The Journal of Bone and Joint Surgery (American). 2005;87:1609-1618.
doi:10.2106/JBJS.D.03032
© 2005 The Journal of Bone and Joint Surgery, Inc.
Bisphosphonates in Orthopaedic Surgery
Carol D. Morris, MD, MS1 and
Thomas A. Einhorn, MD2
1 Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,
Suite A-342, New York, NY 10021. E-mail address:
morrisc{at}mskcc.org
2 Department of Orthopaedic Surgery, Boston University Medical Center, 720
Harrison Avenue, Boston, MA 02116
Investigation performed at Memorial Sloan-Kettering Cancer Center, New
York, NY, and Boston University Medical Center, Boston, Massachusetts
 |
Abstract
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Bisphosphonates are the most clinically important class of antiresorptive
agents available to treat diseases characterized by osteoclast-mediated bone
resorption.
Currently, seven bisphosphonates have the approval of the United States
Food and Drug Administration.
The most common adult diseases treated with bisphosphonates include
osteoporosis, Paget disease, and metastatic bone disease.
The treatment of pediatric disorders such as osteogenesis imperfecta and
fibrous dysplasia with bisphosphonates has gained momentum, and initial
investigations have demonstrated an acceptable safety profile.
Currently, there is a lack of long-term follow-up data, which will be
necessary for the development of responsible guidelines for therapy.
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Introduction
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Bisphosphonates are the most clinically important class of antiresorptive
agents available to treat diseases characterized by osteoclast-mediated bone
resorption such as osteoporosis, Paget disease, and tumor-associated bone
diseases. They are synthetic, metabolically stable analogues of inorganic
pyrophosphate in which the P-O-P bond has been replaced with a
non-hydrolyzable P-C-P bond (Fig.
1). The diphosphate configuration of both P-O-P and P-C-P
contributes to a three-dimensional structure capable of binding divalent ions
such as Ca2+ and is the basis for the bone-targeting property of
these compounds. This feature led to their use as bone-scanning agents when
coupled with a radioisotope such as
technetium-991.
Because the P-O-P compound is rapidly metabolized, it is safe to label with
radioactive isotopes for bone-scanning. However, there is no known enzyme
capable of metabolizing the P-C-P bond of bisphosphonates, which allows
considerable longevity of these compounds after they are administered.
More than three decades of research and development have produced a wide
range of molecules that vary on the basis of the side-chain substituents
(-R1, -R2) attached to the carbon compound; this leads
to variable clinical efficacy for a given bone-resorptive condition based on
the stereochemistry of that side chain
(Table I). Since
bisphosphonates were described more than a century ago, more than 1000 have
been synthesized and more than a dozen have been investigated in humans.
Currently, seven bisphosphonates have been approved by the United States Food
and Drug Administration (FDA) for use for various skeletal indications
(Table I). As a result of
intense clinical interest and a number of compelling preclinical
investigations, several bisphosphonates are being used in an off-label fashion
for a variety of skeletal disorders. In addition, bisphosphonates that have
not yet gained FDA approval are presently under clinical investigation and
have shown promise in a number of therapeutic applications.
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Mechanism of Action
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The cellular and molecular mechanisms by which bisphosphonates inhibit bone
resorption are only just beginning to become clear. The mechanism of action
depends largely on the chemical structure, which can be grouped into two major
pharmacological classes: nitrogen-containing and non-nitrogen-containing
compounds.
The early compounds such as etidronate and clodronate possess simple,
non-nitrogen-containing substituents (-OH, -H, and CH3) and are
metabolized into nonhydrolyzable analogues of adenosine triphosphate (ATP).
The bisphosphonate preferentially binds to the mineral component of bone
exposed by osteoclasts during normal or pathologic bone resorption. Since
osteoclasts have high endocytic activity, in the later cycles of
bone-remodeling these cells resorb both the bone and the bound bisphosphonate,
or the ATP analogue. These cytotoxic ATP analogues are then thought to
accumulate intracellularly, inhibiting osteoclast function and inducing
apoptosis.
A newer class of bisphosphonates, developed by modifying the R2
side chain to include an amino group, was found to be up to 1000-fold more
potent with respect to antiresorptive activity. Further modification of the
primary amine led to even more potent bisphosphonates. Collectively, these are
called the nitrogen-containing bisphosphonates, and they include the commonly
used drugs pamidronate, zoledronic acid, alendronate, and risedronate. They
exert their effects by inhibiting components of the intracellular mevalonate
pathway (Fig.
2)2. The
mevalonate pathway is the biosynthetic pathway responsible for cholesterol
production and perhaps is best known as the target of several
cholesterol-lowering statin drugs such as lovastatin and mevastatin. The
cholesterol precursors farnesyl diphosphate (FPP) and geranylgeranyl
diphosphate (GGPP) are synthesized along the mevalonate pathway. FPP and GGPP,
collectively referred to as isoprenoid lipids, are responsible for
transferring their respective lipid group (farnesyl or geranylgeranyl) onto
the cysteine residue of a protein. This process is called protein prenylation.
GTPase, an important signaling protein, is formed by protein prenylation. The
nitrogen-containing bisphosphonates inhibit protein prenylation, and thus
GTPase formation, by inhibiting enzymes that have yet to be fully identified.
The loss of GTPase prenylation leads to a loss of osteoclast regulation,
including control of cell morphology, disruption of integrin signaling,
altered membrane-protein trafficking, loss of membrane ruffling and
cytoskeleton disruption, and induction of
apoptosis3-5.
The findings of several basic investigations support the hypothesis that
inhibition of protein prenylation is the major molecular mechanism by which
the nitrogen-containing bisphosphonates inhibit bone resorption.
It is a common misconception that the mechanism of action of the
bisphosphonates is specific to the osteoclast. The mevalonate pathway is
present in many cell types. Because osteoclasts are in intimate contact with
the bone surface during resorption and bound bisphosphonates are released
during resorption, osteoclasts are exposed to a very high concentration of the
compound and as such are most affected in this setting. Other cells exposed to
high concentrations of bisphosphonates in cell culture also have problems with
protein prenylation, although the clinical relevance of this observation is
unclear at the present time. While there is no doubt, on the basis of our
current understanding, that osteoclasts are the obvious target of
bisphosphonate therapy, the effect of bisphosphonates on osteogenic and other
cells needs further investigation.
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Clinical Measures of Effectiveness
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A number of outcome parameters are used as surrogate markers of
bisphosphonate efficacy. Bone mineral density as assessed with dual-energy
x-ray absorptiometry (DXA or DEXA) is a measure of clinical efficacy that can
be evaluated noninvasively. Its measurement in clinical investigations of
bisphosphonate is based on the concept that these drugs protect the skeleton
from bone loss and that effect is reflected by stabilization or improvement in
bone density. Biochemical markers of bone turnover—namely,
calcium-creatinine and hydroxyproline-creatinine ratios as well as
measurements of the excretion of the collagen cross links pyridinoline (PYD),
deoxypyridinoline (DPD), n-telopeptide (NTX), and serum cross laps
(CTX)—are useful for monitoring bisphosphonate
therapy6. Of these,
urinary excretion of NTX appears to best reflect decreased bone resorption in
patients receiving anti-resorptive
therapy7. In
addition, the plain radiographic appearance of lytic disease, pain, and the
need for radiation or surgery are used to indicate therapeutic response.
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Clinical Applications
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A number of orthopaedic conditions have the potential to respond to the
antiosteoclastic activity induced by bisphosphonates. On the basis of the
current knowledge of bisphosphonate action and the results achieved in the
treatment of metabolic and metastatic bone diseases, it seems that any
skeletal condition in which osteoclast activity plays a dominant role could
potentially be affected by bisphosphonates. In this review, the clinical
applications of bisphosphonate therapy, including both FDA-approved and
off-label uses, are discussed for a variety of diseases.
Metabolic Bone Diseases
The metabolic bone diseases were among the first conditions to be treated
with bisphosphonates and were the first indications for which the FDA approved
use of these drugs. Postmenopausal osteoporosis and Paget disease are the most
common diseases for which bisphosphonates are prescribed. Because of the
tremendous success in the treatment of those two metabolic conditions,
bisphosphonates are now used to treat secondary osteoporosis due to several
conditions, such as extended glucocorticoid therapy and organ
transplantation.
Osteoporosis
Osteoporosis affects millions of people worldwide, with an estimated 28
million cases in the United States alone and almost 75 million cases when
Europe and Japan are included. For white women over the age of fifty years,
the lifetime risk of a vertebral fracture is one in three and the lifetime
risk of a hip fracture is one in six. Osteoporosis is the primary risk factor
for fractures in the elderly that can be effectively treated to reduce that
risk. The World Health Organization has operationally defined osteoporosis as
a bone mineral density that is 2.5 standard deviations below the mean peak
value in young adults of the same race and
sex8, which is
expressed as a T-score of -2.5. Bone mineral density compared with the mean
value in normal subjects of the same age and sex is represented by the
Z-score. A Z-score of less than -1 reflects the lowest 25% of the reference
range, and a score of less than -2 represents the lowest 2.5%. While
definitions of osteoporosis are largely conceptual, quantitative evaluations
of bone density can aid in diagnosis and assist in therapeutic decision-making
because bone density is one of the factors with a known correlation to
fracture risk.
Therapies that are used to treat osteoporosis act by decreasing bone
resorption. They include hormone-replacement therapy, use of the selective
estrogen-receptor modulator raloxifene, calcitonin therapy, and
bisphosphonates therapy. Bisphosphonates are the most important class of
antiresorptive therapies available and are the only medications that have been
shown to reduce the risk of hip fracture in large randomized trials.
Etidronate, alendronate, and risedronate have been approved by the FDA for the
treatment and prevention of osteoporosis, and clodronate, pamidronate,
tiludronate, zoledronate, and ibandronate have been evaluated in this clinical
setting as well. Etidronate given continuously at high doses can impair
mineralization9.
This drug is therefore usually administered in an intermittent cyclical
fashion at 400 mg/day for two weeks followed by use of supplemental calcium
(usually 500 mg) for eleven weeks. This schedule has resulted in a 2% increase
in the bone mineral density in the femoral neck, a 4% to 8% increase in the
bone mineral density in the lumbar spine, and a decrease in vertebral fracture
rates10-12.
Because of its potential adverse effects on mineralization, etidronate is
rarely used for the management of osteoporosis in the United States.
Alendronate was the first orally active bisphosphonate available in the
United States, and its effectiveness as an osteoporosis drug was investigated
in a large multi-institutional double-blind randomized trial called the
Fracture Intervention Trial
(FIT)13. More than
2000 women who had low bone density in the femoral neck, with or without
vertebral fracture, were randomized to receive alendronate or a placebo for
three years. Both clinically evident vertebral fractures and vertebral
fractures evidenced by a 20% decrease in vertebral height as seen on a lateral
radiograph served as the primary end points. Eight percent of the women
treated with alendronate sustained a radiographically evident vertebral
fracture compared with 15% of those treated with the placebo. In addition, the
risk of any clinical fracture developing was lower in the alendronate group
(2.3%) than in the placebo group (5.0%). The alendronate group had fewer hip
and wrist fractures than did the placebo group. In a ten-year extension of the
FIT study14,
treatment with 10 mg of alendronate daily resulted in a 13.7% increase in bone
mineral density in the lumbar spine as well as increased bone mineral density
at other skeletal sites. A 5-mg daily dose resulted in a more modest increase
in bone mineral density. The efficacy of the drug for preventing fractures did
not appear to diminish during the ten-year period of sustained therapy.
Furthermore, a once-a-week dose of 70 mg of alendronate demonstrated
therapeutic efficacy equivalent to that of a daily dose, and this has become
the standard of
therapy15.
Discontinuation of alendronate therapy resulted in a gradual loss of effect,
as demonstrated by measurement of bone mineral density and n-telopeptide (NTX)
level.
Special Considerations in Osteoporosis
Osteoporosis in men has gained considerable attention in recent years.
Although the disease is less prevalent in men than in women (3% to 6% compared
with 13% to 18%), approximately 25% to 30% of all hip fractures occur in
men16. Also, male
fragility fractures cause the same morbidity, and hip fractures are associated
with double the one-year mortality rate. While the best way to diagnose
osteoporosis in men is somewhat unclear, as there is a lack of consensus on
how the disease should be defined, when treatment is indicated,
bisphosphonates are the drugs of choice. Daily treatment with 10 mg of
alendronate produced positive effects on bone mineral density, serum markers
of bone turnover, and fracture incidence in two large clinical
trials17,18.
It has become clear that all patients with early-stage breast cancer (i.e.,
without evidence of skeletal metastases) are susceptible to the development of
osteoporosis. This at-risk population includes not only postmenopausal women
receiving aromatase inhibitors (which are known to accelerate bone loss) for
estrogen-receptor-positive disease but also premenopausal women who undergo
chemotherapy-associated premature menopause from ovarian suppression resulting
in bone loss equivalent to that following surgical oophorectomy. Therefore, it
is possible that, even in the absence of bone metastases, such patients might
benefit from bisphosphonate therapy to preserve bone mineral density. A strong
body of evidence suggests the benefits of early detection with subsequent
intervention guided by monitoring of bone mineral density, with use of the
same criteria employed for otherwise healthy patients. Glucocorticoids are
used for the treatment of many chronic diseases, including renal, hepatic,
rheumatologic, and pulmonary disorders, as well as an adjuvant to suppressive
therapy during organ
transplantation19,20.
Osteoporosis occurs in 30% to 50% of patients receiving long-term
glucocorticoid therapy ( 7.5 mg/day of prednisone for more than one year).
Fracture incidence is estimated to be 1.3 to 2.6 times higher in patients who
are receiving glucocorticoids than in those who are not. Bisphosphonates are
indicated for the treatment of glucocorticoid-induced osteoporosis, and
risedronate and alendronate have been approved by the FDA for this purpose.
Two randomized trials have demonstrated the efficacy of risedronate therapy,
with a 70% reduction in the rate of vertebral fractures compared with that
following use of a
placebo21,22.
The combined results of two other randomized trials demonstrated an increased
bone mineral density and a decrease in vertebral fractures in patients
receiving treatment with alendronate compared with those receiving a
placebo23. Because
most bone loss occurs in the first six months of glucocorticoid use, strong
consideration should be given to an osteoporosis prevention plan that
incorporates bisphosphonate therapy during the early phases of treatment.
Paget Disease
Paget disease of bone, or osteitis deformans, is characterized by localized
accelerated bone resorption followed by deposition of dense chaotic and thus
ineffectively mineralized bone matrix. It is estimated to occur in 2% to 3% of
the United States population over sixty years
old24. The etiology
of Paget disease is largely unknown, although decades of research have
revealed a possible genetic
component25,26.
Viral transmission has also been implicated in genetically susceptible
individuals27,28.
Symptomatic individuals experience a plethora of symptoms including bone pain,
arthritic pain, headache, and neurological symptoms. Indications for treatment
include those symptoms and the need for elective surgical prophylaxis to
decrease perioperative blood loss in this hypervascular condition.
In the United States, physicians can choose among calcitonin and several
bisphosphonates, including oral etidronate, alendronate, tiludronate, and
risedronate and intravenous pamidronate, for the treatment of Paget disease.
The most potent of these, pamidronate, alendronate, and risedronate, have
achieved sustained remission and normalization of serum alkaline phosphatase
levels in several large clinical trials. Intravenous pamidronate offers the
opportunity to titrate the dose to individuals on the basis of the disease
severity. The optimal regimen of pamidronate remains controversial. Patients
with mild disease may have normalization of the alkaline phosphatase level
after a single 60-mg infusion over three to four hours, whereas patients with
moderate-to-severe disease may require weekly or biweekly 60-mg infusions with
cumulative doses of up to >400
mg29. The
recommended regimen of oral alendronate is 40 mg daily for six months followed
by reevaluation of clinical indices. With use of this dosing scheme, >60%
of patients had normalization of serum alkaline phosphate
levels30. Similar
observations have been reported with the use of risedronate and
tiludronate31,32.
Metastatic Disease
More than 400,000 patients are diagnosed with bone metastases yearly in the
United States alone. Skeletal complications of metastatic disease include
hypercalcemia of malignancy, bone pain, pathologic fracture, and spinal cord
compression. Osseous metastasis is probably the most symptomatic metastatic
disease, as there is a tremendous impact on quality of life, mobility, and
independence. Bone metastases eventually develop in >80% of patients with
carcinoma of the breast, prostate, or kidney. The invasion of malignant cells
into the bone microenvironment causes a breakdown in the normal, tightly
controlled bone-remodeling process, leading to an un-coupling of cellular
function and an excess of osteoclastic over osteoblastic activity. This
disruption of bone homeostasis leads to osteolysis, skeletal destruction, and
a risk of pathologic
fracture33.
Bisphosphonates have been incorporated as part of the management strategy
for almost all cancers that exhibit skeletal metastases. The effects of
bisphosphonates in patients with cancer are multifold: not only do
bisphosphonates inhibit osteoclastic function, but they reduce the local
release of factors that stimulate tumor growth and hence even potentially
extend overall
survival33. In
fact, there is a growing body of evidence that bisphosphonates possess direct
antitumor activity against a variety of cancers as well as act synergistically
when combined with other anticancer
agents34,35.
It is unclear and probably unlikely that all cancers mediate osteolysis by the
same mechanisms. For example, the molecules responsible for the metastatic
potential of multiple myeloma may be different from those implicated in
metastases of carcinomas. These different molecular pathways may account for
the variable efficacy of a given drug when used for different tumor types.
Hypercalcemia
Hypercalcemia of malignancy is the most common life-threatening metabolic
complication of advanced cancer, affecting up to 20% of patients, although the
incidence varies considerably according to the cancer subtype. It is most
frequently observed in patients with multiple myeloma and those with carcinoma
of the lung, breast, or kidney, and it is mediated by soluble factors such as
parathyroid-related hormone-related peptide (PTHrP) and cytokines secreted by
tumor cells and the immune system. Bisphosphonates are the most effective
therapy for hypercalcemia of malignancy. The most commonly used drugs are
pamidronate and zoledronic acid. Two identical, concurrent, parallel,
multicenter, randomized trials were performed to compare the efficacy and
safety of pamidronate (90 mg infused over two hours) and zoledronic acid (4 or
8 mg infused over five minutes) for treating this
disorder36. The
primary end points were a complete response by the tenth day and the duration
of the response. Both doses of zoledronic acid were superior to pamidronate
with respect to both clinical end points. In the group of 287 patients, 87% of
those who had received 8 mg of zoledronate and 70% of those who had received
pamidronate had a complete response (p = 0.002). Safety profiles were
equivalent for all groups, although the higher dose of zoledronic acid
required lengthening of the infusion time to fifteen minutes secondary to
renal dysfunction. Although pamidronate has a lengthy track record in this
clinical setting, it is likely that zoledronic acid will replace it as the
first-line therapy for the treatment of hypercalcemia of malignancy given that
it is more effective and has a more convenient dosing schedule.
Pain and Pathologic Fracture
The role of bisphosphonates in treating painful bone metastases and
preventing pathologic fracture has been extensively investigated for many
cancers. As it is not practical to present the results of all clinical trials
of the use of bisphosphonates for metastatic cancer, breast cancer, which is
the largest source of symptomatic metastases and has probably been the most
extensively investigated in clinical trials, will be highlighted. While the
data are specific for patients with breast cancer, some of the principles can
be extrapolated to any patient with symptomatic or potentially symptomatic
bone metastases.
The American Society of Clinical Oncology publishes evidence-based clinical
practice guidelines for a variety of cancer treatments derived from up-to-date
reviews of published data, meeting abstracts, and clinical trials and
subsequent recommendations by an expert panel based on these reviews. What
follows are their guidelines on the role of bisphosphonates in women with
breast cancer37.
These guidelines can be divided into three clinical scenarios: imaging
evidence of bone metastases, evidence of extraskeletal metastases without bone
metastases, and adjuvant systemic therapy.
The recommended treatment for patients with evidence of lytic disease on
plain radiographs consists of 90 mg of pamidronate delivered intravenously
over two hours or 4 mg of zoledronic acid delivered over fifteen minutes every
three to four weeks. There is insufficient evidence to support one
bisphosphonate over another. It is considered reasonable to begin
administering bisphosphonates to women who have an abnormal bone scan and a
computed tomography or magnetic resonance imaging scan showing bone
destruction but normal findings on plain radiographs. Bisphosphonates are not
recommended for women with an abnormal bone scan but no evidence of bone
destruction on plain radiographs, computed tomography scans, or magnetic
resonance imaging. When bisphosphonates are administered according to the
recommended infusion doses, times, and intervals, the risk of renal
dysfunction is low and if renal dysfunction does occur it is usually
reversible if it is detected early. Biochemical markers of bone resorption
have not proved to be as reliable as radiographic evidence for monitoring
clinical response and adjusting therapy. Once therapy is initiated, it is
recommended that treatment continue until there is a substantial decline in
the patient's performance status. There is no evidence to support the use of
bisphosphonates alone as a replacement for analgesics or radiation in the
setting of bone pain, or even as an adjuvant to these therapies in a patient
with refractory pain.
Starting bisphosphonates without evidence of bone metastases in a patient
with other, extraskeletal metastases for the purpose of preventing future
skeletal events is not recommended. This scenario will likely be the focus of
future clinical trials.
The data regarding adjuvant use of bisphosphonates to prevent osseous
disease in patients with early breast cancer is evolving and inconsistent. The
current recommendations do not support the routine use of bisphosphonates at
any stage of nonosseous disease despite the high risk of future bone
metastases. Most recently, the results of three phase-III trials of oral
clodronate (not approved by the FDA) as adjuvant therapy for patients with
either lymph-node-positive disease or positive immunocytochemical evidence
(bone marrow aspirate positive for tumor-associated glycoprotein-12) were
reported. Two of these trials yielded favorable results, with a decrease in
skeletal and nonskeletal metastases as well as improvement in disease-free and
overall survival38.
In the third trial, clodronate had a negative impact on disease progression
and the development of skeletal metastases.
While the above guidelines are specific for patients with breast cancer,
bisphosphonate therapy has the potential to have a beneficial effect as a
treatment for virtually every cancer that is known to metastasize to bone, and
most patients with bone metastases, regardless of the carcinoma subtype, are
treated with bisphosphonates. Clinical trials have shown outcomes favoring the
use of bisphosphonates for patients with multiple myeloma, renal cancer,
prostate cancer, and thyroid
cancer39,40.
Although the advantage of bisphosphonates with regard to increasing bone
mineral density, reducing fracture risk, and alleviating pain varies among
different tumors, their beneficial role is clear and will become better
defined as more data become available.
Arthroplasty
As the population ages and more total joint replacements are performed,
complications related to loosening and periprosthetic fracture are on the
rise. The use of bisphosphonate therapy in an effort to sustain and improve
the clinical survival of total joint implants has thus generated great
interest. Mechanisms causing undesired bone loss following total joint
arthroplasty include wear-debris-induced osteolysis, stress-shielding,
immobilization, and operative trauma, with the first two mechanisms being the
most important. It has been well established that the macrophages that absorb
small particles of wear debris cytokinetically signal osteoclasts to resorb
bone41. The
resultant osteolytic defect has the potential to compromise the surrounding
host bone, leading to a variety of problems requiring surgical intervention.
The surrounding bone's ability to adjust to the altered mechanical demands
(so-called stress-shielding) leads to additional undesired bone loss.
Bisphosphonates have been preliminarily shown to intervene in these processes,
although the clinical outcomes of such intervention have not been clearly
defined. Various routes of administration, including intravenous, oral, and
local, have been explored. Bisphosphonates have not been approved by the FDA
for the purpose of decreasing osteolytic-associated complications of
arthroplasty.
Investigations of both animals and humans have demonstrated an increase in
bone mineral density and a reduction in bone loss in the acute postoperative
period following total hip and total knee arthroplasty. At least two
randomized trials have shown that oral alendronate (10 mg) increases bone
mineral density in the distal part of the femur and proximal part of the tibia
for up to one year following total knee arthroplasty compared with that
measured in the immediate preoperative
period42,43.
Patients receiving a placebo actually had a decrease in bone mineral density
at the same anatomic sites. In a prospective, randomized controlled trial,
Wilkinson et al. reported a significant reduction in bone loss in patients who
had received a single dose of intravenous pamidronate (90 mg) on the fifth day
following total hip arthroplasty compared with patients who had received a
placebo44. The
pamidronate group had a significant increase in bone mineral density, as
measured with dual-energy x-ray absorptiometry, in the proximal part of the
femur (p = 0.001) and pelvis (p = 0.01) as well as a reduction of serum and
urine biochemical markers for bone turnover, including bone-specific alkaline
phosphatase, osteocalcin, and the N-terminal propeptide of type-I
collagen45. There
were no adverse effects on hip function or self-assessed health.
Interestingly, similar amounts of heterotopic ossification were observed in
the two treatment groups, supporting the notion that the aminobisphosphonates
have great efficacy in inhibiting bone resorption without interfering with
bone formation.
The data from the trial reported by Wilkinson et
al.44 are
compelling enough to warrant a longer study to determine the effectiveness of
bisphosphonates in preventing late complications associated with loosening, as
the half-life of bisphosphonates is quite long. The use of alendronate has
also been shown to effectively inhibit wear-debris-induced osteolysis in a
canine hip arthroplasty
model46. However,
at this time, there are insufficient clinical data to support the use of
bisphosphonates to prevent the progression of periprosthetic osteolysis once
it has been identified.
While a desired effect of bisphosphonates might be seen in the above
scenarios, an undesired effect is a concern in patients being treated with
bisphosphonate therapy for osteoporosis who may be candidates for hip
replacement without cement. Because bone formation and remodeling are
necessary to establish the initial fixation of uncemented implants and as the
remodeling process is thought to be initiated by and coupled to osteoclasts,
it is prudent to consider the influence of these drugs in this setting. A
number of well-designed animal models have been used to investigate the
consequences of alendronate administration on host-bone integration with
surfaces commonly employed in cementless joint
arthroplasty47. The
data from the animal studies have consistently shown no substantial
discernible effect on radiographic or histologic findings concerning the
initial fixation of these implants. These observations ultimately need to be
confirmed in a human model.
Pediatric Conditions
Use in skeletally immature individuals is perhaps the most controversial
aspect of bisphosphonate treatment. Historically, case reports of
bisphosphonate therapy in children reflected sporadic and limited
experience48,49.
We are aware of only one randomized controlled trial of bisphosphonate use in
children, which involved treatment of osteopenia in patients with quadriplegic
cerebral palsy who could not
walk50. In that
study, Henderson et al. demonstrated that pamidronate improved bone mineral
density, without any symptomatic adverse effects. The off-label use of
bisphosphonates to treat osteolytic and osteoporotic bone conditions in
children has gathered a fair amount of momentum in recent years as a result of
the positive early outcomes. The controversy involves the possibility of
long-term detrimental effects on skeletal development and function, as it has
been suggested that prolonged bisphosphonate administration is associated with
so-called brittle
bones51. This is
particularly troubling given the prolonged half-life of these drugs in bone.
Intravenous administration of pamidronate in children has been shown to cause
substantial increases in vertebral density and elevation of
Z-scores52. These
scores continue to increase and do not plateau until two to three years after
infusion. The resulting stiffness of the treated bone can exceed that of
normal bone, lowering its resistance to bending and subsequent fracture. Whyte
et al. reported the development of bisphosphonate-induced
"osteopetrosis" in a boy who had received 60 mg of pamidronate
every three weeks over a 2.5-year period for treatment of a disorder of bone
metabolism of uncertain
etiology53. This
report highlighted the lack of firm end points of therapy for children and the
need to monitor therapeutic status, perhaps on the basis of biochemical
markers of bone turnover. To our knowledge, no evidence of decreased linear
growth has been reported. In addition, the drug's potential teratogenicity,
later in life, after it has mobilized from the bone of adolescent girls is
largely unknown, although no congenital abnormalities have been reported in
the children of the few patients who have received alendronate and
subsequently given birth. Studies of animals suggest that bisphosphonates
cross the placenta and have similar expected pharmacological effects on both
the mother and the
fetus54.
In general, bisphosphonates should be used with caution in children. While
the described reservations do not preclude a role for bisphosphonates in the
treatment of pediatric bone disorders, in the absence of large controlled
trials the decision to use bisphosphonate therapy in children requires careful
consideration, with weighing of the expected benefits against the risks, and
treatment should be administered under the guidance of a clinician who has
experience in caring for children with bone disorders. It is imperative to
develop responsible guidelines for the use of bisphosphonates in pediatric
clinical practice.
Osteogenesis Imperfecta
Severe osteogenesis imperfecta is a disorder that principally affects
type-I collagen and is characterized by osteopenia, frequent fractures,
progressive deformity, loss of mobility, and chronic bone pain. Four discrete
types (I through IV) are commonly distinguished on the basis of clinical and
genetic features that vary in the degree of severity. Historically, there was
no accepted medical treatment for the condition other than pain relief and
surgical correction of deformities.
The medical literature is now replete with case series touting the
remarkable success of treating osteogenesis imperfecta with
bisphosphonates55.
As a result, bisphosphonates are now widely used to treat children,
adolescents, and adults with osteogenesis imperfecta. Almost all
investigations have involved the use of intravenous pamidronate, with doses
ranging from 0.5 to 1.5 mg/kg. The drug was usually administered over three
consecutive days every three to four months. The outcomes are almost
universal: increased bone mineral density, decreased Z-scores, decreased
fracture rates, decreased pain, improved walking, decreased levels of urinary
biochemical markers of bone turnover, and increased cortical thickness as seen
on plain radiographs. Histologically, these changes are reflected in increased
cortical width and cancellous volume due to higher trabecular numbers as
opposed to increased trabecular thickness. Such investigations have included
patients ranging in age from less than three years old to adulthood, and the
results have been consistent regardless of age. While historical controls were
used in all studies, all data strongly indicate that the observed changes
reflect the drug effect rather than an evolution in the natural history of the
disease.
Munns et al. retrospectively reviewed the effects of pamidronate on
fracture and osteotomy-site healing in patients with osteogenesis
imperfecta56. They
found that pamidronate had little effect on fracture-healing, but healing was
delayed following osteotomies used for extremity realignment. Older age and
tibial location were independent predictors of delayed healing, with odds
ratios of 1.25 and 3.5, respectively. Although pamidronate does not alter the
genetic defect underlying osteogenesis imperfecta and therefore is not
curative, it is a promising modality for symptomatic relief in patients with
an otherwise debilitating disease. The optimal therapeutic dose and schedule
remain unclear. Other bisphosphonates are currently under clinical
investigation to compare their effects with those of pamidronate.
Fibrous Dysplasia
Fibrous dysplasia of bone is characterized by the production of fibrous
tissue and woven bone at sites where normal bone should develop. The abnormal
bone leaves the skeleton weak and prone to fractures. The fundamental defect
is somatic mutation in the gene coding for the alpha subunit of Gs,
the G protein that stimulates cAMP formation. Overproduction of cAMP in turn
causes overexpression of c-fos, which plays an important role in regulating
the interplay of osteoblastic and osteoclastic proliferation and
differentiation. The resulting excessive osteoclastic activity is thought to
be a potential therapeutic target, and bisphosphonates have been investigated
in this regard.
Bisphosphonate therapy for the treatment of fibrous dysplasia has been
examined in several clinical
series57-62.
Intravenous pamidronate was administered in all of those studies, with the
exception of the one by Lane et
al.60, who combined
pamidronate therapy, and then later replaced it, with oral alendronate.
Bisphosphonates universally improved pain analogue scores and N-telopeptide
values. Cortical thickening and progressive ossification were seen on
radiographs of skeletally mature patients. Results in children were less
consistent, with most patients lacking evidence of radiographic healing. While
the early data are hardly definitive, they are encouraging for a disease for
which there have been few gains in treatment options.
Legg-Calvé-Perthes Disease
Legg-Calvé-Perthes disease is a childhood form of osteonecrosis of
the femoral head with an incidence of 8.5 to twenty-one per 100,000 children
per year63. The
most serious sequela of this condition is femoral head deformity leading to
premature degenerative arthritis in early adult life. Because osteoclastic
resorption of necrotic subchondral bone may lead to mechanical weakening of
the femoral head, resulting in collapse, a down-regulation of osteoclastic
activity may attenuate or prevent the progression of this disease. Using a
model of atraumatic osteonecrosis induced in young rats, Little et al. found
preservation of femoral head architecture six weeks after treatment with
zoledronic acid64.
A more recent study of pigs treated with ibandronate demonstrated similar
findings, with preservation of the femoral head epiphyseal quotient (height
divided by diameter) in animals treated with prophylactic and moderately high
doses of the
drug63. While we
are not aware of any clinical data regarding the use of bisphosphonates in
preventing or slowing the progression of this disease, these results are very
encouraging and follow-up studies are currently in progress.
Fracture-Healing
Since osteoclasts are essential to the normal remodeling activities in bone
and are involved in bone growth, development, and repair, it is important to
recognize situations in which the use of a bisphosphonate may inhibit or
impair a normal physiological process. One of the most commonly asked
questions is whether bisphosphonates affect fracture-healing. As it is well
known that bone formation and resorption are coupled through molecular and
metabolic
pathways65,66
and as it is also known that the ability of newly formed fracture callus to be
remodeled into mechanically competent lamellar bone is
osteoclast-mediated67,
several investigators have examined the role of bisphosphonates during
fracture-healing. An early study on the effects of ethane-1-hydroxy-1,
1-diphosphonate (EHDP), a so-called first-generation bisphosphonate that
inhibits mineralization at high doses, showed dose-dependent and reversible
inhibition of fracture-healing in mature beagle
dogs68. More recent
studies of more potent, less toxic bisphosphonates have shown different
results. An investigation in which mature beagle dogs were treated with
therapeutic doses of alendronate nine weeks preceding a radial osteotomy,
sixteen weeks after the osteotomy, or continuously from nine weeks to sixteen
weeks after the osteotomy showed no adverse effects on fracture union,
strength, or callus mineralization. However, dogs treated with alendronate
during the healing period were found to have a delay in callus remodeling
compared with the remodeling seen in dogs treated with a
placebo69. More
recent investigations in which incadronate was used showed similar findings,
with high, continuously administered doses delaying the process of
fracture-healing but not impairing the ultimate recovery of mechanical
integrity of the
callus70,71.
Despite the large number of patients treated with bisphosphonates, the
effects of these drugs on fracture-healing have not been investigated in
humans and thus are not known. One prospective clinical trial was performed to
examine bone mineral density in the fracture callus of thirty-two
postmenopausal women with a distal radial fracture treated with cast
immobilization72.
At two months after the fracture, patients treated with bisphosphonates had a
20% increase in bone mineral density at the fracture site compared with that
in a placebo group, but this magnitude of difference diminished with time.
There was no difference in pain or function between the two groups. On the
basis of the evidence available from preclinical investigations, it may be
reasonable to suggest that, at doses comparable with those used in the
treatment of osteoporosis, administration of a bisphosphonate in the presence
of a fracture will not inhibit healing, although the remodeling of the callus
may be mildly delayed. Guidelines for patients receiving larger doses, such as
those used to treat Paget disease or metastatic bone disease, are more
difficult to extrapolate.
|
Overview
|
|---|
Bisphosphonates are a fascinating and promising therapeutic entity for the
treatment of skeletal disorders characterized by increased osteoclastic
activity. Their journey from laboratory bench to clinical practice is a
success story. While this review summarized only the most common applications
of bisphosphonate therapy, its potential benefits in the treatment of a number
of conditions continue to be revealed almost daily. As our understanding of
the basic mechanisms of action and the clinical translations of those
mechanisms continues to evolve, the benefits and drawbacks of therapy will
become clearer. Certainly, there is a lack of long-term follow-up data, which
are necessary to develop responsible guidelines for therapy.
|
Acknowledgments
|
|---|
The authors did not receive grants or outside funding in support of their
research or preparation of this manuscript. They did not receive payments or
other benefits or a commitment or agreement to provide such benefits from a
commercial entity. No commercial entity paid or directed, or agreed to pay or
direct, any benefits to any research fund, foundation, educational
institution, or other charitable or nonprofit organization with which the
authors are affiliated or associated.
|
References
|
|---|
-
Bisaz S, Jung A, Fleisch H. Uptake by
bone of pyrophosphate, diphosphonates and their technetium derivatives.Clin Sci Mol Med.
1978;54:265
-72.[Medline]
-
Amin D, Cornell SA, Gustafson SK, Needle
SJ, Ullrich JW, Bilder GE, Perrone MH. Bisphosphonates used for the treatment
of bone disorders inhibit squalene synthase and cholesterol biosynthesis.J Lipid Res.
1992;33:1657
-63.[Abstract]
-
Luckman SP, Hughes DE, Coxon FP, Graham
R, Russell G, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the
mevalonate pathway and prevent post-translational prenylation of GTP-binding
proteins, including Ras. J Bone Miner Res.1998; 13:581
-9.[CrossRef][Medline]
-
Zhang D, Udagawa N, Nakamura I, Murakami
H, Saito S, Yamasaki K, Shibasaki Y, Morii N, Narumiya S, Takahashi N, Suda T.
The small GTP-binding protein, rho p21, is involved in bone resorption by
regulating cytoskeletal organization in osteoclasts. J Cell
Sci. 1995;108:2285
-92.[Abstract]
-
Fisher JE, Rogers MJ, Halasy JM, Luckman
SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA.
Alendronate mechanism of action: geranylgeraniol, an intermediate in the
mevalonate pathway, prevents inhibition of osteoclast formation, bone
resorption, and kinase activation in vitro. Proc Natl Acad Sci
USA. 1999;96:133
-8.[Abstract/Free Full Text]
-
Vinholes JJ, Purohit OP, Abbey ME,
Eastell R, Coleman RE. Relationships between biochemical and symptomatic
response in a double-blind randomised trial of pamidronate for metastatic bone
disease. Ann Oncol. 1997;8:1243
-50.[Abstract/Free Full Text]
-
Lipton A, Demers L, Curley E, Chinchilli
V, Gaydos L, Hortobagyi G, Theriault R, Clemens D, Costa L, Seaman J, Knight
R. Markers of bone resorption in patients treated with pamidronate. Eur
J Cancer. 1998;34:2021
-6.
-
Kanis JA, Melton LJ 3rd, Christiansen C,
Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner
Res. 1994;9:1137
-41.[Medline]
-
Ott SM, Woodson GC, Huffer WE, Miller
PD, Watts NB. Bone histomorphometric changes after cyclic therapy with
phosphate and etidronate disodium in women with postmenopausal osteoporosis.J Clin Endocrinol Metab.1994; 78:968
-72.[Abstract]
-
Harris ST, Watts NB, Jackson RD, Genant
HK, Wasnich RD, Ross P, Miller PD, Licata AA, Chesnut CH 3rd. Four-year study
of intermittent cyclic etidronate treatment of postmenopausal osteoporosis:
three years of blinded therapy followed by one year of open therapy. Am
J Med. 1993;95:557
-67.[CrossRef][Medline]
-
Storm T, Thamsborg G, Steiniche T,
Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on
bone mass and fracture rate in women with postmenopausal osteoporosis.N Engl J Med.
1990;322:1265
-71.[Abstract]
-
Watts NB, Harris ST, Genant HK, Wasnich
RD, Miller PD, Jackson RD, Licata AA, Ross P, Woodson GC 3rd, Yanover MJ,
Mysiw WJ, Kohse L, Rao MB, Steiger P, Richmond B, Chesnut CH 3rd. Intermittent
cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J
Med. 1990;323:73
-9.[Abstract]
-
Black DM, Cummings SR, Karpf DB, Cauley
JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM,
Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of
alendronate on risk of fracture in women with existing vertebral fractures.
Fracture Intervention Trial Research Group. Lancet.1996; 348:1535
-41.[CrossRef][Medline]
-
Bone HG, Hosking D, Devogelaer JP, Tucci
JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC,
Liberman UA; Alendronate Phase III Osteoporosis Treatment Study Group. Ten
years' experience with alendronate for osteoporosis in postmenopausal women.N Engl J Med.
2004;350:1189
-99.[Abstract/Free Full Text]
-
Rizzoli R, Greenspan SL, Bone G 3rd,
Schnitzer TJ, Watts NB, Adami S, Foldes AJ, Roux C, Levine MA, Uebelhart B,
Santora AC 2nd, Kaur A, Peverly CA, Orloff JJ; Alendronate Once-Weekly Study
Group. Two-year results of once-weekly administration of alendronate 70 mg for
the treatment of postmenopausal osteoporosis. J Bone Miner Res.2002; 17:1988
-96.[CrossRef][Medline]
-
Cooper C, Campion G, Melton LJ 3rd. Hip
fractures in the elderly: a world-wide projection. Osteoporos
Int. 1992;2:285
-9.[CrossRef][Medline]
-
Orwoll E, Ettinger M, Weiss S, Miller P,
Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K,
Lombardi A. Alendronate for the treatment of osteoporosis in men. N
Engl J Med. 2000;343:604
-10.[Abstract/Free Full Text]
-
Ringe JD, Orwoll E, Daifotis A, Lombardi
A. Treatment of male osteoporosis: recent advances with alendronate.Osteoporos Int.
2002;13:195
-9.[CrossRef][Medline]
-
Eggelmeijer F, Papapoulos SE, van
Paassen HC, Dijkmans BA, Breedveld FC. Clinical and biochemical response to
single infusion of pamidronate in patients with active rheumatoid arthritis: a
double blind placebo controlled study. J Rheumatol.1994; 21:2016
-20.[Medline]
-
Eggelmeijer F, Papapoulos SE, van
Paassen HC, Dijkmans BA, Valkema R, Westedt ML, Landman JO, Pauwels EK,
Breedveld FC. Increased bone mass with pamidronate treatment in rheumatoid
arthritis. Results of a three-year randomized, double-blind trial.Arthritis Rheum.
1996;39:396
-402.[Medline]
-
Reid DM, Adami S, Devogelaer JP, Chines
AA. Risedronate increases bone density and reduces vertebral fracture risk
within one year in men on corticosteroid therapy. Calcif Tissue
Int. 2001;69:242
-7.[CrossRef][Medline]
-
Wallach S, Cohen S, Reid DM, Hughes RA,
Hosking DJ, Laan RF, Doherty SM, Maricic M, Rosen C, Brown J, Barton I, Chines
AA. Effects of risedronate treatment on bone density and vertebral fracture in
patients on corticosteroid therapy. Calcif Tissue Int.2000; 67:277
-85.[CrossRef][Medline]
-
Saag KG, Emkey R, Schnitzer TJ, Brown
JP, Hawkins F, Goemaere S, Thamsborg G, Liberman UA, Delmas PD, Malice MP,
Czachur M, Daifotis AG. Alendronate for the prevention and treatment of
glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis
Intervention Study Group. N Engl J Med.1998; 339:292
-9.[Abstract/Free Full Text]
-
Siris ES. Paget's disease of bone.J Bone Miner Res.
1998;13:1061
-5.[CrossRef][Medline]
-
Morales-Piga AA, Rey-Rey JS,
Corres-Gonzalez J, Garcia-Sagredo JM, Lopez-Abente G. Frequency and
characteristics of familial aggregation of Paget's disease of bone. J
Bone Miner Res. 1995;10:663
-70.[Medline]
-
Siris ES, Ottman R, Flaster E, Kelsey
JL. Familial aggregation of Paget's disease of bone. J Bone Miner
Res. 1991;6:495
-500.[Medline]
-
Rebel A, Malkani K, Basle M, Bregeon C.
Is Paget's disease of bone a viral infection? Calcif Tissue
Res. 1977;22 Suppl:283
-6.
-
Mills BG, Singer FR, Weiner LP, Suffin
SC, Stabile E, Holst P. Evidence for both respiratory syncytial virus and
measles virus antigens in the osteoclasts of patients with Paget's disease of
bone. Clin Orthop Relat Res.1984; 183:303
-11.
-
Siris ES. Perspectives: a practical
guide to the use of pamidronate in the treatment of Paget's disease. J
Bone Miner Res. 1994;9:303
-4.[Medline]
-
Siris E, Weinstein RS, Altman R, Conte
JM, Favus M, Lombardi A, Lyles K, McIlwain H, Murphy WA Jr, Reda C, Rude R,
Seton M, Tiegs R, Thompson D, Tucci JR, Yates AJ, Zimering M. Comparative
study of alendronate versus etidronate for the treatment of Paget's disease of
bone. J Clin Endocrinol Metab.1996; 81:961
-7.[Abstract]
-
Siris ES, Chines AA, Altman RD, Brown
JP, Johnston CC Jr, Lang R, McClung MR, Mallette LE, Miller PD, Ryan WG,
Singer FR, Tucci JR, Eusebio RA, Bekker PJ. Risedronate in the treatment of
Paget's disease of bone: an open label, multicenter study. J Bone Miner
Res. 1998;13:1032
-8.[CrossRef][Medline]
-
McClung MR, Tou CK, Goldstein NH, Picot
C. Tiludronate therapy for Paget's disease of bone. Bone. 1995;17(5
Suppl):493S-6. Erratum in: Bone.1996; 18:292
.[CrossRef]
-
Green JR. Antitumor effects of
bisphosphonates. Cancer.2003; 97(3 Suppl):840
-7.[CrossRef][Medline]
-
Clezardin P. The antitumor potential of
bisphosphonates. Semin Oncol.2002; 29(6 Suppl 21):33
-42.[Medline]
-
Lee MV, Fong EM, Singer FR, Guenette RS.
Bisphosphonate treatment inhibits the growth of prostate cancer cells.Cancer Res.
2001;61:2602
-8.[Abstract/Free Full Text]
-
Major P, Lortholary A, Hon J, Abdi E,
Mills G, Menssen HD, Yunus F, Bell R, Body J, Quebe-Fehling E, Seaman J.
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia
of malignancy: a pooled analysis of two randomized, controlled clinical
trials. J Clin Oncol.2001; 19:558
-67.[Abstract/Free Full Text]
-
Hillner BE, Ingle JN, Berenson JR,
Janjan NA, Albain KS, Lipton A, Yee G, Biermann JS, Chlebowski RT, Pfister DG.
American Society of Clinical Oncology guideline on the role of bisphosphonates
in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert
Panel. J Clin Oncol.2000; 18:1378
-91.[Abstract/Free Full Text]
-
Powles T, Paterson S, Kanis JA,
McCloskey E, Ashley S, Tidy A, Rosenqvist K, Smith I, Ottestad L, Legault S,
Pajunen M, Nevantaus A, Mannisto E, Suovuori A, Atula S, Nevalainen J,
Pylkkanen L. Randomized, placebo-controlled trial of clodronate in patients
with primary operable breast cancer. J Clin Oncol.2002; 20:3219
-24.[Abstract/Free Full Text]
-
Rosen HN, Moses AC, Garber J, Ross DS,
Lee SL, Ferguson L, Chen V, Lee K, Greenspan SL. Randomized trial of
pamidronate in patients with thyroid cancer: bone density is not reduced by
suppressive doses of thyroxine, but is increased by cyclic intravenous
pamidronate. J Clin Endocrinol Metab.1998; 83:2324
-30.[Abstract/Free Full Text]
-
Smith MR, McGovern FJ, Zietman AL,
Fallon MA, Hayden DL, Schoenfeld DA, Kantoff PW, Finkelstein JS. Pamidronate
to prevent bone loss during androgen-deprivation therapy for prostate cancer.N Engl J Med.
2001;345:948
-55.[Abstract/Free Full Text]
-
Kim KJ, Hijikata H, Itoh T, Kumegawa M.
Joint fluid from patients with failed total hip arthroplasty stimulates pit
formation by mouse osteoclasts on dentin slices. J Biomed Mater
Res. 1998;43:234
-40.[CrossRef][Medline]
-
Wang CJ, Wang JW, Weng LH, Hsu CC, Huang
CC, Chen HS. The effect of alendronate on bone mineral density in the distal
part of the femur and proximal part of the tibia after total knee
arthroplasty. J Bone Joint Surg Am.2003; 85:2121
-6.[Abstract/Free Full Text]
-
Soininvaara TA, Jurvelin JS, Miettinen
HJ, Suomalainen OT, Alhava EM, Kroger PJ. Effect of alendronate on
periprosthetic bone loss after total knee arthroplasty: a one-year,
randomized, controlled trial of 19 patients. Calcif Tissue Int.2002; 71:472
-7.[CrossRef][Medline]
-
Wilkinson JM, Stockley I, Peel NF, Hamer
AJ, Elson RA, Barrington NA, Eastell R. Effect of pamidronate in preventing
local bone loss after total hip arthroplasty: a randomized, double-blind,
controlled trial. J Bone Miner Res.2001; 16:556
-64.[CrossRef][Medline]
-
Wilkinson JM, Hamer AJ, Rogers A,
Stockley I, Eastell R. Bone mineral density and biochemical markers of bone
turnover in aseptic loosening after total hip arthroplasty. J Orthop
Res. 2003;21:691
-6.[CrossRef][Medline]
-
Shanbhag AS, Hasselman CT, Rubash HE.
Inhibition of wear debris mediated osteolysis in a canine total hip
arthroplasty model. Clin Orthop Relat Res.1997; 344:33
-43.
-
Mochida Y, Bauer TW, Akisue T, Brown PR.
Alendronate does not inhibit early bone apposition to hydroxyapatite-coated
total joint implants: a preliminary study. J Bone Joint Surg
Am. 2002;84:226
-35.[Abstract/Free Full Text]
-
Shaw NJ, Boivin CM, Crabtree NJ.
Intravenous pamidronate in juvenile osteoporosis. Arch Dis
Child. 2000;83:143
-5.[Abstract/Free Full Text]
-
Lepore L, Pennesi M, Barbi E, Pozzi R.
Treatment and prevention of osteoporosis in juvenile chronic arthritis with
disodium clodronate. Clin Exp Rheumatol.1991; 9 Suppl 6:33
-5.
-
Henderson RC, Lark RK, Kecskemethy HH,
Miller F, Harcke HT, Bachrach SJ. Bisphosphonates to treat osteopenia in
children with quadriplegic cerebral palsy: a randomized, placebo-controlled
clinical trial. J Pediatr.2002; 141:644
-51.[CrossRef][Medline]
-
Marini JC. Do bisphosphonates make
children's bones better or brittle? N Engl J Med.2003; 349:423
-6.[Free Full Text]
-
Lee YS, Low SL, Lim LA, Loke KY. Cyclic
pamidronate infusion improves bone mineralisation and reduces fracture
incidence in osteogenesis imperfecta. Eur J Pediatr.2001; 160:641
-4.[Medline]
-
Whyte MP, Wenkert D, Clements KL,
McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J
Med. 2003;349:457
-63.[Free Full Text]
-
French AE, Kaplan N, Lishner M, Koren G.
Taking bisphosphonates during pregnancy. Can Fam Physician.2003; 49:1281
-2.[Abstract/Free Full Text]
-
Glorieux FH, Bishop NJ, Plotkin H,
Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in
children with severe osteogenesis imperfecta. N Engl J Med.1998; 339:947
-52.[Abstract/Free Full Text]
-
Munns CF, Rauch F, Zeitlin L, Fassier F,
Glorieux FH. Delayed osteotomy but not fracture healing in pediatric
osteogenesis imperfecta patients receiving pamidronate. J Bone Miner
Res. 2004;19:1779
-86.[CrossRef][Medline]
-
Isaia GC, Lala R, Defilippi C, Matarazzo
P, Andreo M, Roggia C, Priolo G, de Sanctis C. Bone turnover in children and
adolescents with McCune-Albright syndrome treated with pamidronate for bone
fibrous dysplasia. Calcif Tissue Int.2002; 71:121
-8.[CrossRef][Medline]
-
Liens D, Delmas PD, Meunier PJ.
Long-term effects of intravenous pamidronate in fibrous dysplasia of bone.Lancet.
1994;343:953
-4.[CrossRef][Medline]
-
Chapurlat RD, Delmas PD, Liens D,
Meunier PJ. Long-term effects of intravenous pamidronate in fibrous dysplasia
of bone. J Bone Miner Res.1997; 12:1746
-52.[CrossRef][Medline]
-
Lane JM, Khan SN, O'Connor WJ, Nydick M,
Hommen JP, Schneider R, Tomin E, Brand J, Curtin J. Bisphosphonate therapy in
fibrous dysplasia. Clin Orthop Relat Res.2001; 382:6
-12.
-
Plotkin H, Rauch F, Zeitlin L, Munns C,
Travers R, Glorieux FH. Effect of pamidronate treatment in children with
polyostotic fibrous dysplasia of bone. J Clin Endocrinol Metab.2003; 88:4569
-75.[Abstract/Free Full Text]
-
Lala R, Matarazzo P, Bertelloni S, Buzi
F, Rigon F, de Sanctis C. Pamidronate treatment of bone fibrous dysplasia in
nine children with McCune-Albright syndrome. Acta Paediatr.2000; 89:188
-93.[CrossRef][Medline]
-
Kim H, Randall TS, Bian H, Jenkins JR,
Garces A, Bauss F. Ibandronate decreases femoral head deformity following
ischemic necrosis of the capital femoral epiphysis in immature pigs.Trans Orthop Res Soc.2004; 29:151
.
-
Little DG, Peat RA, Mcevoy A, Williams
PR, Smith EJ, Baldock PA. Zoledronic acid treatment results in retention of
femoral head structure after traumatic osteonecrosis in young Wistar rats.J Bone Miner Res.
2003;18:2016
-22.[CrossRef][Medline]
-
Favus MJ, editor. Primer on the
metabolic bone diseases and disorders of mineral metabolism. 5th ed.
Washington, DC: American Society for Bone and Mineral Research;2003
.
-
Teitelbaum SL. Bone resorption by
osteoclasts. Science.2000; 289:1504
-8.[Abstract/Free Full Text]
-
Einhorn TA. The cell and molecular
biology of fracture healing. Clin Orthop Relat Res.1998; 355 Suppl:S7
-21.
-
Lenehan TM, Balligand M, Nunamaker DM,
Wood FE Jr. Effect of EHDP on fracture healing in dogs. J Orthop
Res. 1985;3:499
-507.[CrossRef][Medline]
-
Peter CP, Cook WO, Nunamaker DM, Provost
MT, Seedor JG, Rodan GA. Effect of alendronate on fracture healing and bone
remodeling in dogs. J Orthop Res.1996; 14:74
-9.[CrossRef][Medline]
-
Li J, Mori S, Kaji Y, Mashiba T,
Kawanishi J, Norimatsu H. Effect of bisphosphonate (incadronate) on fracture
healing of long bones in rats. J Bone Miner Res.1999; 14:969
-79.[CrossRef][Medline]
-
Li C, Mori S, Li J, Kaji Y, Akiyama T,
Kawanishi J, Norimatsu H. Long-term effect of incadronate disodium (YM-175) on
fracture healing of femoral shaft in growing rats. J Bone Miner
Res. 2001;16:429
-36.[CrossRef][Medline]
-
Adolphson P, Abbaszadegan H, Boden H,
Salemyr M, Henriques T. Clodronate increases mineralization of callus after
Colles' fracture: a randomized, double-blind, placebo-controlled, prospective
trial in 32 patients. Acta Orthop Scand.2000; 71:195
-200.[CrossRef][Medline]
-
Green JR, Muller K, Jaeggi KA.
Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic
bisphosphonate compound. J Bone Miner Res.1994; 9:745
-51.[Medline]
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F. A. Matsen III, J. Clinton, J. Lynch, A. Bertelsen, and M. L. Richardson
Glenoid Component Failure in Total Shoulder Arthroplasty
J. Bone Joint Surg. Am.,
April 1, 2008;
90(4):
885 - 896.
[Abstract]
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S. R. Majumdar, L. A. Beaupre, C. H. Harley, D. A. Hanley, D. A. Lier, A. G. Juby, W. P. Maksymowych, J. G. Cinats, N. R. Bell, and D. W. Morrish
Use of a Case Manager to Improve Osteoporosis Treatment After Hip Fracture: Results of a Randomized Controlled Trial
Arch Intern Med,
October 22, 2007;
167(19):
2110 - 2115.
[Abstract]
[Full Text]
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M. Ramachandran, K. Ward, R. R. Brown, C. F. Munns, C. T. Cowell, and D. G. Little
Intravenous Bisphosphonate Therapy for Traumatic Osteonecrosis of the Femoral Head in Adolescents
J. Bone Joint Surg. Am.,
August 1, 2007;
89(8):
1727 - 1734.
[Abstract]
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A. Moroni, C. Faldini, A. Hoang-Kim, F. Pegreffi, and S. Giannini
Alendronate Improves Screw Fixation in Osteoporotic Bone
J. Bone Joint Surg. Am.,
January 1, 2007;
89(1):
96 - 101.
[Abstract]
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M. J. Somerman and L. K. McCauley
Bisphosphonates: Sacrificing the Jaw to Save the Skeleton?
IBMS BoneKEy,
September 1, 2006;
3(9):
12 - 18.
[Abstract]
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S. D. Boden, T. A. Einhorn, T. S. Morgan, L. L. Tosi, and J. N. Weinstein
An AOA Critical Issue. The Future of the Orthopaedic Surgeon-Proceduralist or Keeper of the Musculoskeletal System?
J. Bone Joint Surg. Am.,
December 1, 2005;
87(12):
2812 - 2821.
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Letters to the Editor:
Read all Letters to the Editor
- re: FDA approved Bisphosphonates
- John J Carey, et al.
- JBJS Online, 9 Aug 2005
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Abstract
Introduction
