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Opinion Paper
The relevance of biomaterials to the prevention and treatment of
osteoporosis
D. Arcos
a,b,c
, A.R. Boccaccini
a,d
, M. Bohner
a,e
, A. Díez-Pérez
a,f
, M. Epple
a,g
, E. Gómez-Barrena
a,h
,
A. Herrera
a,i,j
, J.A. Planell
a,b,k
, L. Rodríguez-Mañas
a,l
, M. Vallet-Regí
a,b,c,
⇑
a
Envejecimiento: red de excelencia española y europea para la prevención y tratamiento local de fracturas osteoporóticas, MINECO, Spain
b
Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
c
Dpto. Química Inorgánica y Bioinorgánica, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital, 12 de Octubre i+12, Madrid, Spain
d
University of Erlangen-Nuremberg, Institute of Biomaterials, 91058 Erlangen, Germany
e
RMS Fundation, CH-2544 Bettlach, Switzerland
f
Hospital del Mar-IMIM, Department Internal Medicine, Universidad Autónoma de Barcelona, Barcelona, Spain
g
University of Duisburg-Essen, Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), D-45117 Essen, Germany
h
Servicio Cirugia Ortopedica & Traumatologia, Hospital La Paz, IdiPAZ, Universidad Autonoma Madrid, Madrid 28046, Spain
i
University of Zaragoza, Department of Surgery, E-50009 Zaragoza, Spain
j
Miguel Servet University Hospital, Department of Orthopaedic Surgery & Traumatology, Zaragoza 50009, Spain
k
Institute of Bioengineering of Catalonia IBEC, BaldiriReixac 15-20, Barcelona 08028, Spain
l
University Hospital Getafe, Division Geriatric Medicine, Madrid, Spain
article info
Article history:
Received 6 November 2013
Received in revised form 24 December 2013
Accepted 3 January 2014
Available online xxxx
Keywords:
Osteoporosis
Biomaterials
Ageing
Bone
abstract
Osteoporosis is a worldwide disease with a very high prevalence in humans older than 50. The main clin-
ical consequences are bone fractures, which often lead to patient disability or even death. A number of
commercial biomaterials are currently used to treat osteoporotic bone fractures, but most of these have
not been specifically designed for that purpose. Many drug- or cell-loaded biomaterials have been pro-
posed in research laboratories, but very few have received approval for commercial use. In order to ana-
lyze this scenario and propose alternatives to overcome it, the Spanish and European Network of
Excellence for the Prevention and Treatment of Osteoporotic Fractures, ‘‘Ageing’’, was created. This net-
work integrates three communities, e.g. clinicians, materials scientists and industrial advisors, tackling
the same problem from three different points of view. Keeping in mind the premise ‘‘living longer, living
better’’, this commentary is the result of the thoughts, proposals and conclusions obtained after one year
working in the framework of this network.
Ó2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction and context
Ageing of the musculoskeletal system is a rapidly growing issue
due to the demographics associated with ageing populations
throughout the world. Its consequences on health are linked,
among others, to osteoporosis, degenerative osteoarthritis and
muscle deterioration or sarcopenia. These three elements interact
to produce a picture of frailty, which often leads to bone fracture
when a fall occurs, typically in people of advanced age. Fracture
prevention, patient recovery, and avoidance of subsequent frac-
tures constitute a challenge that has not yet been resolved [1].
No satisfactory solution exists to the problem of bone weaken-
ing due to osteoporosis. Surgical procedures to implant a device in
weakened bone often lead to a clinical result that is worse than if
such an intervention were to be performed on a young and strong
bone. The risk of fracture increases exponentially with age, and the
recovery process from a fracture is often slow, difficult and may
lead to a disability or even to the death of the patient. Up to 25%
of patients who suffer a femur fracture will die within a year. Of
those who survive, approximately half are totally or partially
dependent [2]. Chronic pain, functional limitation, social depen-
dence, psychological disorders, reduced mental health score and
social isolation combine to cause a serious deterioration in the
quality of life.
Various treatments are currently available to reduce the impact
of bone fragility, but there is a lack of alternatives to restore bone
strength. Moreover, there are no comprehensive treatments
http://dx.doi.org/10.1016/j.actbio.2014.01.004
1742-7061/Ó2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
⇑
Corresponding author at: Dpto. Química Inorgánica y Bioinorgánica, Univers-
idad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital, 12 de
Octubre i+12, Madrid, Spain. Tel.: +34 913941861.
E-mail address: vallet@farm.ucm.es (M. Vallet-Regí).
Acta Biomaterialia xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actabiomat
Please cite this article in press as: Arcos D et al. The relevance of biomaterials to the prevention and treatment of osteoporosis. Acta Biomater (2014),
http://dx.doi.org/10.1016/j.actbio.2014.01.004
available for the whole damaged system, i.e. able to address the
three factors of musculoskeletal fragility: bone, cartilage and mus-
cle. These three factors are both the cause and consequence of
osteoporotic fracture [3].
The economic aspects that surround this social and health issue
are also of paramount importance [4], hence any action aimed at
cost reduction need to be seriously considered. It is worth men-
tioning that a surgical intervention for a hip prosthesis implanta-
tion has a health service cost of around €20,000, including direct,
indirect and intangible costs [5]. The total current cost of hip frac-
ture treatments of osteoporotic origin in the US is US$20.3 billion.
This cost, far from diminishing, has experienced continuous
growth throughout the 20th century and the first decade of the
21st century [6–8]. In fact, the total number of osteoporotic frac-
tures in 1950 was 1.47 million and the projection for 2050 is
around 6.3 million [9]. In the European Union, direct costs related
to osteoporotic fractures in 2000 were estimated at €31.7 billion
[10]. Moreover, increasing life expectancy suggests even more seri-
ous difficulties for the future.
In the context of a socio-health problem such as osteoporosis,
we may highlight the three main agents involved:
The patient. All publications and websites devoted to osteopo-
rosis show that there is currently no satisfactory solution and
that it remains one of the major challenges for public health.
This claim is based on significant mortality and disability (per-
sonal costs) caused by osteoporosis and the economic costs of
the management, including treatment, of patients (social costs).
The patient, as a key player in the issue, is therefore still waiting
for a satisfactory solution.
The therapeutic team. Once the fracture (hip, spine, wrist, etc.)
has occurred, the surgeon has very few surgical solutions avail-
able. In addition, other issues concerning general health (frailty,
malnutrition, cognitive disorders, co-morbid conditions, poly-
pharmacy, etc.) may make both the pre- and post-surgical man-
agement of patients difficult. The reports issued by many of
these professionals support the idea that enormous patient ben-
efits could stem from preventive solutions.
The national health system. In the European Union, most
national health systems are the purchasers of prosthetic prod-
ucts and the defrayers of the intervention and hospitalization
costs. Undoubtedly, the gradual ageing of society will entail
an increased number of osteoporotic patients, and this scenario
could challenge the sustainability of some national health sys-
tems in the next few years.
Research into biomaterials over the last 30 years has produced
many variants of technologies, materials and physical forms in-
tended to supplement or replace osteoporotic bone. However, very
few of these have achieved broad application in either prevention
or treatment of osteoporotic bone and its lesions. For those who
are not directly involved with the commercialization of biomateri-
als it may be surprising that so little biomaterials research output
has reached the operating. However, there are many obstacles that
biomaterials and their creators must overcome to prove safety and
efficacy to the level required by the regulatory bodies in each coun-
try. Even where these are overcome it is far from certain that a bio-
material will be commercially exploited. Thus, the position today is
that there are more limitations than opportunities for transferring
biomaterials into clinical use, particularly in the management of
poor bone quality. This opinion article will discuss some of the is-
sues that account for the paucity of biomaterials in clinical use and
also suggest what more might be done to encourage more viable
clinical applications.
To begin with, there are some mismatches between the aspira-
tions of biomaterials researchers and (unmet) clinical needs. The
goals of industry and academia are broadly similar to those of
the surgical community in wanting to improve the clinical out-
comes of a given treatment. However, biomaterials are often devel-
oped by identifying unmet clinical needs (note the terms used here
such as ‘‘user needs’’ are those required in design control and qual-
ity systems for medical device design). Even where the unmet
needs are properly researched, their effective translation from user
needs through to formal clinical outcome studies is quite uncom-
mon. Even rarer is that a proper post-market surveillance is under-
taken to ensure that any adverse outcomes are recognized as part
of a quality-control system.
Considering this scenario, an interdisciplinary group of experts
comprising clinicians, materials scientists and industrial advisors
have initiated the Spanish and European Network of Excellence
for the Prevention and Treatment of Osteoporotic Fractures, ‘‘Age-
ing’’ (www.agening.net). This network shares and puts together
information coming from different specialties and proposes possi-
ble solutions for the treatment of ageing diseases in bone, such as:
identifying the most prevalent clinical problems and the most
relevant clinical solutions;
analyzing and discussing the role of drugs, implants, biomateri-
als and surgical techniques in such treatments; and
thinking about possible innovative treatments and even
prevention.
This article is the result of one year of discussions and thoughts,
proposals and conclusions obtained via the ‘‘Ageing’’ framework.
2. Osteoporosis—a clinician’s point of view
2.1. Significance of osteoporosis to frailty and disability
Over the last hundred years a profound demographic change
has taken place, the main consequence of which has been a signif-
icant increase in the percentage of people older than 65, who now
constitute around 17% of the population. In addition to this demo-
graphic change, a second transition occurred—an epidemiological
transition that produced a shift from the predominance of acute,
single and communicable diseases to a predominance of chronic,
multiple and non-communicable diseases. As a consequence of
these two complementary transitions, the spectrum of diseases
and the mode of illness has dramatically changed. If we finally take
into account that life expectancy will continue to increase slowly
(EUROPOP forecasts support a modest increase in life expectancy
of around 5–7 years in EU countries over the next 50 years), the fo-
cus of health interventions should change from prolonging life to
improving the quality of life.
The most important surrogate of this quality of life is function.
As functional status deteriorates, the quality of life gets worse.
During the last century, as we prolonged life expectancy we were
opening the door to the increased risk of disability that comes with
age. With aging, the loss of functional reserve capacity puts people
at high risk of developing disability. This is the explanation for the
increase in the rates of disability that accompanied the extension
of life expectancy during the last century (Fig. 1). During the last
25 years, however, this tendency has changed in many countries.
Although we do not know the causes explaining this drop in dis-
ability rates, this trend clearly shows that disability is an avoidable
consequence of the ageing process and that if its main causes were
known we could intervene in the hope of decreasing the preva-
lence of disability [11].
The fight against disability has several options, but probably the
least attractive is to passively wait for the development of a dis-
ability. As previously stated, the main cause of disability is the loss
2D. Arcos et al./ Acta Biomaterialia xxx (2014) xxx–xxx
Please cite this article in press as: Arcos D et al. The relevance of biomaterials to the prevention and treatment of osteoporosis. Acta Biomater (2014),
http://dx.doi.org/10.1016/j.actbio.2014.01.004
of functional reserve capacity. However, to successfully recover
from disability a high level of that capacity is needed. In fact, only
a small percentage (30%) of older people with disability are able
to improve functionally during the first year [12]. This is why the
main approach to improving the functional status of the popula-
tion should be the prevention of disability, instead of waiting to
treat it. With this purpose in mind, the concept of frailty has
emerged as a relevant tool to detect people with the highest risk,
both short and long term, of developing a disability (Fig. 2). Frailty
is a state of increased vulnerability to stressors due to a decreased
physiological reserve in multiple systems and a limited capacity to
maintain homeostasis [13]. Its prevalence is around 10%, ranging
from 1% to 3% for 65 year old people to more than 30% in people
over the age of 80. It predicts the risk of suffering from multiple ad-
verse outcomes, including death, hospitalization, disability and
falls [14]. Detecting frailty is of clinical importance [15] as it has
been shown that some therapeutic approaches, mainly based on
physical exercise, are able to bring patients out of a state of frailty,
or at least delay the progression of frailty to full disability [16].
Within this framework, the approach to osteoporosis, as is also
the case for many other chronic conditions prevalent in older peo-
ple, should be focused on the prevention of the clinical problems
associated with frailty and disability. The most frequent of these
conditions is hip fracture. Taking into account that the most impor-
tant risk factor for hip fracture is falling, the right way to manage
these patients is based on a comprehensive assessment and man-
agement of falling patients. For this purpose the introduction of
specialized units to deal with falls and fractures is becoming the
standard approach for managing these patients, as recommended
by a number of different organizations, e.g. World Health Organi-
zation, National Institute for Health and Care Excellence, British
Orthopaedic Association and the US Preventive Services Task Force.
In this regard, the focus in these units is to reinforce the idea of
a continuum of care and a comprehensive approach to avoiding or
preventing disability in these patients, taking advantage of all
available opportunities. One of these opportunities stems from ad-
vances in the biomaterials used in the surgical materials used in
those patients with hip fracture. These materials have a twofold
aim in the prevention of frailty and disability: firstly, to allow an
early mobilization of the patient after surgery; and secondly, to
provide a quick and efficient restoration of bone and, as far as
possible, of the musculoskeletal unit.
2.2. Clinical aspects, prophylaxis and treatment of osteoporosis
Osteoporosis is a common disease the incidence of which is rap-
idly increasing as the population ages [17,18]. The loss of bone and
deterioration in bone quality [19] induce decreased bone strength
with the associated increase in fracture risk [20]. The main clinical
consequences of the condition, therefore, are fractures, which are
associated with significant morbidity [21] and mortality [22].
Several factors contribute to an increased risk of osteoporosis
and fracture. These risk factors have recently been structured in
a decision algorithm, the FRAXÓtool, that allows the clinician to
calculate the absolute risk of fracture in ten years for an individual
patient [23]. This formula has been validated in a number of coun-
tries [24] and is available in several languages and for a large num-
ber of countries. Moreover, and also partially integrated into FRAX,
an important number of comorbidities have been identified that
also influence fracture risk either by deteriorating bone or by
increasing the propensity of patients to fall [25].
The clinical diagnosis of osteoporosis relies mainly in the mea-
surement of bone mineral density by dual-energy X-ray absorpti-
ometry (DEXA) in several skeletal regions [26]. Other methods
also calculate the mineral density by using ultrasound or quanti-
fied computerized tomography (QCT) scanners but their use in
the general population is limited. These methods have in common
the limitation of measuring only one of the determinants of bone
strength, the amount of mineral or bone mass, but do not capture
the quality of the material. For this to be done adequately, labora-
tory testing of ex vivo specimens is required to measure a broad
spectrum of mechanical properties (brittleness, toughness, work
Fig. 1. Three trajectories of ageing, with a differential risk for disability.
Fig. 2. The path from robustness towards frailty and disability: factors, biomarkers and modulators.
D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx 3
Please cite this article in press as: Arcos D et al. The relevance of biomaterials to the prevention and treatment of osteoporosis. Acta Biomater (2014),
http://dx.doi.org/10.1016/j.actbio.2014.01.004
to failure, etc.) [27]. Recently new techniques have been developed
for the direct measurement of bone tissue strength [28,29].
Biochemical markers of bone turnover, reflecting the rate of cell
activity in the bone remodeling cycle, have been also extensively
developed and can predict the future fracture risk [30]. They also
provide the clinician with information about how the patient is
responding to treatment [31]. Last but not least, the simple detec-
tion in a routine radiograph or after a trauma permits the identifi-
cation of fractures, the cornerstone of the disease and the event
responsible for the morbidity and mortality associated with
osteoporosis. Suffering a low-energy traumatic fracture (fragility
fracture) is the ultimate demonstration of osteoporosis and as such
constitutes a diagnostic marker.
Osteoporosis prevention has two phases, primary prevention
and secondary prevention. Primary prevention starts during intra-
uterine life, childhood and adolescence, given that this determines
the development of a healthy strong skeleton in the adulthood.
Even though genetic factors determine to a great extent the nature
of our bones, the promotion of physical activity, adequate nutrition
and the avoidance of negative factors for normal bone develop-
ment are extremely important.
Secondary prevention starts once bone loss or bone fracture has
occurred. Suffering a fracture is the most potent predictor of new
fractures, in a progression of risk referred to as a ‘fracture cascade’.
Two main groups of drugs are currently available for the manage-
ment of the patients with osteoporosis: anticatabolics and anabo-
lics [32]. The anticatabolic or antiresorptive agents suppress or
attenuate the activity of the bone-resorbing cells, the osteoclasts,
hence stopping bone loss and increasing bone strength. On the
other hand, anabolic agents are capable of inducing bone forma-
tion, and therefore can reverse in part the deterioration induced
by the osteoporosis progression. The advances in this therapeutic
field have been very significant over the last two decades since
there are now several classes of drugs, including both chemical
and biological entities, that decrease the risk of vertebral fracture
and in some cases also of non-vertebral fractures (e.g. hip). The
main development in treatment has been in postmenopausal
osteoporosis in women although treatments also exist for gluco-
corticoid-induced osteoporosis [33,34] and osteoporosis in men
[35]. In spite of the substantial body of clinical evidence, the man-
agement of this disease is still highly variable across different
countries [36] and a considerable proportion of cases does not re-
spond to the treatment [37,38]. Whilst antiosteoporosis drugs have
their side effects [39], these bone treatments have shown other
health benefits such as cancer reduction in some instances [40]
and also a decrease of the overall mortality [41]. In summary, there
are now some effective tools that enable detection, diagnosis and
treatment of osteoporosis to combat the progression of this meta-
bolic disease, resulting from the ageing of societies worldwide.
2.3. Surgical treatment of osteoporotic fractures
Osteoporotic bone has special morphological and biological
characteristics. Fracture healing depends mainly on the mechanical
stability at the fracture site and the biological process of bone repair.
Osteoporosis entails a decreased bone mass and an altered bone
structure, leading to a lowered mechanical strength. Therefore, oste-
oporotic fractures are often severely comminuted, especially in tra-
becular bone areas. Fracture comminution and trabecular collapse
not only result in bone defects with impaired fracture stability,
but also make anatomical reduction and surgical reconstruction dif-
ficult. Biologically, the mesenchymal stem cells (MSCs) of osteopo-
rotic bone have less capacity to differentiate into osteoblasts than
those of healthy bone, possibly due to impaired osteoinductive sig-
nals and/or lower expression of bone morphogenetic protein-2
(BMP-2). A decreased angiogenetic capacity at the fracture site is
also common in osteoporotic bone [42].
Fracture fixation planning is determined by the special mechan-
ical properties of osteoporotic bone. It has to be noted that even in
normal everyday activity, the loads supported by bones and joints
are both large and dynamic, changing in both magnitude and direc-
tion with every step the patient makes. While implant failure is
potentially a risk, less rigid fixation devices, such as intramedullary
nails, bridge plates and tension band constructs, are preferred for
minimizing bone–implant interface stress and the concomitant
risk of bone failure. In compromised bone, improved screw-holding
power is essential to prevent screw pullout and/or migration and
to minimize implant loading. Moreover, comminution makes frac-
ture reduction more difficult, requiring the use of autologous bone
grafts or biomaterials to fill bone defects and to augment bone
fragments. It is therefore possible by combining implants and bio-
materials to achieve sufficient overall assembly stability and frac-
ture healing. Less load-resistant materials, even with bioactive
capacity, may be used in the upper limb fractures. However, spine
and lower limb fractures require the use of inert biomaterials with
greater load-bearing capacity, although calcium phosphate ce-
ments may occasionally be used.
The most common osteoporotic fractures involve the spine, the
hip and the distal radius. Surgical treatment of these fractures has
changed in recent years. The distal radius fracture is known as
‘‘sentinel fracture’’ because it is the first warning sign of osteoporo-
sis. We now know that surgical treatment of distal radial fractures,
particularly by plates through palmar or dorsal approaches, does
better than conservative treatment [43]. Severe comminution
and bone fragment collapse are often present, requiring the use
of biomaterials to fill bone defects, achieve fracture stability and
promote bone union.
Spine fracture is the most frequent osteoporotic fracture. Early
diagnosis and medical treatment with anabolic drugs are essential
to increase bone strength and prevent the so-called ‘‘fracture cas-
cade’’. Vertebroplasty and kyphoplastyas minimally invasive tech-
niques show excellent results in terms of quality of life, pain relief
and functional recovery, both short and long term [44]. More
importantly, Edidin et al. [45] showed that the mortality of
patients suffering from a vertebral bone fracture was significantly
reduced when their fractures were treated by vertebroplasty or
kyphoplasty.
Treatment of hip fractures varies according to their anatomical
location and classification. These are divided according to anatom-
ically defined regions: intracapsular neck, extracapsular neck, per-
trochanteric, intertrochanteric and subtrochanteric. Intracapsular
fractures (see Fig. 3) present biological problems due to the loss
of blood supply to the proximal fragment. Osteosynthesis is only
indicated for undisplaced Garden I and II type intracapsular frac-
tures in patients younger than 70 years. Total or partial hip arthro-
plasty, depending on the patient age, is the preferred technique for
displaced grade (Garden III and IV) fractures [46]. The dilemma
over the choice of fixation method of prosthesis to bone (cemented
or uncemented) is solved in favor of cemented prostheses: taking
into account the mean age of our patients (>80 years) more of
95% of arthroplasties are fixed to bone with cement, because loss
of bone mass in osteoporotic bone prevents good primary stability
by press-fitting of uncemented prosthesis and hinders perfect bony
integration of components; on the other hand, cemented prosthe-
ses have lower revision rates than uncemented due to aseptic
loosening and offer excellent clinical results. Uncemented arthro-
plasties are indicated only in younger patients (<70 years) with
good bone quality and long life expectancy [47–51].
The sliding hip screw, a device used in the treatment of trochan-
teric fractures, has been to some extent replaced over the years by
intramedullary nails with a sliding cephalic screw. These are often
4D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx
Please cite this article in press as: Arcos D et al. The relevance of biomaterials to the prevention and treatment of osteoporosis. Acta Biomater (2014),
http://dx.doi.org/10.1016/j.actbio.2014.01.004
made from titanium alloy and may feature reduced diameter and
length to enable implantation by minimally invasive surgery
[52]. The key determinants for good outcome are the correct place-
ment of the cephalic screw and good anatomical fracture reduc-
tion. If a large posteromedial comminution is present, the bone
defect can be augmented with a bone substitute such as a calcium
phosphate cement. In cases of severe osteoporosis, the bone struc-
ture of the femoral head can be strengthened by injecting poly-
methylmethacrylate (PMMA) cement through the cephalic screw,
a technique known as augmentation, which prevents the cut-out.
The challenge for the future will be the development of bioac-
tive biomaterials that combine load bearing, interconnected poros-
ity and the ability to be loaded with biological factors that promote
fracture healing.
3. Osteoporosis. A materials scientist’s point of view
In an osteoporotic scenario, the paucity of bone and the de-
creased osteoblastic function result in an impaired response to im-
plants compared with healthy bones. As mentioned in previous
sections, this evidence is often observed by orthopedic surgeons
in their daily practice of fracture reduction in osteoporotic patients.
The experience of clinicians, outlined in Sec. 2, teaches us that the
primary issue with these patients is that they suffer from fractures
that require some form of fixation, and the fixation devices such as
plates, screws, nails, etc., are difficult to fix in low-quality bone. In
addition, there are scenarios other than the fractures, which also
affect biomaterials performance in osteoporotic patients. For in-
stance, the response of osteoporotic bone to endosseous implants,
such as stems of total joint prostheses or endosseous dental im-
plants, is also strongly impaired. In these cases, the implant failure
is due to poor biological fixation, which is a consequence of insuf-
ficient osteogenesis around the implant [53]. Despite this evidence,
there are no clinically approved biomaterials specifically tailored
for application in osteoporotic bones. Certainly, there are some
examples of medical devices for osteosynthesis with special de-
signs, but they are made of the same biomaterials as the conven-
tional devices, such as titanium alloys, cobalt alloys or stainless
steel.
Attempts to reduce osteoporotic fractures usually involve two
classes of biomaterials: metallic implants and cements. Their func-
tion is slightly different: whereas metallic implants are used as
primary fixation devices, cements are mainly used as reinforce-
ment of the metallic hardware. However, cements are also used
as stand-alone devices, e.g. for bone augmentation procedures
(injection of the cement into osteoporotic bone) [54]. Indeed there
is increasing research in the field of injectable calcium phosphate
cements with recent efforts focusing on incorporating different
additives including inorganic bioactive elements, e.g. bioactive
glass [55], radiopacifiers, e.g. tantalum oxide or barium sulfate
[56], biodegradable polymers to improve the injectability [57]
and modifications to incorporate antibiotic releasing capability
[58]. Another difference between metallic implants and cements
is the way they are adapted for osteoporosis-related indications.
As mentioned above, metallic biomaterials are the same as those
used in non-osteoporotic patients, but the implant shape is modi-
fied to accommodate osteoporosis-specific requirements. Some-
times, even new implants are created. For cements, the accent is
on changing the composition to obtain specific properties such as
constant viscosity or high radiopacity. In addition, bioactive and/
or resorbable ceramics such as calcium phosphates or bioactive
glasses can be used to fill voids, thus avoiding the harvest of autog-
enous bone from the iliac crest.
Besides the osteoporotic fracture reduction, biomaterials sci-
ence also offers a possible approach to dealing with the challenge
of impaired osteointegration of permanent endosseous implants.
Osteointegration in these cases is seriously affected, mainly due
to the decreased osteoblast activity. An osteoporotic environment
strongly affects the primary (short-term) stability of the implant,
because the quality of the host bone is significantly decreased.
Moreover, biological stability (early and long-term) is also im-
paired, as it requires deposition of newly formed bone in intimate
contact with the implant [59]. Since this process involves the bal-
anced action of osteogenic and bone-resorbing cells, osteoporosis
often has a poor prognosis and delayed healing and osteointegra-
tion with endosseous implants. However, similarly to devices for
fracture fixation purposes, research efforts have so far not involved
the preparation of new metal alloys specifically intended to fabri-
cate endosseous implants for osteoporotic patients [60].
On the contrary, research on bioceramics (even playing a minor
role compared with metals in the treatment of osteoporosis)
envisions this scenario in a different way and often deals with
the specific case of osteoporotic bone. In this sense, calcium phos-
phatebioceramics [61,62] and SiO
2
-based mesoporous materials
have been widely proposed as potential local antiosteoporotic drug
delivery systems [63], when used for void fillers in fracture fixa-
tion, bone grafting or augmentation.
Combinations of biomaterials with cellular therapy and local
drug delivery are of enormous interest because of the great oppor-
tunities that they offer to this problem [64–66]. However, the tech-
nical and biological problems associated with the cells or materials
to be used are important. These include (i) the limited cell viability;
(ii) the transient mechanical properties of the materials once im-
planted until they are substituted by regenerated bone; and (iii)
the biological integration at the specific bone site where they are
implanted. To solve these problems, in vitro and in vivo tests
should be performed in experimental conditions that mimic as
much as possible the most prevalent situations associated with
bone pathologies: estrogen depletion, diabetes mellitus, ageing
and treatment with glucocorticoids. To make progress in this area,
standard procedures to collect, manipulate and store mesenchymal
osteoprogenitors (such as the bone marrow) should be defined.
Thereafter, it would be possible to start considering the fabrication
of a medical device following criteria accepted by national and
international regulatory agencies for on-demand administration.
3.1. Metallic implants
Since osteoporotic bone is much more fragile than healthy bone,
metallic implants used to treat osteoporotic bone fractures have to
be designed differently. One strategy consists in increasing the
contact surface area between bone and implant. This can be done
by increasing the diameter of osteosynthesis screws [67]. Another
approach is to use locked osteosynthesis plates [68]. In the latter
case, plate loosening is only possible if all screws become loose
simultaneously. This is in large contrast with unlocked plates
whose fixation onto the bone relies on the compressive action of
screws. A third approach consists in designing completely new
Fig. 3. Displaced intracapsular fracture (left) and trochanteric fracture (right).
D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx 5
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implants, such as expandable spacers for vertebral height restora-
tion (e.g. VBS (DePuy Synthes), Spinejack Vexim (Vexim), Kiva
(Benvenue Medical)) or cannulated screws (e.g. Matrix Spine Sys-
tem (Depuy Synthes)) to permit cement injection through the
screw [69]. Cement injection through the screws (Figs. 4 and 5) re-
sults in an increase in the resistance of the fractured vertebral body
and avoids the pull-out of screws in osteoporotic spine [70,71].
Another interesting topic is the role of surface roughness and
wettability in implant osteointegration [72]. This strategy has
achieved some degree of success especially in metallic implants
for periodontal surgery. For instance, modifications of the microto-
pography of titanium implants have demonstrated enhanced
osteointegration [73]. Prospective studies on implants with rough
surfaces evidence very promising clinical results compared with
those with smoother surfaces [74]. In addition, the recent develop-
ment of nanotechnology in the biomaterials field also allows the
incorporation of nanofeatures on the implant surface. In this sense
there are some studies that evidence the significance of nanoto-
pography in the success of peri-implant bone formation [75,76].
In addition, the surface wettability is closely related to the surface
micro/nanoroughness and also influences the osteoblast behavior.
In principle, hydrophilic surfaces enhance osteoblast maturation
[77], thus leading to better clinical results [78].
The coating of the surface of metallic implants has been suc-
cessfully applied for decades to improve their bone-binding prop-
erties, with the cementless hip endoprosthesis and dental implants
being the best-known examples. In particular, calcium phosphate
coatings have been applied by various techniques, e.g. plasma
spraying, sputtering techniques and sol–gel coating [79–82].
Although an increased bone-binding ability has been found, a re-
cent review points out that long-term clinical studies indicate con-
tradictory results [83]. However, it may be envisioned that in
osteoporotic bone, a surface modification of metallic implants, be
it by calcium phosphate or by drug-releasing coatings, will help
to improve the clinical outcome, at least in the short-term perfor-
mance when the primary stability is needed.
3.2. Cements
PMMA cement is the material of choice for the reinforcement of
metallic implant fixation or osteoporotic bone due to its high
mechanical properties and low cost. However, PMMA cement has
very important drawbacks such as monomer toxicity [84], risk of
bone necrosis due to a highly exothermic setting reaction [85], ab-
sence of biodegradation that may lead to fatigue failure [86], or too
high material stiffness that may increase the fracture risk of verte-
bra adjacent to PMMA-reinforced vertebra [87]. As a result, various
cements have been proposed to replace PMMA cement, but their
success remains very limited due to toxicity, regulatory issues,
price or mechanical properties. For example, a few years ago the
company Orthovita proposed a dual-paste cement called Cortoss.
This cement was inspired from the composition of dental cement,
i.e. it consists of a matrix of bis-GMA (2,2-bis[4-(2-hydroxymeth-
acryloxypropyl)phenyl] propane), bis-EMA (2,2-bis[4-(2-methac-
ryloxyethoxy)]phenyl propane) and TEGDMA (triethylene glycol
dimethacrylate) reinforced with bioactive glass particles [88]. Cor-
toss presents better handling, higher mechanical properties and
lower toxicity than PMMA cements. Unfortunately, it has had lim-
ited success, possibly on the grounds of price (higher production
costs than PMMA cements). More recently, a silicone cement called
VK100 was proposed by the company BonWRX. This dual-paste ce-
ment contains dimethyl methylvinyl siloxanes (87%), barium sul-
fate powder (14%) and a platinum catalyst (15 ppm as metal) in
the first component, and dimethyl methylvinyl siloxanes (78%),
barium sulfate powder (15%) and a methylhydrogensiloxane
cross-linker (7%) in the second component. Unfortunately, preli-
minary results for bone augmentation applications (‘‘elastoplasty’’)
are very poor with more than 60% leakage (cement flowing outside
the targeted location, e.g. into the spinal canal) and pulmonary
embolism [89]. The very slow setting reaction was also mentioned.
Considering the poor biological properties of polymer cements,
quite a few ceramic cements have been proposed for bone aug-
mentation procedures. Interesting candidates have included cal-
cium phosphate cements (CPCs), but the results have been rather
disappointing [90–93]. One main issue with CPCs is their poor
mechanical (shear stress) properties. Thus, CPCs can at most be
used in load-sharing sites. Also, several deaths have been reported
after the use of Norian XR CPC [94,95], suggesting some biocom-
patibility issues of CPCs in spinal applications. Higher mechanical
properties were achieved with a calcium aluminate cement (Xera-
spine from Doxa AB), but the results were not very good either
[96]. The last ceramic cement that should be mentioned here is
Plaster of Paris (calcium sulfate hemihydrate). This material readily
dissolves in vivo due to its comparatively high solubility (i.e. with-
out the help of osteoclasts), but nevertheless has been proposed for
bone augmentation [97,98] and bone void filling applications, e.g.
for the filling of the Kiva device. Besides bone augmentation,
ceramic cements have also been used for screw augmentation
[99–102]. Some results are very promising [103,104], but more
data are needed to assess the long-term success of this approach.
3.3. Bioceramics for bone tissue regeneration
Altogether, calcium phosphate ceramics and related com-
pounds, i.e. calcium phosphate cements, bioglasses and calcium
sulfate cements, represent the most important class of biomateri-
als for bone regeneration. Different types of calcium phosphate
ceramics, glass–ceramics and glasses are currently being used
and further developed for bone reconstruction and repair. In the
present section the most prominent inorganic systems and, where
appropriate, their composites in combination with polymers are
described, highlighting the effects of ion release to induce osteo-
genesis and angiogenesis, i.e. the two functions required for
effective bone tissue regeneration. In this sense, the design and
Fig. 4. Osteoporotic vertebral fractures in T12 and L4. Vertebroplasty in T12 and reduction and fixation with cannulated screws and cement in L4.
6D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx
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development of porous ceramics has attracted much attention in
the last years. Not only pore size, but also pore distribution can
play a fundamental role in bone regeneration, angiogenesis and
implant degradation [105]. The incorporation of free-form prepara-
tion methods such as 3-D printing to the biomaterials field has al-
lowed the design of hierarchical pore structures to facilitate these
processes [106]. An interconnected macropore structure of 150–
1000
l
m allows cell colonization and enhances the diffusion rates
to and from the center of a scaffold, as well as angiogenesis and
bone in growth [107,108]. Small pores allow phagocytic cells to ad-
here and resorb the scaffolds, whereas larger pores encourage the
invasion of new vessels and in growth of bone tissue [109].
3.3.1. Calcium phosphates
Calcium phosphate constitutes the inorganic mineral phase in
mammalian bone and teeth. Therefore it is well recognized by
the body and biocompatible according to all current standards
[110–112]. The calcium phosphate mineral in bone consists of
nanocrystalline platelets of biological apatite, which chemically is
a hydroxyapatite with ionic substitutions, mainly carbonate
[113]. A number of synthetic calcium phosphate ceramics are on
the market as bone substitution material, with hydroxyapatite,
Ca
5
(PO
4
)
3
OH (HAP), and b-tricalcium phosphate, b-Ca
3
(PO
4
)
2
(b-
TCP) and combinations of them (biphasic calcium phosphate(BCP))
being the most prominent. They are available in different morphol-
ogies (typically as solid or porous blocks or as granules with differ-
ent particle sizes) and with different origins (fully synthetic or
derived from biological sources such as animal bone or chemically
transformed calcareous algae) [114]. In general, they are well ac-
cepted by the body, but as ceramics they are brittle by nature
and therefore not able to withstand the mechanical challenge in
a larger defect. With time, newly formed bone grows onto and into
calcium phosphate ceramics and finally leads to stable osteointe-
gration [115]. The resorption of calcium phosphate ceramics typi-
cally involves acidic dissolution by osteoclasts [116,117].
3.3.2. Bioactive glasses
Of all bioceramics, glasses have a special position due to their
ability to rapidly release different ions, but also to strongly bind
to bone through the formation of an apatite-like phase in the
bone–implant interface (‘‘bioactivity’’). Depending on their chemi-
cal composition, bioactive glasses can be resorbed and their degra-
dation byproducts can stimulate the osteogenic pathways in MSCs
present at the fracture location. Indeed, the tailored effect of disso-
lution products from bioactive glasses on cellular responses, e.g. to
upregulate the expression of genes controlling osteogenesis and to
enhance vascular endothelial growth factor (VEGF) secretion
in vitro to induce vascularization, are attractive qualities of bioac-
tive glasses (and their composites) in the context of bone regener-
ation strategies [118]. For instance, the effect of silicate ions was
recently investigated in relation to proliferation, osteogenic differ-
entiation and cell signaling pathways of bone marrow stromal cells
[119]. It has also been shown that cells where the calcium sensing
receptor (CaSR) is present, such as MSCs and endothelial cells, re-
spond to specific calcium concentrations in the environment by
migrating, proliferating and differentiating, expressing alkaline
phosphatase and collagen 1, and mineralizing and forming tubules,
respectively [120]. Therefore, it is hypothesized that any biomate-
rial with the appropriate calcium-releasing capacity would be a
good candidate for bone regeneration where angiogenesis is
necessary.
Typical silicate-based compositions such as 45S5 (45 wt.% SiO
2
,
24.5 wt.% Na
2
O, 24.5 wt.% CaO, 6 wt.% P
2
O
5
) are characterized by a
high surface bioactivity enabling strong bonding to bone tissue
[121,122] leading also to stimulating effects on osteogenesis
[123] and angiogenesis [124]. Starting with the classic 45S5 Bio-
glass
Ò
composition [121], a great number of silicate systems incor-
porating specific ions into the silicate network is continuously
developed. The typical ions that are under investigation are mag-
nesium, strontium, silver, iron, copper, boron, potassium, lithium,
cobalt, fluoride and zinc [121]. Absorbable calcium phosphate
glasses are able to solubilize completely with degradation times
ranging from days to years, depending on their chemical composi-
tion. The vitreous network of [PO
4
] tetrahedra is easily hydrolyzed.
The chemical stability of these glasses can only be modified by
including different metallic oxides, such as Al
2
O
3
, ZnO, Fe
2
O
3
and
TiO
2
, into the 3-D vitreous network. TiO
2
has proved to be very effi-
cient, given its four-valence state, linking to four phosphate tetra-
hedra [125]. The capacity of calcium phosphate glasses to promote
cell adhesion [126] and to induce vessel formation at the site of
implantation [127] can be interpreted in terms of ion release.
Being of great relevance in the context of osteoporosis-combat-
ing materials, the effect of specific ions on bone-resorbing osteo-
clast cells must be considered. For example, some researchers
have investigated the addition of strontium ions into silicate glasses
as an effective approach for developing improved bioactive glasses
[128], considering the positive results achieved with strontium
ranelate (SrR) applied as a drug to treat and prevent osteoporosis
especially in post-menopausal women. Dedicated in vivo studies
to assess potential bone healing enhancement in osteoporotic bone
by grafting with bioactive glasses are still scarce [129], indicating a
need for future research to realistically consider bioactive glasses as
osteoporosis combating substances. It is also important to note that
specific morphologies of silicate bioactive glasses (and silica), e.g.
with a mesoporous structure [130], are attractive systems which
enable the incorporation of a drug delivery function to enhance
the intrinsic bioactive character of the inorganic silicate carrier.
3.4. Associations of biomaterials with biological entities: gene and
cellular therapies
3.4.1. Perspectives of gene therapies for bone regeneration purposes
As there is clearly a need for rapid bone regeneration after a
fracture in osteoporotic bone, people have wondered for decades
Fig. 5. Osteoporotic vertebral fractures treatment. Fixation with cannulated screws and cement.
D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx 7
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how bone growth can be stimulated by adding osteogenic
compounds to biomaterials. This has led to systems providing
local drug delivery, e.g. of bone morphogenetic proteins (BMPs)
[131–133] or of angiogenic proteins such as VEGF [134,135], e.g.
from polymers or ceramics. The release typically consists of a burst
in the first days or weeks. The preparation and incorporation of
proteins into biomaterials are usually costly. Another approach is
a local gene therapy, provided by suitable biomaterials in direct
bone contact. Gene therapy involves the delivery of DNA which
can induce the production of the encoded protein after uptake by
cells (so-called ‘‘transfection’’). To accomplish this goal, suitable
carriers are needed as nucleic acids alone cannot penetrate the
cell wall. Furthermore, they are subject to rapid biodegradation
by nucleases in the body.
Two types of carriers for nucleic acids are currently discussed:
viruses and nanoparticles. These can be taken up by cells, together
with their cargo of DNA. Viral transporter systems have the advan-
tage of a very high transfection efficiency, but concerns remain
about possible side-effects [136–138]. Nanoparticles can be organ-
ic (e.g. liposomes or polymeric nanoparticles) or inorganic in nat-
ure [139,140]. Their efficiency is typically lower than that of
viruses, but they have the advantage that they can be more easily
controlled due to their non-biological nature.
The advantage of such local gene delivery is the comparative
ease of producing DNA on a milligram scale and the long-lasting
action. In principle, all kinds of cells around such a DNA-releasing
implant can take up nanoparticles and start to produce DNA. In this
way, proteins such as BMPs or VEGF can be produced and delivered
in vivo to induce bone growth and vascularization [141–145].It
was recently shown that it is possible to induce the production
of BMP-7 and VEGF-A from a paste of DNA-functionalized calcium
phosphate nanoparticles. Thereby, osteoconductivity (by calcium
phosphate) and osteoinduction (by production of the proteins
around the implantation site) were combined [146].Fig. 6 shows
a scanning electron microscopy image of DNA-carrying calcium
phosphate nanoparticles. Note that in general, nanoparticles have
not only been discussed as delivery agents, but they can also be
used to increase the mechanical strength after embedding into a
polymeric matrix (e.g. [147]). This follows the concept of a biomi-
metic hierarchically structured material, mimicking bone itself
[148–150].
Another option within the framework of gene therapy is the
silencing of selected genes by administration of small-interfering
RNA (siRNA). As such, the production of proteins which, for exam-
ple, inhibit bone growth or vascularization, can be down-regulated.
This is called gene silencing, another highly promising method
within the framework of gene therapy [151]. Again, suitable carri-
ers such as nanoparticles are necessary [152–154]. They have been
successfully tested, for example, to down-regulate inflammatory
genes [155] or osteopontin and osteocalcin in osteoblasts [156].
Transfection by nanoparticles is always temporary, i.e. after a
few weeks or months (depending on the release kinetics from
the scaffold) it ceases, ideally after bone healing in complete. This
increases confidence in this approach after application in a bone
defect.
Subjecting osteoporotic bone to gene therapy to improve its
strength is likely to involve a local delivery of a nanoparticle-based
system which carries suitable DNA. It is conceivable that this might
work to prevent later fractures.
3.4.2. Perspectives in the use of cell therapy in the reconstruction of
osteoporotic bone
Recent developments of biomaterials reviewed in this paper
converge on the requirement for biomaterials that foster
osteoinduction and osteogenesis to support and augment bone
healing after osteoporotic fractures. Indeed, the reconstruction of
osteoporotic bone faces significant difficulties with the solutions
currently available. Osteoporotic bone, currently defined by its de-
creased quality (not quantity) leading to a mechanically incompe-
tent biological material [157], manifests itself by the occurrence of
so-called osteoporosis-related fractures. The immediate conse-
quences are bone collapse in metaphyseal compression fractures
with bone defects and joint malfunction, comminution and de-
layed union or non-union after diaphyseal low-energy fractures
with thin cortices, or periprosthetic complex fractures on sclerotic
bone surrounding implants. These problematic fractures seldom
heal, restricting patient mobility and eventually leading to suffer-
ers becoming bed-ridden or even dying. Therefore, therapeutic tar-
gets can be defined for which advances in biomaterials are badly
needed. Basically, it has become clear that a biological problem is
underlying the occurrence of this brittle, non-resistant bone. Fre-
quently underestimated, biological insufficiency leads to signifi-
cant bone-healing problems.
While some osteoinductivity is observed with various biomate-
rials, osteogenesis is required to obtain satisfactory bone repair
and directly relies on osteoprogenitors and derived osseous cell
lines [158]. However, the number of osteoprogenitors available in
the vicinity of a fracture is unclear and unpredictable. Furthermore,
the number of available progenitors decreases drastically with age,
and estimates of stromal cells in the bone marrow drop to
one-eighth from young adulthood to old age. Consequently, elderly
patients with osteoporosis who are more prone to fractures are
associated with limited biological capabilities to heal bone. In that
context, it is interesting to use a cell-based therapy. However, de-
spite significant advances in this field, efforts are hampered by var-
ious constraints: (i) the large number of in vivo and in vitro studies
that are required in a pre-clinical stage; (ii) the safety and efficacy
issues; and finally (iii) the regulatory and legal constraints.
Three main cellular therapy strategies have been developed and
translated into bone regenerative clinical solutions [159]. Mesen-
chymal stem cells (MSCs) from fresh, concentrated autologous
bone marrow have been widely used to enhance bone healing at
non-unions [160], usually in adults at an early age. Only a slight
improvement in biological regenerative potential can be expected
when 1000–1400 MSCs are obtained per 2 ml bone marrow aspi-
rate in young patients; more than 55,000 MSCs per injury are re-
quired. This autologous treatment allows for augmentation of
surgical treatment without the need to introduce cell-based med-
ication into the patient, avoiding significant legal barriers when the
whole process occurs during surgery.
To further increase the biological regenerative potential, grow-
ing bone marrow MSCs from patients may produce millions of
MSCs within a few weeks. Although this manipulation transforms
the cell product into an advanced therapy medicinal product
Fig. 6. DNA-loaded calcium phosphate nanorods which are able to induce the
formation of BMP and VEGF.
8D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx
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(ATMP) that requires fabrication in certified GMP (good manufac-
turing practices) facilities, proposals are currently being developed
through clinical trials. A major barrier to the use of this solution
with elderly and osteoporotic patients is the limited number of
stromal cells in the bone marrow progenitor pool. Other sources
of MSCs face similar problems in elderly patients and osteogenic
line proliferation and differentiation may be further limited. Allo-
geneic expanded cells would be an ideal solution but their safety
and efficacy remains unproven and the significant problems they
present do not appear to have a clear solution.
A third strategy under development involves MSC growth on
biomaterials. If an appropriate combination of biomaterial, cell
dosage and stimulating molecules could be found, the structural
and biological potential of this approach would facilitate an ade-
quate bone substitute through tissue engineering to create a mate-
rial similar to real bone. Only a few publications have addressed
clinical cases treated with this strategy [161], and in terms of
autologous design, its application in osteoporotic patients is a long
way off.
Major issues remain to be solved before these advances can be
safely applied in clinical trials in elderly patients with osteoporotic
fractures or complications. Many questions remain about the
adherence and osteogenic differentiation of osteoprogenitors on a
variety of biomaterials. Furthermore, it remains unproven whether
osteoprogenitors grown on biomaterials maintain their adherence
and thus their location; or if the functional capabilities, in particu-
lar the osteogenic potential, of these cells are retained after surgi-
cal implantation.
However, even if serious barriers still need to be overcome, re-
search efforts are in place and the confirmed requirements for
these particular targets will probably transform in the coming
years the way we understand the clinical potential of bone tissue
engineering based on advanced biomaterials and cell therapy
solutions.
To conclude, the biomaterials used for osteoporosis-related
clinical indications are fairly traditional, including metals, poly-
mers and ceramics. Their design (shape, composition) is generally
adapted to better accommodate osteoporosis-related require-
ments. Part of the gap between clinical biomaterials and academic
research can be explained by increasingly stringent safety regula-
tions, as well as cost pressures. This will be discussed in more de-
tails in the next sections.
4. Biomaterials and osteoporosis. The industrial view point
The previous sections have shown that there is a great need to
improve the treatment of osteoporotic patients before and after the
occurrence of a bone fracture. Various routes for therapeutic
progress have been highlighted, including tissue engineering,
drug-loaded bone graft substitutes and gene therapy. Despite these
efforts, little progress has been seen clinically. In fact, the launch of
BMP-loaded products a decade ago was the last important innova-
tion. This impression is confirmed by the evolution of pre-market
approvals (PMAs) issued by the FDA (Fig. 7). A PMA is compulsory
for any device that does not have any equivalent on the market. In
other words, the most innovative products have to go through a
PMA review process. Over the last 10 years, the number of PMAs
accepted by the FDA has decreased dramatically. Specifically, 23
PMAs were accepted from 2003 to 2007. This number dropped to
8 from 2008 to 2012. Simultaneously, there was a 50% increase
in 510 k notifications, which are issued for products equivalent
to existing products that already have FDA approval. These two
trends mean that companies in the US are shifting their efforts
from innovation to incremental improvements of existing technol-
ogies. The situation in Europe is similar.
Many factors have contributed to this decrease in the number of
innovations. The most obvious one is related to the laws regulating
medical devices. Over the past decades, the European authorities
have strengthened their directives, not only by asking for more
data per product, but also by transferring certain products into
higher product classes. This is the case for joint prostheses that
were class II products until March 2010, and which are now class
III products. In addition, new ISO standards are continuously ap-
proved, which means that more tests have to be done to apply
for a CE marking. It is clear that ISO standards are not compulsory,
but it is often easier to perform the study than to explain why it
has not been performed. This is particularly disturbing for tests
that have been shown to present important weaknesses, such as
ISO 10993-5 (Biological evaluation of medical devices—Part 5:
Tests for in vitro cytotoxicity), or the so-called ‘‘bioactivity test’’
(ISO 23317; Implants for surgery—In vitro evaluation for apatite-
forming ability of implant materials). In both cases, false positives
and false negatives can be found (for ISO 23317, see Refs.
[162,163]). The trend towards stricter regulations is not expected
to stop soon. In fact, much stricter directives have been proposed
following the recall of PIP breast implants and DePuy metal-on-
metal hip prostheses. These directives are currently awaiting
approval.
In 1985, the European Parliament decided to harmonize the
laws regulating medical devices within Europe to facilitate the
transfer of goods. Directives were defined and implemented. Even
though CE-marked products can access the European market, other
hurdles are still in place. For example, the French authorities ask
companies to register their products prior to any reimbursement.
In the US, the government decided a few years ago to stop reim-
bursing vertebral bone augmentation procedures following the
publication of two articles demonstrating an absence of significant
effect between the treatment group and a ‘‘placebo’’ group
[164,165]. The fact that numerous publications have shown the
limitations of these two studies has not changed the situation. In
fact, medical device companies are increasingly asked to show
the effectiveness of their product before reimbursement is issued.
Since artificial joints may only prove their efficacy after 10 years,
this requirement is particularly questionable and cost-intensive.
In addition, proving the efficacy of an implant may require multi-
ple in vivo or clinical studies to support broad claims. For example,
whereas it was possible in the past to perform only one in vivo
study for a ‘‘bone void filler, the authorities now tend to require
more than one in vivo study. This is often very costly and may take
years. Once a product is accepted for sale, governments may decide
on its value. According to the French ‘‘Liste des Produits et Presta-
tions’’ (LPP), a resorbable interference screw for ligament fixation
is worth €234.16.
Currently, there is a trend towards the alignment of pharma and
orthopedic product approvals. However, there is a major
Fig. 7. FDA pre-market approvals (PMAs) and pre-market notifications (510 k) over
the past 10 years. Sources: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/
cfPMA/pma.cfm and http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/
pmn.cfm.
D. Arcos et al. / Acta Biomaterialia xxx (2014) xxx–xxx 9
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difference: whereas pharma products have generally a systemic
action, orthopedic products have a local action (narrow range of
indication). In other words, osteosynthesis plates or orthopedic im-
plants are bone/joint specific, so each plate/implant requires a sep-
arate registration. The limited market size and increasingly large
regulatory burdens are obviously important aspects of, and brakes
in, the decision-making processes occurring during product devel-
opment. In fact, many R&D departments are nowadays focused on
maintaining the product portfolio and reducing costs, rather than
developing new products.
Governments are facing a dilemma: if they tighten the rules to
obtain the CE mark for a new medical product, they restrict inno-
vation, hence reducing the chances of seeing new therapies; if they
do not tighten the rules after the recent medical device scandals
(PIP breast implants, DePuy metal-on-metal prosthesis), their elec-
tors might punish them at the next elections or even sue them as
seen with the contaminated blood scandal. Currently, the former
strategy is pursued worldwide, to the detriment of all clinical
needs and research efforts [166].
5. Conclusions
Osteoporosis is a disease that has become a worldwide chal-
lenge and comprises clinical, social and economic issues. This is
mainly due to the increase in life expectancy, and therefore society,
health systems and industry should be aware of this problem, as an
ageing population will be more prone to osteoporosis.
The main clinical consequences of osteoporosis are fractures.
The success of biomaterials for fracture fixation in osteoporotic pa-
tients, or simply for bone augmentation treatments, is impaired by
the poor quality of bone and the decreased osteoblastic activity. In
this sense, although there are a number of biomaterials to treat
problems with bone on the market, they are not necessarily appro-
priate to address osteoporotic bone. Unsuccessful implantation can
result in crossing the line between frailty and disability in osteopo-
rotic patients.
Clinicians, biomaterials scientists and industrial advisors are
making important efforts to improve current implants and their
applications, as well as provide new alternatives. Compounds able
to stimulate the bone regeneration such as calcium phosphates
(both ceramics and cements), calcium sulfates or bioglasses are
being widely considered, especially associated with local drug
and/or gene delivery as well as with cell therapy.
However, all these efforts only will be fruitful if these new
biomaterials can be successfully developed and commercialized.
Currently, the level of commercial innovation remains well below
expectation and the situation is only expected to worsen due to
more stringent certification requirements and higher cost pres-
sures. Thus, those biomaterials that will play a major role in the
prevention and treatment of osteoporotic conditions will most
likely feature the following points:
– A well-developed definition of unmet needs.
– It will most likely be indication-specific.
– It will enable quantifiable clinical benefits to be proven in level
11 clinical studies.
– It will be profitable.
– A collaborative petition to agencies such as FDA could be
helpful.
Consequently, more research is necessary, driven by clinical de-
mand, to solve this problem. The fact that the current situation is
difficult to manage should not prevent us from seeking new solu-
tions. For this purpose, a close cooperation between fundamental
research, industrial research, clinical research and regulatory
bodies is required for the future. This will not be available for free
(i.e. without financial costs), but will pay off in the long run for
everybody.
In addition, the presence of new patients with new characteris-
tics and new needs, mainly (but not exclusively) frail older people,
should change not only the way to provide their management and
treatment, but also the aims of the care and the way to assess the
technological improvements. Regarding this last issue it should
concern both the changes on how to organize the delivery of the
care provided to these patients, the characteristics of the devices
and its outcomes as well. This new model to assess the efficacy
and effectiveness of the new technologies in the new patients
should prompt a change in the rules of the regulatory agencies in
order to adapt their procedures to the current needs of both the pa-
tients, the health systems and the industry, thus contributing to
the well-being of the patients, the sustainability of the health sys-
tems and the competitiveness of the industry.
Acknowledgements
The Spanish and European Network of Excellence for the Pre-
vention and Treatment of Osteoporotic Fractures ‘‘Ageing’’ is finan-
cially supported by the Ministerio de Economía y Competitividad
through the project CSO2010-11384-E.
Appendix A. Figures with essential color discrimination
Certain figures in this article, particularly Figs. 1, 2, 5 and 7, are
difficult to interpret in black and white. The full color images can
be found in the on-line version, at http://dx.doi.org/10.1016/
j.actbio.2014.01.004
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