Insogna, Karl

ABSTRACT In this narrative review, we present data gathered over four decades (1980–2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1–MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). Abstract The prevalence and incidence of PHPT vary around the world and depend on a number of factors, the most important being availability of serum calcium (and parathyroid hormone) measurement for screening, which in the Western world has shifted its presentation to an asymptomatic disorder. Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT, which may also occur as a part of inherited syndromes or as a nonsyndromic isolated endocrinopathy in 10% of cases. Genetic testing has roles in establishing the clinical diagnosis, although its value requires assessments using GRADE(176) methodology, which is recommended for future consideration.

ABSTRACT 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. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

Abstract Tumor-induced Osteomalacia (TIO) is a rare condition in which excess FGF23 produced by a tumor leads 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 with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS) were enrolled and received burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were changes in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. This report excludes 3/17 subjects who did not have TIO: 2 subjects diagnosed with X-linked hypophosphatemia post-enrollment and 1 subject with CSHS. Serum phosphorus increased from baseline (BL; 1.60 mg/dL) and was maintained after titration, from Week (W) 22 (2.85 mg/dL, dosing cycle midpoint) to W144 (2.56 mg/dL, dosing cycle endpoint, p<0.0001). Serum TmP/GFR and 1,25(OH)2D also increased with burosumab. Eleven subjects underwent paired bone biopsies at BL and W48. Osteoid volume/bone volume decreased from a mean ± SE of 17.6% ± 5.9% at BL to 12.1% ± 4.7% at W48 (p=0.086). Mean ± SE osteoid thickness decreased from 16.5 ± 3.6 µm to 11.3 ± 2.8 µm (p<0.05). Using imputation (Dempster et al. 2012), mineralization lag time decreased from a mean ± SE of 1598 ± 420 days to 1032 ± 712 days (p=0.41). Osteoid surface/bone surface showed no change from BL (mean ± SE BL: 57% ± 9%, W48: 57% ± 7%). Of 249 areas identified with increased uptake on bone scan at BL, 68 (27%) and 81 (33%) were fully healed at W96 and W144, respectively; 56 (23%) and 32 (13%) were partially healed at W96 and W144, respectively. Mean (SD) Global Fatigue Score decreased from 5.6 (2.5) at BL to 3.5 (3.0) at W48, and to 3.8 (2.2) at W144 (both p<0.01). All 3 domains of the Brief Pain Inventory decreased with burosumab (W144 Pain Severity and Pain Interference p<0.05), indicating reduced pain. The SF-36 mean (SD) physical component summary score increased from 33 (10) at BL to 39 (10) at W48 (p<0.05) and to 41 (12) at W144 (p<0.01), indicating improved physical functioning. The mean (SD) number of sit-to-stand repetitions, an assessment of proximal muscle function, increased from 6.7 (4.2) at BL to 8.5 (4.2) at W48 (n=10; p<0.01). All subjects had ≥1 adverse event (AE). Two subjects discontinued: 1 to undergo chemotherapy to treat an AE of neoplasm progression and 1 failed to meet serum phosphorus dosing criteria and therefore received minimal burosumab dosing. There were 16 serious AEs in 7 subjects, all unrelated to drug. Of the 6 subjects with a serious AE of tumor progression/compression, 5 had a history of tumor progression prior to enrollment. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in phosphate metabolism, osteomalacia, skeletal metabolism/fracture healing, physical functioning, fatigue, pain, and quality of life.