Hypophosphatasia is an inherited disease characterized by reduced alkaline
phosphatase activity, extracellular accumulation of inorganic pyrophosphate,
and impaired bone mineralization. Asfotase alfa (AA) is a recombinant human
alkaline phosphatase therapy approved for treatment of pediatric-onset
hypophosphatasia. Studies show promising outcome in AA-treated children with
hypophosphatasia; however, data on adults with pediatric-onset
hypophosphatasia are scarce. We report on a 59-year-old woman with childhood-
onset hypophosphatasia and a history of multiple fractures and orthopedic
procedures. Owing to renal failure (histological diagnosis: focal segmental
glomerulosclerosis), hemodialysis was started in 2013. By the end of 2015, the
patient was unable to walk, could only stand for 30 seconds, and was
completely dependent on help for activities of daily living. After 13 months
of AA therapy, the patient showed a dramatic increase in quality of life
(increased mobility), reduction in pain medication, and a significant
improvement in bone mineralization throughout the skeleton, including
consolidation of existing fractures and no occurrence of new fractures. This
case report demonstrates a relevant therapeutic success of AA treatment in an
adult hemodialysis patient with childhood onset of hypophosphatasia

Cooper, Mark S.

Quinkler, Marcus

Remde, Hanna

Journal of the Endocrine Society

Institutional Repository of the Freie Universität Berlin

ISSN 2472-1972Successful Asfotase Alfa Treatment in an AdultDialysis Patient With Childhood-OnsetHypophosphatasiaHanna Remde,1,2 Mark S. Cooper,3 and Marcus Quinkler21Charite´–University Medicine Berlin, 10117 Berlin Germany; 2Endocrinology in Charlottenburg, 10627Berlin, Germany; and 3Adrenal Steroid Group, ANZAC Research Institute, Concord RepatriationGeneral Hospital, Concord, New South Wales 2139, AustraliaHypophosphatasia is an inherited disease characterized by reduced alkaline phosphatase activity, ex-tracellular accumulation of inorganic pyrophosphate, and impaired bonemineralization. Asfotase alfa (AA)is a recombinant human alkaline phosphatase therapy approved for treatment of pediatric-onset hypo-phosphatasia. Studies show promising outcome in AA-treated children with hypophosphatasia; however,data on adults with pediatric-onset hypophosphatasia are scarce. We report on a 59-year-old woman withchildhood-onset hypophosphatasia and a history ofmultiple fractures and orthopedic procedures. Owing torenal failure (histological diagnosis: focal segmental glomerulosclerosis), hemodialysis was started in 2013.By the end of 2015, the patient was unable to walk, could only stand for 30 seconds, and was completelydependent on help for activities of daily living. After 13 months of AA therapy, the patient showed adramatic increase in quality of life (increased mobility), reduction in pain medication, and a significantimprovement in bonemineralization throughout the skeleton, including consolidation of existing fracturesand no occurrence of new fractures. This case report demonstrates a relevant therapeutic success of AAtreatment in an adult hemodialysis patient with childhood onset of hypophosphatasia.Copyright © 2017 Endocrine SocietyThis article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Freeform/Key Words: alkaline phosphatase, asfotase alfa, bone mineralization,hypophosphatasiaHypophosphatasia (HPP) is an inherited disease characterized by reduced alkaline phos-phatase (AP) activity leading to extracellular accumulation of inorganic pyrophosphate,which inhibits bone and tooth mineralization. It is caused by recessively or dominantlyinherited mutations within the tissue nonspecific isoenzyme of AP (TNSALP) gene onchromosome 1p36-34 [1]. The prevalence of severe and moderate HPP in Europe has beenestimated at 1 per 300,000 and 1 per 6370, respectively [1].As.330 mutations of the TNSALP gene have been described, patients may present with awide spectrum of clinical characteristics ranging from antenatal death to severe bone de-formities in early childhood, to dental complications without bone involvement in adults. Indecreasing order of severity and according to age of onset, clinicians categorize the perinatal,infantile, childhood, adult, and odontologic forms of HPP [1].No approved therapy for HPP has been available until recently [2]. Asfotase alfa (AA) is arecombinant human TNSALP combined with the constant region of human immunoglobulinG1–Fc domain and deca-aspartate for bone targeting because it has high affinity for hy-droxyapatite [2]. Since late 2015, treatment has been approved in Europe, Canada, and theUnited States for pediatric-onset HPP. So far, studies show excellent outcomes in AA-treatedAbbreviations: AA, asfotase alfa; AP, alkaline phosphatase; CRF, chronic renal failure; HPP, hypophosphatasia; TNSALP, tissue-nonspecific isoenzyme of alkaline phosphatase.Received 6 July 2017Accepted 15 August 2017First Published Online 18 August 2017September 2017 | Vol. 1, Iss. 9doi: 10.1210/js.2017-00307 | Journal of the Endocrine Society | 1188–1193Downloaded from https://academic.oup.com/jes/article-abstract/1/9/1188/4084554by FU Berlin FB Humanmedizin useron 20 April 2018children [2]. The necessity of a treatment option for adult HPP patients has been underlinedby a recent study revealing a substantial burden of disease in adult HPP patients [3]. Eventhough approved for all childhood-onset HPP patients independent of their current age, dataabout the effects of the treatment in adults are scarce.In this report we document a 59-year-old woman with childhood-onset HPP, treated withAA for 13 months, who responded with significant clinical and radiographic improvement.1. CaseIn summer 2009, a 51-year-old woman presented to our clinic. The diagnosis of HPP had beenmade in her first year of life. She reported that early childhood development was accompaniedby feeding problems, delay in the start of walking to age 4 years after several leg surgeries,failure to grow resulting in short stature (130 cm) (father, 173 cm;mother, 155 cm), and loss ofteeth during adolescence. Crutches for walking had been necessary continuously after leftlower leg fracture at age 26 years, followed by pseudoarthrosis of the right tibia and the leftfemur in the following years. Table 1 provides an overview of the main fractures and or-thopedic procedures during her adulthood.Direct sequencing of exons 1 to 12 revealed homozygous TNSALP mutations in exon 5(p.Ala116Ser) andheterozygousmutation in exon11 (p.Asn417Ser). Themutationp.Ala116Seris not functionally characterized; however, a p.Ala116Thr mutation results in negligible ac-tivity [4]. The mutation p.Asn417Ser abolishes AP activity, and as a heterozygous genotypereduces activity to ~25% [5].At referral, she reported pain in all bones, difficulty walking, and poor quality of life. Shehad received bisphosphonate therapy for a year in the past. For analgesia she was taking 4330 drops (=3 g)/d of a nonopiod analgesia (metamizol). In addition to her HPP, she hadhypertension, hypercholesterolemia, chronic kidney disease stage 4 with renal anemia, andnephrolithiasis, with the latter possibly related to HPP.Owing to implant loosening in her left distal humerus and continuous pseudoarthrosis ofthe right humerus, therapywith teriparatide (parathyroid hormone 1-34) was started in 2011but withdrawn after 4 months due to proteinuria (2.6 g/L) and decreased kidney function.Renal biopsy revealed focal segmental glomerulosclerosis (no calcium deposits). Owing to thelack of alternative treatment options, she was given transdermal hormone replacementtherapy (0.025 mg if 17b-estradiol and 0.125 mg of norethisterone acetate) in 2013. In thesame year, hemodialysis was started.Owing to new fractures (Table 1) and failure of prevalent fractures to heal, the patient’shealth and quality of life further deteriorated accompanied by severe bone pain. By the end of2015, the patient could no longer walk, could only stand for 30 seconds, and was completelydependent on help for activities of daily living and personal care.Table 1. Main Orthopedic Events and Procedures During Adulthood in a 59-Year-Old Female With theChildhood-Onset Form of HPPEvents and Procedures· Fracture left lower leg 1984 (age 26 years), intramedullary nailing 1988· Pseudoarthrosis right lower leg and intramedullary nailing 1989 (age 31 years), removal 1990· External fixation right lower leg 1993 to 1994, orthosis and intramedullary nailing 2003· Pseudoarthrosis left femur and intramedullary nailing 2002· Pseudoarthrosis right humerus 2004 and intramedullary nailing July 2008· Pseudoarthrosis and fracture left humerus, plate and screw August 2009· Fracture glenoid bone left September 2010· Implant loosening left distal humerus October 2010 and open reposition and internal refixation with double plateosteosynthesis plus autologous stem cells· Implant removal left distal humerus and neurolysis nervus ulnaris left February 2012· Orthosis left arm· Periprosthetic fracture right humerus April 2013doi: 10.1210/js.2017-00307 | Journal of the Endocrine Society | 1189Downloaded from https://academic.oup.com/jes/article-abstract/1/9/1188/4084554by FU Berlin FB Humanmedizin useron 20 April 20181190 | Journal of the Endocrine Society | doi: 10.1210/js.2017-00307Downloaded from https://academic.oup.com/jes/article-abstract/1/9/1188/4084554by FU Berlin FB Humanmedizin useron 20 April 2018At the end of 2015, AA was approved as therapy for pediatric-onset HPP in Germany.Radiographs of arms, hands, legs, and hips were taken in January 2016 showing widespreadprogressive demineralization (compared with 2013), distinct osseous deformities, and on-going destruction of bone structure, especially of the hands (Fig. 1a and 1b, left side).Compared with previous examinations, new radial and bilateral ulnar fractures, as well as anew fracture around a femoral nail, were apparent. At that time, medical therapy comprisedbisoprolol (1.25 mg/d), ramipril (5 mg/d), torsemide (200 mg/d), sodium polystyrene sulfonate(450 mg twice each week), lanthanum carbonate (750 mg/d), darbepoetin (15 mg every2 weeks), calcium (500 mg), colecalciferol (20,000 IU every 2 weeks), and transdermalestrogen.Given the patient’s progressive skeletal deformity and functional impairment, treatmentwas started with subcutaneous injections of 80 mg of AA three times per week (given directlyafter hemodialysis) after discussion between specialists within our clinic in January 2016.During the first 6 weeks of treatment she reported slight burning of the hands and knees andfatigue directly after injections. Laboratory data before and during treatment are presentedin Table 2.After 13 months of AA treatment the patient could stand and walk independently from thewheelchair to bed (3 m). Her ability to elevate her arms was still significantly impaired, butwas clearly improved compared with January 2016. Bone pain had reduced and less painmedication was necessary. Radiographs in February 2017 showed significantly improvedmineralization at all skeletal sites with greater improvement in the arms and hands than inthe legs, full consolidation of the radial, ulnar, and femoral fractures, and no occurrence of newfractures (Fig. 1a and 1b, right side). Medical therapy was otherwise unchanged.2. DiscussionNo clinical trial data for adults with childhood-onset HPP treated with AA have beenpublished except in abstract form [6]. Data from neonates and infants with severe HPP areavailable showing significantly improved survival and skeletal mineralization after AAtreatment [2, 7, 8].In our patient with the childhood form of HPP, therapy with AA resulted in markedimprovement of mobility and pain, and only mild side effects. In addition to a significantpositive impact on her reported quality of life, bone mineralization and fracture healingimproved significantly and no new fractures occurred.Her chronic renal failure (CRF) was attributed to hypertension, nonsteroidal anti-inflammatory medication taken for bone pain, and chronic nephrolithiasis. Unfortunately,we obtained no bone biopsies of our patient. However, it is likely that she had renal osteo-dystrophy with secondary hyperparathyroidism due to CRF. This was previously shown in anadult HPP patient with CRF requiring hemodialysis [9]. In contrast to the reported case [9],our patient never experienced hypercalcemia after fracture. Recently, a 55-year-old manwithodontohypophosphatasia was reported who was asymptomatic until he developed CRF,resulting in numerous disabling fractures [10]. After successful renal transplantation, thepatient improved significantly, suggesting that renal failure might further deteriorate bonechanges in HPP. Additionally, the administration of bisphosphonate could potentially be anadditional factor in worsening of the bone disease.In our case hemodialysis was an additional challenging point in treatment, and no ex-perience existed regarding hemodialysis and AA treatment. Increased phosphate levelsFigure 1. X-ray images of the right hand (a) and right arm (b) in January 2016 (left side)before asfotase therapy and in February 2017 (right side) after 13 months of asfotase therapyin a 59-year-old female patient with the childhood-onset form of HPP.doi: 10.1210/js.2017-00307 | Journal of the Endocrine Society | 1191Downloaded from https://academic.oup.com/jes/article-abstract/1/9/1188/4084554by FU Berlin FB Humanmedizin useron 20 April 2018previously reported during AA treatment were not seen in our case, probably due to he-modialysis. Under AA treatment we provided calcium and colecalciferol treatment.3. ConclusionThis case report shows a significant therapeutic success of AA treatment in an adult he-modialysis patient with the childhood form of HPP.AcknowledgmentsAddress all correspondence to: Marcus Quinkler, MD, Endocrinology in Charlottenburg, StuttgarterPlatz 1, 10627 Berlin, Germany. E-mail: marcusquinkler@t-online.de.Disclosure Summary: The authors have nothing to disclose.References and Notes1. Whyte MP. Hypophosphatasia—aetiology, nosology, pathogenesis, diagnosis and treatment. Nat RevEndocrinol. 2016;12(4):233–246.2. WhyteMP, Greenberg CR, SalmanNJ, BoberMB,McAlisterWH,Wenkert D, Van Sickle BJ, SimmonsJH, Edgar TS, Bauer ML, HamdanMA, Bishop N, Lutz RE, McGinnM, Craig S, Moore JN, Taylor JW,Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Milla´n JL, Skrinar AM, CrineP, Landy H. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904–913.3. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients withhypophosphatasia: results from two patient-reported surveys. Metabolism. 2016;65(10):1522–1530.4. Ishida Y, KomaruK, OdaK.Molecular characterization of tissue-nonspecific alkaline phosphatasewithan Ala to Thr substitution at position 116 associated with dominantly inherited hypophosphatasia.Biochim Biophys Acta. 2011;1812(3):326–332.5. Sultana S, Al-Shawafi HA,Makita S, SohdaM, AmizukaN, Takagi R, OdaK. An asparagine at position417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed byanalysis of the N417S mutation associated with severe hypophosphatasia. Mol Genet Metab. 2013;109(3):282–288.6. Kishnani P, Rockman-Greenberg C, Whyte MP, Weber T, Mhanni A, Madson K, Reeves A, Mack K,PlotkinH, KreherN, LandyH. Hypophosphatasia: enzyme replacement therapy (ENB-0040) decreasesTNSALP substrate accumulation and improves functional outcome in affected adolescents and adults.In: 15th International and 14th European Congress of Endocrinology; 5–9 May 2012; Florence, Italy.Abstract 29 OC8.1. Available at: http://www.endocrine-abstracts.org/ea/0029/ea0029OC8.1.htm.7. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N,Hofmann C. Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia.J Clin Endocrinol Metab. 2016;101(1):334–342.Table 2. Laboratory Results Before (January 2016) and During Therapy (July 2016 and January 2017)With AA in a 59-Year-Old Female With the Childhood-Onset Form of HPPJanuary 2016 July 2016 January 2017Calcium, mmol/L (n: 2.15–2.5) 2.32 2.30 2.21Phosphate, mmol/L (n: 0.87–1.45) 1.96 1.68 1.35AP, mkat/L (n: ,2.15) 0.33 .110 .110Bone AP, ostase, mg/L (n: 6–22.7) 8.0 3300 3340Parathyroid hormone, ng/L (n: 11–43) 116 331 29325-Hydroxy vitamin D3, mg/L (n: 20–70) 51 68 43Hemoglobin, g/dL (n: 12–16) 12.6 11.6 11.9GFR, mL/min (n: .90) 6.6 6.8 6.7Osteocalcin, mg/L (n: 14–42) nd nd 319Abbreviations: GFR, glomerular filtration rate [calculated with Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI) formula]; n, normal range; nd, not done.1192 | Journal of the Endocrine Society | doi: 10.1210/js.2017-00307Downloaded from https://academic.oup.com/jes/article-abstract/1/9/1188/4084554by FU Berlin FB Humanmedizin useron 20 April 20188. Whyte MP, Madson KL, Phillips D, Reeves AL, McAlister WH, Yakimoski A, Mack KE, Hamilton K,KaganK, Fujita KP, ThompsonDD,Moseley S, Odrljin T, Rockman-Greenberg C. Asfotase alfa therapyfor children with hypophosphatasia. JCI Insight. 2016;1(9):e85971.9. Whyte MP, Leelawattana R, Reinus WR, Yang C, Mumm S, Novack DV. Acute severe hypercalcemiaafter traumatic fractures and immobilization in hypophosphatasia complicated by chronic renal failure.J Clin Endocrinol Metab. 2013;98(12):4606–4612.10. Cundy T, Michigami T, Tachikawa K, Dray M, Collins JF, Paschalis EP, Gamsjaeger S, Roschger A,Fratzl-Zelman N, Roschger P, Klaushofer K. Reversible deterioration in hypophosphatasia caused byrenal failure with bisphosphonate treatment. J Bone Miner Res. 2015;30(9):1726–1737.doi: 10.1210/js.2017-00307 | Journal of the Endocrine Society | 1193Downloaded from https://academic.oup.com/jes/article-abstract/1/9/1188/4084554by FU Berlin FB Humanmedizin useron 20 April 2018

Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With
Childhood-Onset Hypophosphatasia

Hanna Remde

Mark S. Cooper

Marcus Quinkler

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Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With Childhood-Onset Hypophosphatasia

https://refubium.fu-berlin.de/bitstream/fub188/20558/1/js.2017-00307.pdf

Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With Childhood-Onset Hypophosphatasia

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