Hypophosphatasia in adults: current understanding and future perspectives


Year: 2016

Number: 3/4


Hypophosphatasia in adults: current understanding and future perspectives

Muscle, joint and bone pain are common reasons for medical consultations and those complaints have often multiple reasons. The challenge in daily routine is not only to choose the best individual therapy for each patient, but also to address unusual signs and symptoms leading to diagnosis of a rare disease. Impaired bone quality like osteoporosis, osteopenia and osteomalacia are commonly found in clinical practice. In particular, vitamin D deficiency-related deterioration of bone quality leading to the development of stress fractures is well known. But there are also mineralization disorders that are less familiar to the physician and which are not yet diagnosed routinely. A very important and often overlooked mineralization disorder is hypophosphatasia (HPP), a hereditary disease with defective bone and tooth mineralization caused by lack of tissue non-specific alkaline phosphatase (ALPL) activity and subsequent accumulation of metabolites (inorganic pyrophosphate (IPP), pyridoxal phosphate (PLP) and phosphoethanolamine (PEA)). The consequence of this disease is among many other symptoms a disorder of bone mineralization, which can lead to pain, fractures, bone deformities and other problems of the locomotor system. However, the symptoms can be diverse including neurological and muscular symptoms, sometimes hindering fast and correct diagnosis. Also the severity of HPP has a broad spectrum. There are at least five to six different forms known, according to the age of symptom onset. The severity ranges from death at the time around birth to almost healthy adult gene carriers. But adults can also be severely affected with immobilizing musculoskeletal pain and reoccurring fractures. The laboratory tests are of hallmark importance to find the correct diagnosis in theses cases. A lowering of alkaline phosphatase (AP) and / or bone-specific AP is the most important diagnostic indicator, which should be further addressed to rule out or confirm HPP. The diagnosis comprises specific laboratory parameters (AP, bone AP, Ca, P, PLP, iPP, PEA, etc.), gene analysis (mutations in ALPL gene encoding the nonspecific alkaline Tissue phosphatase liver, bone and kidney) as well as imaging procedures (X-ray, CT, MRI) and bone density measurement (DEXA). A correct diagnosis is very important as common Osteoporosis medications such as bisphosphonates may harm HPP patients. A potentially curative approach such as enzyme replacement therapy is more and more integrated in clinical practice. The results of the growing amount of studies covering the subject enzyme replacement therapy in HPP are encouraging and will more and more lead to a better understanding of treating the disease. Also adults, diagnosed for HPP as children or adults with symptoms of HPP as a child are considered for enzyme replacement therapy according to the grade of illness severity. Referring to the striking improvement of bone mineralization, pain reduction and improvement of mobility seen in children getting enzyme replacement therapy, future studies of severely affected adults are needed to further understand the therapeutic effectiveness and the safety profile in adults. Additional symptomatic therapy including anti-inflammatory therapy, nutritional counseling, physiotherapy and if necessary fracture treatment is of clinical importance.