31 / 72
revealing the flexural rigidity of thewhole femur with the cortical bone
as the major contributing structure. This might indicate aweaker effect
of the ovariectomy on the cortical bone compared to the effects on
healing of the osteotomy in the metaphyseal region.
Morphological assessment of fracture healing revealed bridging
cortices and consolidation of the defect in both groups in both groups
without detectable differences in total ossified tissue or vascular
volume fraction. In histology, this bony bridging in the OVX group was
rather in the shape of a bony cortex around the callus than a cortical
bridging. Histology additionally showed differences in bone healing
with a higher amount of cartilaginous remnant and more unminer-
alized tissue in the OVX rats compared to a more mature appearance of
bone consolidation in the sham group.
Osteoporotic fractures mainly affect the metaphyseal part of long
bones. There are relevant differences in the healing of metaphyseal
versus diaphyseal healing patterns after fracture. Therefore, fracture
healing studies for osteoporotic fractures should also focus on
metaphyseal models with plate fixation of the distal femur or proximal
tibia and not only on simple diaphyseal fracture models with
intramedullary roding. Data of two independent studies suggest
differences in fracture healing in metaphyseal fractures in ovariecto-
mized rats versus non-ovariectomized rats.
Conclusion
As the world aging population continues to escalate and the
prevalence of osteoporotic fracture is projected to increase substan-
tially, the healing process and outcome of fractures in osteoporotic
bone caused by postmenopausal estrogen deficiency (type I) or aging
(type II) have been extensively studied in the past decade. The well-
orchestrated healing process in osteoporotic bone seems to be having
one or few of the instruments playing slightly out-of-tune. The
expression of estrogen receptor was shown to be delayed during the
healing process that correlated to impairment in callus formation
capacity. Osteoporotic bone demonstrated no worse mechanical
sensitivity during mechanical stimulation may suggest a promising
therapeutic target for intervention. Other factors including progenitor
cell recruitment, differentiation, and proliferation during the early
phase of fracture healing; angiogenesis and vasculogenesis during the
early to mid-phase of healing; the capacity of extracellular matrix
production and callus formation during the mid-phase of healing; and
finally the capacity of callus remodeling at later phase of the healing
process were also found to be impaired in osteoporotic bone that are
common to both type 1 and type 2 osteoporotic animal models
(Figure 1). These factors are also highly promising therapeutic targets.
Since many of these findings and knowledge were obtained from
studying of mid-shaft femoral fracture in rats; hence, an osteoporotic
fracture model at the metaphyseal region is suggested for future
studies to broaden our understanding to the healing of trabecular bone
dense regions that is mostly affected by osteoporosis and more
clinically relevant.
Conflict of interest
The authors have no conflict of interest.
Acknowledgements
The part
“
Future of Osteoporotic Fracture Research
–
Small Animal
Model for Metaphyseal Fracture Healing
”
was supported by the
Deutsche Forschungsgemeinschaft (DFG) SFB-TRR 79.
The part
“
Mechanical Sensitivity in Estrogen Deficiency-induced
Osteoporotic Fracture (Type I) and the Role of Estrogen Receptors
”
was
supported by the National Natural Science Foundation of China (NSFC)
(Reference: A.03.15.02401).
References
[1]
Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res
1998;355:S7
–
21.
[2]
Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. Molecular mechanisms
controlling bone formation during fracture healing and distraction osteogenesis. J Dent
Res 2008;87:107
–
18.
[3]
Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a
post-natal developmental process: molecular, spatial, and temporal aspects of its
regulation. J Cell Biochem 2003;88:873
–
84.
[4]
Le AX, Miclau T, Hu D, Helms JA. Molecular aspects of healing in stabilized and non-
stabilized fractures. J Orthop Res 2001;19:78
–
84.
[5]
Thompson Z, Miclau T, Hu D, Helms JA. A model for intramembranous ossification during
fracture healing. J Orthop Res 2002;20:1091
–
8.
[6]
Bahney CS, Hu DP, Miclau T, Marcucio RS. The Multifaceted Role of the Vasculature in
Endochondral Fracture Repair. Front Endocrinol 2015;6:4.
[7]
Ortman JM, Velkoff VA, Hogan H. An aging nation: the older population in the United
States. Proc. Economics and Statistics Administration, US Dept. of Comm.; 2014.
[8]
Robinson CM, Court-Brown CM, McQueen MM, Wakefield AE. Estimating the risk of
nonunion following nonoperative treatment of a clavicular fracture. J Bone Joint Surg Am
2004:86-A(7):1359
–
65.
[9]
Müller E, Wick M, Russe O, Muhr G. Management of odontoid fractures in the elderly. Eur
Spine J 1999;8:360
–
5.
[10]
Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical
fractures. Osteoporos Int 2000;11:556
–
61.
[11]
White BL, Fisher WD, Laurin CA. Rate of mortality for elderly patients after fracture of the
hip in the 1980
’
s. J Bone Joint Surg Am 1987;69:1335
–
40.
[12]
Augat P, Simon U, Liedert A, Claes L. Mechanics and mechano-biology of fracture healing
in normal and osteoporotic bone. Osteoporos Int 2005;16(Suppl 2):S36
–
43.
[13]
Namkung-Matthai H, Appleyard R, Jansen J, Hao Lin J, Maastricht S, Swain M, et al.
Osteoporosis influences the early period of fracture healing in a rat osteoporotic model.
Bone 2001;28:80
–
6.
[14]
KuboT, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, et al. Osteoporosis influences
the late period of fracture healing in a rat model prepared byovariectomyand lowcalcium
diet. J Steroid Biochem Mol Biol 1999;68:197
–
202.
[15]
Neidlinger-Wilke C, Stalla I, Claes L, Brand R, Hoellen I, Rubenacker S, et al. Human
osteoblasts from younger normal and osteoporotic donors show differences in
proliferation and TGF beta-release in response to cyclic strain. J Biomech
1995;28:1411
–
8.
[16]
Shiels MJ, Mastro AM, Gay CV. The effect of donor age on the sensitivity of osteoblasts to
the proliferative effects of TGF(beta) and 1,25(OH(2)) vitamin D(3). Life Sci
2002;70:2967
–
75.
[17]
Cheung WH, Sun MH, Zheng YP, Chu WC, Leung AH, Qin L, et al. Stimulated angiogenesis
for fracture healing augmented by low-magnitude, high-frequency vibration in a rat
model-evaluation of pulsed-wave doppler, 3-D power Doppler ultrasonography and
micro-CT microangiography. Ultrasound Med Biol 2012;38:2120
–
9.
[18]
Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, et al. Age-dependent
impairment of angiogenesis. Circulation 1999;99:111
–
20.
[19]
Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased
maximal life span and accelerated senescence of bone marrow stromal cells. Bone
2003;33:919
–
26.
[20]
Leppanen OV, Sievanen H, Jokihaara J, Pajamaki I, Kannus P, Jarvinen TL. Pathogenesis of
age-related osteoporosis: impaired mechano-responsiveness of bone is not the culprit.
PLoS One 2008;3:e2540.
[21]
Jarvinen TL, Kannus P, Pajamaki I, Vuohelainen T, Tuukkanen J, Jarvinen M, et al. Estrogen
deposits extra mineral into bones of female rats in puberty, but simultaneously seems
to suppress the responsiveness of female skeleton to mechanical loading. Bone
2003;32:642
–
51.
[22]
Shi HF, CheungWH, Qin L, Leung AH, Leung KS. Low-magnitude high-frequency vibration
treatment augments fracture healing in ovariectomy-induced osteoporotic bone. Bone
2010;46:1299
–
305.
[23]
Cheung WH, Chin WC, Qin L, Leung KS. Low intensity pulsed ultrasound enhances
fracture healing in both ovariectomy-induced osteoporotic and age-matched normal
bones. J Orthop Res 2012;30:129
–
36.
[24]
Rubinacci A, Marenzana M, Cavani F, Colasante F, Villa I, Willnecker J, et al. Ovariectomy
sensitizes rat cortical bone to whole-body vibration. Calcif Tissue Int 2008;82:316
–
26.
[25]
Aguirre JI, Plotkin LI, Gortazar AR, Millan MM, O
’
Brien CA, Manolagas SC, et al. A novel
ligand-independent function of the estrogen receptor is essential for osteocyte and
osteoblast mechanotransduction. J Biol Chem 2007;282:25501
–
8.
[26]
Batra GS, Hainey L, Freemont AJ, Andrew G, Saunders PT, Hoyland JA, et al. Evidence for
cell-specific changes with age in expression of oestrogen receptor (ER) alpha and beta in
bone fractures from men and women. J Pathol 2003;200:65
–
73.
[27]
Chow SK, Leung KS, Qin L, Wei F, CheungWH. Callus formation is related to the expression
ratios of estrogen receptors-alpha and -beta in ovariectomy-induced osteoporotic
fracture healing. Arch Orthop Trauma Surg 2014;134:1405
–
16.
[28]
Chow SK, Leung KS, Qin L, Cheung WH. Restoration of estrogen receptor expression for
osteoporotic fracture healing by low-magnitude high-frequency vibration therapy.
Annual Meeting of the Orthopaedic Research Society. New Orleans, LA, USA; 2014.
[29]
Wei FY, Leung KS, Li G, Qin J, Chow SK, Huang S, et al. Low intensity pulsed ultrasound
enhancedmesenchymal stem cell recruitment through stromal derived factor-1 signaling
in fracture healing. PLoS One. 2014;9:e106722.
W. H. Cheung et al. / Injury, Int. J. Care Injured 47S2 (2016) S21
–
S26
S25