PTH treatment in adult hypophosphatasia: significant increase in S-AP, improvement of pain and fracture healing in two siblings with ALPL gene mutations G339R and E191K
Camilla Schalin-Jäntti1, Matti Välimäki1 & Etienne Mornet2
Background: Hypophosphatasia (HPP) is characterized by low serum alkaline phosphatase (S-AP) activity due to loss-of function mutations in the ALPL gene. A hallmark of adult HPP is painful, slowly healing metatarsal and femur stress fractures. There is no treatment for the disease but beneficial effects of parathyroid hormone (PTH) treatment was previously demonstrated in one patient. It is unclear how parathyroid hormone (PTH) can stimulate S-AP despite loss-of function mutations.
Aim: To study the effects of PTH treatment on S-AP, bone markers, S-Ca-ion, S-Pi, pain, mobility and femur fracture healing in two siblings with adult HPP and to characterize the underlying molecular defects.
Results: PTH treatment (100 ug s.c daily) significantly increased S-AP in both patients, from 8 U/l (reference 35105) to a peak value of 22 U/l in Patient 1 and 39 U/l in Patient 2, respectively. The increase in S-AP was due to increased bone specific AP. Corresponding increases in S-P1NP were 56.5 to 789 and 61.1 to 552 ug/l, respectively and for U-NTX 43 to 408 nmol/mmolKr and 22 to 98 nmol/mmolKr. Slight increases in S-Ca-ion and S-Pi concentrations were observed. Pain and mobility improved significantly in both patients. For both patients, imaging demonstrated femur fracture healing. Molecular analysis of the ALPL gene revealed two distinct mutations in both patients, a severe G339R and a mild E191K mutation, which is associated with significant residual enzyme activity.
Conclusion: PTH treatment significantly increases S-AP and bone turnover, improves mobility, pain and fracture healing in adult HPP. Despite a severe G339R mutation, the significant residual activity of the E191K ALPL mutation provides an explanation for why PTH is able to stimulate S-AP in these patients.