Disease condition and impact on patients PTH is an essential hormone which is central to maintaining the integrity and physiological function of the skeletal system. The skeletal system is one of the largest organs in the body responsible for providing structural integrity across the lifespan; facilitating movement through the network of joints, connective tissue and muscles; protecting and supporting vital organs, including the brain, heart, lungs, liver and kidneys; and storage of essential minerals such as calcium and phosphate. The skeleton also contains bone marrow, which is responsible for haematopoiesis. The normal physiological functioning of the various organ systems is dependent on a healthy skeleton; conversely, skeletal health is a barometer of overall health. The PTH assay is used to diagnose and monitor disorders of PTH secretion, including hyperparathyroidism (primary, secondary and tertiary), pseudohypoparathyroidism and hypoparathyroidism. These disorders are associated with a significant health and economic burden worldwide such as chronic kidney disease (CKD) and osteoporosis. Bone mineral density (BMD) is predominantly determined by genetics, but adequate physical activity and nutrition both play vital role in attaining optimal peak BMD by young adulthood. Malnutrition is a significant problem affecting children in developing countries which affects growth and survival. In 2020, for children under 5 years of age, WHO estimated that 149 million had stunted growth (short for age), 45 million were underweight, and 45% of deaths were related to undernutrition. CKD is a significant cause of metabolic bone disease too. Causes of primary hyperparathyroidism include solitary adenomas, hyperplasia of the parathyroid glands and parathyroid cancer. The rates of primary hyperparathyroidism have been shown to be increased in populations characterized by social deprivation. Unlike developed countries, where identification and optimal management of predominantly asymptomatic cases of primary hyperparathyroidism are the focus, in developing countries over 70% are symptomatic at presentation with worse clinical outcomes. The widespread availability of PTH assays is important to narrow the gap caused by social disadvantage. Anterior neck surgery is the most common cause of acquired hypoparathyroidism, accounting for 75% of cases, with autoimmune and infiltrative disease also contributing to disease burden in adults. Genetic conditions such as 22q11 deletions are commonly responsible for hypoparathyroidism in the paediatric population. Hypoparathyroidism has been associated with a twofold increase in rates of fractures. Severe vitamin D deficiency with or without hypocalcaemia is characterized by hyperparathyroidism as a homeostatic response. The rates of nutritional rickets in children from developing countries has been estimated to be over 50% and represents a significant disease burden. Does the test meet a medical need? Measurement of PTH will facilitate the diagnosis and assist in the management of conditions which are prevalent and have significant economic costs in both developed and developing countries. These include CKD and osteoporosis, and other causes of abnormal PTH secretion leading to disorders of bone and mineral metabolism. How the test is used Determination of PTH level is useful in the differential diagnosis of both hypercalcaemia and hypocalcaemia, for assessing parathyroid function in CKD and for evaluating parathyroid function in bone and mineral disorders. Readers can refer directly to the application to review diagnostic algorithms on hypercalcaemia, hypocalcaemia, nonsurgical hypoparathyroidism, secondary osteoporosis and hyperparathyroidism. Note: the algorithms mentioned above were provided by the applicant as part of this application and are not WHO algorithms. The original application and the reviews are available in full at: https://www.dropbox.com/sh/dm1026anops6fe8/ AACmVfzPz9Tpn_eT1KGJ1h0Ya?dl=0 (accessed 14 April 2023). ■ CKD – use of PTH in guiding management of CKD In CKD, PTH measurement is utilized to assess parathyroid function, estimating bone turnover and guiding management. Established clinical practice guidelines are available (KDIGO – Kidney Disease Improving Global Outcomes) for the management of CKD mineral and bone disorder. Intact PTH levels are used to guide treatment in CKD, with current recommendations for evaluating modifiable factors (including hyperphosphataemia, hypocalcaemia, high phosphate intake and vitamin D deficiency) if levels are progressively rising or persistently above the upper range of normal in patients with CKD G1–G5, suggesting secondary hyperparathyroidism. Patients with high bone turnover caused by secondary hyperparathyroidism (advanced osteitis fibrosa) have the highest concentrations of PTH, whereas those with low-turnover, adynamic bone disease, including osteomalacia, have the lowest concentrations whether measured by whole or intact PTH assays. ■ Hypoparathyroidism – assessing completeness of parathyroidectomy In parathyroid surgery, intraoperative PTH is used to assess the effectiveness of removal as well as the risk of hypocalcaemia. Because of the short half-life of PTH (< 5 minutes), intraoperative intact PTH is often measured (just before incision and again 20 minutes after resection of hyperfunctioning parathyroid) to assess the completeness of parathyroidectomy. A decline of ≥ 50% or more suggests adequate removal.

Prevalence In a comprehensive systematic review and meta-analysis, the global prevalence of osteoporosis in adults, defined by WHO criteria as BMD that lies 2.5 standard deviations or more below average for age and gender, was estimated to be 18.3% (95% CI: 16.2–20.7) with an age range of 15–105 years and a sample size of 103 334 579 people. In 2017, the GBD Chronic Kidney Disease Collaboration estimated 697.5 million (95% CI: 649.2–752.0) cases of all-stage CKD for a global prevalence of 9.1%. CKD resulted in 35.8 million (95% CI: 33.7–38) DALYs. The burden of CKD was predominantly concentrated in the three lowest quintiles of the sociodemographic index. Socioeconomic impact Not provided.

Primary hyperparathyroidism: Khan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int. 2017;28(1):1–19. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151(10):959–68. Asymptomatic primary hyperparathyroidism: Bilezikian JP, Brandi ML, Eastell R, Silverberg SH, Udelsman R, Marcocci C et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3561–9. Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570–9. Secondary hyperparathyroidism in CKD: Executive summary of the 2017 KDIGO Chronic Kidney Disease – Mineral and Bone Disorder (CKDMBD) Guideline Update: what’s changed and why it matters [published correction appears in Kidney Int. 2017;92(6):1558]. Kidney Int. 2017;92(1):26–36. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009:S1–130. Secondary hyperparathyroidism after bariatric surgery: Fried M, Yumuk V, Oppert JM, Scopinaro N, Torres A, Weiner R et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Surg. 2014;24(1):42–55. Heber D, Greenway FL, Kaplan LM, Livingston E, Salvador J, Still C et al. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(11):4823–43. Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM et al. American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient – 2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Endocr Pract. 2013;19(2):337–72. Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L. American Society for Metabolic and Bariatric Surgery integrated health nutritional guidelines for the surgical weight loss patient 2016 update: micronutrients. Surg Obes Relat Dis. 2017;13(5):727–41. Perioperative use of PTH measurement: AES Guidelines 06/01 Group. Australian Endocrine Surgeons Guidelines AES06/01. Postoperative parathyroid hormone measurement and early discharge after total thyroidectomy: analysis of Australian data and management recommendations. ANZ J Surg. 2007;77(4):199–202. Orloff LA, Wiseman SM, Bernet VJ, Fahey TJ 3rd, Shaha AR, Shindo ML et al. American thyroid association statement on postoperative hypoparathyroidism: diagnosis, prevention, and management in adults. Thyroid. 2018;28(7):830–41. Pseudohypoparathyroidism: Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476–500.

PTH is currently measured by immunoassays, with liquid chromatography- tandem mass spectrometry methods only available in a research capacity. The circulating PTH forms detected by immunoassays include both intact hormone and “inactive” fragments. These fragments, which are devoid of N-terminal regions, are conventionally thought not to possess classic PTH activity. However, more recently, separate receptors for C-terminal PTH have been identified in bone cells and the actions of these fragments may affect the maturation and biological activity of these cells. C-terminal fragments have a very short half-life (< 1 hour) owing to rapid renal clearance via glomerular filtration. In individuals with normal renal function, 5–25% of total circulating PTH is intact hormone and 75–95% is C-terminal fragments. The half-life and circulating concentrations of fragments are increased in individuals with impaired renal function. Three generations of PTH assays have been developed (Henrich et al., 2006), necessitated by the heterogeneity of the PTH molecule in both the physiological state and various pathophysiological conditions (especially CKD). Antibodies used in immunoassays may be monoclonal or polyclonal antibodies purified by affinity chromatography to produce sequence-specific antibodies. For the quantitation of intact PTH (1–84), the carboxyl or middle region of the molecule (e.g. amino acid sequences 39–84, 44–84) are the usual targets of the capture antibody, while signal antibody is directed at the N-terminal amino acid sequence (1–34). However, the detection strategy is reversed in a number of methods, using capture antibodies against the N-terminal amino acid sequence (e.g. amino acids 26–32) and signal antibodies against the middle or C-terminal amino acid sequence (e.g. 55–64). A summary of the main characteristics of each generation of PTH assays follows. First generation (radioimmunoassays; no longer in clinical use): ■ First used in the 1960s. ■ Competitive immunoassay. ■ Used single polyclonal antibodies directed against the mid-, C-terminal portion of PTH. ■ Had issues with clinical sensitivity and specificity due to cross- reactivity with inactive PTH fragments. Second generation: ■ Developed with aim to measure only the intact molecule of PTH (1–84), collectively known as intact assays. ■ Noncompetitive (sandwich) immunometric assays with the capture and signal antibodies directed at different regions, either against the C-terminus or N-terminus (amino acids 1–34). ■ Use in diagnosis of primary hyperparathyroidism and in monitoring secondary hyperparathyroidism is well-established. ■ Overestimates the severity of PTH-related bone disease due to cross-reactivity with N-terminal-truncated fragments (PTH 7–84), which increases with worsening CKD. Third generation: ■ The epitope of N-terminally binding antibody consists of the first four to six amino acids of the PTH molecule. ■ Collectively known as true intact PTH assays, whole PTH assays, bioactive PTH assays or cyclase-activating PTH assays. ■ Currently no clear clinical advantage over second-generation assays. ■ Thought to also detect amino PTH (D’Amour et al., 2003), which has its amino-terminal serine residue in a phosphorylated form. Because early (first-generation) intact PTH assays measured N-terminal- truncated PTH, they overestimated the concentration of biologically intact hormone. The degree of overestimation is method dependent, with intact PTH 50% higher on average than PTH (1–8) measured by third-generation assays in patients with primary hyperparathyroidism or stage 5 CKD (Gao et al., 2001). There is a lack of harmonization between commercial PTH assays (Reichel et al., 2003), especially when measuring samples from patients with CKD or receiving haemodialysis. This has highlighted the importance of the production and implementation of a commutable international standard material (IS 95/646), an endeavour which has been adopted by a committee of the International Federation of Clinical Chemistry and Laboratory Medicine. Optimal sampling conditions: sample tube with EDTA is preferred, though some assays require serum (due to interference from EDTA of assay signal by chelation of divalent cations required for enzymatic action of alkaline phosphatase label). Storage: analysis within 72 hours if stored at 4°C. There is no consensus on the effects of storing samples at –20°C or –80°C. Reference intervals: reference intervals vary significantly with the method used. Typical intervals are: ■ intact PTH: 10–65 pg/mL or 1.1–68 pmol/L; and ■ PTH (1–84): 6–40 pg/mL or 0.6–42 pmol/L.

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No cost–effectiveness data are available.

Diagnosis and management of disorders of PTH secretion and action, including hyperparathyroidism, hypoparathyroidism, CKD and osteoporosis are significantly compromised in developing countries compared to developed countries, resulting in much worse outcomes. The availability of PTH measurement will go a long way to addressing some of these inequities. There are no ethical considerations.