The Effects of Long-term Administration of rhPTH(1-84) in Hypoparathyroidism by Bone Histomorphometry

Abstract

Hypoparathyroidism is a rare disorder that is associated with abnormal bone properties. Recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] in short-term studies has beneficial skeletal effects. Although rhPTH(1-84) will likely be used indefinitely, long-term effects on skeletal microstructure are unknown. We therefore studied histomorphometric changes with transiliac crest bone biopsies before and after 8.3 ± 1 years of rhPTH(1-84) in 13 hypoparathyroid subjects compared with 45 controls. Before institution of rhPTH(1-84), skeletal remodeling indices were markedly suppressed. With long-term treatment, indices of bone remodeling increased. Mineralizing surface increased by 26-fold (0.3 ± 1 to 7.9 ± 7%, p = 0.003), bone formation rate increased by 15-fold (0.003 ± 0.01 to 0.047 ± 0.05 μm² /μm/day, p = 0.007), osteoid width doubled (1.9 ± 1 to 4.3 ± 1 lamellae, p = 0.017), and osteoid surface tripled (3.3 ± 3 to 10.8 ± 6%, p = 0.011). Bone resorption as measured by eroded surface increased (4.6 ± 2 to 7.5 ± 3%, p = 0.021). Structural changes demonstrated intratrabecular tunneling, with increases in cancellous bone volume (19.6 ± 5 to 29.1 ± 11%, p = 0.017) and trabecular number (1.8 ± 1 to 2.5 ± 1 #/mm, p = 0.025). Cortical porosity tended to increase (6.3 ± 5 to 9.5 ± 3%, p = 0.07). Mineralizing surface, osteoid surface, and eroded surface surpassed control levels, as did cancellous bone volume, trabecular number, and cortical porosity. These data, the first to reflect such long exposure of any PTH for any disease, illustrate that PTH establishes and maintains a new skeletal state for at least 8 years in hypoparathyroidism. © 2018 American Society for Bone and Mineral Research.

Trial registration: ClinicalTrials.gov NCT00473265.

Keywords: CORTICAL POROSITY; HISTOMORPHOMETRY; HYPOPARATHYROIDISM; RHPTH(1-84); TRABECULAR TUNNELING.

Fig. 1.

Histomorphometric variables in controls and in hypoparathyroid subjects before and after long-term rhPTH(1–84) treatment. Cancellous bone volume, trabecular number, cortical porosity, mineralizing surface, and eroded surface in the cancellous envelope increased. Hypo-BL = hypoparathyroid baseline; Hypo-LT = hypoparathyroid long-term.

Fig. 2.

Representative histomorphometric images in a control subject and in a hypoparathyroid subject before and after 8 years of rhPTH(1–84) treatment. In comparison with the control image (A), the baseline untreated hypoparathyroid image (B) demonstrates increased cortical width. The long-term image (C) shows an increase in cortical porosity and trabecular tunneling, as well as in unmineralized osteoid (osteoid surface, in red) and eroded surface (arrow) as compared with the baseline hypoparathyroid image.