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. 2021 Sep 1:2021:21-0096.
doi: 10.1530/EDM-21-0096. Online ahead of print.

Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia

Affiliations

Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia

Annabelle M Warren et al. Endocrinol Diabetes Metab Case Rep. .

Abstract

Summary: Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or 'osteoporosis' to identify a low ALP level is recommended.

Learning points: Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

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Figures

Figure 1
Figure 1
Pre-operative X-ray images of bilateral atypical femoral fractures December 2018, showing right symptomatic complete femoral diaphyseal fracture and left asymptomatic partial AFF.
Figure 2
Figure 2
X-ray images in October 2019 showing persistent non-union of bilateral atypical femoral fractures, 10 months post right-sided internal fixation with an intramedullary nail.
Figure 3
Figure 3
X-ray images from September 2020 showing the progression of healing of bilateral atypical femoral fractures following 7 months of teriparatide therapy.

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