ORIGINAL ARTICLE
Comparative effects of treatment with etidronate
and alendronate on bone resorption, back pain,
and activities of daily living in elderly women withvertebral fractures
Jun Iwamoto, Tsuyoshi Takeda, Shoichi Ichimura1 and Mitsuyoshi Uzawa2
Department of Sports Medicine, Keio University School of Medicine
1Department of Orthopaedic Surgery, Kyorin University School of Medicine, Tokyo
2Department of Orthopaedic Surgery, Keiyu Orthopaedic Hospital, Gunma, Japan(Received for publication on May 2, 2003)

Abstract. The purpose of the present study was to compare the effects of treatment with etidronate
and alendronate on bone resorption, back pain, and activities of daily living (ADL) in elderly womenwith vertebral fractures. Fifty elderly women, 63–84 years of age, with back pain due to osteoporotic
vertebral fractures were randomly divided into two groups with 25 patients in each group: the cyclicaletidronate treatment group (200 mg/day for 2 weeks per 3 months) and the alendronate treatmentgroup (5 mg/day). The level of urinary cross-linked N-terminal telopeptides of type I collagen (NTx)measured by an enzyme-linked immunosorbent assay, back pain evaluated with the face scale score,
and the ADL score (disability) determined with a questionnaire were assessed before and 3 and 6
months after the start of treatment. No signiﬁcant differences in these parameters were found between
the two groups before the treatment. The urinary NTx level, the face scale score, and the ADL score
decreased signiﬁcantly in both groups. Although the reduction in the urinary NTx level was signiﬁcantly greater in the alendronate group than in the etidronate group, the reduction in the face scalescore was transiently signiﬁcantly greater in the etidronate group than in the alendronate group.
However, changes in the ADL score did not signiﬁcantly differ between the two groups. The present
study showed that although back pain was reduced and ADL was improved in both treatment groupsof elderly women with vertebral fractures, the mechanism for the reduction in back pain differs to someextent between the two treatment groups. A double-blind placebo-controlled study is needed to conﬁrm the therapeutic effects of these agents on back pain and deterioration of ADL. (Keio J Med 52 (4):230–235, December 2003)
Key words: bone resorption, back pain, urinary cross-linked N-terminal telopeptides of type I collagen(NTx), bisphosphonate

Introduction
Vertebral fractures occur in the natural history ofosteoporosis and are associated with back pain, immobility, and disability. Pain control is a crucial factor determining the activities of daily living (ADL) andsubsequently the quality of life (QOL) in elderly
patients. Since back pain accompanied by osteoporotic
vertebral fracture appears to be linked to increasedbone resorption, drugs affecting bone metabolism suchas bisphosphonates which are anti-resorptive agents
may be useful for pain control in patients with vertebral
fractures.
Etidronate and alendronate are bisphosphonates
commercially available for osteoporosis in Japan. The
efﬁcacy of treatment with cyclical etidronate (200 mg/
day for 2 weeks per 3 months) and alendronate (5 mg/day) to increase bone mineral density and reduce theReprint requests to: Dr. Jun Iwamoto, Department of Sports Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan, e-mail: jiwamoto@sc.itc.keio.ac.jp230Keio J Med 2003; 52 (4): 230–235

incidence of osteoporotic fractures in Japanese patientswith osteoporosis has been clearly demonstrated.1–3
However, very few studies have reported their therapeutic effects on back pain and/or deterioration of ADL
in patients with vertebral fractures.
It has been reported that women randomized toalendronate treatment had a signiﬁcantly lower risk ofoutcomes that are important to patients – number ofdays of bed rest and limited activity due to back pain.4
The results of this report suggest that alendronate
treatment in elderly osteoporotic women is efﬁcacious
for preventing back pain and subsequent deteriorationof ADL (preventative effects). However, the therapeutic effect of alendronate treatment and the preventative
and therapeutic effect of etidronate treatment on backpain and deterioration of ADL in patients with vertebral fractures have rarely been reported. In fact, it may
be difﬁcult ethically to perform double-blind placebocontrolled studies in patients with vertebral fractures inorder to assess the therapeutic effect of some treatments on back pain. Recently, we reported that etidronate treatment transiently reduced metastatic cancerbone pain in patients with painful bone metastases fromprimary cancer sites, by decreasing abnormally raisedbone resorption.5 We surmise that both treatment withetidronate and alendronate may have the potential toreduce back pain and improve ADL in patients withvertebral fractures, helping to improve their QOL. The
aims of the present prospective randomized open-label
study were to determine whether treatment with etidronate and alendronate could reduce back pain and improve ADL in patients with vertebral fractures, andto compare their therapeutic effects on bone resorption,back pain, and ADL.
Subjects and Methods
Subjects
Fifty elderly women, 63–84 years of age, with backpain associated with osteoporotic vertebral fractures
were recruited at our hospitals between October andDecember 2001. Vertebral fracture was deﬁned as described below. They were randomly divided into twotreatment groups with 25 patients in each group: thecyclical etidronate treatment group (200 mg/day for 2
weeks per 3 months) and the alendronate treatmentgroup (5 mg/day). These doses are recognized as effective for Japanese patients with osteoporosis. All subjects did not take medicine such as non-steroidal antiinﬂammatory drugs to relieve back pain. All subjects
were instructed to take 800 mg of calcium daily throughfood intake. All subjects completed the trial without
any adverse effects. Table 1 shows the characteristics ofthe study subjects. Pre- and post-treatment examina-

231
Table 1

Characteristics of Study Subjects

Age (years)
Height (cm)Body weight (kg)BMI (kg/m 2 )Number ofprevalentvertebral fractures
Serum calcium(mg/dl)Serum phosphorus(mg/dl)Etidronate groupn ¼ 25

Alendronate groupn ¼ 2572.1 G 1.2 (63–83)
149.4 G 1.2 (140–170)
48.3 G 1.6 (31–68)
21.6 G 0.6 (14.7–28.3)
3.7 G 0.6 (1–8)

75.0 G 1.0 (65–84)
147.9 G 1.5 (135–165)
48.5 G 1.8 (34–72)
22.1 G 0.6 (16.9–29.6)
3.1 G 0.5 (1–8)

9.5 G 0.1 (8.9–10.5)

9.4 G 0.1 (8.8–9.9)

3.4 G 0. (2.8–3.8)

3.3 G 0.1 (2.9–4.1)

Data are expressed as mean G SE. Unpaired t-test was used to compare the data between the two groups. Numbers in parenthesis areranges. No signiﬁcant differences in any baseline characteristics were
found between the two groups.

tions included medical history, physical examination,and plain X-ray examination of the thoracic and lumbar
spine. A blood sample was also obtained before thestart of treatment, and serum calcium and phosphorus
levels were measured with standard laboratory techniques. The diagnosis of osteoporosis was made according to the Japanese criteria of primary osteoporosis as
described below. None of the subjects suffered fromany metabolic bone disease, and none had a history ofhormone (estrogen) replacement therapy or had evertaken medication that affects bone metabolism prior to
the present study. The level of urinary cross-linked Nterminal telopeptides of type I collagen (NTx) was
measured, and the face scale score as an index of backpain was determined before and 3 and 6 months after
the start of treatment as described below. The ADL
score (disability) was also assessed with a questionnaire6
before and 3 and 6 months after the start of treatment.
Lateral X-ray ﬁlms of the thoracic and lumbar spine
were obtained before and 6 months after the start oftreatment to assess vertebral fractures. Informed consent was obtained from all participants.
Assessment of vertebral fractures
Plain lateral X-ray ﬁlms of the thoracic and lumbar
spine were obtained to ﬁnd evidence of vertebral fractures. Vertebral fractures were deﬁned according to thevertebral height obtained from lateral X-ray ﬁlms basedon the Japanese criteria.7,8 Brieﬂy, the vertebral height
was measured at the anterior (A), center (C), and posterior (P) part of the vertebral body, and the presenceof vertebral fractures was conﬁrmed when (1) morethan a 20% reduction of vertebral height (A, C, and P)
compared with the neighboring vertebrae was observed;(2) C/A or C/P was less than 0.8; or (3) A/P was less

232

Iwamoto J, et al: Bisphosphonate, back pain, and ADL

than 0.75. The assessment of vertebral fractures was
performed for the T4–L4 spine in the present study.

have been demonstrated,9 although pain is a subjective
symptom that is relatively difﬁcult to evaluate.

Diagnosis of osteoporosis

Statistical analysis

The diagnosis of osteoporosis was made from lateral
X-ray ﬁlms of the spine on the basis of the Japanesediagnostic criteria of primary osteoporosis.7,8 Evaluation of bone mass can be made from lateral X-ray ﬁlms
of the spine when a vertebral fracture and/or lumbar
spondylosis is present. Brieﬂy, there are three grades
according to the appearance of the longitudinal trabeculae on lateral X-ray ﬁlms of the spine: Grade I: thelongitudinal trabeculae are prominent, Grade II: thelongitudinal trabeculae are coarse, Grade III: the longitudinal trabeculae are unclear. When a nontraumatic
vertebral fracture is present on lateral X-ray ﬁlms of thespine, Grade I or more severe radiographic osteopenia
should be diagnosed as osteoporosis. When a nontraumatic vertebral fracture is not present on lateral X-rayﬁlms of the spine, Grade II or more severe radiographic
osteopenia should be diagnosed as osteoporosis.

Data are expressed as mean G standard error (SE).
Data comparisons between the two groups were performed by unpaired t-test. The signiﬁcance of longitudinal changes in the urinary NTx levels, the face scalescores, and the ADL scores was also determined by
one-way analysis of variance (ANOVA) with repeatedmeasurements. Furthermore, longitudinal changes inthese three parameters were compared between thetwo groups by two-way ANOVA with repeated measurements. The correlations among the baseline urinary
NTx level, the face scale score, the ADL score, and thenumber of prevalent vertebral fractures in all subjects
were examined by single regression analysis. The correlations among percent changes in the urinary NTx

Measurement of urinary NTx level
Urine samples were collected in the morning afteran overnight fast, and stored at 70C until assayed.
Urinary NTx level (nmol BCE/mmol Cr) was estimatedusing an enzyme-linked immunosorbent assay (ELISA,
Osteomark, Ostex International, Seattle, WA) with amonoclonal antibody against the N-telopeptide to thehelix intermolecular cross-linking domain of type I collagen. All samples were measured in duplicate, and thesamples were analyzed in the same assay to eliminate
inter-assay variations. The assay sensitivity was 20 nM
bone collagen equivalents. The intra-assay coefﬁcientof variation of 5 measurements was less than 7%.
Evaluation of back pain
Back pain was evaluated quantitatively by assessing the mood of patients according to the face scale.
The face scale contains ten drawings of a single face,arranged in serial order by rows, with each face depicting a slightly different mood. Subtle changes in the eyes,
eyebrows, and mouth are used to represent slightly different levels of mood. They are arranged in decreasingorder of mood and numbered from 1–10, with 1 representing the most positive mood and 10 representing themost negative mood. As the examiner pointed to thefaces, the following instructions were given to eachpatient: ‘‘The faces below go from painless at the top
to very painful at the bottom. Point to the face thatbest shows the way you are currently experiencing backpain.’’ Thus, facial expression is used as an indicator ofback pain. The validity and reliability of the face scaleFig. 1 Changes in the urinary NTx level, face scale score, and ADL
score. One-way ANOVA with repeated measurements showed thatthe urinary NTx level, face scale score, and ADL score were signiﬁcantly decreased in both groups (all P < 0:0001). Two-way
ANOVA with repeated measurements showed that longitudinalchanges in the urinary NTx level and face scale score signiﬁcantly
differed between the two groups (P < 0:05 and P < 0:0001, respectively), while longitudinal changes in the ADL score did not signiﬁcantly differ between the two groups. * P < 0:01 vs etidronate
group, ** P < 0:001 vs alendronate group by unpaired t-test. NTx:
cross-linked N-terminal telopeptides of type I collagen, ADL: activities of daily living.

Keio J Med 2003; 52 (4): 230–235

level, the face scale score, and the ADL score in eachgroup were also examined by single regression analysis.
All statistical analyses were performed using the Stat
View-J5.0 program on a Macintosh computer. A significance level of P < 0:05 was used for all comparisons.
Results
Changes in the urinary NTx level, the face scale score,
and the ADL score

233
Table 2 Correlation among Baseline Number of Prevalent Vertebral
Fractures, Urinary NTx Level, Face Scale Score, and ADL Score in
All Subjects

Number of prevalentvertebral fractures
Urinary NTx
Face scale score

Urinary NTx
level

Face scale
score

ADL
score

þ0.360*þ0.114

þ0.121

þ0.103

þ0.011
þ0.252*The baseline urinary NTx level was 67:8 G 31:1 nmol
BCE/mmol Cr in the etidronate group and 65:8 G 19:9
nmol BCE/mmol Cr in the alendronate group. The
respective baseline face scale score was 5:0 G 0:9 and
4:9 G 1:0, and the respective baseline ADL score was
35:2 G 8:9 and 35:1 G 7:0. There were no signiﬁcantdifferences in these baseline parameters between thetwo groups. Fig. 1 shows the changes in these parameters. One-way ANOVA with repeated measurements
showed that the urinary NTx level, face scale score, andADL score decreased signiﬁcantly in both groups (allP < 0:0001). Two-way ANOVA with repeated measurements showed that longitudinal changes in the urinary NTx level and face scale score signiﬁcantly differed between the two groups (P < 0:05 and P < 0:0001,
respectively), while longitudinal changes in the ADL
score did not signiﬁcantly differ between the twogroups. On the unpaired t-test, the urinary NTx level 6months after the start of treatment was signiﬁcantly
lower in the alendronate group than in the etidronate
group (P < 0:01), and the face scale score 3 months
after the start of treatment was signiﬁcantly lower inthe etidronate group than in the alendronate group(P < 0:001).

Data are r values. Single regression analysis was used to examine
the correlation among the number of prevalent vertebral fractures,
urinary NTx level, face scale score, and ADL score in all subjects.
* P < 0:05

Correlation among baseline number of prevalent vertebral fractures, urinary NTx level, face scale score, andADL score in all subjects

The present study showed a signiﬁcant positive correlation between the baseline face scale score and theTable 2 shows that a signiﬁcant positive correlation
was found between the baseline number of prevalentvertebral fractures and the urinary NTx level in all
subjects (r ¼ 0:360, p < 0:05), while no signiﬁcant correlation was found between the baseline number ofprevalent vertebral fractures and the face scale and
ADL scores. A signiﬁcant positive correlation was
found between the baseline face scale and ADL scoresin all subjects (r ¼ 0:252, p < 0:05), while no signiﬁcantcorrelation was found between the baseline urinary
NTx level and the face scale and ADL scores.

Table 3 Correlation among Percent Changes in Urinary NTx Level,
Face Scale Score, and ADL Score in Each Group

Correlation among percent changes in the urinary NTxlevel, face scale score, and ADL score in each group
Table 3 shows that 3 months after the start of treatment, in both groups, no signiﬁcant correlation was

found among percent changes in the urinary NTx level,
face scale score, and ADL score. Six months after thestart of treatment, in the alendronate group, a signiﬁcant positive correlation was found between percent
decreases in the urinary NTx level and face scale score(r ¼ 0:356, p < 0:05), while no signiﬁcant correlation
was found between percent changes in the ADL scoreand urinary NTx level and face scale. In the etidronate
group, no signiﬁcant correlation was found among percent changes in the urinary NTx level, face scale score,and ADL score.
Incident vertebral fractures
Six months after the start of treatment, three incident vertebral fractures (T7, T8, L4) were observed in apatient with a prevalent vertebral fracture (L3) in theetidronate group, while no incident vertebral fractures
occurred in the alendronate group.
Discussion

Etidronate group

3 months
Urinary NTx
Face scale score
6 months
Urinary NTx
Face scale score

Alendronate group

Face scale
score

ADL
score

Face scale
score

ADL
score

þ0.312

0.173
0.373

þ0.290þ0.307
þ0.259

þ0.240þ0.301
þ0.175

þ0.356*

þ0.081
þ0.012

Data are r values. Single regression analysis was used to examine thecorrelation among the percent changes in the urinary NTx level, facescale score, and ADL score by 3 and 6 months of treatment in eachgroup. * P < 0:05

234

ADL score, suggesting that back pain is a signiﬁcantfactor affecting ADL in elderly women with vertebral
fractures. This ﬁnding provides important information
on measures to achieve improvement of deteriorated
ADL and subsequent QOL in elderly people. The
present study also showed a signiﬁcant positive correlation between the baseline number of prevalent vertebral fractures and the urinary NTx level, suggesting thathigh bone turnover may be associated with a higher
risk of vertebral fractures in patients with osteoporosis
as previously reported.10,11 We believe that in elderly
women with vertebral fractures who show higher levelsof bone resorption (turnover) markers, bisphosphonate
treatment may potentially reduce bone resorption andback (bone) pain, because non-traumatic painful vertebral fractures result from increased bone resorption.
Back pain was reduced and ADL was improvedin both treatment groups of elderly women with vertebral fractures. Nevitt et al.4 have reported that longterm alendronate treatment has a signiﬁcantly lower
risk of patients having days of bed rest and limited
activity due to back pain in elderly osteoporotic women,suggesting that alendronate treatment in elderly osteoporotic patients is efﬁcacious not only for preventing
incident vertebral fractures by suppressing bone resorption, but also for reducing the burden of activity
limitation and bed disability caused by back pain.
However, the therapeutic effects of alendronate treatment on back pain and deterioration of ADL in patientswith vertebral fractures have rarely been reported.
Agarwala et al.12 reported that short-term alendronate
treatment improves pain, disability, and standing andwalking capacity in patients with avascular necrosis of
the hip. The mechanism of the beneﬁcial action ofalendronate in avascular necrosis is speculated to be
inhibition of the resorptive action of mature osteoclasts,
an increase in the level of apoptosis of osteoclasts, andprobably a decrease in apoptosis of osteoblasts andosteocytes. The main mechanism by which alendronate treatment prevents and/or reduces pain inpatients with increased bone resorption seems primarily
to be suppression of bone resorption.
The preventative and therapeutic effects of etidronate treatment on back pain and deterioration of ADL
in patients with vertebral fractures have rarely beenreported. In the etidronate treatment group of thepresent study, despite the reductions in the urinary NTxlevel and face scale score over 6 months, the percent
decrease in urinary NTx level was not signiﬁcantly correlated with the percent decrease in the face scalescore. Thus, other mechanisms than suppression ofbone resorption might contribute to the reduction inback pain. Recently, we reported that etidronate treatment transiently reduced metastatic cancer bone pain inpatients with painful bone metastases from primary

Iwamoto J, et al: Bisphosphonate, back pain, and ADL

cancer sites by decreasing abnormally raised bone resorption.5 Metastatic bone pain can be attributed to anindirect effect of osteoclast-mediated bone resorption,and the release of prostaglandins, bradykinin, substanceP, and histamine.13,14 Available evidence suggests that
etidronate decreases pain by suppressing the production of interleukin (IL)-6, IL-12, and prostaglandin
E2.15,16 Thus, a possible explanation for the relief ofmetastatic cancer bone pain achieved by etidronate
may be the combined effects of suppression of bone resorption and a reduction in the production of ILs andprostaglandin. Although alendronate treatment has
also been reported to reduce the levels of cytokines
such as IL-1, IL-6, and tumor necrosis factor (TNF)-a inpatients with early rheumatoid arthritis,17 the pain relief effect of alendronate treatment remains uncertain.
Because the reduction in urinary NTx levels was less inthe etidronate treatment group than in the alendronate
treatment group, the reduction in the production of ILs
and prostaglandin in the etidronate treatment group
might contribute more signiﬁcantly to the reduction inback pain 3 months after the start of treatment. Further
study is needed to conﬁrm the effect of etidronate
treatment on ILs and prostaglandin.
Although a signiﬁcant positive correlation was foundbetween the baseline face scale score and ADL score in
all subjects, no signiﬁcant correlation was found between the reductions in the face scale score and ADL
score in both groups. This ﬁnding suggests that backpain can contribute the deterioration of ADL, but therelief of back pain does not always result in the improvement of ADL. Thus, mechanisms other than pain
relief might contribute to the improvement of ADL.
One possibility is that mental improvement resulting
from precise diagnosis of osteoporosis, proper treatment for it, and pain relief might lead to the improvement of ADL, because there are many elderly womenwith osteoporosis who feel mental depression. Anotherpossibility is that the patient might realize the importance of increasing physical activity in the treatment of
osteoporosis, resulting in the improvement of ADL.
However, further study is needed to conﬁrm theseviews.
Because pain is a subjective symptom of patients, themajor problem of the present study is that there wereno placebo controls. First, in general, placebo effects
tend to appear abruptly in the initial phase and earlier
than true effects, and to be transient in nature. Therefore, whether a transient decline in the face scale scorein the etidronate treatment group reﬂects a true drug
effect is not known. A double-blind placebo-controlled
study is needed to clarify this. Second, because the severe pain of vertebral fractures in some patients may
transient, resolving within a few weeks to a few months,
whether a longitudinal decline in face scale score in the

Keio J Med 2003; 52 (4): 230–235

etidronate and alendronate treatment groups reﬂects
a true drug effect is not also known. However, theefﬁcacy of bisphosphonates for bone pain in patientswith bone resorption-related diseases has been demonstrated. Intravenous pamidronate seems to be a valuable treatment for back pain, as well as rehabilitatingelderly patients suffering from chronic and refractory
back pain due to osteoporotic vertebral fractures,18 andalso reduces skeletal pain and biochemical markers
of bone resorption in patients with skeletal metastases.19,20 Furthermore, risedronate decreases bone painin patients with Paget’s disease of bone.21 In thealendronate treatment group of the present study, thepercent decrease in the urinary NTx level was signiﬁcantly positively correlated with the percent decrease in the face scale score 6 months after the start oftreatment. Thus, we believe that suppressed bone resorption might contribute to the relief of back pain atleast in the alendronate treatment group of patientswith vertebral fractures. However, a double-blind
placebo-controlled study is needed to conﬁrm the efﬁcacy of treatment with etidronate and alendronate forback pain and deterioration of ADL.
In conclusion, the present study showed a reduction in back pain and improvement of ADL was seenin the etidronate and alendronate treatment groups ofelderly women with vertebral fractures. Although the
reduction in the urinary NTx level was greater in thealendronate treatment group than in the etidronate
treatment group, the reduction in the face scale score
was transiently greater in the etidronate treatmentgroup than in the alendronate treatment group. However, changes in the ADL score were similar in the
two treatment groups. Thus, the mechanism for the reduction in back pain differs somewhat between the twotreatment groups. A double-blind placebo-controlled
study is needed to conﬁrm the therapeutic effects ofthese agents on back pain and deterioration of ADL.
References
1. Shiraki M, Kushida K, Fukunaga M, Kishimoto H, Taga M,
Nakamura T, Kaneda K, Minaguchi H, Inoue T, Morii H, et al: A
double-masked multicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis.
The Alendronate Phase III Osteoporosis Treatment ResearchGroup. Osteoporos Int 1999; 10: 183–192
2. Iwamoto J, Takeda T, Ichimura S: Effect of menatetrenone onbone mineral density and incidence of vertebral fractures inpostmenopausal women with osteoporosis: a comparison withthe effect of etidronate. J Orthop Sci 2001; 6: 487–492
3. Fujita T, Orimo H, Inoue T, Kaneda K, Sakurai M, Morita R,
Morii H, Yamamoto K, Sugioka Y, Inoue A, et al: Double-blind
multicenter comparative study with alfacalcidol of etidronate
disodium (EHDP) in involutional osteoporosis. Clin Eval 1993;
21: 261–302 (in Japanese)235
4. Nevitt MC, Thompson DE, Black DM, Rubin SR, Ensrud K,
Yates AJ, Cummings SR: Effect of alendronate on limitedactivity days and bed-disability days caused by back pain inpostmenopausal women with existing vertebral fractures. Fracture Intervention Trial Research Group. Arch Intern Med 2000;
160: 77–85
5. Iwamoto J, Takeda T, Ichimura S: Transient relief of metastatic
cancer bone pain by oral administration of etidronate. J Bone
Miner Metab 2002; 20: 228–234
6. Takahashi H: Assessment of health related quality of life inosteoporotic patients Nippon Rinsho 2002; 60 Suppl 3: 479–484(in Japanese)
7. Orimo H, Sugioka Y, Fukunaga M, Muto Y, Hotokebuchi T,
Gorai I, Nakamura T, Kushida K, Tanaka H, Ikai T, et al: Diagnostic criteria of primary osteoporosis. J Bone Miner Metab
1998; 16: 139–150
8. Orimo H, Hayashi Y, Fukunaga M, Sone T, Fujiwara S, Shiraki
M, Kushida K, Miyamoto S, Soen S, Nishimura J, et al: Diagnostic criteria for primary osteoporosis: year 2000 revision. J
Bone Miner Metab 2001; 19: 331–337
9. Lorish CD, Maisiak R: The Face Scale: a brief, nonverbal
method for assessing patient mood. Arthritis Rheum 1986; 29:
906–909
10. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD: Biochemical markers of bone turnover, endogenous hormones andthe risk of fractures in postmenopausal women: the OFELY
study. J Bone Miner Res 2000; 15: 1526–1536
11. Melton LJ 3rd, Khosla S, Atkinson EJ, O’Fallon WM, Riggs BL:
Relationship of bone turnover to bone density and fractures. J
Bone Miner Res 1997; 12: 1083–1091
12. Agarwala S, Sule A, Pai BU, Joshi VR: Alendronate in thetreatment of avascular necrosis of the hip. Rheumatology(Oxford) 2002; 41: 346–347
13. Averbuch SD: New bisphosphonates in the treatment of bonemetastases. Cancer 1993; 72 (11 Suppl): 3443–3452
14. Nielsen OS, Munro AJ, Tannock IF: Bone metastases: pathophysiology and management policy. J Clin Oncol 1991; 9: 509–
524
15. Nishikaku F, Nakayama T, Nakatsuka M: Analgesic propertyof bisphosphonate, etidronate in animal models. Jpn Pharmacol
Ther 1998; 26: 457–463 (in Japanese)
16. Tanaka T, Nakayama T, Katsumata T: Etidronate: therapeutic
agent for osteoporosis possessing analgesic effect. Bio Clinica
2001; 16: 57–61 (in Japanese)
17. Cantatore FP, Acquista CA, Pipitone V: Evaluation of boneturnover and osteoclastic cytokines in early rheumatoid arthritis
treated with alendronate. J Rheumatol 1999; 26: 2318–2323
18. Gangji V, Appelboom T: Analgesic effect of intravenous
pamidronate on chronic back pain due to osteoporotic vertebral
fractures. Clin Rheumatol 1999; 18: 266–267
19. Glover D, Lipton A, Keller A, Miller AA, Browning S, Fram RJ,
George S, Zelenakas K, Macerata RS, Seaman JJ: Intravenous
pamidronate disodium treatment of bone metastases in patientswith breast cancer. A dose-seeking study. Cancer 1994; 74: 2949–
2955
20. Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton
A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD:
Efﬁcacy of pamidronate in reducing skeletal complications inpatients with breast cancer and lytic bone metastases. Protocol
19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:
1785–1791
21. Siris ES, Chines AA, Altman RD, Brown JP, Johnston CC Jr,
Lang R, McClung MR, Mallette LE, Miller PD, Ryan WG, et al:
Risedronate in the treatment of Paget’s disease of bone: an open
label, multicenter study. J Bone Miner Res 1998; 13: 1032–1038