On behalf of Endocrine Society’s Bone and Mineral Special Interest Group Steering Committee, Anika Anam, MD and Azarmindokht Khosravi, MD, discuss the diagnostic gap in hypophosphatasia (HPP) and preview the SIG’s upcoming October 29 webinar on hypophosphatasia ahead of World HPP Day on October 30, 2026.
Persistently low alkaline phosphatase can be an overlooked indicator of hypophosphatasia, a rare inherited disorder that disrupts mineralization of bone and teeth and can affect multiple organ systems. This article outlines diagnostic clues, management precautions, treatment considerations, and an upcoming professional webinar.
A Common Lab Value Hiding a Rare Diagnosis
Alkaline phosphatase (ALP) is included in routine metabolic panels, yet a low alkaline phosphatase level is often overlooked. Hypophosphatasia (HPP) is caused by loss-of-function mutations in ALPL, the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). Without adequate enzyme activity, inorganic pyrophosphate is not converted to inorganic phosphate. Inorganic phosphate is needed to bind to calcium to form hydroxyapatite crystals that mineralize bone and teeth. As a result, pyrophosphate accumulates and blocks normal mineralization of bone and teeth. In HPP, calcium can accumulate in ectopic locations like kidneys or periarticular tissue.
TNSALP is also required for activation of vitamin B6 in the brain. Active vitamin B6 (pyridoxal 5’-phosphate, PLP) functions as a coenzyme for GABA synthesis in the central nervous system. In children, TNSALP deficiency can cause vitamin B6-responsive seizures. Carrier frequency for pathogenic or likely pathogenic ALPL gene variants is approximately one in 341 (0.3%) in a recent large-scale genomic screening of unselected populations (JBMR 2026).
HPP can be inherited as an autosomal dominant or recessive condition. However, genotype-phenotype correlation is limited.
Diagnostic Pearls and Practical Guidance for HPP Care
HPP is associated with a wide spectrum of severity, ranging from severe life- threatening forms to mild adult-onset disease. Accordingly, HPP is classified into five main types based on the age symptoms first appear: perinatal, infantile, childhood, adult, and odonto (dental only).
HPP commonly affects the musculoskeletal, dental, renal, and central nervous systems. Musculoskeletal symptoms (muscle pain or weakness, bone, and joint pain), renal (hypercalciuria, nephrocalcinosis), dental (abnormal dentition, premature tooth loss), neurologic (fatigue, headache, sleep disturbance) are commonly observed in adults with HPP. HPP is a low bone turnover state; and individuals with HPP are more prone to fractures, particularly stress or atypical fractures.
HPP is associated with a wide spectrum of severity, ranging from severe life- threatening forms to mild adult-onset disease. Accordingly, HPP is classified into five main types based on the age symptoms first appear: perinatal, infantile, childhood, adult, and odonto (dental only).
Individuals with HPP are often misdiagnosed with fibromyalgia, chronic fatigue syndrome, or osteoarthritis. Even when HPP is considered, pitfalls in test interpretation can affect the evaluation. For example, children and adolescents have considerably higher ALP levels compared to adults. Reference ranges differ based on sex, especially during periods of growth and puberty. Measurement of plasma pyridoxal 5′ phosphate (PLP), the active form of vitamin B6, and urinary PEA (phosphoethanolamine), which accumulates in HPP tend to be high and can help establish the diagnosis of HPP.
| Quick Tips for HPP |
| More than 480 pathogenic or likely pathogenic ALPL variants have been cataloged to date Consider HPP when ALP is persistently low, especially alongside stress fractures or atypical fractures, arthralgia, or chondrocalcinosis Ask about early loss of primary teeth with intact roots, especially in children Avoid starting a bisphosphonate for low bone density before excluding HPP Using osteoanabolic agents can avoid oversuppression of bone turnover. If antiresorptive agents are needed, use shortest duration necessary to reduce risk of atypical femur fracture Avoid high doses of calcium and vitamin D supplementation due to increased risk of nephrocalcinosis and nephrolithiasis Consider referral for genetic counseling given the wide range of inheritance patterns and severity, even within the same family |
Prognosis and Treatment: A Multidisciplinary Effort
Since HPP affects multiple organ systems, managing HPP requires a multidisciplinary team approach. Not all patients with low alkaline phosphatase levels have HPP. Other medications and conditions that lower bone turnover can lead to a low alkaline phosphatase level. For example, antiresorptive medications, tamoxifen, hypoparathyroidism, hypothyroidism, Cushing syndrome, and zinc deficiency are associated with low alkaline phosphatase levels.
Since HPP affects multiple organ systems, managing HPP requires a multidisciplinary team approach. Not all patients with low alkaline phosphatase levels have HPP. Other medications and conditions that lower bone turnover can lead to a low alkaline phosphatase level. For example, antiresorptive medications, tamoxifen, hypoparathyroidism, hypothyroidism, Cushing syndrome, and zinc deficiency are associated with low alkaline phosphatase levels.
Asfotase alfa, a bone-targeted recombinant TNSALP, is currently the only approved pharmacologic treatment for perinatal, infantile, and juvenile hypophosphatasia. Enzyme replacement improves skeletal mineralization, pulmonary function, hypercalcemia, and muscle strength, with the most pronounced benefit seen in severely affected patients.
Treatment requires frequent subcutaneous injections, typically three to six times per week, and long-term data in adults remain limited. These factors, together with medication side effects and the cost and burden of ongoing injections, make careful patient selection important. Not every patient with a mild, adult-onset form of hypophosphatasia needs enzyme replacement; the decision should weigh disease severity against the demands of therapy. Monitoring during treatment tracks skeletal, growth, respiratory, and motor function outcomes. Serum alkaline phosphatase rises substantially, often into the thousands, so it cannot be used to titrate dosing. Instead, clinicians should follow serum PLP, calcium, phosphorus, PTH, renal function, and urinary calcium, along with periodic renal and ophthalmic imaging to screen for calcifications.
The Time to Think HPP Is Now
As awareness of HPP grows and diagnostic tools improve, more patients stand to benefit from earlier recognition and treatment. This World HPP Day, and at the SIG’s upcoming webinar, we hope you will join us in spreading the message: low ALP, think HPP.
Anika Anam, MD, is assistant professor of medicine in the Section of Endocrinology, Diabetes, and Metabolism at the Yale School of Medicine, New Haven, Conn.
Azarmindokht Khosravi, MD, is associate professor of medicine and clinical director of the Metabolic Bone Disease Program in the Division of Endocrinology, Diabetes, and Metabolism at Cedars Sinai, Los Angeles, Calif.
