Treatment of hypoparathyroidism with vitamin D analogs and calcium does not restore normal physiologic regulation of calcium homeostasis in the bone and kidney and may lead to renal insufficiency due to progressive nephrocalcinosis. Replacement with PTH potentially addresses this problem but until recently, hypoparathyroidism was the only classic hormonal insufficiency state not treated with its missing hormone.
Over the past two decades, we have evaluated various PTH 1-34 regimens including once-daily and twice-daily PTH 1-34 injections without the use of calcitriol or Ca supplements in adults and children of all etiologies for up to 10 years. With increased frequency of injections, the total daily dose of PTH can be reduced, in most cases by at least 50% and serum calcium can be maintained in the normal range throughout the day with reduced fluctuation. Lower doses produce less stimulation to the bone and reduced the risk of transient episodes of hypercalciuria. For each regimen, the PTH 1-34 dosage was individualized throughout treatment to maintain optimal calcium homeostasis.
To further refine replacement therapy, we recently studied PTH delivery by insulin pump compared with twice daily injections. Pump delivery produced normal, steadystate calcium levels with minimal fluctuation and avoided the rise in serum and urine calcium levels just after a PTH injection. Pump delivery of PTH allowed for simultaneous normalization of bone markers, serum calcium, and urine calcium excretion levels. This represents a significant therapeutic breakthrough, which has not been achieved in any other treatment study of hypoparathyroidism.
The recent approval of PTH 1-84 in the treatment of hypoparathyroidism represents an important milestone in the treatment of this rare disease. Although the two peptides have not been directly compared, PTH 1-84 and PTH 1-34 have similar PK and PD profiles. Thus, one can assume many of the principles learned from studies of PTH 1-34 also apply to PTH 1-84. Therefore, a key area of future study is to determine individualized titrated doses of PTH 1-84 without the simultaneous use of calcitriol and calcium supplementation. Treatment of hypoparathyroidism with both PTH analogs should potentially restore normal physiologic regulation of Ca homeostasis in the bone and kidney.
The essential therapeutic principles that underlie successful treatment of this rare disorder are: i) Every patient has individual PTH requirements based upon their disease etiology and tendency for hypercalciuria. ii) Smaller, more frequent doses of PTH replacement by subcutaneous injection reduces stimulation to bone and kidney and results in lower calcium excretion and markers of bone turnover; iii) PTH delivered by pump produces the most physiologic biochemical profile. The normalization of serum and urine calcium and markers of bone turnover should be the therapeutic treatment goal in the management of hypoparathyroidism with PTH replacement therapy.