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`
`Painful prosthesis: approaching the patient with persistent
`pain following total hip and knee arthroplasty
`
`Mini-review
`
`Prisco Piscitelli1,2
`Giovanni Iolascon2
`Massimo Innocenti1
`Roberto Civinini1
`Alessandro Rubinacci3
`Maurizio Muratore4
`Michele D’Arienzo5
`Paolo Tranquilli Leali6
`Anna Maria Carossino1
`Maria Luisa Brandi1
`on behalf of the BONORTO study group of the Italian
`Society of Orthopedics and Medicine, OrtoMed
`
`1 University of Florence, Florence, Italy
`2 Euro Mediterranean Biomedical Scientific Institute, ISBEM,
`Brindisi, Italy
`3 Second University of Naples, Naples, Italy
`3 S. Raffaele Scientific Institute, Milan, Italy
`4 Local Health Authority Lecce, San Cesario, Italy
`5 University of Palermo, Palermo, Italy
`6 University of Sassari, Sassari, Italy
`
`Address for correspondence:
`Maria Luisa Brandi, MD, PhD
`Department of Surgery and Translational Medicine
`University of Florence
`Viale Pieraccini 6
`50134 Florence, Italy
`Phone/Fax: +39 055 7946303
`E-mail: m.brandi@dmi.unifi.it
`
`Summary
`
`Background. Symptomatic severe osteoarthritis and hip
`osteoporotic fractures are the main conditions requiring
`total hip arthroplasty (THA), whereas total knee arthroplas-
`ty (TKA) is mainly performed for pain, disability or defor-
`mity due to osteoarthritis. After surgery, some patients
`suffer from “painful prosthesis”, which currently repre-
`sents a clinical problem. Methods. A systematic review of
`scientific literature has been performed. A panel of experts
`has examined the issue of persistent pain following total
`hip or knee arthroplasty, in order to characterize
`etiopathological mechanisms and define how to cope with
`this condition. Results. Four major categories (non infec-
`tive, septic, other and idiopathic causes) have been identi-
`fied as possible origin of persistent pain after total joint
`arthroplasty (TJA). Time to surgery, pain level and func-
`tion impairment before surgical intervention, mechanical
`stress following prosthesis implant, osseointegration defi-
`ciency, and post-traumatic or allergic inflammatory re-
`sponse are all factors playing an important role in causing
`
`persistent pain after joint arthroplasty. Diagnosis of per-
`sistent pain should be made in case of post-operative pain
`(self-reported as VAS ≥3) persisting for at least 4 months
`after surgery, or new onset of pain (VAS ≥3) after the first 4
`months, lasting ≥2 months. Acute pain reported as VAS
`score ≥7 in patients who underwent TJA should be always
`immediately investigated. Conclusions. The cause of pain
`needs always to be indentified and removed whenever
`possible. Implant revision is indicated only when septic or
`aseptic loosening is diagnosed. Current evidence has
`shown that peri-and/or post-operative administration of
`bisphosphonates may have a role in pain management
`and periprosthetic bone loss prevention.
`
`KEY WORDS: hip arthroplasty; knee arthroplasty; persistent pain; painful pro-
`sthesis.
`
`Introduction: prosthesis and pain
`
`Symptomatic severe osteoarthritis (OA), usually affecting hip
`and/or knee joints, is a leading cause of disability in elderly
`people and represents the main condition requiring surgical
`treatment with total joint arthroplasty (TJA) (1-3). The second
`major cause requiring TJA is hip fragility fracture due to os-
`teoporosis, which currently represents about 30% of total hip
`replacements (4-6). Considering both severe osteoarthritis
`and osteoporosis, women are affected more frequently than
`men (7, 8). Joint arthroplasty is one of the most successful
`orthopedic interventions (9), and it is performed to reduce
`pain or functional disability (10), but persistent post-operative
`pain represents a problem that in some patients may nega-
`tively influence clinical outcomes (11). The International As-
`sociation for the Study of Pain (IASP) has specifically defined
`persistent post-surgical pain as pain that developed after
`surgery which has been present for at least 3 months, an in-
`terval which is considered to be beyond the time for normal
`healing (12). The prevalence of persistent post-surgical pain
`is not clearly defined, being estimated between 10% and 50%
`of surgical patients (13), but surgery is known to be the sec-
`ond most common cause of persistent pain after degenera-
`tive conditions (14). According to the findings of Wylde et al.,
`44% of patients undergoing total knee arthroplasty (TKA) and
`27% of those undergoing total hip arthroplasty (THA) suffer
`from persistent post-surgical pain of any severity, with severe
`or extremely severe pain being reported by 15% and 6% of
`operated patients, respectively (15).
`It is unclear whether the persistence of pain after joint arthro-
`plasty is a consequence of previous patient-related clinical
`factors, underlying vulnerability to pain, or if it should be sim-
`ply regarded as a surgical complication due to aseptic (i.e.
`mechanical) or septic causes (15, 11). In some patients un-
`dergoing TJA it is very difficult to identify the origin (idiopath-
`ic) of painful symptoms. This latter condition has been de-
`fined as “painful prosthesis” (16, 17), which causes further
`sufferance, impaired function, and reduced quality of life to
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`affected patients (17). In these patients, a re-intervention for
`prosthesis revision may be required, with uncertain clinical
`outcomes in relation to pain relief (16). Our study is aimed at
`providing an experts’ statement addressing the issue of defin-
`ition (including possible causes), diagnosis, prevention, and
`treatment of persistent pain after total hip or knee arthroplas-
`ty. We have preliminary performed a systematic review both
`on Pumbed and Embase databases up to December 2012.
`There were 12 articles explicitly defining the condition of per-
`sistent pain after total hip or knee arthroplasty as “painful
`prosthesis” from 1975 to 2012 but 4 of these articles were
`published in this latter year. Total article generically address-
`ing this issue were 1,559 (82 of which being review articles).
`By limiting the search to the articles specifically addressing
`the problem of pain following the implant of hip or knee pros-
`thesis, we found 301 articles including 10 reviews on Pubmed
`– searching for "Prostheses and Implants"[Majr] AND
`"Pain"[Majr] AND (knee OR hip) – and 210 on Embase data-
`base – searching for 'prosthesis'/exp AND 'pain'/exp AND
`(knee OR hip) AND [embase]/lim. The experts have analyzed
`the available literature and the major topics concerning per-
`sistent pain after hip or knee arthroplasty.
`
`Analysis of predictors in patients with severe osteoarthritis
`
`Recent medical literature has identified some clinical factors
`as predictors of final outcome following TJA and possible on-
`set of persistent post-surgical pain. Assessing predictors of
`clinical outcomes after TJA is becoming a critical issue, as a
`recent study by Judge et al. (the Eurohip study), carried out
`on 1,327 patients receiving primary THA for osteoarthritis
`(OA) across 20 European orthopedic centers, has estimated
`that such a relevant percentage of patients, that is between
`14% and 36%, do not improve at 12 months after total hip
`arthroplasty (18). Similar evidence is available for a cohort of
`more than 8,000 OA patients one year after TKA (19). About
`18% of operated patients declared they were not satisfied
`with the outcome of TKA at 12 months, with patients who re-
`ported higher scores concerning their pain assessment and
`functional evaluation being associated with worse post-opera-
`tive satisfaction (19).
`
`Age, musculoskeletal comorbidities, and preoperative
`pain
`A specific study carried out by Nilsdotter et al. in 2003 (20)
`has assessed physical function of 339 patients undergoing
`THA both pre-operatively and post-operatively, by using the
`36-Item Short-Form Health Survey (SF-36) and Western On-
`tario and McMaster Universities (WOMAC) questionnaires. In
`this study, age, sex, body mass index (BMI), presence of co-
`morbidities (i.e. heart, peripheral arteries or lung, diseases,
`hypertension, diabetes, neurological problems, cancer, ulcer,
`kidney diseases, vision impairment, low back pain, and psy-
`chiatric disorders), widespread pain or pain at controlateral
`hip, the need of walking assistance,walking distance, and liv-
`ing alone, were evaluated both pre- and post-operatively and
`tested as potential predictors of post-operative outcomes. As
`a result, older age and higher preoperative higher scores in
`pain evaluation were shown to be predictors of a poor clinical
`outcome following THA. Moreover, patients with muscu-
`loskeletal comorbidities, such as low back pain and OA af-
`fecting the non-operated hip joint, were found to have less
`long term functional improvement after THA. Both low back
`pain and post-operative complications were associated with
`
`worse outcome. Notably, post-operative presence of low back
`pain was the only finding significantly associated with a non
`successful result in a multivariate analysis (20). The number
`of comorbidities preoperatively reported did not predict a
`worse post-operative outcome when assessed both by the
`WOMAC function and the by SF-36 PF (physical function)
`questionnaires (20). However, a better gradient with a lower
`number of comorbidities was reasonably presented. Low
`back pain and pain in the hip not operated on were character-
`istic of patients who did not reach the same level of function
`post-operatively as the age matched control group (20). Ac-
`cording to a Canadian study carried out on 454 patients un-
`dergoing THA primary total hip arthroplasty (n = 197) or TKA
`(n = 257) who were evaluated within a month prior to surgery
`and 6 months post-operatively, age alone should not be con-
`sidered a factor that affects the outcome of joint arthroplasty
`and should not be a limiting criterion when considering who
`should undergo TJA (21). Similar findings were provided by a
`study performed on 174 patients (mean age 75 years old),
`concluding that elderly patients undergoing THA or TKA for
`severe OA experienced excellent long-term outcomes (22). It
`must be pointed out that the latter evidence was provided by
`using the same evaluation tools for pain, function, and health-
`related quality of life (i.e. WOMAC, SF-36) (21, 22).
`
`Time to surgery and preoperative disability
`An emerging body of evidence has suggested that patients
`affected by symptomatic severe osteoarthritis may experi-
`ence higher pain level and worse function the longer they
`wait for joint arthroplasty (23-26). Specifically, it seems that a
`wait time exceeding 1 year between first indication to surgery
`and surgical intervention is associated with worse clinical out-
`comes after TJA (23-26). It remains controversial whether
`long waiting lists may cause a worsening in pain or function
`of patients eligible for surgery. In fact, a recent metanalysis
`reported no deterioration concerning pain or self-reported
`functional status in OA patients waiting <180 days before re-
`ceiving TJA (27), while other evidence suggested that waiting
`lists worsen both pain and function as measured by visual
`analogic scale (VAS), SF-36 and WOMAC, respectively (28).
`According to a recent study carried out by Vergara et al. (29),
`long wait times are not free from adverse effects and might
`have irreversible consequences on clinical outcomes of
`surgery. Longer waiting time to surgery is possibly due to pa-
`tient hesitation or suboptimal management of waiting lists for
`joint arthroplasty. In the latter case, the adoption of efficient
`procedures in the management of waiting lists – based only
`on pain and function level as selection criteria for prioritizing
`patients to surgery – has been shown to improve clinical out-
`comes after TJA (29). Time to surgery in OA patients under-
`going joint arthroplasty is also a valuable marker of quality of
`care and system equity in terms of citizens’ access to health
`care services (30). Some authors have reported a mean wait-
`ing time to surgery of 6 months in European countries, al-
`though considerable differences between different nations
`and within the same country have been described (31). To
`explain the observed variations in wait times for elective
`surgery in OA patients, several major (demand, quality of life,
`pain, and disability) and minor (age, comorbidities, and other
`social variables such as the presence of caregivers) factors
`have been considered (26, 32, 33). However, opain and im-
`paired function represent the most relevant criteria in the pri-
`oritization process for joint arthroplasty (23-29). All the varia-
`tions in the waiting times observed between different hospi-
`tals are due to different management procedures of waiting
`
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`Painful prosthesis: approaching the patient with persistent pain following total hip and knee arthroplasty
`
`lists or a complete absence of prioritization protocols, so that
`surgeons are allowed to arbitrarily use discretional selection
`criteria in patients eligible for TJA (33). A study performed by
`Quintana et al. (34) has pointed out the risks of not having
`clear and explicit criteria to prioritize patients eligible to
`surgery, which also determine inequality in the access to
`healthcare services.
`
`The role of mechanical stress following prosthesis
`implant
`
`Mechanical factors, both those intrinsically related to prosthe-
`sis design or material, and those related to the implant in the
`bone, obviously play an important role in the onset of post-
`surgical pain. First generation hip prostheses presented a
`metal femoral implant articulating with a polyethylene acetab-
`ular cup that resulted in survival rates of only 34% at 10 years
`(35, 36). Failures were usually due to implant loosening sec-
`ondary to osteolysis. This process was triggered by major
`volumetric wear of the polyethylene component articulating
`with the first generation femoral head (35-37). Relevant im-
`provements have been achieved after the introduction of new
`bearing couples and thanks to the availability of new industri-
`al machines for the production of better prostheses (38), with
`survival rates of last generation implants ranging from 80 to
`95% at 15 years (39-41). Revision rates after TJA have been
`computed to be 6% at 5 years and 12% at 10 years both for
`hip and knee arthroplasties (42). Early revision surgery after
`total hip replacement is frequently associated with instability
`or loosening of the acetabular and femoral components (38,
`43). Mechanical loosening of the prosthesis may also be as-
`sociated with malalignment of the femoral implant, which is
`believed to increase shear forces at the bone-implant inter-
`face (35, 44, 45). Various physiopathological hypotheses
`(mechanical, vascular, biological) have been proposed to ex-
`plain such phenomenon (46, 47). In general, the implantation
`of foreign materials in the human body results in several
`modifications and adaptations within the host tissue. Type
`and extent of these modifications depend on different factors:
`biocompatibility of the material, interference with the biome-
`chanical characteristics of the host tissue, fragments of com-
`ponents from the implanted material, quality of the host tis-
`sue, local and general reactivity. Therefore the bone sur-
`rounding a prosthetic implant, both uncemented and cement-
`ed, normally experiences a progressive quantitative reduction
`(bone loss) as a result of two main factors: stress shielding
`and wear debris production (40).
`Stress shielding is a physical phenomenon occurring when a
`hip-prosthesis is implanted into the bone tissue, so that load-
`ing axes (stresses) are bypassed by the prosthesis implant,
`thus discharging bone from weight bearing (40). The prosthe-
`sis shields bone from mechanical stresses that are necessary
`for maintenance of normal bone structure. When the bone tis-
`sue surrounding the implant is not subject to anabolic strain
`stimulus, bone is reabsorbed through an adaptive bone re-
`modeling process mediated by the osteocytes (40). Under
`these conditions the implant will no longer hold and it slips
`out. Peri-prosthetic bone loss caused by stress shielding,
`which is more frequent in greater size, rigid and cemented
`implants, may be associated with aseptic loosening of femoral
`components (40, 48). The success of a total hip arthroplasty
`is strongly related to the initial stability of the femoral compo-
`nent and to the stress shielding effect. Inefficient primary sta-
`bility is also a cause of thigh pain. In addition, bone adapta-
`
`tion after the surgery can lead to an excessive bone loss and,
`consequently, can compromise the success of the implant.
`However, prosthesis shape, design, material, and interface
`influence stress shielding and post-operative bone adapta-
`tion, so that optimization of implant performance and geome-
`try may be useful in order to reduce the need for revisions
`and post-operative discomfort or pain (48-50). Poor quality of
`intertrochanteric cancellous bone does not seem as crucial
`as previously thought in influencing the risk of implant migra-
`tion (51). It must also be taken into account that attrition of
`the prosthetic surfaces leads to the formation of wear debris,
`which may trigger osteolysis and finally result in the aseptic
`loosening of the implant. This debris is made of polyethylene
`particles originating from the acetabular cup of the prosthesis
`and causes a flogistic response leading to the production of
`inflammation mediators including cytokines (40). This activa-
`tion enhances osteoclast recruitment and activity next to
`bone-implant interfaces, thus causing osteolysis and loosen-
`ing of the implant. The presence of debris particles is not suf-
`ficient to trigger a foreign body reaction, which ultimately oc-
`curs when there is enough mobility of the prosthetic implant
`to increase the “effective articular space”, thus enabling the
`migration of the particles in the interface between bone and
`prosthesis. Therefore, periprosthetic osteolysis is determined
`by the combined action of an increase in bone resorption (di-
`rectly induced by debris or through an inflammation process),
`and a reduced bone formation caused by a depression of os-
`teoblastic activity as a result of debris direct toxicity (40).
`Beyond direct mechanical causes, the role of biological fac-
`tors and inflammation must be properly considered. In fact,
`the trauma resulting from the implant insertion into bone may
`trigger inflammatory response and lead to an activation of
`several cells, including osteoclasts, macrophages and angio-
`genic cells (46, 52). It has also been suggested that the
`apoptosis of osteocytes occurring in the area of the implant
`may foster the activation of osteoclasts, thus possibly result-
`ing in alteration of the balance between bone resorption and
`formation (46). Once the resorption process preponderates,
`an impairment of early fixation might occur shortly after surgi-
`cal intervention (46). On this basis, it has been suggested
`that post-operative pharmacological treatment with antire-
`sorptive drugs may be useful in preventing periprosthetic
`bone loss, thus reducing the risk of implant migration (40).
`Several studies demonstrated that different antiresorptive
`drugs (i.e. ibandronate, alendronate, risedronate, zoledronic
`acid) can modulate periprosthetic bone loss related to osteo-
`clastic activity enhanced by cytokines produced during flogis-
`tic response to wear debris (47, 52-59). Attempts to investi-
`gate the effect of weak antiresorptive – as strontium ranelate –
`periprosthetic bone loss are controversial (60). Dual-energy
`X-ray absorptiometry (DXA) can provide a surrogate measure
`of load redistribution of the prosthetic components after TJA
`and may be useful in monitoring the efficacy of pharmacologi-
`cal therapy to reduce the periprosthetic bone loss (40, 61). In
`this case, DXA is performed by using specific software algo-
`rithms for the evaluation of the bone around the implant. This
`technique provides information about BMD measured around
`the seven Gruen zones, with good reproducibility of the mea-
`surements (coefficients of variation range: 1.8-7.5%). It might
`be also useful to perform a pre-operative DXA analysis to
`support the choice of implant components (61).
`Similar evidence is also available for the loosening of knee
`prostheses (55). The risk of late loosening of cemented knee
`prostheses is related to early fixation, which is defined as mi-
`gration during the first and second year, as measured by ra-
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`diostereometric analysis (RSA) (55, 62). Early fixation was
`considered as a purely mechanical phenomenon, but it is now
`clear that osteocytes next to the implant undergo post-opera-
`tive death because of surgical trauma and circulatory distur-
`bance (55). This leads to increased bone resorption at the in-
`terface, and reduced quality of the fixation (63). A fracture re-
`pair response to the trauma resulting in an increased bone
`formation has also been documented (55). Therefore, early
`knee implant fixation also depends on the balance between
`bone formation and resorption, and the first six months after
`surgical intervention seem to represent the most critical peri-
`od for implant migration (64). In this perspective, the use of
`antiresorptive agents may be proposed in order to achieve a
`positive balance between bone formation and resorption, thus
`leading to a better early fixation of the knee prosthesis. In
`contrast with the normal bone remodeling process (where
`bone resorption and formation are coupled), in implant fixa-
`tion bone resorption and formation are uncoupled processes,
`so that decreased resorption resulting from the action of an-
`tiresorptive agents do not hamper bone formation, thus allow-
`ing the achievement of a positive bone balance in case of
`pharmacological treatment (55). This net gain in bone bal-
`ance has been shown in several animal models (65, 66), in-
`cluding those of early joint implant fixation. In these models,
`an anabolic effect has been recognized to be more important
`for strength of fixation than for preservation of pre-existing
`bone (67). Thus, it seems that patients at increased risk of
`implant loosening, such as young and/or very active people,
`could particularly benefit from possible improvements in im-
`plant fixation that can be achieved thanks to the administra-
`tion of antiresorptive agents, and an increasing body of evi-
`dence seems to confirm the hypothesis that early implant mi-
`gration involves osteoclasts activity (40, 55, 68, 69). Currently
`available data on bisphosphonates also show that post-oper-
`ative oral treatment or peri-operative local application of an-
`tiresorptive agents in patients undergoing joint arthroplasty
`may have a measurable effect on long term mechanics of
`TJA, and can be useful in reducing implant migration (55).
`
`Prosthesis osseointegration
`
`Cementless or hybrid total joint prostheses currently repre-
`sent the standard implants in many orthopedic centers.
`Press-fit insertion makes a cementless component stable im-
`mediately upon implantation, but secondary stability and long
`term survival of joint prostheses depend on osseointegration,
`which is defined as a direct structural and functional connec-
`tion between ordered living bone and the surface of a load-
`carrying implant without intervening fibrous tissue (70). Os-
`seointegration is achieved by the ingrowth of bone into the
`surface of the implant, and porous surfaces of prostheses
`could enhance this process. Preservation of intertrochanteric
`cancellous bone during surgical intervention seems not to
`significantly affect osseointegration of cementless stems (51).
`Titanium or titanium-alloy implants are the most biocompati-
`ble among the different materials investigated (71). Tissue in-
`tegration requires the adherence and proliferation of cells on
`the surface of the implant, which can be further improved by
`coating it with calcium hydroxyapatite (HA), the most common
`constituent of natural bone mineral (71). Thanks to its osseo-
`conductive properties, HA can support the ingrowth of capil-
`laries, perivascular tissues and bone forming cells from the
`host into the structure of the implant (72). It has been shown
`that bone matrix and cells are damaged following the inser-
`
`tion of implants into bone, and that an inflammatory response
`is consequently triggered (73). This inflammatory response
`could foster bone resorption around the implant. Furthermore,
`it is known that disruption of the microcirculation and damage
`occur to the bone matrix resulting in osteocyte death around
`the trauma zone (73). Micro-cracks in bone matrix occurring
`upon surgical trauma lead to osteocyte apoptosis, which is
`supposed to start the resorptive process (74). As already ob-
`served, this remodeling process does not seem to involve the
`normal coupling between osteoclastic and osteoblastic activi-
`ty, and there is a real risk for bone resorption around the im-
`plant (75). This may result in a weakening and potential early
`loss of fixation, and consequently in the loosening of the im-
`plant (76-79). An effective pharmacological strategy aimed to
`improve initial fixation and osseointegration of the implant
`would be particularly valuable. The modulation of the initial
`bone remodeling response towards increased net bone for-
`mation around the implant may represent a possible ap-
`proach to accomplish this objective (75).
`Many studies have addressed the issue of improving the os-
`seointegration of joint implants thanks to different therapeutic
`approaches (55, 68, 69, 79-87). Because growth factors may
`potentially promote bony ingrowth (80), some experimental
`studies have been successfully carried out in order to deter-
`mine whether TGF-h1 (human transforming growth factor-h1)
`and BMP-2 (human bone morphogenetic protein-2) are able
`increase osseointegration, thereby suggesting that early sta-
`bility of joint implants can be improved with the use of these
`factors (80, 81). Also, antiresorptive agents may potentially
`enhance osseointegration of joint implants, because they are
`able to impair osteoclast-mediated bone resorption, with mini-
`mal inhibition of osteoblast activity (52, 82) and they also
`have some direct proliferative effects on osteoblasts (83).
`Bisphosphonates provide robust clinical efficacy in the man-
`agement of osteopenia and osteoporosis by normalizing in-
`creased and negatively balanced bone turnover (84). As pre-
`clinical and clinical evidence suggests that osteoporosis may
`impair osseointegration (85, 86), antiresorptive agents may
`be worthy of further investigation for the enhancement of im-
`plant osseointegration in patients with low bone mass. This is
`of particular interest because the majority of patients under-
`going total hip replacement are elderly people and, therefore,
`many of them may present or will develop osteopenia or os-
`teoporosis (87). Also, mineralization defects (i.e. osteomala-
`cia) may impair osseointegration, and induce prosthesis drift
`or loosening of the components. This has been confirmed by
`studies carried out both in animal models (88) and in patients
`with osteoarthritis undergoing total hip replacement (89), and
`therefore vitamin D deficiency should always be considered
`as a possible risk factor – which can be easily corrected – for
`a suboptimal outcome after TJA.
`Different bisphosphonates have shown good results on pros-
`thesis osseointegration both in animal models (52-57, 65-67,
`90-92), and in vivo (55, 59, 68, 69, 93-98). Bisphosphonates
`act on osteoclasts and inhibit resorption, but the mechanism
`of action differs between bisphosphonates containing amino
`groups and those which do not (53-57). The amino-containing
`bisphosphonates interfere with the mevalonate pathway and
`thus prevent prenylation of down-stream enzymes, such as
`Ras and Rho, vital for cellular function. The non-amino-con-
`taining bisphosphonates are metabolized to non-hydrolyzable
`analogues of ATP and thus interfere with the cells’ ATP-de-
`pendent intracellular enzymes (90, 99). Both these mecha-
`nisms result in the impairment of function and finally in apop-
`tosis of mature osteoclasts, in addition to a reduced recruit-
`
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`ment of these cells (90, 94). There is additional evidence sug-
`gesting that some aminobisphosphonates may also inhibit os-
`teocyte and osteoblast apoptosis (100), induce osteoblast
`proliferation and differentiation, and stimulate osteoprotegerin
`(OPG) production (101). Finally, bisphosphonates may also
`inhibit migration and promote apoptosis of inflammatory cells,
`primarily of the monocyte lineage (101, 102). Despite the fact
`that bisphosphonates are mainly used in clinical practice as
`anti-resorptive agents for the treatment of post-menopausal
`or secondary osteoporosis, they have been tested in clinical
`trials for several indications, and they are finding a role in
`many clinical areas ranging from rheumatology to oncology.
`Animal model (rats) evidence is available concerning the sys-
`temic use of ibandronate in modulating bone turn over at im-
`plantation sites of screws or pins used to stabilize fractures,
`resulting in the improvement of early fixation of implants
`(through dose-dependent effects on osseointegration) (52),
`although at dosages corresponding to those needed to treat
`patients with tumor disease. Lower doses equivalent to those
`for treatment of osteoporosis showed no beneficial effects in
`animals (53). Local applications of ibandronate (55) and alen-
`dronate (56), or systemic zolendronate at doses comparable
`to those used for the treatment of osteoporosis (57), showed
`a positive effect on osseointegration.
`It has been shown that in implantation sites, apoptosis of os-
`teocytes occurs around the inserted implant (50), and bone
`remodeling due to micro-cracks takes place in association
`with osteocytes apoptosis (103). Therefore, osteocytes death
`should lead to osteoclasts activation, together with resorption
`of the bone immediately adjacent to an inserted implant. Peri-
`operative and early post-operative factors influence the long-
`term survival of joint implants. Early migration has been
`shown to be a predicting factor for the survival of implants,
`and bisphosphonates have been proven to reduce prosthesis
`migration during the first post-operative year, thus confirming
`that early bone remodeling events play a crucial role in sub-
`sequent implant loosening (45, 58, 104-105). As bisphospho-
`nates may strongly bind to bone in vivo and are generally
`safe, the major problem in their use for the prevention of im-
`plant loosening consists in the poor bioavailability of these
`drugs. Thus, the means of administration (oral, s.c., intra-op-
`eratory) seems to play a crucial role. This problem seems to
`be overcome by the recent introduction of bisphosphonates
`local administration in surgical practice (55, 105).
`A recent double-blind randomized trial has investigated po-
`tential benefits of peri-operative application (1 minute before
`implant cementation) of 1 mg ibandronate directly to the tibial
`bone surface vs placebo (saline), finding a reduction in im-
`plant migration rate (measured by RSA) after 6, 12 and 24
`months (55). Positive histological effects of local treatment
`with alendronate, with an observed increase in bone forma-
`tion, have been reported (105). Post-operative oral adminis-
`tration of alendronate was proven to be active in reducing
`periprosthetic bone loss with persistence of the effect for two
`years (106). In fact, Arabmotlagh et al. have demonstrated
`(by using DXA measures) that patients undergoing total hip
`replacement experience a beneficial effect persisting at six
`years after surgery (with no significant changes in peripros-
`thetic femoral BMD) when oral alendronate (10 mg/day for 10
`weeks or 20 mg/day for 5 weeks) is administered (107). An
`improvement in the fixation of the tibial component of a total
`knee prosthesis has also been reported in a study with oral
`daily administration of clodronate for the first 6 months after
`TJA, although these data are quite controversial (68). In this
`latter study, authors documented a 25% reduction in implant
`
`migration rate (measured by RSA) at 6 months, with signifi-
`cant differences between treatment vs placebo