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Understanding and Achieving Disease Control in Hypoparathyroidism

2nd European Shire Symposium on Hypoparathyroidism

October 11–12, 2018Prague, Czech Republic

Meeting Highlights

This meeting is initiated, organised and funded by Shire.Presenters are paid an honorarium by Shire for their participation in and consultation to this program.Code: VV-MEDCOM-9853, Date of preparation: December 2018© Shire 2018. SHIRE and the Shire logo are registered trademarksof Shire Pharmaceutical Holdings Ireland Limited or its affiliates.


INDEX Physiology of calcium, magnesium, and phosphate

regulation in the body

Maria Luisa Brandi

Current treatment guidelines: What do we need to update?

Jens Bollerslev

Who is the patient with hypoparathyroidism, with focus on special patient populations

Natalie Cusano

Anabolic and catabolic effects of parathyroid hormonein bone

Erik Fink Eriksen

Point–counterpoint discussion: What is the primary goal of treatment?

Bart Clarke and William Fraser

Hypoparathyroidism secondary to autoimmune disease

Eystein Husebye

Maintenance of mineral homeostasis and beyond: Distribution and actions of parathyroid hormone in multiple organ systems

William Fraser

Biochemical control, symptoms, and comorbidities in patients with hypoparathyroidism

Lars Rejnmark

Considerations for the management of hypoparathyroidism in pregnant, lactating, and postmenopausal patients

Natalie Cusano and Aliya Khan

Renal disease in the patient with hypoparathyroidism

Pascal Houillier

How effective is current therapy for achieving goals in patients with hypoparathyroidism

Moderator: Bart Clarke

Individualizing treatment for different subgroups of patients with hypoparathyroidism

Moderator: Michael Mannstadt

Importance of parathyroid hormone in maintaining mineral homeostasis: Actions at different receptors and importance of the C-terminus

Thomas Gardella

Defining inadequate control in patients with hypoparathyroidism: Results from Delphi panels

Neil Gittoes

Defining inadequate control: Consideration of patient cases

Claudio Marcocci

The nephrologist‘s perspective: Hypoparathyroidism, tissue calcification, and impaired renal function

Pascal Houillier and Gary Curhan

Impact of hypoparathyroidism on quality of life: Approaches to measurement and recent results

Heide Siggelkow

Managing hypoparathyroid patients in the future: New perspectives

Bart Clarke

Biology of calcium receptors: Actions in multiple organs and effects of mutations

Michael Mannstadt

Hypoparathyroidism, abnormal mineral homeostasis,and their consequences

Moderator: Maria Luisa Brandi

Session 1: The biology of mineral homeostasis, imbalance, and complications in hypoparathyroidism

Plenary Keynote Guided discussion Workshop

Session 2: Hypoparathyroidism in specific patient groups

Session 3: Treatment goals and interventions for hypoparathyroidism

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Physiology of calcium, magnesium, and phosphateregulation in the bodyProfessor Maria Luisa BrandiDepartment of Surgery and Translational Medicine University of Florence, Florence, Italy

Maria Luisa Brandi


Prof. Brandi opened the meeting with an overview of mineral homeostasis. Calcium, magnesium, and phosphate are common elements in the body that are highly important for health and are differentially distributed within cells1. Mineral homeostasis is largely regulated by the action of hormones such as parathyroid hormone (PTH) and calcitriol (Figure 1)1. Hormonal imbalance can often lead to abnormal levels of minerals in the body1,2.

Calcium (Ca) is the most abundant mineral in the human body; 99% of calcium is found in bones, about 0.5% in soft tissues, and 0.1% in the extracellular fluid.1 Normally, the body maintains calcium concentration within a narrow range.1 Multiple factors

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influence calcium absorption. Calcitriol facilitates intestinal absorption. Parathyroid hormone activates vitamin D by enhancing 1α-hydroxylase activity and thus indirectly induces intestinal absorption of Ca. In addition, PTH acts at the distal tubule of the nephron to stimulate reabsorption of Ca and thus increases Ca serum levels. Elevated phosphate levels cause precipitation of Ca as calcium phosphate.1 Calcium homeostasis can be disrupted by multiple diseases. Hypercalcemia can result from hyperparathyroidism and malignancy (due to tumor secretion of PTH-related peptide (PTHrP). Hypocalcemia may result from vitamin D inadequacy or resistance. HypoPT may follow surgery or may have autoimmune disease or genetic causes, among others.3

Figure 1. Role of PTH in mineral homeostasis1

CaSR, calcium sensing receptor; HypoPT, hypoparathyroidism; 25(OH)D, 25-hydroxycholecalciferol

Parathyroid glandsThyroid gland

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Session 1: The biology of mineral homeostasis, imbalance, and complications in hypoparathyroidism Back to index

REFERENCES:1. Blaine J, et al. Clin J Am Soc Nephrol. 2015;10:1257-1272.2. Hu MC, et al. Annu Rev Physiol. 2013;75:503-533. 3. Fong, J, Khan A. Canadian Fam Physician. 2012;58:158–162.4. Azevedo C, Saiardi A. Trends Biochem Sci. 2017;42:219-231. 5. Manghat P, et al. Ann Clin Biochem. 2014;51:631-656.6. Komaba H, Fukagawa M. Kidney Int. 2016;90:753-763.7. Bergwitz C, Jüppner H. Annu Rev Med. 2010;61:91-104.8. Lederer E. J Physiol. 2014;592:3985–3995.

9. Smith ER. Clin J Am Soc of Nephrol. 2014;9:1283-1303.10. Acar S, et al. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):88-105. 11. Gröber U, et al. Nutrients. 2015;7:8199-8226.12. de Baaij JH, et al. Clin Kidney J. 2012;5(Suppl 1):i15-i24. 13. Jahnen-Dechent W, Ketteler M. Clinical Kidney J. 2012;5(Suppl 1):i3-i14. 14. Quinn SJ, et al. Am J Physiol Endocrinol Metab. 2013;304:E724-E733.15. Riccardi D, Brown EM. Am J Physiol Renal Physiol. 2010;298:F485-F499.16. Hansen B-A, Bruserud Ø. J Intensive Care. 2018;6:21. 17. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-20.

Phosphorus is a structural component of nucleic acids, adenosine triphosphate, and the phospholipids of cell membranes. It plays a critical role in cellular signaling through phosphorylation reactions.4 About 85% of all phosphate in the body is in bone, 15% is intracellular and about 0.1% is extracellular. Phosphate is absorbed from the diet, stored in the skeleton, and excreted by the kidneys. 1,25(OH)2D stimulates absorption of phosphate from the intestine and phosphate is actively transported (by NPT2a, b, and c) from the intestinal lumen into the bloodstream.5,6 Reabsorption from the proximal tubule contributes to the maintenance of serum phosphate levels.1 Fibroblast growth factor 23 (FGF23) and PTH increase renal phosphate clearance,7 whereas calcitriol increases its reabsorption and raises serum phosphate levels.8 Fibroblast growth factor 23 can now be measured in blood9 and this may be useful for patient monitoring. Major causes of hyperphosphatemia include phosphate overload, excess bone resorption, decreased renal excretion, and deficiency of or resistance to FGF23.5 Hypophosphatemia may result from respiratory alkalosis, receipt of parenteral nutrition, hyperparathyroidism, and a large number of other conditions.5 Hypophosphataemic rickets results from abnormally elevated FGF23.10

Magnesium is an important mineral as it acts as a cofactor for about 300 enzymes; important physiological systems that require magnesium include the muscles and the cardiovascular and nervous systems.1,11 Magnesium absorption is dependent on two pathways present in both the intestine and the kidneys: passive paracellular transport via claudins and active transcellular pathways.12 Insufficient magnesium transport in the distal convoluted tubule owing to mutated magnesiotropic proteins leads to magnesium loss that cannot be compensated for in downstream tubule segments.12 Hypomagnesemia may be the result of diabetes mellitus, alcoholism, liver cirrhosis, protein malnutrition, diuretic therapy, and either hypocalcemia or hypokalemia.1,13 Hypermagnesemia may occur in patients taking lithium and in those with hypothyroidism, Addison disease, familial hypocalciuric hypercalcemia, or milk alkaline syndrome.1,13 It has also been suggested that mutations in the calcium-sensing receptor may disrupt magnesium homeostasis.14 Magnesium can also activate the calcium-sensing receptor (CaSR), and hypermagnesemia may lead to hypocalcemia.15,16 Therefore, normal magnesium levels must be maintained in patients with hypoPT.17

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Maintenance of mineral homeostasis and beyond:Distribution and actions of parathyroid hormone in multiple organ systemsProfessor William FraserUniversity of East Anglia, Norwich, UK

William Fraser

REFERENCES:1. Ureña P, et al. Endocrinology. 1993;133:617-623. 2. Usdin TB, et al. Front Neuroendocrinol. 2000;21:349-383.3. Levine MA. Endocr Dev. 2003;6:14-33.4. Khan M, Sharma S. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;

2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK499940/5. Silver J, et al. Nephrol Dial Transplant. 2012;27:1715-1720.6. Rattanakul C, et al. Biosystems. 2003;70:55-72. 7. Schaefer F. Novartis Found Symp. 2000;227:225-239.8. Logue FC, et al. J Clin Endocrinol Metab. 1990a;71:1556-1560. 9. Logue FC, et al. Clin Endocrinol. 1990b;32:475-483.10. Fraser WD, et al. Osteoporosis Int. 1998;8:121-126.11. Nickols GA. Blood Vessels. 1987;24:120-124.12. Enishi T, et al. J Med Invest. 2015;62:93-96.13. Zhang Y, Zhang DZ. Clin Chim Acta. 2018;482:40-45.


Dr. Fraser explained that the receptor for parathyroid hormone (PTH)-related peptide (PTHrP) is distributed in multiple organs, including the kidney, bone, cardiovascular system, adrenal gland, bladder, brain, breast, lungs, liver, skeletal muscle, ovaries, placenta, skin, spleen, stomach, uterus, and testes.1 The PTH type 2 receptor is present at high densities in many parts of the brain.2 Parathyroid hormone has multiple roles in the maintenance of mineral homeostasis. It promotes calcium reabsorption via the kidneys, stimulates resorption of bone, or alternatively, stimulates resorption of bone to release calcium, and drives 1,25 (OH)2D production in the kidneys, which results in increased calcium absorption via the gut.3 It also contributes to phosphate homeostasis.4 Hypoparathyroidism results in decreased serum calcium, calciuria, decreased activated vitamin D levels, increased serum phosphate, and increased fibroblast growth factor (FGF) 23 levels.5

Dr. Fraser emphasized that, in bone, PTH influences both resorption and formation.6 Stimulation of resorption or rebuilding depends on the pattern of exposure to PTH with anabolic effects depending on regular pulsatile exposure.7 The measurement of serum PTH over a 24-hour period has shown the existence of a circadian rhythm (Figure 1) that is absent in patients with primary hyperparathyroidism. Serum PTH showed a circadian rhythm in normal subjects, and an attenuated rhythm persisted in primary

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hyperparathyroidism.8-10 Parathyroid hormone has significant effects on the cardiovascular system.11 Acute administration of PTH relaxes smooth muscle and has vasodilatory and blood-pressure lowering effects.11 These actions of PTH may be related to the occurrence of hypotensive episodes that have been reported for patients treated with PTH(1–34).12 In contrast to the acute blood-pressure lowering effects of PTH, chronic exposure to high PTH is associated with hypertension, which was demonstrated in a meta-analysis of the clinical literature.13 However, the authors noted that due to the limited number of studies included in this analysis, more well-designed prospective cohort evaluations are needed to further understand this putative effect of the hormone.13 Thus, PTH has many important actions outside calcium and phosphate homeostasis and this may be reflected in the symptoms seen in hypoparathyroidism and the response to administration of this hormone.

Figure 1. Circadian rhythm for PTH in men and women8-10

Adapted from Logue FC, et al. J Clin Endocrinol Metab. 1990a;71:1556-1560; Logue FC, et al. Clin Endocrinol. 1990b;32:475-483; and Fraser WD, et al. Osteoporosis Int. 1998;8:121-126.

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Importance of parathyroid hormone in maintaining mineral homeostasis: Actions at different receptors and importance of the C-terminusProfessor Thomas GardellaMassachusetts General Hospital, Massachusetts, USA

Thomas Gardella


Dr. Gardella reflected that parathyroid hormone (PTH) and PTH-related peptide (PTHrP) act through the PTH type 1 receptor (PTH1R) to play important roles in facilitating calcium homeostasis and bone remodeling.1 He also emphasized that the N-terminal 34 amino acids of both peptides contain the minimal sequence required for PTH1R activation and signal transduction.1 He then described the actions of a long-acting PTH analogue that bound with enhanced affinity to the R0 conformation of the PTH1R, promoted sustained signaling after removal of the PTH analogue, and led to sustained increases in blood calcium in mice.2,3

Dr. Gardella continued his presentation with a discussion of carboxyl-terminal parathyroid hormone fragments (C-PTH). These are generated by both direct secretion from the parathyroid gland in relation to serum calcium levels and catabolism of PTH by Kupffer cells in the liver. Results from pre-clinical studies have suggested that C-PTH interacts with a putative C-PTH receptor

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to exert effects on calcium homeostasis and bone metabolism.4,5 It has been shown that levels of C-PTH are regulated by both extracellular calcium levels and renal function6 and that C-PTH fragments have distinct biologic effects. For example, the human PTH 7-84 fragment antagonizes the actions of the full-length hormone when given to parathyroidectomized rats.7 In addition, three residues in the PTH 58-84 fragment appear to play a key role in binding to the putative C-PTH receptor.8 The PTH 7-84 fragment acts via receptors that are presumably specific for C-PTH to exert a direct antiresorptive effect on bone that appears to be due, at least in part, to interference with osteoclast differentiation (Figure 1).9 In addition, C-PTH fragments have been shown to decrease levels of 1,25(OH)2D and to prevent hypocalcemia-induced 1,25(OH)2D synthesis.10

Figure 1. PTH(7-84) inhibits vitamin D-stimulated release of calcium from as well as vitamin D-stimulated proliferation of tartrate-resistant acid phosphatase multinucleated cell9

C-PTH, Carboxyl (C)-terminal fragments of parathyroid hormone; IL, interleukin; PGE, prostaglandin E; TRAP, tartrate-resistant acid

phosphatase; MNC, multinucleated cells; ctrl, control

(7–84) inhibits 45Ca release induced by VitD (also PGE2 and IL-11); (7–36) has no effect.

Mouse calvaria45Ca release

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REFERENCES:1. Cupp ME, et al. J Pharmacol Exp Ther. 2013;345:404-418.2. Maeda A, et al. Proc Natl Acad Sci U S A. 2013;110:5864-5869.3. Shimizu M, et al. J Bone Miner Res. 2016;31:1405–1412.4. Inomata N, et al. Endocrinology. 1995;136:4732-4740.5. Murray TM, et al. Endocr Rev. 2005;26:78-113.6. Brossard JH, et al. Clin Chem. 2000;46:697-703.7. Slatopolsky E, et al. Kidney Int. 2000; 58:753-761.8. Divieti P, et al. Endocrinology. 2005;146:1863-1870.9. Divieti P, et al. Endocrinology. 2002;143:171-176.10. Usatii M, et al. Kidney Int. 2007;72:1330-1335.

Attempts to clone this receptor have not yet been successful. Thus, there are a number of questions that remain to be answered regarding the C-PTH receptor, including whether or not it is a multi-subunit protein, the potential need for a companion/accessory protein for function, the nature of any signal transduction pathways, and the cells expressing the receptor. Dr. Gardella noted that there are a number of approaches that can be used to learn more about

the C-PTH receptor. CRISPR-Cas–gene-knockout libraries can be employed to identify genes required for C-PTH binding; antibodies or nanobodies can be used to tag, track, and purify the receptor; phosphoproteomics might permit identification of signaling pathways activated by the receptor; and RNA sequencing can be employed to identify gene pathways regulated by C-PTH.

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Biology of calcium receptors: Actions in multiple organs and effects of mutationsProfessor Michael MannstadtMassachusetts General Hospital, Boston, Massachusetts, USA

Michael Mannstadt


Dr. Mannstadt stated that the parathyroid hormone (PTH) is the principal regulator of calcium and that there are three mechanisms by which it can increase serum calcium: 1) promoting release from bone; 2) increasing reabsorption by the kidneys; and 3) elevating formation of calcitriol and thus absorption of calcium from the intestine.1 Release of PTH is modulated by calcium-sensing receptors (CaSRs), which belong to the family C G-protein-coupled receptors and are located on cells in the parathyroid gland and kidneys, as well as other organs including the duodenum.2 X-ray crystallography studies have shown that calcium alone is

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insufficient for full activation of these receptors. The presence of extracellular calcium ions above a threshold level is required for amino-acid-mediated CaSR activation, and amino acids (most notably tryptophan) increase the sensitivity of the receptor toward calcium. Thus, amino acids and calcium ions are best considered as co-agonists of CaSR.3 X-ray crystallography also revealed multiple binding sites for PO4

3- ions which are also crucial for structural integrity of the receptor. While Ca2+ ions stabilize the active state, PO4

3- ions reinforce the inactive conformation (Figure 1).3

Several different diseases are caused by mutations that alter the function of the CaSRs. Dr. Mannstadt presented the case of a patient with autosomal-dominant hypocalcemia (ADH) type 1, which is caused by activating mutations of the gene encoding the CaSR. These gain-of-function CaSR mutations result in increased sensitivity of parathyroid and renal cells to calcium levels, leading to hypocalcemia being perceived as normal.2,4 ADH type 1 is characterized by low calcium, elevated phosphate, often low magnesium, low but detectable PTH, and high urinary calcium clearance. Patients may be asymptomatic but may also present with muscle spasms and muscle cramping, paresthesias, and/or neuromuscular irritability.2

Dr. Mannstadt noted that two mechanisms lead to hypocalcemia in patients with ADH type 1: 1) low PTH levels for a given blood calcium concentration; and 2) decreased renal reabsorption of calcium.4 Patients with ADH and high urinary calcium are at high risk for renal complications, including nephrocalcinosis, kidney stones, and renal insufficiency.5 Management of patients with this disease is challenging and may involve no treatment in asymptomatic patients, calcium plus calcitriol (aiming for low serum calcium), thiazides, a PTH analog, and possibly new calcilytic agents that are currently in development.4-6

Figure 1. Activation mechanism of CaSR. Schematic diagram shows the equilibrium between the resting and active states of CaSR and the effects of L-amino acid and Ca2+ binding3

Extracellular

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REFERENCES:1. Mannstadt M, et al. Nat Rev Dis Primers. 2017;3:17055.2. Hannan FM, et al. J Mol Endocrinol. 2016;57:R127-142.3. Geng Y, et al. Elife. 2016 Jul 19;5:e13662.4. Roszko KL, et al. Frontiers Physiol. 2016;7:458.5. Mayr B, et al. Eur J Endocrinol. 2016;174:R189-208.6. Hannan FM, et al. Br J Pharmacol. 2018;175:4083-4094.7. Afzal M, Kathuria P. StatPearls Publishing; 2018. Available from: https://www.ncbi.

nlm.nih.gov/books/NBK459190/ Accessed October 2018.

Dr. Mannstadt continued by describing familial hypocalciuric hypercalcemia, which is associated with loss-of-function mutations in CaSR and can result in lifelong, mild hypercalcemia and PTH levels that are often normal or only slightly elevated as well as low urinary calcium. Patients are usually asymptomatic and may develop chondrocalcinosis with advancing age.6,7 He concluded by re-emphasizing the central importance of the CaSR in calcium homeostasis and the need for calcilytics to treat patients with gain-of-function mutations and calcimimetics to treat patients with loss-of-function mutations.6

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Anabolic and catabolic effects of parathyroid hormone in boneProfessor Erik Fink EriksenOslo University Hospital, Oslo, Norway

Erik Fink Eriksen

REFERENCES:1. Clarke B. Clin J Am Soc Nephrol. 2008;3: S131-S139.2. Melton LJ 3rd, et al. J Bone Miner Res. 1997;12:1083-1091.3. Kraenzlin ME, Meier C. Nat Rev Endocrinol. 2011;7:647-656.4. Langdahl BL, et al. Bone. 1996;18:103-108.5. Rubin MR, et al. J Bone Miner Res. 2008;23:2018-2024.6. Cusano NE, et al. J Clin Endocrinol Metab. 2013;98:137-144.7. Rubin MR, et al. J Bone Miner Res. 2011;26:2727-2736.8. Rubin MR, et al. J Bone Miner Res. 2018 Jul 4. doi: 10.1002/jbmr.3543. [Epub

ahead of print]9. Black DM, et al. N Engl J Med. 2003;349:1207-1215.10. Vahle JL, et al. Toxicol Pathol. 2004;32:426-438.11. Jolette J, et al. Regul Toxicol Pharmacol. 2017;86:356-365.12. Cipriani C, et al. J Bone Miner Res. 2012;27:2419-2428. 13. Natpar SmPC. 2018. http://www.ema.europa.eu/docs/en_GB/document_library/

EPAR_-_Product_Information/human/003861/WC500226450.pdf


Dr. Eriksen defined bone remodeling as a process by which bone is renewed to maintain strength and mineral homeostasis.1 He emphasized that low turnover is "good for bone" and that reducing turnover may decrease risk for fractures in patients with osteoporosis.2 Parathyroid hormone (PTH) acts on the bone to promote resorption and release of calcium into the circulation. In addition, it stimulates osteoblast differentiation and therefore bone formation.3 In patients with hypoparathyroidism (hypoPT), this remodeling sequence is prolonged vs healthy individuals (Figure 1).4 Dr. Eriksen suggested that this may have a positive effect on bone strength. It has been shown that patients with hypoparathyroidism (hypoPT) have bone mineral density (BMD) that is higher than age-matched controls as measured by dual-energy X-ray absorptiometry (DXA) and that markers of remodeling reflecting bone formation and bone resorption were significantly reduced in hypoPT patients compared to normal controls.5

Dr. Eriksen summarized data from clinical studies that have evaluated the effects of hormonal treatment on the bone in patients

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with hypoPT. Results from these trials indicated that this treatment was associated with increases in remodeling rate in both the trabecular and cortical compartments.6-8 He noted that the increase in bone remodeling in these patients was most pronounced during the first year of treatment and gradually declined thereafter.6 Dr. Eriksen hypothesized that this increase in remodeling rate might be associated with increased risk for fractures, but also noted that there are no data supporting this suggestion. He added that concurrent use of alendronate may reduce the anabolic effects of PTH in patients with osteoporosis.9

Toxicology studies revealed that lifelong treatment with PTH induced a dose-dependent increase in osteosarcoma in rats.10,11 In the case of rhPTH(1-84), evidence of an association with osteosarcoma exists in one animal species (rat), but this has not been seen in other animal species (e.g., monkey).12 He also emphasized that no cases of osteosarcoma were reported in clinical studies of rhPTH(1-84),13 and none have been reported to date in patients treated with rhPTH(1-84).

Figure 1. The cycle of bone remodeling in hypoPT and in normals4

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Renal disease in the patient with hypoparathyroidismProfessor Pascal HouillierUniversité Paris Descartes, Paris, France

Pascal Houillier

REFERENCES:1. Houillier P. Curr Opin Nephrol Hypertens. 2013;22:566-571.2. Nordin BEC. Clinical physiology and diagnostic procedures. Churchill Livingstone,

1976.3. Houillier P. Annu Rev Physiol. 2014;76:411-430. 4. Yamamoto M, et al. J Clin Endocrinol Metab. 2000;85:4583-4591.5. Maruani G, et al. J Clin Endocrinol Metab. 2003;88:4641-4648.6. Mitchell DM, et al. J Clin Endocrinol Metab. 2012;97:4507-4514.7. Underbjerg L, et al. J Bone Miner Res. 2013;28:2277-2285.8. Underbjerg L, et al. J Bone Miner Res. 2018;33:822-831.


Dr. Houillier began his presentation by noting that abnormal renal function can be a cause of hypocalcemia, and the kidneys are also adversely affected in patients with hypoparathyroidism (hypoPT). Changes in the extracellular calcium concentration affect several functions of the renal tubule. The calcium-sensing receptor (CaSR), initially identified in parathyroid gland cells, is also expressed in the kidneys and mediates effects of extracellular calcium on the renal tubule.1 Dr. Houillier emphasized that a very important abnormality in patients with hypoPT is the increased calcium excretion for a given calcium load that results from decreased reabsorption in the thick ascending limb (TAL) of the loop of Henle due to the deficiency of parathyroid hormone (PTH) (Figure 1).2

Parathyroid hormone and the CaSR determine handling of calcium and other divalent cations in the TAL of the loop of Henle. At low physiological concentrations, the parathyroid hormone (PTH) enhances calcium absorption via an increase in the permeability of the paracellular pathway. At higher concentrations, PTH also increases sodium chloride (NaCl) absorption and the transepithelial potential difference, which further increases divalent cation absorption. CaSR activation decreases paracellular pathway permeability to calcium and thereby inhibits divalent cation absorption in the TAL.3

The altered renal calcium handling in patients with hypoPT results in increased urinary loss (i.e., hypercalciuria).4,5 Results from adults with hypoPT have indicated that the disease is associated with impairment of renal function across all age groups6 as well as increased risk for nephrolithiasis.7 The long-term risk for renal disease in patients with hypoPT also increases with the level of calcium x phosphorus product, duration of disease, and number of hypercalcemic episodes.8 Dr. Houillier stated that these results support the need for tight control over serum and urinary calcium concentrations in patients diagnosed with hypoPT and the need for careful monitoring for the early development of renal disease.

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Figure 1. Renal tubular handling of calcium in patients with hypoPT2

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Impact of hypoparathyroidism on quality of life: Approaches to measurement and recent resultsProfessor Heide SiggelkowMVZ Endokrinologikum Göttingen, Göttingen, Germany

Heide Siggelkow


Dr. Siggelkow stated that the journey for patients with hypoparathyroidism (hypoPT) is complex and many patients may have a long delay in diagnosis1 and/or be poorly informed about the full spectrum of potential complications of their disease.2 Limited communication between healthcare professionals and patients may also result in doubts about the need for treatment, lack of preparation for potential complications, and poor adherence to therapy.3 Symptoms of hypoPT (e.g., fatigue, pain, muscle spasms, cognitive impairment, depression, anxiety), lack of adequate support, and disease-associated changes in relationships may all contribute to decreased well-being.4-6

She continued by noting that the negative impact of hypoPT on quality of life is supported by results from an investigation of well-being and mood in 25 female patients with postoperative hypoPT—who received standard treatment compared to age- and

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sex-matched controls who had developed hypothyroidism but not hypoparathyroidism. There was a clearly higher global complaint score and reduced quality of life for the patients with hypoPT vs those for women who had postsurgical hypothyroidism but normal parathyroid function.7,8 Results from other studies also indicated a high frequency of symptoms and decreased quality of life in patients with hypoPT.6,9-11 It has also been noted that the impairment of quality of life in patients with hypoPT was comparable to that for patients with depression, heart disease, or diabetes.11 A large-scale survey that included patients with hypoPT from multiple countries indicated a strong relationship between symptom severity and impairment of quality-of-life scores across all domains of SF-36 (Figure 1).12 Results from this study showed further that hypoPT also had adverse effects on sleep, ability to exercise and work, and on family relationships.12

Figure 1. Impact of hypoparathyroidism on health-related quality of life as assessed in the first large patient survey performed in multiple countries12

*Higher score indicates higher level of functioningSD, standard deviation

An apparently inverse relationship was observed between scores for hypoparathyroidism symptom severity and both HRQoL assessments (SF-36 and EQ-5D-5L), such that the higher the severity scores, the lower the HRQoL and health status

Mean ± SD SF-36 physical component summary scores were 44.3 ± 10.1, 36.6 ± 8.6, and 28.2 ±8.5 and mental health component summary scores were 44.4 ± 11.1, 33.9 ± 9.58, and 31.4 ±10.89 for patients with mild, moderate, and severe hypoparathyroidism symptoms, respectively

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REFERENCES:1. Li L, et al. Medicine (Baltimore). 2018;97:e9884.2. Cho NL, et al. Endocr Pract. 2014;20:427-446.3. Chapman SC, et al. Clin Endocrinol (Oxf). 2016;84:664-671.4. Shoback DM. N Engl J Med. 2008;359:391-403.5. Bilezikian JP, et al. J Bone Miner Res. 2011;26:2317-2337.6. Hadker N, et al. Endocr Pract. 2014;20:671-679.7. Arlt W, et al. Eur J Endocrinol. 2002;146:215-222.8. Sikjaer T, et al. J Bone Miner Res. 2016;31:1440-1448.

9. Bohrer T, et al. Zentralbl Chir. 2005;130:440-448.10. Astor MC, et al. J Clin Endocrinol Metab. 2016;101:3045-3053.11. Underbjerg L, et al. Clin Endocrinol (Oxf). 2018;88:838-847.12. Siggelkow H, et al. Poster presented at the 20th European Congress of Endocrino-

logy; 19–22 May, 2018; Barcelona, Spain.13. Cusano NE, et al. J Clin Endocrinol Metab. 2014;99:3694-3699.14. Vokes TJ, et al. J Clin Endocrinol Metab. 2018;103:722-731.15. Sikjaer T, et al. Osteoporos Int. 2014;25:1717-1726.

Results from studies of patients treated with recombinant human parathyroid hormone (rhPTH[1-84]) have indicated significant improvements from baseline in quality of life,13 and a post hoc comparison of changes in quality of life for Western European and North American patients who had rhPTH(1-84) or placebo added to standard therapy indicated that addition of hormonal treatment significantly improved role physical, vitality, and the physical component score on the SF-36 compared to placebo.14 In contrast, results from a 6-month study that included 62 patients with hypoPT indicated no significant effect of rhPTH(1-84) on quality of life.15

14

Guided discussion: Hypoparathyroidism, abnormal mineral homeostasis, and their consequencesModerator: Maria Luisa Brandi


• Dr. Brandi discussed whether a patient should be considered to be doing well if serum calcium levels are normal. Dr. Eriksen commented that PTH secretion is dependent on magnesium, and that serum magnesium should be in the upper end of the normal range (about 0.8 mmol/L). However, he also noted that serum magnesium may not accurately reflect intracellular magnesium levels. • One participant asked about the best approach for the management of a patient with ADH type 1. Dr. Mannstadt responded that administration of calcium and calcitriol should be targeted to achieve low-normal calcium levels and that administration of a thiazide diuretic might also be useful in these patients. He emphasized that calcilytics are the holy grail for the management of patients with ADH type 1.• Dr. Bollerslev commented that patients with both hypoPT and hyperPT have reduced quality of life and wondered why this is the case and whether there are studies comparing these two groups of patients. He also asked whether quality of life was more closely related to PTH levels or CaSR function. Dr. Mannstadt stated that there are no clear answers to these questions, but he did note that PTH1R in the brain could be activated by PTHrP. Dr. Siggelkow suggested pooling all available data from quality-of-life studies in patients with either hypoPT or hyperPT to address Dr. Bollerslev's initial question.

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• A participant asked whether there were differences in effects of rhPTH(1-84) on quality of life in patients from the RACE trial who were or were not responders to treatment. Dr. Mannstadt replied that subgroup analyses carried out to date have indicated that low quality of life at baseline is the only predictor of magnitude of improvement with rhPTH(1-84) treatment. • Dr. Siggelkow stated that her data suggests that biochemical control is associated with better quality of life in patients with hypoPT.• Another participant asked about the relationship between PTH levels and vascular calcification and Dr. Mannstadt stated that vascular calcification is related to the level of calcium x phosphate product.• It was asked how often magnesium should be monitored in patients with hypoPT. Dr. Mannstadt stated that our inability to monitor intracellular magnesium makes monitoring meaningless. Dr. Eriksen agreed, but also stated that serum and intracellular calcium are correlated. Dr. Fraser also thought that monitoring serum magnesium was not useful and suggested magnesium supplementation be tried in clinical practice for patients with signs/symptoms suggesting low magnesium. He also cautioned about the possibility of hypermagnesemia, particularly in patients with renal impairment.

15

Who is the patient with hypoparathyroidism, with focus on special patient populationsProfessor Natalie E. CusanoLenox Hill Hospital, New York, NY, USA

Natalie Cusano

REFERENCES:1. Powers J, et al. J Bone Miner Res. 2013;28:2570-2576.2. Underbjerg L, et al. J Bone Miner Res. 2013;28:2277-2285. 3. Underbjerg L, et al. J Bone Miner Res. 2015;30:1738-1744.4. Astor MC, et al. J Clin Endocrinol Metab. 2016;101:3045-3053.5. Hadker N, et al. Endocr Pract. 2014;20:671-679.6. Underbjerg L, et al. J Bone Miner Res. 2014;29:2504-2510.


Dr. Cusano noted that numerous studies have provided information about the demographics of hypoparathyroidism (hypoPT) in different countries and the characteristics of individuals with this condition. A report from the United States indicated that approximately 77,000 people have hypoPT. About 75% of this population have postsurgical hypoPT and approximately 75% are women.1 Data from the Danish National Hospital Patient Registry indicated that the overall prevalence of postsurgical hypoPT was approximately 22/100,000 people2 and for nonsurgical hypoPT it was 2.3/100,000.3 The prevalence of hypoPT in Norway has been estimated to be 9.4/100,000 people in the population.4 Assessment of biochemical data from a cohort of 197 patients with postsurgical hypoPT and 69 patients with nonsurgical disease indicated individuals in both groups had elevated urinary calcium.4 Interestingly, most of the patients in this study had not had urinary calcium prior to inclusion, suggesting that more education about the importance of this parameter is needed.

The web-based PARADOX study addressed demographics, diagnosis perceptions, current attitudes, medical management, current symptoms, acute episodes, comorbidities, personal life, and employment in 374 adults with hypoPT and showed that >50% of respondents experienced fatigue, muscle pain/cramping, paresthesia, tetany, joint or bone pain, pain or weakness in the extremities, mental lethargy, memory loss, anxiety, and/or sadness/depression.5 Data from the Danish National Patient Registry also

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showed an increased risk for psychiatric disease in patients with hypoPT (Figure 1).6

Many patients are being treated with moderate-to-high doses of active vitamin D analogs and many have hypercalciuria. Large percentages of patients with hypoPT complain of significant physical and mental health impacts of their disease. More research is needed to fully understand these patients.

Figure 1. Risk for psychiatric disease in patients with hypoPT6

CI, confidence interval; HR, hazard ratio; ICD, International Classification of Diseases

Risk for Psychiatric Disease

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16

Considerations for the management of hypoparathyroidism in pregnant, lactating, and postmenopausal patientsProfessor Natalie E. CusanoLenox Hill Hospital, New York, NY, USA

Natalie Cusano

REFERENCES:1. Brandi ML, et al. J Clin Endocrinol Metab. 2016;101:2273-2283.2. Shoback DM, et al. J Clin Endocrinol Metab. 2016;101:2300-2312. 3. Santoro N, et al. Endocrinol Metab Clin North Am. 2015;44:497-515.4. McKane WR, et al. J Clin Endocrinol Metab. 1995;80:3458-3464.5. Prince RL, Draper C. In. Lobo RA, Kelsey J, Marcus R (eds). Menopause: Biology

and Pathobiology. San Diego, CA: Academic Press; 2000:287-307. 6. Khosla S, et al. Trends Endocrinol Metab. 2012;23:576-581.7. Clarke BL, et al. Radiol Clin North Am. 2010;48:483-495.8. Duan Y, et al. J Clin Endocrinol Metab. 1999;84:718-722.9. Chawla H, et al. J Clin Endocrinol Metab. 2017;102:251-258.10. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-G20. 11. Shifren JL, Gass ML. Menopause. 2014;21:1038-1062.12. US Preventive Services Task Force. JAMA. 2017;318:2224-2233.


Dr. Cusano noted that menopause is associated with signs and symptoms that may be difficult to differentiate from those of hypoPT. For example, both conditions may be associated with cognitive dysfunction, depression, anxiety, and fatigue.1-3 Decreased estrogen levels during and after menopause can result in either increases or decreases in calcium levels (Figure 1).4,5

The main effect of estrogen is to inhibit bone resorption while maintaining bone formation.6,7 Estrogen inhibits bone resorption by direct effects on osteoclasts, and indirectly through effects on osteoblast/osteocyte and T cell regulation of osteoclasts.6 Removal of estrogen-mediated suppression of bone resorption allows calcium to move from the bone compartment to the extracellular compartment contributing to early postmenopausal bone loss.5 Decreased estrogen also increases renal excretion of calcium due to reduced tubular re-absorption,4 and decreased estrogen can also decrease absorption of calcium in the gut.5

Dr. Cusano stated that postmenopausal women with hypoPT have been reported to lose bone to a lesser extent than healthy controls; however, the impact on bone health (fragility, ability to withstand stress) is unknown.8 Results from one analysis of fractures in patients with hypoPT indicated that the risk for these events was significantly increased vs healthy controls and that it was particularly high in postmenopausal women.9

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Guidance for the management of postmenopausal women with hypoPT includes monitoring and adjusting standard therapy as needed and understanding that estrogen fluctuations may transiently impact serum calcium and alter symptoms.5 Treatment should be personalized and focused on patient well-being and quality of life,1,10 and a bone density scan should be considered at the time of menopause.11 As for all patients with hypoPT, one should consider reducing elevated urine calcium levels to within recommended levels, managing hyperphosphatemia to prevent a calcium-phosphate product that exceeds 55 mg2dL, and monitoring for long-term impact on kidney function and extraskeletal calcifications.1,10 Hormone replacement might be useful for symptom management, if the benefits outweigh therisks.12

Figure 1. Reduced estrogen levels can impact calcium homeostasis4,5

Increased Bone Resorption of Calcium

and Bone Loss4

Increased Renal Excretion of Calcium Due to Reduced Tubular

Reabsorption4,5

Decreased Calcium Absorption in the Gut4

EstrogenDeficiency

IncreasedExtracellular Calcium

Decreased Estrogen Can Increase or Decrease Calcium Levels

DecreasedExtracellular Calcium

DecreasedExtracellular Calcium

17

Considerations for the management of hypoparathyroidism in pregnant, lactating, and postmenopausal patientsProfessor Aliya Khan MDMcMaster University, Oakville Ontario, Canada

Aliya Khan

REFERENCES:1. Kovacs CS. Physiol Rev. 2016;96:449-547.2. Ardawi MS, et al. Eur J Endocrinol. 1997;137:402-409.3. Khan AA, et al. Eur J Endocrinol. 2018 Nov 1. doi: 10.1530/EJE-18-0541.4. Sefa R, et al. Urol Res. 2006;34:244-248.

5. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-20.6. Eastell R, et al. Br Med J. 1985;291:955-956.7. Bulloch MN, Carroll DG. J Pharm Pract. 2012;25:352-367.


Dr. Khan stated that there are several important considerations that should be addressed in the management of hypoparathyroidism in pregnant women: 1) What are the physiologic changes in serum calcium and the calcium regulating hormones during pregnancy? 2) What are the treatment targets for serum calcium during pregnancy? 3) How should management be modified to reduce the risk of maternal and fetal complications?

There are significant changes in mineral homeostasis during pregnancy in healthy women. These include a decrease in total albumin-bound calcium, initially decreased parathyroid hormone (PTH) which returns to low-normal levels in the third trimester,1 and a rise in calcitriol levels which increases by 2–3-fold by term.2 The elevated calcitriol leads to increased intestinal calcium absorption and suppression of PTH.1,3,4 Calcitonin also rises during pregnancy and may protect the maternal skeleton from demineralization.3 PTHrP rises by 3-fold and also contributes to the suppression of PTH.2 Calcium requirements increase during pregnancy due to fetal demand,1 but the rise in 1,25 dihydroxyvitamin D and PTHrP usually result in lower dose requirements for calcium and active vitamin D metabolites; however, increased requirements have been observed in some patients.3,5

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Hypoparathyroidism and hypocalcemia during pregnancy can lead to miscarriage, stillbirth, premature labor, and neonatal death.5,6 Maternal hypocalcemia can also cause a compensatory increase in PTH secretion by the newborn with skeletal demineralization.5 Maternal hypercalcemia will in turn suppress the fetal parathyroid glands and can result in hypocalcemia in the newborn.3

Dr. Khan continued with a summary of important considerations for decreasing the risk for maternal and fetal complications in the pregnant patient with hypoPT. Hydrochlorothiazide should be avoided during pregnancy3,7 and the dose of calcium and active vitamin D metabolites should be adjusted to achieve and maintain low- to mid-normal serum calcium levels.5 The patient should be closely monitored with assessment of albumin-corrected serum calcium, phosphate, and magnesium every 3 weeks, and she should be educated about the symptoms of hypo- and hypercalcemia.3,5 In addition, the pediatrician should be advised to assess the neonate immediately after birth and to monitor serum calcium.3,5,7 There should also be close coordination of care among the endocrinologist, obstetrician/gynecologist, pediatrician, and family physician.3

18

The nephrologist‘s perspective: Hypoparathyroidism, tissue calcification, and impaired renal functionProfessor Pascal HouillierUniversité Paris Descartes, Paris, France

Pascal Houillier

REFERENCES:1. Curhan G, Taylor EN. Kidney Int. 2008;73:489-496.2. Lemann J Jr. Raven Press. 1992;685-706.


Dr. Houillier presented a case focused on postsurgical hypoparathyroidism complicated by paresthesias, tetany, and nephrolithiasis. The case illustrated the increased risk for renal stones in a patient with hypercalciuria and the steps that can be taken to decrease the risk for calcium stone recurrence. It also underscores the importance of diet in management of patients at risk for renal stones. Additional key points during presentation of this case included the fact that the risk for renal stones increases with increased 24-hour urinary calcium in patients with idiopathic hypercalciuria (Figure 1).1 He also noted that high sodium intake increases urinary calcium excretion.2

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Figure 1. Relationship between urinary calcium excretion and the risk of renal stone occurrence in patients with idiopathic hypercalciuria1

CI, confidence interval; h, hour

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19

Session 2: Hypoparathyroidism in specific patient groups Back to index

The nephrologist‘s perspective: Hypoparathyroidism, tissue calcification, and impaired renal functionProfessor Gary Curhan Harvard Medical School, Boston, MA, USA

Gary Curhan

REFERENCES:1. Leaf DE, et al. Clin J Am Soc Nephrol. 2012;7:829-834.

The case presented by Dr. Curhan also focused on a patient with recurrent kidney stones, a young man with Diamond-Blackfan anemia who required frequent blood transfusions and chelating therapy with deferasirox for iron overload. The differential diagnosis for the patient’s recurrent stone formation was discussed as well as potential treatments to reduce his risk of stone recurrence. This probable diagnosis in this case was secondary hypoPT and it illustrates the fact that multiple conditions can lead to excess 1,25-vitamin D and that this, in turn, results in increased calcium absorption, risk for hypercalciuria, and increased risk for nephrolithiasis. Dr. Curhan concluded his presentation by observing that among stone formers with vitamin D deficiency a limited course of vitamin D repletion does not appear to increase mean urinary calcium excretion, although some individuals may have an increase. This suggests that vitamin D therapy, if indicated, should not be withheld solely on the basis of stone disease, but that 24-hour urinary calcium excretion should be monitored after repletion (Figure 1)1. He also emphasized that single urinary calcium measurements are not useful because of the high variability in urinary electrolyte concentrations over the course of the day. Twenty-four-hour urine collection is essential for accurate determination of urinary calcium levels.

Figure 1. Urinary calcium before and after vitamin D repletion in stone formers1

Baseline and follow-up (A) urinary calcium and (B) urinary sodium excretion for individual participants. Thick line indicates mean change.

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20

Hypoparathyroidism secondary to autoimmune diseaseUniversity of Bergen, Karolinska Institutet, Stockholm, Sweden

Eystein Husebye

REFERENCES:1. Husebye ES et al. N Engl J Med. 2018;378:1132-1141.2. Bruserud Ø, et al. J Clin Endocrinol Metab. 2016;101:2975-2983.3. Su MF, Anderson MS. Nature Rev Immunol. 2016;16:247-258.4. Alimohammadi M, et al. N Engl J Med. 2008;358:1018-1028.5. Kemp EH, et al. J Clin Endocrinol Metab. 2014;99:1064-1071.6. Li Y, et al. J Clin Invest. 1996;97:910-914.7. Chazenbalk GD, et al. J Clin Invest. 2002;110:209-217.8. Mahtab S, et al. J Clin Endocrinol Metab. 2016;102:167-175.9. Kemp EH, et al. J Clin Endocrinol Metab. 2009;94:4749-4756.


Autoimmune hypoparathyroidism is mainly seen as part of autoimmune polyendocrine syndrome type 1 (APS-1), which consists of hypoparathyroidism, Addison disease, and chronic mucocutaneous candidiasis.1 Other conditions that may be observed in these patients include insulin-dependent diabetes, primary hypogonadism, autoimmune thyroid disease, pernicious anemia, enteritis, alopecia, vitiligo, and enamel hypoplasia. The disease usually presents in childhood and adolescence, but many patients are not diagnosed until reaching adulthood.2 In most countries, APS-I is a rare disease with a prevalence of 1:100,000, but it may be more common in some countries or populations (e.g., 1:25,000 in Finland, 1:14,000 in Sardinia, and 1:9,000 in Persian Jews living in Israel).1

The diagnosis of APS-1 can be made by finding disease-causing mutations in the autoimmune regulator (AIRE) gene aided by clinical manifestations and presence of interferon omega auto-antibodies.1 Dr. Husebye emphasized that interferon omega auto-antibodies are a very good marker to the disease and that almost all patients are positive for them. He also mentioned that the AIRE gene encodes a critical transcription factor, which is primarily expressed in medullary thymic epithelial cells and contributes to the generation of central immune tolerance by promoting killing of autoreactive T cells.3 If the protein coded by AIRE is either nonfunctional or absent, autoreactive T cells can escape deletion and can initiate autoimmune disease.

NLRP5 (also termed NALP5) appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1.4 In one study, NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism and are absent in patients with APS-1 without hypoparathyroidism and healthy subjects.4 Thus, autoantibodies against NALP5 appear to be a diagnostic marker for this prominent component of APS-1.

Other investigations indicate that auto-antibodies directed against the calcium-sensing receptor (CaSR) and consequently cause it to be constantly stimulated are associated with autoimmune hypoparathyroidism (Figure 1).5,6 Dr. Husebye emphasized that auto-antibodies against APS-1 might be considered as analogous to auto-antibodies to the thyroid stimulating hormone receptor in Graves’ disease.7 He also noted that about 80% of patients with idiopathic hypoparathyroidism have evidence of T cell reactivity to CaSRs.8

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Dr. Husebye concluded by stating that autoimmune hypoPT is acquired and often seen in the context of APS-1. The most important diagnostic tools for APS-1 are interferon auto-antibodies and AIRE sequencing. NALP5 antibodies and CaSR autoimmunity are associated with hypoPT in patients with APS-1.

Figure 1. Analysis of CaSR, NALP5, and cytokine antibodies in APS-1 patient and control sera9

IL, interleukin

Antibody Assay

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Guided discussion: Individualizing treatment for different subgroups of patients with hypoparathyroidismModerator: Michael Mannstadt


• It was noted that some patients with hypoPT are asymptomatic and not diagnosed. It was discussed whether there would be any benefit in diagnosing these patients. Dr. Cusano suggested that these patients may not recognize their symptoms and might benefit from diagnosis and treatment. However, she also noted that there is not sufficient data to substantiate this suggestion. It was also noted that diagnosis of asymptomatic patients might also lead to identification of other family members with hypoPT. Checking for hypoPT in asymptomatic relatives of a hypoPT patient may reveal the presence of this disease.• An attendee asked whether there are differences between countries regarding replacement of calcium vs vitamin D supplementation as the predominant means of treatment? Dr. Mannstadt stated that he mainly uses calcitriol in his patients. Dr. Cusano stated that many of her patients lack sufficient calcium in their diets and require calcium supplementation. Dr. Khan suggested that calcium supplements are an excellent approach to lowering increased phosphate, especially when taken with food. Dr. Clarke stated that there are clear trends toward more use of calcium supplementation in the US and administration of vitamin D in Europe. He noted that these two approaches have never been compared in a clinical trial. Dr. Rejnmark remarked that hypoPT reflects reduced levels of two hormones (PTH and active vitamin D) and that the focus of treatment should be replacement of both hormones.

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• Another participant asked about the role of residual PTH in patients with hypoPT. Dr. Khan believed that residual PTH may have benefit in decreasing symptoms. She also noted that serum magnesium must be maintained at adequate levels to allow PTH secretion. Dr. Mannstadt also believed that patients with residual PTH have better outcomes than those without it.• Another attendee asked about the effects of chronic kidney disease on the risk for nephrolithiasis. Dr. Curhan stated that large cohort studies are needed to address this issue. • It was also asked whether there is any information regarding hypoPT patients who require dialysis? Drs. Curhan, Houillier, Khan, and Mannstadt all noted that very few of their patients were on dialysis. The challenge in these patients is to avoid recurrence of renal calcification after renal transplant which might result in renal failure and the requirement for a second transplant.• An attendee asked about the best approach for management of hypercalciuria in a patient with APS-I and Addison disease. Dr. Husebye stated that he had no clinical experience with such a patient.• A participant asked about the potential risks associated with the use of calcium-containing phosphate binders in patients with hypoPT. Dr. Curhan stated there is no conclusive evidence that calcium-containing phosphate binders increase the risk for adverse events compared to other binders.

22

Current treatment guidelines: What do we need to update?Professor Jens BollerslevFaculty of Medicine, University of Oslo, Norway

Jens Bollerslev

REFERENCES:1. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1–20.2. Astor MC, et al. J Clin Endocrinol Metab. 2016;101:3045-3053.

3. Cusano NE, et al. J Clin Endocrinol Metab. 2014;99:3694-3699.4. Vokes TJ, et al. J Clin Endocrinol Metab. 2018;103:722-731.5. Meola A, et al. J Endocrinol Invest. 2018;41:1221-1226.


Dr. Bollerslev stated that the European Society of Endocrinology (ESE) Clinical Guideline: Treatment of chronic hypoparathyroidism in adults, published in 2015, used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as the basis for the development process. This stepwise method involves defining clinical questions to be addressed in the guideline, carrying out systematic literature searches, and assessing the quality of the evidence to inform development of answers/recommendations.1 The analysis that provided the basis for the current guidelines indicated the existence of moderate evidence that most treatment regimens are capable of achieving normocalcemia, but there is no evidence for optimal treatment (drug choice, calcium target) with respect to mortality, cardiovascular disease, long-term renal function/nephrolithiasis, disability/sick leave, seizures/tetany, or severe hypocalcemia.1

The timing of guideline updates depends on whether new clinical data or treatments are available. Currently, a literature search has provided relatively little new clinical trial data, but some interesting and important results were recently reported. Patient surveys revealed that quality of life (QoL) was reduced in patients with hypoPT compared to normative data and even compared to patients with Addison disease. It was especially low among females with postsurgical disease. Importantly, 40% of patients with postsurgical hypoPT were receiving social benefits vs 10%

in the general population.2 Results from studies of patients treated with recombinant human parathyroid hormone (rhPTH[1-84]) have indicated significant improvements from baseline in quality of life,3 and a post hoc comparison of changes in quality of life for Western European and North American patients who had rhPTH(1-84) or placebo added to standard therapy indicated that addition of hormonal treatment significantly improved role physical, vitality, and the physical component score on the SF-36 compared to placebo.4 Dr. Bollerslev noted that the development of disease-specific questionnaires will help to clarify the effects of treatment on QoL in patients with hypoPT.

Dr. Bollerslev noted that the goals set forth in the ESE guidelines are achieved in only a minority of patients with hypoPT. An assessment of goal achievement indicated that 34% of patients met treatment targets on conventional therapy, 55% had increased urinary calcium excretion, and that 30% had nephrolithiasis (Figure 1).5 Therapy with parathyroid hormone (PTH) is reported to control these biochemical parameters, but there is a need for more data to fully understand the effects of this therapy on QoL. Dr. Bollerslev concluded by noting that the aim of guidelines is to help physicians navigate treatment options and that ultimately treatment must reflect what patients want. He also noted that more data from clinical trials may help to identify not adequately controlled patients.

Figure 1. Achievement of ESE treatment goals5

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PO, post-operative; Alb, albumin; h, hour

• Ninety patients with PO-HypoPT• Standard treatment for 3 years• Four targets:

• Alb-corrected calcium • Phosphate • Ca-phosphate product • 24 h calcium excretion

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Biochemical control, symptoms, and comorbidities in patients with hypoparathyroidismProfessor Lars RejnmarkAarhus University Hospital, Aarhus, Denmark

Lars Rejnmark


Dr. Rejnmark began his presentation by noting that patients with hypoparathyroidism (hypoPT) are at increased risk for comorbidities, such as renal insufficiency, nephrolithiasis, nephrocalcinosis, neuropsychiatric complications, infections, cardiovascular disease, and impaired quality of life.1-3 Renal complications may be particularly problematic. The risk for renal calcifications in patients with hypoPT is significantly higher than that in the general population1,4 and as many as 41% of patients with hypoPT may have estimated glomerular filtration rates <60 mL/minute.5 Dr. Rejnmark mentioned that it is not clear whether renal complications in patients with hypoPT are permanent or can be reversed by effective treatment. Other complications of hypoPT that occur significantly more often in patients with this disease vs the general population include ischemic heart disease, seizures, cataract, and neuropsychiatric disorders.1-3

Dr. Rejnmark stated that we know relatively little about the relationship between biochemical control and risk for complications in patients with hypoPT. However, a recent case-control study carried out by his group assessed correlations between indices of biochemical control and adverse health outcomes in postsurgical hypoPT.6 Results from this analysis indicated that lower time-weighted calcium levels were correlated with an increased risk for cardiovascular disease, and that elevated serum phosphate

levels were significantly related to increased risk for mortality and infections. A high-calcium x phosphate product was associated with increased mortality and elevated risk for renal disease. Mortality and risk of infections, cardiovascular diseases, and renal diseases increased with the number of episodes of hypercalcemia and with longer disease duration. Treatment with a relatively high dose of active vitamin D was associated with decreased mortality and lower risks for renal diseases and infections (Table 1)6.

Dr. Rejnmark concluded that the results presented support the view that biochemical regulation in hypoPT is of major importance for decreasing the risk of disease complications. Treatment should be titrated to avoid calcium levels that are too high or low and at keeping the calcium x phosphate product in the lower end of the normal range.

Table 1. Relationship between biochemical parameters and risk for complications in patients with hypoPT6

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REFERENCES:1. Underbjerg L, et al. J Bone Miner Res. 2013;28:2277-2285. 2. Underbjerg L, et al. J Bone Miner Res. 2014;29:2504-2510.3. Underbjerg L, et al. J Bone Miner Res. 2015;30:1738-1744. 4. Meola A, et al. J Endocrinol Invest. 2018;41:1221-1226. 5. Mitchell DM, et al. J Clin Endocrinol Metab. 2012;97:4507-4514.6. Underbjerg L, et al. J Bone Miner Res. 2018;33:822-831.

Values are adjusted ORs with 95% CIs.

Bold values indicate significant findings

(P<0.05).

Mortality Any cardiovascular disease

Any renal disease Any infection

Ionized calciumtw (mmol/L)

≤1.15 0.70 (0.22–2.28) 3.01 ( 1.03–8.82) 0.98 (0.51–1.90) 0.71 (0.37–1.36)

1.16–1.19 Reference Reference Reference Reference

≥1.20 0.99 (0.29–3.41) 3.01 (0.96–9.48) 1.32 (0.70–2.48) 0.95 (0.50–1.79)

Phosphatetw (mmol/L)≤1.14 Reference Reference Reference Reference

1.15–1.27 2.42 (0.66–8.86) 1.42 (0.52–3.85) 1.37 (0.72–2.62) 1.53 (0.77–3.04)

≥1.28 8.43 (2.26–31.53) 1.35 (0.50–3.68) 1.24 (0.65–2.40) 2.18 (1.12–4.26)Calcium phosphate producttw (mmol2/L 2)

≤2.61 Reference Reference Reference Reference

2.62–2.92 4.47 (1.11–17.94) 0.50 (0.17–1.44) 1.02 (0.49–2.11) 0.76 (0.37–1.55)

≥2.93 6.85 (1.75–28.88) 0.65 (0.24–1.78) 2.07 (1.04–4.14) 1.28 (0.64–2.55)

Hypercalcemic episodes0 Reference Reference Reference Reference

1 to 3 3.39 (1.05–10.91) 1.19 (0.47–3.06) 3.05 (1.56–5.97) 1.65 (0.85–3.18)

≥4 2.09 (0.48–9.11) 9.69 (2.63–35.79) 3.31 (1.55–7.08) 2.74 (1.19–S.14)

Duration of disease (years)

≤7.2 Reference Reference Reference Reference

7.3–20.1 1.29 (0.33–5.09) 0.52 (0.16–1.76) 1.52 (0.77–3.02) 2.36 (1.17–4.77)

≥20.2 4.72 (1.09–20.43) 3.67 (1.11–12.05) 3.32 (1.58–6.96) 1.89 (0.88–4.05)

24

Defining inadequate control in patients withhypoparathyroidism: Results from Delphi panelsProfessor Neil GittoesUniversity Hospitals Birmingham, Birmingham, UK

Neil Gittoes


Dr. Gittoes, like other speakers, emphasized that the signs and symptoms of hypoparathyroidism (hypoPT) extend across multiple organ systems and that patients with this condition may present with central and peripheral nervous system, cardiovascular, respiratory, and renal complications, as well neuropsychiatric, ophthalmologic, dermatologic, dental, and musculoskeletal disease.1 The European Society of Endocrinology has provided recommendations for the personalized management of patients with hypoPT that are focused on achievement of biochemical control, restoring quality of life, and avoiding/managing complications.2 Conventional treatment for hypoPT consists primarily of calcium and active (or activated) vitamin D supplementation and this treatment may not achieve biochemical control in some patients. Even when biochemical control is achieved, quality of life may still be impaired and complications requiring hospitalization may occur. This raises the question of what constitutes inadequate control in a patient

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with hypoPT: biochemistry or more patient-focused outcome measures? A second important question is: What is the interface between biochemistry and perceived “wellness”?

Dr. Gittoes noted that many patients with hypoPT are not adequately controlled biochemically;3 and that hypoPT-associated symptoms and comorbidities result in the majority of patients reporting hospital stays or emergency department visits.4

Concerns about the burden of hypoPT have resulted in an organized effort to develop a consensus regarding what constellation of signs, symptoms, and patient-reported outcomes constitutes not adequately controlled hypoPT (Figure 1).2,5-9

Figure 1. Parameters important for defining adequate control, based on guidelines and evidence2,5-9

Adapted from Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-20;Clarke BL, et al. Endocrine. 2017;55:273-282;Brandi ML, et al. J Clin Endocrinol Metab. 2016;101:2273-2283;Sikjaer T, et al. J Bone Miner Res. 2016;31:1440-1448;Astor MC, et al. J Clin Endocrinol Metab. 2016;101:3045-3053; andUnderbjerg L, et al. Clin Endocrinol (Oxf). 2018;88:838-847.

*Values of normal serum calcium levels may vary by laboratory SF-36, 36-item short-form health survey; PO43-, phosphate; NAC, not adequately controlled

Bio

chem

istr

y

Symptoms, comorbidities and QoL impairment

Serum calcium level2• Reference range: 2.1–2.6 mmol/L*24-hr urinary calcium excretion5

• Reference ranges:• <7.5 mmol/24-hr (300 mg/24-hr) in men• <6.25 mmol/24-hr (250 mg/24-hr) in

womenCalcium x phosphate product2,5

• Reference range: <4.4 mmol2/L2

Serum phosphate level2• Reference range: 0.8–1.6 mmol/LSerum magnesium level2• Reference range: 0.65–1.05 mmol/L

Ca2+ PO43-

Abno

rmal

Nor

mal

Low High

Comorbidities• Continued monitoring and

management of renal stone disease, renal complications and other comorbidities5,6

QoL and symptoms• SF-367-9

• Prevent signs or symptoms of hypocalcemia5

More likely to be not adequately

controlled

More likely to be adequately

controlled

The darker the region in the graph the more likely is for the HypoPT patient to be NAC

25

Session 3: Treatment goals and interventions for hypoparathyroidism Back to index

REFERENCES:1. Mannstadt M, et al. Nat Rev Dis Primers. 2017;3:17080.2. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-20.3. Meola A, et al. J Endocrinol Invest. 2018;41:1221-1226.4. Hadker N, et al. Endocr Pract. 2014;20:671-679.5. Clarke BL, et al. Endocrine. 2017;55:273-282. 6. Brandi ML, et al. J Clin Endocrinol Metab. 2016;101:2273-2283.

7. Sikjaer T, et al. J Bone Miner Res. 2016;31:1440-1448.8. Astor MC, et al. J Clin Endocrinol Metab. 2016;101:3045-3053. 9. Underbjerg L, et al. Clin Endocrinol (Oxf). 2018;88:838-847.10. Rylands A, et al. Poster presented at the SfE BES Conference, Nov 6–8 2017,

Harrogate, UK.11. Virhage M, et al. Poster presented at SHEA Conference, Mar 14–15 2017, Lin-

köping, Sweden.

Delphi panel exercises have been carried out to gain insight into the variables that are most important to address in patients with hypoPT.10,11 These studies represent the first steps in defining patients with chronic hypoPT that are not adequately controlled on standard therapy. Results to date have indicated a high degree of consensus for defining not adequately controlled patients with hypoPT with respect to comorbidities and biochemical characteristics, particularly serum calcium levels. Other characteristics considered important or very important (≥80% consensus) included renal stones, renal calcification, chronic kidney disease, gastrointestinal

disorders, urinary calcium levels, serum creatinine, and muscle abnormalities (twitching or trembling). Dr. Gittoes concluded his presentation by stating that it is hoped that clearer identification of patients with not adequately controlled hypoPT may help to improve their management of long-term clinical outcomes and quality of life. He also noted that it is important for physicians to carry out extended discussions with patients so they are better informed about the consequences of hypoPT that, although they cannot feel symptoms, may result in long-term complications.

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Defining inadequate control: Consideration of patient casesProfessor Claudio MarcocciDepartment of Clinical & Experimental Medicine, University of PisaPisa, Italy

Claudio Marcocci


Dr. Marcocci presented several cases focused on defining inadequate control in patients with hypoparathyroidism (hypoPT). The first was a 56-year-old woman with postsurgical hypoPT after total thyroidectomy (5 years previously) for multinodular goiter and intermittent paresthesia. She was being treated with calcitriol 0.5 μg, twice daily, calcium (as carbonate) 500 mg, twice daily, a calcium-rich diet, and levothyroxine 100 μg daily. The patient had elevated serum phosphate and hypercalciuria. Her treatment was altered by reduction of calcitriol to 0.25 and 0.5 μg daily doses and calcium was reduced to 500 mg once daily. Amiloride/hydrochlorothiazide was added to treatment and the patient was placed on a low-sodium diet. Serum phosphate and urinary calcium declined into their respective normal ranges.

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The second case was a 48-year-old woman with postsurgical hypoPT after total thyroidectomy (3 years previously) for Graves’ disease. Her hypoPT was well controlled until 1 month prior to presentation when she began to experience paresthesia and intermittent muscle twitching and cramps. Her treatment regimen included calcitriol 0.25 μg, twice daily, calcium (as carbonate) 500 mg, three times per day, and levothyroxine 125 μg daily. Her serum calcium was slightly below the normal range and her serum phosphate was at the upper end of the normal range. The patient's medical history revealed that 3 months before she was advised to take pantoprazole 20 mg daily for reflux esophagitis. She is now asymptomatic. Her treatment was changed by increasing the daily dose of calcitriol 0.5 and 0.25 μg and substituting calcium citrate (two 200-mg tablets, twice daily). The patient's serum calcium moved into the normal range and she only occasionally experienced paresthesia.

Table 1. Drug therapy and diseases that may interfere with calcium1

Drug/disease Mechanism Possible adverse effects in HypoPT Action

Loop diuretics Increased urinary calcium losses May aggravate hypercalciuria and lower serum calcium levels

Avoid if possible

Thiazide diuretics Decreased urinary calcium losses May increase serum calcium levels May be used in a patient with HypoPT(see section “Treatment”)

Systemic glucocorticoids Decreased intestinal calcium absorption and increased urinary calcium losses

May cause hypocalcemia Avoid if possible

Antiresorptive drugs Decreased bone turnover May cause hypocalcemia Rarely needed, as HypoPT is a state of (very) low bone turnover

Proton pump inhibitors May cause hypomagnesaemia May lower serum calcium levels and cause symptoms similar to hypocalcemia

Avoid if possible – otherwise magnesium supplements, as needed

Chemotherapy: cisplatin, 5-fluorouracil, and leucovorin

May cause hypomagnesaemia May lower serum calcium levels and cause symptoms similar to hypocalcemia

Magnesium supplements, as needed

Cardiac glycosides (e.g. digoxin)

Hypercalcemia may predispose to digoxin toxicityHypocalcemia may reduce the efficacy of digoxin

Arrhythmias Avoid if possible. If needed, close monitoring by a cardiologist

Diarrhea/gastrointestinal disease

May reduce intestinal absorption of calcium and vitamin D

May cause hypocalcemia Close monitoring of serum calcium levels with dose adjustments as needed

Changes in (correction of) acid-base balance

The affinity of calcium to bind to. Proteins in serum is highly pH dependent – only the free fraction in physiological active

Correction of metabolic acidosis may cause hypocalcemiaCorrection of metabolic acidosis may cause hypercalcemia

Immobilization Increased bone resorption.In healthy individuals, PTH and 1,25-dihydroxyvitamin D levels are suppressed

May cause hypercalcemia

27


REFERENCES:1. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1–20. 2. Yang Y-X. Curr Gastroenterol Rep. 2012;14:473–479.

The third case was a 57-year-old woman with postsurgical hypoPT after total thyroidectomy (5 years previously) for Graves’ disease. Postoperative symptomatic hypocalcemia was treated with calcitriol 0.25 μg daily and calcium (as carbonate) 1000 mg, three times per day. The patient had low serum calcium and frequent emergency admissions for tetanic crises that were treated with intravenous calcium. Renal ultrasound revealed thinning of the renal cortex, initial nephrocalcinosis, and small kidney stones. Her treatment was changed to calcitriol 0.5 μg daily, calcium (as carbonate, 2500 mg divided in three doses), magnesium 250 mg daily, cholecalciferol 25,000 IU monthly, furosemide 25 mg daily, and levothyroxine 87.5 μg daily. Her serum calcium remained low, phosphate was elevated, urinary calcium was within the normal range, and her estimated glomerular filtration rate (eGFR) was 60 mL/minute. Further changes in treatment failed to achieve control in this patient and she was ultimately treated (off-label) with teriparatide (20 μg, twice daily) and this resulted in normal serum calcium levels, variable 24-hour urinary calcium, and eGFR of 72 mL/min.Dr. Marcocci emphasized that there are many potential reasons for failure of therapy to achieve adequate biochemical control. Importantly, one size does not fit all in the treatment of hypoPT, and conventional treatment is a "slippery road." Undertreatment may result in muscle cramps, paresthesias, and seizures; overtreatment may result in hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. Dr. Marcocci also noted that high doses of calcium are not completely absorbed and, if such doses are required, they should be split with administration 2 or 3 times per day. He also stated that concurrent diseases and additional drug therapy may interfere with calcium homeostasis (Table 1).1 Dr. Marcocci emphasized the potential complications that may arise with proton pump inhibitor treatment, including magnesium loss and increased gastric pH that may decrease calcium available for intestinal absorption.2

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Point–counterpoint discussion: What is the primary goal of treatment?Professor Bart L. ClarkeMayo Clinic College of Medicine, Rochester, MN, USA

Professor William FraserUniversity of East Anglia, Norwich, UK

Bart L. Clarke William Fraser


Dr. Clarke's discussion focused on prioritization of treatment goals in patients with hypoparathyroidism (hypoPT). It considered achievement of mineral homeostasis, relief of symptoms, prevention of long-term complications, and improvement of patients’ quality of life. He presented the case of a woman with chronic postsurgical hypoPT. She developed tingling paresthesia and muscle cramps without tetany on the day after surgery and was diagnosed with hypocalcemia and hyperphosphatemia. The patient was treated with calcium citrate 600 mg twice daily and calcitriol 0.5 mcg twice daily; vitamin D3 1000 IU was added after 3 months. Her 24-hour urine calcium 3 months later was 180 mg (normal female, <250 mg) and she felt well, with occasional muscle cramps and fatigue after exercise and with travel. There was no neurocognitive dysfunction and she has been maintained on this regimen for the last 5 years. Dr. Clarke mentioned that the subjective impression of patients as feeling well or unwell often corresponds to biochemical parameters and that patients may be able to verbalize their calcium requirements based on symptoms.

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Dr. Fraser's presentation concentrated on the treatment goals and approaches to patient management set forth in the European Society of Endocrinology Guideline.1 He considered the impairment in quality of life for patients with hypoparathyroidism (hypoPT)2 and reviewed a schema for evaluation of patients with hypoPT along two dimensions: 1) abnormal biochemical parameters, a failure to reach the target ranges for biochemical measurements as defined by current guidelines following treatment optimization regardless of whether or not they have symptoms; and 2) persisting symptoms and/or comorbidities that impact the management of the disease, complications resulting from the disease and/or its management, and/or requirement for substantial co-medication related to hypoPT regardless of their biochemical measurements.3

Dr. Fraser also provided practical advice for patient management. He noted some individuals with hypoPT cannot tolerate calcium supplementation and will not take it. These patients have to be managed with activated vitamin D and diet. He also mentioned that switching from calcitriol to alfacalcidol may result in a recovery of target calcium levels in a patient who is not adequately controlled. He also favored changing treatment guidelines to support the use of PTH administration in patients with hypoPT.

REFERENCES:1. Bollerslev J, et al. Eur J Endocrinol. 2015;173:G1-20.2. Sikjaer T, et al. J Bone Miner Res. 2016;31:1440-1448.3. Rylands A, et al. Poster presented at the SfE BES Conference, Nov 6–8 2017,

Harrogate, UK.

29


Guided discussion: How effective is current therapy for achieving goals in patients with hypoparathyroidismModerator: Bart Clarke

• One participant asked how we can increase adherence to the ESE treatment guidelines for hypoPT. Dr. Bollerslev answered that it was important to increase awareness about the disease and current approaches to treatment. Knowledge has to be spread. Dr. Gittoes stated that it may be useful to audit current treatment patterns as a first step to increasing adherence to guidelines. He said further that European reference networks for rare diseases may help with this process, but that some pressure needs to be applied. Dr. Rejnmark suggested that there is only limited data supporting the guidelines and that may be part of the reason that they are not followed. Dr. Clarke believed that there were too many guidelines available and that this creates confusion. Dr. Marcocci suggested that the "take home" messages in the guidelines should be incorporated into a short pocket guide. He also believed that education should be extended to general practitioners. • Another attendee asked how calcium samples should be measured? Dr. Marcocci stated that it was important to remember that calcium has a circadian rhythm. Dr. Fraser stated that it should be measured at a consistent time and before PTH administration if that is part of the treatment regimen. • A participant asked about the best time to administer PTH. The prescribing information for rhPTH(1-84) recommends once-daily administration at a dose ranging from 50-100 μg once daily.1

• There was considerable theoretical discussion regarding alternative approaches that might be employed for PTH administration. Dr. Fraser noted that PTH can have an acute hypotensive effect and that administering it at night might avoid a drop in blood pressure. However, he also suggested that the anabolic response to PTH might be better when it is delivered in the morning. Dr. Bollerslev believed that twice daily administration of PTH might more closely match normal physiological levels and Drs. Mannstadt and Houillier thought that delivery of PTH with a pump would be beneficial for some patients. Drs. Fraser and Gittoes both thought that therapy should be individualized to meet patients' needs. Dr. Fraser suggested that induction with PTH and conventional therapy followed by maintenance with conventional treatment may be effective in some patients.• It was asked whether a continuous ionized calcium monitoring option should be developed and employed in patients with hypoPT? Dr. Rejnmark suggested that this may make people more aware of their disease and it might permit them to react more quickly to changes in their symptoms. He also suggested that an algorithm would also have to be developed for adjustment of vitamin D dosing. Dr. Fraser emphasized that we do not yet have data indicating that this more complex approach to treatment would result in better outcomes than once- or twice-daily dosing. Dr. Bollerslev concluded this discussion by noting that treatment of hypoPT today is similar to the way in which diabetes was managed many years ago. The current guidelines raise many questions that can only be answered in new clinical trials.

REFERENCES:1. Natpar SmpC. 2018. Available at: https://www.ema.europa.eu/documents/pro-

duct-information/natpar-epar-product-information_en.pdf.

30

Managing hypoparathyroid patients in the future: New perspectivesProfessor Bart L. ClarkeMetabolic Bone Disease Core Group, Division of Endocrinology, Diabetes, Metabolism, and Nutrition; Mayo Clinic College of Medicine, Rochester, MN, USA

Bart L. Clarke


Dr. Clarke began his closing keynote presentation with an image from a study published in 1929 in which bovine parathyroid hormone (PTH) was administered to a 14-year-old boy with hypoparathyroidism (hypoPT).1 He used this study to make the point that it has long been recognized that replacing PTH is a highly desirable approach for patients with hypoPT, and multiple approaches have been employed to achieve this goal. Both rhPTH(1-84) and PTH(1 34) have been employed for the treatment of hypoPT.2-4, and rhPTH(1-84) is approved as adjunctive treatment of adult patients with chronic hypoPT who cannot be adequately controlled with standard therapy alone.5 Clinical study results have indicated that addition of rhPTH(1-84) to calcium and vitamin D supplementation was significantly superior to addition of placebo

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with respect to the proportion of patients at week 24 who achieved all 3 of the following criteria: 50% or greater reduction from baseline of oral calcium dose; 50% or greater reduction from baseline of active vitamin D dose; and maintenance of a stable albumin-corrected total serum calcium concentration greater than or equal to baseline concentration and less than or equal to the upper limit of normal, but ideally within the target range of 2.0–2.25 mmol/L.2 Results from the RACE trial further documented the safety and long-term efficacy of rhPTH(1-84).6 Dr. Clarke also presented results indicating that rhPTH(1-84) administration can significantly lower serum phosphate (Figure 1).3 Recently published results have also indicated that treatment with PTH(1-34) may result in hypocitraturia, a risk factor for nephrolithiasis, in some patients.7

Figure 1. Reduction in serum phosphate with rhPTH(1-84) treatment3

0.1

Seru

m P

hosp

hate

Cha

nge

From

Base

line,

mm

ol/L

0.0

-0.1

-0.2

-0.30 2 4 6 8 10 12 14 16 18 20 22 24

Week

rhPTH(1–84)Placebo

31


REFERENCES:1. Albright F, Ellsworth RJ. J Clin Invest. 1929;7:183-201.2. Mannstadt M, et al. Lancet Diabetes Endocrinol. 2013;1:275–283.3. Clarke BL, et al. Endocrine. 2017;55:273-282.4. Winer KK, et al. JAMA. 1996;276:631-636.5. Natpar SmPC. 2018. https://www.ema.europa.eu/medicines/human/EPAR/natpar.

Accessed October 2018.6. Clarke BL, et al. Poster GP180, presented at the ECE Congress 2018, Barcelona,

Spain.7. Gafni RI, et al. J Bone Miner Res. 2018; June 7 [Epub ahead of print].

8. Winer KK et al. J Clin Endocrinol Metab. 2012;97:391-399.9. Farra R, et al. Sci Transl Med. 2012;4:122ra21.10. Bi R, et al. J Bone Miner Res. 2016;31:975-984. 11. Karpf D, et al. Endocrine Absts. 2018;56:GP174.12. Krishnan V, et al. Br J Pharmacol. 2018;175:262-271.13. Al Riyami S, et al. J Bone Miner Res. 2017;SUN0284.14. Tamura T, et al. Nat Comm. 2016;7:13384.15. Codrons V, et al. J Pharm Sci. 2003;92:938-950.16. Schlosser K, et al. Trials. 2007;8:22.17. Hyun H et al. Nat Med. 2015;21:192-197.

Dr. Clarke continued by reviewing multiple approaches that have been or are being explored to increase patient convenience and to more closely match the temporal profile of PTH delivery/exposure to that in normal individuals. Approaches that employ current PTH molecules/analogues include twice- vs once-daily administration, the use of a pump to deliver PTH in a manner similar to that employed for insulin,8 and administration via an implantable wirelessly controlled microchip, which has been evaluated in women with osteoporosis, but not in patients with hypoPT.9 Another potential approach to delivery of existing PTH preparations suggested by Dr. Clarke is a closed loop system (bionic parathyroid gland) that includes a calcium sensor linked to a PTH pump.Several groups are engaged in efforts to develop longer-acting

PTH analogs.10-12 Other options being explored include orally bioavailable PTH analogues,13 oral PTH type 1 receptor agonists,14 and inhaled PTH.15 Transplantation of parathyroid glands (e.g., in the forearm) has also been carried out. This may result in restoration of a physiological PTH response, but the approach is limited by transplant rejection and a lifelong requirement for immunosuppression.16

Finally, improvements in neck surgery, such as better visualization of the parathyroid glands via administration of a fluorophore and near infrared illumination may decrease the rate of postsurgical hypoparathyroidism, which would be preferable to even the best treatment options.17

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2nd European Shire Symposium on Hypoparathyroidism

October 11–12, 2018Prague, Czech Republic

Meeting Highlights

This meeting is initiated, organised and funded by Shire.Presenters are paid an honorarium by Shire for their participation in and consultation to this program.Code: VV-MEDCOM-9853, Date of preparation: December 2018© Shire 2018. SHIRE and the Shire logo are registered trademarksof Shire Pharmaceutical Holdings Ireland Limited or its affiliates.

understanding and achieving disease control in ...€¦ · the nephrologist‘s perspective:...

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