Skeletal complications of bisphosphonate use: what the
radiologist should know
A E HAWORTH, MB ChB, FRCR and J WEBB, DMRD, FRCR
Department of Radiology, University Hospital Aintree, Liverpool, UK
ABSTRACT. Bisphosphonates are widely used for prevention of fractures in patients at
risk, mainly in the presence of osteoporosis and bone metastases. A number of adverse
effects of prolonged bisphosphonate treatment have emerged. We would like to
highlight the skeletal complications from which a radiologist may be the first
healthcare professional to recognise the association with bisphosphonate therapy. We
illustrate these complications (namely osteonecrosis of the jaw and less well-known
atypical femoral shaft fractures), presenting radiological findings in our patients.
Recommendations for safer use of bisphosphonates are included in the conclusion of
Received 27 August 2011
Revised 11 January 2012
Accepted 8 February 2012
’ 2012 The British Institute of
Bisphosphonates are non-metabolic synthetic analo-
gues of pyrophosphate and have a significant effect on
bone turnover, inhibiting osseous resorption by suppres-
sing osteoclast activity [1, 2]. This results in bone
microarchitecture modifications. As they are metaboli-
cally inactive, they bind to bone, creating a reservoir that
remains even after discontinuation of treatment .
Studies have shown antifracture efficacy to persist for
1–2 years following discontinuation of aledronate, and
between 3 and 5 years following risedronate use .
Bisphosphonates are the treatment of choice in condi-
tions characterised by an increase in bone resorption. In
the UK they are used in the treatment of lytic metastases
arising from breast cancer, osteoporosis, hypercalcaemia
secondary to malignancy, Paget’s disease of bone and
multiple myeloma . Less well-known indications
include osteogenesis imperfecta and juvenile idiopathic
arthritis. Worldwide, their indications are extending to
include lytic metastases from other solid tumours .
Two forms of the drug are used: intravenous (iv) and
oral. In 2009–10 alone over 1 million people in the UK
were prescribed bisphosphonates and over 6.5 million
prescriptions were issued . In the USA, an estimated
30 million prescriptions for bisphosphonates are written
every year . There is abundant evidence in the
literature extolling the benefits of bisphosphonate use,
and indeed these are multiple and often provide sig-
nificantincreases inqualityof lifefor patients.Thenumber
of patients needed to be treated with bisphosphonates for
3 years to prevent 1 vertebral and 1 hip fracture are 14
and 91, respectively . There are, however, several
potential side-effects relating to their use. These include
gastrointestinal discomfort, influenza-like illness (due to
acute phase reaction), renal complications (rare even in
high-dose iv treatment) and a theoretical link to accelera-
tion of coronary artery disease.
More importantly for a radiologist, there is increasing
evidence to suggest a separate subset of complications
affecting the skeleton. Although they are well described in
metabolic and orthopaedic journals, they are less well
known to the radiological community. These are compli-
cations that might be expected from the mechanism of
action of bisphosphonates, and, in view of their rising
usage, are likely to be seen with increasing frequency.
In this article we describe the skeletal complications of
bisphosphonate use and the radiographic findings of each.
Bisphosphonate-related osteonecrosis of the
(BRONJ) is a painful destructive process, which is
distinguishable from other impaired healing conditions
by the following features:
N current or previous treatment with a bisphosphonate;
N exposed bone in the maxillofacial region that has
persisted for more than 8 weeks; and
N no history of radiation therapy to the jaws .
Causes, predisposing factors and histopathological
The exact underlying aetiology of BRONJ is unknown.
It tends to affect the mandible rather than the maxilla,
although both jaws can be affected simultaneously. The
maxilla is thought to be relatively spared because of its
Address correspondence to: Dr Jolanta Webb, Department of
Radiology, University Hospital Aintree, Lower Lane, Liverpool L9
7AL, UK. E-mail: email@example.com
The British Journal of Radiology, 85 (2012), 1333–1342
The British Journal of Radiology, October 20121333
The suggested mechanism is via the inhibition of bone
turnover. Bisphosphonates are thought to incorporate at
sites of high osseous turnover (e.g. the mandible, where
marked suppression of bone metabolism results in accu-
mulation of physiological microdamage, occurring as a
result of mastication).
The thin mucosa and periosteum covering the jaws are
easily breached by infection (oral flora) or local trauma
(dental procedures) and the presence of either micro-
trauma, infection or iatrogenic damage can increase
demand for osseous repair beyond the capacity of the
newly hypodynamic bone, resulting in local osteonecro-
sis. Commonly, oral flora such as Actinomyces israelii are
found colonising biopsy specimens of BRONJ; however,
while some lesions have responded to antibiotic therapy
it is unclear whether the organisms are causative or
Generally there is no classic histopathological appear-
ance for BRONJ. Specimens from exposed bone often
show non-vital bone with rough margins and empty
lacunae, consistent with necrosis. Unexposed bone speci-
mens contain hypervascular fibrotic tissue with inflam-
matory infiltrates filling the trabecular space, which is
often seen in chronic osteomyelitis. Fungal contamination
is common in exposed specimens .
Incidence and prevalence
The estimated risk of BRONJ in patients receiving anti-
resorptive therapy is rare. The occurrence in oral bisphos-
phonate use is estimatedto be between 1 in 10 000and1 in
100 000 patient years, with more frequent occurrences in
females and age groups older than 60 years [13, 14].
The majority of reported cases of BRONJ (approxi-
mately 95%) are associated with iv bisphosphonate
therapy in the management of metastatic bone disease
(often with doses up to 12 times greater than those used
in oral treatment regimes for osteoporosis) [14, 15].
Woo et al , in a systematic review of 368 published
cases of BRONJ, suggested a prevalence of between 6%
and 10% for patients on iv therapy for metastatic bone
disease . There is also evidence to suggest an
association between subtypes of bisphosphonates and
risk. Pamidronate (containing an aminoterminal group)
was less commonly associated with osteonecrosis of the
jaw than zoledronate (containing a nitrogen side-chain)
. In addition, the chemotherapeutic agents and
steroids taken by many of the patients receiving bisphos-
phonate treatment will almost certainly contribute to
impaired wound healing, and so exacerbate osteonecro-
Thediagnosis of BRONJisoftenclinical,with a relatively
consistent symptomatology. However, it is frequently de-
tected late as the patient becomes symptomatic only after
osteonecrosis is well established. It usually presents with
pain and/or a non-healing extraction socket. This leads to
exposed, non-vital bone with subsequent sequestrum
formation and associated swelling or purulent discharge.
Sometimes it can be recognised solely by the exposed bone
As BRONJ occurs most commonly in oncology
patients receiving iv bisphosphonate therapy for bone
Figure 1. (a) Female patient diagnosed with metastatic breast
cancer. Increasing pain following left lower premolar extrac-
tions 5 years after commencing on intravenous pamidronate.
Photograph of exposed bone at presentation post extraction.
(b) Two orthopantomograms1 yearapartshowing lytic process
developing at the site of tooth extraction (arrows).
A E Haworth and J Webb
1334 The British Journal of Radiology, October 2012
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1342The British Journal of Radiology, October 2012