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Summary <p>Hypophosphatasia (HPP) occurs in patients referred for suspected osteoporosis. In our cohort, ALP below 25&#xa0;IU/L predicted a positive genetic diagnosis, yet higher values did not rule out the clinical diagnosis of HPP. Lower ALP correlated with increased fracture risk independent of genetic results, underscoring the clinical importance of recognising HPP to prevent use of contraindicated treatments.</p> Purpose <p>Hypophosphatasia (HPP) is a rare inherited metabolic disorder affecting bone and teeth, characterised by osteomalacia, stress fractures, and pseudofractures. It remains underdiagnosed and may coexist with osteoporosis, risking inappropriate anti-resorptive therapy. This study characterised the biochemical, clinical, and densitometric features of adults with low alkaline phosphatase (ALP) and identified predictors of genetically confirmed HPP.</p> Methods <p>We retrospectively analysed adults referred to our centre for thyroid, endocrine, osteoporosis, or rheumatological conditions in whom low ALP was identified. Data extracted included fracture history, dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), biochemical parameters including pyridoxal-5-phosphate (PLP), and ALPL variant testing. ALPL-positive and ALPL-negative groups were compared using regression analyses.</p> Results <p>Of 33 patients, 20 carried pathogenic ALPL variants. All individuals with ALP ≤ 25&#xa0;IU/L had a detectable disease-causing variant, though ALP was often higher in variant-positive patients. PLP levels differed significantly between groups, whereas bone-specific ALP, standard biochemical markers, and DXA T-scores did not. Overall fracture prevalence was similar between groups; however, each 7.8&#xa0;IU/L decrease in ALP significantly increased fracture probability, independent of genotype. Peripheral fractures predominated, consistent with adult HPP. One patient received bisphosphonates before diagnosis.</p> Conclusion <p>Very low ALP strongly indicates HPP, yet the clinical spectrum extends beyond strict biochemical thresholds. ALP level—independent of genetic status—predicts fracture risk, suggesting residual enzyme activity is clinically relevant. These findings highlight the limitations of DXA and FRAX in HPP and underscore the need for thorough biochemical evaluation and broader clinical awareness to prevent contraindicated osteoporosis treatments.</p>

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Low alkaline phosphatase in adults: implications for the diagnosis of hypophosphatasia during evaluation for osteoporosis

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • Leonhard S. Hummel,
  • Martina Blaschke,
  • Annette Lamersdorf,
  • Gabriele Lehmann,
  • Uwe Kornak,
  • Heide Siggelkow

摘要

Summary

Hypophosphatasia (HPP) occurs in patients referred for suspected osteoporosis. In our cohort, ALP below 25 IU/L predicted a positive genetic diagnosis, yet higher values did not rule out the clinical diagnosis of HPP. Lower ALP correlated with increased fracture risk independent of genetic results, underscoring the clinical importance of recognising HPP to prevent use of contraindicated treatments.

Purpose

Hypophosphatasia (HPP) is a rare inherited metabolic disorder affecting bone and teeth, characterised by osteomalacia, stress fractures, and pseudofractures. It remains underdiagnosed and may coexist with osteoporosis, risking inappropriate anti-resorptive therapy. This study characterised the biochemical, clinical, and densitometric features of adults with low alkaline phosphatase (ALP) and identified predictors of genetically confirmed HPP.

Methods

We retrospectively analysed adults referred to our centre for thyroid, endocrine, osteoporosis, or rheumatological conditions in whom low ALP was identified. Data extracted included fracture history, dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), biochemical parameters including pyridoxal-5-phosphate (PLP), and ALPL variant testing. ALPL-positive and ALPL-negative groups were compared using regression analyses.

Results

Of 33 patients, 20 carried pathogenic ALPL variants. All individuals with ALP ≤ 25 IU/L had a detectable disease-causing variant, though ALP was often higher in variant-positive patients. PLP levels differed significantly between groups, whereas bone-specific ALP, standard biochemical markers, and DXA T-scores did not. Overall fracture prevalence was similar between groups; however, each 7.8 IU/L decrease in ALP significantly increased fracture probability, independent of genotype. Peripheral fractures predominated, consistent with adult HPP. One patient received bisphosphonates before diagnosis.

Conclusion

Very low ALP strongly indicates HPP, yet the clinical spectrum extends beyond strict biochemical thresholds. ALP level—independent of genetic status—predicts fracture risk, suggesting residual enzyme activity is clinically relevant. These findings highlight the limitations of DXA and FRAX in HPP and underscore the need for thorough biochemical evaluation and broader clinical awareness to prevent contraindicated osteoporosis treatments.