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[Wellness] Article on Fosamax/See Links to other articles onBisphosphonates at the bottom of this page.
Title: Severely Suppressed Bone Turnover: A Potential Complication of Alendronate Therapy -- Odvina et al. 90 (3): 1294 -- Journal of Clinical Endocrinology & Metabolism
  
Journal of Clinical Endocrinology & Metabolism,
doi:10.1210/jc.2004-0952
The
Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3
1294-1301
Copyright © 2005 by The Endocrine Society
Severely Suppressed Bone Turnover: A Potential Complication of Alendronate
Therapy Clarita V. Odvina, Joseph E. Zerwekh, D. Sudhaker Rao, Naim
Maalouf, Frank A. Gottschalk and Charles Y. C. Pak
Center for Mineral Metabolism and Clinical Research (C.V.O., J.E.Z.,
N.M., C.Y.C.P.) and Division of Orthopedic Surgery (F.A.G.), University of Texas
Southwestern Medical Center, Dallas, Texas 75390-8885; and Division of Bone and
Mineral Metabolism (D.S.R.), Henry Ford Hospital, Detroit, Michigan 48202
Address all correspondence and requests for reprints to: Dr.
Clarita V. Odvina, Center for Mineral Metabolism and Clinical Research,
University of Texas Southwestern Medical Center, Dallas, Texas 75390-8885.
E-mail: clarita.odvina{at}utsouthwestern.edu
.
 |
Abstract |
Alendronate,
an inhibitor of bone resorption, is widely used in osteoporosis
treatment. However, concerns have been raised about potential
oversuppression of bone turnover during long-term use. We report on
nine patients who sustained spontaneous nonspinal fractures while on
alendronate therapy, six of whom displayed either delayed or absent
fracture healing for 3 months to 2 yr during therapy.
Histomorphometric analysis of the cancellous bone showed markedly
suppressed bone formation, with reduced or absent osteoblastic
surface in most patients. Osteoclastic surface was low or low-normal
in eight patients, and eroded surface was decreased in four.
Matrix synthesis was markedly diminished, with absence of
double-tetracycline label and absent or reduced single-tetracycline
label in all patients. The same trend was seen in the intracortical
and endocortical surfaces.
Our findings raise the possibility that severe suppression of bone
turnover may develop during long-term alendronate therapy, resulting
in increased susceptibility to, and delayed healing of, nonspinal
fractures. Although coadministration of estrogen or glucocorticoids
appears to be a predisposing factor, this apparent complication can
also occur with monotherapy. Our observations emphasize the need for
increased awareness and monitoring for the potential development of
excessive suppression of bone turnover during long-term alendronate
therapy.
|
Introduction |
ALENDRONATE,
A POTENT inhibitor of bone resorption, is now widely used in the
treatment of osteoporosis. A number of randomized clinical trials
have shown that it significantly increases bone density of spine and
hip and reduces the incidence of fractures in osteoporotic patients
(1, 2, 3, 4).
Although alendronate is generally safe and effective, it carries
the potential risk of oversuppressing bone turnover that can
potentially impair some of the biomechanical properties of bone.
In experimental animals, alendronate has been shown to inhibit
normal repair of microdamage arising from marked suppression of
bone turnover, which, in turn, results in accumulation of microdamage
(5, 6, 7). A 2- to 7-fold
increase in microdamage accumulation after pharmaceutical suppression
of bone remodeling was associated with a 20% reduction in bone
toughness (the ability to sustain deformation without breaking),
without reduction in bone strength (6, 7, 8). However, the clinical significance
of these changes in biomechanical measurements has not yet been
well defined.
In addition to microdamage accumulation, chronic oversuppression
of bone turnover by alendronate may allow secondary mineralization
to continue (9), producing hypermineralized bone that
may be more brittle (10, 11).
The degree of mineralization has been shown to affect the material
properties of bone, with low mineralization levels (as seen in
osteomalacia) causing reduced stiffness and strength, and
hypermineralization likely contributing to reduced fracture toughness
(10, 11).
Ott (12) speculated that chronic alendronate therapy in
humans might impair mechanical strength of bone. This suggestion
was based on the apparent increase in fracture rate with
prolonged therapy (2), though challenged by the
authors of that report (13). Recently, Whyte et
al. (14) described a 12-yr-old boy who, after
3 yr of treatment with iv bisphosphonate (pamidronate), presented
with findings consistent with osteopetrosis, i.e. increased
bone density and impaired remodeling. The authors, however,
acknowledged that the dose of pamidronate given to the patient was
more than four times the amount typically given to children with
osteogenesis imperfecta.
In this report, we describe bone biopsy data from nine patients
with osteoporosis or osteopenia treated with alendronate for
38 yr alone or in combination with estrogen. All patients had
spontaneous nonspinal fractures that developed after 18 yr of
alendronate treatment. Histomorphometric analysis of bone biopsy
samples revealed a marked suppression of bone turnover.
|
Subjects and Methods |
Patients
Nine patients (eight postmenopausal women and one man) on long-term
alendronate treatment were included in this report. Four patients
(patients 14) were from the Henry Ford Hospital in Detroit,
and five (patients 59) were from the University of Texas
Southwestern Medical Center in Dallas. Alendronate was given at
a dose of 10 mg/d or 70 mg/wk for 38 yr along with supplemental
calcium. Eight patients were also given vitamin D, 400800 IU/d,
whereas one patient was maintained on a pharmacological dose of
vitamin D. Relevant clinical data are summarized in Table 1 .
In
patients 14, alendronate was given alone, without estrogen or
glucocorticoid (group A, Table 1 ). Patients 13 were
postmenopausal women without prevalent fractures, in whom alendronate
treatment was started elsewhere because of either osteoporosis or
osteopenia by bone density. Patient 4 was started on alendronate when
he presented with metatarsal stress fractures and was found to have
osteopenia by bone density.
In patients 57 (group B, Table 1), alendronate was
administered with estrogen. Patients 5 and 7 took estrogen
continuously for 12 and 15 yr, respectively, whereas patient 6
received it intermittently for 3 yr. Although none had prevalent
fractures, alendronate was started elsewhere for postmenopausal
osteoporosis (patients 5 and 6) or osteopenia (patient 7) of spine or
hip by bone density.
Patients 8 and 9 were given alendronate for glucocorticoid-induced
osteoporosis (GIO; group C, Table 1). Patient 8 has been taking
glucocorticoid for asthma for 20 yr, and patient 9 for fibromyalgia
for 8 yr, before alendronate was begun. Glucocorticoid was continued
during and after alendronate was stopped in patient 9 and was
tapered and eventually discontinued in patient 8. Patient 9 was
on vitamin D, 50,000 IU thrice a week, for postsurgical
hypoparathyroidism. Both women had fractures of the femoral
shaft and metatarsal bones after minimal trauma before alendronate
treatment.
Nonspinal fractures during alendronate therapy
All nine patients developed atraumatic nonspinal fractures while
on alendronate treatment (Table 1) and while performing normal
daily activities such as walking, standing, or turning around.
Among the seven patients who were not on glucocorticoid (patients
17), atraumatic nonspinal fractures (sacrum, rib, ischium,
pubic rami, femoral shaft) developed after 38 yr of alendronate
treatment. One patient (patient 2) also had a lumbar vertebral
fracture. Among those with GIO, patient 8 developed a separation
of previously formed callus of the fractured femoral shaft 1 yr
after starting alendronate. Patient 9 fractured the right femoral
shaft, at the site of a previous fracture, while walking, after 2 yr
of alendronate treatment.
Because the patients continued taking alendronate after the
fracture(s), we had the opportunity to radiographically assess
fracture healing while still on treatment (Table 1). In six
patients (patients 3 and 57 without glucocorticoid, and
patients 8 and 9 on glucocorticoid), evidence of delayed fracture
healing (lack of adequate callus formation and filling in of
fracture gap) was observed 3 months to 2 yr after fracture occurrence
in the ischium, pubic rami, and femoral shaft. In one (patient
8), delayed healing of the femoral fracture persisted for 2 yr
despite internal fixation and bone graft. In the remaining patients
(patients 1, 2, and 4), fracture healing could not be assessed
because bone biopsy was obtained shortly after the incident
fractures.
Bone biopsy
The decision to perform bone biopsy was based on the unusual
clinical presentation of these patients. First, the fracture
sites (e.g. bilateral femoral shaft, pubic bone, ischium) were
not the typical sites for osteoporotic fractures. Second, a
majority of these patients (patients 17) were fracture-free in
the intervening years before the presentation. Last, six of nine
patients (patients 3 and 59) presented with delayed fracture
healing. After obtaining an informed consent, bone biopsies were
performed while patients were still on alendronate therapy (38 yr)
and about 1 month to 2 yr after incident fractures (Table 1).
A transiliac bone biopsy was obtained using a 7.5-mm diameter
trocar under local anesthesia, following in vivo
double-tetracycline labeling as previously described (15). A 2-10-4-4 labeling regimen with declomycin was
used in Dallas, and a 3-11-3-4 regimen with oxytetracycline was used
for the patients at the Henry Ford Hospital. Specimens were
prestained for 72 h in Villanueva, Osteochrome (Polysciences, Inc.,
Warrington, PA). After dehydration in increasing concentrations of
alcohol, the specimens were embedded in methylmethacrylate and kept
at 37 C until fully polymerized. The embedded biopsy samples were
then sectioned on a Reichert-Jung model E microtome (Cambridge
Instruments, Heidelberg, Germany) at a thickness of 10 ΅m. A
total of six sequential sections were cut from each specimen.
Sections 1, 3, and 5 were mounted directly to slides and were
examined under UV light for tetracycline uptake. Sections 2, 4, and
6 were mounted to slides, deplasticized in xylene, stained with
toluidine blue, and examined for static measurements.
Histomorphometric measurements were made with an Aus Lena microscope
video camera, and an image capture program (Bioquant Bone Morphometry
Program; R & M Biometrics, Nashville, TN). Histomorphometric
measurements and calculations were based on modifications of
previously published methods (16, 17, 18). The bone formation rate (BFR) was
calculated as half of the single-labeled surfaces plus all the
double-labeled surfaces multiplied by mineral apposition rate in
΅m3/΅m2/d (19). When no
double-labeled surfaces were observed, BFR was calculated as half of
the single-labeled surfaces multiplied by 0.3 ΅m/d as previously
described (19). The nomenclature of the measured
and calculated variables is according to the criteria established by
the Committee on Bone Histomorphometry of the American Society for
Bone and Mineral Research (20). Slides, both for
fluorochrome assessment and toluidine blue stained for static
measurements, were analyzed by a single investigator (J.E.Z.) at the
University of Texas Southwestern Medical Center, who was blinded to
the patients identity. For patients in whom no tetracycline double
labels were observed, all three cut sections were examined for the
presence of any tetracycline labeling.
Biochemical measurements and bone densitometry
Laboratory studies were done either on the day of, or shortly
before, bone biopsy. In some patients, not all tests could be
obtained. Serum samples were assayed for calcium, phosphorous,
creatinine, PTH (ELISA kit; Alpco Diagnostics, Windham, NH),
25-hydroxyvitamin D (ELISA, Alpco Diagnostics), bone-specific
alkaline phosphatase (BsAP-Alkphase-B; Quidel, Mountain View,
CA), and osteocalcin (Oc, ELISA; Diagnostic Systems Laboratories,
Webster, TX). Urine was collected in 24-h pools for calcium,
creatinine, N-telopeptide (NTx, Osteomark; Ostex International,
Seattle, WA), and hydroxyproline (OH-pro, Hypro-nosticon; Organon
Teknika Corp., Durham, NC). Spot fasting urine samples were
used for the analysis of NTx and creatinine in patients 14.
Except for serum calcium, phosphorous, and creatinine, the remaining
serum and urine analyses from all patients were performed at
the Mineral Metabolism laboratory in Dallas.
Bone mineral density (BMD) of L2L4 vertebrae, femoral neck, and
distal third of the radius was measured by dual-energy x-ray
absorptiometry (Hologic QDR, Waltham, MA). Selected x-rays and bone
scans were obtained to confirm the presence of fractures and to
determine the status of fracture healing (callus formation and
filling in of fracture gap).
|
Results |
Bone
histomorphometry
Quantitative bone histomorphometric findings of the cancellous
bone are summarized in Table 2. Bone volume was reduced in
all patients, but the most striking finding was severe
depression of bone formation with absence of double-tetracycline
labeling in all nine patients (Fig. 1, A and B). Five of the
nine biopsy specimens revealed occasional single tetracycline labels
(patients 1, 3, 4, 7, and 9). The mean calculated BFR was almost
100-fold lower than in healthy postmenopausal women (Ref. 16 ; see Table 4). In seven patients (patients
27 and 9), cancellous bone surfaces were quiescent with minimal, or
no, identifiable osteoblasts (Fig. 2, A and B). Osteoid
thickness and volume were either normal or reduced, excluding the
possibility of osteomalacia. In addition, there was a trend toward
low bone resorption; osteoclastic surface was low or low-normal,
except in patient 1, who received alendronate without estrogen,
and eroded surface was also reduced in four patients (patients
5, 6, 8, and 9).
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FIG. 1. A,
Photomicrograph under UV light from patient 5, showing absence of
double label (yellow arrow). B, Photomicrograph under UV
light from a normal subject, showing two distinct areas of double
label with tetracycline. The faint inner label is from the first
course of tetracycline (yellow arrow), and the more prominent
outer label is from the course of tetracycline given 10 d later
(orange arrow).
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FIG. 2. A,
Trabecular bone from patient 5, showing absence of surface osteoid,
osteoclasts, and osteoblasts (x160). B, Trabecular bone from a normal
subject, showing abundant osteoid (black arrow), surface
osteoclasts (yellow arrow), and osteoblasts (red
arrow) (x160).
| |
All
patients had decreased intracortical osteoid surface (Table 3A). Osteoblast surface was also reduced except in patient 1.
Five patients (patients 2, 3, 5, 6, and 8) displayed low osteoclast
and eroded surfaces. The same trend was observed for endocortical
surface, with reduced osteoid and osteoblast surfaces in all
patients. Osteoclast surface was low, except in three (patients
2, 4, and 7), and eroded surface was reduced except in four
(patients 14). Dynamic parameters were also markedly reduced
for both intracortical and endocortical bone surfaces, although a
greater reduction was seen at the endocortical bone surfaces (Table
3B).
Table
4 summarizes the mean values for the different
histomorphometric measurement at the three bone compartments
(cancellous, endocortical, and intracortical bone surfaces) compared
with control subjects. Except for the intracortical osteoclast
surface, all the surface and dynamic parameters were significantly
lower in the patients with severe suppression of bone turnover (SSBT)
compared with the published controls. The mean BFR at the three bone
surfaces was 30- to 100-fold lower than the corresponding values in
healthy controls (15).
Laboratory findings at the time of bone biopsy
Serum calcium, phosphorus, creatinine, 25-hydroxyvitamin D, and
PTH were within the reference range (Table 5). Although serum BsAP
ranged widely, serum Oc was either low or at the lower limit of the
reference range. Urinary NTx was low to midnormal in seven and
high-normal in two. Urinary OH-pro was low or low-normal in all five
patients in whom it was measured.
BMD
before and after alendronate therapy
BMD results before the initiation of alendronate therapy, obtained
from outside institutional records, were limited. Among the six
postmenopausal women not on glucocorticoids, four had osteoporosis
and two had osteopenia when alendronate treatment was begun.
Among four patients with osteoporosis, the T-score of at least
one site was still in the osteoporotic range (below 2.5 SD) in two patients (patients 2 and 6) but was in the
osteopenic range (1.0 to more than 2.5 SD) in
two patients (patients 1 and 5) after alendronate treatment (Table
5). Among two with osteopenia, patient 7 was no longer
osteopenic, whereas data for patient 3 were unavailable. In patient
4, T-scores were reported to be in the osteopenic range before
alendronate treatment and remained in the osteopenic range after
treatment. Baseline BMD data were reportedly in the osteopenic range
in the two patients on glucocorticoids, and both had normal BMD
after 34 yr of alendronate treatment.
Fracture healing after stopping alendronate
Therapy was stopped after obtaining a bone biopsy in all patients.
Assessment of fracture healing after discontinuation of treatment
was available in all patients (Table 1). Four patients had delayed
healing. Patients 1, 3, and 4, who were on alendronate alone,
continued to have evidence of nonhealing fractures 12, 8, and 9
months off treatment, respectively, and patient 8 (GIO) continued to
have poor fracture healing 8 months after discontinuation of
alendronate. The remaining four patients had satisfactory fracture
healing. In patient 2, fracture healing was noted at 6 months. In
patient 5, callus formation was noted at 3 months, and a significant
reduction in pain and improvement in mobility occurred after being
off of treatment for 8 months. Patient 6 showed robust callus
formation in the nonhealing pelvic fracture 4 months after stopping
alendronate, with associated improvement in pain. Patient 7 had
evidence of fracture healing at 5 months associated with resolution
of pain. In patient 9 (GIO), femoral shaft fracture showed complete
healing at 3 months. None of the patients developed new fractures
after alendronate was discontinued.
|
Discussion |
We
describe our clinical observations in nine unselected patients
maintained on long-term alendronate therapy for
osteoporosis/osteopenia who developed biopsy-proven SSBT. The
universal presentation of these patients was spontaneous or
atraumatic nonvertebral fracture(s), with delayed or nonhealing of
fractures exhibited by six patients while still on alendronate, and
by four patients after discontinuation of therapy.
All nine patients displayed histomorphometric evidence of SSBT,
similar to the so-called adynamic bone or low turnover described
in patients on chronic maintenance hemodialysis (21).
The bone surfaces were virtually devoid of cellular elements, BFR
was reduced, and matrix formation was severely impaired. In
addition, bone resorption was reduced in most patients. Reduced
rates of bone formation and resorption were also found on both
intracortical and endocortical bone surfaces, indicative of a
generalized involvement. To distinguish from adynamic bone, we refer
to the condition described in this report as SSBT, defined
histologically by reduced osteoblastic and osteoclastic surfaces with
decreased or absent tetracycline labeling.
Clinically, SSBT was characterized by incident nontraumatic
fractures involving the skeletal areas that are rich in cortical
bone, with fractures usually occurring at atypical sites such
as femoral shafts, pubic bone, and ischium. In addition, fracture
healing appeared to be impaired in most patients with SSBT.
Fracture healing was absent or incomplete in six patients, who
continued alendronate therapy for 3 months to 2 yr after the
onset of incident nonspinal fractures. When alendronate was
stopped, fracture healing was still incomplete at 812 months
in four patients.
There is some evidence that alendronate may have contributed to
the histological and clinical picture of SSBT described above.
Suppression of bone turnover, to the degree we encountered here,
by bone histomorphometry is uncommon in untreated postmenopausal
osteoporosis. Coadministration of estrogen has been shown to
exaggerate suppression of bone turnover (22, 23), as was seen in three of our patients. However,
fractures occurred at sites not typically seen in osteoporosis.
Moreover, in some patients, the nonspinal fractures healed poorly
while on alendronate, but healed satisfactorily after stopping
treatment in most patients. Glucocorticoids alone could suppress
osteoblastic bone formation, but sometimes increase osteoclastic
resorption, a feature not seen in our two patients with GIO. Chronic
steroid treatment in a patient with hypoparathyroidism (as in patient
9) may suppress both bone formation and resorption, but we are
unaware of any report showing histomorphometric abnormality with
nonspinal fractures.
Prior reports support the view that SSBT may be pathogenetically
related to chronic bisphosphonate treatment. In experimental
animals, alendronate can impair microdamage repair and compromise
some of the biomechanical properties of bone (5, 6, 7, 8). In
humans, a clinical picture resembling so-called marble bone
disease was described after intermittent iv pamidronate treatment
(14). Based on an apparent increase in fracture rate
after long-term alendronate treatment, a concern has previously been
raised that alendronate might impair bone strength (12). More recently, osteonecrosis of the jaw
requiring surgical removal of affected tissue was reported in 59
patients who had received iv bisphosphonate for malignancy and in
seven patients who took oral bisphosphonate for osteoporosis (24). Although the mechanism was not clearly defined,
low bone remodeling was cited as a possible cause of this condition.
A recent article reported that alendronate given over a period of 10
yr was safe and effective (25). However, the
nonvertebral fracture rate appeared to be numerically the same or
higher (three and four women with nonvertebral facture/100
subject-year for the 10- and 5-mg groups, respectively) during
the late period of alendronate treatment, compared with the
early period (three women with fracture/100 subject-year), despite
a higher bone density. Although this trial was not designed to
test fracture efficacy, apparently no attempt was made to ascertain
whether patients who sustained nonspinal fractures displayed evidence
of impaired fracture healing. Overall, the above reports suggest that
excessive suppression of bone turnover by bisphosphonate may affect
biomechanical competence of bone (26).
Several factors may have contributed to the development of SSBT.
One factor is concurrent diseases: GIO in two patients and
postsurgical hypoparathyroidism in one patient. Both chronic
glucocorticoid treatment (27) and parathyroid
insufficiency (28) are known to reduce bone
turnover and could have exaggerated the effect of alendronate. Thus,
the nonspinal fractures appeared to develop sooner compared with the
patients on alendronate alone (13 yr vs. 68 yr,
respectively).
Another factor may have been concurrent estrogen therapy. Among
six postmenopausal women with osteoporosis/osteopenia, three
were on both estrogen and alendronate, whereas three received
alendronate alone. The onset of spontaneous fractures was earlier
among patients on combination therapy, compared with those on
monotherapy (35 yr vs. 68 yr), and the indices of bone
resorption on bone biopsy tended to be lower in those taking
estrogen. Thus, combination therapy with another antiresorptive
agent, such as estrogen, might cause a more severe suppression
of bone turnover (21, 22) and might
have increased the potential for developing SSBT.
The third factor may be the duration of alendronate therapy. The
skeletal half-life of alendronate is long (29), which
could explain the residual effect on bone density 3 yr after
withdrawal of the drug (30). It is therefore
possible that the suppressive effect of this drug on bone resorption
might be cumulative over time. Four patients in this report were
treated with alendronate without estrogen or glucocorticoid; they
developed spontaneous nonspinal fractures 68 yr after alendronate
therapy, compared with 35 yr for those taking alendronate with
estrogen and 13 yr for patients who also received glucocorticoids.
We acknowledge that this report has some limitations and unanswered
questions. First, the biochemical markers did not reveal as
prominent a suppression of bone turnover as the histomorphometric
indices. Most patients displayed low or low-normal urinary NTx,
OH-proline, and serum Oc, but serum BsAP was inconsistent. The
results are compatible with previous reports showing that alendronate
may exert a more marked suppression (9095%) of bone turnover
at the tissue level (31) compared with only a 50%
reduction from baseline in biochemical markers (32, 33). The discordance between
the histomorphometric and biochemical markers of bone turnover could
be related to the variable degree of suppression at different
skeletal sites. Although bone histomorphometry reflects local bone
turnover, the changes in biochemical markers are more reflective of
changes in the whole skeleton. Another possible explanation is the
effect of fractures on bone turnover. Development of fractures has
been shown to significantly increase bone turnover markers (34). Last, the less impressive or inconsistent
changes in biochemical markers of bone turnover may have been
due to inherent analytical and biological variability of the
assays. The key issue to consider is that the quantitative
histomorphometric analysis, upon which we based the bone turnover
state in the diagnosis of SSBT, is generally regarded as the gold
standard for the assessment of bone turnover.
Second, the presentation of patient 1 appears to be somewhat
different than in others. Serum BsAP and urinary NTx were higher
than in others, and osteoclastic and osteoblastic surfaces did
not differ from the control group on the cancellous and intracortical
bone surfaces. However, the patient shared many of the features
of the other eight patients, both clinically and objectively,
with BFR being markedly decreased on the cancellous and endocortical
bone surfaces. It is possible that this case represents one end
of the spectrum of varying degrees of bone turnover suppression
manifested by SSBT.
Third, three of seven patients without GIO had the unusual occurrence
of femoral shaft fractures. We offer no explanation for this
finding except to note that the reduction in elastic modulus
reported to occur during bisphosphonate treatment was more marked
in cortical than in trabecular bone (35).
An important limitation of this report is the lack of a control
group. Published randomized trials with alendronate showed that
some patients developed nontraumatic appendicular fractures
while receiving either alendronate or placebo (1, 2, 3). Thus, although arguments were
presented earlier linking SSBT to bisphosphonate therapy, a
definitive causal relationship cannot be made. It is also possible
that the development of SSBT in the cases described in this report
represents an atypical response to alendronate therapy. However, most
of our patients demonstrated the expected treatment outcomes, at
least in the first few years of therapy, such as a satisfactory rise
in BMD. The absence of SSBT despite a substantial suppression of bone
turnover in a previous bone histomorphometric study (31) might be a reflection of a relatively short
duration of alendronate therapy of 23 yr. In our patients, nonspinal
fractures did not develop during the first 36 yr of treatment among
those maintained on alendronate alone or with estrogen. Except for
the two patients with GIO, we do not believe that there was an
underlying condition that predisposed to the development of SSBT.
Seven patients on alendronate alone or with estrogen did not have
prevalent fractures. Vitamin D deficiency and osteomalacia were
excluded as potential reasons for poor fracture healing.
Finally, we cannot infer from our observations whether SSBT is
unique to alendronate or can also develop with other bisphosphonates.
That all nine patients with SSBT described here took alendronate
may simply reflect the longer availability and wider usage of
this bisphosphonate.
In conclusion, our clinical experience suggests that alendronate
can potentially cause SSBT, resulting in increased susceptibility
to nonspinal fractures that heal poorly. This complication appears
to occur earlier when alendronate is coadministered with either
glucocorticoids or estrogen. However, it can also develop after
treatment with alendronate alone if the treatment is prolonged.
Our observation does not diminish the important role of alendronate
in the management of osteoporosis. Rather, it emphasizes the
need for awareness of this potential complication during therapy.
Although biochemical markers of bone turnover appear to be of
limited value, the onset of spontaneous nonspinal fractures,
particularly of femoral shaft on alendronate treatment, should
raise the level of suspicion for this complication. Additional
studies are needed to determine how long bisphosphonates can
safely be given.
|
Footnotes |
This work was supported by United States Public Health
Service Grant M01-RR00633 and by discretionary funds of the Center
for Mineral Metabolism and Clinical Research.
This study was presented, in part, at the 25th
Annual Meeting of The American Society for Bone and Mineral Research,
Minneapolis, MN, September 1923, 2003.
None of the authors have any known conflict of
interest in the conduct of this study.
First Published Online December 14,
2004
Abbreviations: BFR, Bone formation rate; BMD,
bone mineral density; BsAP, bone-specific alkaline phosphatase; GIO,
glucocorticoid-induced osteoporosis; NTx, N-telopeptide; SSBT, severe
suppression of bone turnover.
Received May 19, 2004.
Accepted December 1, 2004.
|
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Abstract
Introduction
