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EDITORIAL |
Division of Endocrinology and Metabolism, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Mara J. Horwitz, M.D., Division of Endocrinology, Falk 560, University of Pittsburgh School of Medicine, 3601 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: horwitz{at}pitt.edu.
Endocrine diseases caused by hormone deficiencies are commonly treated by replacement of the deficient hormones. For example, Addison’s disease is treated with oral glucocorticoids, autoimmune hypothyroidism with oral thyroxine, and premature ovarian failure with oral estrogen and progesterone. The availability of orally deliverable drugs makes this straightforward. However, when the deficient hormone in question is a protein, oral treatment presents problems because proteins are generally degraded by proteolytic digestive enzymes when delivered orally. This obstacle commonly is circumvented by sc injection of the peptide hormone in question (i.e. GH, insulin, 1-desamino-β-D-arginine vasopressin). So what is different about hypoparathyroidism, which also results from deficiency of PTH, a protein hormone? Why is this disorder not routinely treated by replacement of PTH? This is the subject of a series of reports by Winer et al. (1, 2, 3, 4), the most recent of which is included in this month’s Journal (4).
Hypoparathyroidism results from deficiency of PTH (5, 6, 7, 8, 9). This may be a congenital abnormality resulting in failure of the parathyroid glands to form, as exemplified by the DiGeorge syndrome, or may result from inactivating mutations in the parathyroid-specific transcription factor, glial-cell missing B. It may result from mutations in the PTH gene itself. A functional, congenital form of hypoparathyroidism results from activating mutations in the calcium-sensing receptor that tricks the parathyroid gland into believing that the host is hypercalcemic and, therefore, induces suppression of PTH secretion (5, 6, 8, 9). This syndrome is called autosomal dominant hypoparathyroidism. Hypoparathyroidism may also be an intentional or unintentional result of thyroid, parathyroid, and laryngeal surgery. It may also result from autoimmune attack on the parathyroid glands as a part of the type 1 polyglandular failure syndrome, or from the accumulation of copper (Wilson’s disease), or iron (hemochromatosis) in parathyroid cells, and/or their destruction by metastatic cancer, or invading sarcoid granulomas. Postsurgical, autoimmune/idiopathic, and autosomal dominant hypoparathyroidism are the most common varieties.
Why does PTH deficiency cause hypocalcemia? Although bone turnover is dramatically reduced in hypoparathyroidism, it does not play a major role in causing hypocalcemia in hypoparathyroidism. Instead, the hypocalcemia in hypoparathyroidism results principally from two other mechanisms (5, 6, 7, 8, 9). First, the loss of PTH results in a failure of renal 1,25 dihydroxyvitamin D [1,25(OH)2D] production, with a resultant reduction in the ability to absorb dietary calcium. Second, PTH is a potent anticalciuric agent in the distal convoluted tubule. Therefore, its loss results in striking increases in renal calcium excretion. As an illustration, the extracellular fluid compartment contains approximately 1,000 mg calcium; the glomerulus filters 10,000 mg/d, and the distal tubule reabsorbs 1,000 mg/d. PTH, through its anticalciuric actions on the distal convoluted tubule, can reduce renal calcium excretion to essentially zero. These numbers quantify the critical role of the kidney, and the potent anticalciuric effect of PTH. Thus, in pathophysiological mechanistic terms, the loss of PTH causes hypocalcemia through an indirect failure [through 1,25(OH)2D] of intestinal calcium absorption, and a direct failure to prevent renal calcium losses.
The standard treatment of hypoparathyroidism attempts to correct hypocalcemia with oral vitamin D analogs and calcium rather than with PTH replacement (5, 6, 8, 9). Large doses of oral calcium are given to augment intestinal calcium absorption. This is accompanied by large doses of vitamin D [to mimic the intestinal effects of the missing 1,25(OH)2D] or physiological doses of 1,25(OH)2D itself. The combined goal is to forcibly drive calcium transport across the intestinal epithelium in quantities sufficient to overwhelm the ability of the kidney to clear this intestinally derived calcium load, forcing the serum calcium to increase.
Although this is standard therapy, it is a slippery slope. Undertreatment or missed doses may result in persistent muscle cramps, paresthesias, and seizures. A much more worrisome problem is overtreatment, which results in hypercalciuria, hypercalcemia, nephrolithiasis, nephrocalcinosis, and renal failure, a regrettably common and severe adverse outcome in subjects with hypoparathyroidism (1, 2, 3, 4, 5, 6, 7, 8, 9). On reflection, this is not surprising. First, this therapeutic model is a tightrope walk, attempting to precisely balance forced intestinal calcium overabsorption with unavoidable, indeed intentional, renal calcium overexcretion. However, this is not a steady state. If the patient decides to ingest extra dietary calcium or if the subject becomes dehydrated, doses of calcium and vitamin D that had permitted a steady state of serum calcium with a normal glomerular filtration rate now cause mild to severe hypercalcemia. Thiazide diuretics, which stimulate calcium reabsorption at the distal convoluted tubule and are, therefore, also anticalciuric, are commonly used as an addendum to therapy in hypoparathyroidism for these reasons. However, they simply shift the tightrope to a new location, without changing its fragility.
Another reason for poor outcomes in hypoparathyroidism is that the therapeutic goal is often mistakenly believed to be achievement of a normal serum calcium, in the 9.0–10.5 mg/dl (2.25–2.63 mM) range. However, if the serum calcium is driven up to this degree by large doses of calcium and vitamin D, in the absence of PTH, massive and chronic hypercalciuria will occur, and this may lead to nephrolithiasis, nephrocalcinosis, and renal failure. Thus, the therapeutic goal is not to achieve eucalcemia but, instead, to provide the minimal amount of calcium and vitamin D required to achieve symptom relief without causing hypercalciuria. This means that routine 24-h urinary calcium measurements are de rigueur in the management of these patients and that the serum calcium target should be in the range of 8.0–9.0 mg/dl (2.00–2.25 mM), while maintaining a normal 24-h urine calcium excretion. There is one subset of patients with hypoparathyroidism who are particularly prone to hypercalciuria: those with autosomal dominant hypoparathyroidism (5, 6, 8, 9). This is because at baseline, before treatment, the constitutively active calcium receptor in the kidney activates renal calcium excretion. Thus, these patients are commonly hypercalciuric before treatment, and treatment inevitably worsens this, no matter what serum calcium concentration is desired.
Obviously, any therapy that might permit correction of hypocalcemia and its symptoms, without causing hypercalciuria and the risk of renal complications, would be an advance. Exogenous PTH may be capable of accomplishing these goals. So why do we not use PTH for the treatment of hypoparathyroidism? This is the subject of the studies by Winer et al. (1, 2, 3, 4). One reason is that hypoparathyroidism is not common and could be considered an orphan disease in pharmaceutical industry parlance. The market is too small to generate sufficient revenue to warrant the development of PTH as a drug for hypoparathyroidism and as a replacement hormone. It is also difficult to enroll a sufficient number of subjects to determine safety and dosing. In addition, because PTH has been used since the 1920s experimentally to treat hypoparathyroidism, it has no patent protection. Yet another reason is that PTH peptide is only available as an injection. Who would want to have daily injections, if an oral treatment like calcium and vitamin D was available? Finally, PTH is a peptide with a half-life of 5 min once it enters the circulation (10); it seems unlikely that a single daily dose would correct the mineral metabolic abnormalities 24 h/d.
This landscape has changed with the widespread availability since 2002 of injectable PTH(1–34) for the treatment of osteoporosis (11). Because PTH is now a drug, is available in a conveniently used pen, and because the pain of injection is minimal, it is possible and reasonable to ask whether PTH might be as effective as standard vitamin D and calcium therapy. One obvious advantage might be that PTH, with its anticalciuric efficacy, might permit correction of serum calcium without inducing hypercalciuria, nephrocalcinosis, or nephrolithiasis, an outcome that would be particularly attractive in patients with autosomal dominant hypoparathyroidism.
Collectively, the prior studies of the National Institutes of Health group (1, 2, 3) highlight the precarious renal status of these patients treated conventionally: 80% had reductions of glomerular filtration rate after years of conventional treatment with vitamin D and calcium, and 40% had nephrocalcinosis. Winer et al. (1, 2, 3) have shown that PTH can be effectively and safely administered to adults with several different types of hypoparathyroidism, and that this treatment compares very favorably to conventional therapy with calcium and vitamin D analogs. The serum calcium concentration can be maintained at slightly but statistically significantly higher levels, yet the PTH therapy results in lower urine calcium excretion than with conventional therapy, as one might have hoped with the use of PTH. This is particularly apparent in the group with autosomal dominant hypoparathyroidism. Given the brief half-life of PTH(1–34) (11), it is not surprising that in most of the studies, administration of PTH every 12 h results in superior (more stable) serum calcium profiles than once-daily treatment. The dose of PTH in these studies (25–75 µg/d) is slightly higher than that used therapeutically for the treatment of osteoporosis. This may reflect the lack of endogenous PTH in these subjects, the requirement of multiple dosing, or other factors. As anticipated, bone formation and resorption markers are low in subjects treated conventionally, but increase in response to PTH treatment. In the single study that lasted long enough to measure bone densitometry, no medically important changes in bone mineral density or bone mineral content were observed with PTH treatment (3).
The study in the current issue of the Journal (4) is important because it is the first to be directed toward children with hypoparathyroidism. Although the study is brief, it demonstrates that reasonable and stable serum calcium values can be obtained while acceptable urine calcium values are also obtainable. No control group treated with conventional oral vitamin D and calcium therapy was included, so whether the effects on renal calcium excretion were superior to conventional therapy, the principal goal of this strategy, remains unknown for now. One also wonders if even lower doses of PTH might have been satisfactory for serum calcium outcomes, and superior for urinary calcium outcomes, which seem to be trending upwards in the group receiving PTH every 12 h.
In the aggregate, these studies strongly suggest that there is a place for PTH in the therapeutic armamentarium for hypoparathyroidism. Obvious targets are: patients with autosomal dominant hypoparathyroidism who have hypocalcemic symptoms but cannot avoid significant hypercalciuria with standard therapy; patients with autoimmune or surgical hypoparathyroidism who have developed nephrocalcinosis and in whom hypercalciuria is particularly worrisome; perhaps patients who require short-term treatment of partial hypoparathyroidism after subtotal parathyroidectomy or thyroidectomy to allow earlier hospital discharge and outpatient tapering of PTH; or for patients with well-controlled, effectively treated hypoparathyroidism on oral calcium and vitamin D, who no longer can take oral medications.
As the authors are careful to point out, caveats are also in order. First, the Food and Drug Administration does not permit administration of PTH to children or adults younger than 24 yr of age because of the unknown risk of osteosarcoma (12, 13). Second, even in adults, PTH is not approved by the Food and Drug Administration for use in hypoparathyroidism. Third, the studies of Winer et al. are brief, and we have no information on the long-term skeletal effect of PTH in children or adults treated in this manner. Will it resemble the long-term skeletal loss of primary hyperparathyroidism (14), or will it mimic the anabolic skeletal effects of once per day treatment of osteoporosis (12)? And will it have beneficial or adverse effects on the growth plates of children with open epiphyses? We still need to see a head-to-head comparison of PTH vs. conventional therapy in children, and a dose-ranging study to define the optimal dose of PTH for this purpose. Finally, in the age of structural and empirical modeling of peptides, can a PTH analog be developed that provides long-term agonism and/or stability in the circulation, as for example occurs with 1-desamino-β-D-arginine vasopressin, long-acting insulins, and GnRH analogs? The studies of Winer et al. provide an important and novel advance in the conceptualization of the treatment of hypoparathyroidism. Hopefully, the authors and other investigators will continue to address the questions raised in this editorial in future studies.
Footnotes
This work was supported by National Institutes of Health Grants R-01 DK51081 and R-01 DK 073039.
Disclosure Statement: The authors have no conflicts to report related to the content of this article.
Abbreviation: 1,25(OH)2D, 1,25 dihydroxyvitamin D.
Received June 4, 2008.
Accepted July 15, 2008.
References
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