Usual Suspects

A DISEASE IN DISGUISE

Delayed identification and misdiagnoses often happen in hypophosphatasia cases because of how well it masks itself as other more common diseases.1-5

Symptoms of hypophosphatasia are often common across other metabolic disorders and various diseases, which can impact timely and accurate diagnosis.1-5

Common suspects in:

Common suspects in:

Differential diagnoses for hypophosphatasia with shared symptoms:

Osteopenia/
Osteoporosis

AKA Oswaldo Porosis6-9

Note: Patient may have osteopenia as a symptom of hypophosphatasia

  • Decrease in bone mineral density
  • Fractures (from fragile bones)

Differential diagnoses for hypophosphatasia with shared symptoms:

Differential diagnoses for hypophosphatasia with shared symptoms:

Osteopenia/
Osteoporosis

AKA Oswaldo Porosis6-9

Note: Patient may have osteopenia as a symptom of hypophosphatasia

  • Decrease in bone mineral density
  • Fractures (from fragile bones)

Differential diagnoses for hypophosphatasia with shared symptoms:

Chondrocalcinosis/
pseudogout

AKA Sue Dogout10,11

Note: Patient may have pseudogout as a symptom of hypophosphatasia

  • Inflammation of the joint (most commonly knee, wrist, ankle, elbow, toe, shoulder, and hip)

Differential diagnoses for hypophosphatasia with shared symptoms:

Fibromyalgia

AKA Phil “Big Bro”
Myalgia12

  • Fatigue
  • Pain
  • Muscle and joint stiffness
  • Trouble sleeping

Differential diagnoses for hypophosphatasia with shared symptoms:

Osteogenesis
imperfecta

AKA Mr. Imperfect2,13,14

  • Reduced bone density
  • Bowed long bones
  • Fractures
  • Gracile ribs
  • Metaphyseal flaring
  • Brittle teeth

View the full list of suspects, shared symptoms, and how to differentiate from hypophosphatasia:

A misdiagnosis can do damage

Misdiagnosis of a patient with hypophosphatasia is common and can lead to ineffective management that can compound the clinical picture and worsen hypophosphatasia. Certain therapies used for other disorders can interfere with or dramatically worsen hypophosphatasia. 4,5,7,15-17

Make sure to rule out hypophosphatasia before starting patients on bisphosphonates or some commonly used supplements that may end up causing your patients harm4,5,7

A misdiagnosis can do damage

Misdiagnosis of a patient with hypophosphatasia is common and can lead to ineffective management that can compound the clinical picture and worsen hypophosphatasia. Certain therapies used for other disorders can interfere with or dramatically worsen hypophosphatasia.5,13,14,16-18

Make sure to rule out hypophosphatasia before starting patients on bisphosphonates or some commonly used supplements that may end up causing your patients harm15,17,18

A misdiagnosis can do damage

Misdiagnosis of a patient with hypophosphatasia is common and can lead to ineffective management that can compound the clinical picture and worsen hypophosphatasia. Certain therapies used for other disorders can interfere with or dramatically worsen hypophosphatasia.4,5,11-14

Make sure to rule out hypophosphatasia before starting patients on bisphosphonates or some commonly used supplements that may end up causing your patients harm4,5,14

Treatments for other similar disorders

Bisphosphonates

Patient populations

  • Bisphosphonates are commonly used in adult patients with osteoporosis19

Risk of treatment in patients with hypophosphatasia:

Based on a study examining bisphosphonates in osteoporosis, the half-life of bisphosphonates was shown to be greater than 10 years and may have detrimental effects on a patient's condition if a wrongful diagnosis is made. Make sure to rule out hypophosphatasia before starting patients on bisphosphonates.20

  • The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), with the accumulation of PPi associated with skeletal and systemic symptoms seen in hypophosphatasia, which may result in a worsening of presenting symptoms19,21,22
  • Bisphosphonates may directly or indirectly worsen hypophosphatasia by binding zinc or magnesium, compromising alkaline phosphatase activity19,21,22
  • Possible increased risk of fracture at growth plate19,21,22
  • Increased risk of atypical femoral fractures in adults19,21,22
  • Excessively high doses have led to osteopetrosis and persistent remodeling defects, persisting more than 6 years after discontinuation19,21,22

Supplements:
Vitamin D and calcium

Patient populations

  • Vitamin D and calcium supplementation can be used for a myriad of conditions, ranging from rickets to depression, in adults, children, and infants7,21,23

Patient populations

  • Hypercalcemia7,21,23
  • Hypercalciuria7,21,23
  • Kidney stones7,21,23
Treatments for other similar disorders PATIENT POPULATIONS RISK OF TREATMENT IN PATIENTS WITH HYPOPHOSPHATASIA

Bisphosphonates
  • Bisphosphonates are commonly used in adult patients with osteoporosis19

Based on a study examining bisphosphonates in osteoporosis, the half-life of bisphosphonates was shown to be greater than 10 years and may have detrimental effects on a patient's condition if a wrongful diagnosis is made. Make sure to rule out hypophosphatasia before starting patients on bisphosphonates.20

  • The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), with the accumulation of PPi associated with skeletal and systemic symptoms seen in hypophosphatasia, which may result in a worsening of presenting symptoms19,21,22
  • Bisphosphonates may directly or indirectly worsen hypophosphatasia by binding zinc or magnesium, compromising alkaline phosphatase activity19,21,22
  • Possible increased risk of fracture at growth plate19,21,22
  • Increased risk of atypical femoral fractures in adults19,21,22
  • Excessively high doses have led to osteopetrosis and persistent remodeling defects, persisting more than 6 years after discontinuation19,21,22

Supplements:
Vitamin D and calcium

  • Vitamin D and calcium supplementation can be used for a myriad of conditions, ranging from rickets to depression, in adults, children, and infants7,21,23
  • Hypercalcemia7,21,23
  • Hypercalciuria7,21,23
  • Kidney stones7,21,23

Treatments for other similar disorders

Bisphosphonates

Patient populations

  • Bisphosphonates are commonly used in adult patients with osteoporosis19

Risk of treatment in patients with hypophosphatasia:

Based on a study examining bisphophonates in osteoporosis, the half-life of bisphosphonates was shown to be greater than 10 years and may have detrimental effects on a patient's condition if a wrongful diagnosis is made. Make sure to rule out hypophosphatasia before starting patients on bisphosphonates.20

  • The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), with the accumulation of PPi associated with skeletal and systemic symptoms seen in hypophosphatasia, which may result in a worsening of presenting symptoms19,21,22
  • Bisphosphonates may directly or indirectly worsen hypophosphatasia by binding zinc or magnesium, compromising alkaline phosphatase activity19,21,22
  • Possible increased risk of fracture at growth plate19,21,22
  • Increased risk of atypical femoral fractures in adults19,21,22
  • Excessively high doses have led to osteopetrosis and persistent remodeling defects, persisting more than 6 years after discontinuation19,21,22

Supplements:
Vitamin D and calcium

Patient populations

  • Vitamin D and calcium supplementation can be used for a myriad of conditions, ranging from rickets to depression, in adults, children, and infants18,21,23

Patient populations

  • Hypercalcemia18,21,23
  • Hypercalciuria18,21,23
  • Kidney stones18,21,23
Treatments for other similar disorders PATIENT POPULATIONS RISK OF TREATMENT IN PATIENTS WITH HYPOPHOSPHATASIA

Bisphosphonates
  • Bisphosphonates are commonly used in adult patients with osteoporosis19

Based on a study examining bisphosphonates in osteoporosis, the half-life of bisphosphonates was shown to be greater than 10 years and may have detrimental effects on a patient's condition if a wrongful diagnosis is made. Make sure to rule out hypophosphatasia before starting patients on bisphosphonates.20

  • The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), with the accumulation of PPi associated with skeletal and systemic symptoms seen in hypophosphatasia, which may result in a worsening of presenting symptoms19,21,22
  • Bisphosphonates may directly or indirectly worsen hypophosphatasia by binding zinc or magnesium, compromising alkaline phosphatase activity19,21,22
  • Possible increased risk of fracture at growth plate19,21,22
  • Increased risk of atypical femoral fractures in adults19,21,22
  • Excessively high doses have led to osteopetrosis and persistent remodeling defects, persisting more than 6 years after discontinuation19,21,22

Supplements:
Vitamin D and calcium

  • Vitamin D and calcium supplementation can be used for a myriad of conditions, ranging from rickets to depression, in adults, children, and infants18,21,23
  • Hypercalcemia18,21,23
  • Hypercalciuria18,21,23
  • Kidney stones18,21,23

Treatments for other similar disorders

Bisphosphonates

Patient populations

  • Bisphosphonates are commonly used in adult patients with osteoporosis15

Risk of treatment in patients with hypophosphatasia:

Based on a study examining bisphosphonates in osteoporosis, the half-life of bisphosphonates was shown to be greater than 10 years and may have detrimental effects on a patient's condition if a wrongful diagnosis is made. Make sure to rule out hypophosphatasia before starting patients on bisphosphonates.16

  • The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), with the accumulation of PPi associated with skeletal and systemic symptoms seen in hypophosphatasia, which may result in a worsening of presenting symptoms15,17,18
  • Bisphosphonates may directly or indirectly worsen hypophosphatasia by binding zinc or magnesium, compromising alkaline phosphatase activity.15,17,18
  • Possible increased risk of fracture at growth plate15,17,18
  • Increased risk of atypical femoral fractures in adults15,17,18
  • Excessively high doses have led to osteopetrosis and persistent remodeling defects, persisting more than 6 years after discontinuation15,17,18

Supplements:
Vitamin D and calcium

Patient populations

  • Vitamin D and calcium supplementation is recommended in adults, children, and infants10

Patient populations

  • Hypercalcemia10,14,17
  • Hypercalciuria10,14,17
  • Kidney stones10,14,17
Treatments for other similar disorders PATIENT POPULATIONS RISK OF TREATMENT IN PATIENTS WITH HYPOPHOSPHATASIA

Bisphosphonates
  • Bisphosphonates are commonly used in adult patients with osteoporosis15

Based on a study examining bisphosphonates in osteoporosis, the half-life of bisphosphonates was shown to be greater than 10 years and may have detrimental effects on a patient's condition if a wrongful diagnosis is made. Make sure to rule out hypophosphatasia before starting patients on bisphosphonates.16

  • The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), with the accumulation of PPi associated with skeletal and systemic symptoms seen in hypophosphatasia, which may result in a worsening of presenting symptoms15,17,18
  • Bisphosphonates may directly or indirectly worsen hypophosphatasia by binding zinc or magnesium, compromising alkaline phosphatase activity15,17,18
  • Possible increased risk of fracture at growth plate15,17,18
  • Increased risk of atypical femoral fractures in adults15,17,18
  • Excessively high doses have led to osteopetrosis and persistent remodeling defects, persisting more than 6 years after discontinuation15,17,18

Supplements:
Vitamin D and calcium

  • Vitamin D and calcium supplementation can be used for a myriad of conditions, ranging from rickets to depression, in adults, children, and infants10,14,17
  • Hypercalcemia10,14,17
  • Hypercalciuria10,14,17
  • Kidney stones10,14,17

WEEDING OUT SUSPECTS

Persistently low alkaline phosphatase differentiates hypophosphatasia from other conditions1,9,21,24

WEEDING OUT SUSPECTS

Persistently low alkaline phosphatase differentiates hypophosphatasia from other conditions1,21,24,25

WEEDING OUT SUSPECTS

Persistently low alkaline phosphatase differentiates hypophosphatasia from other conditions1,17,19,20

Persistently low ALP may differentiate HPP from other conditions1

While some conditions may lead to transient decreases in ALP, patients with HPP have persistently low* ALP levels.† Persistently low ALP levels should raise suspicion of HPP, especially when coupled with common symptoms of HPP such as musculoskeletal pain and/or weakness, premature tooth loss, or previous nontraumatic fractures.1,3

  • *Persistently low alkaline phosphatase can be defined as having 2 exams below normal value at intervals of more than 30 days.3,24
  • †Alkaline phosphatase ranges must be age- and sex-adjusted.3,26

Tab 2

Persistently low ALP may differentiate HPP from other conditions1

While some conditions may lead to transient decreases in ALP, patients with HPP have persistently low* ALP levels.† Persistently low ALP levels should raise suspicion of HPP, especially when coupled with common symptoms of HPP such as musculoskeletal pain and/or weakness, premature tooth loss, or previous nontraumatic fractures.1,3

  • *Persistently low alkaline phosphatase can be defined as having 2 exams below normal value at intervals of more than 30 days.3,24
  • †Alkaline phosphatase ranges must be age- and sex-adjusted.3,26

Persistently low ALP may differentiate HPP from other conditions1

While some conditions may lead to transient decreases in ALP, patients with HPP have persistently low* ALP levels.† Persistently low ALP levels should raise suspicion of HPP, especially when coupled with common symptoms of HPP such as musculoskeletal pain and/or weakness, premature tooth loss, or previous nontraumatic fractures1,3

  • *Persistently low alkaline phosphatase can be defined as having 2 exams below normal value at intervals of more than 30 days.3,19
  • †Alkaline phosphatase ranges must be age- and sex-adjusted.3,21

ALP Levels1‡

Precipitously low

  • Multiple myeloma or other cancers
  • Cardiac bypass surgery
  • Major trauma or surgery
  • Chemotherapy
  • Transfusion (often massive)
  • Starvation
  • Sepsis/multi-organ/hepatic failure

Transiently low

  • Osteogenesis imperfecta type II
  • Profound hypothyroidism
  • Cushing disease
  • Bisphosphonate therapy
  • Adynamic renal osteodystrophy
  • Milk-alkali syndrome
  • Wilson disease
  • Celiac disease
  • Zinc/magnesium deficiency

Persistently low

  • Hypophosphatasia
  • Cleidrocranial dysostosis
  • Mseleni joint disease

‡Not an exhaustive list of conditions associated with low levels of ALP.

Build the case for hypophosphatasia
Identifying HPP

References: 1. McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014;29(7):1651-1660. 2. Offiah AC, Vockley J, Munns CF, Murotsuki J. Differential diagnosis of perinatal hypophosphatasia: radiologic perspectives. Pediatr Radiol. 2019;49(1):3-22. 3. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 4. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metabolism. 2016;65(10):1522-1530. 5. Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987-994. 6. Varacallo M, Seaman TJ, Jandu JS, Pizzutillo P. Osteopenia. StatPearls [Internet]. 2022. Accessed March 30, 2023. https://www.ncbi.nlm.nih.gov/books/NBK499878/ 7. Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res. 2017;32(10):1977-1980. 8. Desborough R, Nicklin P, Gossiel F, et al. Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic. Bone. 2021;144:115795. 9. Bloch-Zupan A. Hypophosphatasia: diagnosis and clinical signs - a dental surgeon perspective. Int J Paediatr Dent. 2016;26(6):426-438. 10. Macmullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Muscoloskelet Dis. 2012;4(2):121-131. 11. Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med. 2016;374(26):2575-2584. 12. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Fibromyalgia. Accessed March 30, 2023. https://www.niams.nih.gov/health-topics/fibromyalgia 13. National Institute of Child Health and Human Development. What are the symptoms of osteogenesis imperfecta (OI). 2021. Accessed March 30, 2023. https://www.nichd.nih.gov/health/topics/osteogenesisimp/conditioninfo/symptoms 14. Marini JC, Cabral WA. Osteogenesis imperfecta. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. Academic Press; 2018;397-420. 15. Mornet E, Nunes ME. Hypophosphatasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2011. Accessed April 3, 2023. http://www.ncbi.nlm.nih.gov/books/NBK1150/?report=reader 16. Mohn A, De Leonibus C, de Giorgis T, Mornet E, Chiarelli F. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011;100(7):e43-e46. 17. Whyte MP, Wenkert D, McAlister WH, et al. Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia. J Bone Miner Res. 2009;24:1493-1505. 18. Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res. 2017;32(10):1977-1980. 19. Boyce AM, Tosi LL, Paul SM. Bisphosphonate treatment for children with disabling conditions. PM R. 2014;6(5):427-436. 20. Stadecker WJ. Bisphosphonates 101: an update for the general dentist. Inside Dentistry. 2008. 21. Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015; 26(12):2743-2757. 22. Choida V, Bubbear JS. Update on the management of hypophosphatasia. Ther Adv Musculoskelet Dis. 2019;11:1759720X19863997. 23. Martos-Moreno GA, Calzada J, Couce ML, Argente J. Hypophosphatasia: clinical manifestations, diagnostic recommendations and therapeutic options. An Pediatr (Engl Ed). 2018;88(6):356.e1-356.e11. 24. Vieira LHR, Peixoto KC, Flósi CL, Fleiuss de Farias ML, Madeira M. Active search of adult patients with persistently low serum alkaline phosphatase levels for diagnosis of hypophosphatasia. Arch Endocrinol Metab. 2021;65(3):289-294. 25. Bianchi ML, Bishop NJ, Guañabens N, et al; Rare Bone Disease Action Group of the European Calcified Tissue Society. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(8):1445-1460. 26. Bishop N, Munns CF, Ozono K. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016;101(6):514-515.