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From synthesis to replacement of parathyroid hormone
Comment
Laguna Design/Science Photo Library
From synthesis to replacement of parathyroid hormone
Published Online October 7, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70145-1 See Articles page 275
260
40 years after human parathyroid hormone (hPTH) was first synthesised by John Potts at the Massachusetts General Hospital in Boston, and more than 10 years after the US Food and Drug Administration approved recombinant PTH for the treatment of osteoporosis,1 The Lancet Diabetes & Endocrinology report the results of Michael Mannstadt and colleagues’2 study of the efficacy of recombinant hPTH (rhPTH) to treat hypoparathyroidism. Hypoparathyroidism is a rare disease caused by deficient PTH production. This deficiency is revealed by clinical symptoms of neuromuscular excitability caused by hypocalcaemia, ranging from paraesthesia and muscle cramps to tetany and seizures. In infants, chronic hypocalcaemia can lead to stunted growth and developmental delay. Besides head and neck surgery and other procedures that can cause irreversible damage to the parathyroid tissue, known causes are autoimmunity to parathyroid cells, and genetic defects affecting parathyroid gland development or secretory function.3 In most patients, once diagnosed, hypoparathyroidism cannot be cured. The typical biochemical triad of untreated hypoparathyroidism consists of hypocalcaemia, inadequately low or absent PTH, and hyperphosphataemia. Hypocalcaemia results from decreased hydroxylation of 25-hydroxyvitamin D by the kidneys, causing reduced calcium absorption from the gut, diminished calcium reabsorption in the distal renal tubule, and reduced bone turnover. Hyperphosphataemia is secondary to decreased PTH-mediated phosphate excretion in the proximal renal tubule. Until now, treatment of hypoparathyroidism relied on oral vitamin D analogues and calcium supplements to force intestinal calcium absorption. Although this treatment abolishes symptoms of hypocalcaemia in most patients, it increases the filtered load of calcium in absence of PTH-driven calcium reabsorption, and often leads to nephrocalcinosis, renal stones, and chronic kidney disease.4 Physicians face a therapeutic challenge in managing chronic hypocalcaemia without causing longterm damage, and therefore advise their patients to avoid trying to reach normal serum concentrations of calcium. In the era of recombinant hormones, why is hypoparathyroidism not treated with hPTH? Currently,
the only commercially available PTH is teriparatide, a fully active peptide made of the N-terminal fragment (1–34) of rhPTH. Teriparatide restores normal calcium concentrations in patients affected with hypoparathyroidism,5 but has a half-life of only 1 h in the circulation unless it is administered via a subcutaneous pump.6 Another limitation to the development of rhPTH comes from one report of increased incidence of osteosarcoma in rats injected with very high doses of teriparatide.7 Subsequent studies in macaques and rats, and results from postmarketing surveillance, have not confirmed the association with cancer.8 But the restriction that was initially put on the use and development of rhPTH for treatment of hypoparathyroidism has remained. This restriction is why use of vitamin D and calcium supplements continues to outweigh teriparatide for treating hypoparathyroidism in clinical practice. In 2011, favourable effects of full-length rhPTH(1–84) as an add-on to conventional treatment were reported in a randomised controlled trial of 62 patients with deficient PTH.9 This finding led Mannstadt and colleagues2 to test rhPTH(1–84) in their large randomised, placebocontrolled, double-blind registration trial (REPLACE), in which 90 patients were randomly assigned to receive the recombinant hormone and 44 to receive placebo over a treatment period of 24 weeks. During treatment with rhPTH(1–84), vitamin D and calcium doses were reduced progressively when possible. The primary endpoint was a 50% or greater reduction in the daily doses of oral calcium and vitamin D with serum calcium concentration being maintained equal to or greater than baseline concentrations and less than or equal to the upper limit of normal at study end. Although 48 (53%) patients in the rhPTH(1–84) group achieved the primary endpoint, the endpoint was achieved by only one (2%) patient in the placebo group. Results of the REPLACE study show the efficacy, safety, and tolerability of a once-daily flexible-dose (ranging from 50 μg to 100 μg) of rhPTH(1–84) for 24 weeks in adults with hypoparathyroidism. However, several important issues should be considered in future studies. Renal protection should remain a high priority, and might be achieved with flexible rhPTH doses, regimens of administration, www.thelancet.com/diabetes-endocrinology Vol 1 December 2013
Comment
and routes of administration, and by monitoring 25-hydroxyvitamin D to enable long-term optimisation of the serum calcium to urinary calcium excretion ratio. Physicians should not overlook the pivotal role of PTH in the reduction of serum phosphate and prevention of calcium-phosphate precipitation within tissues such as kidneys and brain. In the REPLACE study,2 rhPTH(1–84) administration significantly reduced serum phosphate concentration and calcium– phosphate product from baseline, despite increasing serum calcium concentrations. Although this study only had a short-term follow-up, these findings are very encouraging for the long-term health of patients with hypoparathyroidism, and should be discussed with patients and their families when choosing a treatment. Children aged younger than 18 years and patients with a known activating mutation in the calciumsensing receptor gene10 did not take part in the study. Although allosteric modulators that target the calciumsensing receptor seem to be a more specific therapeutic approach in patients with an activating mutation, they have not yet been developed for clinical use. Until they are, further studies should assess the efficacy and safety of rhPTH in these patients, who can still have problems with cognitive development and a high risk of renal insufficiency. Mannstadt and colleagues2 confirmed the shortterm efficacy of rhPTH(1–84) to increase calcium and lower phosphate concentrations in patients with hypoparathyroidism. Their results now allow physicians to target normal calcium concentrations in their patients without constantly fearing hypercalciuria. Replacing full-length PTH in patients with hypoparathyroidism seems, unsurprisingly, to be more appropriate than
forcing absorption of calcium through the gut, and new indications and clinical development of this therapy are eagerly awaited by adult and paediatric endocrinologists. *Agnès Linglart, Anya Rothenbuhler Paediatric Endocrinology and Diabetology, French National Reference Centre for Rare Disorders of the Mineral Metabolism, AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre 94270, France (AL, AR); and Faculté de Médecine, Université Paris Sud, le Kremlin-Bicêtre, France (AL) [email protected] We declare that we have no conflicts of interest. We thank Pierre Bougnères and Caroline Silve for their thoughtful support. 1
2
3
4 5
6
7
8
9
10
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434–41. Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol 2013; published online Oct 7. http://dx.doi. org/10.1016/S2213-8587(13)70106-2. Bilezikian JP, Khan A, Potts JT Jr, et al. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res 2011; 26: 2317–37. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012; 97: 4507–14. Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1–34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA 1996; 276: 631–36. Linglart A, Rothenbuhler A, Gueorgieva I, Lucchini P, Silve C, Bougneres P. Long-term results of continuous subcutaneous recombinant PTH (1–34) infusion in children with refractory hypoparathyroidism. J Clin Endocrinol Metab 2011; 96: 3308–12. Vahle JL, Long GG, Sandusky G, Westmore M, Ma YL, Sato M. Bone neoplasms in F344 rats given teriparatide [rhPTH(1–34)] are dependent on duration of treatment and dose. Toxicol Pathol 2004; 32: 426–38. Andrews EB, Gilsenan AW, Midkiff K, et al. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years. J Bone Miner Res 2012; 27: 2429–37. Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L. The effect of adding PTH(1–84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study. J Bone Miner Res 2011; 26: 2358–70. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet 1994; 8: 303–07.
Restoring immune balance in type 1 diabetes Insulin replacement therapies—which include multiple daily doses of short-acting and long-acting insulin analogues, insulin pumps, and continuous glucose monitoring—have revolutionised the management of type 1 diabetes. Achieving near-normal glucose control and reduced rates of severe hypoglycaemia are feasible. However, even the most advanced insulin delivery technologies do not replace the capabilities of native β cells. Maintaining even partial β-cell function has www.thelancet.com/diabetes-endocrinology Vol 1 December 2013
consistently been shown to improve glucose control, and reduce the rates of secondary end-organ complications and severe hypoglycaemia. Therefore, to arrest the progression of β-cell destruction remains the ultimate target in managing this condition. But interventions that can achieve these goals need to have sustained effects without the risks of chronic immune suppression. The immune cells that are thought to cause destruction of insulin-producing β cells reside in the effector and
Published Online September 23, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70123-2 See Articles page 284
261
Laguna Design/Science Photo Library
From synthesis to replacement of parathyroid hormone
Published Online October 7, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70145-1 See Articles page 275
260
40 years after human parathyroid hormone (hPTH) was first synthesised by John Potts at the Massachusetts General Hospital in Boston, and more than 10 years after the US Food and Drug Administration approved recombinant PTH for the treatment of osteoporosis,1 The Lancet Diabetes & Endocrinology report the results of Michael Mannstadt and colleagues’2 study of the efficacy of recombinant hPTH (rhPTH) to treat hypoparathyroidism. Hypoparathyroidism is a rare disease caused by deficient PTH production. This deficiency is revealed by clinical symptoms of neuromuscular excitability caused by hypocalcaemia, ranging from paraesthesia and muscle cramps to tetany and seizures. In infants, chronic hypocalcaemia can lead to stunted growth and developmental delay. Besides head and neck surgery and other procedures that can cause irreversible damage to the parathyroid tissue, known causes are autoimmunity to parathyroid cells, and genetic defects affecting parathyroid gland development or secretory function.3 In most patients, once diagnosed, hypoparathyroidism cannot be cured. The typical biochemical triad of untreated hypoparathyroidism consists of hypocalcaemia, inadequately low or absent PTH, and hyperphosphataemia. Hypocalcaemia results from decreased hydroxylation of 25-hydroxyvitamin D by the kidneys, causing reduced calcium absorption from the gut, diminished calcium reabsorption in the distal renal tubule, and reduced bone turnover. Hyperphosphataemia is secondary to decreased PTH-mediated phosphate excretion in the proximal renal tubule. Until now, treatment of hypoparathyroidism relied on oral vitamin D analogues and calcium supplements to force intestinal calcium absorption. Although this treatment abolishes symptoms of hypocalcaemia in most patients, it increases the filtered load of calcium in absence of PTH-driven calcium reabsorption, and often leads to nephrocalcinosis, renal stones, and chronic kidney disease.4 Physicians face a therapeutic challenge in managing chronic hypocalcaemia without causing longterm damage, and therefore advise their patients to avoid trying to reach normal serum concentrations of calcium. In the era of recombinant hormones, why is hypoparathyroidism not treated with hPTH? Currently,
the only commercially available PTH is teriparatide, a fully active peptide made of the N-terminal fragment (1–34) of rhPTH. Teriparatide restores normal calcium concentrations in patients affected with hypoparathyroidism,5 but has a half-life of only 1 h in the circulation unless it is administered via a subcutaneous pump.6 Another limitation to the development of rhPTH comes from one report of increased incidence of osteosarcoma in rats injected with very high doses of teriparatide.7 Subsequent studies in macaques and rats, and results from postmarketing surveillance, have not confirmed the association with cancer.8 But the restriction that was initially put on the use and development of rhPTH for treatment of hypoparathyroidism has remained. This restriction is why use of vitamin D and calcium supplements continues to outweigh teriparatide for treating hypoparathyroidism in clinical practice. In 2011, favourable effects of full-length rhPTH(1–84) as an add-on to conventional treatment were reported in a randomised controlled trial of 62 patients with deficient PTH.9 This finding led Mannstadt and colleagues2 to test rhPTH(1–84) in their large randomised, placebocontrolled, double-blind registration trial (REPLACE), in which 90 patients were randomly assigned to receive the recombinant hormone and 44 to receive placebo over a treatment period of 24 weeks. During treatment with rhPTH(1–84), vitamin D and calcium doses were reduced progressively when possible. The primary endpoint was a 50% or greater reduction in the daily doses of oral calcium and vitamin D with serum calcium concentration being maintained equal to or greater than baseline concentrations and less than or equal to the upper limit of normal at study end. Although 48 (53%) patients in the rhPTH(1–84) group achieved the primary endpoint, the endpoint was achieved by only one (2%) patient in the placebo group. Results of the REPLACE study show the efficacy, safety, and tolerability of a once-daily flexible-dose (ranging from 50 μg to 100 μg) of rhPTH(1–84) for 24 weeks in adults with hypoparathyroidism. However, several important issues should be considered in future studies. Renal protection should remain a high priority, and might be achieved with flexible rhPTH doses, regimens of administration, www.thelancet.com/diabetes-endocrinology Vol 1 December 2013
Comment
and routes of administration, and by monitoring 25-hydroxyvitamin D to enable long-term optimisation of the serum calcium to urinary calcium excretion ratio. Physicians should not overlook the pivotal role of PTH in the reduction of serum phosphate and prevention of calcium-phosphate precipitation within tissues such as kidneys and brain. In the REPLACE study,2 rhPTH(1–84) administration significantly reduced serum phosphate concentration and calcium– phosphate product from baseline, despite increasing serum calcium concentrations. Although this study only had a short-term follow-up, these findings are very encouraging for the long-term health of patients with hypoparathyroidism, and should be discussed with patients and their families when choosing a treatment. Children aged younger than 18 years and patients with a known activating mutation in the calciumsensing receptor gene10 did not take part in the study. Although allosteric modulators that target the calciumsensing receptor seem to be a more specific therapeutic approach in patients with an activating mutation, they have not yet been developed for clinical use. Until they are, further studies should assess the efficacy and safety of rhPTH in these patients, who can still have problems with cognitive development and a high risk of renal insufficiency. Mannstadt and colleagues2 confirmed the shortterm efficacy of rhPTH(1–84) to increase calcium and lower phosphate concentrations in patients with hypoparathyroidism. Their results now allow physicians to target normal calcium concentrations in their patients without constantly fearing hypercalciuria. Replacing full-length PTH in patients with hypoparathyroidism seems, unsurprisingly, to be more appropriate than
forcing absorption of calcium through the gut, and new indications and clinical development of this therapy are eagerly awaited by adult and paediatric endocrinologists. *Agnès Linglart, Anya Rothenbuhler Paediatric Endocrinology and Diabetology, French National Reference Centre for Rare Disorders of the Mineral Metabolism, AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre 94270, France (AL, AR); and Faculté de Médecine, Université Paris Sud, le Kremlin-Bicêtre, France (AL) [email protected] We declare that we have no conflicts of interest. We thank Pierre Bougnères and Caroline Silve for their thoughtful support. 1
2
3
4 5
6
7
8
9
10
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434–41. Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol 2013; published online Oct 7. http://dx.doi. org/10.1016/S2213-8587(13)70106-2. Bilezikian JP, Khan A, Potts JT Jr, et al. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res 2011; 26: 2317–37. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012; 97: 4507–14. Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1–34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA 1996; 276: 631–36. Linglart A, Rothenbuhler A, Gueorgieva I, Lucchini P, Silve C, Bougneres P. Long-term results of continuous subcutaneous recombinant PTH (1–34) infusion in children with refractory hypoparathyroidism. J Clin Endocrinol Metab 2011; 96: 3308–12. Vahle JL, Long GG, Sandusky G, Westmore M, Ma YL, Sato M. Bone neoplasms in F344 rats given teriparatide [rhPTH(1–34)] are dependent on duration of treatment and dose. Toxicol Pathol 2004; 32: 426–38. Andrews EB, Gilsenan AW, Midkiff K, et al. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years. J Bone Miner Res 2012; 27: 2429–37. Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L. The effect of adding PTH(1–84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study. J Bone Miner Res 2011; 26: 2358–70. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet 1994; 8: 303–07.
Restoring immune balance in type 1 diabetes Insulin replacement therapies—which include multiple daily doses of short-acting and long-acting insulin analogues, insulin pumps, and continuous glucose monitoring—have revolutionised the management of type 1 diabetes. Achieving near-normal glucose control and reduced rates of severe hypoglycaemia are feasible. However, even the most advanced insulin delivery technologies do not replace the capabilities of native β cells. Maintaining even partial β-cell function has www.thelancet.com/diabetes-endocrinology Vol 1 December 2013
consistently been shown to improve glucose control, and reduce the rates of secondary end-organ complications and severe hypoglycaemia. Therefore, to arrest the progression of β-cell destruction remains the ultimate target in managing this condition. But interventions that can achieve these goals need to have sustained effects without the risks of chronic immune suppression. The immune cells that are thought to cause destruction of insulin-producing β cells reside in the effector and
Published Online September 23, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70123-2 See Articles page 284
261