotes had maximal calcium above 4.5 mM. Whenever tested early, this extreme hypercalcemia was usually recognized in the first week of life.

Conclusions: Extreme hypercalcemia greater than 4.5 mM was newly identified as a conservative cutoff that was 100% predictive of homozygosity for pathogenic CASR variants. Extreme hypercalcemia in NSHPT is an early, facile, rapid, and inexpensive determinant of homozygosity for pathogenic variants of the CASR. It should be sought and used to promote early and definitive total parathyroidectomy, whenever it is identified in NSHPT.

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<![CDATA[SUN-345 Use of Anti-FGF23 Monoclonal Antibody in the Treatment of Children and Adolescents with X-Linked Hypophosphatemic Rickets]]> https://www.researchpad.co/article/elastic_article_6877 Background: X-linked hypophosphataemia is the most common heritable form of rickets in children, disorder caused by mutations in PHEX, leading to elevated secretion of FGF23, renal phosphate wasting with consequent hypophosphataemia, diminish synthesis of 1,25(OH)2 vitamin D, rickets/osteomalacia, and disproportionate short stature. Conventional treatment with oral phosphate supplementation and active vitamin D heals rickets, prevents progressive growth failure, but in a substantial proportion of patients treatment is unsuccessful and/or associated with adverse effects. Since 2018, burosumab, a human monoclonal antibody against FGF23, was approved for the treatment of X-linked hypophosphataemia.Aim: We report a pilot experience on the efficacy and safety of treatment with burosumab in children and adolescents with X-linked hypophosphataemia (XLH). Methods and patients: Eight XLH patients (5 males) (5 pre pubertal and 3 Tanner IV) with an age range from 2.9 to 16.2 years, were recruited, 6/8 had family history of XLH, the remaining two were confirmed with molecular study. All discontinue conventional therapy at least 7 days before treatment with Burosumab which was administered every 2 weeks SC for 6 months, at a starting dose of 0.8 mg/kg/dose. Growth velocity, Thacher Rickets Severity Score, fasting serum calcium (mg/dl), phosphorus (P)(mg/dl), alkaline phosphatase (ALP)(IU/L), PTH (pg/dl), 25OH Vitamin D (ng/ml) and tubular phosphate reabsorption (TPR) (X±SD) were evaluated at basal, 3, and 6 months of treatment. Results: All patients had normal 25OH2 Vitamin D: 35.3±8.6 ng/ml at the start of therapy and had significantly improvement of serum P: basal 2.2±0.51, 3 months: 3.24±0.43 and at 6 months 3.01±0.38 mg/dl (p<0.005). The mean serum ALP level decreased from 686.9±410.8 to 535.8±302.4 and 402.5±106.7 IU/L (p<0.05) respectively. TPR normalized during treatment: 67.3±9, 86±3.1, and 86.9±6.1 %(p<0.001). The severity of rickets, as well, showed a significant improvement: 4.0±2.0, 2.3±1.2, and 1.0±0.8 (p<0.005), respectively. The non-pubertal children increased their growth velocity from 3.7±1.2 cm/yr to 7.0±1.4, and 7.9±2.0 cm/yr (p<0.05) respectively. Serum calcium and PTH levels did not show any significantly variation. Mild adverse events such as local reactions and headaches were observed. Conclusions: 1) Treatment with burosumab restores phosphate metabolism, 2) Growth and the Thacher Rickets Severity Score improved during treatment, 3) all patients showed a good safety profile with only minor adverse events. This is the first report of children with XLH treated with burosumab in Latin-America.

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<![CDATA[SUN-336 Obesity and Impaired Glucose Metabolism in Adult Patients with X-Linked Hypophosphatemia]]> https://www.researchpad.co/article/elastic_article_6846 Background: X-linked hypophosphatemia (XLH) is characterized by increased activity of circulating FGF23 resulting in renal phosphate wasting and abnormal bone mineralization. Epidemiologic studies suggest a relationship between FGF23, obesity and metabolic syndrome. However, the prevalence of metabolic complications in adult XLH patients is not known.

Study design: We conducted a prospective cohort study (CNIL 2171036 v 0) in a single tertiary referral center.

Subjects: Patients were adult subjects with XLH, defined as hypophosphatemia due to renal phosphate wasting with either documented PHEX mutation (92%) and/or family history of rickets. Healthy controls were selected among adult participants of the AcroCut cohort and matched for sex, age and body mass index (BMI).

Methods: Prevalence of obesity and diabetes in patients was compared with the general French population (ObEpi 2012; Bonaldi C. et al., Bulletin épidemiologique hebdomadaire 2016) and prevalence of glucose intolerance in patients, assessed by standard 75-g OGTT, was compared to matched controls. Resistance to insulin was evaluated with HOMA-IR index.

Results: 107 patients (79 women and 28 men) were recruited. Median age at evaluation was 35.5 years (range 16.9-74.2) and median BMI was 25 kg/m2 (range 18-48). Thirty-eight (35.5%) patients were overweight (29 women) and 22 (20.5%) patients were obese (16 women). Distribution of normal weight, overweight and obesity in adult XLH patients differed from that seen in the general French population. We observed an excess of overweight and obesity (+20%, 95% CI [+6; +33], P=0.013) in comparison to general population, especially in younger age categories (under 45 years of age). Three (2.8%) out of the 107 patients were treated for diabetes which did not differ from the expected frequency of type 2 diabetes of 5% in the French population. Twelve (13%) out of 90 patients with available OGTT were glucose intolerant or diabetic compared to ten (12%) of the 82 matched controls (P=0.995). Decreased insulin sensitivity assessed by HOMA-IR was found in fourteen (15.6%) adult XLH patients. Comparison of insulin and glucose curves obtained during the OGTT in patients and matched controls are planned to analyze insulin sensitivity in both populations.

Conclusion: Adult XLH patients are prone to develop overweight and obesity, particularly adolescents and young adults. This excess of weight does not seem to result in increased prevalence of metabolic disorders. Insulin sensitivity, yet, needs to be further evaluated in these patients and compared to appropriate controls. FGF23 concentrations will also be assessed to search for determinants of insulin sensitivity in patients. Lifestyle recommendations to prevent obesity, promoting physical activity, are thus essential in the management of XLH patients.

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<![CDATA[SUN-335 Abaloparatide Prevents Unloading-Induced Bone Loss in Adult Rats]]> https://www.researchpad.co/article/elastic_article_6740 Disuse osteoporosis (bone loss resulted from a reduction in mechanical loading) occurs in patients due to prolonged bed rest, paralysis and application of braces. Abaloparatide (ABL) is a synthetic peptide analog of PTHrP that has been shown to promote bone formation with limited bone resorption. ABL was approved by the FDA in 2017 to treat osteoporosis in postmenopausal women at high fracture risk. Yet, the ability of ABL to prevent bone loss in disuse is unknown. We hypothesized that ABL would prevent bone loss in the hindlimb unloading (HLU) rat model of disuse osteoporosis.

Adult male Wistar rats, 13–14 weeks of age, were assigned to 1 of 4 groups (10 rats/group): ambulatory + vehicle (CON-VEH), ambulatory + ABL (CON-ABL), HLU + vehicle (HLU-VEH) or HLU + ABL (HLU-ABL). The rats received a daily subcutaneous injection of ABL (25µg/kg/day) or vehicle for 28 days. Blood serum was collected on day 0, 7, 14 and 28 to examine the expression of bone markers such as osteocalcin (OCN) and TRAcP5b. pQCT scans were acquired at the proximal tibia at day 0 and 28 to measure changes in the total and trabecular vBMD. Following euthanasia, trabecular (Tb) and cortical (Ct) bone microarchitecture from femurs, tibias and L4 vertebrae were assessed using µCT. Femurs were mechanically tested to failure in 3-point bending to determine ultimate load (N) and stiffness (N/mm). Treatment effects were evaluated using 2-way ANOVA. Effects were considered significant at p < 0.05. Data reported as mean±SD.

HLU led to loss of bone density and structure that were prevented by ABL. Longitudinal pQCT revealed significant increases in total vBMD in ABL-CON (52±17%) vs. VEH-CON (20±5%); and in HLU-ABL (24±6%) vs. HLU-VEH (-2±3%) (p<0.001 for both). Significant differences were observed in the µCT analysis of the distal femur: Tb.BV/TV, thickness and BMD were 43.7%, 12.9% and 27.4% lower, respectively, in HLU-VEH compared to CON-VEH (p<0.05 for all). ABL prevented these negative effects, such that Tb.BV/TV, thickness and BMD were 66.5%, 39% and 50.3% higher in HLU-ABL compared to HLU-VEH (p<0.01 for all). A positive impact of ABL on bone morphology was also seen in the CON-VEH rats. CON-ABL had greater femoral stiffness (+22.9%, p=0.03) and ultimate load (+20.5%, p=0.01) than CON-VEH. Vertebral and tibial trabecular parameters mimicked the distal femur parameters. Serum TRAcP5b did not differ among groups, yet both ABL groups had higher OCN levels than the VEH-treated control groups (+63%, p<0.05).

We demonstrated positive effects of ABL on BMD, trabecular bone mass and structure in both ambulating and unloaded rats. These results are consistent with prior studies showing positive effects of ABL on bone mass, structure and strength in OVX and ORX rats. Limits include only male rats and 1 dose of ABL. However, the results observed in this study provide a strong rationale for investigating the ability of ABL to prevent disuse bone loss in humans.

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<![CDATA[SUN-348 Growth Hormone Replacement in Adults During 8 Years Leads to Sustained Increase in Bone Mineral Density]]> https://www.researchpad.co/article/elastic_article_6532 Introduction: Adult growth hormone deficiency (AGHD) is associated with lower bone mass and likely with increased risk of fragility fractures. GH replacement leads to increase in bone mineral density (BMD).However, only few studies longer than 2 years exist. Aim: To assess long-term effect of recombinant GH replacement on BMD and bone turnover markers duringperiod of 8 years. Patients & Methods: Prospective follow-up of all (N=63) AGHD patients at one single center. All patients with adult GHD followed at single center. All participants were replaced with daily injection of recombinant human (rh) GH in IGF-1 normalizing regimen according to Endocrine Society Guidelines. Every 2 years, lumbar spine (L-spine) and total hip (TH) BMD using dual X-ray absorptiometry on Hologic Discovery device, was assessed. All patients were assessed for bone turnover markers; carboxy-terminal collagen crosslinks (CTx) and osteocalcin (OC), and 25(OH)D levels. Deficiencies of other pituitary axes were treated if necessary. All patients were supplemented with 800 IU /day of cholecalciferol and 1000-1200mg/day of calcium as recommended by International Osteoporosis Foundation. Results: Study group consisted of 38 males and 25 females (35 with adult onset (AO) /28 with childhood onset (CO); mean age at diagnosis 25,1 yrs) AGHD patients. All patients ended 8 years follow-up period without any treatment discontinuation during this period. Treatment was well tolerated, without any serious adverse event. IGF-1 has reached the normal ranges during first 6 months and remains normal during whole study period documenting good adherence to treatment (average dose of rhGH=0,4 mg/day). Both, L-spine and TH BMD increased significantly after 8 years of GH replacement (+8 % for L-spine BMD, +7,7% for TH BMD, both p<0,01). The highest peak of BMD was observed after 6 years of treatment. CTx increased by 35% (p<0,05) and remain stable, and no significant change in OC was observed during study period. Levels of 25(OH)D increased by 32% (p<0,05) from baseline. No clinical fractures were observed. Conclusion: Long-term GH replacement in adult GHD together with sufficient levels of vitamin D levels led to increase in BMD and CTx. This study supported fact that GH has sustained effect on bone mass and bone turnover and is safe and well -tolerated for the long time period.

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<![CDATA[SUN-LB65 Circulating Micrornas Linked to Bone Metabolism Are Affected by Sequential Anti Osteoporotic Treatment in Postmenopausal Osteoporosis]]> https://www.researchpad.co/article/elastic_article_6306 Depending on osteoporosis severity a long-term treatment, often in the form of a sequential regimen, may be required. The expression of microRNAs (miRs) related to bone metabolism in the serum is potentially affected by anti-osteoporotic treatment. Here, we investigated the effect of sequential treatments on microRNA expression profile in the serum.

Methods: This is an observational, open label, non-randomized clinical trial that included 37 postmenopausal women with osteoporosis who were treated with denosumab (Dmab) for 1 year. Patients had been previously treated for 2 years with either teriparatide (n=20), or zolendronate (n=6), or were treatment-naïve (n=11). We evaluated changes in the relative serum expression of selected miRs linked to bone metabolism at 3 and 12 months of Dmab treatment at each group separately.

Results: In the group of patients who were previously treated with teriparatide, the relative expressions of miR-21a-5p, miR-29a, and miR-2861 were significantly decreased at both 3 months (fold change 0.13, p<0.001 for miR-21a-5p; fold change 0.68, p=0.044 for miR-29a; fold change 0.16, p<.0001 for miR-2861), and 12 months (fold change 0.09, p<0.001 for miR-21a-5p; fold change 0.65, p=0.044 for miR-29a; fold change 0.19, p<0.001 for miR-2861) of Dmab treatment. The relative expression of miR-23a-3p was also significantly decreased (fold change 0.65, p<0.001) at 12 months of Dmab treatment. The relative expression of miRs was not changed among patients previously treated with zolendronate. No change was also observed during Dmab treatment in previously treatment-naïve osteoporotic women.

Conclusions: The expression of circulatings miRs linked to bone metabolism during Dmab treatment is depended on previous treatment status. Patients previously on teriparatide treatment present alterations of the relative expression of miRs related to the expression of key osteoblastic genes such as RUNX-2 (miR-23), collagen type 1 (miR-29a) and HDAC5 gene (miR-2861) during subsequent treatment with Dmab Our data suggest that teriparatide may influence the subsequent anti-resorptive effect of Dmab on bone metabolism at post-transcriptional level.

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<![CDATA[SUN-343 Prevalence and Incidence of Hypomagnesemia and Hypermagnesemia in Medical Settings]]> https://www.researchpad.co/article/elastic_article_6105 Electrolytes disturbances are commonly observed in clinical practice. However, magnesium (Mg) disorders are often poorly considered. Our primary aim was to update the prevalence and the incidence of hypomagnesemia and hypermagnesemia in a real-life scenario. The secondary aim was to investigate the association of Mg disturbances with age and gender. Data from patients whose Mg serum levels were measured between January 2015 and December 2017 at our University Hospital were recorded. Hypomagnesemia was defined by Mg levels <1.5 mg/dL and hypermagnesemia by levels> 3.8 mg/dL. Hypo and hypermagnesemia cases were considered according to age, gender, year of observation and setting of subjects including outpatients and inpatients. In particular, inpatients were recruited from a total of 25 Hospital Divisions (i.e. Cardiology, Endocrinology, Geriatrics, Hematology, Intensive Care, Internal Medicine, Infectious Disease, Nephrology, Neonatal Intensive Care, Neurology, Neuropsychiatry, Neuroradiology, Oncology, Pulmonology, Pediatrics, Psychiatry, Rheumatology and Surgical Area that included 8 Units). Over the observation period, we recognized 12,696 patients whose Mg levels were checked. Prevalences of hypomagnesemia and hypermagnesemia were 8.43% (n=1071) and 1.78% (n=226) respectively. Hypomagnesemia was encountered more frequently in female [53.3% (n=560)] rather than in male patients [47.7 % (n=511)] (χ2= 4.03, p<0.045) and was significantly influenced by age: the higher prevalence of hypomagnesemia was found in patients over 65 yr. [59.01% (n=632)], whereas a lower prevalence was detected in the other age groups, specifically in 9.52 % (n=102) of patients aged 0-18 yr. and in 31.46 % (n=337) of patients between 19 and 65 yr. (χ2= 592.64; p<0.0001). Incidence of hypomagnesemia decreased over time with a borderline significance only in subjects over 65 yr. (r=-0.99; p=0.07). Geriatrics, Oncology and Intensive Care Division showed the highest incidences of hypomagnesemia. The hypermagnesemia prevalence was observed higher in outpatients in comparison with inpatients from any other Hospital Division and the hypermagnesemia incidence did not significantly change over time (r=0.96; p=0.16). Mg disorders, mainly hypomagnesemia, are quite common in clinical practice particularly in older hospitalized patients. Among the other electrolytes’ disturbances, Mg disorders, because of life-threatening significances, may be checked and corrected.

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<![CDATA[SUN-347 Glucagon-like Peptide 1 (GLP-1) Acts Directly On Human Osteoclasts To Increase Differentiation And Bone Resorptive Activity]]> https://www.researchpad.co/article/elastic_article_6042 Glucagon-like peptide 1 (GLP-1) is an intestinal hormone released in response to nutrient intake that promotes glucose-dependent insulin secretion by acting upon the pancreatic GLP-1 receptor (GLP-1R). GLP-1R agonists (GLP-1RAs) are widely used in treatment of type 2 diabetes. Preclinical data indicate that GLP-1RAs could be repurposed to treat low bone mass as GLP-1R-depleted mice have higher bone resorption and thinner cortical bones, while insulinopenic and insulin resistant rats have improved bone formation and reduced bone mass deterioration when treated with GLP-1 or GLP-1RAs. However, the effect of GLP-1 and GLP-1RAs on human bone cells remains undetermined. We aimed to elucidate the effect of GLP-1 on primary human osteoclast (OC) and osteoblast (OB) cultures. OCs were differentiated over 10 days from human blood-derived CD14+ monocytes and OBs over 4–6 weeks from human bone. Cells were seeded on bovine bone slices and studies performed using fetal bovine serum, MCSF and RANKL (OC monocultures) or MCSF only (OB monocultures and OB+OC co-cultures). We first investigated the effect of GLP-1 on bone resorptive activity of mature OCs on bovine bone slices. GLP-1 increased the eroded bone surface percentage compared to vehicle in both OC monocultures (1nM P=0.002; 10nM P=0.023; n=8 donors) and OC+OB co-cultures (1nM P=0.013; 10nM P=0.012; n=8 donors). We then tested the effects of GLP-1 on osteoblast activity in OC+OB co-cultures by measuring alkaline phosphatase (ALP). We found that GLP-1 increased ALP in OC+OB cultures (1nM, P=0.049; 10nM, P=0.019) and these effects were reversed by the GLP-1R antagonist exendin 9–39 (1nM, P=0.93, 10nM, P=0.64). However, in OB monocultures GLP-1 had no effects on ALP (1nM P=0.93, 10nM P=0.64) indicating a GLP-1-driven increase in osteoblast activity through osteoclast-osteoblast coupling. We then assessed the effect of GLP-1 on OC differentiation by assessing TRAcP activity. Although there was a trend towards increased TRAcP activity upon stimulation with GLP-1 on day 10 of osteoclastogenesis, this was not statistically significant (1nM P=0.12; n=8 donors; 10nM P=0.29, n=4 donors). Our studies indicated GLP-1 may have a direct effect on osteoclasts, and we therefore sought to characterise GLP-1-mediated signalling in these cells. We assessed the effect of GLP-1 on cAMP signalling using LANCE assays and assessed phosphorylation of ERK proteins by Western blot analysis in human OC cultures. OCs treated with 10nM GLP-1 for 30 minutes had increased cAMP signaling (P=0.004, n=12 bone slices from 2 donors) when compared to vehicle. Furthermore, 10nM GLP-1 induced rapid increases in phosphorylated ERK (P=0.03 following 2 minutes exposure, n=4 blots). In conclusion, our studies reveal that GLP-1 increases activity in primary mature human OCs, and OBs, via OCs. Our signaling studies in OCs indicate this is mediated by direct action of GLP-1 on human bone cells.

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<![CDATA[SUN-337 Low Dose Ethinyl Estradiol in Women with Cystic Fibrosis Does Not Preserve Bone Mass]]> https://www.researchpad.co/article/elastic_article_5923 BACKGROUND: Cystic fibrosis-related bone disease (CFBD) affects 26% of adults with cystic fibrosis (CF). CFBD increases the risk for fractures, which in turn limits patients’ ability to effectively perform daily therapies necessary to maintain health. Factors contributing to CFBD include nutritional deficiencies, inflammation, glucocorticoid use, CF-related diabetes and untreated hypogonadism. Hypogonadism in CF is thought to be functional, although the distribution of etiologies of female hypogonadism in the modern era of CF therapies is unknown. Estrogen supplementation is commonly prescribed in the form of oral contraceptives to women with low bone mineral density (BMD). At our CF center, the average dose of ethinyl estradiol prescribed to women is 20 mcg. Recent evidence suggests that oral estrogen is ineffective for restoring bone health in women with functional hypogonadism and specifically that doses < 30 mcg oral ethinyl estradiol are inadequate. It is unknown if estradiol supplementation will restore and/or maintain BMD in women with CFBD.

METHODS: The purpose of this study was to examine the skeletal health of a cross-section of premenopausal women seen at a single CF center taking 20 mcg or less of ethinyl estradiol daily (low-dose estrogen) compared to women not taking estrogen supplement. As screening for an IRB-approved intervention study, we collected health information by chart review.

RESULTS: In a 12-week period, 98 women were seen in CF clinic. Of women 18 - 50 years old with CF and a documented DXA, 37 women were not taking estrogen supplement (mean age 30.8 ± 5.9 years) and 6 women were taking low-dose estrogen (mean age 30.4 ± 7.1 years). There were not statistically significant differences in other baseline characteristics known to modify CFBD. Women not taking estrogen had higher lumbar spine z-score: -0.04 ± 1.0, compared to women taking low-dose estrogen, z-score: -0.7 ±, 0.5 (p-value 0.01). Women not taking estrogen had higher BMD at the lumbar spine: 1.02 ± 0.1 g/cm2, compared to women taking low-dose estrogen: 0.95 ± 0.1 g/cm2 (p-value 0.03). Similar trends were seen at the total hip and femoral neck (p-values > 0.05).

DISCUSSION: In this retrospective single-center chart review, women not taking estrogen supplement compared to women taking low-dose estrogen supplement had higher BMD. This was statistically significant at the lumbar spine, the DXA site with mostly trabecular bone. Estrogen deficiency causes trabecular bone loss, which can be restored with estrogen supplementation. These findings raise concern that low-dose estrogen supplementation for women with CF is inadequate for optimal bone accrual and may be detrimental. The ideal route and dose of estrogen supplementation for skeletal health of premenopausal women with CF still needs to be clarified.

REFERENCES: CFF Patient Registry 2017; Aris JCEM 2005; Ackerman JCEM 2019; Anabtawi J CF 2019; Hughan J CF 2019

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<![CDATA[SUN-LB64 Urine Phosphoethanolamine Is an Underutilized Biomarker for Hypophosphastasia]]> https://www.researchpad.co/article/N61348196-7bf5-4b31-9f4a-d8aeb628c9dc 53.5 ng/ml (sensitivity=79.5%) with an NPV of 65.2% and PPV of 100%. Initial PEA values in patients with HPP and not on ERT were higher (median 117.0, N=39) than patients on ERT (median 65.0, N=16, p=0.004). Patients who began ERT had a decline in PEA levels after treatment (mean decrease 68.1%). PEA is a specific diagnostic marker for HPP in patients undergoing investigation for HPP and may be used as a surrogate marker to monitor ERT compliance. Future studies are necessary to evaluate the association between PEA levels and functional performance. ]]> <![CDATA[SUN-349 Characterizing Functional Performance in Adults with Hypophosphatasia]]> https://www.researchpad.co/article/N516e9af5-da60-48c1-ae13-6d1a89348cd8 <![CDATA[SUN-350 Bone Marrow Adipose Tissue Is Associated with Fracture Prevalence in Anorexia Nervosa]]> https://www.researchpad.co/article/N4715d384-31ca-474e-bd82-f426b9d4f314

Abstract

Anorexia nervosa, a psychiatric disorder predominantly affecting women, is characterized by self-induced starvation, low body weight, low subcutaneous and visceral fat depots, and low bone mass. More than 85% of women with anorexia nervosa have bone mineral density (BMD) values more than one standard deviation below the mean of women of comparable age. Although there is a significantly increased risk of fracture in women with anorexia nervosa, low BMD has not been shown to consistently predict the increased fracture rate in this population. Despite low subcutaneous and visceral adipose tissue stores, women with anorexia nervosa have increased bone marrow adiposity, which is inversely associated with BMD. We hypothesized that increased bone marrow adipose tissue would be associated with the increased fracture rate in women with anorexia nervosa. We studied sixty-two women: 34 with anorexia nervosa (mean age

SEM: 28.3

0.9 years) and 28 normal-weight controls of similar age (28.3

1.1 years;

=0.72). We examined associations between lifetime self-reported fracture history and 1) BMD of the lumbar spine (L1-L4), lateral spine (L2-L4), total hip, and femoral neck measured by dual energy X-ray absorptiometry and 2) bone marrow adipose tissue at the spine (L4 vertebra) and hip (femoral metaphysis, diaphysis and epiphysis) measured by

H-magnetic resonance spectroscopy. Women with anorexia nervosa had significantly lower BMD at the spine and hip (

<0.0001 at all sites) and significantly higher bone marrow adipose tissue at the L4 vertebra (

<0.0001) and femoral metaphysis (

=0.001) as compared to normal-weight controls. Forty-seven percent (n=16) of women with anorexia nervosa versus 39% (n=11) of normal-weight controls reported a lifetime history of fracture (

=0.54). In women with anorexia nervosa, there was no significant association between fracture history and BMD at the spine or hip (

=0.27-0.98). In the group as a whole, bone marrow adipose tissue was greater in the L4 vertebra in individuals with a history of fracture compared to those without a fracture history (

=0.02). In subjects with anorexia nervosa, those with a history of fracture had greater bone marrow adipose tissue at the L4 vertebra (

=0.01) and femoral diaphysis (

=0.01) compared to those without a history of fracture; these differences in bone marrow adipose tissue remained significant after controlling for BMI (

=0.01-0.03) and also after controlling for BMD (

<0.01 for both). Higher bone marrow adipose tissue is associated with increased fracture prevalence and may be a better predictor of fracture risk than BMD in women with anorexia nervosa. Future prospective studies will be necessary to better understand the association between bone marrow adiposity and fracture risk in this population.

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<![CDATA[SUN-367 Changes in Bone and Glucose Metabolism in Patients Post Solid Organ Transplant]]> https://www.researchpad.co/article/N3c44e49f-df59-44db-92d2-8f8fe7ec598a <![CDATA[SUN-355 Associations of Trabecular Bone Score and Bone Mineral Density with Cardiorespiratory Fitness and Body Composition in Men with and Without Paraplegia]]> https://www.researchpad.co/article/N3dce3ae2-2a12-4bdf-a355-a6b1042651b5 <![CDATA[SUN-361 Cultured Murine Osteoblasts Convert DHEA to Testosterone]]> https://www.researchpad.co/article/Nf4f99640-c4c4-4d0d-9de7-2dcb17c3ad70 85%, and caused an osteoblast growth defect compared to an shRNA control. 3βHSD7 has known functions in bile acid synthesis, converting 7α-hydroxycholesterol to 7α-hydroxycholestenone (7HC). Treatment of Hsd3b7 knockdown osteoblasts with 7HC rescued the growth defect suggesting that osteoblasts might generate 7HC or a subsequent metabolite as a trophic factor. We now report an unreported function of bone as a source of T, by conversion of the adrenal androgen precursor DHEA, using 3βHSD7 as a common enzyme for androgen and bile acid synthesis, and leading to the activation of osteoblast AR signaling. These data suggest that the skeleton has evolved protective mechanisms against hypogonadal bone loss that exploits the continued production of adrenal DHEA. This concept is especially important in men with prostate cancer bone metastasis undergoing testicular-targeted therapies whereby adrenal DHEA may continue to fuel cancer growth, and in bone maturation during adrenarche before the pubertal rise in gonadal androgens. ]]>