Bone mineralization8,21
Under normal conditions, ALP dephosphorylates PPi and releases Pi, which then binds with calcium to form hydroxyapatite crystals—the building blocks of strong bones.
Deficient alkaline phosphatase (ALP) can
make any day with hypophosphatasia
(HPP) feel like Everest
make any day with hypophosphatasia
(HPP) feel like Everest
HPP is caused by deficient ALP activity. It is an inherited, multisystemic metabolic disease that can progress.5-7*
ALP deficiency can lead to:
Impaired mineral metabolism and skeletal complications, including fractures.8-10
- Chronic pain affects up to 95% (119/125) of adults with HPP, including bone (82%, 73/89), joint (73%, 65/89), and muscle (53%, 47/89) pain, which often requires medication (69%, 61/89).1†
- Chronic pain also affects 86.4% (51/59) of children with HPP, with joint (61.4%, 27/44) and bone pain (52.3%, 23/44) being most frequently reported.15‡
- 86% (107/125) of adults with HPP experienced fractures; however, bone density measured by DEXA is frequently not low in HPP1,16†
- Approximately 36% (32/89) of adults with HPP experienced non-healing or poor healing fractures and 44% (39/89) reported incomplete or pseudofractures1†
- Chondrocalcinosis due to calcium pyrophosphate deposition is a frequent complication of HPP and has been reported in up to 21.4% (9/42) of adult patients with a confirmed ALPL variant17§
Functional impairments, including muscle weakness, fatigue, pain, and neurologic complications.4,11-14
In one study of adults with HPP (N=82), the prevalence of neurologic symptoms was reported as follows18II:
- fatigue 66%
- headache 61%
- sleep disturbance 51%
- gait changes 44%
- vertigo 43%
- depression 39%
- neuropathy 35%
- anxiety 35%
- hearing loss 33%
- seizure 16%
- memory loss 12%
- tinnitus 9%
- syncope 7%
- ADHD 6%
- In a study of children with HPP between 3 and 16 years old, 67% (20/30) showed clinically significant behavioral health challenges such as pain interference, sleep disturbance, and mood/anxiety symptoms2¶
- In one study, 62% (77/124) of adults reported muscle weakness, and 52% (46/89) had difficulty walking (unusual gait). In another study, 83% (10/12) of patients surveyed also reported muscle weakness1,19†#
*HPP is a rare disease; the true prevalence is unknown.20
†Patient survey (N=125) evaluating the symptomology and burden of disease in HPP via the Hypophosphatasia Impact Patient Survey (HIPS; n=89) and Hypophosphatasia Outcomes Study Telephone interview (HOST; n=36). Survey results are based on patient-reported data and have not been formally validated in individuals with HPP.1
‡Data collected from pediatric patients (<18 years) and caregivers via 2 survey instruments (web-based and telephone interviews) to evaluate patient-reported symptomatology and burden of disease in pediatric hypophosphatasia (N=59).15
§Longitudinal study (N=78) conducted to estimate the prevalence of chondrocalcinosis and calcium pyrophosphate deposition (CPPD) in patients with low ALP levels and a positive genetic test (n=42/78) compared to those with similar biochemical abnormality and a negative genetic test (n=36/78).17
IIRetrospective chart review (N=82) of patients with HPP examining possible presence and onset of 14 common neurologic symptoms.18
¶Cross-sectional survey of parents of 30 children with HPP assessing psychopathological comorbidity, emotional and behavioral well-being, and quality of life.2
#Retrospective analysis of 12 adults who were subsequently diagnosed with HPP.19
I started having horrible peripheral neuropathy and the pain got so bad, I went to the ER.
— Patient, living with HPP
The role of elevated PEA in the pathogenesis of HPP is not fully understood.
The understanding of the impact of deficient ALP on PPi, PLP, and PEA, as well as other substrates in the body, including phosphate metabolism in energy-critical organs, continues to evolve, with current understanding based primarily on preclinical studies using mouse models of HPP.11,29
Normal Function of ALP
Neurotransmitter synthesis and intracellular PLP uptake2,8,31,32
ALP is also responsible for dephosphorylating PLP, the active form of vitamin B6, to its precursor PL, allowing PL to cross cell membranes, including muscle cells and the blood-brain barrier, where it is re-phosphorylated as PLP.
Figures adapted from Rockman-Greenberg, 2013.
When ALP Activity Is Low
PPi accumulation in bone7,33
Low ALP activity leads to extracellular PPi accumulation and an increased PPi:Pi ratio, impairing hydroxyapatite deposition and mineralization of bone and teeth.
Clinically, this may present as fractures or pseudofractures, skeletal deformities, and early tooth loss.
Decreased PLP in cells, including the muscle and CNS17,33
The buildup of PLP in systemic circulation leads to an intracellular deficiency of vitamin B6 in muscle and the CNS, which may manifest clinically as muscle weakness, impaired physical function, and neurologic symptoms, including seizures.
Figures adapted from Rockman-Greenberg, 2013.
Ca2+, calcium; CNS, central nervous system; HA, hydroxyapatite; Pi, inorganic phosphate; PL, pyridoxal.
Ca2+, calcium; CNS, central nervous system; HA, hydroxyapatite; Pi, inorganic phosphate; PL, pyridoxal.
While physical therapy and pain management may help lessen some symptoms of HPP, disease progression, including physical and functional decline, may still occur7,15,35,36
Kaplan-Meier analysis shows that the probability of being event-free
ultimately decreases toward zero over a patient’s lifetime37**
ultimately decreases toward zero over a patient’s lifetime37**
The important thing is to recognize patients in your practice with persistently low levels of alkaline phosphatase. It's important to recognize those patients and to refer them to an appropriate HPP specialist.
— Dr Chad Deal, Rheumatologist
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