Hypophosphatasia: An Inherited Disease That Affects the Bones and Teeth
What is Hypophosphatasia?
Hypophosphatasia (HPP) (also known as “deficiency of alkaline phosphatase” or “phosphoethanalominuria”) is an inherited disorder that affects the development of bones and teeth. This metabolic bone condition can affect bone mineralization, leading to softer and weaker bones and causing skeletal abnormalities that may present similarly to Rickets seen in children and Osteomalacia in adults.
It is due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene which can lead to low alkaline phosphatase activity.
What is Alkaline Phosphatase (ALP)?
ALP is an enzyme that assists in many functions including bone mineralization and tooth development. The main sources of ALP in the body include:
- placenta (in pregnant women)
Abnormal high levels of this enzyme could indicate liver, bone and gallbladder problems. In HPP, the levels are low <40 IU/L.
HPP is Classified into Two Forms
1. Autosomal Recessive
Autosomal Recessive means that two copies of the gene in each cell is altered. This is the severe form that appears early in life (infancy).
2. Autosomal Dominant
Autosomal Dominant means that one copy of the gene in each cell is altered. This is the milder form that appears mostly in childhood and adulthood.
How Common is Hypophosphatasia?
Severe forms of hypophosphatasia are said to affect about 1 in 100,000 newborns. Milder forms are more common in adulthood, and probably occur more frequently and are later diagnosed or misdiagnosed.
Hypophosphatasia has been reported in various ethnicities. This condition is commonly seen in white populations. It is particularly frequent in a Mennonite population in Manitoba, Canada, where about 1 in 2,500 infants is born with severe features of the condition.
What are the Clinical Signs and Symptoms of Hypophosphatasia?
The signs and symptoms of hypophosphatasia can vary greatly between children and adults and are often more severe if present in early childhood or infancy.
For children affected with hypophosphatasia, the common symptoms are often:
- Softening of bones (similar to Rickets)
- Early loss of teeth before the age of 5 with root intact
- Poor feeding and failure to gain weight
- Short stature
- Abnormally shaped chest
- Bow legged, knocked knees
Alternatively, for adults affected with hypophosphatasia, the common symptoms are often:
- Softening of the bones leading to recurrent fractures (osteomalacia)
- Poor healing of fractures
- Arthritic conditions such as chondrocalcinosis and calcific periarthritis
How do you Diagnose Hypophosphatasia?
- People with hypophosphatasia have low levels of ALP, often times less than 40. Blood work must be done fasting for adequate phosphate analysis.
- People also present with elevated B6/pyridoxine levels as B6 is a substrate of ALP and as a result, it is not broken down and levels remain elevated.
- Additional laboratory testing that may be helpful are calcium, magnesium, phosphorous, creatinine (kidney function), parathyroid hormone, and vitamin D levels.
- On radiographic imaging, evidence of old and new fractures may appear, in addition to rachitic changes that are seen in children. In children, there can be radiolucent projections from the endplates of bone that differentiate it from rickets.
- Occasionally, ultrasound of the kidneys may be performed and reveal nephrocalcinosis, or excess calcium deposits in the kidneys.
What are the Treatment Options for Hypophosphatasia?
Currently, Strensiq® or asfotase alfa, is the only FDA approved treatment of perinatal/infantile and juvenile onset hypophosphatasia. The medication works by replacing the TNSALP enzyme and reduces the enzyme substrate levels which works to reverse bone de-mineralization. It is administered via subcutaneous injection in one of two ways:
- One daily injections 6 days a week.
- Two injections daily 3 days a week.
Patients who used the treatment have noted a significant improvement in bone mineralization, and a bone biopsy revealed an improvement in both osteoid volume and thickness during treatment.
Side effects of Strensiq®
- Hypersensitivity reactions
- Ectopic calcifications
- Injection site reactions
The treatment is very expensive - the average cost for children is about $300,000/year and because it is weight based, it is often more expensive in adult patients.
While hypophosphatasia is a rare disorder, it can have serious long term effects on bone mineralization and other organ systems. If you or someone you know has clinical signs or symptoms of hypophosphatasia, be sure to speak with your physician regarding a formal evaluation and blood work. And remember, to optimize your bone health, be sure to engage in regular aerobic activity with weight bearing exercises, supplement with vitamin D3, and be sure to get adequate dietary calcium!
Be Strong. Be Healthy. Be In Charge!
Chad Deal, MD CCD, Anna Camille Moreno, DO NCMP and Sabrina K. Sahni, MD, NCMP
Chad Deal, MD, is Head of the Center for Osteoporosis and Metabolic Bone Disease and a board-certified Rheumatologist at Cleveland Clinic. He has specialty interests in osteoporosis and related conditions. Dr. Deal did his undergraduate work at Washington University, St. Louis, Mo. He attended medical school at the University of Arkansas, was inducted into Alpha Omega Alpha, and graduated in 1977. His internship and residency were at Boston City Hospital in Boston, Mass. He completed a fellowship in arthritis and connective tissue diseases at Boston University School of Medicine in 1982.
Dr. Moreno is an assistant professor and medical director of the Midlife Women's Health program at University of Utah OBGYN. Her focused training includes midlife care involving perimenopause, menopause, hormone therapy, bone health (osteoporosis management and treatment), sexual dysfunction, vulvar disorders, and genital chronic graft versus host disease. She is also a medical consultant and a freelance medical writer for GoodRx, Inc. Dr. Moreno is a graduate of the Specialized Women's Health Fellowship Program at Cleveland Clinic.
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