Abstract
PurposeThe study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP).MethodsTwenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5’-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies.ResultsPathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive breast cancer. Mineral and bone markers were similar in the three groups. Mean urine PEA levels were significantly higher in patients harboring pALPL than those detected in patients harboring bALPL and wtALPL; by contrast, serum PLP levels were similar in the three groups. A 6-points score, considering clinical and biochemical features, was predictive of pALPL detection [P = 0.060, OR 1.92 (95% CI 0.972, 3.794)], and more significantly of pALPL or bALPL [P = 0.025, OR 14.33 (95% CI 1.401, 14.605)].ConclusionIn osteopenic/osteoporotic patients, single clinical or biochemical factors did not distinguish hypophosphatasemic patients harboring pALPL or bALPL from those harboring wtALPL. Occurrence of multiple clinical and biochemical features is predictive of ALPL anomalies, and, therefore, they should be carefully identified. Tamoxifen emerged as a hypophosphatasemic drug.
Highlights
Hypophosphatasemia can be detected during the diagnostic workup in adult patients with osteopenia/osteoporosis and/or bone fragility
PALPL variants occurred in 23% of hypophosphatasemic osteopenic/osteoporotic patients, while benign ALPL variants (bALPL) variants occurred in 36% of patients
Of note, looking at the group of hypophosphatasemic patients harboring wtALPL, we found that seven patients experiencing low levels of serum alkaline phosphatase (ALP) were treated with tamoxifen after diagnosis of hormone-sensitive breast cancer, referred for evaluation of cancer treatment-induced bone loss (CTIBL)
Summary
Hypophosphatasemia can be detected during the diagnostic workup in adult patients with osteopenia/osteoporosis and/or bone fragility. It is mandatory to distinguish the genetic disease from acquired disorders for the following reasons: (1) the genetic disorder, known as hypophosphatasia (HPP), may be inherited and, genetic counseling in adult patients should be. Journal of Endocrinological Investigation considered; (2) HPP may potentially benefit of the specific enzymatic asfotase alpha replacement therapy [1, 2]; (3) in patients with HPP, treatment with antiresorptive drugs may increase the risk of atypical fractures [3, 4], and, it should be avoided; (4) secondary causes of hypophosphatasemia need targeted therapeutic interventions. HPP is a rare genetic disease characterized by low tissue-non-specific alkaline phosphatase (ALP) activity and hypophosphatasemia. It is caused by loss-of-function coding mutations of the tissue-nonspecific isoenzyme of alkaline phosphatase (ALPL) gene or large genomic deletion mapping at the corresponding locus on chr.1p36.1p34. HPP displays a wide range of severity in its phenotype, from death in utero to asymptomatic disease accidentally diagnosed in adult life [6]
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