8 Bisphosphonates and Bone
Sirmahan Cakarer, Firat Selvi and Cengizhan Keskin
Istanbul University, Dentistry Faculty,
Department of Oral and Maxillofacial Surgery
Bisphosphonates are pyrophosphate analogues which were used for over a century in
industry (mainly in the textile and oil industries) as antiscaling and anticorrosive agents
because of their property of inhibition of calcium carbonate precipitation. After the
discovery of biological effects of bisphosphonates more than 30 years ago, they have now
become indispensable in medicine for the treatment of skeletal complications of
malignancy, Paget’s disease, osteoporosis, multiple myeloma, hypercalcemia and fibrous
Bisphosphonates can be classified into two groups regarding their administration routes as
orally or intravenously. The biological action mechanism of bisphosphonates on bone is
maintained by their inhibitory effects on osteoclasts.
The general side effects and complications associated with bisphosphonates are esophageal
or gastric irritation, atypical bone fractures, osteonecrosis of the jaws and ocular
inflammation. Among these complications, Bisphosphonate-related Osteonecrosis of the
Jaws (BRONJ) attracts clinical attention because of it’s difficult management and its
pathogenesis still being unclear.
The present chapter reviews history, classification, pharmacokinetics, clinical relevance and
the mechanism of action of bisphosphonates. This chapter also focuses on the common side
effects associated with these drugs, including mainly the Bisphosphonate-related
Osteonecrosis of the Jaws (BRONJ). The importance of the consultation in between the
medical doctors and the maxillofacial surgeons who experience the complications of
bisphosphonates is emphasized. The practitioners who commonly prescribe
bisphosphonates, should be aware of the complications of these drugs which may strongly
diminish the quality of life of the patiens.
2. History and development of bisphosphonates
The bisphosphonates, in the past erroneously called diphosphonates, have been known to
chemists since the middle of the 19th century, the first synthesis dating back to 1865 in
Germany. Their use was industrial (mainly in the textile, fertilizer and oil industries) and,
because of their property of inhibiting calcium carbonate precipitation, as preventors of
scaling (1). Their use as ‘water softeners’was based on their ability to act as sequestering
142 Orthopedic Surgery
agents for calcium, and in particular their ability to inhibit calcium carbonate precipitation,
as do polyphosphates (2).
In the early 1960s, it is showed that body fluids such as plasma and urine contained
inhibitors of calcification. Since it had been known since the 1930s that trace amounts of
polyphosphates were capable of acting as water softeners by inhibiting the crystallization of
calcium salts, such as calcium carbonate, they proposed that compounds of this type might
be natural regulators of calcification under physiological conditions. Fleisch and his
colleagues showed that inorganic pyrophosphate, a naturally occurring polyphosphate and
a known by-product of many biosynthetic reactions in the body, was present in serum and
urine and could prevent calcification by binding to newly forming crystals of
hydroxyapatite. It was therefore postulated that pyrophosphate (PPi) might be the agent
that normally prevents calcification of soft tissues, and regulates bone mineralization.
Pathological disorders, such as the formation of kidney stones, might be linked to
disturbances in PPi metabolism. The concentrations of pyrophosphate would be expected to
be regulated by hydrolytic enzymes. Studies of the rare inherited disorder,
hypophosphatasia, in which lack of alkaline phosphatase is associated with mineralization
defects, showed that PPi levels were elevated in both plasma and urine, and verified that
alkaline phosphatase was the key extracellular enzyme that hydrolyzes pyrophosphate.
Attempts to exploit these concepts by using pyrophosphate and polyphosphates to inhibit
ectopic calcification in blood vessels, skin, and kidneys in laboratory animals were
successful only when the compounds were injected. Orally administered pyrophosphate
and polyphosphates were inactive, due to the hydrolysis of pyrophosphate in the
gastrointestinal tract, probably by mucosal brush border phosphatases. During the search
for more stable analogues of pyrophosphate that might also have the antimineralization
properties of pyrophosphate but that would be resistant to hydrolysis, several different
chemical classes were studied. The bisphosphonates (at that time called diphosphonates)
were among those studied. Like pyrophosphate, bisphosphonates had high affinity for bone
mineral and were found to prevent calcification both in vitro and in vivo, but, unlike
pyrophosphate, were also able to prevent pathological calcification when given orally to rats
in vivo. This property of being active by mouth was key to their future use in humans.
Perhaps the most important step towards the future use of bisphosphonates occurred when
we found that bisphosphonates also had the novel property of being able to inhibit the
dissolution of hydroxyapatite crystals. This led to studies to determine whether they might
also inhibit bone resorption. Many studies using a variety of experimental systems showed
that they were able to inhibit osteoclast-mediated bone resorption, both in organ cultures of
bone in vitro, and in various animal models, e.g. thyroparathyroidectomized rats treated
with parathyroid hormone to stimulate bone resorption in vivo (3).
3. Chemistry of bisphosphonates
Bisphosphonates are stable analogues of naturally-occurring inorganic pyrophosphate.
Stability is conferred by a carbon atom replacing the oxygen atom that connects the two
phosphates. This renders the molecule resistant to biological degradation. The BPs of clinical
interest all have two phosphonate groups that share a common carbon atom (P-C-P). The PC-
P group is resistant not only to chemical but also to enzymatic hydrolysis. As a result, BPs
are not converted to metabolites in the body and are excreted unaltered. The two
Bisphosphonates and Bone 143
phosphonate groups have a dual function. They are required both for binding to bone
mineral and for cell-mediated antiresorptive activity. Modifications to one or both
phosphonate groups can dramatically reduce the affinity of the BP for bone mineral, as well
as reduce biochemical potency. The R1 and R2 side-chains attached to the carbon atom are
responsible for the large range of activity observed among the BPs. R1 substituents such as
hydroxyl or amino enhance chemisorption to mineral, while varying the R2 substituents
results in differences in antiresorptive potency of several orders of magnitude. The
increased antiresorptive potency observed with the different R2 groups is linked to the
ability to affect biochemical activity, e.g., inhibition of the farnesyl pyrophosphate synthase
(FPPS) enzyme (1, 4 ).
There are two classes of bisphosphonate regarding the presence or absence of Nitrogen.
Non-Nitrogen containing bisphosphonates are; Etidronate (Didronel), Clodronate (Bonefos,
Loron) and Tiludronate. The non-nitrogenous bisphosphonates(disphosphonates) are
metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of
ATP, forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in
the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an
overall decrease in the breakdown of bone (5,6).
On the other hand, bisphosphonates can be classified into two groups regarding their
administration routes as orally or intravenously. Orally administered bisphosphonates are;
risedronate, alendronate, tiludronate and etidrontae. These are usually taken weekly
Intravenously administered bisphosphonates are; pamidronate and zoledronic acid. These
are usually administered monthly On the other hand ibandronate and clodronate can be
administered as orally and intravenously (7,8,9).
Alendronate has a greater bone affinity than risedronate. The recommended weekly dose of
alendronate at 70 mg weekly is almost double the potency of the recommended dose of 35
mg risedronate (10).
The duration of effect of bisphosphonates extends far beyond the duration of treatment. The
effect of aledronate may be evident for more than five years after discontinuation of
treatment and zoledronate has been shown to produce a sustained reduction in bone
turnover for 12 months following administration of a single dose (8).
5. Pharmacology of bisphosphonates
Bisphosphonates can be given intravenously or orally. When taken orally, they must be
taken after a prolonged fast (usually first thing in the morning), with water only, followed
by 30–60 min with nothing else by mouth to allow for adequate absorption. Under ideal
conditions, less than 1% of an orally administered dose is absorbed; taking a bisphosphonate
with food or anything containing divalent cations will completely block its absorption.
There is no systemic metabolism. The half-life in plasma is short. Fifty percent of the
absorbed dose binds to bone surfaces, mostly avidly at sites of active remodeling. The
skeletal capacity is large and the binding sites are virtually unsaturable. The 50% or so that
does not bind to bone is excreted rapidly by the kidneys (11).
144 Orthopedic Surgery
The renal/nonrenal clearance ratio differs significantly among bisphosphonates; the ratio is
approximately 2 for clodronate and 0.3 for pamidronate. This may partly explain the higher
dose of clodronate needed for a therapeutic effect. The distribution of the bisphosphonates
within the skeleton is not homogeneous; the drug is targeted to sites of skeletal metabolism,
where bone mineral is exposed to the surrounding fluids. The degree of skeletal uptake is
dependent upon the rate of bone turnover. When the bisphosphonates are incorporated into
bone, the half-life is extremely long, to over 10 years, relating to the turnover time of the
active skeletal sites. After very high intravenous doses some bisphosphonates accumulate in
liver, spleen, lung and kidney (9).
6. Mechanism of action
The mechanisms of action of the bisphosphonates in bone metabolism are complex and
multifactorial. Although complex mechanisms are involved, the side chains influence the
binding affinity (R1 side chain) and the antiresorptive potency (R2 side chain).They act
almost exclusively on bone because of their specific affinity to bone where they are
deposited in newly formed bone and close to osteoclasts. Although the time in the
circulation is short, 30 to 180 minutes, once incorporated into bone they can persist for up to
10 years. Different types of bisphosphonates have differing affinities to bone with the rank
order from greatest to least being zoledronate, alendronate, ibandronate, risedronate,
etidronate and clodronate . Once in the bone they directly affect mononuclear activity,
which is the parent cell of osteoclasts, they disrupt osteoclast mediated, bone resorption and
increase apoptosis of osteoclasts. This in turn reduces bone deposition by osteoblasts. The
net effect of this is to reduce bone resorption and bone turnover. Angiogenesis is reduced by
depression of blood flow and a marked decrease in vascular endothelial growth factor.
Epithelial keratinocytes are also inhibited. The net effect of these actions is to reduce healing
Treatment with bisphosphonates also results in a modest increase in bone mineral density
(BMD). Non-nitrogen-containing bisphosphonates inhibit osteoclastic activity by producing
toxic analogs of ATP that cause cell death. Nitrogen-containing bisphosphonates (e.g.
alendronate, risedronate, ibandronate, and zoledronate) inhibit an enzyme called farnesyl
pyrophosphate synthase, an enzyme in the 3-hydroxy-3- methylglutaryl coenzyme A
reductase pathway. Inhibition of this enzyme interferes with a process called prenylation:
preventing the addition of 15- and 20-carbon side chains that anchor GTP-binding proteins
to the osteoclast cell membrane; this leads to reduced resorptive activity of osteoclasts and
accelerated apoptosis (programmed cell death). The rank order of potency for inhibiting
farnesyl pyrophosphate synthase is zoledronate _ risedronate __ ibandronate _ alendronate,
with the more potent heterocyclic bisphosphonates (zoledronate and risedronate) having a
more optimal fit than the compounds with an alkyl side chain (alendronate and
Each bisphosphonate has a unique profile of binding affinity and antiresorptive potency
that likely results in clinically meaningful differences in the speed of onset and offset of
effect, the degree of reduction of bone turnover, uptake in cortical vs. trabecular bone and
types of antifracture effect (vertebral vs. nonvertebral) (11).
Bisphosphonates and Bone 145
6.1 Effects of bisphosphonates on bone turnover
The degree of reduction of bone turnover achieved by each bisphosphonate, as well as the
duration of action appears to be associated with their mineral-binding affinity and skeletal
retention. Bisphosphonates with higher mineral-binding affinity and potential retention,
such as alendronate and zoledronate, are associated with greater reduction of bone turnover
and have a longer duration of effect after treatment is stopped. Bisphosphonates with lower
mineral-binding affinity and retention, such as risedronate and etidronate, appear to reduce
bone turnover less and this effect seems to be more readily reversible when therapy stops. In
patients treated for 3 years or 7 years with risedronate, bone turnover markers returned to
pretreatment levels within 1 year after discontinuation of treatment (12).
7. Clinical use of bisphosphonates
The most impressive clinical application of bisphosphonates has undoubtedly been as
inhibitors of bone resorption, often for diseases where no effective treatment existed
previously, but it took many years for them to become well established. However, the first
clinical uses of bisphosphonates were as inhibitors of calcification. Etidronate was the only
BP to be used in this way, first in fibrodysplasia ossicans progressiva (FOP, formerly known
as myositis ossificans). Etidronate showed some promise in patients who had undergone
total hip replacement surgery to prevent subsequent heterotopic ossification and to improve
mobility. It was also used to prevent ectopic calcification and ossification, after spinal cord
injury and in topical applications in toothpastes to prevent dental calculus. There is a recent
and renewed interest in devising effective treatments for calcification in renal failure and
vascular disease. One of the other early clinical uses of bisphosphonates was as agents for
bone imaging, “bone scanning,” for which they still remain outstandingly useful for
detecting bone metastases and other bone lesions. The application of pyrophosphate and
simple bisphosphonates as bone scanning agents depends on their strong affinity for bone
mineral, particularly at sites of increased bone turnover, and their ability to be linked to a
gamma-emitting technetiumisotope. Bisphosphonates have become the treatment of choice
for a variety of bone diseases in which excessive osteoclast activity is an important
pathological feature, including Paget’s disease of bone, metastatic and osteolytic bone
disease, and hypercalcaemia of malignancy, as well as osteoporosis.
Currently there are at least eleven bisphosphonates (etidronate, clodronate, tiludronate,
pamidronate, alendronate, ibandronate, risedronate, and zoledronate, and also to a limited
extent olpadronate, neridronate and minodronate) that have been registered for various
clinical applications in various countries (2).
7.1 Bisphosphonates in oncology
Consensus guidance recommendations indicate that all patients with multiple myeloma and
radiologically confirmed bone metastases from breast cancer should receive
bisphosphonates from the time of diagnosis and continue indefinitel. Bisphosphonate
treatment—specifically zoledronic acid—is also appropriate for patients with endocrineresistant
metastatic bone disease from prostate cancer. Patients with other tumours and
symptomatic metastasis to bone
146 Orthopedic Surgery
should be considered for treatment with zoledronic acid if bone is the dominant site of
metastasis, especially if the prognosis is reasonable. Patients with renal cell cancer
particularly appear to benefit from treatment. There is extensive experience with
intravenous bisphosphonates in breast cancer with zoledronic acid, pamidronate and
ibandronate all showing useful clinical activity. For most patients with multiple myeloma
intravenous bisphosphonates have become part of routine clinical management.
Over recent years great advances have been made in the development and use of bonetargeted
therapy in oncology. The use of bisphosphonates in oncology has had a profound
beneficial effect on the management of metastatic bone disease and the prevention of
treatment-induced bone loss. Their use should be considered in all patients with bone
metastases, especially those with symptoms and without immediately life-threatening
extraskeletal disease. Guidelines for the use of the agents in preventing treatment-induced
bone loss are evolving and trials investigating their potential role in the adjuvant setting to
prevent metastasis are ongoing. If proven, the clinician will need to decide if the patient is at
risk of bone loss, bone metastasis or both, as the dose and frequency of bisphosphonate may
differ within each scenario. As a class the agents are well tolerated. Occasional serious
toxicities in terms of renal impairment and osteonecrosis of the jawcan be largely avoided
through adhering to the recommended dose and infusion times and good preventative
dental care respectively (13).
7.2 Bisphosphonates in Paget’s disease of bone
Paget’s disease is characterised by focal abnormalities of increased bone turnover affecting
one or more sites throughout the skeleton. The axial skeleton is preferentially affected, and
common sites of involvement include the pelvis (70% of cases), femur (55%), lumbar spine
(53%), skull (42%), and tibia (32%). Paget’s disease was the first clinical disorder in which a
dose dependent inhibition of bone resorption could be demonstrated using bisphosphonates
in man, and was well established by the 1980s. The medical treatment of Paget’s disease is
now reliant almost exclusively on the use of the bisphosphonate class of drugs. There have
been gradual improvements in the ability of these drugs to keep the disease under control,
starting with etidronate in the 1970s, and progressing through the use of other BPs given by
mouth, such as clodronate, tiludronate, alendronate, and risedronate. These days most
patients are treated with BPs given by infusion, either as pamidronate or more recently as
zoledronic acid (2, 14).
7.3 Bisphosphonates in osteoporosis
Osteoporosis is an emerging medical and socioeconomic threat characterised by a systemic
impairment of bone mass, strength, and microarchitecture, which increases the propensity
of fragility fractures. Bone mineral density (BMD) can be assessed with dual x-ray
absorptiometry (DXA), and osteoporosis is defined by a T score of less than 2.5, ie, more
than 2.5 standard deviations below the average of a young adult. About 40% of white
postmenopausal women are affected by osteoporosis and, with an ageing population, this
number is expected to steadily increase in the near future. The lifetime fracture risk of a
patient with osteoporosis is as high as 40%, and fractures most commonly occur in the spine,
hip, or wrist, but other bones such as the trochanter, humerus, or ribs can also be affected.
Bisphosphonates and Bone 147
From a patient’s perspective, a fracture and the subsequent loss of mobility and autonomy
often represent a major drop in quality of life. Additionally, osteoporotic fractures of the hip
and spine carry a 12-month excess mortality of up to 20%, because they require
hospitalisation and they have subsequently enhanced risk of other complications, such as
pneumonia or thromboembolic disease due to chronic immobilisation (15).
A number of bisphosphonates have been evaluated in postmenopausal osteoporosis and
investigated in large clinical trials with fracture as an end-point. This has resulted in the
licensing of alendronate, risedronate, ibandronate and zoledronic acid for the treatment of
postmenopausal osteoporosis. Bisphosphonate therapy acts by lowering the activation
frequency and so slows the deterioration in bone architecture. Bisphosphonates are effective
in reducing bone turnover, with an earlier decrease in bone resorption than bone formation;
there are differences in the time course and magnitude of response, depending on the type
and route of administration of the bisphosphonate. There is an increase in BMD that
results from filling in of the remodeling space and increasing mineralization of bone
tissue. In consequence, there is a reduction in fracture risk in postmenopausal women
with osteoporosis. The licensed bisphosphonates exhibit some differences in potency and
speed of onset and offset of action. These differences mean that different agents may be
more advantageous in different situations. Uncertainties remain around the optimum
duration of treatment and treatment holidays, how best to use bisphosphonates with
anabolic treatments, and the benefits of treatment in patients who do not have a BMD Tscore
below −2.5. (16).
7.4 Bisphosphonates in orthopedic interventions
The rationale for the potential use of bisphosphonates in orthopedics is similar to that of
other uses to limit bone resorption. Recent years have seen a great many studies, both preclinical
and clinical, exploring the potential application of the BPs to the problems of bone
catabolism encountered in orthopedics. To date, the most promising roles for the BPs have
been found in prevention of bone collapse following osteonecrosis and in enhancing
implant fixation. Combination therapies that have both bone anti-resorptive and anabolic
agents also show great promise for orthopedic applications. However, further large scale
clinical trials are required to confirm whether these observations translate into a clinical
benefit for patients and the development of robust indications for these therapies in
orthopedic practice (17).
8. Side effects of bisphosphonates
The esophageal or gastric irritation caused by the oral preparations is an established adverse
effect. However, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures have attracted
most of the attention mainly because their pathophysiology remains unclear.
8.1 Acute-phase reaction/response
Twenty four to seventy two hours or even several days after the first administration of an IV
nitrogen-containing bisphosphonate, approximately 40% of the patients will experience
influenza-like illness with pyrexia, chills, myalgia and arthralgia that tend to resolve within
148 Orthopedic Surgery
3 days. This symptomatology can also occur after high oral doses and is associated with an
acute-phase reaction. Supportive and symptomatic management with NSAIDs and
acetaminophen is sufficient. The proportion of patients affected is decreased substantially
following subsequent infusions (18).
8.2 Ocular inflammation
Nitrogen-containing bisphosphonates, usually IV pamidronate administration, have been
associated with the development of ocular inflammation in the form of nonspecific
conjunctivitis, uveitis, iritis, episcleritis and scleritis, with incidence ranging from 0.046% to
1%. Ocular inflammation can resolve after a short course of corticosteroid treatment and in
cases of scleritis bisphosphonate administration must be discontinued. Also, avoidance of
bisphosphonates or caution in their use (especially IV) for those with a history of
inflammatory eye disease or uveitis is recommended (18).
8.3 Gastrointestinal side effects
Gastrointestinal (GI) problems are often considered to be an inevitable consequence
associated with the oral use of bisphosphonates, which are currently extensively prescribed
(alendronate, risedronate, and ibandronate) for the prevention and treatment of
osteoporosis. However, the results from the major prospective RCTs assessing the reduction
of fractures are notable in not showing an excess of GI problems. It is generally
acknowledged that upper GI symptoms are very common in elderly patients whether or not
bisphosphonates are given. In contrast, the more severe side effects associated with
esophageal events such as ulceration are rare but potentially more serious, and were noted
in particular after giving oral pamidronate or alendronate. In terms of practical
management, the interference of absorption by food as well as these esophageal problems
are minimized in patients taking oral bisphosphonates on an empty stomach, first thing in
the morning, with sufficient plain water, while remaining in an upright position without
eating or further drinking for at least 30 minutes (60 minutes in the case of ibandronate).
Strict adherence to these instructions is thought to reduce the incidence of serious
esophageal adverse events (12).
8.4 Atrial fibrillation
An international, multicenter, randomized, double-blind, placebo-controlled trial raised by
the HORIZON found an increased incidence of serious atrial fibrillation in patients which
use zoledronic-acid, as compared with the placebo group (19). While bisphosphonates are
targeted to a patient group that is already at higher risk of atrial fibrillation than the
background population, current studies from large health databases have identified either
no increase or only a small increase in the risk of atrial fibrillation with oral bisphosphonate
use, with no apparent added risk of thromboembolic complications (20). Despite the lack of
a known biologically plausible explanation for bisphosphonate-induced atrial fibrilation,
several potential mechanisms have been hypothesized. Given the absence of any proven
mechanism for bisphosphonate-induced arrhythmia formation, continued reports of a
possible association will justify the need for additional studies to more fully explore these
and other potential mechanisms (21).
Bisphosphonates and Bone 149
8.5 Atypical femoral fractures
Although bisphosphonates reduce the rates of fractures due to osteoporosis, recent reports
suggested a link between bisphosphonate use and the development of atypical insufficiency
fractures. This is thought to be due to long term oversuppression of bone turnover leading
to impaired bone remodeling, accumulation of microdamage in bone and increased skeletal
Several publications demonstrated the occurrence of femoral fractures associated with longterm
bisphosphonate use (22,23,24,25,26).
These fractures appear to be more common in patients who have been exposed to longterm
BPs, usually for more than 3 years (median treatment 7 years). It must be
emphasized that these fractures are rare, particularly when considered in the context of
the millions of patients who have taken BPs and also when compared with typical and
common femoral neck and intertrochanteric fractures. It also must be emphasized that
BPs are important drugs for the prevention of common osteoporotic fractures. However,
atypical femoral fractures are of concern, and more information is urgently needed both
to assist in identifying patients at particular risk and to guide decision making about
duration of BP therapy. Physicians and patients should be made aware of the possibility
of atypical femoral fractures and of the potential for bilaterality through a change in
labeling of BPs. Given the relative rarity of atypical femoral fractures, to facilitate future
research, specific diagnostic and procedural codes should be created for cases of atypical
femoral fractures, an international registry should be established,and the quality of case
reporting should be improved. Research directions should include development of animal
models, increased surveillance, and additional epidemiologic data to establish the true
incidence of and risk factors for this condition and studies to address their surgical and
medical management (27).
A position paper reported by Rizzoli et al, reviewed the evidence for an association between
atypical subtrochanteric fractures and longterm bisphosphonate use. They demonstrated
that the available evidence does not suggest that the well-known benefits of bisphosphonate
treatment are outweighed by the risk of these rare, atypical, low-trauma subtrochanteric
fractures. Nevertheless, it is recommended that physicians remain vigilant in assessing their
patients treated with bisphosphonates for osteoporosis or associated conditions. They
should continue to follow the recommendations on the drug label when prescribing
bisphosphonates and advise patients of the potential risks. Patients with pain in the hips,
thighs or femur should be radiologically assessed and, where a stress fracture is evident, the
physician should decide whether bisphosphonate therapy should be discontinued pending
a full evaluation, based on an individual benefit–risk assessment. The radiographic changes
should be evaluated for orthopaedic intervention—since surgery prior to fracture
completion might be advantageous—or be closely monitored (28).
8.6 Bone, joint, or muscle pain
In postmarketing experience, there are infrequent case reports describing severe and
occasionally incapacitating bone, joint, and/or muscle pain in patients taking
bisphosphonates. The pain could occur days, months, or even years after starting
bisphosphonates. It is probably different or, at least, not only associated with the acutewww.
150 Orthopedic Surgery
phase response and presents within the first few days after the first treatment with an IV
bisphosphonate. Most patients reported relief of symptoms after discontinuing therapy and
a subset had recurrence of pain when restarting treatment with the same or a different
8.7 Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ)
To distinguish BRONJ from other delayed healing conditions, the following working
definition of BRONJ has been adopted by the American Association of Oral and
Maxillofacial Surgeon. Patients may be considered to have BRONJ if all of the following 3
characteristics are present:Current or previous treatment with a bisphosphonate ; exposed
bone in the maxillofacial region that has persisted for more than 8 weeks and no history of
radiation therapy to the jaws. It is important to understand that patients at risk of, or with
established, BRONJ can also present with other common clinical conditions not to be
confused with BRONJ. Commonly misdiagnosed conditions can include, but are not limited
to, alveolar osteitis, sinusitis, gingivitis/periodontitis, caries, periapical pathologic findings,
and temporomandibular joint disorders (29,30).
A disease remarkably similar to the presentation of BRONJ was initially described in the
match-making industry at the end of the 18th century. Considered by some to be the first
identified instance of a disease caused by occupational exposure of a chemical (elemental
phosphorus), “phossy jaw” was characterized by bone necrosis and infection that was
isolated to the jaw. Recently, some reports have attempted to establish parallels with
BRONJ and “phossy jaw.” Although the clinical presentations of BRONJ and phossy jaw
are quite similar, the chemical agents known to be the cause of these diseases are very
different in structure and chemical properties. In reality, BRONJ is likely a disease entity
that was no nexistent prior to the late 1990s, and is linked to the emergence of
bisphosphonates as a popular mode of therapy for the treatment of osteolytic bone disease
and osteoporosis (31).
BRONJ was first described by Marx and Stern in 2002. At that time it was only a curious
finding of exposed, nonhealing bone when debridement was performed, the condition
worsened and led to increased amounts of exposed bone. In 2003; Marx described 36 cases
associated with intravenous bisphosphonates (pamidronate or zoledronate) in a medical
alert published in the Journal of Oral and Maxillofacial Surgery (30,32). Since the original
2003 publication, more than 1,100 additional reports by over 4,500 authors and at least 14
position papers have been written about BRONJ (30).
8.8 Osteomyelitis, osteoradionecrosis and BRONJ
Microscopically, BRONJ presents a picture that may be either suppurative osteomyelitis or
osteoradionecrosis. However representative central bone biopsy specimens identify distinct
and unique histopathologies that underscore the separate mechanisms of each. Suppurative
osteomyelitis shows inflammatory cells in the marrow space. It shows also necrotic bone
and viable reactive bone. Osteoradionecrosis, similarly shows necrotic bone but without any
marrow inflammation. Instead, the marrow space contains poorly cellular or acellular
collagen consistent with marrow fibrosis and the well-documented hypocellular,
hypovascular, hypoxic characteristics of radiated tissue. Microorganisms colonize on the
Bisphosphonates and Bone 151
bone surface but do not invade the tissue because osteoradionecrosis is an effect of radiation
tissue damage and is not a primary bacterial process. BRONJ, in contrast, shows neither
marrow inflammation nor marrow fibrosis. Instead, the marrow has empty acellular
marrow spaces along with necrotic bone with numerous Howship lacunae. Surface
microorganisms are frequently seen in associaton with necrotic bone and often prompt an
inaccurate diagnosis of osteomyelitis. The clinical description and history remain the best
tools available for distinguishing BRONJ from these other conditions of delayed bone and
wound healing (30).
8.9 Comparison of long bone to alveolar bone and BRONJ
Alveolar bone exists to support the teeth. Its structure varies between individuals and
generally it gets denser with age. Broadly, there is a dense bone wall near the gingivae and
then the middle portion of the tooth root. There are larger marrow spaces near the tooth
apex. The alveolar bone walls at the attachment of the periodontal membrane have a
cribiform structure with open channels. The bone structure follows that of bone structure
throughout the body with cortical bone containing osteons and Haversian systems. New
bone is formed in a lamellar structure by osteoblasts with the osteocytes being incorporated
within the bone. Older bone, or bone in the path of erupting or moving teeth is resorbed by
osteoclasts. In keeping with all bone in the body, alveolar bone is a dynamic structure with
the bone constantly remodelling and adapting to functional needs. The key question
however, is whether alveolar bone is exactly the same as the long bones or whether it is
subtly different. Alveolar bone develops as a membrane bone whereas the limbs and
vertebrae develop as endochondral bones. The mandible is of neural crest origin whereas
the limbs and vertebral column are of mesodermal origin. There are minor phenotypic
differences between osteoblasts depending on their site of origin and anatomical location,
which can be demonstrated biochemically. Membrane bone osteoblasts also have an
increased rate of cell division as compared to iliac crest osteoblasts. Osteoclasts are derived
from mononuclear precursor cells which migrate from the bone marrow via the vasculature
to the bone site. Their function is dictated largely by interaction with the osteoblasts in the
area. There are biochemical differences between osteoclasts of membrane bone origin and
long bone origin. There are also differences in behaviour between giant cell tumours of the
jaws and of the long bones. The long bone is deeply covered in soft tissue and they are not
commonly exposed. On the other hand the alveolar bone is covered only mucoperiostally.
The long bones are low vascular than the alveolar bone (10).
The alveolar crest remodels at 10 times greater than the rate of tibia, 5 times the rate of the
mandible at the inferior border, and 3-5 times the rate of the mandible at the level of the
mandibular canal. As a result, the alveolar bone of the jaws has a greater uptake of
bisphosphonates and readily accumulates at higher concentrations. It is also reported that
the alveolar bone depends more on osteoclastic bone resorption/remodeling and renewal
than any other bone in the adult skeleton. The jaws are repeatedly traumatised by
mastication and they expose to the oral environment and commensal micro-organisms more
than the long bones. All these differences between the jaws and the other bones, explain
why only the jaws are affected. To date it has not been reported in other skeletal sites as
exposed bone; however, recent reports have identified femur fractures caused by long-term
use of bisphosphonates (30).
152 Orthopedic Surgery
8.10 Causality of BRONJ
Epidemiologic studies have established a compelling, albeit circumstantial, association
between IV bisphosphonates and BRONJ in the setting of malignant disease. An association
between IV bisphosphonate exposure and BRONJ may be hypothesised based on the
following observations: (i) a positive correlation between bisphosphonate potency and risk
for developing BRONJ; (ii) a negative correlation between bisphosphonate potency and
duration of bisphosphonate exposure prior to developing BRONJ; and (iii) a positive
correlation between duration of bisphosphonate exposure and developing BRONJ.
However, the current level of evidence does not fully support a cause and effect relationship
between bisphosphonate exposure and necrosis of the jaw. Although causality may never be
proven, emerging iexperimental and epidemiologic studies have established a firm
foundation for a strong association between monthly IV bisphosphonate therapy and
BRONJ. The causal association between oral or IV bisphosphonates for treating osteoporosis
and BRONJ is much more difficult to establish (29).
8.11 Incidence of BRONJ
IV bisphosphonate exposure in the setting of managing malignancy remains the major risk
factor for BRONJ. According to case series, casecontrolled studies, and cohort studies,
estimates of the cumulative incidence of BRONJ have ranged from 0.8% to 12%. Patients
receiving oral bisphosphonate therapy are at a considerably lower risk of BRONJ than
cancer patients treated with monthly IV bisphosphonates.
The clinical efficacy of oral bisphosphonates for the treatment of osteopenia/osteoporosis is
well established and is reflected in the fact that over 190 million oral bisphosphonate
prescriptions have been dispensed worldwide. Based on available data, the risk of BRONJ
for patients receiving IV bisphosphonates is significantly greater than that for patients
receiving oral bisphosphonates.Regardless, given the large number of patients receiving oral
bisphosphonates for the treatment of osteoporosis/osteopenia, it is likely that most
practitioners will encounter some patients with BRONJ. It is important to accurately
determine the incidence of BRONJ in this population and to assess the risk associated with
long-term use (ie, longer than 3 years) of oral bisphosphonates. The low prevalence of
BRONJ in osteoporosis patients poses a significant challenge for future clinical trials aimed
at establishing accurate incidence data (29).
8.12 Risk factors of BRONJ
BRONJ risks were categorized as drug-related, local, and demographic, systemic, genetic
and preventative factors. Other medications, such as steroids and thalidomide, and other
chemotherapeutic agents were thought to be risk factors, but no measurable associations
were identified (29).
Drug-related risk factors include bisphosphonate potency and duration of therapy.
Zoledronate (Zometa®) is more potent than pamidronate (Aredia®) and pamidronate
(Aredia®) is more potent than the oral bisphosphonates; the IV route of administration
results in a greater drug exposure than the oral route. Using a number of different risk
measures, the BRONJ risk among cancer patients given IV bisphosphonate exposure
Bisphosphonates and Bone 153
ranged from 2.7 to 4.2, suggesting that cancer patients receiving IV bisphosphonates have
a 2.7- to 4.2-fold increased risk for BRONJ than cancer patients not exposed to IV
bisphosphonates. Longer duration od the use of bisphosphonates appears to be associated
with increased risk.
Local risk factors include; dentoalveolar surgery, including, but not limited to extractions,
dental implant placement, periapical surgery, periodontal surgery involving osseous injury.
Patients receiving IV bisphosphonates and undergoing dentoalveolar surgery are at least
seven times more likely to develop BRONJ than patients who are not having dentoalveolar
It has been observed that lesions are found more commonly in the mandible than the
maxilla (2:1 ratio) and more commonly in areas with thin mucosa overlying bony
prominences such as tori, bony exostoses and the mylohyoid. No data are available to
provide risk estimates for anatomic structures and BRONJ.
Cancer patients exposed to IV bisphosphonates with a history of inflammatory dental
disease, for example periodontal and dental abscesses, are at a sevenfold increased risk for
8.12.1 Demographic and systemic factors
Sex was not statistically associated with BRONJ. Race was reported in one study to be a risk
factor, with Caucasians having an increased risk for BRONJ compared with blacks. Other
systemic factors or conditions, that is renal dialysis, low haemoglobin, obesity and diabetes,
were variably reported to increase the risk for BRONJ. Malignancy type was not statistically
associated with an increased risk for BRONJ.
8.12.2 Genetic factors
It is reported that genetic perturbations, that is single nucleotide polymorphisms (SNPs), in
the cytochrome P450-2C gene (CYP2C8) gene were associated with an increased risk for
BRONJ among multiple myeloma patients treated with IV bisphosphonates.
8.12.3 Preventative factors
Alternative dosing schedules that reduce IV bisphosphonate exposure have comparable
outcomes in terms of preventing a decreased risk of BRONJ.
The two largest risk factors for BRONJ are IV bisphosphonate exposure and dentoalveolar
procedures. Recent studies suggest that manipulation of IV bisphosphonates dosing may be
effective for minimising BRONJ risk. In addition, preventative dental interventions before
initiating IV bisphosphonate treatment can also effectively reduce, but not eliminate, the risk
of BRONJ (29).
8.13 Clinical management of BRONJ
The management of BRONJ currently is a dilemma. No effective treatment has yet been
developed and interrupting bisphosphonate therapy does not seem to be beneficial because
154 Orthopedic Surgery
the drugs accumulate at high levels inside the bone matrix. However, cessation of
bisphosphonate therapy can have severe problems, such as bone metastasis, multiple
myeloma or hypercalcemia associated with tumors. In general all the guidelines related to
the management of BRONJ recommended a nonsurgical approach consisting of a mix of
Treatment of BRONJ focuses on controlling pain, limiting secondary infection and extension
of the exposed bone and maintaining function. These are achieved with the use of 0.12 %
clorhexidine, 15 mL oral swish and spit three times daily. To control the pain of initial
secondary infection Penicilin VK 500 mg by mouth four times daily can be used. If the
patient is allergic to penicilin, alternatives are; doxycycline 100 mg once daily, levofloxacin
500 mg once daily, azithromycin 500 mg once daily. In patients who have a minimal
response to these antibiotic regimens, adding metronidazole 500 mg three times daily for 10
days can resolve the secondary infection. More or less aggresive surgery is recommended
only in advanced, nonresponsive cases. Surgical treatment, in accordance to AAOMS
position paper, is reserved to patients affected by BRONJ lesions (30).
9. Clinical cases
The present chapter presents 3 clinical cases that were managed by the authors in Istanbul
University, Dentistry Faculty, Department of Oral and Maxillofacial Surgery. The cases
presented here show the importance of the clinical situation, to the all medical doctors
which prescribe bisphosphonates. Theses cases presents also that the life quality of the
patients can be very low because of this situation.
9.1 CASE 1
A 65-year-old woman has presented with a complaint of pain in the right side of the
maxilla. Clinical examination of the patient showed a large necrotic mass of bone on the
right half of the maxilla (Figure 1). The patients’s medical history involved multiple
myeloma disease resisting for more than 3 years. She informed that she had been using
zoledronic acid for the last 1 year for the management of this disease. During this period,
she had undergone multiple tooth extractions at the right side of the maxilla. MRI
findings and orthopantomograph showed the necrotic bone (Figure 2, Figure 3). Clinical
and radiological examinations, along with the medical anemnesis taken, revealed the
diagnosis of ‘‘BRONJ’’.
Initially, a drug holiday has started for zoledronic acid after consultation with the patient’s
physician. Along with this, oral amoxicillin with clavulanic acid 1000 mg two times daily,
combined with oral metronidazole 500 mg two times daily were prescribed. These were
used for two months. 0.12% chlorhexidine oral rinsing 3 times daily was also used during
this period for maintaining good oral hygiene. This type of treatment resolved the acute
reactions and pain. Even though this treatment did not help the formation of a demarcation
line of the necrotic bone, there wasn’t either a progress in the enlargement of the necrotic
area too. Bone resection was not permitted because of the severe multiple myeloma. The
patient is still followed up continuously every three months.
Bisphosphonates and Bone 155
Fig. 1. Clinical view of the necrotic bone.
Fig. 2. Orthopantomograph showing the necrotic bone.
Fig. 3. MRI showing the infected right maxillary sinus.
156 Orthopedic Surgery
9.2 CASE 2
A 75-year-old male patient has presented with a complaint of pain in the right side of the
maxilla. Clinical examination has shown a large mass of exposed necrotic bone in the right
side of the maxilla with the swelling of the palatal mucosa (Figure 4). The patient has been
diagnosed with multiple myeloma for two years. He has informed that he had been using
zoledronic acid since the beginning of his disease. Orthopantomograph has shown the
necrotic area (Figure 5).
Initially, a drug holiday has started for zoledronic acid after consultation with the patient’s
physician. Along with this, oral amoxicillin with clavulanic acid 1000 mg two times daily,
combined with oral metronidazole 500 mg two times daily were prescribed. These were
used according to two months usage and one month holiday protocol. 0.12% chlorhexidine
oral rinsing 3 times daily was also used during this period for maintaining good oral
hygiene. This type of treatment resolved the acute reactions and pain. After one and a half
years of conservative treatment, sequestrum formation was observed and it was peeled off
by itself. (Figure 6 and Figure 7). The patient is followed up continuously every three
Fig. 4. Clinical view of the exposed bone.
Bisphosphonates and Bone 157
Fig. 5. Orthopantomograph showing the necrotic bone.
Fig. 6. Sequestrum’s clinical appearence at the right side of the mandible.
Fig. 7. Clinical view of the affected area after the removal of the sequestrum.
158 Orthopedic Surgery
9.3 CASE 3
52-year-old woman was referred to our clinic with pain and exposed bone at the right
mandibular posterior area (Figure 8). In 1997, she had undergone mastectomy for her breast
cancer. In between the years 2001 and 2006, she had used zoledronic acid for her bone
metastasis related with her breast cancer. In 2006, bisphosphonate related osteonecrosis of
the right mandibular area was diagnosed in a private clinic. Her physician had decided to
discontinue zoledronic acid and instead had prescribed ibandronat. A local curettage and
debridement was performed in the private clinic before applying to our clinic. In the
orthopantomograph, the necrotic bone was clearly observed (Figure 9). Amoxicillin with
clavulonic acid combined with metronidazole was used to supress her infection. After a
drug holiday of three month; in december 2010, we performed local curettage and
debridement using Er,Cr: YSGG laser and the wound was closed primarily (Figure 10,
Figure 11). Postoperative clinical and radiological examination did not reveal any sign of
osteonecrosis or infection, 6 months after the operation (Figure 12, Figure 13) The patient is
followed up continuously every three months.
Fig. 8. Clinical view of the exposed bone at the vestibular and lingual part of the posterior
right side of the mandible.
Bisphosphonates and Bone 159
Fig. 9. Orthopantomograph showing the necrotic bone at the posterior right side of the
mandible. Note the line of the demarcation.
Fig. 10. Removed sequestrum and the associated teeth.
160 Orthopedic Surgery
Fig. 11. Clinical view of the bone after the removal of the sequestrum and laser application.
Fig. 12. Orthopantomograph showing the affected area 6 months after the operation.
Bisphosphonates and Bone 161
Fig. 13. Clinical appearence of the patient free of infection after 6 months post-operatively.
Note that there’s only a single small area of exposed bone.
10. Future research
Retrospective and prospective case studies have certainly established an association
between bisphosphonates and jaw necrosis but the true incidence of this complication
remains unknown. Clinical studies in the form of practitioner surveys or retrospective and
prospective cohort investigations are needed to establish a more meaningful assessment
of the associated risk factors and incidence of this problem in the population at risk. In
addition, basic science research with the development of animal model system is needed
to elucidate the cellular, molecular, and genetic mechanisms responsible for this process.
Also, the development of an animal model for this disease process is important to
establish treatment strategies that are evidenced based and associated with valid outcome
The effect of bisphosphonates on intraoral soft tissue wound healing; analysis of alveolar
bone hemostasis and the response to bisphosphonate therapy; the antiangiogenic properties
of bisphosphonates and their effects on jaw bone healing, pharmacogenetic research; and the
development of valid BRONJ risk assessment tools should also be investigated in future.
Continued governmental and institutional support is required to elucidate the underlying
pathophysiologic mechanisms of BRONJ at the cellular and molecular level. Moreover,
novel strategies for the prevention, risk reduction, and treatment of BRONJ need to be
developed further so that more accurate judgments about risk, prognosis, treatment
selection, and outcome can be established for patients with BRONJ (29).
162 Orthopedic Surgery
All the medical doctors, who prescribe bisphosphonates, should strictly inform their
patients about possible side effects of these drugs. One of the most important adverse effects
of these drugs is BRONJ. This may occur spontaneously or following an oral surgical
intervention such as a simple extraction, in patients with a history of bisphosphonate
treatment. Prevention plays a crucial role since its management is difficult. Before
prescribing these drugs, medical doctors should refer their patients to the dentists and
maxillofacial surgeons in order to maintain optimum oral hygiene. All oral surgical
operations should be completed prior to bisphosphonate therapy. Bisphosphonate therapy
should only be started when the whole mucosal epithelization is formed.
BRONJ therapy has a more complicated management than the therapies for osteomyelitis
and osteoradionecrosis. Its success rate is also less. These difficulties in the management of
BRONJ leeds to a very diminished life quality for the patients. Therefore, consultation in
between medical doctors and dentists and oral and maxillofacial surgeons gains importance.
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Edited by Dr Zaid Al-Aubaidi
Hard cover, 220 pages
Published online 09, March, 2012
Published in print edition March, 2012
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