Review Article

The Orthopaedic Implications of

Diphosphonate Therapy

Abstract
Michael J. Weaver, MD Diphosphonates are among the many commonly prescribed drugs
Micah A. Miller, BS for osteoporosis management. These synthetic analogues of
physiologically occurring inorganic pyrophosphate bind to the
Mark S. Vrahas, MD
hydroxyapatite crystals of bone. Diphosphonates act by decreasing
the amount of osteoclast-mediated bone resorption by inducing
apoptosis and disrupting the mevalonate biosynthetic pathway.
Prospective clinical trials have shown that diphosphonates increase
bone mineral density and reduce the risk of fracture.
Diphosphonates are generally well tolerated, with a low incidence
of side effects. They may be administered orally or intravenously;
infusions are the most potent. Few studies have directly studied
the effect of diphosphonates on the rate of fracture or time to
union. Concern exists regarding the long-term safety of
diphosphonates, particularly in patients with osteoporosis. New
evidence suggests that long-term therapy may increase the risk of
fracture of the femoral shaft, with possible morphologic and
prodromal warning signs. Further prospective research into the
consequences of diphosphonate-mediated suppressed bone
turnover is needed to elucidate a safe duration of treatment.

From Partners Orthopaedic Trauma

Service, Brigham and Women’s
Hospital and Massachusetts General
Hospital, Boston, MA.
Dr. Weaver or an immediate family
member has received research or
institutional support from Synthes
and Zimmer. Dr. Vrahas or an
immediate family member has
received research or institutional
support from Synthes; DePuy, a
Johnson & Johnson company;
Zimmer; and AO. Neither Mr. Miller
nor any immediate family member
has received anything of value from
or owns stock in a commercial
company or institution related
directly or indirectly to the subject of
this article.
J Am Acad Orthop Surg 2010;18:
367-374
Copyright 2010 by the American
Academy of Orthopaedic Surgeons.
D iphosphonates are a class of
drugs widely used in the treat-
ment of such varied conditions as
heritable skeletal disorders in chil-
dren, hypercalcemia, metastatic car-
cinoma, multiple myeloma, Paget
disease of bone, and osteoporosis.
Since their initial development for
clinical use, hundreds of different
compounds have been synthesized,
and dozens have undergone clinical
trials.
Diphosphonates remain among the
most common drug treatments for
osteoporosis. Research continues to
elucidate the exact mechanisms of
action of these medications as well as
the implication of their long-term use
on bone remodeling, the biomechan-
ical properties of bone, and bone
healing. Diphosphonates act by de-
creasing the amount of osteoclast-
mediated bone resorption. Recent re-
ports have suggested that long-term
diphosphonate use may play a role
the development of stress fractures of
the femoral shaft.
Pharmacology and
Mechanism of Action
Diphosphonates are synthetic ana-
logues of physiologically occurring
inorganic pyrophosphate (PPi), in
which the oxygen bridge has been re-
placed with a carbon atom (P-C-P).
The carbon center is resistant to heat
and enzymatic hydrolysis, which al-
lows the molecules to pass intact to
sites of bone resorption without be-
ing metabolized. Once in the blood

June 2010, Vol 18, No 6 367

The Orthopaedic Implications of Diphosphonate Therapy

Figure 1 sorption of bone.1 Aminodiphospho-

nates contain an amino group on R2,
with ring-configured amino groups
yielding much greater potency than
simple amino groups. For example,
zoledronate is 20,000 times more
potent per equivalent dose than eti-
dronate, the original non-amino-
diphosphonate. It appears that these
Chemical structure of pyrophosphate (A), simple diphosphonate (B), and two classes of drug affect osteoclastic
aminodiphosphonate (C). The moiety in the place of R1 and R2 determines resorption of bone in different ways.
the specific chemical characteristics of the diphosphonate. The P-C-P portion
Simple diphosphonates act by being
is responsible for the high affinity for the hydroxyapatite in bone. N = amino
metabolized into nonhydrolyzable
adenosine triphosphate analogues.
Figure 2 These metabolites accumulate within
osteoclasts, inhibiting cellular metab-
olism, leading to apoptosis and cell
death1 (Figure 2, A). Aminodiphospho-
nates appear to act primarily by disrupt-
ing the mevalonate biosynthetic path-
way. The mevalonate pathway is
responsible for cholesterol production
and is perhaps best known as a target
for common cholesterol-lowering stat-
ins. Aminodiphosphonates act by inhib-
iting protein prenylation, which causes
loss of the ruffled border and results in
apoptosis2 (Figure 2, B). The primary
target appears to be farnesyl pyro-
phosphate synthase, although other
enzymes may also be affected.
The selectivity of diphosphonates
is a function of their affinity to bone
rather than to their specific intracel-
lular activity. Diphosphonates bind
to hydroxyapatite crystals in bone.3
They are not integrated directly into
hydroxyapatite but rather bind to
the surface of the crystal and are
A, Mechanism of action of simple diphosphonates. Diphosphonates are then trapped as new crystals form.
taken up by osteoclasts (left), where they are metabolized into Diphosphonates have been shown to
nonhydrolyzable adenosine triphosphate analogues (center). Right,
accumulate at the site of bone re-
Accumulation leads to induction of apoptosis. B, Aminodiphosphonate
mechanism of action within osteoclasts. The mevalonate pathway is blocked, sorption where bone mineral is most
thus inhibiting protein prenylation. Cell morphology is disrupted, leading to exposed.4 As activated osteoclasts re-
loss of the ruffled border and eventual apoptosis. DP = diphosphonate, sorb bone, the deposited diphospho-
HMG-CoA = hydroxymethylgutaryl-coenzyme A, PP = pyrophosphate
nate is released into the local mi-
croenvironment and is preferentially
stream, diphosphonates demonstrate (Figure 1), or first- and second-gen- taken up by osteoclasts. Once inter-
an affinity for bone. eration diphosphonates, respectively. nalized, diphosphonates inhibit bone
Diphosphonates can be classified in Aminodiphosphonates are 10 to 10,000 resorption and eventually induce ap-
two general categories: simple diphos- times more potent than simple diphos- optosis.5,6 Approximately 50% to
phonates and aminodiphosphonates phonates in inhibiting osteoclastic re- 80% of diphosphonates are cleared

368 Journal of the American Academy of Orthopaedic Surgeons


Table 1
Diphosphonates Listed in Order of Increasing Potency With Current Dosing Recommendations9
Drug
Etidronatea (Didronel [Procter & Gam-
ble Pharmaceuticals, Cincinnati, OH])
Tiludronatea (Skelid, [sanofi-aventis,
Bridgewater, NJ])
Pamidronatea,b (Aredia [Novartis Phar-
maceuticals, Basel, Switzerland])
Alendronatea,c (Fosamax, Fosamax
Plus D [Merck, Whitehouse Station,
NJ])
Ibandronatec (Boniva [Roche Laborato-
ries, Nutley, NJ])
Risedronatea,c (Actonel, Actonel with
Calcium [Procter & Gamble])
Zoledronic acidb (Reclast, Zometa
[Novartis])
a
US FDA approved in the treatment of Paget disease of bone
b
US FDA approved in the treatment of skeletal metastatic disease
c
US FDA approved in the treatment of osteoporosis
from the blood stream by renal ex-
cretion, and approximately 1% are
cleared through biliary excretion.7
The remainder of the drug is incor-
porated into the crystalline structure
of bone and may persist for the life-
time of the patient, with an esti-
mated half-life in bone of 10 years.7
Dosage and Side Effects
Diphosphonates can be administered
either orally or intravenously. Oral
bioavailability is poor; only 1% to
5% of the drug is absorbed.8 Diphos-
phonates should be taken with water
on an empty stomach, and the pa-
tient should remain upright for 2 to
3 hours to minimize the risk of
esophagitis. Dosage and frequency of
administration vary by drug, with
daily, weekly, and monthly dosing
schedules. Typical regimens are pre-
sented in Table 1.
Diphosphonates are generally well
tolerated, with a low incidence of side
effects. Upper gastrointestinal side ef-
fects have been reported, including dys-
pepsia, dysphagia, esophagitis, and
June 2010, Vol 18, No 6
Daily Weekly
5 mg/kg PO — —
400 mg PO — —
— —
10 mg PO 70 mg PO
2.5 mg PO — 150 mg PO
5 mg PO 35 mg PO
— —
esophageal ulcers.10 Symptomatic hy-
pocalcemia has been reported in pa-
tients with hypoparathyroidism and
vitamin D deficiency.11 Ocular side
effects, including pain, blurred vi-
sion, scleritis, and uveitis, have also
been reported with diphosphonate
use.12 There are sporadic reports of
myalgia and arthralgia in patients on
diphosphonate therapy.13
Osteonecrosis of the jaw is a rare
complication of diphosphonate ther-
apy. Reports of “phossy jaw” date as
far back as the mid 19th century in
factory workers exposed to white
phosphorus.14 The incidence of jaw
osteonecrosis is approximately 1 in
50,000 patient-years when oral
diphosphonates are taken for os-
teoporosis.15 The risk of osteonecro-
sis is higher in oncology patients, pa-
tients undergoing chemotherapy, and
patients undergoing significant den-
tal procedures.15 This complication
may be dose-specific; oncology pa-
tients typically receive much higher
doses of diphosphonates than do
those treated for osteoporosis.
The mechanisms involved in necro-
Michael J. Weaver, MD, et al
Monthly Yearly
—
—
— 30-90 mg infusion
— —
—
150 mg PO —
— 4-mg infusion
sis of the jaw bones are poorly un-
derstood, but several theories exist.
The unique environment of the oral
cavity normally facilitates quick and
uncomplicated healing after a surgi-
cal insult, such as tooth extraction.
When this environment is disturbed,
however, either by loss of vascular-
ization of the jawbones from tumori-
cidal radiation or some other agent
or pathology, then minor injury may
increase the risk of osteonecrosis and
possible secondary osteomyelitis.
The mandible and maxilla are also
sites of high bone turnover, so the
possibility exists that diphospho-
nates are selectively deposited in jaw-
bones more than in other bony tis-
sues. However, we are unaware of
any study demonstrating selective in-
crease in diphosphonate deposition
in certain bones, such as the jaws.
Another possibility is that other con-
comitant medications may exacer-
bate wound healing problems and
could be considered to be possible
cofactors.
Infusion reactions have been re-
ported with the use of zoledronic
369
The Orthopaedic Implications of Diphosphonate Therapy
acid and pamidronate. Symptoms in-
clude low-grade fever, myalgia, ar-
thralgia, and malaise persisting for
24 to 72 hours following drug ad-
ministration. As many as 32% of pa-
tients may experience such symp-
toms following the first infusion,
with reduced incidence following
subsequent infusions.13 Zoledronic
acid has also been associated with a
slight increase in the risk of atrial fi-
brillation.13 The US FDA issued an
alert in 2008 regarding the asso-
ciation between diphosphonate use
and transient musculoskeletal pain,
which may occur days, months, or
years after therapy is begun.16 This
phenomenon is distinct from acute
infusion response, whose frequency
and contributing risk factors be-
tween severe musculoskeletal pain
and diphosphonate use are currently
unknown.
Analysis of human iliac crest biop-
sies suggests that microdamage will
accumulate after 5 years of alendro-
nate therapy, particularly in patients
with low bone mineral density
(BMD).17 Microdamage is generally
defined as matrix failure detectable
with light microscopy. This likely be-
gins with debonding of the collagen
fiber matrix, progressing through the
hierarchy of bone architecture until
very fine cracks coalesce into dye-
penetrable cracks that are visible un-
der a light microscope. The cracks
may also compound upon one an-
other, changing the stress state to
produce more and larger cracks.
Some authors advise checking mark-
ers of bone metabolism in patients
taking diphosphonates and consider-
ing a drug holiday if turnover has
stopped.18 Markers of bone resorp-
tion seem to be stronger predictors
of future bone loss than are markers
of bone formation; these markers are
correlated more strongly in elderly
women than in younger women.19
Currently available markers of bone
resorption include pyridinoline,
370
deoxypyridinoline, N-telopeptides of
type 1 collagen, and C-telopeptides
of type 1 collagen. Pyridinolines are
measured in urine, whereas telopep-
tides can be measured in urine or se-
rum. The advantage of using bone
markers instead of BMD to assess
bone turnover is that significant
changes in bone markers can be ob-
served at 3 to 6 months after the
start of therapy, whereas significant
BMD changes may take 18 months
to materialize.
Currently there is no consensus on
how long to continue diphosphonate
therapy. However, stopping therapy
after 5 years may be reasonable for
some patients because there appears
to be a residual benefit on BMD and
fracture prevention for up to 5 years
following cessation of therapy. This
was demonstrated in the Fracture In-
tervention Trial Long-Term Exten-
sion (ie, FLEX), a study involving
1,099 postmenopausal women who
had previously undergone alendro-
nate therapy for 5 years.20
Reduction in Risk of
Osteoporotic Fracture
Several prospective randomized clini-
cal trials have shown that diphospho-
nates, including alendronate, rised-
ronate, ibandronate, and zoledronic
acid, increase BMD and decrease the
risk of fragility fracture.13,20-25 Alen-
dronate was the first orally active
aminodiphosphonate available in the
United States. Its effectiveness in re-
ducing the incidence of osteoporotic
fractures was investigated in the
Fracture Intervention Trial (FIT),21
which involved 2,027 women with
low BMD in the femoral neck, with
or without vertebral fracture. Pa-
tients were randomized to receive
alendronate or a placebo for 3 years.
Clinically and radiographically evi-
dent vertebral fractures served as the
primary end point. Fifteen percent of
Journal of the American Academy of Orthopaedic Surgeons
patients in the placebo group sus-
tained vertebral fracture, versus 8%
in the alendronate group—a 47%
lower risk (P = 0.001). Additionally,
the incidence of any clinical fracture
was lower in the alendronate group
than in the placebo group (13.6%
versus 18.2%, respectively), and pa-
tients in the alendronate group had
fewer hip and wrist fractures than
did those in the placebo group. In a
10-year extension of the study pub-
lished by Bone et al,26 treatment with
10 mg alendronate daily resulted in a
significant increase in BMD in the
lumbar spine as well as at other skel-
etal sites. The reduction in fracture
risk appears to be most pronounced
in patients with osteoporosis.22
Liberman et al23 found that alendro-
nate therapy of 10 mg/d increased
bone density of the spine and proxi-
mal femur by 8.8% and 7.8%, re-
spectively, over a 3-year period com-
pared with placebo (P < 0.001).
Recent meta-analyses of both alen-
dronate and risedronate therapy in
postmenopausal women demonstrated
a low relative risk of vertebral and non-
vertebral fracture.27,28 Zoledronic acid
has also been shown to decrease the rate
of fragility fracture and mortality com-
pared with placebo. In a benchmark
randomized, double-blind, placebo-
controlled trial, 2,127 patients were as-
signed to receive yearly zoledronic acid
infusion or placebo. Administration of
a single intravenous dose of zoledronic
acid within 90 days following hip frac-
ture resulted in a 35% reduction in the
incidence of second fracture.24 A
28% reduction in deaths from any
cause was seen in the zoledronic acid
group, and no cases of osteonecrosis
of the jaw or adverse effects on frac-
ture healing were noted.
These data collectively demonstrate
the utility of diphosphonate therapy in
reducing the risk of osteoporotic frac-
tures and subsequent mortality, most
notably from hip fracture. The signif-
icance of this cannot be overstated,

given the very high rate of mortality fol-
lowing hip fracture in elderly persons.
Diphosphonate therapy is a relatively
cost-effective intervention that can de-
monstrably reduce the risk of such a
common problem in elderly persons
and in persons with osteoporosis.
Diphosphonates and
Fracture Healing
There is concern that diphosphonates
may hamper the normal healing process
following fracture; however, there is a
paucity of studies directly examining the
effect of diphosphonates on the rate of
or time to union in fracture patients.
Munns et al29 reported that pamidro-
nate treatment was associated with de-
layed healing after osteotomy but not
after fracture in children with moder-
ate to severe osteogenesis imperfecta.
Adult studies are lacking. Animal stud-
ies have shown that the effect of
zoledronic acid on fracture repair is
characterized by a larger trabecular
bone volume, increased callus size and
bone mineral content, and improved
mechanical strength.30,31 However, a
delay in remodeling of the hard cal-
lus during endochondral fracture re-
pair was observed.30,31
Recent studies have provided evi-
dence that diphosphonates stimulate
the proliferation of osteoblasts and
osteoblast-like cells. They enhance
the proliferation of bone marrow
stromal cells and promote osteoblas-
tic differentiation, primarily medi-
ated through bone morphogenetic
protein-2.32 Diphosphonates may also
prevent osteoblast apoptosis through an
unknown mechanism, thereby indi-
rectly contributing to the relative in-
crease in active cell numbers.
Primary bone healing is dependent
on osteoclast function at the leading
edge of cutting cones to cross the
fracture site. There are no clinical
data to support or refute the use of
diphosphonates in this setting. Fur-
June 2010, Vol 18, No 6
ther research into the effects of
diphosphonates on primary bone
healing is required, although indirect
evidence suggests that diphospho-
nates are safe to use following surgi-
cal fixation of fractures. Data from
animal studies have demonstrated a
delay in union following spinal fu-
sion while the animals were on
diphosphonates.33 The proper dose
and timing of administration during
the postoperative period following
fracture or spinal fusion remains to
be defined.
Diphosphonates and Total
Joint Arthroplasty
Data regarding the use of diphospho-
nates in patients undergoing total hip
arthroplasty (THA) and total knee ar-
throplasty (TKA) are limited. Peripros-
thetic bone loss after THA and TKA is
thought to occur primarily because of
a stress-shielding phenomenon. Bone
surrounding the new joint adjusts its
mineral density and structure to meet
the changed mechanical demands. Lo-
cal surgical trauma and immobilization
can also negatively affect bone quality.
Poor bone density and structure around
the implant may place the recipients of
these implants at greater risk of asep-
tic loosening and periprosthetic frac-
ture. There is some evidence that pa-
tients on diphosphonate therapy may
have a lower incidence of these postop-
erative complications after THA or
TKA.
In a randomized controlled trial of
19 patients with TKA, patients who
took alendronate and calcium were
found to maintain distal femoral
BMD values close to baseline values,
whereas patients who received only
calcium showed significant bone loss
at 1-year follow-up.34 Bhandari et
al35 conducted a meta-analysis of six
randomized controlled trials and
found that diphosphonates have a
beneficial effect in maintaining
Michael J. Weaver, MD, et al
periprosthetic BMD compared with
controls. Friedl et al36 randomized
patients undergoing cementless THA
to receive either a single infusion of
zoledronic acid or placebo. They
demonstrated a statistically signifi-
cant reduction in acetabular compo-
nent subsidence (P < 0.05) and a
trend for less femoral subsidence in
patients treated with zoledronic acid.
Neither acetabular or femoral failure
of ingrowth was observed.
Diphosphonates and
Femoral Shaft Stress
Fracture
Recent case series have implicated
diphosphonate therapy—specifically,
alendronate—with low-energy frac-
tures of the subtrochanteric region of
the femur. The earliest report of frac-
tures associated with alendronate use
was by Odvina et al37 in 2005. They
reported a series of nine spontaneous
fractures of the pelvis, femur, and
sacrum. More recent series focus spe-
cifically on fractures of the femoral
shaft, particularly in the subtrochan-
teric region.38,39
Goh et al38 and Neviaser et al39
presented case series of 13 and 70
patients, respectively, who sustained
subtrochanteric femur fractures. A
high proportion of patients treated
with alendronate had a cortical beak
on the anterolateral aspect of the fe-
mur (Figure 3). The cause and im-
portance of this abnormality is un-
known. Five of the 13 patients in the
study by Goh et al38 recalled prodro-
mal pain prior to their fractures.
In a case-control study, Lenart
et al40 linked long-term diphosphonate
use with insufficiency fractures of the
femur in postmenopausal women.
Diphosphonate use was observed in 15
of the 41 cases of subtrochanteric/shaft
fracture, compared with 9 of the 82
intertrochanteric/femoral neck controls.
The beaking pattern was identified ra-
371
The Orthopaedic Implications of Diphosphonate Therapy

Figure 3 Large-scale randomized controlled

trials demonstrate a decrease in over-
all fracture risk; however, most of
these studies are of <5 years dura-
tion.25 It is possible that longer-term
use of diphosphonates may lead to
an increased risk of fracture. With-
out the extension of previous studies
or the undertaking of a direct obser-
vational study, the nature and mag-
nitude of this potential risk will re-
main unknown.

Summary
Diphosphonates are among the most
Preoperative (A) and postoperative (B) AP radiographs of a 61-year-old commonly prescribed treatments for
woman who sustained a femoral shaft fracture following a ground-level fall.
The patient had been on alendronate therapy for 5 years preinjury. She osteoporosis. They have been shown
reported no prodromal symptoms. The arrows indicate the classic beak to increase BMD over time and re-
appearance of the lateral femur. C, AP radiograph of the contralateral femur duce the rate of fragility fractures. In
demonstrating a stress reaction and beaking (arrow) at the level of the
fracture on the injured side. general, this class of medication is
well tolerated, with few side effects.
Further study is necessary to deter-
mine proper dosing regimens follow-
diographically in 10 of the 15 sub- sue, or advanced glycation end prod- ing surgical fixation of fractures.
trochanteric/shaft cases managed with ucts. Glycation of bone tissue has Diphosphonate use appears to be
a diphosphonate. been shown to make bone more brit- safe in patients undergoing cement-
Animal studies suggest that pro- tle, with a decrease in the deform- less total joint arthroplasty, although
longed diphosphonate use may lead ability of bone before fracture.43 Ani- detailed studies are lacking. Recent
to the accumulation of microdamage mal models suggest that there is an case series suggest a possible associa-
over time and that high doses of accumulation of advanced glycation tion between long-term diphospho-
diphosphonate are associated with end products in cortical and trabecu- nate therapy and the development of
weakened mechanical properties of lar bone with diphosphonate thera- stress fractures of the femoral shaft,
bone.41 Diphosphonate-mediated py.44 Glycation of bone is a common and the optimum duration of ther-
turnover suppression in a canine problem in persons with diabetes apy remains unclear. Direct study
model was associated with a four- to and is one reason for the increased into the mechanism of this associa-
sevenfold increase in microdamage risk of fracture in persons with type tion as well as the magnitude of the
and a 20% to 40% reduction in en- II diabetes, despite normal BMD lev- clinical problem is required to obtain
ergy to fracture.42 However, the nor- els. a clear picture of this emerging con-
mal rate of turnover in the human The aforementioned cases series cern.
femoral shaft is low (<3% per year), have been refuted by a recent study
and it seems implausible that a fur- of the Danish National Hospital
ther reduction in this turnover rate Register.45 Abrahamsen et al45 could References
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Glycation of bone tissue has also long-term alendronate use was re- evidence are described in the table of
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of femoral shaft fracture. As bone of atypical femur fractures. However, 20-28, 35, and 36 are level I studies.
tissue ages, the bone accumulates this study was based on discharge di- References 10, 19, and 34 are level II
products of processes leading to non- agnoses and did not include direct studies. References 17, 29, and 40
enzymatic glycation of the bone tis- patient or radiographic evaluation. are level III studies. References 11,

372 Journal of the American Academy of Orthopaedic Surgeons


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