Biological activity is not suppressed in mid-shaft stress fracture of the bowed femoral shaft unlike in “typical” atypical subtrochanteric femoral fracture:​ a proposed theory of atypical femoral fracture subtypes

Oh, Yoto<sup>1</sup>; Yamamoto, Kouhei<sup>2</sup>; Hashimoto, Jun<sup>3</sup>; Fujita, Koji<sup>3</sup>; Yoshii, Toshitaka<sup>3</sup>; Fukushima, Kazuyuki<sup>4</sup>; Kurosa, Yoshiro<sup>4</sup>; Wakabayashi, Yoshiaki<sup>5</sup>; Kitagawa, Masanobu<sup>2</sup>; Okawa, Atsushi<sup>3</sup>

Affiliations

¹Department of Orthopaedic and Trauma Research, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

²Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

³Department of Orthopaedic and Spinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

⁴Department of Orthopaedic Surgery, Saku Central Hospital, Nagano, Japan

⁵Department of Orthopaedic Surgery, Yokohama City Minato Red Cross Hospital, Kanagawa, Japan

Abstract and keywords

Background: We have investigated mid-shaft stress fractures of the bowed femoral shaft (SBFs), well before the first report of an association between suppression of bone turnover and atypical femoral fractures (AFFs). Although all cases of SBF meet the criteria for AFF, SBFs can also occur in patients with no exposure to bone turnover suppression-related drugs (e.g., bisphosphonates). Using bone morphometry and biomechanical analyses, we devised a theory of AFF subtypes, dividing AFFs into fragility SBFs in the mid-shaft and “typical” subtrochanteric AFFs caused by suppressed bone turnover. The aim of this multicenter prospective study was to provide evidence for this novel concept in terms of biological activity.

Methods: The study was conducted at 12 hospitals in Japan from 2015 through 2019. Thirty-seven elderly women with AFF were included and classified according to location of the fracture into a mid-shaft AFF group (n = 18) and a subtrochanteric AFF group (n = 19). Patient demographics and clinical characteristics were investigated to compare the two groups. The main focus was on histological analysis of the fracture site, and bone metabolism markers were evaluated to specifically estimate biological activity.

Results: All patients in the subtrochanteric AFF group had a history of long-term (>3 years) exposure to specific drugs that have been reported to cause AFF, but 5 of the 18 patients in the mid-shaft AFF group had no history of exposure to such drugs. Femoral bowing was significantly greater in the mid-shaft AFF group (p < 0.001). In the histological analysis, active bone remodeling or endochondral ossification was observed in the mid-shaft AFF group, whereas no fracture repair-related biological activity was observed in the majority of patients in the subtrochanteric AFF group. Levels of tartrate-resistant acid phosphatase-5b and undercaroxylated osteocalcin were significantly lower in the subtrochanteric AFF group (p < 0.05).

Conclusion: The possibility of our devised AFF subtype theory was demonstrated. Biological activity tends not to be suppressed in mid-shaft SBFs unlike in “typical” subtrochanteric AFFs involving bone turnover suppression. Although validation of the proposed theory in other populations is needed, we suggest that the pathology and treatment of AFFs be reconsidered based on its subtype.

Keywords: Atypical femoral fracture; Stress fracture; Fragility fracture; Femoral shaft; Bone turnover; Biological activity

Links

DOI: 10.1016/j.bone.2020.115453

PubMed: 32470545

WoS: 000547005800053

History

Received: 2020-02-14

Revised: 2020-05-22

Accepted: 2020-05-22

Online: 2020-05-26

Cited Works (5)

Year	Entry
2005	Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. March 2005;90(3):1294-1301.
2014	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. 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. January 2014;29(1):1-23.
2011	Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. NEJM. May 5, 2011;364(18):1728-1737.
2010	Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MCH, Weinstein RS, Whyte M. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. November 2010;25(11):2267-2294.
1917	Koch JC. The laws of bone architecture. Am J Anat. March 1917;21(2):177-298.

Cited By (3)

Year	Entry
2022	Borggaard XG, Roux J-P, Delaisse J-M, Chavassieux P, Andreasen CM, Andersen TL. Alendronate prolongs the reversal-resorption phase in human cortical bone remodeling. Bone. July 2022;160:116419.
2022	Gani LU, Anthony NF, Dacay LM, Tan PT, Chong LR, King TFJ. Characteristics of bisphosphonate and non-bisphosphonate related atypical femoral fracture in a South East Asian population: secondary analysis. Bone. September 2022;162:116455.
2023	Haider IT, Loundagin LL, Sawatsky A, Kostenuik PJ, Boyd SK, Edwards WB. Twelve months of denosumab and/or alendronate is associated with improved bone fatigue life, microarchitecture, and density in ovariectomized cynomolgus monkeys. J Bone Miner Res. March 2023;38(3):403-413.