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Evidence for anti-osteoporosis therapy in acute fracture situations—recommendations of a multidisciplinary workshop of the international society for fracture repair

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b o n e Evidence for anti-osteoporosis therapy in acute fracture situations—Recommendations of a multidisciplinary workshop of the International Society for Fracture Repair The International Society for Fracture Repair convened a multidisciplinary workshop to assess the current evidence around the interaction between anti-osteoporosis drugs and the healing of incident fractures, with a view to making recommendations for clinical practice. The consensus was that there is no evidence-based reason to withhold anti-resorptive therapy while a fracture heals, whether or not the patient was taking such therapy when the fracture occurred. The workshop also considered existing models of service provision for secondary prevention and concluded that the essential ingredient for reliable delivery is the inclusion of a dedicated coordinator role. Several unresolved issues were defined as subjects for further research, including the question of whether continuous long-term administration of anti-resorptives may impair bone quality.
The rapidly changing area requires re-assessment of drugs and their interaction with fracture healing in the 2009 Elsevier Inc. All rights reserved.
opportunity to intervene in one half of future hip fracture cases.
Pharmacological intervention at this “signal” fracture stage has the A recent study of the global burden of osteoporotic fractures potential to halve future fracture incidence, including hip fractures, estimated that 9 million new osteoporotic fractures occurred during within 3 years treatment, contingent upon good persistence and the year 2000. The number of individuals suffering from the compliance with treatment Thus, in a relatively short time frame, consequences of osteoporotic fractures in the year 2000 was up to one quarter of hip fractures could be averted in addition to conservatively estimated to be 50 million worldwide A previous substantial numbers of fractures at other skeletal sites. Health study from the same authors, based upon data from 1990, estimated economic assessments have demonstrated such intervention to be the global prevalence of hip fracture with disability at 4.5 million highly cost-effective which has resulted in endorsement of patients , which corresponded to 1.4% of the burden of disease secondary fracture prevention by Health Technology Appraisal amongst women in the established market economies. An ongoing demographic shift within the worldwide human population is fuelling Accordingly, this provides the orthopaedic surgeon with an an epidemic of fragility fractures. Currently, 323 million people opportunity to play a central role in preventing future fracture.
worldwide are aged over 65 years, a figure which is predicted to rise Surgical treatment of the fragility fracture and liaison regarding the to 1.6 billion by 2050 . Consequently, the global incidence of hip initiation of pharmaceutical treatment of the underlying osteoporosis fracture is anticipated to reach 6.3 million by 2050, with three should occur simultaneously. However, a concern over possible quarters of these fractures occurring in the rapidly ageing Asian and delayed fracture healing associated with bisphosphonates, the most Latin American populations. Accordingly, if healthcare systems are to commonly prescribed anti-osteoporosis treatment, and the lack of avoid being overwhelmed by cases of elderly trauma, determined guidelines detailing the context of this concern may discourage efforts need to be applied worldwide to curb the rising prevalence of surgeons from initiating secondary prevention.
fragility fracture, particularly at the hip.
A workshop was undertaken by the International Society for Fracture predicts fracture. Two major meta-analyses have estab- Fracture Repair (ISFR) in order to reach a consensus about the current lished that a prior fracture at least doubles a patient's future fracture evidence of the interaction of fracture healing with currently available osteoporosis drugs and subsequent recommendations for secondary Osteoporosis is a chronic disease that many patients will endure prevention after fracture. The faculty comprised leading experts in the for several decades, during which time they will suffer multiple field of orthopaedic surgery, endocrinology, bone biology, biome- fracture events. Unfortunately, osteoporosis often remains undetect- chanics, pharmaceutics, healthcare systems and radiology.
ed or untreated until a fragility fracture occurs. Furthermore, in the The specific goals of the ISFR workshop were absence of a systematic approach to delivery of secondary fractureprevention, the majority of patients fail to receive treatment 1. to review the preclinical and clinical evidence of the interaction of designed to reduce future fracture risk Accordingly, the osteoporosis drugs and fracture healing or fixation; delivery of secondary preventative intervention when patients 2. to review the issues around secondary prevention of fragility present with fragility fracture at any skeletal site provides an fractures, including long-term management; 8756-3282/$ – see front matter 2009 Elsevier Inc. All rights reserved.
doi: 3. to discuss what clinical healthcare systems are required for 4. to identify research questions that need to be addressed to facilitate more effective secondary prevention.
Clinical observations indicate that fragility fractures heal despite the abnormality of bone remodelling in osteoporosis. There is no clearevidence yet as to whether complications during the course of healingare attributable to implant anchorage problems in osteoporotic boneor to possibly delayed healing in elderly patients. In animal models offracture, fracture healing takes longer in older animals Thereis conflicting evidence as to whether ovariectomy adds an additionalimpediment to healing. Some animal studies show deficient healing,especially in the early response [], and some do not .
Differences in the timing of ovariectomy, age of the animals anddietary factors make comparisons and conclusions difficult.
The seemingly normal fracture healing potential in patients with compromised bone structure and turnover can be explained by the Fig. 1. Illustration of the main consequences of common osteoporosis drugs for fracture different pathways of fracture repair and bone remodelling. Fracture repair involves different stages of tissue differentiation that resembleaspects of embryological skeletal development Recently, the role ties but did not improve mechanical parameters such as strength .
of osteoclasts in fracture repair has begun to be elucidated. The initial To date, there are no reported suggestions of negative effects on inflammatory phase and subsequent bone formation during the repair fracture healing from PTH treatment.
phase are largely osteoclast independent, whereas the coupled A newer anti-osteoporosis drug, strontium ranelate, showed no remodelling of woven bone to lamellar bone during the remodelling effect on fracture healing in the one animal study (in rats) published phase at the end of fracture repair does depend on osteoclast activity.
In addition to PTH, some interesting anabolic drugs are currently being developed. However, while animal models are appropriate forexploring mechanisms, underlying pathophysiology and specific It is expected that anabolic agents used to treat osteoporosis would biological hypotheses, they do not always accurately predict human have a beneficial effect on fracture healing. However, most patients treatment efficacy and preclinical findings need to be confirmed who need treatment for osteoporosis will currently receive anti- catabolic agents, and it is important to know whether this may haveany disadvantage for the healing of incident fractures.
Numerous animal experiments have addressed the interaction between drugs used for osteoporosis treatment and different aspects Biomechanical tests and clinical experience have shown that of fracture healing (see and ) . However, it remains implant anchorage is impaired in osteoporotic bone. In animal unclear to what extent the findings can be extrapolated to humans studies, implants failed earlier (via cut-out or cut-through) in due to the known limitations of animal models compromised bone structures than in healthy bone Osteopo- There is no evidence in preclinical studies that anti-catabolic drugs rosis drugs can improve implant fixation. This was shown in a impair the restoration of mechanical integrity, irrespective of when variety of animal experiments using different types of systemic or they are administered or their mechanism of action, despite the fact locally applied bisphosphonates This effect has been repro- that they may delay remodelling Several animal experiments duced in a patient level 1 study utilizing an external fixator for have shown that different anti-catabolic drugs lead to larger callus of treatment of proximal femur fractures. Extraction torque was increased mechanical stiffness and strength. However, it is not clear if significantly higher in patients treated with bisphosphonate .
there is a critical upper limit of callus stiffness and strength with Both systemic and local peri-operative treatment with bispho- respect to the strength of the adjacent intact bone. In a comparative sphonates have been shown to improve the fixation of total knee study in ovariectomized rats, Cao et al. found no major effect of replacements, measured as a reduction of the postoperative raloxifene and oestrogen on fracture healing responses. Alendronate did not interfere with initial union but led to increased callus size anddecreased remodelling. However ultimate load and stiffness at16 weeks post fracture was highest in the alendronate group. Although most fractures heal by secondary healing via external callus formation, Classification of osteoporosis drugs based on their mode of action and their currentlyknown consequences for fracture healing.
it has been suggested bisphosphonates might have an effect on (callus-free) direct fracture healing . Direct healing in a mechanically rigid fixation relies on osteoclastic activity for the remodelling of the fracture surfaces. However, neither preclinical nor clinical data are available that support the theoretical concerns. The clinical relevance seems limited since absolute stability and subsequent possible primary fracture healing without callus formation is not the goal of today's fracture treatment in osteoporotic patients In rodents, intermittent PTH stimulated fracture healing , with doses as low as 10 μg/kg/day having a positive effect . In primates, Increased rate of remodellingIncreased strength in animal models larger doses accelerated remodelling and improved material proper- Improved implant anchorage was also achieved in animal measurement of bone turnover markers (within the first week, before experiments with PTH ], though to date no data are available fracture healing elevates them) will give guidance .
that support these findings in humans. The reproduction of findings There have been recent reports of femoral diaphyseal fractures in from animal experiments in clinical studies is complicated by the fact patients on long-term bisphosphonate treatment . Schilcher that there is no universally accepted measure of fracture healing in and Aspenberg calculated an incidence density for a patient on humans. Alternatively, the rate of prospectively defined bone-related bisphosphonate of 1/1000 per year (95% CI = 0.3–2). These subjects complications, or measurement of function and radiological status at are unlikely to benefit from continuation of bisphosphonate treat- defined time points of healing, could be used ment and may need consideration of an anabolic agent, eithersystemically (e.g. PTH) or locally. However, Schilcher and Aspenberg concluded that “a treatment-associated incidence density of 1/1,000 is Osteonecrosis of the jaw (ONJ) is a complex adverse event of acceptable, considering that bisphosphonate treatment is likely to uncertain causal mechanism associated with bisphosphonate use. It reduce the incidence density of any fracture by 15/1000 according to a can be defined as a non-healing extraction socket or exposed bone in the oral cavity that does not heal after 6 weeks of appropriate therapy,sometimes with progression to sequestration associated with puru- Clinical systems for reliably delivering secondary prevention lent discharge into the oral cavity or onto the skin surface. ONJ ismostly reported in cancer patients receiving intravenous bispho- Integrated secondary fracture prevention delivery systems need to sphonate therapy and rarely in patients receiving low doses of be tailored to individual healthcare systems. They should be intravenous or oral bisphosphonates for non-cancer indications such integrated into multimodal care, which includes acute geriatric and as fracture prevention in osteoporosis A recent review medical support, appropriate supplementation with calcium and summarized the current knowledge: “The incidence or prevalence vitamin D and nutrition as well as falls assessment. Comanagement of of ONJ in patients taking bisphosphonates for osteoporosis seems to the patient by geriatricians, rheumatologists or endocrinologists, be very low No causal relationship has been unequivocally gynaecologists, radiologists and general practitioners together with demonstrated between ONJ and bisphosphonate therapy.” allied healthcare professionals is required for effective long-term careand also has the potential to increase the uptake of secondaryprevention.
Initiation of osteoporosis treatment after fracture Recently, several international organisations, including the Inter- national Osteoporosis Foundation, the Bone and Joint Decade and the The evidence base for prevention overwhelms the non-evidence- International Society for Fracture Repair, have jointly advocated a based concerns about the adverse consequences of pharmaceutical systematic approach to the provision of secondary prevention as a treatment of osteoporosis on fracture healing The choice of drug means to close the current worldwide fragility fracture management should take into account long-term compliance with medication gap . Services based upon the dedicated coordinator model have and should be in accordance with national guidelines.
been successfully implemented in many countries. A recent editorialin the orthopaedic literature titled “Time to invest in a fracture liaison When should the first dose be given after fracture? nurse!” recommends investment in the dedicated coordinatorapproach as a priority for all trauma units Treatment should be initiated before discharge from the acute fracture ward to ensure follow-up. It is important that patients are rendered vitamin D-replete and have an adequate oral calcium intakebefore the administration of anti-catabolic drugs, both to maximize efficacy and to avoid the risk of hypocalcaemia.
During the time that a fracture callus is actively forming bone, • Can we develop a valid system that can monitor the progress of there is an increased sequestration of bisphosphonates zoledronic fracture healing and the mechanical properties in fracture repair, in acid and pamidronate at the fracture site . Evidence for other a way not limited by the type of fixation? bisphosphonates is lacking, but it is likely to be a class effect. In the • Can we define or quantify the effect of (a) ageing and (b) recurrent fracture trial concerns have been raised that a possible loss osteoporosis on fracture healing in humans? of systemic efficacy may have resulted from the timing of drug • Are there appropriate animal models to study drug and fracture administration relative to the fracture event. If this were true, then it healing interactions, especially in osteoporosis? would be logical to give intravenous bolus bisphosphonate either very • What more can be discerned about osteoporosis drugs and fracture soon after fracture or after the major mineralisation of the callus has occurred. Loss of efficacy due to sequestration is likely to be less of an • Does the state of bone turnover affect the ability to heal a fracture? issue with more frequent dosing, such as weekly or monthly oral • Can we optimise bisphosphonate regimens so that we achieve both bisphosphonates, as less of the total dose would be given during the whole-skeleton protection and late fracture remodelling? avid uptake phase. There is to date no direct evidence that initiation of • Does the long term suppression of bone turnover have adverse treatment should be delayed, and so the recommendation of effects on bone quality (e.g. microcrack accumulation) and fracture commencing as soon as practical currently stands.
risk? Does this depend on the anti-catabolic mechanism of action? Isthe type and location of fracture different after long term anti- The response to fracture in patients already on osteoporosis treatment • What more can be discerned about osteoporosis drugs and fracture The occurrence of a fragility fracture while on osteoporosis treatment does not necessarily mean that the treatment wasineffective, as it is known that fracture rates are only reduced by25–60% .
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Royal National Orthopaedic Hospital, Stanmore, United Kingdom on behalf of the ISFR working group drugs and fracture repair1 AO Clinical Priority Program Fracture Fixation in Osteoporotic Bone 1Members of the ISFR working group drugs and fracture repair The Children's Hospital at Westmead, New South Wales, Australia (in alphabetical order): Aspenberg Per, Sweden; Augat Peter, Germany; Bavonratanavech Suthorn, Thailand; Bostrom Mathias, USA; Chehade Mellick, Australia; Chenu Chantal, United Kingdom; Faculty of Education Health and Sciences, University of Derby, Claes Lutz, Germany; Dunstan Colin, Australia; Falb Dean, USA (Stryker Biotech); Fazzalari Nicola, Australia; Findlay David, Australia;Friedlaender Gary, USA; Genant Harry, USA; Gilchrist Nigel, Australia; Goldhahn Jörg, Switzerland; Goodship Allen, UK; Hoang-Kim Amy, Bone and Joint Research Laboratory, SA Pathology and Hanson Institute, Italy; Hooper Michael, Australia; Inderjeeth Charles, Australia; Little David, Australia; Marsh David, United Kingdom; Matsushita Takashi, Japan; Mitchell Paul, United Kingdom; Mori Satoshi, Japan; Moroni Antonio, Italy; Parkinson Ian, Australia; Phipps Roger, USA Department of Medicine, Faculty of Medical and Health Sciences, (Sanofi- Aventis/P&G); Pohl Tony, Australia; Reid Ian, New Zealand; University of Auckland, Auckland, New Zealand

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