Long-term antifracture efficacy and safety of antiosteoporotic treatments: the hidden part of the iceberg




Jorge B. CANNATA-ANDÍA
MD, PhD


J. Bernardino DÍAZ-LÓPEZ,
MD, PhD
Bone and Mineral Research Unit
Instituto Reina Sofía
de Investigación
Hospital Universitario Central
de Asturias, Oviedo
Asturias, SPAIN

Long-term antifracture
efficacy and safety of
antiosteoporotic treatments:
the hidden part of the iceberg

by J . B. Díaz- López and
J . B. Cannata-Andía,Spain

Long-term antifracture efficacy and safety are the two major goals of any antiosteoporotic treatment. To date, several drugs have proved to be effective and safe during the 2-to-3-year period of a controlled clinical trial, but only a few of themhave shown bone protection lasting up to 5 years, which is the minimum time period needed in order to ascertain if there is sustained fracture risk reduction. Raloxifene has shown efficacy in vertebral fracture risk reduction for up to 5 years, but no effect in nonvertebral fracture. The antifracture efficacy of risedronate versus placebo over 5 years has not been proven. Furthermore, although the bone mineral density (BMD) of women on alendronate increases up to 7 and 10 years, this increase is not associated with antifracture efficacy, especially in nonvertebral fractures. In contrast, strontium ranelate has demonstrated sustained fracture risk reduction up to 5 years in vertebral, nonvertebral, and hip fractures in double-blind, randomized, placebo- controlled trials. In addition, a complementary analysis of 8 years’ treatment has shown the same trend in vertebral and nonvertebral fracture risk reduction. In summary, several drugs have demonstrated long-term benefit on BMD, but only strontium ranelate has proven to be efficient on vertebral, nonvertebral, and hip fractures in the long term.

Medicographia. 2010;32:18-24 (see French abstract on page 24)

After beginning therapy, clinicians must confront the question of how long therapy should continue for and how we should evaluate its efficacy and safety. Unless there are obvious safety issues, long-term therapy is generally considered for chronic disorders such as osteoporosis; however, how many years “long-term” means has not yet been clearly defined. The second issue is how efficacy and safety should be evaluated. For both considerations, well-designed, randomized controlled trials are the answer. When compared with placebo, fractures determine efficacy outcomes, whereas a negative increment in morbidity defines safety outcomes. Postmarketing surveillance is also valid for safety.

Because of possible safety issues, long-term estrogen replacement therapy is not currently recommended for the management of postmenopausal osteoporosis, even though it has been demonstrated that estrogen therapy helps to prevent fractures.1 The optimal length of use of the other current medications for osteoporosis remains to be established. With respect to trials, a panel of experts representing the American Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF)2 have provided an answer as to how many years the efficacy and safety an antiosteoporotic agent should be evaluated for. They reached a consensus that trials should last at least 18 to 24 months to test efficacy with fracture end points, and 5 years to properly test safety and to demonstrate sustained fracture reduction.2

Table I
Table I. Pivotal trials for osteoporotic fracture risk reduction in postmenopausal women.

Trial acronyms: BONE, oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe; FIT VF, Fracture Intervention Trial (Vertebral Fracture); FPT, Fracture Prevention Trial; HIP, Hip Intervention Program; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid ONce yearly; MORE, Multiple Outcomes of Raloxifene Evaluation; PROOF, Prevent Recurrence Of Osteoporotic Fracture; SOTI, Spinal Osteoporosis Therapeutic Intervention; TROPOS, TReatment Of Peripheral OSteoporosis; TOP, Treatment of Osteoporosis with Parathyroid hormone; VERT MN, Vertebral Efficacy with Risedronate Therapy (Multinational); VERT NA, Vertebral Efficacy with Risedronate Therapy (North America).

Nowadays, many drugs have proven to be effective in reducing new osteoporotic fractures in postmenopausal women3-16 (Table I). Most of these major clinical trials lasted no more than 3 years. In addition, in some of them (such as the calcitonin trial), only 46% of the initial participants completed the preprogrammed five-year follow-up; as a result, the grade of evidence was lower and just concerned the 200 IU nasal spray dose, but not the 100 IU and 400 IU sprays.12 Hence, any assumptions about long-term treatments based on the findings of any type of study, even with 3 years’ follow-up, should be made with great caution and by analyzing the strength of the evidence. Moreover, despite the fact that nonvertebral fractures are more prevalent and present a substantial burden for the patient, most of the osteoporosis treatments that have proven efficacy in reducing the risk of vertebral fracture have not shown reductions in nonvertebral fracture risk (Table I). Furthermore, information on the clinical efficacy and safety of several active antiosteoporosis treatments at more than 4 to 5 years follow-up is limited. Currently, for a 5-year time period, the only treatment to have demonstrated its antifracture efficacy in a double-blind, randomized, placebocontrolled trial is strontium ranelate. However, information on bone mineral density (BMD) is also available with raloxifene, alendronate, and risedronate, but with different strengths of evidence as described below and summarized in Tables II and III (page 20).

_ Raloxifene
Studies of raloxifene have shown a vertebral fracture risk reduction after 4 years similar to that after 3 years, and it has also shown benefit at 5 years in postmenopausal women not selected on the basis of osteoporosis or increased fracture risk.17,18 However, this latest study is different to the others as the incidence of vertebral fracture in the placebo group was very low (1.9% over 5 years), reflecting a low risk of fracture in the population included in the study, and thus difficulties in extrapolating these results to other studies in osteoporotic patients. Similar to what was shown in the pivotal trial, raloxifene had no effect on nonvertebral fracture risk after 5 and 8 years.18,19 In addition, the absence of effect of raloxifene on nonvertebral fracture was consistent across different subgroups, characterized by the presence or absence of risk fac- tors at baseline (including a summary of nonvertebral fracture risk score).18 The effect on BMD observed after 3 and 4 years persisted when the drug was administered for 8 years.19 However, as was seen with estrogen replacement therapy, a sharp drop in BMD occurred upon raloxifene discontinuation.17 The long-term safety profile is also similar to that observed in the first 3 years, with an increase in the risk of deep vein thrombosis and a significant decrease in the incidence of invasive estrogen receptor–positive breast cancer.20,21 In contrast to the findings relating to estrogen replacement therapy, no evidence of coronary or cerebrovascular events has been found in postmenopausal osteoporotic women at relatively low risk of cardiovascular events.21

Table II
Table II. Studies and patient characteristics of placebocontrolled trials of osteoporotic fracture risk lasting at least 5 years.

Abbreviations: CHD, coronary heart disease; FIT, Fracture Intervention Trial; TROPOS, TReatment Of Peripheral OSteoporosis; VERT, Vertebral Efficacy with Risedronate Therapy.

_ Bisphosphonates
Long-term bone protection provided by alendronate and risedronate has been examined in a series of extensions of previously reported pivotal clinical trials.22-26 These trials included a limited number of patients and did not assess antifracture efficacy versus a placebo group. For instance, the long-term efficacy of risedronate was estimated by comparing the cumulative incidence of fractures during the last 2 years and the first 2 years of treatment in patients treated with risedronate for 7 years. The analysis was performed in 68 patients treated over 7 years with risedronate. Despite a similar incidence, the comparison limits a definitive conclusion on the long-term efficacy of risedronate. A similar approach to assess the efficacy of alendronate against fractures was used after 4 and 5 years in the Fracture intervention trial Longterm EXtension (FLEX) study. In the latter, the long-term effect of alendronate on BMD in patients treated first over 5 years with alendronate and then either switched to placebo or continued alendronate treatment was assessed. In absence of a “real” placebo group, any strong conclusion regarding the antifracture efficacy of alendronate in the long term is not possible. In fact, fractures were recorded as an “exploratory” outcome in the study. The results mentioned allow discussion on the possible long-term efficacy on vertebral fractures, but the efficacy on nonvertebral fractures is still missing.23,26 In addition, between the 5th and the 10th year of treatment, alendronate only reduced the incidence of clinical vertebral fractures (exploratory outcome), not morphometric vertebral fractures when compared with a group first treated for 5 years with alendronate and then 5 years with placebo.26 In the case of risedronate, there was no antifracture efficacy against nonvertebral fractures demonstrated in years 4 and 5 (Table III). Thus, definitive evidence for nonvertebral fracture benefit with risedronate or alendronate up to 5 years of treatment is lacking.

Table III
Table III. Vertebral and nonvertebral fracture incidence by treatment (trials described in Table II).

Abbreviations: CI, confidence interval; NS, nonsignificant; RR, relative risk.

With regard to bone mass, alendronate and risedronate maintained BMD gains for 10 and 7 years, respectively.23,25 Cumulative increases in BMD at the hip and spine and reductions in bone turnover markers (BTMs) were greater for women who kept receiving these aminobisphosphonates compared with those who discontinued it.23-26 However, in women who discontinued alendronate or risedronate who then subsequently received placebo in the extension studies, BMD remained high and BTM reduction was greater than values at baseline.23-25

Overall, alendronate and risedronate were well tolerated during the 10 and 7 years of the extension studies.22-26 No new safety concerns were observed during the extension studies of alendronate and risedronate when compared with safety observations gathered during the first 3 years of the pivotal studies. Nevertheless, there is growing concern that longterm suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage and that it may be associated with a new form of insufficiency fracture of the femur.27-29

In the last few years, there have been reports about the association between subtrochanteric and diaphyseal femur fractures and long-term alendronate treatment.27-29 However, we would advise caution. According to national observational register-based studies and recent case control studies, further trials are necessary to fully understand the pathophysiology of this side effect.30,31 The same comment is valid for osteonecrosis of the jaw—another potential side effect related to bisphosphonates—that was first reported following the administration of very high intravenous doses of aminobisphosphonates in cancer patients.32,33

The report describing a significant increase in the risk of serious atrial fibrillation associated with once-yearly infusions of intravenous zoledronic acid in the Health Outcomes and Reduced Incidence with Zoledronic Acid ONce yearly (HORIZON) trial10 prompted an investigation into the possibility of increased atrial fibrillation risk with other bisphosphonates used to treat osteoporosis in postmenopausal women. The first report reviewing the Fracture Intervention Trial (FIT) did show a trend towards an increased risk of serious adverse events with alendronate that resembled the pattern observed in the HORIZON study,34 but there was no increase in atrial fibrillation. A later population-based case control study showed that the use of alendronate was never associated with an increased risk of incident atrial fibrillation in clinical practice.35

As one of the features of bisphosphonates is a long residual time in bone and concerns about this have emerged, the concept of “drug holidays” has been coined for this kind of drug.36 Drug holiday time varies depending on the type of aminobisphosphonate. With alendronate, which appears to have a longer skeletal retention time than risedronate,37 the drug holiday period could be longer (up to 5 years), especially for women who were compliant for prolonged periods of time. Although we need more data before issuing any definitive recommendations regarding the optimal length of drug holiday for alendronate and risedronate, such strategies deserve consideration, especially if we take into account the recently reported side effects associated with long-term alendronate treatment.27-29

_ Strontium ranelate
The efficacy of strontiumranelate has been assessed in 2multicenter, randomized, double-blind, placebo-controlled trials originally planned for 5 years.13,14 Five-year data, including 4 years against placebo, are now available for the Spinal Osteoporosis Therapeutic Intervention (SOTI) study and for the TReatment Of Peripheral OSteoporosis (TROPOS) study, which includes 5 years against placebo.38,39 Furthermore, since the acquisition procedures and central readings were the same, data could be pooled in order to obtain a large database in which subanalyses could be conducted to appropriately assess the determinants of efficacy and safety for strontium ranelate.40-42

The main result of these preplanned analyses is that longterm treatment (4 and 5 years) with strontium ranelate significantly reduced not only the risk of vertebral fractures, but also the risk of nonvertebral and hip fractures.38,39 With regard to nonvertebral fractures, it is important to note that strontium ranelate is the only antiosteoporotic treatment that has shown long-term efficacy in nonvertebral fractures compared with placebo. Moreover, in a post hoc analysis, there was a 43% decrease in the risk of hip fracture in a subset of 1128 patients defined as a group at high risk of fractures.38 The antifracture efficacy of strontium ranelate has been documented across a wide range of patient profiles, including osteopenia and in very elderly women.40-42 Besides this, the reduction in fractures came together with a significant improvement in quality of life and an increase in the number of patients free of back pain.38,39

Recently, the extension of up to 8 years of follow-up of the previous pivotal studies was presented43 (Figure 1, page 22). The efficacy of strontium ranelate in preventing fractures was analyzed by comparing the annual cumulative fracture incidence between the first and the last 3 years of the 8-year follow-up. The long-term results demonstrated that strontium ranelate maintains its antifracture efficacy with incidences of vertebral fractures (13.7%) and nonvertebral fractures (12.0%) after 8 years of treatment that were not significantly different to those obtained after 3 years of treatment (11.5%and 9.6%, respectively).43 The reduction in fracture risk was associated with a progressive BMD increase in the lumbar and hip regions throughout the whole treatment period,38,39 with a continuous and significant increase in BMD over 8 years at the lumbar spine and over 7 years at the femoral neck.43

Figure 1
Figure 1. Reduction in the risk of vertebral, nonvertebral, and any osteoporotic fracture with strontium ranelate after 8 years of follow-up.

Modified from reference 43: Reginster JY, Bruyere O, Sawicki A, et al. Bone. 2009;45:1059-1064. Copyright © 2009, Elsevier Inc.

After treatment withdrawal, patients in SOTI who switched to placebo at 4 years experienced a progressive reduction in BMD, by 3.2% and 2.5% at lumbar spine and hip, respectively, reflecting the prompt clearance of strontium ranelate.38 According to the dual mode of action of the drug, a significant decrease in bone alkaline phosphatase and increase in the serum C-telopeptide cross-link of type 1 collagen was observed after treatment withdrawal. These changes were already detectable 3 months after treatment discontinuation, suggesting a relatively rapid release of strontium from bone.38,39

In the context of clinical trials, the safety of strontium ranelate was good. The most common adverse events related to strontium ranelate were transient nausea and diarrhea during the first 3 months.38-40 A slight increase in the annual incidence of venous thromboembolism (0.9% vs 0.6%) was observed at 3 years, and this remained unchanged from the third year on without any known underlying potential mechanism.38-40 A recent analysis of the General Practice Research Database (GPRD) database in the UK showed no difference in the incidence of venous thromboembolism events between patients treated with strontium ranelate and untreated patients. Furthermore, the incidence of thromboembolism events in the same study were similar in patients treated with strontium ranelate or alendronate, a treatment not known to increase this kind of risk.44 During postmarketing surveillance, very rare cases of hypersensitivity syndrome or DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) have been reported. The clinical manifestations typically occur within 2 to 6 weeks after initiating therapy and, in most cases, resolve upon discontinuation. This syndrome has been very rarely reported (1 case per 73 000 patient years).45 Nevertheless, due to the potentially fatal outcome linked to this syndrome, treatment should be discontinued immediately and permanently in case of skin rash, and medical follow-up should be initiated.

Summary

To date, many pharmacological agents having demonstrated their efficacy in decreasing fracture risk over 3 years, even though not all of them have demonstrated their efficacy in preventing nonvertebral fractures. In most other diseases, the equivalence of acute and chronic treatment is implicit; osteoporosis is, however, a rare example of a chronic disease in which controlled studies have been extended up to 10 years. Several studies have investigated the efficacy of these drugs, but their conclusions are limited by the designs of the studies and the low number of patients generally included. Alendronate or risedronate have demonstrated their efficacy on BMD in the long term, but only sparse data are available regarding their long-term efficacy on vertebral fractures and there is no strong data regarding nonvertebral fractures. At present, strontium ranelate is the only treatment to have proved its long-term efficacy in vertebral, nonvertebral, and hip fractures using the most rigorous approach. This longterm efficacy coupled with its wide spectrum of efficacy allows the use of strontium ranelate as a first-line intervention for the long-term treatment of postmenopausal women with osteoporosis. Finally, two important practical remarks. Firstly, all the controlled studies with active antiosteoporotic agents included supplementation with calcium and vitamin D; thus, adequate nutrition and optimal vitamin D dosage always seem to be necessary to maximize the response of all antiosteoporotic drugs.46 Secondly, another crucial aspect to be borne in mind for any long-term treatment is adherence to the prescribed intervention.47 _

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