SPECIAL FEATURE

Editorial

Hypoparathyroidism: Is It Time for Replacement ?

Mara J. Horwitz and Andrew F. Stewart

Division of and Metabolism, The University of Pittsburgh School of , Pittsburgh, Pennsylvania 15213

ndocrine diseases caused by hormone deficiencies are com- iopathic, and autosomal dominant hypoparathyroidism are Downloaded from https://academic.oup.com/jcem/article/93/9/3307/2596495 by guest on 01 October 2021 E monly treated by replacement of the deficient hormones. the most common varieties. For example, Addison’s disease is treated with oral glucocorti- Why does PTH deficiency cause ? Although coids, autoimmune hypothyroidism with oral thyroxine, and bone turnover is dramatically reduced in hypoparathyroidism, it premature ovarian failure with oral estrogen and progesterone. does not play a major role in causing hypocalcemia in hypopar- The availability of orally deliverable drugs makes this straight- athyroidism. Instead, the hypocalcemia in hypoparathyroidism forward. However, when the deficient hormone in question is a results principally from two other mechanisms (5–9). First, the protein, oral treatment presents problems because proteins are loss of PTH results in a failure of renal 1,25 dihydroxyvitamin D generally degraded by proteolytic digestive enzymes when de- [1,25(OH)2D] production, with a resultant reduction in the abil- livered orally. This obstacle commonly is circumvented by sc ity to absorb dietary . Second, PTH is a potent antical- injection of the peptide hormone in question (i.e. GH, insulin, ciuric agent in the distal convoluted tubule. Therefore, its loss 1-desamino-␤-D-arginine vasopressin). So what is different results in striking increases in renal calcium excretion. As an about hypoparathyroidism, which also results from deficiency of illustration, the extracellular fluid compartment contains ap- PTH, a protein hormone? Why is this disorder not routinely proximately 1,000 mg calcium; the glomerulus filters 10,000 treated by replacement of PTH? This is the subject of a series of mg/d, and the distal tubule reabsorbs 1,000 mg/d. PTH, through reports by Winer et al. (1–4), the most recent of which is included its anticalciuric actions on the distal convoluted tubule, can re- in this month’s Journal (4). duce renal calcium excretion to essentially zero. These numbers Hypoparathyroidism results from deficiency of PTH (5–9). quantify the critical role of the kidney, and the potent antical- This may be a congenital abnormality resulting in failure of ciuric effect of PTH. Thus, in pathophysiological mechanistic the parathyroid glands to form, as exemplified by the Di- terms, the loss of PTH causes hypocalcemia through an indirect

George syndrome, or may result from inactivating mutations failure [through 1,25(OH)2D] of intestinal calcium absorption, in the parathyroid-specific transcription factor, glial-cell and a direct failure to prevent renal calcium losses. missing B. It may result from mutations in the PTH gene itself. The standard treatment of hypoparathyroidism attempts to A functional, congenital form of hypoparathyroidism results correct hypocalcemia with oral analogs and calcium from activating mutations in the calcium-sensing receptor that rather than with PTH replacement (5, 6, 8, 9). Large doses of oral tricks the into believing that the host is calcium are given to augment intestinal calcium absorption. This hypercalcemic and, therefore, induces suppression of PTH is accompanied by large doses of vitamin D [to mimic the intes- secretion (5, 6, 8, 9). This syndrome is called autosomal dom- tinal effects of the missing 1,25(OH)2D] or physiological doses inant hypoparathyroidism. Hypoparathyroidism may also be of 1,25(OH)2D itself. The combined goal is to forcibly drive an intentional or unintentional result of , parathyroid, calcium transport across the intestinal epithelium in quantities and laryngeal . It may also result from autoimmune sufficient to overwhelm the ability of the kidney to clear this attack on the parathyroid glands as a part of the type 1 intestinally derived calcium load, forcing the serum calcium to polyglandular failure syndrome, or from the accumulation of increase. copper (Wilson’s disease), or iron (hemochromatosis) in para- Although this is standard therapy, it is a slippery slope. Un- thyroid cells, and/or their destruction by metastatic cancer, or dertreatment or missed doses may result in persistent muscle invading sarcoid granulomas. Postsurgical, autoimmune/id- , , and . A much more worrisome

0021-972X/08/$15.00/0 Abbreviation: 1,25(OH)2D, 1,25 dihydroxyvitamin D. Printed in U.S.A. Copyright © 2008 by The Endocrine Society doi: 10.1210/jc.2008-1216 Received June 4, 2008. Accepted July 15, 2008.

For article see page 3389

J Clin Endocrinol Metab, September 2008, 93(9):3307–3309 jcem.endojournals.org 3307 3308 Horwitz and Stewart Hypoparathyroidism J Clin Endocrinol Metab, September 2008, 93(9):3307–3309 problem is overtreatment, which results in hypercalciuria, hy- the circulation (10); it seems unlikely that a single daily dose percalcemia, nephrolithiasis, nephrocalcinosis, and renal failure, would correct the mineral metabolic abnormalities 24 h/d. a regrettably common and severe adverse outcome in subjects This landscape has changed with the widespread availability with hypoparathyroidism (1–9). On reflection, this is not sur- since 2002 of injectable PTH(1–34) for the treatment of osteo- prising. First, this therapeutic model is a tightrope walk, attempt- porosis (11). Because PTH is now a drug, is available in a con- ing to precisely balance forced intestinal calcium overabsorption veniently used pen, and because the pain of injection is minimal, with unavoidable, indeed intentional, renal calcium overexcre- it is possible and reasonable to ask whether PTH might be as tion. However, this is not a steady state. If the patient decides to effective as standard vitamin D and calcium therapy. One obvi- ingest extra dietary calcium or if the subject becomes dehydrated, ous advantage might be that PTH, with its anticalciuric efficacy, doses of calcium and vitamin D that had permitted a steady state might permit correction of serum calcium without inducing hy- of serum calcium with a normal glomerular filtration rate now percalciuria, nephrocalcinosis, or nephrolithiasis, an outcome cause mild to severe hypercalcemia. Thiazide , which that would be particularly attractive in patients with autosomal Downloaded from https://academic.oup.com/jcem/article/93/9/3307/2596495 by guest on 01 October 2021 stimulate calcium reabsorption at the distal convoluted tubule dominant hypoparathyroidism. and are, therefore, also anticalciuric, are commonly used as an Collectively, the prior studies of the National Institutes of addendum to therapy in hypoparathyroidism for these reasons. Health group (1–3) highlight the precarious renal status of these However, they simply shift the tightrope to a new location, with- patients treated conventionally: 80% had reductions of glomer- out changing its fragility. ular filtration rate after years of conventional treatment with Another reason for poor outcomes in hypoparathyroidism is vitamin D and calcium, and 40% had nephrocalcinosis. Winer that the therapeutic goal is often mistakenly believed to be et al. (1–3) have shown that PTH can be effectively and safely achievement of a normal serum calcium, in the 9.0–10.5 mg/dl administered to adults with several different types of hypopar- (2.25–2.63 mM) range. However, if the serum calcium is driven athyroidism, and that this treatment compares very favorably to up to this degree by large doses of calcium and vitamin D, in the conventional therapy with calcium and vitamin D analogs. The absence of PTH, massive and chronic hypercalciuria will occur, serum calcium concentration can be maintained at slightly but and this may lead to nephrolithiasis, nephrocalcinosis, and renal statistically significantly higher levels, yet the PTH therapy re- failure. Thus, the therapeutic goal is not to achieve eucalcemia sults in lower urine calcium excretion than with conventional but, instead, to provide the minimal amount of calcium and therapy, as one might have hoped with the use of PTH. This is vitamin D required to achieve symptom relief without causing particularly apparent in the group with autosomal dominant hypercalciuria. This means that routine 24-h urinary calcium hypoparathyroidism. Given the brief half-life of PTH(1–34) measurements are de rigueur in the management of these patients (11), it is not surprising that in most of the studies, administra- and that the serum calcium target should be in the range of tion of PTH every 12 h results in superior (more stable) serum 8.0–9.0 mg/dl (2.00–2.25 mM), while maintaining a normal calcium profiles than once-daily treatment. The dose of PTH in 24-h urine calcium excretion. There is one subset of patients with these studies (25–75 ␮g/d) is slightly higher than that used ther- hypoparathyroidism who are particularly prone to hypercalci- apeutically for the treatment of osteoporosis. This may reflect the uria: those with autosomal dominant hypoparathyroidism (5, 6, lack of endogenous PTH in these subjects, the requirement of 8, 9). This is because at baseline, before treatment, the consti- multiple dosing, or other factors. As anticipated, bone formation tutively active calcium receptor in the kidney activates renal cal- and resorption markers are low in subjects treated convention- cium excretion. Thus, these patients are commonly hypercalci- ally, but increase in response to PTH treatment. In the single uric before treatment, and treatment inevitably worsens this, no study that lasted long enough to measure bone densitometry, no matter what serum calcium concentration is desired. medically important changes in density or bone Obviously, any therapy that might permit correction of hy- mineral content were observed with PTH treatment (3). pocalcemia and its symptoms, without causing hypercalciuria The study in the current issue of the Journal (4) is important and the risk of renal complications, would be an advance. Ex- because it is the first to be directed toward children with hypo- ogenous PTH may be capable of accomplishing these goals. So parathyroidism. Although the study is brief, it demonstrates that why do we not use PTH for the treatment of hypoparathyroid- reasonable and stable serum calcium values can be obtained ism? This is the subject of the studies by Winer et al. (1–4). One while acceptable urine calcium values are also obtainable. reason is that hypoparathyroidism is not common and could be No control group treated with conventional oral vitamin D and considered an orphan disease in pharmaceutical industry par- calcium therapy was included, so whether the effects on renal lance. The market is too small to generate sufficient revenue to calcium excretion were superior to conventional therapy, the warrant the development of PTH as a drug for hypoparathy- principal goal of this strategy, remains unknown for now. One roidism and as a replacement hormone. It is also difficult to also wonders if even lower doses of PTH might have been sat- enroll a sufficient number of subjects to determine safety and isfactory for serum calcium outcomes, and superior for urinary dosing. In addition, because PTH has been used since the 1920s calcium outcomes, which seem to be trending upwards in the experimentally to treat hypoparathyroidism, it has no patent group receiving PTH every 12 h. protection. Yet another reason is that PTH peptide is only avail- In the aggregate, these studies strongly suggest that there is a able as an injection. Who would want to have daily injections, if place for PTH in the therapeutic armamentarium for hypopar- an oral treatment like calcium and vitamin D was available? athyroidism. Obvious targets are: patients with autosomal dom- Finally, PTH is a peptide with a half-life of 5 min once it enters inant hypoparathyroidism who have hypocalcemic symptoms J Clin Endocrinol Metab, September 2008, 93(9):3307–3309 jcem.endojournals.org 3309

but cannot avoid significant hypercalciuria with standard ther- Disclosure Statement: The authors have no conflicts to report related apy; patients with autoimmune or surgical hypoparathyroidism to the content of this article. who have developed nephrocalcinosis and in whom hypercalci- uria is particularly worrisome; perhaps patients who require short-term treatment of partial hypoparathyroidism after sub- References total or to allow earlier hos- pital discharge and outpatient tapering of PTH; or for patients 1. Winer KK, Yanovski JA, Cutler GB 1996 Synthetic human parathyroid hor- mone 1–34 vs. and calcium in the treatment of hypoparathyroidism. with well-controlled, effectively treated hypoparathyroidism on JAMA 276:631–636 oral calcium and vitamin D, who no longer can take oral 2. Winer K, Yanovski JA, Sarani B, Cutler GB 1998 A randomized cross-over trial medications. of once-daily versus twice-daily 1–34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab 83:3480–3486 As the authors are careful to point out, caveats are also in 3. Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, Gerber LH, order. First, the Food and Drug Administration does not permit McGarvey C, Cutler GB 2003 Long-term treatment of hypoparathyroidism: a Downloaded from https://academic.oup.com/jcem/article/93/9/3307/2596495 by guest on 01 October 2021 administration of PTH to children or adults younger than 24 yr randomized controlled study comparing parathyroid hormone-(1–34) versus of age because of the unknown risk of osteosarcoma (12, 13). calcitriol and calcium. J Clin Endocrinol Metab 88:4214–4220 4. Winer KK, Sinaii N, Peterson D, Sainz Jr B, Cutler Jr GB 2008 Effects of once Second, even in adults, PTH is not approved by the Food and versus twice-daily parathyroid hormone 1–34 therapy in children with hypo- Drug Administration for use in hypoparathyroidism. Third, the parathyroidism. J Clin Endocrinol Metab 93:3389–3395 studies of Winer et al. are brief, and we have no information on 5. Thakker RV 2006 Hypocalcemia: pathogenesis, differential diagnosis and management. In: Favus MJ, American Society for Bone and Mineral Research, the long-term skeletal effect of PTH in children or adults treated eds. Primer on metabolic bone diseases and disorders of mineral metabolism. in this manner. Will it resemble the long-term skeletal loss of 6th ed. Washington, DC: American Society for Bone and Mineral Research; primary (14), or will it mimic the anabolic 213–215 skeletal effects of once per day treatment of osteoporosis (12)? 6. Goltzman D, Cole DEC 2006 Hypoparathyroidism. In: Favus MJ, American Society for Bone and Mineral Research, eds. Primer on metabolic bone diseases And will it have beneficial or adverse effects on the growth plates and disorders of mineral metabolism. 6th ed. Washington, DC: American of children with open epiphyses? We still need to see a head-to- Society for Bone and Mineral Research; 216–219 head comparison of PTH vs. conventional therapy in children, 7. Stewart AF 2007 Disorders of serum minerals. In: Andreoli TE, ed. Andreoli and Carpenter’s Cecil essentials of medicine. 7th ed. Philadelphia: Saunders/ and a dose-ranging study to define the optimal dose of PTH for Elsevier; 761–773 this purpose. Finally, in the age of structural and empirical mod- 8. Levine MA 2006 Hypoparathyroidism and . In: eling of peptides, can a PTH analog be developed that provides DeGroot L, Jameson LJ, eds. Endocrinology. 5th ed. Philadelphia: Elsevier Saunders; 1611–1636 long-term agonism and/or stability in the circulation, as for ex- 9. Stewart AF 2004 Translational implications of the parathyroid calcium re- ample occurs with 1-desamino-␤-D-arginine vasopressin, long- ceptor. N Engl J Med 351:324–326 acting insulins, and GnRH analogs? The studies of Winer et al. 10. Lindsay R, Nieves J, Henneman E, Shen V, Cosman F 1993 Subcutaneous provide an important and novel advance in the conceptualization administration of the amino-terminal fragment of human parathyroid hor- mone-(1–34): kinetics and biochemical response in estrogenized osteoporotic of the treatment of hypoparathyroidism. Hopefully, the authors patients. J Clin Endocrinol Metab 77:1535–1539 and other investigators will continue to address the questions 11. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, raised in this editorial in future studies. Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH 2001 Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344: 1434–1441 Acknowledgments 12. Tashjian AH, Gagel RF 2006 [human PTH(1–34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Min Res 21:354–365 Address all correspondence and requests for reprints to: Mara J. 13. Tashjian AH, Goltzman D 2008 On the interpretation of rat carcinogenicity Horwitz, M.D., Division of Endocrinology, Falk 560, University of Pitts- studies for human PTH(1–34) and human PTH(1–84). J Bone Min Res 23: burgh School of Medicine, 3601 Fifth Avenue, Pittsburgh, Pennsylvania 803–811 15213. E-mail: [email protected]. 14. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP 1999 A 10-year pro- This work was supported by National Institutes of Health Grants spective study of primary hyperparathyroidism with or without parathyroid R-01 DK51081 and R-01 DK 073039. surgery. N Engl J Med 341:1249–1255