Skip to main content

Advertisement

SpringerLink
Log in

Subtrochanteric and diaphyseal femoral fractures in hypophosphatasia—not atypical at all

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Risk for subtrochanteric and diaphyseal femoral fractures is considered increased in patients with hypophosphatasia (HPP). Evaluating a large cohort of HPP patients, we could for the first time quantify the prevalcence and identify both morphometric features as well as predisposing factors for this complication of severe HPP.

Introduction

Subtrochanteric and diaphyseal femoral fractures have been associated with both, long-term antiresorptive treatment and metabolic bone disorders, specifically Hypophosphatasia (HPP). Building on a cross-sectional evaluation of real-world data, this study reports risk factors, prevalence, treatment outcome and morphometric particularities for such fractures in HPP as compared to Atypical Femoral Fractures (AFF) in long-term antiresorptive treatment.

Methods

For 15 out of 150 HPP patients identified with having experienced at least one such fracture, medical records were reviewed in detail, extracting medical history, genotype, lab assessments, bone mineral density (DXA), radiographic data on femoral geometry and clinical aspects of fracture etiology and healing.

Results

Bilateral fractures were documented in 10 of these 15 patients, yielding a total of 25 fractures for evaluation. Disease-inherent risk factors included autosomal-recessive, childhood onset HPP, apparently low alkaline phosphatase (ALP) ≤ 20 U/l and substantially elevated pyridoxal 5′-phosphate (PLP) > 3 times upper limit of normal as well as high lumbar spine BMD. Fracture morphology met definition criteria for AFF in 88% of cases. Femoral geometry revealed additional risk factors previously described for AFF, including decreased femoral neck-shaft angle and increased femoral offset. Extrinsic risk factors include Hypovitaminosis D (80%) and pre-treatment with bisphosphonates (46,7%) and Proton-Pump Inhibitors (40%).

Conclusions

Increased risk for subtrochanteric and diaphyseal femoral fractures in HPP appears to result from both compromised bone metabolism as well as disease-associated bone deformities. In severe HPP, generous screening for such fractures seems advisable. Bisphosphonates and Hypovitaminosis D should be avoided. Healing is compromised and requires mindful consideration of both pharmacological and surgical options.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Howe TS, van der Meulen MCH, Weinstein RS, Whyte MP (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 29(1):1–23

    Article  PubMed  Google Scholar 

  2. Schilcher J, Michaelsson K, Aspenberg P (2011) Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 364(18):1728–1737

    Article  PubMed  CAS  Google Scholar 

  3. Gedmintas L, Solomon DH, Kim SC (2013) Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 28(8):1729–1737

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K (2014) Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med 371(10):974–976

    Article  PubMed  Google Scholar 

  5. Maravic M, Ostertag A, Cohen-Solal M (2012) Subtrochanteric/femoral shaft versus hip fractures: incidences and identification of risk factors. J Bone Miner Res 27(1):130–137

    Article  PubMed  Google Scholar 

  6. Napoli N, Schwartz AV, Palermo L, Jin JJ, Wustrack R, Cauley JA, Ensrud KE, Kelly M, Black DM (2013) Risk factors for subtrochanteric and diaphyseal fractures: the study of osteoporotic fractures. J Clin Endocrinol Metab 98(2):659–667

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Franceschetti P, Bondanelli M, Caruso G, Ambrosio MR, Lorusso V, Zatelli MC, Massari L, degli Uberti EC (2013) Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy. Bone 56(2):426–431

    Article  PubMed  CAS  Google Scholar 

  8. Ng AC, Koh JS, Howe TS (2013) Vitamin D and atypical femoral fractures. Osteoporos Int 24(5):1767

    Article  PubMed  CAS  Google Scholar 

  9. Girgis CM, Sher D, Seibel MJ (2010) Atypical femoral fractures and bisphosphonate use. N Engl J Med 362(19):1848–1849

    Article  PubMed  CAS  Google Scholar 

  10. Kim JW, Kim JJ, Byun YS, Shon OJ, Oh HK, Park KC, Kim JW, Oh CW (2017) Factors affecting fracture location in atypical femoral fractures: a cross-sectional study with 147 patients. Injury 48:1570–1574

    Article  PubMed  Google Scholar 

  11. Schilcher J, Howe TS, Png MA, Aspenberg P, Koh JSB (2015) Atypical fractures are mainly subtrochanteric in Singapore and diaphyseal in Sweden: a cross-sectional study. J Bone Miner Res 30(11):2127–2132

    Article  PubMed  Google Scholar 

  12. Feldstein AC, Black D, Perrin N, Rosales AG, Friess D, Boardman D, Dell R, Santora A, Chandler JM, Rix MM, Orwoll E (2012) Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res 27(5):977–986

    Article  PubMed  Google Scholar 

  13. Koh A, Guerado E, Giannoudis PV (2017) Atypical femoral fractures related to bisphosphonate treatment: issues and controversies related to their surgical management. Bone Joint J 99-B(3):295–302

    Article  PubMed  CAS  Google Scholar 

  14. Schilcher J (2015) High revision rate but good healing capacity of atypical femoral fractures. A comparison with common shaft fractures. Injury 46(12):2468–2473

    Article  PubMed  Google Scholar 

  15. Miyakoshi N, Aizawa T, Sasaki S, Ando S, Maekawa S, Aonuma H, Tsuchie H, Sasaki H, Kasukawa Y, Shimada Y (2015) Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: a comparison between treatment with and without teriparatide. J Bone Miner Metab 33(5):553–559

    Article  PubMed  CAS  Google Scholar 

  16. Gomberg SJ, Wustrack RL, Napoli N, Arnaud CD, Black DM (2011) Teriparatide, vitamin D, and calcium healed bilateral subtrochanteric stress fractures in a postmenopausal woman with a 13-year history of continuous alendronate therapy. J Clin Endocrinol Metab 96(6):1627–1632

    Article  PubMed  CAS  Google Scholar 

  17. Huang HT, Kang L, Huang PJ, Fu YC, Lin SY, Hsieh CH, Chen JC, Cheng YM, Chen CH (2012) Successful teriparatide treatment of atypical fracture after long-term use of alendronate without surgical procedure in a postmenopausal woman: a case report. Menopause 19(12):1360–1363

    Article  PubMed  Google Scholar 

  18. Yates CJ, Bartlett MJ, Ebeling PR (2011) An atypical subtrochanteric femoral fracture from pycnodysostosis: a lesson from nature. J Bone Miner Res 26(6):1377–1379

    Article  PubMed  Google Scholar 

  19. Sonohata M, Mawatari M, Hotokebuchi T, Okubo T, Ono H (2011) Bipolar hip arthroplasty for subtrochanteric femoral nonunion in an adult with autosomal dominant osteopetrosis type II. J Orthop Sci 16(5):652–655

  20. Birmingham P, McHale KA (2008) Case reports: treatment of subtrochanteric and ipsilateral femoral neck fractures in an adult with osteopetrosis. Clin Orthop Relat Res 466(8):2002–2008

  21. Trejo P, Fassier F, Glorieux FH, Rauch F (2017) Diaphyseal femur fractures in osteogenesis imperfecta: characteristics and relationship with bisphosphonate treatment. J Bone Miner Res 32(5):1034–1039

    Article  PubMed  CAS  Google Scholar 

  22. Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP (2012) “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res 27(5):987–994

    Article  PubMed  CAS  Google Scholar 

  23. Whyte MP (2009) Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res 24(6):1132–1134

    Article  PubMed  Google Scholar 

  24. Sharma N, Bache E, Clare T (2015) Bilateral femoral neck fractures in a young patient suffering from hypophosphatasia, due to a first time epileptic seizure. J Orthop Case Rep 5(3):66–68

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Schalin-Jantti C et al (2010) Parathyroid hormone treatment improves pain and fracture healing in adult hypophosphatasia. J Clin Endocrinol Metab 95(12):5174–5179

    Article  PubMed  CAS  Google Scholar 

  26. Fielding JW, Magliato HJ (1966) Subtrochanteric fractures. Surg Gynecol Obstet 122(3):555–560

    PubMed  CAS  Google Scholar 

  27. Chen LP, Chang TK, Huang TY, Kwok TG, Lu YC (2014) The correlation between lateral bowing angle of the femur and the location of atypical femur fractures. Calcif Tissue Int 95(3):240–247

    Article  PubMed  CAS  Google Scholar 

  28. Kim JM, Hong SH, Kim JM, Lee BS, Kim DE, Kim KA, Bin SI (2015) Femoral shaft bowing in the coronal plane has more significant effect on the coronal alignment of TKA than proximal or distal variations of femoral shape. Knee Surg Sports Traumatol Arthrosc 23(7):1936–1942

    Article  PubMed  Google Scholar 

  29. Kim D, Sung YK, Cho SK, Han M, Kim YS (2016) Factors associated with atypical femoral fracture. Rheumatol Int 36(1):65–71

    Article  PubMed  CAS  Google Scholar 

  30. Saita Y, Ishijima M, Mogami A, Kubota M, Baba T, Kaketa T, Nagao M, Sakamoto Y, Sakai K, Kato R, Nagura N, Miyagawa K, Wada T, Liu L, Obayashi O, Shitoto K, Nozawa M, Kajihara H, Gen H, Kaneko K (2014) The fracture sites of atypical femoral fractures are associated with the weight-bearing lower limb alignment. Bone 66:105–110

    Article  PubMed  Google Scholar 

  31. Khandwala HM, Mumm S, Whyte MP (2006) Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood. Endocr Pract 12(6):676–681

    Article  PubMed  Google Scholar 

  32. Ivkovic A, Bojanic I, Pecina M (2006) Stress fractures of the femoral shaft in athletes: a new treatment algorithm. Br J Sports Med 40(6):518–520 discussion 520

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Marini F, Brandi ML (2017) Atypical femur fractures: a distinctive tract of adult hypophosphatasia. Clin Cases Miner Bone Metab 14(3):324–328

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cundy T, Michigami T, Tachikawa K, Dray M, Collins JF, Paschalis EP, Gamsjaeger S, Roschger A, Fratzl-Zelman N, Roschger P, Klaushofer K (2015) Reversible deterioration in Hypophosphatasia caused by renal failure with bisphosphonate treatment. J Bone Miner Res 30(9):1726–1737

    Article  PubMed  CAS  Google Scholar 

  35. Whyte MP, Mahuren JD, Vrabel LA, Coburn SP (1985) Markedly increased circulating pyridoxal-5′-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J Clin Invest 76(2):752–756

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Mahjoub Z, Jean S, Leclerc JT, Brown JP, Boulet D, Pelet S, Grondin C, Dumont J, Belzile ÉL, Michou L (2016) Incidence and characteristics of atypical femoral fractures: clinical and geometrical data. J Bone Miner Res 31(4):767–776

    Article  PubMed  CAS  Google Scholar 

  37. Whyte MP, Zhang F, Wenkert D, McAlister WH, Mack KE, Benigno MC, Coburn SP, Wagy S, Griffin DM, Ericson KL, Mumm S (2015) Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone 75:229–239

    Article  PubMed  CAS  Google Scholar 

  38. Whyte MP (2016) Hypophosphatasia—aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 12(4):233–246

    Article  PubMed  CAS  Google Scholar 

  39. McKiernan FE, Berg RL, Fuehrer J (2014) Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res 29(7):1651–1660

    Article  PubMed  CAS  Google Scholar 

  40. Barvencik F, Beil FT, Gebauer M, Busse B, Koehne T, Seitz S, Zustin J, Pogoda P, Schinke T, Amling M (2011) Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis. Osteoporos Int 22(10):2667–2675

    Article  PubMed  CAS  Google Scholar 

  41. Bhattacharyya T, Jha S, Wang H, Kastner DL, Remmers EF (2016) Hypophosphatasia and the risk of atypical femur fractures: a case-control study. BMC Musculoskelet Disord 17:332

    Article  PubMed  PubMed Central  Google Scholar 

  42. Maman E, Briot K, Roux C (2016) Atypical femoral fracture in a 51-year-old woman: revealing a hypophosphatasia. Joint Bone Spine 83(3):346–348

    Article  PubMed  Google Scholar 

  43. Coe JD, Murphy WA, Whyte MP (1986) Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am 68(7):981–990

    Article  PubMed  CAS  Google Scholar 

  44. Watts NB, Aggers D, McCarthy EF, Savage T, Martinez S, Patterson R, Carrithers E, Miller PD (2017) Responses to treatment with teriparatide in patients with atypical femur fractures previously treated with bisphosphonates. J Bone Miner Res 32(5):1027–1033

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Jasmin Baumann, Silke Achtziger, Ursula Hellwich, and Nicole Luksche for their highly valued assistance with data collection and archiving.

Author information

Authors and Affiliations

  1. Clinical Trial Unit, Orthopedic Department, University of Wuerzburg, Brettreichstrasse 11, 97074, Wuerzburg, Germany

    F. Genest & L. Seefried

Authors
  1. F. Genest
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Seefried
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Seefried.

Ethics declarations

Conflicts of interest

FG reports personal fees from Lilly during the course of the study.

LS reports grants and personal fees from Novartis and Alexion and personal fees from Lilly and Amgen during the course of the study.

Statement

This study is a retrospective evaluation of clinical routine data. For this type of study, formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Genest, F., Seefried, L. Subtrochanteric and diaphyseal femoral fractures in hypophosphatasia—not atypical at all. Osteoporos Int 29, 1815–1825 (2018). https://doi.org/10.1007/s00198-018-4552-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-018-4552-3

Keywords

Search

Navigation