This case highlights the value of genetic screening for idiopathic osteoporosis with recurrent fractures. This case highlights the variability in clinical expression of LRP5 polymorphisms and suggests that standard treatment in cases of recurrent fracture may be ineffective. (AACE Clinical Case Rep. 2019;5:e362-e364)
Trang 1e362 AACE CLINICAL CASE REPORTS Vol 5 No 6 November/December 2019
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Case Report
ADULT OSTEOPOROSIS WITH A HISTORY OF CHILDHOOD-ONSET FRACTURE DUE TO AN LRP5 RECEPTOR VARIANT MUTATION
Terry Shin, MD, MAJ 1 ; Jay R Shapiro, MD 2
Submitted for publication May 11, 2019
Accepted for publication July 11, 2019
From 1 Walter Reed National Military Medical Center, Bethesda, and
2 Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Address correspondence to Dr Terry Shin, Walter Reed Military Medical
Center, 8901 Rockville Pike, Bethesda, MD 20889.
E-mail: terry.shin.mil@mail.mil.
DOI: 10.4158/ACCR-2019-0219.R1
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2019 AACE.
ABSTRACT
Objective: This case highlights the value of
genet-ic screening for idiopathgenet-ic osteoporosis with recurrent
fractures
Methods: Case report and review of the literature
Results: A 52-year-old Caucasian female with
idio-pathic osteoporosis with recurrent fractures was
identi-fied with a heterozygous low-density lipoprotein receptor
related protein 5 (LRP5) mutation
Conclusion: This case highlights the
variabil-ity in clinical expression of LRP5 polymorphisms and
suggests that standard treatment in cases of recurrent
fracture may be ineffective (AACE Clinical Case Rep
2019;5:e362-e364)
Abbreviations:
LRP5 = low-density lipoprotein receptor related protein
5; SNP = single nucleotide polymorphism
CASE REPORT
A 52-year-old Caucasian nulliparous woman with
a history of osteoporosis was evaluated in the clinic for recurrent fractures despite antiresorptive and anabolic ther-apy She initially suffered her first nontraumatic fracture at age 5 in her tibia with subsequent nontraumatic fractures at age 13, 18, and 24, involving the patella, clavicle, and ribs She developed a fracture of her humerus at age 35, a pelvic fracture at age 36, a heel fracture at age 49, and a metatar-sal fracture at age 50 She was treated with alendronate for
1 year at age 45, and zoledronic acid for 1 year at age 46
A trial of teriparatide was initiated at age 49 for 6 months but was discontinued due to the development of nonspe-cific gastrointestinal symptoms She received topical estra-diol patch therapy for approximately 2 years starting at age
47 for unknown reasons
Surgical history was notable for a partial
hysterecto-my at age 44 for anovulatory bleeding Additional surger-ies included right ankle surgery and foot surgery Family history was notable for a mother who was osteoporotic and also experienced recurrent nontraumatic fractures
Physical examination of the patient was unremarkable with normal vital signs, white sclerae, normal ophthalmo-logic examination, normal dentition, and no gross skel-etal deformities Biochemical screening that included a complete blood count, renal panel, thyroid panel, corrected calcium, and alkaline phosphatase were within normal limits Osteocalcin levels were not tested at the time of evaluation She was found to have an elevated urinary N-terminal telopeptide (NTX) level at 105 nmol BCE/mmol creatinine (normal, 4 to 65 nmol/BCE/mmol creatinine for
a premenopausal female) Postmenopausal urinary NTX reference ranges were not available at the reference lab at time of testing Available dual-energy X-ray absorptiome-try (DXA) study at age 45 reported a T-score in the lumbar spine at –3.2, in the left hip at –3.2, and in the left femoral
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Copyright © 2019 AACE
neck at –3.4 Plain film imaging of the cervical, thoracic,
and lumbar spine revealed a slight loss of height at C3 to
C6, minimal anterior wedging in the lower thoracic
verte-bral bodies, generalized osteopenia, and multiple healed
rib fractures A genetic screen for osteogenesis imperfecta
was negative and genetic workup revealed a mutation in
the gene encoding low-density lipoprotein receptor
relat-ed protein 5 (LRP5; chromosome 11 in-frame
duplica-tion, exon 1, c.52_60dup Leu18_Leu20dup, involving 1
allele) The patient was planned for trial of an alternative
antiresorptive therapy, but she was lost to follow-up
DISCUSSION
Failure to improve bone mass on DXA and occurrence
of recurrent fractures in the setting of conventional
osteo-porosis treatment should raise questions about the
under-lying cause of osteoporosis irrespective of age or gender
of the affected individual In an analysis of factors
asso-ciated with osteoporosis treatment failures, Diez-Pérez et
al (1) highlighted the following 3 variables predictive of
treatment failure: low SF-36 vitality score, 2 or more falls
within in the past year, and prior fracture Our patient had
an elevated vitality score and experienced multiple
frac-tures starting in early childhood, an important fact that was
overlooked in earlier evaluations Clinical features
sugges-tive of osteogenesis imperfecta or endocrine disorder were
not present in this patient, and her history ultimately led
to further investigation via genetic testing identifying an
LRP5 mutation
LRP5 is a coreceptor along with low-density
lipo-protein related lipo-protein 6 and the frizzled family of
trans-membrane receptors that facilitate Wnt protein activated
Wnt/β-catenin signaling in the Wnt signaling pathway (2)
Components of the Wnt pathway are essential for normal
bone development including osteoblast differentiation and
function, osteocyte directed bone formation, and
osteo-clast bone resorption (3) LRP5-mediated Wnt signaling
significantly contributes to maintenance of bone mass and
bone mechanical properties (4) The role of LRP5 in
osteo-blast function is illustrated in murine studies in which Cre
recombinase-mediated LRP5 gene recombination is
asso-ciated with a decrease in whole-body bone mineral density
and a deficiency in trabecular and cortical bone mass with
increasing age (5)
Gain-of-function mutations in LRP5 lead to increased
bone density known as sclerosteosis and van Buchem
syndrome These conditions are also characterized by
elevated bone density, hyperostosis with mandibular
enlargement, and thickening of the skull (6,7) Roetzer et
al (8) reported high bone mass associated with an LRP5
gain-of-function mutation in a 53-year-old mother and her
23-year-old daughter These patients also had increased
calvarial thickness and thickened long bone cortices
with-out any history of fractures (8)
Loss-of-function mutations of LRP5 in osteocytes are associated with suppression of mechanoresponsiveness to mechanical loading and a decrease in Young’s modulus leading to low bone mass (5) Homozygous loss-of-func-tion mutaloss-of-func-tions of the LRP5 receptor are associated with the osteoporosis-pseudoglioma syndrome Heterozygous LRP5 mutations are known as juvenile onset osteoporo-sis (9) This patient did not have features of the homozy-gous LRP5 loss-of-function mutation known as osteopo-rosis pseudoglioma/familial exudative vitreoretinopathy syndrome, but she did mirror case reports of juvenile-onset primary osteoporosis (10,11) These patients are known to have a heterozygous missense or frameshift LRP5 muta-tion and this explains the early occurrence of fractures in this patient (10,11)
Several studies report single nucleotide polymor-phisms (SNPs) involving the LRP5 receptor in women with age-related osteoporosis (12) In 2008, collaborators
in the GENOMOS study assessed the association of LRP5 variants (Val667Met, and Ala1330Val) with bone
miner-al density (BMD) and fracture risk in 37,534 individuminer-als from 18 participating teams in Europe and North America (13) Both the Met667 and Val667met allele of LRP5 was associated with reduced lumbar spine femoral neck BMD (12) However, the role of LRP5 mutations as the etiol-ogy of spine or hip fractures remains unclear Riancho et al (14) analyzed 39 single nucleotide LRP5 SNPs in a group
of 1,043 postmenopausal women and 394 women with hip fractures (14) Several LRP5 SNPs were associated with
vertebral fractures (odds ratio [OR] 0.67; P = 01) and with hip fractures (unadjusted ORs between 0.59 and 1.21; P
= 005 to 033), but were not significant after multivari-ate analysis adjusted for age and height (14) Thus, while several polymorphisms of the LRP5 gene tend to be asso-ciated with fractures, the significance remains to be deter-mined It is clear, however, that patients with recurrent fractures at a young age may have an underlying mutation variant in LRP5
CONCLUSION
In summary, we report a unique case of a woman with recurrent unexplained osteoporotic fractures despite anti-resorptive and anabolic treatment of osteoporosis in the setting of LRP5 mutation This case raises several ques-tions First, how common does this LRP5 polymorphism occur in treatment-refractory osteoporosis with recurrent fractures? Second, what is the basis for the marked vari-ability in the clinical expression of LRP5 polymorphisms? And third, what interventions could help limit fracture risk in this genetic disorder? Clinicians should consider referral to a geneticist for genetic testing in patients with unexplained fractures which could lead to early identifica-tion and potential prevenidentifica-tion treatment strategies for this unique patient population As genetic testing for the LRP5
Trang 3e364 Osteoporosis from LRP5 Mutation, AACE Clinical Case Rep 2019;5(No 6) Copyright © 2019 AACE
mutation is limited, we believe the accessibility of LRP5
testing should be expanded in commercial labs given the
possibility of a higher prevalence of disease in this unique
patient group Though there has been no reported use in this
specific condition, the recent development of antisclerostin
antibodies may theoretically be a therapeutic option for
these patients through direct targeting of the Wnt LRP5/6
signaling pathway The patient described in this case was
planned for trial on antisclerostin therapy, but she was lost
to follow-up
DISCLOSURE
The authors have no conflicts of interest to disclose
We certify that all individuals who qualify as authors have
been listed; that each has participated in the conception
and design of this work, the analysis of data, the writing
of the document, and the approval of the submission of
this version; that the document represents valid work; that
if we used information derived from another source, we
obtained all necessary approvals to use it and made
appro-priate acknowledgements in the document; and that each
takes public responsibility for it
The authors are employees of the United States
Government This work was prepared as part of their
offi-cial duties Title 17 U.S.C §105 provides that “Copyright
protection under this title is not available for any work of the
United States Government.” Title 17 U.S.C §101 defines
a U.S Government work as a work prepared by a military
service member or employee of the U.S Government as
part of that person’s official duties
The views expressed in this article are those of the
authors and do not necessarily reflect the official policy or
position of the Departments of the Navy/Army/Air Force,
Uniformed Services University of the Health Sciences, the
Department of Defense, or the U.S Government
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