Abstract
The clinical spectrum of hypophosphatasia (HPP) is broad and variable within families. Along severe infantile forms, adult forms with mild manifestations may be incidentally discovered by the presence of low alkaline phosphatase (ALP) activity in serum. However, it is still unclear whether individuals with persistently low levels of ALP, in the absence of overt manifestations of HPP, have subclinical abnormalities of bone remodeling or bone mass. The aim of this study was to obtain a better understanding of the skeletal phenotype of adults with low ALP by analyzing bone mineral density (BMD), bone microarchitecture (trabecular bone score, TBS), and bone turnover markers (P1NP and ß-crosslaps). We studied 42 individuals with persistently low serum ALP. They showed lower levels of P1NP (31.4 ± 13.7 versus 48.9 ± 24.4ng/ml; p = 0.0002) and ß-crosslaps (0.21 ± 0.17 versus 0.34 ± 0.22ng/ml, p = 0.0015) than individuals in the control group. There were no significant differences in BMD, bone mineral content, or TBS. These data suggest that individuals with hypophosphatasemia have an overall reduction of bone turnover, even in the absence of overt manifestations of HPP or low BMD. We evaluated bone mineral density (BMD), bone microarchitecture, and bone turnover markers in patients with low serum levels of alkaline phosphatase. Our results show that these patients have low bone remodeling even in the absence of BMD abnormalities, thus supporting the recommendation of avoiding antiresorptives such as bisphosphonates in these subjects.
Highlights
Hypophosphatasia (HPP) is a rare genetic condition caused by loss-of-function mutations of the gene that encodes the tissue nonspecitific alkaline phosphatase (ALPL or TNSALP) located on chromosome 1p36.12 [1]
In a previous report [5] we studied 42 individuals with persistent and unexplained low levels of ALP and found that 50% of them carried a mutation in the ALPL coding region
The clinical spectrum of HPP is widely variable, with severe forms usually manifesting during perinatal and/or infantile periods, while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed
Summary
Hypophosphatasia (HPP) is a rare genetic condition caused by loss-of-function mutations of the gene that encodes the tissue nonspecitific alkaline phosphatase (ALPL or TNSALP) located on chromosome 1p36.12 [1]. There are four alkaline phosphatase (ALP) isoenzymes which are encoded by separate genes. Three of them are expressed in a tissue specific distribution and produce the intestinal, placental, and germ cell (placental-like) ALP. The fourth gene (ALPL) encodes the tissuenonspecific ALP [2] and is mainly expressed in bone, liver and kidneys. In HPP, deficient phosphohydrolase activity leads to extracellular accumulation of its natural substrates, including inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite cristal formation and propagation. The accumulation of extracelular PPi blocks mineralization and the patients develop abnormalities of tissues with a mineralized matrix, including teeth and bone [3]. Most of them are missense mutations and the inheritance pattern can be recessive or dominant
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