HPP, or hypophosphatasia, is a rare genetic disease in which the body doesn’t produce enough of an enzyme needed to build and maintain strong bones and teeth. The missing enzyme, alkaline phosphatase, plays a critical role in mineralizing bone tissue. Without enough of it, bones stay soft, fracture easily, and teeth can fall out years before they should. HPP ranges from life-threatening in newborns to so mild in adults that it goes undiagnosed for decades.
How HPP Affects the Body
Alkaline phosphatase helps deposit minerals like calcium and phosphorus into bone. When enzyme levels are too low, a compound called pyrophosphate builds up instead. Pyrophosphate actively blocks mineralization, so bones remain soft and poorly formed. The same process disrupts tooth roots: the layer of tissue (called cementum) that anchors a tooth into the jawbone either fails to develop or develops so thinly that teeth literally detach from the surrounding tissue and fall out with their roots intact.
Because alkaline phosphatase is involved in processing vitamin B6, severe HPP in infants can also cause seizures. In the most serious early-onset cases, excess calcium spills into the bloodstream and urine, sometimes leading to kidney calcifications or even kidney damage.
Six Clinical Forms, One Spectrum
HPP isn’t a single presentation. Six forms have been described, though they exist on a continuum of severity rather than in neat categories.
- Perinatal lethal HPP is the most severe form. Bones are so poorly mineralized that infants may be born with short, bowed limbs and underdeveloped ribs. Chest weakness leads to life-threatening breathing problems. Without treatment, survival past the first year is low.
- Prenatal benign HPP shows skeletal abnormalities on ultrasound before birth, but these slowly improve after delivery and do not become life-threatening.
- Infantile HPP appears between birth and six months. Babies may feed poorly, vomit frequently, fail to gain weight, or develop seizures. The bones of the skull can fuse prematurely, putting pressure on the growing brain.
- Childhood HPP often becomes noticeable once a child starts walking. Signs include a waddling gait, bowed legs or knock knees, swollen wrists and ankles, bone and joint pain, and muscle weakness. Some children experience unexplained fractures or low bone density without obvious skeletal deformities.
- Adult HPP may not be diagnosed until middle age. Repeated stress fractures in the legs, early loss of adult teeth, chronic muscle pain, and joint swelling are common. Some adults present only with vague musculoskeletal pain or osteoporosis that doesn’t respond to typical treatments.
- Odontohypophosphatasia (odonto-HPP) is the mildest form, affecting only the teeth. Early loss of baby teeth, sometimes with the roots still attached, may be the sole symptom. Adult teeth can also develop abnormally.
Why Teeth Fall Out Early
One of HPP’s most distinctive signs is premature tooth loss, particularly baby teeth falling out before age five. This happens because the cementum layer on tooth roots either doesn’t form at all or is too thin to hold. Normally, tiny fibers connect the cementum to the surrounding ligament, locking the tooth in place. In HPP, pyrophosphate accumulation prevents cementum from adhering to the underlying root surface, so those connecting fibers never attach properly. The tooth essentially sits loose in its socket.
Children with HPP often lose teeth with the full root intact, which is unusual. In healthy children, baby teeth fall out because the root gradually dissolves as the adult tooth pushes through. In HPP, the tooth simply separates from the jawbone. This pattern is a red flag that should prompt testing, but because early tooth loss can be attributed to other causes, HPP diagnosis is frequently delayed by years.
Adult HPP Is Often Missed
Adults with HPP frequently go undiagnosed or are misdiagnosed with osteoporosis. The adult form is characterized by recurring stress fractures, muscle weakness, chronic pain, and calcium crystal deposits in cartilage. Some adults look back and realize they lost baby teeth unusually early or had unexplained fractures in childhood, but no one connected the dots at the time.
Fractures in adult HPP can be especially problematic because they heal slowly or not at all. Delayed healing, fracture nonunion (where the bone simply stops trying to mend), and repeated orthopedic surgeries are common complications. Cleveland Clinic researchers have noted that some adults with HPP require chronic prescription pain medications, including opioids, for musculoskeletal pain that doesn’t resolve. Others develop disabling joint disease affecting multiple joints. The fractures tend to cluster in weight-bearing areas: the spine, hips, pelvis, and long bones of the legs.
Kidney and Seizure Complications
In severe early-onset HPP, excess calcium in the blood and urine can damage the kidneys. Calcium deposits may form in kidney tissue, a condition called nephrocalcinosis. In one Japanese series of 52 patients, kidney calcifications appeared in those with the most severe perinatal form of the disease. In milder forms diagnosed later in life, blood calcium and vitamin D levels are typically normal, though the body handles phosphate differently, with increased absorption of phosphate by the kidneys.
Seizures in infantile HPP are tied to impaired vitamin B6 metabolism. Because alkaline phosphatase is needed to convert vitamin B6 into its active form in the brain, infants with very low enzyme activity can develop seizures that respond to vitamin B6 supplementation. These seizures can sometimes be the first recognizable symptom of the disease.
How HPP Is Treated
For decades, there was no effective treatment for HPP. Early attempts at enzyme replacement using purified plasma enzyme showed little benefit. That changed with the approval of an enzyme replacement therapy that delivers a functional version of the missing enzyme directly to bone.
This treatment, given by injection under the skin, was approved based on four studies involving 99 patients who developed HPP before birth, in infancy, or during childhood, with some treated for up to 6.5 years. The results were striking: 97% of treated infants with perinatal or infantile HPP were alive at age one, compared with just 42% of untreated patients from historical records. Treated patients also showed improved bone mineralization, better respiratory function, and in some cases, the ability to breathe without a ventilator. Children with later-onset HPP experienced improved growth and bone health.
For adults with milder HPP, treatment decisions are more nuanced. Not everyone with low alkaline phosphatase activity needs enzyme replacement. Experts generally recommend considering treatment when the disease causes significant problems: major fractures, fractures that won’t heal, disabling joint disease, or chronic pain severe enough to require prescription medications. Supportive care, including physical therapy, dental management, and pain control, remains important across all forms of the disease.
Getting the Right Diagnosis
HPP is diagnosed primarily through a blood test showing low alkaline phosphatase levels. This is ironic, because alkaline phosphatase is measured on nearly every routine blood panel, yet abnormally low values are often overlooked. Most labs flag high alkaline phosphatase but don’t call attention to low levels. If you or your child has unexplained fractures, early tooth loss, or chronic bone pain along with persistently low alkaline phosphatase on blood work, genetic testing can confirm the diagnosis by identifying mutations in the gene responsible for the enzyme.
Because HPP is rare and its symptoms overlap with common conditions like osteoporosis and rickets, the average time to diagnosis can stretch for years or even decades in milder cases. Dental professionals are sometimes the first to suspect HPP, especially when a young child loses multiple teeth prematurely with roots intact.