Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism

Abstract

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

Hypocitraturia Is an Untoward Side Effect of Synthetic Human Parathyroid Hormone (hPTH) 1-34 Therapy in Hypoparathyroidism That May Increase Renal Morbidity

“…Subjects were evaluated at the Clinical Center of the NIH (Bethesda, MD, USA) every 6 months. After the last visit on hPTH 1‐34, the drug was weaned as previously described, with all subjects resuming conventional therapy with calcium and calcitriol. Subjects then returned to the NIH for a follow‐up visit (FU) 6 to 12 months after the last visit on hPTH 1‐34.…”

A Novel Human PTH Analog [Cys25]hPTH(1–34) Restores Bone Mass in Ovariectomized Mice

“…The anabolic effects of hPTH(1-34) are followed by excessive bone resorption. Increasing the dosage of PTH treatment is complicated, involving serious side effects of hypercalcemia and cortical porosity (26,27). Therefore, new development of PTH or PTHrp analogues with purer anabolic activity, such Abaloparatide, is warranted.…”

Optimal dosing and delivery of parathyroid hormone and its analogues for osteoporosis and hypoparathyroidism – translating the pharmacology

“…Gafni et al . also showed in a small cohort followed for 20–60 months, a small effect of PTH (1–34) to reduce BMD at the distal 1/3 radius and the lumbar spine .…”

“…BMD Z‐scores were +2.2 at the lumbar spine, +1.3 at the femoral neck, +1.1 at the total hip and +0.64 at the distal 1/3 radius . Treatment with PTH either by teriparatide [PTH (1–34)] or PTH (1–84) generally shows an increase or unchanged BMD at the lumbar spine and hip, but a small decrease at the distal 1/3 radius. Further work by Cusano et al ., in a 4‐year longitudinal study, showed that the small decline in the distal 1/3 radius site was, at the end of the study period, not different from baseline .…”