(19.16) Concern for Hypophosphatasia in Patient with Early-onset Osteoporosis and Chronically Low Alkaline Phosphatase Levels

Hypophosphatasia (HPP) is a rare genetic disorder arising from mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene that leads to low alkaline phosphatase (ALP) activity and impaired bone mineralization. This disorder typically presents with low ALP levels, elevated vitamin B6 and urinary phosphoethanolamine (PEP) levels, and can manifest in adults as recurrent fractures, bone and joint pain, short stature, and tooth loss.

Case(s) Description :

We discuss a 48-year-old female with a past medical history of secondary amenorrhea on oral contraceptives, osteoporosis diagnosed at age 35 and complicated by fractures of her foot, ankle, tibia/fibula, pelvis, and ribs all occurring while on therapy. In addition, patient has a significant GI history which includes a total colectomy for Meckel’s diverticulum as well as small bowel obstruction with partial small bowel resection, now complicated by short bowel syndrome. She endorses occasional alcohol use, though denies any smoking or other illicit drug use. Denies family history of calcium or bone disorders, though maternal family history is largely unknown.

Our patient endorses chronic diffuse body pain, loss of height, as well as chronic loose stools following her bowel surgeries. Her labs have been remarkable for hypercalcemia and normal vitamin D levels on supplementation, low parathyroid hormone, persistently low ALP levels, and negative celiac workup. A vitamin B6 level was obtained and found to be elevated at over five times the normal limit. She is scheduled for genetic testing to definitively evaluate for hypophosphatasia.

Discussion :

Given the rarity of HPP, low ALP levels are often overlooked and HPP often undiagnosed. Unfortunately, the consequences of delayed or misdiagnoses can be significant, as many adults with HPP suffer from debilitating pain and fractures that greatly reduce their quality of life. In addition, early recognition and diagnosis is imperative in patients who also have concomitant osteoporosis. Although there are no current evidence-based treatment guidelines for adult-onset HPP, there is still harm that can be done by placing patients on bone-resorptive therapies for osteoporosis which can increase the risk for fracture in the setting of underlying bone fragility. There have been documented cases of patients with HPP suffering fractures while on bisphosphonates, as well as on denosumab. Our case, if genetic testing is consistent with HPP, underscores the need for greater discussion around - and understanding of - HPP in order to better recognize its presentation, and avoid delays in diagnosis and potentially inappropriate medical therapy that could increase fracture risk and worsen quality of life.