Bisphosphonates (BP) have been used successfully for over a decade to prevent and treat osteoporosis and reduce osteoporotic fractures. However, since 2005 there have been many reports of atypical femoral fractures (AFF) in patients on prolonged BP therapy. Recently, it has been found that a prodromal bone deterioration (PBD) usually appears before the development to AFF. However, many PBDs may be asymptomatic, not necessarily progress to AFF, and heal spontaneously after discontinuation of BP therapy. Therefore, the prevalence of PBD may be much higher than AFF. To date, there is no evidence to support this hypothesis. It has been reported that many patients with PBD and AFF have severely suppressed bone turnover (SSBT). However, since not all patients with PBD/AFF also have SSBT, factors other than SSBT might contribute to the development of PBD/AFF. Our preliminary study suggests that PBD/AFF may be associated with osteocyte death, bone hypermineralization, and microdamage accumulation which compromise bone mechanical properties. These facts collectively led us to formulate the hypothesis that BP treated patients who develop SSBT and consequent increase in bone age, in conjunction with previous osteocyte deficiency, are predisposed to micropetrosis, accumulation of fatigue microdamage, PBD, and eventually to stress fracture manifested as AFF. To pursue this hypothesis we propose the following specific aims:
Aim 1 is to determine the prevalence of PBD and AFF in 1,000 patients with postmenopausal osteoporosis, either treated with BP for more than 2 years (500 subjects), or never BP treated (500 subjects). X-rays of the femurs will be performed to systematically screen the patients for PBD/AFF. PBD can be defined as an X-ray finding of focal cortical thickening associated with a fracture line at the lateral femoral cortex. Suspected PBD patients, whose x-ray does not show clear fracture line at focally thickened cortex, will be evaluated further using x-ray tomosynthesis, isotope bone scan or MRI.
Aim 2 will determine the contribution of osteocyte deficit to PBD/AFF and SSBT in iliac bone biopsies obtained from long term BP treated patients. Degree of bone mineralization and bone nano-mechanical properties will also be assessed on these biopsies.

Public Health Relevance

Bisphosphonates (BP) have been successfully used for treatment and prevention of osteoporosis for over a decade. However, there is growing concern about atypical femoral fractures (AFF), and its necessary precedent, referred to as prodromal bone deterioration (PBD), in patients on prolonged BP therapy. Based on our preliminary studies we assume that AFF and PBD are associated with severely suppressed bone turnover (SSBT), an entity we defined first in 2005, and osteocyte loss, both of which compromise bone quality and increase the risk of AFF. The proposed study will investigate the prevalence of PBD and AFF in patients on long-term (>2 years) BP therapy and the contribution of SSBT and osteocyte deficiency to AFF and PBD.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Chen, Faye H
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Henry Ford Health System
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