Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 33, Pages 8722-8727Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704460114
Keywords
atypical fracture; bisphosphonates; subtrochanteric fracture; fracture toughness; FTIR imaging
Categories
Funding
- NSF Civil, Mechanical and Manufacturing Innovation Grant [1452852]
- American Society for Bone and Mineral Research Junior Faculty Osteoporosis Research Award
- German Research Foundation (DFG) [BU 2562/2-1/3-1]
- NSF Graduate Research Fellowship [DGE-1144153]
- NSF Materials Research Science and Engineering Centers program [DMR-1120296]
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1452852] Funding Source: National Science Foundation
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Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+ BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; + BIS Typical: n = 10, 7.7 (5.0) y; + BIS Nonfx: n = 5, 6.4 (3.5) y; -BIS Typical: n = 11; -BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonatetreated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naive patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.
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