Metabolic bone disease: Atypical femoral fractures

doi:10.1016/j.jbiomech.2010.10.013

Journal of Biomechanics

Volume 44, Issue 2, 11 January 2011, Pages 244-247

https://doi.org/10.1016/j.jbiomech.2010.10.013 Get rights and content

Abstract

Since 2005 reports have been published describing unusual femoral shaft fractures primarily in postmenopausal women treated for prolonged periods with a bisphosphonate drug for osteoporosis. In some patients pain develops in the femur prior to a completed fracture. Bilateral fractures have occurred in some patients. It is unclear whether oversuppression of bone cell activity is a major factor in the pathogenesis of the fractures, or whether these are a rare manifestation of the underlying bone disease. Such fractures do occur in other metabolic bone disorders in which there are marked abnormalities of bone structure.

Introduction

During the past five years femoral shaft fractures have been reported to occur in primarily postmenopausal women treated for long periods of time with alendronate. Is this a new entity or a rare occurrence in patients with osteoporosis? The small literature dealing with this issue will be discussed.

Section snippets

Femoral fractures in postmenopausal women

Femoral fractures increase in incidence after the age of 65 years in women with postmenopausal osteoporosis. They occur after a fall in about 95% of patients and there are no prodromal symptoms. The fracture site is located at the trochanter or above in 95–97% of cases. The fractures are usually spiral in character. Treatment of postmenopausal women with the most effective bisphosphonate therapies reduces the incidence of fractures by 30–50% in those at the highest risk (Bilezikian, 2009).

Conclusions and the future

Subtrochanteric femoral fractures are a relatively rare event in patients with postmenopausal osteoporosis. The patients may have pain days or weeks before the fracture occurs, the fracture may occur spontaneously and fractures may be bilateral. Considerable publicity has been given to their association with long-term bisphosphonate therapy but the largest studies, although not perfect, do not support the hypothesis that the drugs cause the fracture. Some of the patients have increased

Conflict of interest statement

None declared.

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2017, Materials and Devices for Bone Disorders
Bone has multiple functions which dictate the material properties. Bone is composed of minerals, organic matrix, and water. Bone is constantly remodeled by cells in the osteoclast and osteoblast families. These cells respond to mechanical stress and hormonal signals. Alterations in remodeling change bone strength, by changing the shape, volume, density, and mircoarchitecture. Additionally crystal size, collagen structure, and bone marrow affect strength. Hormones and cytokines act on bone cells to alter bone. Bone is lost with aging and disease, and several drugs are used to treat osteoporosis. These drugs can have various effects on the bone properties, some of which are harmful after long-term use.
Sporadic Acquired and Genetic Disorders of Bone
2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
Disorders due to widespread death of bone matrix, osteonecrosis, and focal or systemic bone thickening are reviewed here. Osteonecrosis is a common problem and may be caused by trauma, with direct damage to blood vessels supporting bone or due to fractures that interrupt vascular supply. Osteonecrosis is also caused by metabolic imbalance, commonly due to glucocorticoid administration with secondary ACTH suppression, receptors for both of which are important in bone. Osteonecrosis also occurs with bone-binding antimetabolites, and bisphosphonate osteonecrosis, particularly of the jaw, is an important problem where type and length of treatment affect likelihood of the complication. Sclerotic disorders generally reflect local or systemic changes in bone morphogenetic protein signaling or other signals including sclerostin. Benign focal ossification and several rare diseases reflect this imbalance, including fibrodysplasia ossificans progressiva (FOP), sclerosteosis, osteopoikilosis, and melorheostosis.
1. Focal osteonecrosis occurs as a consequence of metabolic or traumatic events. Trauma that interrupts the blood supply to a bone, such as the femoral head, causes osteonecrosis. Regions with abundant trabecular bone are subject to osteonecrosis with disruption of microvascular support by high glucocorticoids especially when ACTH is depressed. Joint replacement is often required. Regions of bone that normally have low turnover, such as the femoral or mandibular cortex, are subject to necrosis in bisphosphonate toxicity. Conditions that increase the likelihood of osteonecrosis should be avoided.
2. Myositis ossificans circumscripta, or traumatica, and other heterotopic ossification events are manifest as focal calcification, often with differentiation of true bone, usually at sites of injury. Usually no management is required, although surgical excision may be useful. Localized TGF-β and activin activity has been noted during the development of these lesions.
3. FOP is a rare, aggressive disease where many tissues calcify progressively. Most, if not all, of the cases have a constitutively active BMP type I receptor subunit, the activin-like kinase 2. Management is very difficult; attempts to reverse activin signaling are in development.
4. Rare diseases with focal cortical thickening may be systemic or local. The syndromes need to be identified as nonmalignant, but specific therapy is not available; symptomatic treatment may be required. Systemic forms include osteosclerosis due to sclerostin defects with diffuse cortical thickening. Osteopoikilosis, characterized by scattered foci of thick bone, is usually associated with dominant mutations in the LEMD3 gene, which regulates BMP signaling. Melorheostosis is an acquired disorder with focal or segmental thickening of the bone cortex likened to dripping candle wax without a known mechanism. It usually involves a segmental region of the skeleton or one bone and may cause deformity and local functional defects in mobility or circulation.
Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy
2013, Bone
Citation Excerpt :
It has been hypothesized that cortical thickening represents a pre-existing defect in bone metabolism influenced by BPs therapy or rather a localized stress reaction in response to the accumulation of cortical micro-damage, as shown in animal studies [29]. These disorders can generate abnormalities of bone structure, which are responsible for the fragility of bone and radiologic abnormalities regardless of BPs use [30]. The healing time of AFF was longer than that normally required for other femoral fractures.
Bisphosphonates (BPs) are the first-line therapy for osteoporosis. In recent years, atypical femoral fractures (AFF) have been described in patients on BPs therapy. However, the relationship between BPs and AFF remains to be clarified. We evaluated clinical and hormonal characteristics of AFF patients, in order to determine AFF risk factors. We studied 11 females with AFF and 58 females with typical femoral fractures (TFF), admitted to our Department for surgical repair between January 2008 and December 2011. All AFF patients received BPs therapy for 6 to 13 yrs, whereas 36.2% (p < 0.0001) of TFF patients received BPs for shorter period (TFF, 6.1 ± 1.8 yr vs. AFF, 8.6 ± 1.9 yr, p < 0.0001). A higher prevalence of hypocalcemia was observed in AFF patients compared with TFF (p < 0.02), with significantly (p < 0.05) lower corrected calcium levels in AFF patients. By contrast a reduced prevalence of elevated PTH levels (p < 0.05) was found in AFF patients. No significant difference in prevalence of vitamin D defect was observed between the two groups. Younger age (p < 0.004), higher BMI (> 30 kg/m², p < 0.03) and early menopausal age (p < 0.05) were observed in AFF patients. At time of fracture, prevalence of osteopenia/osteoporosis and levels of bone turnover markers were significantly (p < 0.01) lower in AFF compared with TFF patients. By multivariate analysis hypocalcemia, obesity, and younger age (< 70 yr) were confirmed to be independent predictors of AFF; elevated PTH level was the predominant independent protective factor (p < 0.004). In conclusion, our data indicate that clinical characteristics and metabolic factors may favor the development of AFF in BP treated patients. We identified hypocalcemia due to latent hypoparathyroidism as primary risk factor for AFF; age, obesity, early menopause, and BMD may also influence the development of AFF. An adequate clinical and metabolic assessment is suggested to prevent the development of AFF in BP treated patients.
Bisphosphonate-related atypical femoral fracture
2013, Kaohsiung Journal of Medical Sciences
Toxicity of bone-targeted agents in malignancy
2018, Side Effects of Medical Cancer Therapy: Prevention and Treatment: Second Edition

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Metabolic bone disease: Atypical femoral fractures

Abstract

Introduction

Section snippets

Femoral fractures in postmenopausal women

Conclusions and the future

Conflict of interest statement

Journal of Structural Biology

Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study

Journal of Bone and Mineral Research

Orthopaedic problems in adult hypophosphatasia: a report of two cases

Journal of Bone and Joint Surgery Br

Orthopedic management of osteopetrosis—results of a survey and review of the literature

Journal of Pediatric Orthopaedics

The micromechanics versus the macromechanics of cortical bone - a comprehensive presentation

Journal of Biomechanical Engineering

Single osteon micromechanical testing

Bilateral atypical femoral fractures after long-term alendronate therapy: a case report

Journal of the Medical Association of Thailand

Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis

American Journal of Medicine

Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur

New England Journal of Medicine

A rational approach to management of alendronate-related subtrochanteric fractures

Journal of Bone and Joint Surgery British

Complete fractures of the femur in Paget’s disease of bone

Journal of Bone and Joint Surgery British

Alendronate-related femoral diaphysis fracture—what should be done to predict and prevent subsequent fracture of the contralateral side?

Osteoporosis International