Estimating Lumbar Spine Least Significant Change for Fewer than Four Vertebrae: The Manitoba BMD Registry.

INTRODUCTION: The International Society of Clinical Densitometry recommends omitting lumbar vertebrae affected by structural artifact from spine BMD measurement. Since reporting fewer than 4 vertebrae reduces spine BMD precision, least significant change (LSC) needs to be adjusted upwards when reporting spine BMD change based on fewer than 4 vertebrae. METHODOLOGY: In order to simplify estimating LSC from combinations of vertebrae other than L1-L4 (denoted LSCL1-4 ), we analyzed 879 DXA spine scan-pairs from the Manitoba BMD Program's ongoing precision evaluation. The additional impact on the LSC of performing the second scan on the same day vs different day was also assessed. RESULTS: LSC progressively increased when fewer vertebrae were included, and also increased when the scans were performed on different days. We estimated that the LSCL1-4 should be adjusted upwards by 7 %, 24 % and 65 % to approximate the LSC for 3, 2, or 1 vertebral body, respectively. To additionally capture the greater LSC when the precision study was done on different days, LSCL1-4 derived from a precision study where scans were done on the same day should be adjusted upwards by 39 %, 60 % and 112 % for 3, 2, or 1 vertebral body, respectively. CONCLUSION: LSCL1-4 derived from a precision study where scans are performed on the same day can be used to estimate LSC for fewer than 4 vertebrae and for scans performed on different days.

Assessing Change in Spine Bone Density from Different Numbers and Combinations of Lumbar Vertebrae: The Manitoba BMD Registry.

INTRODUCTION: Change in bone mineral density (BMD) is considered significant when it exceeds the 95 % least significant change (LSC) derived from that facility's precision study. The lumbar spine is often affected by structural artifact such that not all four lumbar vertebrae are evaluable. Guidelines suggest using a site-matched LSC when omitting vertebrae from the BMD measurement. The current study describes significant BMD change related to intervening anti-osteoporosis treatment for different numbers and combinations of lumbar vertebrae using site-matched LSC values. METHODOLOGY: We identified 10,526 untreated adult women mean age 59.6 years with baseline and repeat spine BMD testing (mean interval 4.7 years) where all 4 lumbar vertebrae were evaluable. Change in spine BMD for different combinations of lumbar vertebrae was assessed in relation to intervening anti-resorptive treatment, contrasting women with high treatment exposure (medication possession ratio, MPR ≥ 0.8) versus women who remained untreated. Site-matched LSC values were derived from 879 test-retest precision measurements. RESULTS: There was consistent linear trend between increasing MPR and BMD change exceeding the LSC for all lumbar vertebral combinations, positive with BMD increase and negative with BMD decrease (all p-trend <0.001). In the high treatment exposure group, mean percent increases in spine BMD were similar for all vertebral combinations, from L1-4 to a single vertebra. In untreated women, mean percent decreases in spine BMD were also similar for all vertebral combinations. The net treatment response (proportion of women with treatment-concordant changes minus proportion with treatment-discordant changes exceeding the LSC) was 29.7 % for 4 vertebrae, 27.5-30.0 % for 3 vertebrae, 22.4-28.5 % for 2 vertebrae, and 18.1-21.9 % for a single vertebra. CONCLUSIONS: All numbers and combinations of lumbar vertebrae, when used in conjunction with site-matched LSC values, can provide clinically meaningful follow-up in treated and untreated patients, even when spine BMD is based on a single vertebral body.

Executive Summary of the 2023 Adult Position Development Conference of the International Society for Clinical Densitometry: DXA Reporting, Follow-up BMD Testing and Trabecular Bone Score Application and Reporting.

After 15 months of preparation by task force chairs and teams, ISCD's 9th Position Development Conference (PDC) convened in Northbrook, IL, USA on March 28th and 29th, 2023 to approve new ISCD Official Positions in the topic areas of DXA Reporting, Follow-up BMD Testing and TBS Application and Reporting. Three teams of participants work to bring the PDC to fruition: the Steering Committee, Task Forces and Chairs, and the Expert Panel. To reach agreement on draft Official Positions, the PDC follows a scripted process with the UCLA/RAND Appropriateness Method (UCLA/RAM) as its foundation. Multiple rounds of data review, public debate and voting resulted in 32 new or modified Official Positions. Six companion position papers are also published along with this Executive Summary, serving as the detailed substantiation for the Official Positions. This Executive Summary reviews the personnel groups, activities and products of the 2023 PDC, with the entirety of the updated 2023 Official Positions presented in Appendix A. New Official Positions are highlighted in bold.

Reporting of Full-Length Femur Imaging to Detect Incomplete Atypical Femur Fractures: 2023 Official Positions of the International Society for Clinical Densitometry.

Incomplete atypical femur fractures (iAFFs) are associated with the long-term use of anti-resorptive therapies. Although X-rays are typically used to screen for iAFFs, images from dual-energy X-ray absorptiometry (DXA) offer an alternate method for detecting iAFFs. Although a previous 2019 ISCD Official Position on this subject exists, our task force aimed to update the literature review and to propose recommendations on reporting findings related to iAFFs that may be observed on DXA images. The task force recommended that full-length femur imaging (FFI) from DXA can be used as a screening tool for iAFFs. The presence of focal lateral cortical thickening and transverse lucencies should be reported, if identified on the FFI. This task force proposed a classification system to determine the likelihood of an iAFF, based on radiographic features seen on the FFI. Lastly, the task force recommended that the clinical assessment of prodromal symptoms (pain) is not required for the assessment of FFI.

DXA Reporting Updates: 2023 Official Positions of the International Society for Clinical Densitometry.

INTRODUCTION: Professional guidance and standards assist radiologic interpreters in generating high quality reports. Initially DXA reporting Official Positions were provided by the ISCD in 2003; however, as the field has progressed, some of the current recommendations require revision and updating. This manuscript details the research approach and provides updated DXA reporting guidance. METHODS: Key Questions were proposed by ISCD established protocols and approved by the Position Development Conference Steering Committee. Literature related to each question was accumulated by searching PubMed, and existing guidelines from other organizations were extracted from websites. Modifications and additions to the ISCD Official Positions were determined by an expert panel after reviewing the Task Force proposals and position papers. RESULTS: Since most DXA is now performed in radiology departments, an approach was endorsed that better aligns with standard radiologic reports. To achieve this, reporting elements were divided into required minimum or optional. Collectively, required components comprise a standard diagnostic report and are considered the minimum necessary to generate an acceptable report. Additional elements were retained and categorized as optional. These optional components were considered relevant but tailored to a consultative, clinically oriented report. Although this information is beneficial, not all interpreters have access to sufficient clinical information, or may not have the clinical expertise to expand beyond a diagnostic report. Consequently, these are not required for an acceptable report. CONCLUSION: These updated ISCD positions conform with the DXA field's evolution over the past 20 years. Specifically, a basic diagnostic report better aligns with radiology standards, and additional elements (which are valued by treating clinicians) remain acceptable but are optional and not required. Additionally, reporting guidance for newer elements such as fracture risk assessment are incorporated. It is our expectation that these updated Official Positions will improve compliance with required standards and generate high quality DXA reports that are valuable to the recipient clinician and contribute to best patient care.

Reporting Fewer Than Four Vertebrae: 2023 Official Positions of the International Society for Clinical Densitometry.

The precision for spine bone mineral density (BMD) worsens as vertebrae are excluded, so recommendations are needed for least significant change (LSC) for spine BMDs based on fewer than 4 vertebrae. The task force recommends re-analysis of each facility's L1-L4 in-house precision study to determine the precision in order to calculate the LSC for each combination of 2 or 3 reported vertebrae. The task force recommended not reporting spine BMDs based on single vertebral bodies for either the diagnosis or monitoring of osteoporosis. Specific data for studies assessing the precision of two non-contiguous vertebrae are mixed, but ultimately the task force recommended that spine BMD based on 2 non-contiguous vertebrae can be used for the diagnosis and monitoring of osteoporosis.

Bilateral hip DXA Reporting: 2023 Official Positions of the International Society for Clinical Densitometry.

INTRODUCTION: This position development conference (PDC) Task Force examined the use and reporting of bilateral hip bone mineral density (BMD) measurements. This was deemed appropriate as increased availability of Dual-energy X-ray Absorptiometry (DXA) technology offering bilateral hip measurement resulted in more routine clinical use. The International Society for Clinical Densitometry Official Positions accept bilateral hip BMD measurement for clinical use but currently do not include recommendations for reporting those studies. METHODS: Four key questions regarding bilateral hip reporting were proposed by the PDC Steering Committee. Relevant literature was identified using PubMed. Questions included whether bilateral hip measurements are appropriate for diagnostic classification or monitoring, as well as which bilateral hip regions of interest should be reported for diagnosis and monitoring. Additionally, the appropriate nomenclature for bilateral hip acquisition was defined. RESULTS: The literature review demonstrated that bilateral hip measurement is appropriate and diagnostic classification should be based on the lowest T-score at the right or left side femoral neck or total hip; the mean T-score should not be used for diagnostic purposes. Mean bilateral total hip is preferred for BMD monitoring. The terms hip, or total hip were deemed appropriate nomenclature instead of femur or total proximal femur. CONCLUSION: Bilateral hip acquisition is clinically appropriate and reporting and nomenclature standards are offered herein when a bilateral hip study is acquired. In terms of future research, the impact of discordant hips on diagnosis and monitoring was identified as a significant knowledge gap.

Deliberate Compensated Vasoplegia-A Novel Pharmaceutical Approach for Controlling Blood Pressure During Surgery for Pheochromocytoma.

BACKGROUND: The most dreaded adverse event of pheochromocytoma surgery is operative severe blood pressure fluctuations. Preoperative protocols with alpha-blockade have achieved controversial results. No study to date evaluated the use of operative protocols in pheochromocytoma patients. Deliberated compensated vasoplegia (DCV) is a novel pharmaceutical regimen developed at our institution to decrease severe hypertensive events. The aim of this study is to compare outcomes of pheochromocytoma resection with and without DCV protocol. METHODS: A retrospective analysis of all pheochromocytoma resections between the years 2012 and 2021 was performed. Resections performed with and without DCV protocol were compared. The primary outcome measured was the incidence of severe hypertension (MAP > 150 mmHg) during surgery. Secondary outcomes included other abnormal blood pressure measurements as well as perioperative data and complications. RESULTS: A total of 41 resections were included, 21 performed under DCV protocol, and 20 without the protocol. Analysis demonstrated no significant difference in preoperative parameters including tumor size, catecholamine levels, and preoperative alpha-blockade protocol. The use of DCV protocol resulted in significant decrease in severe hypertension incidence from 1.95 ± 3.6 to 0.03 ± 0.13 events/h, p = 0.008. Application of the DCV protocol was not associated with any other adverse events. CONCLUSIONS: This study suggests that DCV anesthesia protocol significantly decreases the incidence of severe hypertensive episodes during pheochromocytoma resection. This is the first study that describes a highly effective protocol for controlling hypertension in pheochromocytoma patients.

VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report.

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.

Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors.

BACKGROUND: Inhibitors of sodium-glucose co-transporter-2 (SGLT2i) were found to improve renal outcome in diabetic patients in large prospective randomized trials. Yet, SGLT2i may acutely reduce kidney function through volume depletion, altered glomerular hemodynamics or intensified medullary hypoxia leading to acute tubular injury (ATI). The aim or this study was to prospectively assess the pathophysiology of acute kidney injury (AKI) in patients hospitalized while on SGLT2i, differing ATI from pre-renal causes using renal biomarkers. METHODS: Serum and urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Ischemia Molecule (KIM)-1, markers of distal and proximal tubular injury, respectively, were determined in 46 diabetic patients who were on SGLT2i upon hospitalization with an acute illness. RESULTS: Serum and urine NGAL, but not KIM-1, were significantly increased in 21 of the patients who presented with AKI upon admission, as compared with 25 patients that maintained kidney function. Both serum and urinary NGAL correlated with the degree of impaired renal function, which in many cases was likely the result of additional acute renal perturbations, such as sepsis. CONCLUSIONS: Increased urinary and serum NGAL indicates that ATI, principally affecting distal tubular segments, may develop in some of the patients hospitalized with an acute illness and AKI while on SGLT2i. It is suggested that intensified medullary hypoxia by SGLT2i might be detrimental in this injury. By contrast, concomitantly unaltered KIM-1 might reflect improved cortical oxygenation by SGLT2i, and may explain an overall reduced risk of AKI with SGLT1i in large series. The independent potential of SGLT2i to inflict medullary hypoxic damage should be explored further.

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family.

We previously identified a highly consanguineous familial hypercholesterolemia (FH) family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect. LDL cholesterol (LDLc) values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a genome-wide association study could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole exome sequencing. After prioritizing all potential mutations, we identified the most promising candidate genes and tested them for segregation with the lowering trait. We transfected a plasmid carrying the top candidate mutation, microsomal triglyceride transfer protein (MTTP) R634C, into COS-7 cells to test enzymatic activity. The SNP score explained 3% of the observed variability. MTTP R634C showed reduced activity (49.1 nmol/ml) compared with the WT allele (185.8 nmol/ml) (P = 0.0012) and was marginally associated with reduced LDLc in FH patients (P = 0.05). Phenotypic variability in a FH pedigree can only partially be explained by a combination of common SNPs and a rare mutation and a rare variant in the MTTP gene. LDLc variability in FH patients may have nongenetic causes.

OPPORTUNISTIC EVALUATION OF BONE MINERAL DENSITY BY PET-CT IN HODGKIN LYMPHOMA PATIENTS.

Objective: Bone density loss and increased risk for osteoporosis are of concern in Hodgkin lymphoma (HL) patients. Routinely performed positron emission tomography-computed tomography (PET-CT) scans could be informative in assessing bone mineral density (BMD). Methods: This retrospective study included 80 adults with newly diagnosed HL treated with standard first-line chemotherapy regimens. PET-CT scans performed at diagnosis (PET-CT1), at the end of chemotherapy (PET-CT2), and at follow-up after remission (PET-CT3) were used to assess BMD changes by measuring lumbar vertebrae CT attenuation. A CT attenuation threshold of 160 Hounsfield units was used to define abnormal BMD. Results: Following chemotherapy, comparison of PET-CT2 with PET-CT1 revealed a mean (standard deviation) 14.2% (10.4%) BMD reduction (P<.001). On PET-CT3 performed at 14.6 (3.25) months after the last course of chemotherapy, a slight improvement (4.6% [10.4%]) in comparison to PET-CT2 was noted. Twelve patients (15%) converted from normal baseline BMD on PET-CT1 to abnormal BMD after chemotherapy on PET-CT2. Age, baseline BMD, and steroid cumulative dose were associated with BMD decline and risk for abnormal BMD after chemotherapy. No clinical fractures were reported, and only one rib fracture was incidentally captured (1.25%). Conclusion: HL patients treated with common first-line chemotherapies demonstrate a significant decline in bone density on routine PET-CT scans. Opportunistic use of PET-CT scan has the potential to detect HL patients at high risk for developing osteoporosis and to guide clinicians regarding monitoring and intervention. Abbreviations: BMD = bone mineral density; CT = computed tomography; DXA = dual-energy X-ray absorptiometry; HL = Hodgkin lymphoma; HU = Hounsfield units; L = lumbarvertebra; PET-CT = positron emission tomography-computed tomography; T = thoracic vertebra.

Clinical Spectrum and Mechanism of Acute Kidney Injury in Patients with Diabetes Mellitus on SGLT-2 Inhibitors.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) (such as canagliflozin, empagliflozin, and dapagliflozin) are widely used to treat patients with type 2 diabetes mellitus (T2DM) to improve glycemic, cardiovascular and renal outcomes. However, based on post-marketing data, a warning label was added regarding possible occurrence of acute kidney injury (AKI). OBJECTIVES: To describe the clinical presentation of T2DM patients treated with SGLT2i who were evaluated for AKI at our institution and to discuss the potential pathophysiologic mechanisms. METHODS: A retrospective study of a computerized database was conducted of patients with T2DM who were hospitalized or evaluated for AKI while receiving SGLT2i, including descriptions of clinical and laboratory characteristics, at our institution. RESULTS: We identified seven patients in whom AKI occurred 7-365 days after initiation of SGLT2i. In all cases, renin-angiotensin-aldosterone system blockers had also been prescribed. In five patients, another concomitant nephrotoxic agent (injection of contrast-product, use of nonsteroidal anti-inflammatory drugs or cox-2 inhibitors) or occurrence of an acute medical event potentially associated with AKI (diarrhea, sepsis) was identified. In two patients, only the initiation of SGLT2i was evident. The mechanisms by which AKI occurs under SGLT2i are discussed with regard to the associated potential triggers: altered trans-glomerular filtration or, alternatively, kidney medullary hypoxia. CONCLUSIONS: SGLT2i are usually safe and provide multiple benefits for patients with T2DM. However, during particular medical circumstances, and in association with usual co-medications, particularly if baseline glomerular filtration rate is decreased, patients treated with SGLT2i may be at risk of AKI, thus warranting caution when prescribed.

Hypoparathyroidism and central diabetes insipidus: in search of the link.

UNLABELLED: Two siblings (a 15-year-old boy and an 11-year-old girl) who presented with hypocalcemic seizure at the age of 2 years and 2 months (boy) and 2 years and 4 months (girl) were diagnosed with hypoparathyroidism. At the age of 3 years, the girl developed central diabetes insipidus with good response to desmopressin acetate treatment. The family history was unremarkable, and there was no consanguinity between the parents. The father is of Iraqi/Egyptian Jewish origin and the mother is of Iranian/Romanian Jewish origin. Sequence analysis of the candidate genes for isolated hypoparathyroidism encoding calcium-sensing receptor, parathyroid hormone, and glial cells missing homolog B did not reveal any mutations. Whole-exome sequencing identified a homozygous mutation in the autoimmune regulatory gene (AIRE), c.374A>G;p.Y85C, characteristic for Jewish Iranians with autoimmune polyendocrine syndrome type 1 (APS1), which was confirmed by the Sanger sequencing. Antibodies against the adrenal, pancreatic islet cell, ovary, thyroid, pituitary, celiac, and parietal cell were negative in both siblings, while anti-diuretic hormone antibodies were positive only in the girl. No other symptoms or signs of APS1 developed during all the years of follow-up. CONCLUSION: APS1 should be part of the differential diagnosis in children presenting with isolated hypoparathyroidism or hypoparathyroidism with central diabetes insipidus (CDI). These cases show that the AIRE mutation characteristic of Iranian Jews can also be found in non-Iranian Jews.

Cardiovascular Safety of Romosozumab vs. PTH Analogs for Osteoporosis Treatment: a Propensity Score Matched Cohort Study.

CONTEXT: Romosozumab, a monoclonal sclerostin antibody, is a recently approved highly potent anti-osteoporotic agent with osteoanabolic properties. Clinical use of Romosozumab is hindered by the fear of adverse cardiovascular (CV) events raised following the pivotal ARCH-trial. OBJECTIVE: To assess real-world CV safety of romosozumab vs. alternative osteoanabolic therapies used for treatment of severe osteoporosis. DESIGN: Data was obtained from TriNetX, a global federated health research network including real-time electronic medical records from 113 healthcare organizations with a total of 136,460,930 patients across 16 countries at time of analysis. Inclusion criteria were age ≥ 40 years, a diagnosis of osteoporosis and prescription of romosozumab or a PTH analog (teriparatide/abaloparatide) during 8.2019-8.2022. 1:1 propensity score matched cohorts were created using demographic variables, comorbidities, and medications. Kaplan-Meier analysis was used to estimate the probability of the outcomes. OUTCOMES: Incident 3-point major adverse CV event or death (3P-MACE) during 1-year of follow-up after the initial prescription. RESULTS: 5,626 and 15,986 patients met the criteria for romosozumab and PTH analog cohorts, respectively, with 5,610 patients per group following propensity score matching. 3P-MACE was significantly less frequent in the romosozumab vs. PTH analog cohort (158 vs 211 patients with an outcome, p=0.003) with reductions in the individual components of the composite outcome: myocardial ischemic events (31 vs 58, p=0.003); cerebrovascular events 56 vs 79, p=0.037; deaths (83 vs 104, p=0.099). CONCLUSIONS: In a diverse real-world setting, prescription of romosozumab for osteoporosis is associated with less adverse CV events when compared to PTH analog therapy.

Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, six-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered parathyroid hormone (PTH) tablet on serum markers of bone formation [N-terminal propeptide of Type I procollagen (PINP) and osteocalcin (OC)] and bone resorption [crosslinked C-telopeptide (CTX)], bone mineral density (BMD) and safety in postmenopausal women with low BMD or osteoporosis. In this 6-month, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3 and 6 months and BMD of lumbar spine, total hip and femoral neck was measured at 6 months. Biochemical marker changes were dose dependent with minimal or no effect at the two lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 month after oral PTH initiation (p < 0.0001), remained elevated through 3 months and were back to baseline at 6 months. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 months respectively (both p ≤ 0.02). At 6 months, 2.5 mg tablets increased mean BMD vs placebo of the lumbar spine by 2.7%, total hip by 1.8%, and femoral neck by 2.8% (all p ≤ 0.01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low bone mineral density or osteoporosis were treated with varying doses of the active part of parathyroid hormone [PTH(1-34)] or placebo given in daily oral tablets for 6 months. The highest oral PTH tablet dose (2.5 mg), produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in bone mineral density of the spine and hip were observed at the end of the 6-month study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). Objective: To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Method: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. Results: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. Conclusion: In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.