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

2021 ◽  
Vol 2021 ◽  
Author(s):  
Annabelle M Warren ◽  
Peter R Ebeling ◽  
Vivian Grill ◽  
Ego Seeman ◽  
Shoshana Sztal-Mazer
Keyword(s):  
Alkaline Phosphatase ◽  
Vitamin B6 ◽  
Serum Alkaline Phosphatase ◽  
Serum Vitamin ◽  
Femoral Fractures ◽  
Adult Onset ◽  
Antiresorptive Therapy ◽  
Atypical Femoral Fractures ◽  
Asfotase Alfa ◽  
Low Serum

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.

scholarly journals Case of Juvenile Onset Hypophosphatasia Diagnosed in an Adult Patient

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A187-A188
Author(s):  
Nirmal Nair
Keyword(s):  
Alkaline Phosphatase ◽  
Dental Caries ◽  
Ankle Fracture ◽  
Vitamin B6 ◽  
Serum Alkaline Phosphatase ◽  
Bone Mineralization ◽  
Multiple Fractures ◽  
History Of ◽  
Tissue Nonspecific Alkaline Phosphatase ◽  
Low Serum

Abstract Background: Hypophosphatasia is a rare multisystem disease caused by mutations in genes encoding tissue nonspecific alkaline phosphatase, a key player in promoting bone mineralization1. Here we present a case of hypophosphatasia in a patient with history of recurrent fractures and dental caries since childhood. Case Report: Patient is a 52-year-old woman with history of multiple fractures who initially presented for follow up of osteoporosis following an atraumatic ankle fracture. Further questioning revealed a history of 16 atraumatic fractures since the age of 4, involving ankles, toes, and fingers. Several adult teeth had never developed requiring braces to fill in gaps at age 13, dental caries and tooth fractures involving the majority of her adult teeth. DEXA scan in 2019 revealed T score of -2.4 in the left femoral neck. Suspicion for hypophosphatasia in February 2019 following an ankle fracture and patient’s prior history prompted further workup, revealing low serum alkaline phosphatase levels of 29 and 32 (bone fraction 62 percent, liver fraction 38 percent), and Vitamin B6 levels elevated to 66.2. Remainder of workup, with Vitamin D, PTH, Magnesium, and Calcium was normal. A childhood history of multiple atraumatic fractures, various dental issues, with elevated Vitamin B6 and low serum alkaline phosphatase suggested Hypophosphatasia. As bisphosphonates are contraindicated in these patients due to their potential to reduce ALP, teriparatide was initiated. Discussion: Hypophosphatasia involves mutations in tissue nonspecific alkaline phosphatase, a key player in bone mineralization. In normal individuals, this enzyme dephosphorylates inorganic pyrophosphate (PPi), which otherwise inhibits bone mineralization. The mutated TNSALP leads to accumulation of PPi, and thereby unmineralized osteoid.1 Although individual presentations can vary, developmental abnormalities, such as delayed growth, early loss of primary or secondary teeth, or history of multiple fractures are characteristic. Due to the rarity of the disease, and its potential to be confused for more common bone and rheumatologic diseases, diagnosis is often delayed1. Patients in whom suspicion for hypophosphatasia is present, should undergo further testing with bone specific Alkaline phosphatase and Vitamin B6 which would be low and elevated, respectively and may be candidates for enzyme replacement therapy with bone-targeting recombinant alkaline phosphatase1. Traditional treatments such as bisphosphonates potentially decrease ALP and worsen disease, making accurate diagnosis all the more crucial. References1 Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. 2015;12(2):170–173.

scholarly journals Evaluation of the nature and etiologies of risk factors for diaphyseal atypical femoral fractures

2021 ◽  
Author(s):  
Hiroyuki Tsuchie ◽  
Naohisa Miyakoshi ◽  
Yuji Kasukawa ◽  
Koji Nozaka ◽  
Kimio Saito ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analyses ◽  
Femoral Fractures ◽  
Japanese Patients ◽  
High Serum ◽  
Control Group ◽  
Atypical Femoral Fractures ◽  
Factors Affecting ◽  
Lateral Curvature ◽  
Low Serum

Objectives: Differences in the mechanisms of subtrochanteric and diaphyseal atypical femoral fractures (AFFs) have been speculated in studies that have analyzed differences in the patients’ backgrounds. However, the etiologies of each type of AFF have not been investigated in detail. Therefore, this study aimed to investigate the nature and etiologies of the risk factors for diaphyseal AFFs. Materials and Methods: Eighty consecutive Japanese patients with 91 diaphyseal AFFs (the AFF group) and 110 age-matched female patients with osteoporosis (the non-AFF control group) were included. Their clinical data were compared and the factors affecting AFFs were investigated. Furthermore, the etiologies of the risk factors for diaphyseal AFFs were examined. Results: Multivariate analysis revealed that femoral serrated changes, bisphosphonate or denosumab usage, and lateral and anterior femoral curvatures were the risk factors for diaphyseal AFFs (p<0.0011, p=0.0137, and p<0.0001, respectively). Multivariate analyses also revealed that serrated changes and low serum 25(OH)D levels affected the lateral curvature (p=0.0088 and 0.0205, respectively), while serrated changes affected the anterior curvature (p=0.0006); each significantly affected the femoral curvature. In addition, a high serum calcium (Ca) level, lateral femoral curvature, and anterior femoral curvature were the predictors of serrated changes (p=0.0146, 0.0002, and 0.0098, respectively). Conclusion: The risk factors for diaphyseal AFFs were bone resorption inhibitor usage, a strong femoral curvature, and serrated changes. A low serum 25(OH)D level and serrated changes are the risk factors for lateral curvature, while a high serum Ca level is a risk factor for serrated changes.

scholarly journals Hypophosphatasia

2021 ◽  
Vol 10 (23) ◽  
pp. 5676
Author(s):  
Symeon Tournis ◽  
Maria P. Yavropoulou ◽  
Stergios A. Polyzos ◽  
Artemis Doulgeraki
Keyword(s):  
Alkaline Phosphatase ◽  
Autosomal Dominant ◽  
Serum Alkaline Phosphatase ◽  
Severe Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Live Births ◽  
Enzyme Replacement ◽  
Asfotase Alfa ◽  
Reduced Activity

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

Sign in / Sign up

Export Citation Format

Share Document