Tumor-Induced Osteomalacia : A Systematic Clinical Review of 895 Cases

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months–90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ − 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences

OR13-1 Burosumab Improves the Biochemical, Skeletal, and Clinical Symptoms of Tumor-Induced Osteomalacia Syndrome

Tumor-induced Osteomalacia (TIO) and Epidermal Nevus Syndrome with osteomalacia (ENS) are rare conditions in which ectopic production of FGF23 by tumor (TIO) and bone (ENS) lead to renal phosphate wasting, impaired 1,25(OH)2D synthesis, osteomalacia, fractures, weakness, fatigue and decreased mobility. In an ongoing open-label Phase 2 study (NCT02304367), 17 adults were enrolled and treated with burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were change in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. The per protocol (PP) analysis included 14/17 subjects who received 0.3-2.0 mg/kg burosumab every 4 weeks (W). Three subjects were excluded: 1 received subthreshold dosing (0.3 mg/kg at Day 0 and 0.15 mg/kg at W8, W32, and W72); 2 were diagnosed with X-linked hypophosphatemia post-enrollment. Ten subjects in the PP group had paired bone biopsies at baseline and W48. Mean ± SE histomorphometric values for the 8/10 subjects with osteomalacia at baseline were 20.4 ± 4.2 µm for osteoid thickness (OT), 23.0 ± 7.2% for osteoid volume/bone volume (OV/BV), and 66.1 ± 10.6% for osteoid surface/bone surface (OS/BS); baseline median (Q1, Q3) for mineralization lag time (MLT) was 1672 (1102, 2929) days. At W48, histomorphometric indices improved as shown by mean percentage changes in OT (37%), OV/BV (40%), OS/BS (-5%), and MLT (median percentage change -78%). Serum phosphorus, fatigue, and physical functioning are reported for the PP group. Mean (SD) serum phosphorus was 1.5 (0.3) mg/dL at baseline and 2.6 (0.8) mg/dL when averaged across the mid-point of the dose interval through W24. After W24, serum phosphorus, assessed only at the end of the dose interval, maintained this increase through W72. Mean (SD) Global Fatigue Score decreased from 5.3 (2.8) at baseline to 3.6 (2.9) at W48 (p=0.020) and to 3.3 (2.7) at W72 (p=0.004). The SF-36 mean (SD) physical component summary score increased from 34 (11) at baseline to 39 (10) at W48 (p=0.059) and to 42 (10) at W72 (p=0.003). Mean (SD) vitality score increased from 41 (14) to 47 (12) at W48 (p=0.075) and to 49 (12) at W72 (p=0.012). The mean (SD) number of sit-to-stand repetitions increased from 6.9 (4.0) at baseline to 8.6 (4.2) at W48 (n=10; p=0.004). By W72, all 17 subjects had ≥1 adverse event (AE). There were 13 serious AEs in 6 subjects, none were considered drug-related. Tumor progression occurred only in subjects with a history of tumor progression prior to enrollment. One subject discontinued treatment prior to W48 to treat tumor progression with chemotherapy. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in serum phosphorus, osteomalacia, mobility, quality of life, and reductions in fatigue

Burosumab for the Treatment of Tumor‐Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia

Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia:Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24-48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments

Working to Increase Stability through Exercise (WISE): screening, recruitment, and baseline characteristics

Background The aim of this paper is to describe the utility of various recruitment modalities utilized in the Working to Increase Stability through Exercise (WISE) study. WISE is a pragmatic randomized trial that is testing the impact of a 3-year, multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers or delivered via DVD on the rate of serious fall-related injuries among adults 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The modified goal was to recruit 1130 participants over 2 years in three regions of Pennsylvania. Methods The at-risk population was identified primarily using letters mailed to patients of three health systems and those over 65 in each region, as well as using provider alerts in the health record, proactive recruitment phone calls, radio advertisements, and presentations at community meetings. Results Over 24 months of recruitment, 209,301 recruitment letters were mailed, resulting in 6818 telephone interviews. The two most productive recruitment methods were letters (72% of randomized participants) and the research registries at the University of Pittsburgh (11%). An average of 211 letters were required to be mailed for each participant enrolled. Of those interviewed, 2854 were ineligible, 2,825 declined to enroll and 1139 were enrolled and randomized. Most participants were female (84.4%), under age 75 (64.2%), and 50% took an osteoporosis medication. Not having a prior fragility fracture was the most common reason for not being eligible (87.5%). The most common reason provided for declining enrollment was not feeling healthy enough to participate (12.6%). Conclusions The WISE study achieved its overall recruitment goal. Bulk mailing was the most productive method for recruiting community-dwelling older adults at risk of serious fall-related injury into this long-term physical activity intervention trial, and electronic registries are important sources and should be considered

Discordance between Genetic and Epigenetic Defects in Pseudohypoparathyroidism Type 1b Revealed by Inconsistent Loss of Maternal Imprinting at GNAS1

Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A–containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b

Madelung-like deformity in pseudohypoparathyroidism type 1b

Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. Patients were studied in an academic medical center. We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought

Madelung-Like Deformity in Pseudohypoparathyroidism Type 1b

CONTEXT: Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. DESIGN: Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. SETTING: Patients were studied in an academic medical center. RESULTS: We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1–13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. CONCLUSION: The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought