Elsevier Editorial System(tm) for Acta Biomaterialia 
                                  Manuscript Draft 
 
 
Manuscript Number: AB-13-2081R1 
 
Title: The relevance of biomaterials to the prevention and treatment of osteoporosis. Opinion paper
  
 
Article Type: Brief Communication 
 
Keywords: Osteoporosis; biomaterials; Ageing 
 
Corresponding Author: Dr. M. Maria Vallet-Regi,  
 
Corresponding Author's Institution: School of Pharmacy, UCM 
 
First Author: M. Maria Vallet-Regi 
 
Order of Authors: M. Maria Vallet-Regi; Daniel Arcos; Aldo R. Boccaccini; Marc Bohner; Adolfo Díez-
Pérez; Matthias Epple; Enrique Gómez-Barrena; Antonio Herrera; Josep A Planell; Leocadio Rodríguez-
Mañas 
 
Abstract: Osteoporosis is a worldwide disease with a very high prevalence in humans older than 50. 
The main clinical consequence is bone fractures, which often lead to patient disability or even death. 
Currently, there are a number of commercial biomaterials used to treat osteoporotic bone fractures, 
but most of them have not been specifically designed for that purpose.  Simultaneously, many drug- or 
cell-loaded biomaterials have been proposed in research laboratories, but hardly any has received 
approval for commercial use. In order to analyze this scenario and propose alternatives to overcome 
this scenario, the Spanish and European Network of Excellence for the Prevention and Treatment of 
Osteoporotic Fractures "Ageing" was created. This network 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. 
 
 
 
 



Dear editor, 

Please find the detaield answers to reviewers, indicating the changes introduced in the text. We 

hope that this revised version will satisfy the standards of Acta Biomaterialia. 

Sincerely 

Maria Vallet-Regí 

  

Response to Reviewers



Reviewer #1: General comments 

This is a summary of expert opinion on using biomaterials in the treatment of osteoporosis, 

especially fractures.  The perspective taken is novel and speaks directly to factors limiting 

application of biomaterials clinically. Interestingly, while regulatory concerns are discussed, part 

of the "blame" is on the research community which has not focused on developing materials 

specifically for osteoporosis and osteoporotic fractures.  The broad perspective on fraility and 

disability provided by this article will be helpful to the biomaterials community.  A key concept 

is early return to function, which is important because it dictates design criteria for biomaterials.   

Thank you for your positive comments 

The discussion of regulatory requirements will be helpful to the basic scientist, but the 

description of why so few devices have been approved could be improved.  Besides factors 

mentioned by the authors, key limitations often include lack of clear-cut, simple clinical 

endpoints for trials, and the cost-benefit analyses that companies perform to decide if there will 

ever be profit for a relatively small indication.  With regard to fracture, a limitation is that 

approval for a device is often for only one type or a very limited set of fractures (i.e., very narrow 

range of indications). 

Our intention was not to list all factors hindering innovation, but mentioning a few important 

ones. Nevertheless, the reviewer is perfectly correct in his/her statements. We propose the 

following modifications: 

We added the following text (page 24) : 

Since artificial joints may only prove their efficacy after 10 years, this requirement is particularly 

questionable and cost-intensive. Also, proving the efficacy of an implant may require multiple in 

vivo or clinical studies to support broad claims. For example, whereas it was possible in the past 

to only make one in vivo study for a “bone void filler, the authorities tend to require now more 

than one in vivo study. 

Further, we added (page 24): 

Currently, there is a trend towards the alignment of pharma and orthopedic product approvals. 

However, there is a major 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 implants are bone / joint specific, so each plate / implant 

requires a separate registration. The limited market size and increasingly large regulatory 

burdens are obviously important aspects / brakes in the decision processes occurring during 

product development. In fact, many R&D departments are nowadays focused on maintaining the 

product portfolio and reducing the costs, rather than developing new products. 

 

 



 

 

Reviewer #2: This manuscript reviews possible solutions for preventing and treating 

osteoporosis.  It integrates the communications from clinicians, materials scientists and industrial 

advisors.  The review is very comprehensive and will serve as a good reference for r searchers 

working in the field.  There are a few grammar mistakes within the article.  It would be helpful if 

the authors proofread the manuscript prior to finalizing it. 

Here are a few examples: 

 

Page 2, Abstract, line 10, it should be ".such as clinicians, materials scientists and .." 

Page 4, 1st paragraph, line 1, it should be: ".may make it difficult for both the pre-.." 

Page 4, 2nd paragraph, line 1: it should be "..most of national health systems.." 

Page 4, 2nd paragraph, line 5: it should be "...the sustainability of some national health systems in 

the next a few years" 

Page 4, 4th paragraph, line 6, it should be ".from user needs to formal clinical outcome .." 

Page 5, 3rd bullet point, it should be "think about possible innovative treatments." 

 

The authors thank your possitive comments. The grammar mistakes have been removed. 

 

 

  



 

Reviewer #3: General comments: 

 

1) There are two clinical approaches in total hip replacement surgery. Hip prostheses can be fixed 

to bone with or without bone cements. The proportion of total hip replacements utilizing each 

type of fixation and the advantages and drawbacks of the approaches may be added. 

Following the reviewer suggestion, discussion about using bone cements in hip prostheses is 

added. We have added the following text (page 10) with the corresponding references (refs  47 to 

51 in the revised version): 

The dilemma in the choice of fixation method of prosthesis to bone (cemented or uncemeted ) is 

solved in favor of cemented prostheses ,taking into account the mean age of our patients ( more 

80 years ) more of 95% of arthroplasties are fixed to bone whit cement , because loss of bone 

mass in osteoporotic bone prevents good primary stability by press-fit of the uncemented 

prosthesis and less to achieve perfect bony integration of components , on the other hand the 

cemented prosthesis have less revision rates that uncemented for aseptic loosenig and excelent 

clinical results. Only in younger patients (less 70 years) with good bone quality and long life 

expectancy can be indicated uncemented arthroplasties. 

 

2) In section 3.1 the authors discuss the strategies used to increase the contact surface between 

bone and implant suggesting various approaches for implant designs related to improved 

osteointegration. The authors should also discuss the surface material properties of the materials 

related to their osseointegration. Surface roughness and wettability of the material are of crucial 

importance when trying to establish good bioactivity an osseointegration. 

The authors agree with the reviewer about the significance of roughness and wettabilty on the 

osteointegration of bone implants. We propose to add the following text (page 14) with the 

corresponding references references (refs  72 to 78 in the revised version): 

Another interesting topic is the role of surface roughness and wettability in implants 

osteointegration . This strategy has reached some degree of success especially in metallic 

implants for periodontal surgery.  For instance, modifications of microtopography in titanium 

implants have demonstrated enhanced osteointegration  . Prospective studies on implants with 

rough surfaces evidence very promising clinical results compared with those with smoother 

surfaces. In addition, the recent development of nanotechnology in biomaterials filed also allows 

the incorporation of nanofeatures onto implants surface. In this sense there are some studies that 

evidence the significance of nanotopography in the success of peri-implant bone formation , . 

Besides, the surface wettability is closely related with the surface micro/nanoroughness and also 

influences the osteoblast behavior. In principle, hydrophilic surfaces enhanced the osteoblast 

maturation , thus leading to better clinical results . 

3) The concept of implant coating is not discussed in the paper which may also be of interest for 

the readership. This reviewer recommends the following papers for further information: Bream et 



al. Acta Biomater 2013 Oct 22, Nguyen et al. Biomaterials. 2004; 25:865-76, Yang et al. 

Biomaterials. 2005 ;26:327-37, Surmenev et al. Acta Biomater. 2013 Nov 5. 

Following the reviewer’s comment, the following text (page 14) and the corresponding references  

(79 to 83 in the revised version) has been added to the manuscript: 

The coating of the surface of metallic implants has been successfully applied for decades to 

improve their bone-binding properties, with the cementless hip endoprosthesis and dental 

implants as 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. 

Although an increased bone-binding ability has been found, a recent review points out that long-

term clinical studies lead to contradictory results. 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 

performance when the primary stability is needed. 

 

4) Another important issue that could be added when describing the physical properties of the 

materials is a comparison of the materials' pore size and distribution as they greatly affect the 

ingrowth of new tissue and the degradation of the implanted material. 

In agreement whit the reviewer’s comment, the following paragraph has been added (page 16) 

together with the corresponding references (refs  105 to 109 in the revised version) 

In this sense, the design and development of porous ceramics have attracted much attention in the 

last years. Not only pore size, but also pore distribution can play a fundamental role in the bone 

regeneration, angiogenesis and implant degradation.  The incorporation of free form preparation 

methods such as 3D printing to the biomaterials field, allow the design of hierarchical pore 

structures to facilitate these processes. An interconnected macropore structure of 150- 1000 m 

allows cell colonization and enhances the diffusion rates to and from the center of a scaffold, as 

well as angiogenesis and bone ingrowth . Small pores allow phagocytic cells to adhere and resorb 

the scaffolds whereas larger pores encourage the invasion of new vessels and ingrowth of bone 

tissue . 

5) When discussing the properties of calcium silicate cements the authors may also mention 

injectable bone cements and  carriers for local drug delivery is nicely explained in the article. The 

authors may also add their beneficial influence on the mechanical properties of biological 

materials (Liu et al. Int Journal of Nanomedicine 2010, 5: 299 -313). 

The field of calcium silicate cements is not relevant for this review and such materials were not 

discussed in our paper. The report covers where appropriate the more relevant calcium phosphate 

cements. Regarding injectable calcium phosphate cements (assuming the referee refers to this 

group of biomaterials), the following statement has been added to the manuscript (page 12) to 

address the referee's comment (and 4 new relevant references (55 – 58) have been added): 



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, radiopacifiers, e.g. tantalum oxide or barium sulfate , 

biodegradable polymers to improve the injectability and modifications to incorporate antibiotic 

releasing capability. 

6) The usage of nanoparticles as carriers for local drug delivery is nicely explained in the article. 

The authors may also add their beneficial influence on the mechanical properties of biological 

materials (Liu et al. Int Journal of Nanomedicine 2010, 5: 299 -313). 

 

Following the reviewers comment the following text has been added to the manuscript (page 20), 

together with the corresponding references (148 -151 in the revised version) 

Note that in general, nanoparticles have not only been discussed as delivery agents, but that they 

can also be used to increase the mechanical strength after embedding into a polymeric matrix. 

This follows the concept of a biomimetic hierarchically structured material, mimicking bone 

itself. 

 



1 

 

The relevance of biomaterials to the prevention and 

treatment of osteoporosis. Opinion paper 

 

D. Arcos
1,2,3

, A. R. Boccaccini
1,4

, M. Bohner
1,5

, A. Díez-Pérez
1,6

, M. Epple
1,7

, E. 

Gómez-Barrena
1,8

, A. Herrera
1,9,10

, J. A. Planell
1,2,11

, L. Rodríguez-Mañas
1,12

,  M. 

Vallet-Regí*
1,2,3

 

 

1 Envejecimiento: red de excelencia española y europea para la prevención y 

tratamiento local de fracturas osteoporóticas. MINECO. Spain. 
2
Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y 

Nanomedicina (CIBER-BBN), Madrid, Spain. 
3
Dpto. Química Inorgánica y Bioinorgánica. Universidad Complutense de Madrid. 

Instituto de Investigación Sanitaria Hospital 12 de Octubre i+12. Madrid, Spain. 
4
University of Erlangen-Nuremberg, Institute of Biomaterials, 91058 Erlangen, 

Germany. 
5
RMS Fundation, CH-2544 Bettlach, Switzerland. 

6
Hospital del Mar-IMIM, Dept Internal Medicine, Barcelona, Universidad Autónoma de 

Barcelona, Spain. 
7
 University of Duisburg-Essen, Inorganic Chemistry and Center for Nanointegration 

Duisburg-Essen (CeNIDE), D-45117 Essen, Germany. 
8
Servicio Cirugia Ortopedica & Traumatologia, Hospital La Paz, IdiPAZ, Universidad 

Autonoma Madrid, Madrid 28046, Spain. 
9
Univ Zaragoza, Dept Surgery, E-50009 Zaragoza, Spain. 

10
Miguel Servet University Hospital, Dept Orthopaedic Surgery & Traumatology 

Zaragoza 50009, Spain. 
11

Inst. Bioengineering of Catalonia IBEC, Baldiri Reixac 15-20, Barcelona 08028, 

Spain. 
12

University Hospital Getafe, Division Geriatric Medicine, Madrid, Spain. 

   

 
* Corresponding author 

 

 

 

 

 

 

 

 

 

 

 

 

*Text only
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2 

 

Abstract 
 

Osteoporosis is a worldwide disease with a very high prevalence in humans older than 

50. The main clinical consequence is bone fractures, which often lead to patient 

disability or even death. Currently, there are a number of commercial biomaterials used 

to treat osteoporotic bone fractures, but most of them have not been specifically 

designed for that purpose.  Simultaneously, many drug- or cell-loaded biomaterials have 

been proposed in research laboratories, but hardly any has received approval for 

commercial use. In order to analyze this scenario and propose alternatives to overcome 

this scenario, the Spanish and European Network of Excellence for the Prevention and 

Treatment of Osteoporotic Fractures “Ageing” was created. This network 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. 

 

1. Introduction and put in 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 fractures constitute a challenge not yet resolved [1]. 

 

Bone weakening due to osteoporosis is far from finding a satisfactory solution. As a 

consequence of poor bone quality, surgical procedures performed to implant a device in 

weakened bone often lead to a clinical result that is worse than if such an intervention 

was 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 in the following year. Of those who survive, approximately half 

are totally or partially dependent [2]. Chronic pain, functional limitation, social 



3 

 

dependence, psychological disorders, reduced mental health score and social isolation 

converge on a serious deterioration in the quality of life.  

 

There are treatments available today to reduce the impact of bone fragility, but there is a 

lack of alternatives to restore bone strength. Moreover, there are no comprehensive 

treatments available for the whole damaged system, i.e. able to address the three factors 

of musculoskeletal unit fragility: bone, cartilage, and muscle. These three factors are 

both cause and consequence of the 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 should be seriously 

considered. It is worth mentioning that a surgical intervention for a hip prosthesis 

implantation has a health service cost of around €20,000, including direct, indirect and 

intangible costs [5]. For instance, the total current cost for hip fracture treatments with 

osteoporotic origin in the U.S. is 20.3 billion of U.S. dollars. 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 fractures 

in 1950 was 1.47 million and the projection for 2050 is around 6.3 million [9]. In the 

framework of the European Union, direct costs related to osteoporotic fractures in 2000 

were estimated to €31.7 billions [10]. Moreover, the increase in life expectancy of an 

increasingly ageing population leads to predict even more serious difficulties for the 

future.  

In the context of a socio-health problem such as osteoporosis, we may highlight 

three main agents involved in it: 

• The patient. All publications and web sites devoted to osteoporosis show that 

there is currently no satisfactory solution and that it remains as one of the major 

challenges for public health. This claim is based on significant mortality and disability 

(personal costs) and its relationship with the economic costs of the management, 

including treatment, of the 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 (whether of hip, spine, wrist, etc.) has 

occurred, the surgeon has only very few surgical solutions. In addition, other issues 

concerning general health (frailty, malnutrition, cognitive disorders, co-morbid 

conditions, polypharmacy, etc.) may make it difficult both the pre- and post-surgical 



4 

 

management of the patients. The reports issued by many of these professionals support 

the idea that enormous patient benefits could stem from preventive solutions.  

• The National Health System. In the European Union, most of national health 

systems are the purchasers of the prosthetic products and the defrayers of the 

intervention and hospitalization costs. Undoubtedly, the gradual ageing of society 

entails an increased number of osteoporotic patients, and this scenario could challenge 

the sustainability of some national health systems in the next a few years. 

Research into biomaterials has produced many variants of technologies, materials and 

physical forms intended to supplement or replace osteoporotic bone over the last 30 

years. 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 biomaterials it may be surprising that so little 

biomaterials research output reaches the operating theatre as part of a clinical treatment. 

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 

country. Even where these are overcome it is far from certain that a biomaterial 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 issues 

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 aspirations of biomaterials 

researchers and (unmet) clinical needs. The goals of industry and academia are broadly 

similar to the surgeon community in wanting to improve clinical outcomes in a given 

clinical treatment. However, biomaterials are often developed by identifying the unmet 

clinical needs (note the terms used here such as “user needs” are as required in design 

control and quality 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 uncommon. Even rarer is that a proper post-market 

surveillance is undertaken to ensure that any adverse outcomes are recognized as part of 

a quality system.  

 



5 

 

Considering this scenario, an interdisciplinary group of experts comprising clinicians, 

materials scientists and industrial advisors have constituted the Spanish and European 

Network of Excellence for the Prevention and Treatment of Osteoporotic Fractures 

“Ageing” (www.agening.net). This network shares and puts together information 

coming from different specialties and proposes possible solutions for the treatment of 

ageing diseases in bone, such as: 

 identify the most prevalent clinical problems and the most relevant 

clinical solutions, 

 analyze and discuss the role of drugs, implants, biomaterials and surgical 

techniques in such treatments, and 

 think about possible innovative treatments and even prevention. 

 

This article is the result of one year of discussions and thoughts, proposals and 

conclusions obtained in the “Ageing” framework. 

 

2. Osteoporosis. A clinician’s point of view. 

2.1. Significance of osteoporosis to frailty and disability.  

 

Last century a profound demographic change took place, the main consequence of 

which was a significant increase in the percentage of people older than 65, reaching 

levels of around 17%. In addition to this demographic change, a second transition 

occurred: the epidemiological transition, which produced a shift from the predominance 

of acute, single and communicable disease to a predominance of chronic, multiple and 

non-communicable diseases. As a consequence of these two complementary transitions 

the spectrum of diseases and the way of being ill has dramatically changed. If we finally 

take into account that life expectancy will slowly continue extending (EUROPOP 

forecasts support a modest increase in life expectancy around 5-7 years in the European 

Union countries for the next 50 years), the focus of health interventions should change 

from prolonging life to improve 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 with age, that 

would not be the case with a relatively young population. With agening, the loss of 

http://www.agening.net/


6 

 

functional reserve capacity put people at risk of developing disability, even under low-

power stressors. 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). But 

during the last 25 years, this tendency has changed in many countries. Although we do 

not know the causes explaining this drop in disability rates, this fact 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 prevalence of disability
 

[11].  

 

The fight against disability has several options, but probably the least attractive is to 

passively wait for the development of a disability. As previously stated, the main cause 

of disability is the loss of functional reserve capacity. But to successfully recover from 

disability a high level of that capacity is needed. In fact, only a small percentage 

(around 30%) of older people with incident disability is able to improve functionally 

during the first year [12]. This is why the main approach to improve the population 

functional status is 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 of developing a disability, both at short- and long-term (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 1-3% for 65 years old people to more than 30% 

in people older than 80. It predicts the risk of suffering from multiple adverse 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 pull out patients from a frailty state, or at least delay 

frailty progression to full disability [16]. 

 

Within this framework, the approach to osteoporosis, as it is also the case for many 

other chronic conditions usually present in older people, should be focused on the 

prevention of the clinical pictures associated with frailty and disability. The most 

frequent of these conditions is the hip fracture. Taking into account that the most 

important risk factor for hip fracture is the risk of falls, the right way to manage these 

patients is based on a comprehensive assessment and management of falling patients. 

For this purpose the introduction of specialized Falls and Fracture Units is becoming the 



7 

 

standard approach to manage these patients, as recommended by different organizations, 

e.g. WHO, NICE, British Orthopaedic Association and the US Preventive Services Task 

Force. 

In this regard, the focus in these Units is to reinforce the idea of the continuum of care 

and a comprehensive approach to avoid or prevent disability in these patients, taking 

advantage of all available opportunities. One of these opportunities stems from the 

advances in the biomaterials used in the surgical materials used in those patients with 

hip fracture. These materials should have a double 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 with a rapidly increasing incidence associated to the 

population ageing [17,18]. The loss of bone and deterioration in its quality [19] induce 

decreased bone strength with the associated increase in fracture risk [20]. The main 

clinical consequences of the condition, therefore, are the fractures, 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 FRAX
©

 tool, 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 countries [24] 

and is available in several languages and for a large number 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 measurement of bone mineral 

density by dual energy X-ray absorptiometry (DEXA) in several skeletal regions [26]. 

Other methods also calculate the mineral density by using ultrasound or quantified 

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 



8 

 

the quality of the material. For this to be adequately done, laboratory testing of “ex 

vivo” specimens is required for measuring a broad spectrum of mechanical properties 

(brittleness, toughness, work 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 inform the clinician about the response to treatments [31]. Last but not least 

the simple detection in a routine radiograph or after a trauma permits the identification 

of fractures, the cornerstone of the disease and the responsible event for the morbidity 

and mortality associated with osteoporosis. Suffering a low-energy traumatic fracture 

(fragility fracture) is the ultimate demonstration of osteoporosis and constitutes per se a 

diagnostic marker.  

Osteoporosis prevention has two phases, primary prevention and secondary prevention. 

Primary prevention starts during intrauterine 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 how our bones are, the promotion of 

physical activity, adequate nutrition and the avoidance of negative factors for the 

normal bone development 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 of a so 

called “fracture cascade”.  Two main groups of drugs are currently available for the 

management of the patients with osteoporosis: anticatabolics and anabolics [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 formation and, 

therefore, can revert 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 to 

biological entities, that decrease the risk of vertebral fracture and some also of non-

vertebral fractures (e.g. hip). The main development in treatment has been in 

postmenopausal osteoporosis in women although we have also treatments for 

glucocorticoid-induced osteoporosis [33,34] and osteoporosis in men [35]. In spite of 

the substantial body of clinical evidence, the management of this disease is still largely 

variable across different countries [36] and a considerable part of cases does not 



9 

 

respond 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 metabolic disease, resulting from agening 

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. So, osteoporotic fractures are often 

severely comminuted, especially in trabecular 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 difficult. Biologically, the 

mesenchymal stem cells (MSCs) of osteoporotic bone have less capacity to differentiate 

into osteoblasts than those of healthy bone, possibly due to impaired osteoinductive 

signals 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 mechanical conditions 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 direction 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 fracture 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 biomaterials to achieve 

sufficient overall assembly stability and fracture healing. Less load-resistant materials, 

even with bioactive capacity, may be used in the upper limb fractures. However, spine 



10 

 

and lower limb fractures require the use of inert biomaterials with greater load-bearing 

capacity, although calcium phosphate cements may be occasionally 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 

osteoporosis. 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 cascade”. Vertebroplasty and kyphoplasty as minimal-invasive 

techniques show excellent results on 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 anatomically defined region: Intracapsular 

neck, extracapsular neck, pertrochanteric, intertrochanteric and subtrochanteric. 

Intracapsular fractures (see figure 3) have 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 fractures in patients younger than 70 years. Total or 

partial hip arthroplasty, depending on the patient age, is the preferred technique for the 

displaced grades (Garden III and IV) fractures [46]. The dilemma in the choice of 

fixation method of prosthesis to bone (cemented or uncemeted ) is solved in favor of 

cemented prostheses ,taking into account the mean age of our patients ( more 80 years ) 

more of 95% of arthroplasties are fixed to bone whit cement , because loss of bone mass 

in osteoporotic bone prevents good primary stability by press-fit of the uncemented 

prosthesis and less to achieve perfect bony integration of components , on the other 

hand the cemented prosthesis have less revision rates that uncemented for aseptic 

loosenig and excelent clinical results. Only in younger patients (less 70 years) with 



11 

 

good bone quality and long life expectancy can be indicated uncemented arthroplasties 

[47-51]

The sliding hip screw, a device used in the treatment of trochanteric fractures, has been 

to some extent replaced over the years by intramedullary nails with a sliding cephalic 

screw. These are often 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 placement of the cephalic screw and good anatomical 

fracture reduction. 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, bone structure of the femoral head can be strengthened by injecting 

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 bioactive biomaterials that 

combine load bearing, interconnected porosity and the ability to be loaded with biologic 

factors that promote fracture healing.  

3. Osteoporosis. A materials scientist’s point of view.    

       

In an osteoporotic scenario, the paucity of bone and the decreased osteoblastic function 

result in an impaired response to implants 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 section 2, teaches us that the primary issue with these patients is 

that they suffer from fractures that require some form of fixation, and the osteosynthesis 

elements such as plates, screws, nails, etc. are difficult to fix in low-quality bone. 

Besides, other scenarios different of fractures also affect the biomaterials performance 

in osteoporotic patients. For instance, the response of osteoporotic bone to endosseous 

implants, such as stems of total joint prostheses or endosseous dental implants, is also 

strongly impaired. In these cases, the implant failure is due to the poor biological 

fixation, which is consequence of an insufficient osteogenesis around the implant [53]. 

Despite of these evidences, there are no clinically approved biomaterials specifically 

tailored for application in osteoporotic bones. Certainly, there are some examples of 



12 

 

medical devices for osteosynthesis with special designs, but they are made of the same 

biomaterials than the conventional ones, such as titanium alloys, cobalt alloys or 

stainless steel.  

Attempting to reduce osteoporotic fractures, two classes of biomaterials are mainly 

used: metallic implants and cements. Their function is slightly different: whereas 

metallic implants are used as primary fixation devices, cements are mainly used as 

reinforcement of the metallic hardware. However, cements are also used as stand-alone 

devices, for example 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 modified to accommodate osteoporosis-specific requirements. Sometimes, even 

new implants are created. For cements, the accent is set on a change of 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 autogenous bone from the iliac 

crest.  

Besides the osteoporotic fractures reduction, biomaterials science also faces the quest of 

the impaired osteointegration of permanent endosseous implants.  The 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 impaired, as it requires deposition of 

newly formed bone in intimate contact with the implant [59]. Since this process 

involves the balanced action of osteogenic and bone resorbing cells, osteoporosis often 

has a poor prognosis and delayed healing and osteointegration with endosseous 

implants. However, similarly to devices for fracture fixation purposes, the research 



13 

 

efforts do not comprise the preparation of new metal alloys specifically intended to 

fabricate 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 

phosphates bioceramics [61, 62] and SiO2 based mesoporous materials have been 

widely proposed as potential local antiosteoporotic drugs delivery systems [63], when 

used for void fillers in fracture fixation, bone grafting or augmentation.  

Combinations of biomaterials with cellular therapy and local drug delivery are of 

enormous interest because of the great opportunities that they offer to this problem [64-

66]. However, the technical and biological problems of the cells or materials to be used 

are important. These include (1) the limited cell viability; (2) the transient mechanical 

properties of the materials once implanted until they are substituted by regenerated 

bone; and (3) 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: estrogens depletion, diabetes mellitus, ageing, and 

treatment with glucocorticoids. To 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 get 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 implants, for example expandable 

spacers for vertebral height restoration (e.g. “VBS” (DePuy Synthes), “Spinejack 



14 

 

Vexim” (Vexim), “Kiva” (Benvenue Medical)) or cannulated screws (e.g. “Matrix 

Spine System” (Depuy Synthes)) to permit cement injection through the screw [69]. The 

cement injection through the screws (figures 4 and 5) gets 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 implants 

osteointegration [72]. This strategy has reached some degree of success especially in 

metallic implants for periodontal surgery. For instance, modifications of 

microtopography in 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 

development of nanotechnology in biomaterials filed also allows the incorporation of 

nanofeatures onto implants surface. In this sense there are some studies that evidence 

the significance of nanotopography in the success of peri-implant bone formation 

[75,76]. Besides, the surface wettability is closely related with the surface 

micro/nanoroughness and also influences the osteoblast behavior. In principle, 

hydrophilic surfaces enhanced the osteoblast maturation [77], thus leading to better 

clinical results [78]. 

The coating of the surface of metallic implants has been successfully applied for 

decades to improve their bone-binding properties, with the cementless hip 

endoprosthesis and dental implants as 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 recent review points out that long-term clinical studies lead to 

contradictory 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 

performance when the primary stability is needed. 

 

3.2. Cements 

 

Polymethylmethacrylate (PMMA) cement is the material of choice for the 

reinforcement of metallic implant fixation or osteoporotic bone due to its high 



15 

 

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], absence of biodegradation that may lead to fatigue 

failure [86] , or too high material stiffness that may increase the fracture risk of vertebra 

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, price, or mechanical issues. For example, a few years ago the 

company “Orthovita” proposed a few years ago a dual paste cement called “Cortoss”. 

This cement is inspired from the composition of dental cement i.e. it consists of a matrix 

of Bis-GMA (2,2-bis [4-(2-hydroxymethacryloxypropyl)phenyl] propane), Bis-EMA 

(2,2-bis [4-(2-methacryloxyethoxy)] phenyl propane), and TEGDMA (triethylene glycol 

dimethacrylate) and is reinforced with bioactive glass particles [88]. “Cortoss” presents 

better handling, higher mechanical properties, and lower toxicity than PMMA cements. 

Unfortunately, it has a limited success, possibly due to price issues (higher production 

costs than PMMA cements). More recently, a silicone cement called “VK100” was 

proposed by the company “BonWRX”. This dual paste cement contains dimethyl 

methylvinyl siloxanes (87 %), barium sulfate 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, preliminary 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 too slow setting reaction was also mentioned. 

Considering the poor biological properties of polymer cements, quite a few ceramic 

cements have been proposed for bone augmentation procedures. Interesting candidates 

have been calcium phosphate cements (CPCs), but the results have been rather 

disappointing [90-93]. One main issue is the CPCs 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 

biocompatibility issues of CPCs in spinal applications. Higher mechanical properties 

were achieved with a calcium aluminate cement (“Xeraspine” 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 



16 

 

dissolves in vivo due to its comparatively high solubility (i.e. without the help of 

osteoclasts), but nevertheless has been proposed for bone augmentation [97,98] and 

bone void filling applications, for example 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 compounds, i.e. calcium phosphate 

cements, bioglasses and calcium sulfate cements, represent the most important class of 

biomaterials 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 effects of ion release to induce osteogenesis and angiogenesis both 

functions required for effective bone tissue regeneration. In this sense, the design and 

development of porous ceramics have attracted much attention in the last years. Not 

only pore size, but also pore distribution can play a fundamental role in the bone 

regeneration, angiogenesis and implant degradation [105].  The incorporation of free 

form preparation methods such as 3D printing to the biomaterials field, allow the design 

of hierarchical pore structures to facilitate these processes [106]. An interconnected 

macropore structure of 150- 1000 m allows cell colonization and enhances the 

diffusion rates to and from the center of a scaffold, as well as angiogenesis and bone 

ingrowth [107,108]. Small pores allow phagocytic cells to adhere and resorb the 

scaffolds whereas larger pores encourage the invasion of new vessels and ingrowth 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 known to the body and biocompatible by 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, 



17 

 

mainly carbonate [113]. A number of synthetic calcium phosphate ceramics are on the 

market as bone substitution material, with hydroxyapatite, Ca5(PO4)3OH (HAP), and -

tricalcium phosphate, -Ca3(PO4)2 (-TCP) and combinations of them ("biphasic 

calcium phosphate"; BCP) being the most prominent ones. They are available in 

different morphologies (typically as solid or porous blocks or as granules with different 

particle size) and with different origin (fully synthetic or derived from biological 

sources like animal bone or chemically transformed calcareous algae) [114]. In general, 

they are well accepted 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 

a stable osteointegration [115]. The resorption of calcium phosphate ceramics typically 

involves acidic dissolution by osteoclasts [116,117].   

 

 

3.3.2. Bioactive glasses. 

Among 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 

chemical composition, bioactive glasses can be resorbed and their degradation 

byproducts can stimulate the osteogenic pathways in mesenchymal stem cells present at 

the fracture location. Indeed, the tailored effect of dissolution 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 bioactive glasses (and their 

composites) in the context of bone regeneration strategies [118]. For instance, the effect 

of silicate ions was recently investigated in relation to proliferation, osteogenic 

differentiation 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 mesenchymal stem cells and endothelial cells, respond 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 biomaterial with the 



18 

 

appropriate calcium-releasing capacity would be a good candidate for bone regeneration 

where angiogenesis is necessary. 

Typical silicate-based compositions such as “45S5” (wt.%: 45 SiO2, 24.5 Na2O, 24.5 

CaO, 6 P2O5) 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 Bioglass®” composition [121], a 

great number of silicate systems incorporating specific ions into the silicate network is 

continuously developed. The typical ions that are under investigation are magnesium, 

strontium, silver, iron, copper, boron, potassium, lithium, cobalt, fluoride and zinc 

[125]. At variance, absorbable calcium phosphate glasses are able to solubilize 

completely with degradation times ranging from days to years, depending on their 

chemical composition. The vitreous network of [PO4] tetrahedra is easily hydrolyzed. 

The chemical stability of these glasses can only be modified by including different 

metallic oxides, such as Al2O3, ZnO, Fe2O3, and TiO2, into the three dimensional 

vitreous network. TiO2 has proved to be very efficient, given its four valences that link 

to four phosphate tetrahedral [126]. The capacity of calcium phosphate glasses to 

promote cell adhesion [127] and to induce vessels formation at the site of implantation 

[128] can be interpreted in terms of ion release. 

 

Being of high relevance in the context of osteoporosis-combating materials, the effect of 

specific ions on bone-resorbing osteoclast cells must be considered. For example, some 

researchers investigated the addition of strontium ions into silicate glasses as an 

effective approach to develop improved bioactive glasses [129], 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 [130], 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 [131] are attractive systems which enable the incorporation of a 

drug delivery function to enhance the intrinsic bioactive character of the inorganic 

silicate carrier. 

 



19 

 

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 since decades how bone growth can be stimulated by 

adding osteogenic compounds to biomaterials. This has led systems with a local drug 

delivery, e.g. of bone morphogenetic proteins (BMPs) [132-134] or of angiogenic 

proteins like VEGF [135,136], 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. They can be taken up by cells, together with their cargo of DNA. Viral 

transporter systems have the advantage of a very high transfection efficiency, but 

concerns remain about possible side-effects [137-139]. Nanoparticles can be organic 

(like liposomes or polymeric nanoparticles) or inorganic in nature [140, 141]. 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 a local gene delivery is the comparatively easy way to produce 

DNA in mg-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. Thereby, 

proteins like BMPs or VEGF can be produced and delivered in vivo to induce bone 

growth and vascularization [142-146]. 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 [147]. Figure 6 shows an SEM-image of DNA-carrying calcium phosphate 



20 

 

nanoparticles. Note that in general, nanoparticles have not only been discussed as 

delivery agents, but that they can also be used to increase the mechanical strength after 

embedding into a polymeric matrix (see, e.g., ref [148]). This follows the concept of a 

biomimetic hierarchically structured material, mimicking bone itself [149-151]. 

 

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, e.g., inhibit bone growth or vascularization, can be down-regulated. 

This is called gene silencing, another highly promising method within the framework of 

gene therapy [152]. Again, suitable carriers like nanoparticles are necessary [153-155]. 

They have been successfully tested, e.g. to down-regulate inflammatory genes [156] or 

osteopontin and osteocalcin in osteoblasts [157]. A 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 completed bone healing. This adds to the 

confidence after application in a bone defect. 

If osteoporotic bone shall be subjected to gene therapy to improve its strength, it would 

probably involve a local delivery of a nanoparticle-based system which carries suitable 

DNA. It is conceivable that this might work as a prevention of later fracture. 

 

3.4.2. Perspectives in the use of cell therapy in the reconstruction of 

osteoporotic bone.  

Recent developments of biomaterials largely reviewed in this paper converge on the 

needs of biological enhancement of biomaterials fostering osteoinduction and 

osteogenesis to support and augment bone healing after osteoporotic fractures. Indeed, 

the reconstruction of osteoporotic bone yields significant difficulties with the solutions 

available today. The osteoporotic bone, currently defined by its decreased quality (not 

quantity) leading to a mechanically incompetent biological material [158] manifests 

itself by the so-called osteoporosis-related fractures. Immediate consequences are bone 

collapse in metaphyseal compression fractures with bone defects and joint malfunction, 

comminution and delayed 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 bed-ridden patients or even death. Therefore, therapeutic targets 



21 

 

can be defined, where advances in biomaterials are strongly needed. Basically, it has 

become clear that a biological problem is underlying this brittle, non-resistant bone. 

Frequently underestimated, biological insufficiency leads to significant bone healing 

problems. 

While some osteoinductive effect is observed with various biomaterials, osteogenesis is 

required to obtain satisfactory bone repair and directly relies on osteoprogenitors and 

derived osseous cell lines [159]. Yet the number of osteoprogenitors available in the 

surroundings of a fracture is unclear and unpredictable. Furthermore, the number of 

available progenitors seriously decreases 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, despite significant advances in this field, efforts are hampered 

by various 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 [160]. Mesenchymal stem cells (MSCs) from fresh, 

concentrated autologous bone marrow have been widely used to enhance bone healing 

at non-unions [161], usually in adults at an early age. Only a slight improvement of 

biological regenerative potential can be expected when 1000-1400 MSCs are obtained 

per 2 mL bone marrow aspirate in young patients with an aim of injecting more than 

55000 MSCs per injury. This autologous treatment allows for augmentation of surgical 

treatment without the consideration of introducing a cell-based medication into the 

patient, avoiding significant legal barriers when the whole process occurs during 

surgery.  

To further increase the biological regenerative potential, an expansion of bone marrow 

MSCs from the patient may lead to millions of MSCs within a few weeks. Although this 

manipulation transforms the cell product into an Advanced Therapy Medicinal Product 

(ATMP) that requires fabrication in certified GMP facilities (under Good 

Manufacturing Practices), proposals are being developed currently through clinical 

trials. A major barrier to the use of this solution today with elderly and osteoporotic 

patients is the limited amount of stromal cells in the bone marrow progenitor pool. 



22 

 

Other sources of MSCs face similar problems in elderly patients and the osteogenic line 

proliferation and differentiation may be further limited. Allogeneic expanded cells 

would be an ideal solution but safety and efficacy remains unproven and significant 

problems do not hold a clear solution. 

A third strategy under development involves MSC expansion on biomaterials. If an 

appropriate combination of biomaterial, cell dosage and stimulating molecules was 

found, structural and biological potential would facilitate and adequate bone substitute 

through tissue engineering closer to real bone. Only a few publications address clinical 

cases treated with this strategy [162], and in the autologous design, it is far from 

application in osteoporotic patients.  

Major issues remain to be solved before these advancements can be solidly applied into 

clinical trials in elderly patients with osteoporotic fractures or complications. Many 

questions are unclear about the adherence and osteogenic differentiation of 

osteoprogenitors on many biomaterials. Furthermore, it remains unproven whether 

osteoprogenitors expanded on biomaterials maintain the adherence and thus the 

location; or else, if the functional capabilities of these cells are kept after surgical 

implantation, in particular the osteogenic potential.  

However, even if serious barriers should be overcome, research lines are in place and 

the confirmed needs in 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, biomaterials used for osteoporosis-related clinical indications are fairly 

traditional, including metals, polymers, and ceramics. Their design (shape, composition) 

is generally adapted to better accommodate osteoporosis-related requirements. Part of 

the gap between clinical biomaterials and academic research can be explained by 

increasingly stringent safety regulations, as well as cost pressures. This will be 

discussed in more details in the next sections. 

 

4. Biomaterials and osteoporosis. The industrial’s point of view. 

 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 needs and efforts, little 



23 

 

progress is seen clinically. In fact, the launch of BMP-loaded products a decade ago was 

the last important innovation. This impression is confirmed by the evolution of pre-

market approvals (PMA) issued by the FDA (Fig 7). A PMA is compulsory for any 

device that does not have its 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 of the 510k notifications, which are issued 

for products equivalent to other products already FDA approved. These two trends 

mean that companies in the US are shifting their efforts from innovations to incremental 

improvements of existing technologies. This situation in Europe is similar. 

Many aspects 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 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. Also, new ISO standards are continuously approved, 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 was not 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 references [163] and [164]). 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 prosthesis. 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 



24 

 

years ago to stop reimbursing vertebral bone augmentation procedures following the 

publication of two articles demonstrating an absence of significant effect between the 

treatment group and a “placebo” group [165, 166]. 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. 

Also, proving the efficacy of an implant may require multiple in vivo or clinical studies 

to support broad claims. For example, whereas it was possible in the past to only make 

one in vivo study for a “bone void filler, the authorities tend to require now more than 

one in vivo study. This is often very costly and may take years. Once a product is 

accepted for reimbursement, governments may decide on the product value. According 

to the French “Liste des Produits et Prestations” (LPP), a resorbable interference screw 

for ligament fixation is worth 234.16 Euros.  

Currently, there is a trend towards the alignment of pharma and orthopedic product 

approvals. However, there is a major 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 implants are bone / joint 

specific, so each plate / implant requires a separate registration. The limited market size 

and increasingly large regulatory burdens are obviously important aspects / brakes in 

the decision processes occurring during product development. In fact, many R&D 

departments are nowadays focused on maintaining the product portfolio and reducing 

the costs, rather than developing new products. 

Nowadays, governments are facing a dilemma: if they tighten the rules to obtain the CE 

mark of a new medical product, they restrict innovation, hence reducing chances to see 

new therapies; if they do not tighten the rules after the recent medical device scandals 

(PIP breast implants, DePuy metal-on-metal prosthesis), their electors 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, detrimentally to all 

clinical needs and research efforts. [167] 

  

 

 



25 

 

5. Conclusions 
 

Osteoporosis is a disease that has become a worldwide challenge and comprises clinical, 

social and economic issues. This is mainly due to the increase of life expectancy, so the 

society, the 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 the fractures. The success of 

biomaterials for fracture fixation in osteoporotic patients, 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 in the market, they are not necessarily appropriate to address 

osteoporotic bone. Unsuccessful implantation can result in overpassing the line between 

frailty and disability in osteoporotic 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 are 

successfully developed and commercialized. Currently, the level of commercial 

innovation remains well below expectations and the situation is only expected to worsen 

due to more stringent certification requirements and higher cost pressures. Thus, those 

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 of evidence 

1 clinical studies 

- It will be reimbursable 

- A collaborative petition to agencies such as FDA could be helpful 

 

Consequently, more research is necessary, driven by the clinical demand, to solve this 

problem. The fact that the current situation is difficult to manage should not prevent us 



26 

 

to seek new solutions. 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 money), but will pay off in the 

long run for everybody 

In addition, the presence of new patients with new characteristics and new needs, 

mainly (but not exclusively) older people with frailty, 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 patients, the health systems and the industry, thus contributing 

to the well-being of the patients, the sustainability of the health systems and the 

competitiveness of the industry. 

 

Acknowledges 

 

The Spanish and European Network of Excellence for the Prevention and Treatment of 

Osteoporotic Fractures “Ageing” is financially supported by the Ministerio de 

Economía y Competitividad through the project CSO2010-11384-E. 

 

References 

1. Planell J A, Navarro M. Challenges of bone repair, in Bone Repair Biomaterials. 

Planell, Best, Lacroix and Merolli eds. 2009, CRC Press, Cambridge. 

2.  Streubel PN, Ricci WM, Wong A, Gardner MJ. Mortality after distal femur 

fractures in elderly patients. Clin Orthop Relat Res 2011; 469: 1188-96. 

3.  National Osteoporosis Foundation. http://www.nof.org  

4. Hoerger TJ, Downs KE, Lakshmanan MC, Lindrooth RC, Plouffe Jr L, Wendling 

B, et al. Healthcare use among U.S. women aged 45 and older: Total costs and 

costs for selected postmenopausal health risks. J Womens Health Gend Based 

Med 2007; 8: 1077-89. 

5. Rissanen P, Aro S, Sintonen H, Asikainen K, Slätis P, Paavolainen P. Costs and 

Cost-Effectiveness in Hip and Knee Replacements: A Prospective Study?. 

http://www.nof.org/


27 

 

International Journal of Technology Assessment in Health Care 1997; 13: 574-

588. 

6.  Day JC. Population projections of the United States by age, sex, race and 

Hispanic origin: 1995 to 2050. US Government Printing Office, Washington, DC. 

7.  Ray NF, Chan JK, Thamer M, Melton III LJ. Medical expenditures for the 

treatment of osteoporotic fractures in the United States in 1995: Report from the 

National Osteoporosis Foundation. J Bone Miner Res 1997; 12: 24-35. 

8.  Chrischilles E, Shireman T, Wallace R. Costs and health effects of osteoporotic 

fractures. Bone 1994; 15: 377-86. 

9. Melton LJ. Hip fractures: a worldwide problem today and tomorrow. Bone 1993; 

14: 1-8. 

10. Kanis JA, Johnell O. Requeriments for DXA for the management of osteoporosis 

in Europe. Osteopor Int 2005; 16: 229-238. 

11. Manton KG, Gu X. Changes in the prevalence of chronic disability in the United 

States black and nonblack population above age 65 from 1982 to 1999. Proc Natl 

Acad Sci U S A. 2001; 98: 6354-9. 

12. Boyd CM, Landefeld CS, Counsell SR, Palmer RM, Fortinsky RH, Kresevic D et 

al. Recovery of activities of daily living in older adults after hospitalization for 

acute medical illness. J Am Geriatr Soc. 2008; 56: 2171-9. 

13. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. 

Lancet 2013; 381: 752-62. 

14. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J et al. 

Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 

2001; 56: M146–56. 

15. Rodríguez-Mañas L, Féart C, Mann G, Viña J, Chatterji S, Chodzko-Zajko W et 

al. Searching for an operational definition of frailty: a Delphi method based 

consensus statement: the frailty operative definition-consensus conference project. 

J Gerontol A Biol Sci Med Sci. 2013; 68: 62-7. 

16. Espeland MA, Gill TM, Guralnik J, Miller ME, Fielding R, Newman AB et al. 

Designing clinical trials of interventions for mobility disability: results from the 

lifestyle interventions and independence for elders pilot (LIFE-P) trial. J Gerontol 

A Biol Sci Med Sci. 2007; 62: 1237-43. 



28 

 

17. Felsenberg D, Silman AJ, Lunt M, Armbrecht G, Ismail AA, Finn JD et al. 

Incidence of vertebral fracture in europe: results from the European Prospective 

Osteoporosis Study (EPOS). Journal of bone and mineral research: the official 

journal of the American Society for Bone and Mineral Research 2002; 17: 716-24. 

18. Gauthier A, Kanis JA, Jiang Y, Martin M, Compston JE, Borgstrom F et al. 

Epidemiological burden of postmenopausal osteoporosis in the UK from 2010 to 

2021: estimations from a disease model. Archives of osteoporosis 2011; 6: 179-

88. 

19. Seeman E, Delmas PD. Bone quality--the material and structural basis of bone 

strength and fragility. The New England journal of medicine 2006; 354: 2250-61. 

20. Consensus conference: Osteoporosis. JAMA: the journal of the American Medical 

Association 1984; 252: 799-802. 

21. Ismail AA, Cooper C, Felsenberg D, Varlow J, Kanis JA, Silman AJ et al. 

Number and type of vertebral deformities: epidemiological characteristics and 

relation to back pain and height loss. European Vertebral Osteoporosis Study 

Group. Osteopor Int 1999; 9: 206-13. 

22. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK 

et al. Reduction of vertebral fracture risk in postmenopausal women with 

osteoporosis treated with raloxifene: results from a 3-year randomized clinical 

trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. J Am 

Med Assoc 1999; 282: 637-45. 

23. Lewiecki EM, Compston JE, Miller PD, Adachi JD, Adams JE, Leslie WD et al. 

Official Positions for FRAX(R) Bone Mineral Density and FRAX(R) 

simplification from Joint Official Positions Development Conference of the 

International Society for Clinical Densitometry and International Osteoporosis 

Foundation on FRAX(R). J Clin Densitom 2011; 14: 226-36. 

24. Gonzalez-Macias J, Marin F, Vila J, Diez-Perez A. Probability of fractures 

predicted by FRAX(R) and observed incidence in the Spanish ECOSAP Study 

cohort. Bone 2012; 50: 373-7. 

25. Dennison EM, Compston JE, Flahive J, Siris ES, Gehlbach SH, Adachi JD et al. 

Effect of co-morbidities on fracture risk: findings from the Global Longitudinal 

Study of Osteoporosis in Women (GLOW). Bone 2012; 50: 1288-93. 



29 

 

26. Hans DB, Kanis JA, Baim S, Bilezikian JP, Binkley N, Cauley JA et al. Joint 

Official Positions of the International Society for Clinical Densitometry and 

International Osteoporosis Foundation on FRAX((R)). Executive Summary of the 

2010 Position Development Conference on Interpretation and use of FRAX(R) in 

clinical practice. J Clin Densitom 2011; 14: 171-80. 

27. Zioupos P, Hansen U, Currey JD. Microcracking damage and the fracture process 

in relation to strain rate in human cortical bone tensile failure. J Biomechanics 

2008; 41: 2932-9. 

28. Diez-Perez A, Guerri R, Nogues X, Caceres E, Pena MJ, Mellibovsky L et al. 

Microindentation for in vivo measurement of bone tissue mechanical properties in 

humans. J Bone Miner Res 2010; 25: 1877-85. 

29. Guerri-Fernandez RC, Nogues X, Quesada Gomez JM, Torres Del Pliego E, Puig 

L, Garcia-Giralt N et al. Microindentation for in vivo measurement of bone tissue 

material properties in atypical femoral fracture patients and controls. J Bone 

Miner Res 2013; 28: 162-8. 

30. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of 

bone turnover, endogenous hormones and the risk of fractures in postmenopausal 

women: the OFELY study. J Bone Miner Res 2000; 15: 1526-36. 

31. Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A et al. 

Markers of bone turnover for the prediction of fracture risk and monitoring of 

osteoporosis treatment: a need for international reference standards. Osteoporos 

Int 2011; 22: 391-420. 

32. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY. 

European guidance for the diagnosis and management of osteoporosis in 

postmenopausal women. Osteoporos Int 2013;24:23-57. 

33. Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgstrom F et 

al. A framework for the development of guidelines for the management of 

glucocorticoid-induced osteoporosis. Osteoporos Int 2012; 23: 2257-76. 

34. Rizzoli R, Adachi JD, Cooper C, Dere W, Devogelaer JP, Diez-Perez A et al. 

Management of glucocorticoid-induced osteoporosis. Calcif Tiss Int 2012; 91: 

225-43. 

35. Kaufman JM, Reginster JY, Boonen S, Brandi ML, Cooper C, Dere W et al. 

Treatment of osteoporosis in men. Bone 2013; 53: 134-144. 



30 

 

36. Diez-Perez A, Hooven FH, Adachi JD, Adami S, Anderson FA, Boonen S et al. 

Regional differences in treatment for osteoporosis. The Global Longitudinal Study 

of Osteoporosis in Women (GLOW). Bone 2011; 49: 493-8. 

37. Diez-Perez A, Olmos JM, Nogues X, Sosa M, Diaz-Curiel M, Perez-Castrillon JL 

et al. Risk factors for prediction of inadequate response to antiresorptives. J Bone 

Miner Res 2012; 27: 817-24. 

38. Diez-Perez A, Adachi JD, Agnusdei D, Bilezikian JP, Compston JE, Cummings 

SR et al. Treatment failure in osteoporosis. Osteoporos Int 2012; 23: 2769-2774. 

39. Rizzoli R, Reginster JY, Boonen S, Breart G, Diez-Perez A, Felsenberg D et al. 

Adverse reactions and drug-drug interactions in the management of women with 

postmenopausal osteoporosis. Calcif Tiss Int 2011; 89: 91-104. 

40. Pazianas M, Abrahamsen B, Eiken PA, Eastell R, Russell RG. Reduced colon 

cancer incidence and mortality in postmenopausal women treated with an oral 

bisphosphonate--Danish National Register Based Cohort Study. Osteoporos Int 

2012; 23: 2693-701. 

41. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C 

et al. Zoledronic acid and clinical fractures and mortality after hip fracture. The 

New Eng Journal of Medicine 2007; 357: 1799-809. 

42. Kwong FN ,Harris MB Recent developments in the biology of fracture repair. J 

Am Acad Orthop Surg 2008;16:619-625. 

43. Diaz-Garcia RJ, Oda T, Shauver MJ, Chung KC A systematic review of outcomes 

and complications of treating unstable distal radius fractures in the elderly. J Hand 

Surg Am. 2011 May;36(5):824-35. 

44. Papanastassiou ID, Phillips FM, Van Meirhaeghe J, Berenson JR, Andersson GB, 

Chung G, et al .Comparing effects of kyphoplasty, vertebroplasty, and non-

surgical management in a systematic review of randomized and non-randomized 

controlled studies. Eur Spine J. 2012 ;21:1826-43. 

45. Edidin AA, Ong KL, Lau E, Kurtz SM. Mortality Risk for Operated and 

Nonoperated Vertebral Fracture Patients in the Medicare Population. J Bone 

Miner Res 2011,26; 1617-1626. 

46. Gao H, Liu Z, Xing D, Gong M. Which is the best alternative for displaced 

femoral neck fractures in the elderly?: A meta-analysis. Clin Orthop Relat Res. 

2012 ; 470:1782-91. 



31 

 

47.  Keating JF, Grant A, Masson M, Scott NW, Forbes JF. Randomized comparison 

of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. 

Treatment of displaced intracapsular hip fractures in healthy older patients. J Bone 

Joint Surg Am. 2006 ;88:249-60. 

48. Morshed S, Bozic KJ, Ries MD, Malchau H, Colford JM Jr. Comparison of 

cemented and uncemented fixation in total hip replacement: a meta-analysis. Acta 

Orthop. 2007;78:315-26. 

49. Yamada H, Yoshihara Y, Henmi O, Morita M, Shiromoto Y, Kawano T, Kanaji 

A, Ando K, Nakagawa M, Kosaki N, Fukaya E.Cementless total hip replacement: 

past, present, and future. J Orthop Sci. 2009 ;14:228-41. 

50. Parker MJ, Gurusamy KS, Azegami S.Arthroplasties (with and without bone 

cement) for proximal femoral fractures in adults. Cochrane Database Syst Rev. 

2010; 16:CD001706. 

51. Abdulkarim A, Ellanti P, Motterlini N, Fahey T, O'Byrne JM.Cemented versus 

uncemented fixation in total hip replacement: a systematic review and meta-

analysis of randomized controlled trials. Orthop Rev (Pavia). 2013 ;5:e8. 

52. Lorich DG, Geller DS, Nielson JH. Osteoporotic pertrochanteric hip fractures. 

Management and current controversies. J Bone Joint Surg Am 2004; 86:398- 410. 

53. Fini M, Giavaresi G, Torricelli P, Krajewski A, Ravaglioli A, Mattioli Belmonte 

M, et al. Biocompatibility and osteointergration in osteoporotic bone. J Bone Joint 

Surg Br 2001, 83:139-143. 

54. Heini PF, Berlemann U, KaufmanM, Lippuner K, Fankhauser C, Van Landuyt P. 

Augmentation of mechanical properties in osteoporotic vertebral bones – a 

biomechanical investigation of vertebroplasty efficacy with different bone 

cements. Eur Spine J. 2001, 10, 164-171. 

55. Yu L, Li Y, Zhao K, Tang Y, Cheng Z, Chen J, et al. A Novel Injectable Calcium 

Phosphate Cement-Bioactive Glass Composite for Bone Regeneration, PlOSOne 

(2013) DOI: 10.1371/journal.pone.0062570. 

http://www.ncbi.nlm.nih.gov/pubmed?term=Keating%20JF%5BAuthor%5D&cauthor=true&cauthor_uid=16452734
http://www.ncbi.nlm.nih.gov/pubmed?term=Grant%20A%5BAuthor%5D&cauthor=true&cauthor_uid=16452734
http://www.ncbi.nlm.nih.gov/pubmed?term=Masson%20M%5BAuthor%5D&cauthor=true&cauthor_uid=16452734
http://www.ncbi.nlm.nih.gov/pubmed?term=Scott%20NW%5BAuthor%5D&cauthor=true&cauthor_uid=16452734
http://www.ncbi.nlm.nih.gov/pubmed?term=Forbes%20JF%5BAuthor%5D&cauthor=true&cauthor_uid=16452734
http://www.ncbi.nlm.nih.gov/pubmed/16452734
http://www.ncbi.nlm.nih.gov/pubmed/16452734
http://www.ncbi.nlm.nih.gov/pubmed?term=Morshed%20S%5BAuthor%5D&cauthor=true&cauthor_uid=17611843
http://www.ncbi.nlm.nih.gov/pubmed?term=Bozic%20KJ%5BAuthor%5D&cauthor=true&cauthor_uid=17611843
http://www.ncbi.nlm.nih.gov/pubmed?term=Ries%20MD%5BAuthor%5D&cauthor=true&cauthor_uid=17611843
http://www.ncbi.nlm.nih.gov/pubmed?term=Malchau%20H%5BAuthor%5D&cauthor=true&cauthor_uid=17611843
http://www.ncbi.nlm.nih.gov/pubmed?term=Colford%20JM%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=17611843
http://www.ncbi.nlm.nih.gov/pubmed/17611843
http://www.ncbi.nlm.nih.gov/pubmed/17611843


32 

 

56. Hoekstra JWM, van den Beucken JJJP, Leeuwenburgh SCG, Bronkhorst EM, 

Meijer GJ, Jansen JA. Tantalum oxide and barium sulfate as radiopacifiers in 

injectable calcium phosphate-poly(lactic-co-glycolic acid) cements for monitoring 

in vivo degradation J Biomed Mater Res 2014; A102: 141-149. 

57.  Chen W, Zhou H, Weir MD, Tang M, Bao C, Xu HHK. Human Embryonic Stem 

Cell-Derived Mesenchymal Stem Cell Seeding on Calcium Phosphate Cement-

Chitosan-RGD Scaffold for Bone Repair, Tiss Eng Part A. 2013 ;19 :915-927. 

58. Vorndran E, Geffers M, Ewald A, Lemm M, Nies B, Gbureck U. Ready-to-use 

injectable calcium phosphate bone cement paste as drug carrier, Acta 

Biomaterialia 2013; 9: 9558–9567. 

59. Franchi M, Fini M, Giavaresi G, Ottani V. Peri-implant osteogenesis in health and 

osteoporosis. Micron 2005; 36:630-644. 

60. Fini M., Giavaresis G, Torricelli P, Borsari V, Giardino R, Nicolini A, et al. 

Osteoporosis and biomaterial osteointegration. Biomedicine & Pharmacotherapy 

2004; 58: 487-493. 

61. Verron E, Gauthier O, Janvier P, Pilet P, Lesouer J, Bujoli B, et al. In vivo bone 

augmentation in an osteoporotic environment using bisphosphonate-loaded 

calcium deficient apatite. Biomaterials 2010; 31: 7776-7784. 

62. Manzano M, Lozano D, Arcos D, Portal-Nuñez S, López C, Esbrit P, et al. 

Comparison of the osteoblastic activity conferred to si-doped hydroxyapatite 

scaffolds by different osteostatin coating. Acta Biomaterialia. 2011; 7: 3555-3562. 

63. Arcos D, Vallet-Regi M,. Bioceramics for drug delivery. Acta Materialia 

2013;61:890-911. 

64. Verron E, Bouler JM, Guicheux J. Controlling the biological function of calcium 

phosphate bone substitutes with drugs. Acta Biomaterialia 2012, 8:3541-3551. 

65. Trejo CG,  Lozano D, Manzano M, Doadrio JC, Salinas AJ, Dapia S, et al. The 

osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit 

femur cavity defect model. Biomaterials 2010; 31: 8564-8573. 

66. Manzano M, Vallet-Regí M. Revisiting bioceramics: bone regenerative and local 

drug delivery systems. Prog. Solid State Ch. 2012;40: 17-30. 

67. Chapman JR, Harrington RM, Lee KM, Anderson PA, Tencer AF, Kowalski D. 

Factors affecting the pullout strength of cancellous bone screws. Journal of 

Biomechanical Engineering 1996;118:391-398. 



33 

 

68. Frigg R, Frenk A, Wagner M. Biomechanics of plate osteosynthesis. Tech Orthop 

2007;22:203-8. 

69. McKoy BE, An YH. An injectable cementing screw for fixation in osteoporotic 

bone. J Biomed Mater Res 2000;53:216-20. 

70. Hu MH, Wu HT, Chang MC, Yu WK, Wang ST, Liu CL. 

Polymethylmethacrylate augmentation of the pedicle screw: the cement 

distribution in the vertebral body. Eur Spine J. 2011; 20:1281-8. 

71. Choma TJ, Pfeiffer FM, Swope RW, Hirner JP. Pedicle screw design and cement 

augmentation in osteoporotic vertebrae: effects of fenestrations and cement 

viscosity on fixation and extraction. Spine (Phila Pa 1976) 2012; 37:E1628-32. 

72. Gittens RA, Olivares-Navarrete R, Cheng A, Anderson DM, McLachlan T, 

Stephan I, et al. The roles of titanium surface micro/nanotopography and 

wettability on the differential response of human osteoblast lineage cells. Acta 

Biomaterialia 2013; 9:6268-77. 

73. Buser D, Schenk RK, Steinemann S, Fiorellini JP, Fox CH, Stich H. Influence of 

surface characteristics on bone integration of titanium implants – a 

histomorphometric study in miniature pigs. J Biomed Mater Res 1991; 25:889-

902. 

74. Cocharan DL, Jackson JM, Bernard JP, ten Bruggenkate CM, Buser D, Taylor 

TD, et al.A 5-year prospective multicenter study of early loaded titanium implants 

with a sandblasted and acid-etched surface. Int Oral Maxillofac Implants 2011; 

26:1324-32. 

75. Orsini G, Piattelli M, Scarano A Petrone G, Kenealy J, Piattelli A, et al. 

Randomized, controlled histologic and histomorphometric evaluation of implants 

with nanometer-scale calcium phosphate added to the dual acid-etched surace in 

the human posterior maxilla. J Periodontol 2007; 78:209-18. 

76. Collaert B, Wijnen L, De Bruyn H. A 2-year prospective study on immediate 

loading with fluoride-modified implants in the edentulous mandible. Clin Oral 

Implants Res 2011;22:1111-6. 

77. Park JH, Wasilewski CE, Almodovar N, Olivares-Navarrete R, Boyan BD, 

Tannenbaum R, et al. The responses to surface wettability gradientes induced by 

chitosan nanofilms on microtextured titanium mediated by specific integrin 

receptors. Biomaterials 2012; 33: 7386-93. 



34 

 

78. Bornstein MM, Wittneben JG, Bragger U, Buser D. Early loading at 21 days of 

non-submerged titanium implants with a chemically modified sandblasted and 

acid-etched surface. 3-year results of a prospective study in the posterior 

mandible. J Periodontol 2010;81:809-18. 

79. Nguyen HQ, Deporter DA, Pilliar RM, Valiquette N, Yakubovich R. The effect of 

sol-gel-formed calcium phosphate coatings on bone ingrowth and 

osteoconductivity of porous-surfaced Ti alloy implants. Biomaterials 

2004;25:865-76. 

80. Yang Y, Kim KH, Ong JL. A review on calcium phosphate coatings produced 

using a sputtering process - an alternative to plasma spraying. Biomaterials 

2005;26:327-37. 

81. Surmenev RA. A review of plasma-assisted methods for calcium phosphate-based 

coatings fabrication. Surf Coat Technol 2012;206:2035-56. 

82. Heimann RB. Thermal spraying of biomaterials. Surface Coatings Technol 

2006;201:2012-9. 

83. Surmenev RA, Surmeneva MA, Ivanova AA. Significance of calcium phosphate 

coatings for the enhancement of new bone osteogenesis – A review. Acta 

Biomater 2014:(in press). 

84. Bright DS, Clark HG, McCollum DE. Serum analysis and toxic effects of 

methylmethacrylate. Surgical Forum 1972; 23:455-457. 

85. Leeson MC, Lippitt SB. Thermal aspects of the use of polymethylmethacrylate in 

large metaphyseal defects in bone: A clinical review and laboratory study. Clin 

Orthop Relat Res 1993:239-45. 

86. Topoleski LDT, Ducheyne P, Cuckler JM. A fractographic analysis of in vivo 

poly(methyl methalcrylate) bone cement failure mechanisms. J Biomed Mater Res 

1990;24:135-54. 

87. Berlemann U, Ferguson SJ, Nolte LP, Hein PF. Adjacent vertebral failure after 

vertebroplasty - A biomechanical investigation. J Bone Joint Surg Br 

2002;84B:748-52. 

88. Lewis G. Injectable bone cements for use in vertebroplasty and kyphoplasty: 

State-of-the-art review. J Biomed Mater Res B Appl Biomater 2006;76:456-68. 

89. Urlings TAJ, Van Der Linden E. Elastoplasty: First experience in 12 patients. 

Cardiovasc Intervent Radiol 2013;36:479-83. 



35 

 

90. Blattert TR, Jestaedt L, Weckbach A. Suitability of a calcium phosphate cement 

in osteoporotic vertebral body fracture augmentation: a controlled, randomized, 

clinical trial of balloon kyphoplasty comparing calcium phosphate versus 

polymethylmethacrylate. Spine 2009;34:108-14. 

91. Piazzolla A, De Giorgi G, Solarino G. Vertebral body recollapse without trauma 

after kyphoplasty with calcium phosphate cement. Musculoskeletal Surgery 

2011;95:141-5. 

92. Boszczyk B. Prospective study of standalone balloon kyphoplasty with calcium 

phosphate cement augmentation in traumatic fractures (G. Maestretti et al.). Eur 

Spine J 2007;16:611. 

93. Maestretti G, Cremer C, Otten P, Jakob RP. Prospective study of standalone 

balloon kyphoplasty with calcium phosphate cement augmentation in traumatic 

fractures. European Spine Journal 2007;16:601-10. 

94. Bernards CM, Chapman JR, Mirza SK. Lethality of embolized norian bone 

cement varies with the time between mixing and embolization.  50th Annual 

Meeting of the Orthopaedic Research Society. San Fransisco2004. p. 0254. 

95.  Krebs J, Aebli N, Goss BG, Sugiyama S, Bardyn T, Boecken I, et al. 

Cardiovascular changes after pulmonary embolism from injecting calcium 

phosphate cement. J Biomed Mater Res B Appl Biomater 2007;82:526-32. 

96.  Dressel S, Jarvers JSG, Josten C, Blattert TR. Percutaneous balloon kyphoplasty 

in osteoporotic vertebral body fracture with a calcium aluminate ceramic 

(Xeraspine©). European Musculoskeletal Review 2012;7:209-12. 

97. Rauschmann M, Vogl T, Verheyden A, Pflugmacher R, Werba T, Schmidt S, et 

al. Bioceramic vertebral augmentation with a calcium sulphate/hydroxyapatite 

composite (Cerament™ SpineSupport) in vertebral compression fractures due to 

osteoporosis. European Spine Journal 2010;19:887-92. 

98. Masala S, Nano G, Marcia S, Muto M, Fucci FPM, Simonetti G. Osteoporotic 

vertebral compression fractures augmentation by injectable partly resorbable 

ceramic bone substitute (Cerament™|SPINE SUPPORT): A prospective 

nonrandomized study. Neuroradiology 2012;54:589-96. 

99. Bai B, Kummer FJ, Spivak J. Augmentation of anterior vertebral body screw 

fixation by an injectable, biodegradable calcium phosphate bone substitute. Spine 

2001;26:2679-83. 



36 

 

100. Bohner M, Lemaitre J, Cordey J, Gogolewski S, Ring TA, Perren SM. Potential 

use of biodegradable bone cement in bone surgery: holding strength of screws in 

reinforced osteoporotic bone. Orthopaedic Transactions 1992;16:401-2. 

101. Mermelstein LE, Chow LC, Friedman C, Crisco Iii JJ. The Reinforcement of 

Cancellous Bone Screws with Calcium Phosphate Cement. Journal of Orthopaedic 

Trauma 1996;10:15-20. 

102. Stankewich CJ, Swiontkowski MF, Tencer AF, Yetkinler DN, Poser RD. 

Augmentation of femoral neck fracture fixation with an injectable calcium-

phosphate bone mineral cement. Journal of Orthopaedic Research 1996;14:786-

93. 

103. Larsson S, Stadelmann VA, Arnoldi J, Behrens M, Hess B, Procter P, et al. 

Injectable calcium phosphate cement for augmentation around cancellous bone 

screws. In vivo biomechanical studies. Journal of Biomechanics 2012;45:1156-60. 

104. Stadelmann VA, Bretton E, Terrier A, Procter P, Pioletti DP. Calcium phosphate 

cement augmentation of cancellous bone screws can compensate for the absence 

of cortical fixation. Journal of Biomechanics 2010;43:2869-74. 

105. Vallet-Regí M, Colilla M, Izquierdo-Barba I. Bioactive mesoporous silicas as 

controlled delivery systems: Aplication in bonetissue regeneration. J Biomed 

Nanotechnol 2008;4:1-15. 

106. Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials 

2000; 2529-43. 

107. Stevens, MM, George, J. (2005). Exploring and Engineering the Cell Surface 

Interface. Science 2005; 310: 1135-38. 

108. Schieker M, Seitz H, Drosse I, Seitz S, Mutschler W. Biomaterials as scaffolds for 

bone tissue engineering. Eur J Trauma 2006;32:114-24. 

109. Kruyt MC, de Bruijn JD, Wilson CE, et al. Viable osteogenic cells are obligatory 

for tissue-engineered ectopic bone formation in goats. Tissue Eng 2003;9:327–36. 

110. Dorozhkin SV, Epple M. Biological and medical significance of calcium 

phosphates. Angew Chem Int Ed 2002;41:3130-46. 

111. Vallet-Regí M, González-Calbet JM. Calcium phosphates as substitution of bone 

tissues. Progr Solid State Chem 2004;32:1-31. 

112. Bohner M. Resorbable biomaterials as bone graft substitutes. Mater Today 

2010;13:24-30. 



37 

 

113. Weiner S, Wagner HD. The material bone: structure-mechanical function 

relations. Annu Rev Mater Sci 1998;28:271-9. 

114. Tadic D, Epple M. A thorough physicochemical characterisation of 14 calcium 

phosphate-based bone substitution materials in comparison to natural bone. 

Biomaterials 2004;25:987-94. 

115. Weiss P, Obadia L, Magne D, Bourges X, Rau C, Weitkamp T, et al. Synchrotron 

X-ray microtomography (on a micron scale) provides three-dimensional imaging 

representation of bone ingrowth in calcium phosphate biomaterials. Biomaterials 

2003;24:4591-601. 

116. Schilling AF, Linhart W, Filke S, Gebauer M, Schinke T, Rueger JM, et al. 

Resorbability of bone substitute biomaterials by human osteoclasts. Biomaterials 

2004;25:3963-72. 

117. Detsch R, Hagmeyer D, Neumann M, Schaefer S, Vortkamp A, Wuelling M, et al. 

The resorption of nanocrystalline calcium phosphates by osteoclast-like cells. 

Acta Biomater 2010;6:3223-33. 

118. Xynos ID, Hukkanen MVJ,  Batten JJ, Buttery LD, Hench LL, Polak JM. 

Bioglass (R) 45S5 stimulates osteoblast turnover and enhances bone formation in 

vitro: Implications and applications for bone tissue engineering. Calcified Tissue 

Int 2000; 67:321-329. 

119. Han P, Wu C, Xiao Y. The effect of silicate ions on proliferation, osteogenic 

differentiation and cell signaling pathways (WNT and SHH) of bone marrow 

stromal cells. Biomater Sci 2013; 1: 379-392. 

120. Aguirre A, González A, Planell JA, Engel E. Extracellular calcium modulates in 

vitro bone marrow-derived Flk-1+ CD34+ progenitor cell chemotaxis and 

differentiation through a calcium-sensing receptor. Biochem Biophys Res Comm 

2010; 393: 156–161. 

121. Hench LL. Genetic design of bioactive glass, J. Eur Ceram Soc 2009;29 :1257–

1265. 

122. Rahaman MN, Day DE, Bal BS, Fu Q, Jung SB, Bonewald LF, Tomsia AP. 

Bioactive glass in tissue engineering, Acta Biomater 2011; 7: 2355-2373. 

123. Xynos ID, Edgar AJ, Buttery LDK, Hench LL, Polak JM. Gene-expression 

profiling of human osteoblasts following treatment with the ionic products of 

Bioglass® 45S5 dissolution. J Biomed Mater Res 2001; 55: 151-157. 



38 

 

124. Gorustovich AA, Roether JA, Boccaccini AR. Effect of Bioactive Glasses on 

Angiogenesis: In-vitro and In-vivo Evidence. A Review. Tissue Eng. Part B 

2010;16 199-207. 

125. Hench LL. Genetic design of bioactive glass, J. Eur Ceram Soc 2009;29 :1257–

1265. 

126. Navarro M, Ginebra MP, Planell JA. Cellular response to calcium phosphate 

glasses with controlled solubility. J Biomed Mater Res 2003; 67A: 1009-1015. 

127. Charles-Harris M, Koch M, Navarro M, Lacroix D, Engel E, Planell JA. A 

PLA/calcium phosphate degradable composite material for bone tissue 

engineering: an in vitro study. J Mater Sci: Mater Med, 2008;19:1503–1513. 

128. Navarro M, Sanzana ES, Planell JA, Ginebra MP, Torres PA. In Vivo behavior of 

calcium phosphate glasses with controlled solubility. Key Engineering Materials 

200;5 284-286: 893-896. 

129. Gentleman E, Fredholm YC, Jell G, Lotfibakhshaiesh N, O'Donnell MD, Hill RG, 

et al. The effects of strontium-substituted bioactive glasses on osteoblasts and 

osteoclasts in vitro. Biomaterials 2010; 31: 3949-3956. 

130. Teofilo JM, Brentegani LG, Lamano-Carvalho TL. Bone healing in osteoporotic 

female rats following intra-alveolar grafting of bioactive glass. Archives Oral 

Biol. 2004; 49: 755-762. 

131. Vallet-Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angew 

Chem Int Ed 2007;46:7548-7558. 

132. Schliephake H, Weich HA, Dullin C, Gruber R, Frahse S. Mandibular bone repair 

by implantation of rhBMP-2 in a slow release carrier or polylactic acid - An 

experimental study in rats. Biomaterials 2008;29:103-110. 

133. Devescovi V, Leonardi E, Ciapetti G, Cenni E. Growth factors in bone repair. 

Chir Organi Mov 2008;92:161-168. 

134. Lissenberg-Thunnissen SN, de Gorter DJJ, Sier CFM, Schipper IB. Use and 

efficacy of bone morphogenetic proteins in fracture healing. Int Orthop 

2011;35:1271-1280. 

135. Wernike E, Montjovent MO, Liu Y, Wismeijer D, Hunziker EB, Siebenrock KA, 

et al. VEGF incorporated into calcium phosphate ceramics promotes 

vascularisation and bone formation in vivo. Eur Cells Mater 2010;19:30-40. 



39 

 

136. Lode A, Wolf-Brandstetter C, Reinstorf A, Bernhardt A, Koenig U, Pompe W, et 

al. Calcium phosphate bone cements, functionalized with VEGF: release kinetics 

and biological activity. J Biomed Mater Res 2007;81A:474-483. 

137. Evans CH. Gene therapy for bone healing. Exp Rev Molec Med 2010 23;12:e18. 

138. Bushman FD. Retroviral integration and human gene therapy. J Clin Invest 

2007;117:2083-2086. 

139.  Yi Y, Hahm SH, Lee KH. Retroviral gene therapy: Safety issues and possible 

solutions. Curr Gene Therapy 2005;5: 25-35. 

140. Sokolova V, Epple M. Inorganic nanoparticles as carriers of nucleic acids into 

cells. Angew Chem Int Ed 2008;47:1382-1395. 

141. Guo X, Huang L. Recent advances in nonviral vectors for gene delivery. Acc 

Chem Res 2012;45:971-979. 

142. Wegman F, Bijenhof A, Schuijff L, Oner FC, Dhert WJA, Alblas J. Osteogenic 

differentiation as a result of BMP-2 plasmid DNA based gene therapy in vitro and 

in vivo. Eur Cell Mater 2011;21:230-242. 

143.  Zhang C, Wang KZ, Qiang H, Tang YL, Li QA, Li MA, et al. Angiopoiesis and 

bone regeneration via co-expression of the hVEGF and hBMP genes from an 

adeno-associated viral vector in vitro and in vivo. Acta Pharmacol Sin 

2010;31:821-830. 

144. Krebs MD, Salter E, Chen E, Sutter KA, Alsberg E. Calcium phosphate-DNA 

nanoparticle gene delivery from alginate hydrogels induces in vivo osteogenesis. J 

Biomed Mater Res A 2010;92A:1131-1138. 

145. Keeney M, van den Beucken JJJP, van der Kraan PM, Jansen JA, Pandit A. The 

ability of a collagen/calcium phosphate scaffold to act as its own vector for gene 

delivery and to promote bone formation via transfection with VEGF165. 

Biomaterials 2010;31:2893-2902. 

146. Cheang TY, Wang SM, Hu ZJ, Xing ZH, Chang GQ, Yao C, et al. Calcium 

carbonate/CaIP6 nanocomposite particles as gene delivery vehicles for human 

vascular smooth muscle cells. J Mater Chem 2010;20:8050-8055. 

147. Chernousova S, Klesing J, Soklakova N, Epple M. A genetically active nano-

calcium phosphate paste for bone substitution, encoding the formation of BMP-7 

and VEGF-A. RSC Adv 2013:(in press). 



40 

 

148. Liu H, Webster TJ. Mechanical properties of dispersed ceramic nanoparticles in 

polymer composites for orthopedic applications. Int J Nanomedicine 2010;5:299-

313. 

149. Dunlop JWC, Fratzl P. Biological composites. Ann Rev Mater Res 2010;40:1-24. 

150. Weiner S, Wagner HD. The material bone: structure-mechanical function 

relations. Annu Rev Mater Sci 1998;28:271-98. 

151. Nikolov S, Petrov M, Lymperakis L, Friak M, Sachs C, Fabritius HO, et al. 

Revealing the design principles of high-performance biological composites using 

ab initio and multiscale simulations: The example of lobster cuticle. Adv Mater 

2010;22:519. 

152. Kurreck J. RNA Interference: From basic research to therapeutic applications. 

Angew Chem Int Ed 2009;48:1378-1398. 

153. Kesharwani P, Gajbhiye V, Jain NK. A review of nanocarriers for the delivery of 

small interfering RNA. Biomaterials 2012;33:7138-7150. 

154. Reischl D, Zimmer A. Drug delivery of siRNA therapeutics: potentials and limits 

of nanosystems. Nanomedicine 2009;5:8-20. 

155. Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev 

Genet 2009;10(2):94-108. 

156. Laroui H, Theiss AL, Yan Y, Dalmasso G, Nguyen HTT, Sitaraman SV, et al. 

Functional TNF-a gene silencing mediated by polyethyleneimine/TNF-a siRNA 

nanocomplexes in inflamed colon. Biomaterials 2011;32:1218-1228. 

157. Zhang X, Kovtun A, Mendoza-Palomares C, Oulad-Abdelghani M, Facca S, 

Fioretti F, et al. SiRNA-loaded multi-shell nanoparticles incorporated into a 

multilayered film as a reservoir for gene silencing. Biomaterials 2010;31:6013-

6018. 

158. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and 

Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001; 

14:285:785-95. 

159. Arvidson K, Abdallah BM, Applegate LA, Nicola Baldini N, Cenni E, Gomez-

Barrena E, Granchi D, Kassem M, Konttinen T, Mustafa K, Pioletti DP, Sillat T, 

Wistrand AF. Bone regeneration and stem cells. J Cell Mol Med. 2011;15:718-

746. 



41 

 

160. Gómez-Barrena E, Rosset P, Muller I, Giordano R, Bunu C, Laroylle P, Konttinen 

YT, Luyten FT. Bone regeneration: stem cell therapies and clinical studies in 

orthopaedics and traumatology. J Cell Mol Med. 2011;15:1266-1286. 

161. Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous autologous bone-

marrow grafting for nonunions. Influence of the number and concentration of 

progenitor cells. J Bone Joint Surg Am 2005; 87 1430-1437. 

162. Jakob F, Ebert R, Ignatius A, Matsushita T, Watanabe Y, Groll J et al. Bone tissue 

engineering in osteoporosis. Maturitas 2013; 75: 118-124. 

163. Bohner M, Lemaitre J. Can bioactivity be tested in vitro with SBF solution? 

Biomaterials 2009; 30: 2175-2179. 

164. Pan H, Zhao X, Darvell BW, Lu WW. Apatite-formation ability – Predictor of 

“bioactivity”?. Acta Biomaterialia 2010; 6: 4181-4188. 

165. Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, Wilson DJ, Diamond TH et 

al. A Randomized Controlled Trial of Vertebroplasty for Osteoporotic Spine 

Fractures. N Engl J Med 2009; 361: 69-579. 

166. Buchbinder R, Osborne RH, Ebeling PR, Wark JD, Mitchell P, Wriedt C, et al. A 

randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N 

Engl J Med 2009; 361: 557-568. 

167. (http://en.wikipedia.org/wiki/Contaminated_haemophilia_blood_products). 

 

 

  



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Figure captions 

 

Figure 1. Three trajectories of aging, with a differential risk for disability. 

Figure 2. The path from robustness towards frailty and disability: factors, biomarkers 

and modulators. 

Figure 3. Displaced intracapsular fracture (left) and trochanteric fracture (right). 

Figure 4. Osteoporotic vertebral fractures in T12 y L4 . Vertebroplasty in T12 and 

reduction and fixation with cannulated screws and cement in L4. 

Figure 5. Osteoporotic vertebral fractures treatment .Fixation with cannulated screws  

and cement 

Figure 6. DNA-loaded calcium phosphate nanorods which are able to induce the 

formation of BMP and VEGF.  

Figure 7. FDA pre-market approvals (PMAs) and pre-market notifications (510k) 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 

 

 



Figure 1
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*Graphical Abstract