CASE REPORT
Effect of treatment with alendronate in osteogenesis
imperfecta type I: a case report
Jun Iwamoto, Tsuyoshi Takeda and Yoshihiro Sato1
Department of Sports Medicine, School of Medicine, Keio University, Tokyo, 1Department of Neurology, Mitate
Hospital, Fukuoka, Japan(Received for publication on December 15, 2003)

Abstract. A case of osteogenesis imperfecta (OI), which was successfully treated with alendronate isreported. A 41-year-old premenopausal woman with OI type I, who had frequently been experiencing
fragile fractures, consulted our clinic because of back pain associated with spinal osteoporosis. She had
experienced heart surgery (aortic valve replacement) due to aortic regurgitation 5 years before her ﬁrst
consultation with our clinic. After the surgery, she had been taking warfarin 3 mg/day, and this treatment was continued during our follow-up period. She was treated with alendronate (5 mg/day, daily)
for 18 months. The bone mineral density of the lumbar spine (L2–L4) measured by dual energy X-ray
absorptiometry (Norland XR-36) increased for 18 months, and back pain markedly decreased. The
urinary cross-linked N-terminal telopeptides of type I collagen and serum bone-speciﬁc alkaline phosphatase, osteocalcin, and undercarboxylated osteocalcin levels also markedly decreased. No new fragile vertebral or non-vertebral fractures were observed during the 18 months of treatment. This reportprovides evidence indicating that treatment with oral alendronate may have the potential to decreasebone turnover, improve the lumbar BMD, reduce back pain, and prevent new fragile fractures in premenopausal women with OI type I. (Keio J Med 53 (4): 251–255, December 2004)
Key words: osteogenesis imperfecta, alendronate, bone mineral density (BMD), fracture, bone turnover

Introduction
Osteogenesis imperfecta (OI) is a heterogeneousgroup of genetic disorders that affect connective tissue
integrity. The hallmark of OI is bone fragility, althoughother manifestations, which include osteoporosis, dentigenesis imperfecta, blue sclera, easy bruising, joint
laxity, and scoliosis, are also common among OI
patients. The severity of OI ranges from prenatal deathto mild osteopenia without limb deformity. Most formsof OI result from mutations in the genes that encode
either the pro a1 or pro a2 polypeptide chains thatcomprise type I collagen molecules, the major structuralprotein of bone.1
Although OI is a heritable disorder of bone formation, resulting in bone fragility, the activity of cancellous bone remodeling, bone resorption, and/or boneturnover are also increased,2–6 and the efﬁcacy oftreatment with cyclical intravenous pamidronate forbone fragility in children with OI is established.7–12
The fracture rate decreases with maturation inpatients with OI.2,13 This clinical stability of the disease
may be associated with the maturation of bone. Despite
the reduced fracture rate, bone mineral density (BMD)
usually remains low in adults with OI; however, very
few studies have been reported concerning treatment of
osteopenia in adults with OI.
A nitrogen-containing bisphosphonate like alendronate is generally accepted as a safe, effective, andwell-tolerated treatment for postmenopausal osteoporosis;14–17 it increases the lumbar and femoral neck
BMD and prevents new vertebral and femoral neckfractures. Alendronate preferentially binds hydroxyapatite and inhibits osteoclast-mediated bone resorption by suppressing the recruitment and activity ofosteoclasts and shortening their life span.18 Because
alendronate is effective for high turnover osteoporosis
including postmenopausal osteoporosis, it may be use-

Reprint 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.jp
251

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Iwamoto J, et al: Osteogenesis imperfecta and alendronate

ful for adults with OI who show increased bone resorption or high bone turnover. An adult case of OI
type I with high bone turnover and high fracture rate,
which was successfully treated with alendronate, isreported.
Case Report
A premenopausal woman, 41 years of age, consulted
our clinic because of back pain. Despite the subjective
symptom of chronic back pain continuing for a coupleof years, she had never received treatment for it. Her
height was 132 cm, body weight was 31 kg, and bodymass index was 17.7 kg/m 2 . She had experienced heart
surgery (aortic valve replacement) due to aortic regurgitation 5 years before her ﬁrst consultation with ourclinic. After the surgery, she had been taking warfarin 3
mg/day until her ﬁrst consultation, and this treatment
was continued during our follow-up period. The patient
had no past history of metabolic bone diseases otherthan OI, and had never taken medicine that affectedbone metabolism other than warfarin. Three clinicalcriteria of OI – history of fractures, blue sclera, positive
family history – were present. Deformities in the legssuch as antero-lateral bowing of the femurs and anterior bowing of the tibiae and deformity in the thoracic
and lumbar spine were observed. The patient belonged
to Sillence Type I OI.19 Back pain level was 7, evaluated quantitatively by assessing the mood of the patient according to face scale score (scores are arranged
in decreasing order of mood and numbered from 1–10,
with 1 representing the most positive mood and 10
representing the most negative mood). The radiographsof the thoracic and lumbar spine showed scoliotic deformity. Because of this scoliotic deformity, vertebral
fractures could not be diagnosed precisely according to
the Japanese criteria of vertebral fracture.20,21 The patient had experienced more than 20 fractures in the femurs, toes, ribs, and scapulae. Of these fractures, 13
were observed in the femurs. Most of the fractures wereexperienced during infancy, and the fracture frequency
gradually decreased with maturation. Three weeks before her ﬁrst consultation with our clinic, a fracture in
the scapula was experienced. To understand the pathogenesis of bone fragility and establish an effective treatment using medication, BMD and biochemical markers
were measured. Informed consent was obtained from thepatient in accordance with the Declaration of Helsinki.
Table 1 shows the characteristics of the present patient. The BMD of the lumbar spine (L2–L4) measured
by dual energy X-ray absorptiometry (DXA) using a
Norland XR-36 instrument (Norland, Fort Atkison, WI,USA) was 0.579 g/cm 2 , with a T score of 55.7%. In
particular, the setting of region of interest was carefully
performed. The serum calcium and phosphorus levels

Table 1

Characteristics of the Patient

Lumbar BMD (g/cm 2 )T score of lumbar BMD (%)
Z score of lumbar BMD (%)
Face scale score
Serum
TP (g/dl)
AST (IU/l)
ALT (IU/l)
ALP (IU/l)
BUN (mg/dl)
Creatinine (mg/dl)
Calcium (mg/dl)
Phosphorus (mg/dl)
Intact PTH (pg/ml)
BAP (U/l)
OC (ng/ml)
Undercarboxylated OC (ng/ml)
Urine
NTX (nmol BCE/mmol Cr)
Calcium/creatinine

0.579
55.7
55.9
7

(1–10)

7.0
31
26
394
11.7
0.4
8.8
3.2
44
54.7
9.4
28.6

(6.5–8.2)(14–32)(8–41)(135–310)(8.0–19.0)(0.4–0.8)(8.5–10.2)(2.8–4.6)(12–61)(9.6–35.4)(3.1–12.7)(< 4.3)96.2
0.43(13.0–73.0)(< 0.3)

Numbers in parentheses are normal ranges. BMD: bone mineraldensity, TP: total protein, AST: aspartate aminotransferase, ALT:
alanin aminotransferase, ALP: alkaline phosphatase, BUN: bloodurea nitrogen, PTH: parathyroid hormone, BAP: bone speciﬁc alkaline phosphatase, OC: osteocalcin, NTX: cross-linked N-terminal
telopeptides of type I collagen.

were within the normal range. The serum bone speciﬁc
alkaline phosphatase (BAP) and undercarboxylated
osteocalcin (OC) levels measured by enzyme immunoassay (EIA), the serum OC level measured byimmonoradiometric assay (IRMA), and the urinary
cross-linked N-terminal telopeptides of type I collagen(NTX) level measured by enzyme-linked immunosorbent assay (ELISA) were high. The intact parathyroid
hormone (PTH) level measured by chemiluminescentimmunoassay (CLIA) was within the normal range.
Osteoporosis and bone fragility due to OI werediagnosed 2 weeks after her ﬁrst consultation. Since
then, the patient was treated with alendronate (5 mg/day) for 18 months. This is a standard alendronate dosein Japan. Table 2 shows the changes in the lumbar (L2–
L4) BMD, the serum calcium, phosphorus, BAP, OC,
and undercarboxylated OC, and urinary NTX levels,and face scale score. In particular, back pain markedly
reduced within a couple of months (face scale score
decreased from 7 to 2). The lumbar (L2–L4) BMD in
the same region of interest as that at baseline increased,
and the urinary NTX and serum BAP, OC, and undercarboxylated OC levels, and face scale score decreased,
and no new non-vertebral fractures were observed
during the 18 months of treatment. The radiographs ofthe thoracic and lumbar spine obtained after the 18
months of treatment did not show any marked changes
in scoliotic deformity and the height of each vertebra,
suggesting that no new vertebral fractures had occurred.

Keio J Med 2004; 53 (4): 251–255

253

Table 2 Changes in Lumbar BMD, Serum and Urinary BiochemicalMarkers, and Face Scale Score

Lumbar BMD (g/cm 2 )Serum
Calcium (mg/dl)
Phosphorus (mg/dl)
BAP (U/l)
OC (ng/ml)
Undercarboxylated
OC (ng/ml)
UrinneNTX (nmol
BCE/mmol Cr)
Calcium/creatinine
Face scale score

Baseline

Month 6

Month 12Month 18

0.579

0.656

0.678

0.684

8.8
3.2
54.7
9.4
28.6

9.0
3.7
32.4
8.8
27.0

9.7
3.7
23.6
2.9
7.3

9.8
3.6
27.0
2.8
4.2

96.2

46.6

32.6

24.3

0.43
7

0.32
2

0.26
2

0.24
2

BMD: bone mineral density, BAP: bone speciﬁc alkaline phosphatase,
OC: osteocalcin, NTX: cross-linked N-terminal telopeptides of type I
collagen.

Discussion
Osteogenesis imperfecta is a congenital disease ofwhich main characteristic is fragility of bones. Althoughfragile fractures occur frequently in children with OI,
the fracture rate decreases after adolescence due to theinﬂuences of sex hormones and maturation.2,13 Thus,
clinical stability of OI is usually observed with age, andthis is an important characteristic of the disease. The
present patient had been experiencing fragile fractures
frequently during infancy, and the rate of fractures, especially at the long bones, decreased with maturation.
However, back pain associated with spinal osteoporosis
remained, and she had a fragile fracture in the scapula
3 weeks before her ﬁrst consultation with our clinic.
The serum undercarboxylated OC level was extremely high in the present patient. The reason for thisremains uncertain. It was reported that long-term warfarin treatment impaired carboxylation of osteocalcin,22
although the issue of whether long-term warfarin
treatment results in decreased the BMD is controversial.23,24 A higher incidence of femoral neck fractures
is observed in patients with higher levels of undercarboxylated OC,25–27 suggesting that serum undercarboxylated OC may be associated with the incidenceof osteoporotic fractures. Thus, warfarin treatment
might play a role in the high level of serum undercarboxylated OC in the present patient, and the highfracture rate might also be associated with the highlevel of undercarboxylated OC.
The efﬁcacy of treatment with cyclical intravenous
pamidronate for bone fragility in children with OI
is established;7–12 intravenous pamidronate preventsfragile fractures without inhibiting bone growth. However, oral bisphosphonates may be applicable for adultpatients with OI who show high bone turnover as well
as for postmenopausal women with osteoporosis, although their efﬁcacy is not yet established.
Osteoporosis in the present patient, a premenopausal woman, was associated with high boneturnover. Available evidence suggests that the classically observed osteopenia in children with OI is associated with increased bone turnover.2–4 A histomorphometric study showed that osteoporosis in adultmale with OI was associated with increased bone turnover on bone marker measurements, and increasedbone resorption and decreased osteoblastic activity attissue level.28 These histomorphometric data support
our results.
Treatment with alendronate (5 mg/day) decreases
bone turnover, increases the lumbar BMD (6.21% for
one year), and reduces the incidence of osteoporotic
fractures including vertebral fractures in Japanesepatients with osteoporosis.16 In the present patient,treatment with alendronate (5 mg/day) decreased boneturnover, improved the lumbar BMD (18.1% increasefor 18 months), reduced back pain, and prevented newvertebral or non-vertebral fractures with a reduction in
the serum undercarboxylated OC level. The reductionin the serum undercarboxylated OC as well as OClevels might result from the decreased osteoblastic
recruitment following suppressed osteoclast-mediatedbone resorption, with blood coagulation system unaffected.29 The primary endpoint of our treatment was
relief of back pain and prevention of new fragile fractures. Treatment with alendronate could achieve ourprimary endpoint. However, a further period of observation may be needed to determine the long-term efﬁcacy of this treatment for adult patients with OI.
In regard to back pain and treatment with alendronate, Nevitt et al.30 have reported that in elderly osteoporotic women those with long-term alendronate treatment showed a signiﬁcantly lower risk of patients
having days of bed rest and limited activity due to backpain. These results suggest that treatment with alendronate in elderly osteoporotic women is efﬁcacious forpreventing back pain and subsequent deterioration ofactivities of daily living. However, the mechanism forreduction of back pain by treatment with alendronate
remains uncertain.
The efﬁcacy of bisphosphonates for bone pain inpatients with bone resorption-related diseases has been
demonstrated. Intravenous pamidronate seems to be avaluable treatment for back pain, as well as rehabilitating elderly patients suffering from chronic and refractory back pain due to osteoporotic vertebral fractures,31 and also reduces skeletal pain and biochemicalmarkers of bone resorption in patients with skeletal
metastases.32–34 Furthermore, risedronate decreases
bone pain in patients with Paget’s disease of bone.35

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Iwamoto J, et al: Osteogenesis imperfecta and alendronate

Thus, we believe that suppressed bone resorption might
contribute to the relief of back pain in the present
patient.
We have already reported the efﬁcacy of treatment
with etidronate and alfacalcidol for OI type I;36 the 18
months of treatment with cyclical oral etidronate andalfacalcidol increased the lumbar BMD by 3.9%,
reduced back pain caused by thoracic vertebral fractures (face scale score was reduced from 7 to 2), andprevented new fragile vertebral or non-vertebral fractures in an adult patient with OI type I who had frequently been experiencing fragile fractures in the longbones of the upper and lower extremities. Although theincrease in the lumbar BMD seemed to be greater intreatment with alendronate than in that with cyclicaletidronate and alfacalcidol, oral bisphosphonates may
be efﬁcacious in adult patients with OI type I, who haveback pain caused by spinal osteoporosis and have frequently been experiencing fragile fractures.
Side effects of bisphosphonate treatment in children
have been reported. First, transient hypocalcemia could
be observed during the early period of intravenous
pamidronate treatment in children with OI.37 Second,acquired osteopetrosis could result from treatment withhigh dose intravenous pamidronate in a child with
unexplained skeletal pain who needed antiresorptive
therapy,38 suggesting that excessive doses of bisphosponates may compromise skeletal quality in growing
patients. However, the safety and tolerability of oralalendronate (5 mg daily, physiological dose) have already been established in adult patients with osteoporosis.16,17 Thus, we could demonstrate the efﬁcacy oforal alendronate (5 mg daily) in our patient with absence of drug-induced toxicities such as sustained
hypocalcemia and osteopetrosis.
In conclusion, this report provides evidence indicating that treatment with oral alendronate may have thepotential to decrease bone turnover, improve the lumbar BMD, reduce back pain, and prevent new fragile
fractures in premenopausal women with OI type I whoshow high bone turnover.

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