Reversible Deterioration in Hypophosphatasia Caused by Renal Failure With Bisphosphonate Treatment.
Hypophosphatasia is an inborn error of metabolism caused by mutations in the ALPL gene. It is characterized by low serum alkaline phosphatase (ALP) activity and defective mineralization of bone, but the phenotype varies greatly in severity depending on the degree of residual enzyme activity. We describe a man with compound heterozygous mutations in ALPL, but no previous bone disease, who suffered numerous disabling fractures after he developed progressive renal failure (for which he eventually needed dialysis treatment) and was prescribed alendronate treatment. A bone biopsy showed marked osteomalacia with low osteoblast numbers and greatly elevated pyrophosphate concentrations at mineralizing surfaces. In vitro testing showed that one mutation, T117H, produced an ALP protein with almost no enzyme activity; the second, G438S, produced a protein with normal activity, but its activity was inhibited by raising the media phosphate concentration, suggesting that phosphate retention (attributable to uremia) could have contributed to the phenotypic change, although a pathogenic effect of bisphosphonate treatment is also likely. Alendronate treatment was discontinued and, while a suitable kidney donor was sought, the patient was treated for 6 months with teriparatide, which significantly reduced the osteomalacia. Eighteen months after successful renal transplantation, the patient was free of symptoms and the scintigraphic bone lesions had resolved. A third bone biopsy showed marked hyperosteoidosis but with plentiful new bone formation and a normal bone formation rate. This case illustrates how pharmacological (bisphosphonate treatment) and physiologic (renal failure) changes in the "environment" can dramatically affect the phenotype of a genetic disorder.
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Aukland, New Zealand.
Tim
T
Cundy
Department of Bone and Mineral Research, Osaka Medical Center for Maternal and Child Health, Osaka, Japan.
Toshimi
T
Michigami
Department of Bone and Mineral Research, Osaka Medical Center for Maternal and Child Health, Osaka, Japan.
Kanako
K
Tachikawa
Department of Pathology, Middlemore Hospital, Auckland, New Zealand.
Michael
M
Dray
Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand.
John F
JF
Collins
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Eleftherios P
EP
Paschalis
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Sonja
S
Gamsjaeger
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Andreas
A
Roschger
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Nadja
N
Fratzl-Zelman
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Paul
P
Roschger
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Klaus
K
Klaushofer
D019386:Alendronate / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D003720:Densitometry; D004164:Diphosphonates / Q000627:therapeutic use*; D050723:Fractures, Bone / Q000150:complications; D056726:Genetic Association Studies; D006801:Humans; D007014:Hypophosphatasia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010018:Osteomalacia / Q000188:drug therapy; D010641:Phenotype; D010710:Phosphates / Q000737:chemistry; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D019379:Teriparatide / Q000737:chemistry; D016896:Treatment Outcome
D004164:Diphosphonates; D010710:Phosphates; D019379:Teriparatide; D019386:Alendronate
BISPHOSPHONATES; GENOTYPE-PHENOTYPE; HYPOPHOSPHATASIA; OSTEOMALACIA; RENAL FAILURE