a Departamento de Ortopedia, Santa Casa de São Paulo, São Paulo, SP, Brasil
b Serviço de Ortopedia e Traumatologia, Hospital Israelita Albert Einstein, Universidade Federal de São Paulo (Unifesp), São Paulo, SP,Brasil
c Instituto de Ortopedia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP, Brasil
d Escola Paulista de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
Introduction
The potential for accelerating or improving the formationof a callus and preventing progression of fractures to pseu-darthrosis has been correlated with mechanical proceduresfor stabilizing bone fragments. However, this reality haschanges in the light of the proven efficacy of physical methodsor medications.
Bisphosphonates have been studied regarding their pos-sible positive or negative influence on formation of bonecalluses. This gives rise to questions that relate to how bis-phosphonates might interfere with bone consolidation; whattheir influence on the histology, morphology and biomechan-ics of the callus might be; what the best time after the fracturefor starting medication would be; whether bisphosphonatesmight have any effect on consolidation among patients whoused them previously, before the fracture; and whether alltypes of bisphosphonates act in the same manner with regardto formation of the bone callus.
At therapeutic doses for osteoporosis, different bis-phosphonates have not shown negative effects on boneconsolidation but have shown improvements to the biome-chanical aspects of bone.5-9Experimental studies usingrisedronate have shown that consolidation occurs, withoutany change to the time taken, but with bone callus of betterhistological quality.
The aims of the SOLID study were as follows: 1 - primaryaim: to evaluate the efficacy of preservation of bone mineraldensity (BMD) provided by 35 mg of Actonel®in the proximalforearm, named the region of interest (RI 33%), after 90 daysof treatment, based on the difference between treatments(sodium risedronate plus calcium and vitamin D versus cal-cium and vitamin D alone); 2 - secondary aim: to evaluate theefficacy of preservation of BMD provided by 35 mg of Actonel®in the proximal forearm (RI 33%), after 180 days of treatment;to evaluate the differences in ultradistal BMD between thetreatment groups, in the region of callus formation, after 90and 180 days of treatment; to evaluate the radiological iden-tification of the callus, defined by identifying the bone bridgein three of the four cortical areas identifiable by means of APand lateral X-ray views during the follow-up; and to evaluatesafety.
Materials and methods
Study design
This was a comparative parallel-group open randomized mul-ticenter phase IV study conducted in six study centers inBrazil: Goiânia (one), Fortaleza (one), Niterói (one), São Luís doMaranhão (one) and São Paulo (two). The study was approvedby the appropriate ethics committees and the patients gavetheir free and informed consent in writing, before any pro-cedures relating to the study were started. Furthermore, thestudy was conducted in accordance with good clinical prac-tices and with the ethical principles that originated from theDeclaration of Helsinki.
Each patient was evaluated over a 180-day period, throughseven evaluation visits: VO (baseline): visit made seven daysafter Colles fracture occurred; VR, randomization visit (day0), made seven days after the baseline; and subsequent vis-its made 15 (V1), 30 (V2), 45 (V3), 90 (V4) and 180 (V5) days afterthe randomization date. Among the visits, an interval of threedays was allowed.
Patients
Women who had been postmenopausal for at least two yearswere eligible to participate if they presented a Colles fracturethat was confirmed within a period of seven days before entryinto the study. The patients were stratified by age in a 1:1 ratio(< 65 and = 65 years) and according to T-score = -2.0 standarddeviations in the lumbar spine (L1-L4 and/or L2-L4) and/orfemoral neck and/or total femur and/or 33% radius.
The main inclusion and exclusion criteria were as follows:
Inclusion criteria: postmenopausal for at least two years;Colles fracture confirmed with occurrence seven days beforeentry into the study; T-score = -2.0 standard deviations in thelumbar spine (L1-L4 and/or L2-L4) and/or femoral neck and/ortotal femur and/or 33% radius.
Exclusion criteria: previous fracture in the same wrist or fore-arm; fracture that, in the opinion of the orthopedic surgeonor person responsible for the case, should only be treatedsurgically; distal fracture of the radius or fractures in contralat-eral bones that occurred previously or concomitantly, whichmight impede comparisons of the BMD evaluations over thecourse of the study; use of medications concomitantly thatmight affect the calcium metabolism; previous treatment withbisphosphonates for more than 12 months over the last 36months; use of bisphosphonates for any period of time overthe last three months; cumulative use of bisphosphonates formore than 36 months on any occasion; rheumatoid arthri-tis or any other disease with involvement of the wrist; hyperor hypothyroidism that is known to be stable, with or with-out treatment; hypocalcemia, liver disease, kidney disease orrheumatic diseases.
Study treatments
At the randomization visit, the eligible patients weredesignated to receive one of the two study treatments:Actonel®+ Oscal®group (GAO): 35 mg of sodium risedronate once a week plus 1000 mg of calcium and 400 IU of vitamin Don six days a week (i.e. not on the day on which risedronatewould be taken); or Oscal®group (GO): 1000 mg of calcium and400 IU of vitamin D daily (i.e. seven days a week).
Efficacy assessments
Efficacy was based on the changes seen in the T scores inthe proximal region of the forearm (33% of the region of theradius), from the baseline to V4 (90 days) and V5 (180 days)after the treatment and was expressed as percentages for thetwo arms fractured and non-fractured).
The difference was calculated in the following manner: Tscore at V4 minus T score at baseline, divided by T score atbaseline.
The same calculation was used for the change in T scorefrom the baseline to V5 (180 days); the mean change in T scorein the proximal forearm (33% of the region of the radius) fromthe baseline to V4 and V5 in the two arms (fractured and non-fractured), with radiological identification of callus formationby means of X-rays.
Bone mineral density (BMD): BMD was measured by meansof dual-energy X-ray absorptiometry (DXA), using a GE/Lunardensitometer (DPXIQ, DPXNT, MD + Prodigy) or Hologic densit-ometer (QDR 2000, QDR 200 +, QDR 4500, Delphi or Discovery)on the lumbar spine and proximal femur (femoral neck andtotal hip) and the distal region of the forearm (fractured andnon-fractured), at the baseline and then at 90 and 180 days.The BMD measurements were repeated using DXA for the dis-tal region of the forearm (fractured and contralateral).
X-rays: Radiological images of the wrist and arm (fracturedand contralateral) were obtained in two views (posteroanteriorand lateral), at the baseline and 15, 30, 45 and 180 days afterthe fracture. The main X-ray parameters for monitoring theconsolidation of the fracture were formation and viewing ofbone bridges along the fracture lines, identified in the cortex ineach view. Fracture consolidation was defined as the presenceof bone bridges in three of the four cortical images evaluatedin these views.
Quality control procedures were established by means oftraining and certification of the team involved in using thedensitometry and X-ray equipment, with central analysis ofthe tests performed, performed by the coordinator of theOsteoporosis Research and Diagnosis Center (CEDOES). Theexaminers were blinded with regard to the study treatmentadministered in each case.
Safety assessments
Safety was assessed according to the type and severity of theadverse events that were reported by the patients or observedin some other way by the investigator.
Definition of the study population
All the randomized patients who received at least one dose ofthe study medication were included in the intention-to-treat(ITT) population. The modified intention-to-treat population(ITTm) was formed by treated patients who presented changesin T scores starting from the baseline. The protocol population (PP) consisted of patients who were treated without significantviolations of the protocol who had at least one BMD evaluationin the proximal region of the forearm (33% of the region of theradius) on the side of the fracture, at the baseline and at V4(90 days).
Statistical plan
All the tests applied were performed using SAS v 9.1 and thestatistical significance level was taken to be 5%.
Calculations were based on comparison of the groupsregarding the mean change in BMD after 90 days of treat-ment, expressed as a percentage. Power of 80%, significancelevel of 5% and discontinuation rate of 10% were used. Thestandard deviation was assumed to be 0.08, with a differenceof interest of 4% between the groups (mean percentage changein BMD after 90 days of treatment). Therefore, the estimatedtotal number to be recruited was 140 patients (70 per group).
The percentage change (%) in BMD after 90 days (V4) and180 days of treatment was calculated in the following manner:
- % change at V4 = [(T-scoreV4 - T-scoreV0)/|T-scoreV0|] * 100
- % change at V5 = [(T-scoreV5 - T-scoreV0)/|T-scoreV0|] * 100
The demographic variables of continuous nature weredescribed separately for the two treatment groups usingmeans, standard deviations and ranges. Comparisonsbetween the treatment groups were indicated using Student'st test values. The discrete demographic variables were sum-marized in frequency tables and comparisons between thetreatment groups were based on p values from the chi-squaretest or Fisher test, depending on the frequency of the events.
The Mann-Whitney U test (independent observations)was applied for comparison between the treatment groupsregarding changes in T-scores (%) from the visit V0 to the visitV4 and from the visit V0 to the visit V5.
The Wilcoxon signed rank test (dependent observations)was applied to compare the visits (V4 and V5) regardingchanges in T-score (%), in each treatment group. To comparethe treatment groups between the visits regarding mean T-scores, a model of analysis of variance (ANOVA) was applied,with the factors from the treatment groups (Actonel + Oscaland Oscal), visits (V0, V4 and V5) and the respective interac-tions between them. To compare the treatment groups withregard to radiological identification of the callus, the chi-square test or Fisher F test was applied, according to thefrequency of the events.
Results
Patients
The patients' distribution is presented in Fig. 1. At the end ofthe study, 59 patients in GAO and 56 in GO had completedall the evaluations as planned. A total of 137 patients (70in GAO and 67 in GO) received at least one dose of studymedication and were evaluated regarding efficacy and safety.The groups were shown to be homogenous at the baselineregarding demographic and clinical characteristics (Table 1).
There were no statistically significant differences betweenthe groups in relation to the side on which the fractureoccurred: 36/71 patients (50.7%) had a Colles fracture in theleft forearm in GAO and 38/70 (54.3%) in GO (p = 0.670). Forthe majority of the patients, the universal classification of
the Colles fracture was I or II/IIa: 15/71 patients (21.1%) and46/71 (64.8%), respectively, in GAO; and 16/70 (22.9%) and 43/70(61.4%), respectively, in GO (p = 0.917).
The BMD measurement (evaluated by means of the T score)did not show any statistically significant difference betweenthe treatment groups at the baseline, in forearms diagnosedwith fractures, in forearms without fractures and in the lum-bar spine, femoral neck and total femur. The majority of thepatients in the two treatment groups used at least 80% of thetotal number of pills planned per visit.
Findings on the side of the fractured forearm
On the side of the fractured forearm, a decrease in BMD wasobserved (evaluated using the % of the T score) from V0 toV4 (90 days) and V5 (180 days) in the two treatment groups,ranging from 20.8% to 32.8% (Table 2).
There was a tendency toward greater reduction in BMD(evaluated using the T score) among the patients in GO. AtV4, this reduction was approximately 15% in GAO and 21% inGO. At V5, this loss of BMD was approximately 9% in GAO and19% in GO. No statistically significant difference between thegroups was reached at either visit: p = 0.352 and 0.069 for V4and V5, respectively (Table 2). Likewise, no statistically signif-icant difference in T score variation was found in comparingV4 and V5 in the two groups (p = 0.727 and 0.769 for GAO andGO, respectively).
The same tendency toward greater reduction in BMD wasobserved in the protocol population (PP) for GO, in comparisonwith GAO, and there was no statistically significant differencebetween the groups (p = 0.110) (Table 3).
From V0 to V4 (day 90), most of the patients in the twotreatment groups presented loss of BMD: 46/63 (73.0%) in GAOand 46/60 (76.7%) in GO. The mean ± SD for the loss of BMDwas -0.5 (0.4) in GAO and -0.7 (0.4) in GO. Comparing V0 withV5 (day 180), a loss of BMD could be seen in 39/59 patients(66.1%) in GAO and in 43/56 (76.8%) patients in GO. The mean± DP of the difference in BMD between V0 and V5 was -0.5(0.4) for GAO and -0.7 (0.4) for GO.
Findings on the non-fractured side
In the non-fractured forearm, the BMD evaluated according tothe change in T score (%) from V0 until the visits V4 and V5ranged from 4.2% upwards (an increase from V0 to V4, i.e. day90) to -6.0% downwards (a reduction from V0 to V5, i.e. day180) (Table 4).
At V4, the increase in BMD (evaluated according to the Tscore) was seen to be greater in GO (4.2%) than in GAO (1.9%);and at V5, there was a reduction in BMD (evaluated accordingto the T score) in the two groups. It was greater in GO (-5.7%)than in GAO (-2.2%). No statistically significant differenceswere observed between the treatment groups at the two visitsor between the visits for the two treatment groups (Table 4).
Furthermore, approximately 30% and 42% of the patientsin the two treatment groups showed losses of BMD from thebaseline to V4 (day 90) and to V5 (day 180), respectively.
In relation to the proportion of patients with losses ofBMD at V4, there was a statistically significant difference
between the fractured and non-fractured sides in the twotreatment groups (GAO and GO; p < 0.0001 for both). This dif-ference in pattern observed in the forearms between the sideswas probably related to the immobilization of the fracturedside (Table 5).
The ANOVA model compared the mean T scores in thetwo treatment groups between the visits, using the treatmentgroup (GAO or GO) and the visits (V0, V4 and V5) as factors,along with their respective interactions. There was no evi-dence of significant interaction between the factors, either forthe side with the fracture (p = 0.134) or for the non-fracturedside (p = 0.982). This suggests that the two treatment groupshad similar patterns over the course of time (Figs. 2 and 3).
On the side with the fracture, there was a statistically sig-nificant difference between the visits, such that the mean Tscores were significantly lower at V4 and V5, in relation toV0 (p < 0.001), although no differences were found betweenthe treatment groups (p = 0.825) (Fig. 2). On the side with thefracture, there was no evidence of any statistically signifi-cant variation between the groups (p = 0.554) or visits (p = 0.081)(Fig. 3).
Radiological evaluation
The results from radiological identification of the callus overthe course of the visits did not show any evidence of any sig-nificant difference between the treatment groups at the visits
V1 (p = 0.674), V2 (p = 0.755) and V3 (p = 0.749), with regard to theproportion of the patients in whom the callus was identifiedon X-rays. At the other visits (V4 and V5), the callus was seenby means of X-rays in almost all the patients, in both groups,and no statistical comparison was made.
Safety
In GAO, 23/71 randomized patients (32.4%) reported that atleast one adverse event occurred during the study period,totaling 34 such events. In GO, 23/70 randomized patients(32.9%) reported that adverse events occurred during the studyperiod, totaling 41 such events. Three adverse events wereconsidered by the investigator to be serious. In GAO, one caseof renewed fracturing of the wrist was reported. This was con-sidered to be of moderate intensity and needed hospitalizationand surgery for external fixation to be implemented. It wasreported that the patient had recovered. In GO, two cases ofadverse events occurred. One of these consisted of a hypoe-choic accumulation in the right calf, which was considered tobe of moderate intensity. This case required hospitalizationand the patient was still recovering at the time of this report.The other adverse event comprised cardiorespiratory arrest,which occurred at the patient's home, was of severe intensityand resulted in death.
None of these three adverse events was considered by theinvestigator to be related to the study medication. In GO, bothof the adverse events led to interruption of the treatment. Forthe patient in GAO, administration of the study medicationwas not immediately stopped because of the adverse event,but the event led to withdrawal from the study.
Overall, the treatments were withdrawn in the cases ofthree patients because of adverse events relating to the treat-ment: 1/71 patients (1.4%) in GAO presented acute gastritisand one patient (1.4%) in GO presented epigastric burningand discomfort and another patient (1.4%) presented gastricpain. In addition, another two patients were withdrawn fromthe study, but without any relationship with the study treat-ment. In GO, one case of cardiorespiratory arrest was reported;another patient was reported to have had a psychotic episodeand a further patient presented a hypoechoic accumulation inthe right calf.
Discussion
In the present study, after 90 days of risedronate use, no signifi-cant variation in the loss of BMD was seen in the fractured arm,or in the non-fractured arm. The same pattern was observedafter 180 days of treatment, which suggests that risedronatehas a protective effect due to the immobilization.
Several medications have been used to improve boneconsolidation, both for accelerating the process and alsofor improving the quality of the bone callus, i.e. throughimproving the microarchitecture, volume and biomechanicalstrength of the callus. These medications include strontiumranelate and drugs that act on the Wnt signaling system, suchteriparatide and the antibodies anti-sclerostin and DKK-1.12-15Some medications have been recognized as harmful to cal-lus formation and these include corticoids, chemotherapeuticagents, antibiotics, anti-inflammatory agents, anticoagulantsand anticonvulsants.
However, bisphosphonates are the drugs that have beenstudied most. These favor formation of a more voluminouscallus with mineralization and make the callus mechani-cally more competent, but with a slower remodeling rate.17-22Another factor discussed in the literature has been the timeat which bisphosphonate use should start, after a fracture hasoccurred. Some evidence favors starting to use bisphospho-nates 15 days after the event, while other evidence suggeststhat, independent of the time at which they are admin-istered, they do not interfere with bone consolidation orwith postoperative healing following occurrences of osteo-porotic fractures.23,24The time taken to reach consolidationis unrelated to the severity of the osteoporosis or the typeof fracture.25Therapy using bisphosphonates can be contin-ued after occurrences of fractures of the distal radius, withoutdeleterious clinical effects on consolidation.
When used for long periods, bisphosphonates mayincrease the occurrences of micro and macrofractures in ani-mals and humans. They also give rise to preferential fracturesites. However, biomechanical gains regarding the bone cal-lus are observed (size and external diameter). It seems thatthe organism compensates for the negative effect of the med-ication and modulates the morphology of the callus so as toobtain better biomechanical function (mechanostat).
The effects of risedronate have been studied both in rela-tion to improvement of bone mineral density and fractureprevention in patients with osteoporosis and in relation touse during bone consolidation. It has been observed thatrisedronate does not interfere negatively with bone callusformation and can be used without deleterious effects on con-solidation. On the contrary, it increases the volume of thecallus and its biomechanical resistance.
The BMD of 33% of the radius on the fractured side atthe end of six months (V5) presented a negative change of32.8% in the Oscal group and only 20.8% in the Actonel + Oscalgroup, which showed that risedronate had a tendency towardhaving a protective effect against loss of BMD caused by post-fracture immobilization (p = 0.069). Even though there was nostatistically significant difference between the two groups, itwas seen that there was lower loss of BMD (evaluated usingT scores) in the group treated with Actonel + Oscal (mean decrease of -0.5), in relation to the group that used Oscal alone(mean decrease of -0.7), as shown in Table 5. This was possiblydue to the great variability of the data.
The BMD of 33% of the radius on the non-fractured side atthe end of six months (V5) presented a negative change of 5.7%in GO and only 2.2% in GAO, with a difference of 3% in favorof risedronate. However, there was no statistically significantdifference (p = 0.861) (Table 4).
As shown in Fig. 2, the initial BMD of 33% of the radiuson the fractured side (measured using the T score) decreasedsignificantly (p < 0.001) during the treatment (from V0 to V5),while this difference was not observed on the non-fracturedside. This shows the significant influence of immobiliza-tion of a fracture on bone loss. Regarding the proportion ofpatients with loss of BMD at V5, there was a statistically sig-nificant difference between the fractured and non-fracturedsides, for both treatment groups (GAO, p = 0.010; GO, p = 0.0003)(Table 5). This pattern of difference observed between thegroups was probably related to immobilization of the fracturedside (Table 5). These data show that risedronate provided pro-tection in relation to loss of BMD during the immobilizationof a limb (osteoporosis of disuse), which is discussed in otherstudies.
There was no significant difference in radiological identifi-cation of the bone callus at the times of the visits (V1 to V5),or between the treatment groups. Thus, use of risedronate inour study did not present any negative clinical effect on boneconsolidation. In most of the patients, radiological identifica-tion of the callus occurred at V3, with a similar pattern in thetwo groups. Furthermore, the safety profile of risedronate wasshown to be similar to that of the control group.
Limitations of the study: Given that this study was designedwithout comparison with placebo, we believe that there mayhave been an important effect on BMD, since the tests wereevaluated centrally, as described in the methodology. How-ever, based on the well-established side effects that have beendescribed previously for this class of medications, an effect ininterpreting the safety data cannot be totally ruled out.
Conclusions
Postmenopausal women with Colles fractures who receivedsodium risedronate plus calcium and vitamin D, in compar-ison with calcium and vitamin D only, did not show anysignificant difference regarding loss of BMD in the fracturedand non-fractured forearm after 90 days (primary objective)and 180 days (secondary objective). Risedronate was shownto have a tendency toward a protective effect regarding lossof BMD due to immobilization. The time taken to reach frac-ture consolidation was unaffected and the two groups showedsimilar safety patterns.
Conflicts of interest
Dr. Lindomar G. Oliveira, Dr. Frederico Barra de Moraes, Dr. LuizAntônio Silveira Simões Pires and Dr. José Wanderley Vascon-celos declare that they did not have any conflicts of interest.Dr. Henrique Mota Neto Júnior received fees from Novar-tis, Servier and GlaxoSmithKline and participated in studies sponsored by Servier Laboratories, Sanofi-Aventis, Lilly andBlau Farmacêutica.
This study received financial support and backing fromSanofi for its design, conduction, data-gathering, manage-ment, data analysis and data interpretation, along witheditorial assistance for the manuscript.
Acknowledgments
Our special thanks to Drs. Ben Hur Albergaria, Márcio Passinide Souza, Jorge dos Santos Silva and Edson Cerqueira Gar-cia de Freitas for their valuable contributions toward thedesign of this research project and collaboration in discus-sions regarding the project, and in drafting the final text ofthis manuscript.
Conflicts of interest
The authors declare no conflicts of interest.
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