Possible role of bone turnover markers in the diagnosis of adult hypophosphatasia

Hypophosphatasia (HPP) is a rare disorder of the bone metabolism, characterized by genetically determined low alkaline phosphatase (ALP) activity. Low ALP may also be observed in some common causes of bone fragility, such as in osteoporosis treated with antiresorptive drugs. This study aimed to verify whether differences in bone turnover markers (BTMs) could help differentiate adult patients with HPP from those with osteoporosis undergoing antiresorptive treatment. In this multicenter study, we enrolled 23 adult patients with a diagnosis of HPP and compared them with 46 osteoporotic subjects previously treated with zoledronic acid or denosumab. BTMs such as CTX, N-terminal propeptide of type I procollagen (P1NP), total ALP, and bone ALP (bALP) were measured, and ratios between BTMs were also calculated. Considering that the control group included only females, in the primary analysis we compared their characteristics with that of the 16 female patients with HPP. Both individual BTMs (CTX and P1NP) and 4 BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an area under the curve (AUC) of 0.962 with a cut-off of 32 mu g/L, while as for the BTMs ratios, the ALP/P1NP ratio had an AUC of 0.964 with a cut-off of 1.114. Similar results were confirmed when including male HPP patients, when adjusting for age and sex, and finally when performing a sensitivity analysis only in patients with ALP less than or equal to 32 U/L (ie, the median of the distribution of the entire population). In cases of low ALP and bone fragility, BTM and their ratios could help distinguish HPP patients from osteoporotic individuals treated with antiresorptive drugs, aiding in accurate diagnosis and reducing the risk of inappropriate treatment. Hypophosphatasia (HPP) is a rare bone disease caused by mutations in the ALPL gene, leading to low activity of alkaline phosphatase (ALP). This enzyme deficiency affects bone mineralization, causing a wide range of symptoms, with severe cases potentially resulting in stillbirth. In contrast, milder forms can be mistaken for common bone diseases like antiresorptive-treated osteoporosis, leading to misdiagnosis and inappropriate treatments that may worsen bone fragility in HPP patients. Diagnosing HPP primarily relies on measuring plasma ALP activity, but low ALP is not specific to HPP and can occur in other conditions. Confirmatory tests, including specific biomarkers and genetic analysis, are often expensive and not widely available. Our study explores the use of bone turnover markers (BTMs) to help diagnose HPP. We found that HPP patients show distinct patterns in BTMs compared to those with antiresorptive-treated osteoporosis. These findings suggest that measuring BTMs and their ratios could help distinguish HPP from primary osteoporosis in patients with low ALP and bone fragility. This approach could lead to earlier and more accurate diagnoses, prompting further specific tests for HPP. More research is needed to confirm these findings in other conditions with low ALP activity.