An Inherited Metabolic Disorder That Masquerades as Osteoporosis

Introduction:
Hypophosphatasia is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene, which encodes tissue non-specific alkaline phosphatase. The enzyme defect results in the accumulation of substrates like inorganic pyrophosphate, thereby inhibiting mineralization of bones and teeth. Clinical features include premature loss of deciduous teeth, bowed legs, lower extremity stress fractures, bone pain and impaired mobility. Serum alkaline phosphatase (ALP) is a marker of bone turnover. Low ALP, high serum vitamin B6 and high urine phosphoethanolamine are diagnostic hallmarks of hypophosphatasia.

Case Description:
A 54-year-old lady was referred to the endocrinology clinic for severe osteoporosis, characterized by an olecranon fracture and low bone mineral density (T score -3.0 at the left femoral neck). Bone disease risk factors included premature menopause at age 38 years and maternal history of hip fracture. There was no personal or family history of recurrent fractures, impaired mobility, or unexplained tooth loss. Despite treatment with ibandronate, zoledronic acid and teriparatide, her bone mineral density declined over the course of a decade .

Physical examination revealed low BMI (18.07 kg/m2), normal gait and intact muscle strength. Lab testing disclosed low serum alkaline phosphatase (ALP) 18 units/L [reference 45 to 117 units/L], high serum vitamin B6 131.8 nmol/L [reference 20.0 to 125.0 nmol/L] and high urine phosphoethanolamine 104 nmol/mg Cr [reference < 48]. ALP results prior to bisphosphonate exposure were unavailable. Vitamin D status, thyroid function, parathyroid hormone, corrected serum calcium, ceruloplasmin and zinc levels were normal. Exome sequencing identified a pathogenic heterozygous nonsense ALPL gene mutation, c.1282C >T (p.Arg428X).

She was counselled to avoid bisphosphonate therapy indefinitely. ALP measurement was advised for her blood relatives since hypophosphatasia is an autosomal recessive or dominant disorder. With asfotase alfa, the only FDA-approved therapy for juvenile-onset hypophosphatasia, there have been no further fractures to date, and her mobility remains unimpaired.

Discussion:
Hypophosphatasia can be mistaken for osteoporosis since both conditions present with low bone mineral density on DEXA scan. Furthermore, bisphosphonate therapy and hypophosphatasia are mutually exclusive entities that can present with low ALP. Thus, bisphosphonate exposure may pose a diagnostic quandary when distinguishing between osteoporosis and hypophosphatasia. This case highlights the importance of assessing ALP when evaluating osteoporosis with atypical features such as age of onset under fifty years, remarkably low bone mineral density, fracture(s), and inadequate response to anti-osteoporosis agents. Moreover, if ALP is low, some index of suspicion for hypophosphatasia ought to be maintained, even if dental or lower extremity bone symptoms are absent. Genetic testing is confirmatory. Bisphosphonate therapy and parathyroid hormone analogs are not established treatment modalities for hypophosphatasia. Instead, enzyme replacement with asfotase alfa is recommended.