The majority of our patients with osteonecrosis of the femoral head
initially present with Steinberg stage-II or III
osteonecrosis18
(see Appendix). These are also the stages in which the treatment strategies
are most varied, so we focused on this subgroup. Inclusion criteria for this
study consisted of nontraumatic osteonecrosis of one or both femoral heads,
Steinberg stage-II or III osteonecrosis, a necrotic area of >30% (a class-C
lesion)19, and no
previous treatment of the femoral head. In patients in whom only one femoral
head met the inclusion criteria, the status of the contralateral side (normal,
collapsed, previous treatment with a hip arthroplasty, etc.) was noted.
Specific diagnoses, if any, and known risk factors associated with
osteonecrosis were noted, along with all medications taken.
This study was approved by our institutional human experiment and ethics
committee. All patients consented to participate in this study. Patients were
informed regarding other treatment options and their possible outcomes. They
were allowed to choose these treatments at the beginning of or during the
study. Because of national health insurance reimbursement regulations and the
lack of a suitable placebo, the patients were not blinded with regard to their
treatment group.
From June through October 2002, forty patients were enrolled and randomly
assigned to the alendronate group or the control group. The study period
ranged from twenty-four to twenty-eight months. The alendronate group
consisted of fifteen men (twenty-three hips) and five women (six hips) with a
mean age of 42.6 years (range, twenty-two to sixty-five years). Seven of them
had a history of glucocorticosteroid intake: one used it for the treatment of
systemic lupus erythematosus; one, for nephrotic syndrome; and the others, for
allergic conditions. The other thirteen patients reported no history of taking
a steroid medication or having a disease related to osteonecrosis. The control
group consisted of fifteen men (eighteen hips) and five women (seven hips)
with a mean age of 42.4 years (range, twenty to sixty-four years). Six of them
had a history of glucocorticosteroid intake: two took it for the treatment of
systemic lupus erythematosus and four used it because of allergic conditions.
The other fourteen patients had no known diseases and had not taken
medications that were related to osteonecrosis. The two groups had similar
demographics with regard to etiology, known risk factors, and other
medications. The initial evaluation included anteroposterior radiographs of
the pelvis with the hips in neutral position and in a position of abduction
and external rotation (the so-called frog-leg view), magnetic resonance
imaging of the hips, and a clinical evaluation with use of the Harris hip
score. All patients were given nonsteroidal anti-inflammatory agents to take
as needed. Daily activities were not restricted. Weight-bearing was not
specifically forbidden (since this restriction is impossible to enforce in
patients with bilateral involvement), but it was usually avoided by the
patient because of pain.
Patients in the alendronate group took 70 mg of Fosamax (alendronate;
Merck, Whitehouse Station, New Jersey) orally every week for twenty-five
weeks, while the patients in the control group were not given this medication
or a placebo. This dosage regimen was chosen because it is the one currently
recommended for the treatment of osteoporosis. The patients were followed
radiographically every ten weeks. All radiographs were read in a blinded
fashion by experienced surgeons not involved in the care of these patients.
The indication for total hip arthroplasty was collapse of the femoral head
(stage IV or V) with intractable pain, and it was applied uniformly throughout
the study. At the time of the last follow-up, or before surgery in those who
went on to femoral head collapse, the patients were evaluated with
radiographs, the Harris hip score, and magnetic resonance imaging. The results
were analyzed with use of the chi-square test. Kaplan-Meier survivorship
analysis was done with total hip arthroplasty as the end point of this study.
The hips that underwent core decompression at the beginning of or during the
study were not excluded in order to retain the integrity of the demographic
data.
Commencement of Study
In the control group, the mean Harris hip score at the beginning of
the study was 67.6 points (range, 26 to 88 points). Thirteen hips were in
stage II, and twelve hips were in stage III. Three hips (all in stage II)
underwent core decompression at the beginning of the study. On the
contralateral side, three hips had previously been treated with a total hip
arthroplasty, four hips were beyond stage IV, one hip was classified as stage
I, and seven were normal.
In the alendronate group, the mean Harris hip score was 65.7 points (range,
34 to 84 points). Seventeen hips were in stage II, and twelve hips were in
stage III. Two hips (both in stage III) underwent core decompression at the
beginning of the study. On the contralateral side, four hips had already had
total hip surgery, three hips were beyond stage IV, one hip was at stage I,
and three hips were normal.
Radiographic Follow-up
In the control group, twenty of the twenty-five hips had an increase in the
Steinberg stage, with nineteen hips having collapsed by the time of the final
follow-up. More specifically, of the thirteen hips at stage II at the
beginning of the study, three remained at stage II, one progressed to stage
III, and nine collapsed. Of the twelve hips at stage III at the beginning of
the study, two remained at stage III, and ten collapsed. On the contralateral
side, one hip in stage I progressed to stage V.
In the alendronate group, four of the twenty-nine hips progressed one stage
or more during the observation period, which was significantly different from
the findings in the control group (chi-square test, p < 0.001). Of those
four hips, two progressed from stage II to stage III and two progressed from
stage III to stage IV (both hips collapsed); these findings were significantly
different from those in the control group (chisquare test, p < 0.001). On
the contralateral side, the three initially normal hips remained normal and
one hip progressed from stage I to stage II. No evidence of reduction in or
resolution of the necrotic area could be detected by either radiographs or
magnetic resonance imaging in any of these osteonecrotic femoral heads.
Surgery and Survival of the Femoral Head
Seventeen of the twenty-five hips in the control group underwent twenty-one
operations (five core decompressions, which were all unsuccessful, and sixteen
total hip replacements during the study period), and three of the twenty-nine
hips in the alendronate group had four operations (three core decompressions,
one of which was unsuccessful, and one total hip replacement); the difference
between the groups was significant (chi-square test, p < 0.001).
Kaplan-Meier survivorship curves, with prosthetic hip replacement as the end
point of survival, were generated for both groups
(Fig. 1). In the control group,
seven hips had a total hip arthroplasty in the first twelve months and that
increased to twelve hips by eighteen months. This contrasts markedly with the
alendronate group, in which only one total hip arthroplasty was done at
twenty-six months after the initiation of treatment.
Harris Hip Score
At the end of the study, the mean Harris hip score (and standard deviation)
was 49.2 ± 9.2 points (range, 28 to 87 points) in the control group and
74.4 ± 7.8 points (range, 39 to 98 points) in the alendronate
group.
Osteonecrosis of the femoral head is a clinical condition with a
very complex
pathophysiology13,20.
Because osteonecrosis commonly affects young adults, the economic consequences
are often more severe for such patients than they are for individuals with
osteoarthritis, who are typically somewhat older. Furthermore, the results
after total hip arthroplasty are not as good in patients with
osteonecrosis21.
Any modality that can delay or prevent disease progression would be clinically
important, particularly in Asian populations, as 40% of the primary total hip
arthroplasties in such populations are performed for the treatment of
osteonecrosis2. It
is unknown why certain ethnic Asians are more susceptible. Liberal steroid use
is probably a factor. Recent genetic linkage studies have identified mutations
in the type-II collagen gene in chromosome 12q13 in a Taiwanese pedigree that
strongly predispose to
osteonecrosis22,23.
Typical findings upon histological examination of a collapsed femoral head
include bone necrosis, osteoclastic resorption, and bone
regeneration24. We
do not yet understand the exact mechanism by which osteoclasts act, but a
likely mechanism is through absorption of the necrotic bone, which then
weakens the structure of the cancellous bone between the viable and the
necrotic areas, resulting in multiple microfractures and gross collapse.
Alendronate, a bisphosphonate compound, inhibits the resorptive action of
mature osteoclasts. It increases apoptosis of osteoclasts and may reduce
apoptosis in osteoblasts and
osteocytes16,
thereby reducing the turnover rate of bone.
In a bone chamber study utilizing a rat model, necrotic bone was not
resorbed in the rats treated with alendronate, whereas it was almost entirely
resorbed in the controls. The authors concluded that systemic alendronate
treatment prevented resorption of necrotic bone during
revascularization25.
The optimum dosage of alendronate is not known. The dosage regimen used in
the present study was chosen because it is the one currently recommended for
the treatment of osteoporosis. Astrand and Aspenberg showed in a rat model
that reduction of instability-induced bone resorption is
dose-dependent26.
This finding may well apply to the treatment of osteonecrosis, and further
study is necessary.
The size of the necrotic area is directly related to the probability of
collapse19,27.
Koo and Kim observed that collapse of Steinberg class-C femoral heads (the
focus of this study) usually occurs within the first eighteen months after
diagnosis27. The
survivorship curves in our study show that alendronate prevented or at least
delayed the collapse of the femoral head and averted the need for a total hip
arthroplasty in the first twenty-four months. However, imaging studies did not
demonstrate a reduction in or resolution of the area of necrotic bone.
The present study is not the only one that has found alendronate to be
effective. In a recently published study of a noncontrolled case series of
sixty patients (100 hips) with osteonecrosis who were treated with
alendronate, Agarwala et al. concluded that early surgical intervention could
be avoided in most
patients28.
The limitations of the present study included the small number of patients
and the follow-up period of two years, which may have been too short to
demonstrate failure. The study was prospective and randomized, but it was only
single-blinded radiographically and was not blinded clinically. We were not
able to determine the effect of confounding risk factors because of the small
numbers. Nevertheless, our preliminary results indicate that alendronate is
highly effective, at least in the short term.
We will continue to follow the patients in this study to see whether the
short-term results are maintained. Furthermore, a multicenter, double-blind,
prospective trial with use of different dosages and durations of alendronate
as well as a combination therapy with electric stimulation, shock wave
treatment, and alendronate is currently under way.
Tables presenting patient details for both groups are available with the
electronic versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?