Bone Disease in Adult Onset Hypophosphatasia: A Management Dilemma

Presentation Number: SUN 303
Date of Presentation: April 2nd, 2017

Richa M Patel* and Abid Yaqub
University of Cincinnati, Cincinnati, OH


Hypophosphatasia (HPP) is a rare disorder with defects in bone and teeth mineralization due to loss of function mutation in ALPL gene on chromosome 1 which encodes tissue non-specific alkaline phosphatase (TNSALP). It is a heterogeneous disease ranging from intrauterine lethality to mild adult onset disease. Variable patterns of inheritance lead to different phenotypes. Adults often have mild disease with autosomal dominant inheritance.

A 67-year-old male with a history of papillary thyroid cancer was incidentally noted to have low alkaline phosphatase (ALP). Repeat labs showed low ALP levels of 6-10 U/L (36-125) an elevated vitamin B6 >100 µg/L (5.3-46.7) and normal 25-hydroxy vitamin D, parathyroid hormone (PTH), calcium, phosphorus, renal and liver panel. He had a history of poor dentition and dental decay requiring multiple dental crowns. He denied history of fractures, musculoskeletal pain, gait issues, seizures and respiratory or growth problems. He reported childhood onset HPP in his brother and sister with multiple fractures. No nephrocalcinosis seen on renal ultrasound and 24-hour urine calcium was normal. DXA scan showed lowest T-score of -2.4 at left femoral neck.

Adult onset HPP was diagnosed with significantly low ALP levels, pertinent family history and elevated levels of vitamin B6, a substrate of TNSALP. He declined genetic testing, but he likely has a heterozygous mutation of ALPL, with autosomal dominant inheritance and mild phenotype.

Our case highlights a dilemma in management of bone disease in adult onset mild HPP. Recent data about adult HPP showed a significant positive correlation between the number of fractures and vitamin B6 levels. Based on this our patient may be at high risk for fractures. However, there is no evidence to guide diagnosis or management of low bone mass in such patients. DXA scan and fracture risk assessment tool (FRAX) have shown inconsistent results for evaluating or selecting patients for treatment. Bisphosphonate use is contraindicated because it inhibits ALP activity. Case reports of teriparatide use in HPP have shown transient biochemical improvement and improved fracture healing in patients with mild mutations. Nevertheless, bone mineral density data was inconsistent. Asfotase Alpha, a bone targeted recombinant human TNSALP, has improved skeletal abnormalities in patients with perinatal/infantile onset HPP but there are no published studies evaluating its use in adult onset, mild disease. There are also no published studies about the use of denosumab, raloxifene or other osteoporosis agents in adult HPP. It is possible that emerging therapy options like sclerostin monoclonal antibody and PTH-rP analogs may have a role in prevention and treatment of HPP related bone disease. All in all, the question of when to start treatment or what to treat our patient with remains unanswered at this time.


Nothing to Disclose: RMP, AY