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Going on a Drug Holiday?
Journal of Clinical Densitometry: Assessment of Skeletal Health, vol. 14, no. 4, 377e383, 2011 Ó Copyright 2011 by The International Society for Clinical Densitometry 1094-6950/14:377e383/$36.00 DOI: 10.1016/j.jocd.2011.07.006
Editorial
Going on a Drug Holiday? Sydney Lou Bonnick 1,2,* 1
Clinical Research Center of North Texas, Denton, TX, USA; and 2Department of Kinesiology and Biological Sciences, University of North Texas, Denton, TX, USA
therapy electively be stopped either temporarily or indefinitely? There are 3 potential reasons. First, if efficacy could be maintained after a certain period of use after the drug was stopped, then clearly, there would be no reason to continue such a drug after that period of use. Second, if efficacy was lost after a certain period of use, then once again there would clearly be no reason to continue the drug after that point in time. And third, if after a certain period of use, the risk/benefit ratio favored risk over benefit, or if a risk accrued after a certain period of use that was deemed by the patient or by the physician more horrific than efficacy beneficial, then the drug should be stopped. Each of these potential reasons can be examined in the specific context of the use of bisphosphonates for the treatment of PMO.
The concept of a ‘‘drug holiday’’ in the context of bisphosphonate treatment for postmenopausal osteoporosis (PMO) has gained popularity during recent years. The driving force behind such gains would seem to be a combination of beliefs regarding sustained efficacy after discontinuation of the bisphosphonate and safety concerns, the latter having arisen largely in the postmarketing period for the various bisphosphonates. First, let us make sure that we understand what is really being suggested by the phrase ‘‘drug holiday.’’ The phrase, as used in this context, suggests that the bisphosphonate is being electively stopped and that the stoppage is only temporary. This is what the word ‘‘holiday’’ implies, that is, a temporary interruption of the drug, not a permanent cessation of the drug. If it is a holiday that is intended, then not only should there be a reason to interrupt the drug to begin this holiday, there should also be a plan for monitoring the patient for the triggers that would prompt a resumption of therapy or a plan that includes a specific time frame after which the drug would be restarted. Only those who use this phrase can say if this is what they really mean. If there is no plan for monitoring some relevant parameter, a change in which would potentially trigger reinstitution of the therapy, or no plan for a specific temporal duration for the holiday, one must assume that it is not a holiday that is intended at all. Rather, it is simply a discontinuation of the therapy. In the treatment of any chronic disease or disorder that we have not claimed to cure, why would any
If Efficacy is Maintained After a Certain Period of Use . In the context of the treatment of PMO, an ancillary and relevant issue is the definition of efficacy. Efficacy is a significant reduction in fracture risk. The cessation of bone loss and suppression of bone turnover are considered intermediate and incomplete surrogates for fracture risk reduction efficacy during bisphosphonate therapy. Alendronate, risedronate, ibandronate, and zoledronic acid (in the formulation known as Reclast [Novartis, East Hanover, New Jersey]) are approved by the Food and Drug Administration (FDA) for both the prevention and treatment of PMO. For each of these, the phase III trials in the treatment of PMO were 3 yr of duration and resulted in statistically significant demonstrations of vertebral fracture risk reduction for the particular bisphosphonate (1e4). Significant reductions in hip fracture risk were also demonstrated for alendronate (1) and
Received 6/20/2011; Revised 7/21/2011; Accepted 7/29/2011. *Address correspondence to: Sydney Lou Bonnick, MD, FACP, Clinical Research Center of North Texas, 2921 Country Club Road, Suite 101, Denton, Texas 76210-8625. E-mail: [email protected]
377
378 zoledronic acid (4), and a significant reduction in the composite endpoint of nonspine fracture risk was demonstrated for risedronate (2)and zoledronic acid (4). But what do we know about the persistence of efficacy for these drugs if the drug is stopped after a certain period of use? There are published clinical trial data for alendronate (5e7) and risedronate (8), which give some insight into the persistence of effect after the drug is stopped. Data for zoledronic acid have not yet been published, but preliminary data have been publicly presented (9). There have been no studies in which the effect of discontinuation of ibandronate has been examined. In the Long-term Extension of the Fracture Intervention (FLEX) Trial (5), women who had previously received alendronate in the phase III Fracture Intervention Trial (FIT) (10) were re-randomized to discontinue alendronate or continue alendronate in a dose of either 5 or 10 mg daily for an additional 5 yr. On entry into FLEX, these women had a mean duration of 5 yr of prior therapy with alendronate. At the end of the 5-yr FLEX Study in the women who discontinued alendronate 5 yr earlier, total-hip bone mineral density (BMD) declined 3.4%, which was only 0.16% greater than that at the FIT baseline, some 10 yr earlier. In the women who continued alendronate, the total-hip BMD declined by 1.02%. The 2.4% difference in decline between the groups was statistically significant. At the lumbar spine, the women who discontinued alendronate had a 1.52% increase over the 5 yr of the FLEX Trial compared with an increase of 5.26% in the women who had continued alendronate, for a statistically significant 3.7% difference. Discontinuation of alendronate resulted in a gradual increase in bone turnover markers, which was statistically significantly different from the markers in the group continuing alendronate. At the end of FLEX, both serum C-telopeptide and bone-specific alkaline phosphatase were only 7% lower than those at FIT baseline in the group that discontinued alendronate. There was no statistically significant difference in the incidences of nonvertebral (19% placebo vs 18.9% alendronate) or morphometric vertebral fractures (11.3% placebo vs 9.8% alendronate) between the 2 groups in FLEX. There was, however, a statistically significant 55% reduction in the relative risk of clinical spine fractures in the women who continued alendronate for an additional 5 yr compared with those who discontinued it for 5 yr after 5 yr of therapy (5.3% placebo vs 2.4% alendronate). In a post Journal of Clinical Densitometry: Assessment of Skeletal Health
Bonnick hoc analysis of the FLEX Trial (6), women without a vertebral fracture at FLEX baseline but with a femoral neck T-score of 2.5 or lesser who continued alendronate had a significantly reduced incidence of nonvertebral fractures compared with those who discontinued alendronate, but those with a femoral neck T-score greater than 2.5 did not. No difference in morphometric spine fracture risks was seen in this subgroup, regardless of femoral neck T-score. In an earlier phase III study (7) in which women received either 5 or 10 mg of alendronate daily for 10 yr or 20 mg of alendronate in years 1 and 2 followed by 5 mg daily in years 3e5 and then placebo for 5 yr, changes in bone density and bone turnover markers with discontinuation of alendronate were similar to those seen in FLEX. In this trial, fracture incidence was assessed as a measure of safety rather than efficacy. No statistically significant differences in morphometric spine fracture incidence or nonvertebral incidence were seen between the groups. The effects of discontinuation of risedronate after 3 yr of therapy have been evaluated in 1 study (8). Women who previously participated in the phase III North American Risedronate Fracture Trial (2) were eligible to participate in a 1-yr extension of that trial, in which all the participants continued to receive calcium and vitamin D but no active study drug. Thus, participants had received either 3 yr of 5 mg risedronate daily or placebo before entering the 1-yr extension. There was no group that continued risedronate for a fourth year in this study. At the end of the 1-yr extension, BMD in the lumbar spine, femoral neck, and trochanter declined significantly in the former risedronate-treated women although the bone densities at all 3 sites were still significantly higher than those in the former placebo group. Bone turnover markers increased over the course of the year in the former risedronate-treated women and were not significantly different from those of the placebo group by the end of the year. In spite of these changes in the intermediate endpoints, the relative risk of new morphometric vertebral fractures was reduced 46% in the former risedronate-treated women compared with that in the placebo group. Nonvertebral fracture incidence was not an efficacy endpoint in this study but, as an adverse event, was not different between the 2 groups. From this study, one would reasonably conclude that a year after stopping therapy it is still better to have taken risedronate for 3 yr than to have not taken it, in terms of vertebral fracture risk reduction efficacy. Because of the lack of a group that continued on risedronate for an additional year with Volume 14, 2011
Drug Holiday which to compare, one cannot draw any conclusions as to how much, if any, efficacy is lost by discontinuing the drug as opposed to continuing it. The data from the 3-yr extension of the original phase III fracture trial (4) in PMO of zoledronic acid have not yet been published, but preliminary data have been presented (9). At the end of the original 3-yr trial, the women who received zoledronic acid intravenously once a year during the original trial were re-randomized in a blinded fashion to continue to receive once-yearly zoledronic acid for an additional 3 yr or a placebo infusion. The placebo group from the original phase III trial received once-yearly zoledronic acid during the 3-yr extension. The primary endpoint in the extension, as in the FLEX Trial, was the change in femoral neck bone density, although changes in bone density at other skeletal sites and fracture incidence were evaluated as well. In the women who received zoledronic acid for 6 yr, femoral neck bone density remained stable during years 3e6, whereas in the women who received zoledronic acid for 3 yr followed by 3 yr of placebo, femoral neck bone density declined 1.04%. Although this was a statistically significant decline in the extension placebo group, the femoral neck bone density remained well greater than the baseline values obtained 6 yr earlier. Results for the lumbar spine and total-hip BMD were similar. Bone turnover markers remained reduced and stable in the women who continued zoledronic acid for a total of 6 yr, and although they rose significantly in the extension-placebo group, the markers were still significantly less than the baseline values obtained 6 yr earlier. The relative risk of new morphometric spine fractures was significantly reduced by 52% in the women who continued zoledronic acid for 6 yr compared with those who received it for 3 yr followed by a placebo infusion for 3 yr. There was no difference in nonvertebral or clinical spine fractures between the 2 groups. There are no data available at present to assess the effects of discontinuation of ibandronate after any period of use. In reviewing the available data for alendronate, risedronate, and zoledronic acid, it would seem clear that the data are unique to each bisphosphonate and for the specific time period of use and time period of discontinuation studied. As a consequence, if we are to make reasonable clinical decisions based on the data that we have, we must consider not only the specific needs and wants of the individual patient but also the evidence that we have for the specific bisphosphonate that they Journal of Clinical Densitometry: Assessment of Skeletal Health
379 are taking. There is no all-encompassing single statement that can be made regarding the sustained efficacy of the various bisphosphonates after the same period of use and the same period of discontinuation.
If Efficacy is Lost After a Certain Period of Use . If the effectiveness of a bisphosphonate in reducing fracture risk was lost after a certain period of use, then there would clearly be no reason to continue it past that time, but there are simply no data to suggest that this is true for any of the bisphosphonates. This observation is limited, of course, by the duration of the studies evaluating efficacy in fracture risk. Alendronate therapy has been evaluated in studies (5e7) spanning a 10-yr period and risedronate therapy (11,12) over a period of 7 yr. In neither case is a loss of efficacy suggested during the time periods studied, based on either the effects on the intermediate endpoints of bone density and bone turnover or on the ultimate evidence of efficacy, reduction in fracture risk. Preliminary data (9) from the 3-yr extension of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) do not suggest any loss of efficacy over 6 yr of treatment. No extension trials beyond the original 3-yr phase III fracture trial of ibandronate have been performed.
If the Risk/Benefit Ratio Favors Risk After a Certain Period of Use . In recent years, the specter of osteonecrosis of the jaw (ONJ), atrial fibrillation, renal failure, esophageal cancer, and atypical femoral shaft fractures have individually and in combination impugned the safety of the bisphosphonates and the feasibility of their use in the prevention and/or treatment of PMO. The simple listing of these safety concerns is sufficient to give most physicians pause. However, although none of these safety issues should be minimized in any way, the attention they have received and continue to receive would seem to be out of proportion to the risk that these entities pose to any individual after any period of bisphosphonate use. The confounding effect of value judgmentsdjudgments of worth or importance made on the basis of personal beliefs or opinions about specific risks and benefitsd in perpetuating this attention must be recognized. The identification of most, but not all, of these issues in the postmarketing phase for these drugs rather than Volume 14, 2011
380 during pre-approval clinical trials is also a source of consternation for physicians and alarm for the public, which may contribute to both the continued attention and nature of the value judgments being made. Osteonecrosis of the Jaw The association between ONJ and bisphosphonate use is very strong, although the specific pathophysiological mechanisms involved remain elusive (13). The clinical implications of this association, however, are most relevant to the oncologic use of vastly higher and more frequent doses of intravenous bisphosphonates than those used in the treatment of PMO. The oncologic use of intravenous bisphosphonates results in a prevalence of ONJ that is estimated to be 1e10 per 100 patients (14). This prevalence would be described as common using the Council for International Organizations of Medical Sciences (CIOMS) terminology (15). Increasing risk with increasing duration of intravenous bisphosphonate use in oncology has also been described (16,17). In spite of this, there has been no great outcry about the use of these agents in oncology, unlike in PMO, where ONJ, with a risk of 1 per 10,000 to less than 1 per 100,000 patienttreatment years (14), is more appropriately described in CIOMS terminology as rare to very rare, and a relationship between increasing duration of use and increasing risk has generally not been found (9,18). The most likely explanation for this is the value judgments that are being made. Our patients make value judgments and we, as health care professionals, make value judgments. There is nothing wrong with that as long as we are aware that we are doing so. The substantial risk of ONJ in the oncology patient who needs the intravenous bisphosphonate pales against the risk of death. And yet, the incredibly small risk of ONJ for the PMO patient may underlie decisions to stop therapy or never begin, even in patients at high risk for fracture. The broken bone with its attendant morbidity and mortality may be farther removed from the osteoporosis patient’s reality than death from cancer for the oncology patient. This is a value judgment that is understandable, both in the context of oncology specifically and oncology and PMO comparatively. It is questionable, however, in the specific context of PMO. Atrial Fibrillation Atrial fibrillation came to the fore with the publication of clinical trial data from the phase III HORIZON-PFT of zoledronic acid (4). Although Journal of Clinical Densitometry: Assessment of Skeletal Health
Bonnick the overall incidence of atrial fibrillation was not different between the zoledronic acid- and placebotreated women, the incidence of serious adverse events involving atrial fibrillation was. The numbers were small, 1.4% in the zoledronic acid-treated women vs 0.4% in the placebo group, but the difference was statistically significant. This finding, however, has not been replicated in any other clinical trial of zoledronic acid in the treatment of osteoporosis (19e21) and has not been clearly seen in any prospective trial in the prevention or treatment of osteoporosis with other bisphosphonates (1e3,22,23). In 2008, after careful review, the FDA concluded (24) that no clear association between bisphosphonate use and the risk of atrial fibrillation could be found and that health care providers should not alter their prescribing practices based on this particular issue. Renal Impairment All bisphosphonates are excreted unchanged by the kidneys. Attention to renal function is mandatory for their safe use. Oral bisphosphonates for the prevention or treatment of PMO have not been linked to adverse effects on renal function, but early studies suggested that rapid intravenous infusions of bisphosphonates were associated with renal failure, perhaps because of the nephrotoxic effects of high systemic drug concentrations on renal tubular cells (25). In 2009, a report (26) from the FDA described 24 cases of renal impairment and acute renal failure associated with the use of zoledronic acid in the formulation known as Reclast. It was noted in the report that most of the patients responded to hydration and that, in several cases, acute renal failure, dialysis, and death occurred in patients with preexisting renal insufficiency or in the presence of other risk factors, such as nephrotoxic medications, severe dehydration, or concomitant diuretic therapy. The FDA appropriately reminded physicians to avoid using Reclast in patients with a creatinine clearance less than 35 mL/min, to monitor the serum creatinine before each dose, to ensure that patients were adequately hydrated before the infusion, and to infuse Reclast for a minimum of 15 min. All of these recommendations can be found in the FDA-approved prescribing information for this bisphosphonate. In an extensive analysis (27) of a renal safety substudy performed in the HORIZON-PFT that included 5035 participants, there were no long-term changes in renal function in the zoledronic acid-treated women that were statistically different from those Volume 14, 2011
Drug Holiday of the controls. Women enrolled in the HORIZONPFT were required to have an estimated creatinine clearance greater than or equal to 30 mL/min (4). In a pooled analysis of more than 3000 women with PMO who received intravenous ibandronate, there were no cases of renal failure or other significant renal adverse effects (23). Guidelines exist for adjustments in dosage and/or frequency of administration based on renal function for the use of zoledronic acid and pamidronate in oncology, but no such adjustment guidelines exist for the use of any oral or intravenous bisphosphonate in the prevention or treatment of PMO. Instead, there are cut points for renal function, which are 30 or 35 mL/min, depending on the particular bisphosphonate, based on the Cockcroft-Gault calculation of estimated creatinine clearance. As long as these FDA-approved cutpoints and administration guidelines are followed, the risk of renal damage in patients receiving an oral bisphosphonate appears to be nil and with intravenous bisphosphonates, extremely small. Esophageal Cancer In 2009 in a letter to the editor in the New England Journal of Medicine, 23 cases from the United States and 31 cases from Europe and Japan of esophageal cancer associated with oral bisphosphonate use were briefly described. The author went so far as to recommend that oral bisphosphonates were not be prescribed to anyone with a history of Barrett’s esophagus and to state that oral bisphosphonates should be considered a risk factor for esophageal cancer. This report was criticized by multiple authors in letters (28) to the editor of the same journal. Two publications (29,30) appeared in 2010 addressing the issue of oral bisphosphonate use and esophageal cancer, both using the UK General Practice Research Database but different statistical approaches. In the study from Cardwell et al (29), the authors concluded that there was no difference in the risk of esophageal cancer between users and nonusers of bisphosphonates and no difference in the risk of esophageal cancer among bisphosphonate users by type or duration of bisphosphonate use. Green et al (30), however, concluded that after 5 yr of bisphosphonate use, the risk for esophageal cancer doubled. The authors pointed out that this would mean that the baseline risk in women for esophageal cancer would increase from 0.5 per 1000 to 1 per 1000. In CIOMS terminology (15), the rare event of esophageal cancer in women would now be called uncommon. Journal of Clinical Densitometry: Assessment of Skeletal Health
381 Atypical Subtrochanteric and Femoral Shaft Fractures Atypical subtrochanteric and femoral shaft fractures have also been considered a possible consequence of bisphosphonate therapy. Bisphosphonates given for the treatment of PMO are to reduce fracture risk. The irony of possibly causing fractures with these drugs has made this issue a particularly ‘‘hot topic’’ and in no small way; concern regarding atypical fractures was one of the driving force behind FDA’s recent addition of the limitationof-use statement in the prescribing information for all bisphosphonates approved for the treatment of PMO. Subtrochanteric and femoral shaft fractures are known to occur as a result of underlying skeletal fragility, although they are considered the least common types of hip fracture. Nieves et al (31) estimated that about 3% of femoral fractures were subtrochanteric in location and 5% were femoral shaft or lower femur in location. It is not the location alone, however, that is the subject of concern here. It is a low-trauma fracture in this location that on X-ray has a transverse or short oblique configuration and is noncomminuted (32). After an exhaustive review of the published literature, a task force of the American Society for Bone and Mineral Research (ASBMR) identified 291 cases associated with bisphosphonate use. They noted that if bisphosphonates were prescribed for women at high risk of fracture, 700e1000 nonvertebral fractures per 100,000 person-years and 1000e2300 clinical spine fractures per 100,000 person-years would be prevented, compared with the reported incidence of atypical femoral fractures from bisphosphonate use of 78e100 per 100,000. A recent report (33) from Sweden concluded that the relative risk of atypical fracture with the use of bisphosphonates was significantly increased at 47.3% and that the risk increased with increasing duration of use, particularly after 2 yr. Although this sounded alarming, the authors noted that this equated to a difference of 5 cases per 10,000 patient-years between bisphosphonate users and nonusers. Much as the ASBMR task force had concluded, the authors observed that the absolute risk to any 1 individual was small and that the benefits of fracture prevention would greatly outweigh the risk of atypical fractures if bisphosphonates were appropriately prescribed. It is reasonable then to look at these specific issues and conclude that the risk of any of these to any Volume 14, 2011
382 1 individual, no matter how long they continue treatment, does not outweigh the benefit of the medication, assuming that the initiation of bisphosphonate therapy in the particular patient was appropriate in the first place. Nevertheless, the patient may conclude that they would prefer to risk having a fracture than risk developing any of these entities. That is a value judgment with which a physician might not agree based on the evidence, but it is a value judgment that must be honored.
So About That Drug Holiday . As our knowledge stands today, there is no reason to routinely plan a drug holiday or cessation of therapy after a fixed period of use in a patient who is appropriately prescribed a bisphosphonate to reduce fracture risk. In the few studies designed to evaluate the persistence of fracture risk reduction benefit after cessation of therapy, it appears that there is some persistence of fracture risk reduction benefit after cessation of therapy for alendronate, risedronate, and zoledronic acid. However, the data for each bisphosphonate are quite specific for a given period of use and a given period of discontinuation. It is not the same for all 3. In the case of alendronate and zoledronic acid, although it appears that there is a persistence of fracture risk reduction in some categories of fracture risk after cessation of the drug, there is risk reduction in additional categories if the drug is continued. Because of the design of the risedronate trial, one simply cannot say whether risk reduction in any category is better if the drug is continued after any particular duration of therapy as opposed to being stopped. In the absence of data, one can only speculate about any persistence of effect with ibandronate. There are no data to suggest that the fracture risk reduction benefit stops after a certain period of use for any of the bisphosphonates over the time periods that they have been studied. Finally, in terms of safety, the occurrence of such things as ONJ and atypical fractures are rare, even after 3 yr or more of use. If the individual truly needs the drug, the risk of any of these entities, as we understand it now, is not likely to exceed the potential benefit. In January 2011, a ‘‘limitations of use’’ statement was added to the FDA-approved prescribing information for all bisphosphonates approved for the treatment of osteoporosis. The statement reads as follows: Journal of Clinical Densitometry: Assessment of Skeletal Health
Bonnick The safety and effectiveness of [insert bisphosphonate name] for the treatment of osteoporosis is based on clinical data of 3-yr duration. The optimal duration of use has not been determined. All patients on bisphosphonate treatment should have the need for continued therapy re-evaluated on a periodic basis.
This statement is both factually and philosophically correct. The trials submitted to the FDA for registration of bisphosphonates for the treatment of PMO were 3 yr in duration. There are trials of longer duration for some of the bisphosphonates, as noted here, but the FDA assessment of each drug was originally based on 3-yr trial data. Hence, although the clinician has data available from which efficacy and safety for a period longer than 3 yr could be evaluated, statements made by the FDA are overwhelmingly based on 3-yr data. It is also true that the ‘‘optimal’’ duration of use for any of these bisphosphonates is not known. In any case, all patients on any treatment for any chronic disease should have the need for continued therapy reevaluated on a periodic basis. That is not the easy answer to whether a patient should have a drug holiday or how long a patient should be treated, but it is the right answer. Given our current knowledge, there should not be a blanket recommendation for an automatic drug holiday or cessation of therapy in all patients treated with any of the bisphosphonates. Each patient, as the individual that he or she is, should have that need reevaluated on a periodic basis, keeping in mind the wishes of the patient and the ever-changing scope of our knowledge.
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versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J Bone Miner Res 25:2239e2250. Reid DM, Devogelaer P, Saag K, et al. 2009 Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomized controlled trial. Lancet 373:1253e1263. Barrett-Connor E, Swern AS, Hustad CM, et al. 2011 Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporos Int. In press. Lewiecki EM, Cooper C, Thompson E, et al. 2010 Ibandronate does not increase risk of atrial fibrillation in analysis of pivotal clinical trials. Int J Clin Pract 64:821e826. FDA. Update of safety review follow-up to the October 1, 2007 early communication about the ongoing safety review of bisphosphonates. Available at: http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/DrugSafetyInformationforHealthcareProfessionals/ ucm136201.htm. Accessed: May 12, 2011. Miller PD. 2011 The kidney and bisphosphonates. Bone 49: 77e81. FDA. 2009 Zoledronic acid. Reports of acute renal impairment and failure associated with once-yearly intravenous treatment for osteoporosis in postmenopausal women. Drug Safety Newsletter 2:13e15. Boonen S, Sellmeyer DE, Lippuner K, et al. 2008 Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int 74:641e648. More on reports of esophageal cancer with oral bisphosphonate use. 2009 N Engl J Med 360:1789e1792. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. 2010 Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 304:657e663. Green J, Czanner G, Reeves G, et al. 2010 Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 341:c4444. Nieves JW, Bilezikian JP, Lane JM, et al. 2010 Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int 21:399e408. Shane E, Burr D, Ebeling PR, et al. 2010 Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25:2267e2294. Schilcher J, Micha€elsson K, Aspenberg P. 2011 Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 364:1728e1737.
Volume 14, 2011
Editorial
Going on a Drug Holiday? Sydney Lou Bonnick 1,2,* 1
Clinical Research Center of North Texas, Denton, TX, USA; and 2Department of Kinesiology and Biological Sciences, University of North Texas, Denton, TX, USA
therapy electively be stopped either temporarily or indefinitely? There are 3 potential reasons. First, if efficacy could be maintained after a certain period of use after the drug was stopped, then clearly, there would be no reason to continue such a drug after that period of use. Second, if efficacy was lost after a certain period of use, then once again there would clearly be no reason to continue the drug after that point in time. And third, if after a certain period of use, the risk/benefit ratio favored risk over benefit, or if a risk accrued after a certain period of use that was deemed by the patient or by the physician more horrific than efficacy beneficial, then the drug should be stopped. Each of these potential reasons can be examined in the specific context of the use of bisphosphonates for the treatment of PMO.
The concept of a ‘‘drug holiday’’ in the context of bisphosphonate treatment for postmenopausal osteoporosis (PMO) has gained popularity during recent years. The driving force behind such gains would seem to be a combination of beliefs regarding sustained efficacy after discontinuation of the bisphosphonate and safety concerns, the latter having arisen largely in the postmarketing period for the various bisphosphonates. First, let us make sure that we understand what is really being suggested by the phrase ‘‘drug holiday.’’ The phrase, as used in this context, suggests that the bisphosphonate is being electively stopped and that the stoppage is only temporary. This is what the word ‘‘holiday’’ implies, that is, a temporary interruption of the drug, not a permanent cessation of the drug. If it is a holiday that is intended, then not only should there be a reason to interrupt the drug to begin this holiday, there should also be a plan for monitoring the patient for the triggers that would prompt a resumption of therapy or a plan that includes a specific time frame after which the drug would be restarted. Only those who use this phrase can say if this is what they really mean. If there is no plan for monitoring some relevant parameter, a change in which would potentially trigger reinstitution of the therapy, or no plan for a specific temporal duration for the holiday, one must assume that it is not a holiday that is intended at all. Rather, it is simply a discontinuation of the therapy. In the treatment of any chronic disease or disorder that we have not claimed to cure, why would any
If Efficacy is Maintained After a Certain Period of Use . In the context of the treatment of PMO, an ancillary and relevant issue is the definition of efficacy. Efficacy is a significant reduction in fracture risk. The cessation of bone loss and suppression of bone turnover are considered intermediate and incomplete surrogates for fracture risk reduction efficacy during bisphosphonate therapy. Alendronate, risedronate, ibandronate, and zoledronic acid (in the formulation known as Reclast [Novartis, East Hanover, New Jersey]) are approved by the Food and Drug Administration (FDA) for both the prevention and treatment of PMO. For each of these, the phase III trials in the treatment of PMO were 3 yr of duration and resulted in statistically significant demonstrations of vertebral fracture risk reduction for the particular bisphosphonate (1e4). Significant reductions in hip fracture risk were also demonstrated for alendronate (1) and
Received 6/20/2011; Revised 7/21/2011; Accepted 7/29/2011. *Address correspondence to: Sydney Lou Bonnick, MD, FACP, Clinical Research Center of North Texas, 2921 Country Club Road, Suite 101, Denton, Texas 76210-8625. E-mail: [email protected]
377
378 zoledronic acid (4), and a significant reduction in the composite endpoint of nonspine fracture risk was demonstrated for risedronate (2)and zoledronic acid (4). But what do we know about the persistence of efficacy for these drugs if the drug is stopped after a certain period of use? There are published clinical trial data for alendronate (5e7) and risedronate (8), which give some insight into the persistence of effect after the drug is stopped. Data for zoledronic acid have not yet been published, but preliminary data have been publicly presented (9). There have been no studies in which the effect of discontinuation of ibandronate has been examined. In the Long-term Extension of the Fracture Intervention (FLEX) Trial (5), women who had previously received alendronate in the phase III Fracture Intervention Trial (FIT) (10) were re-randomized to discontinue alendronate or continue alendronate in a dose of either 5 or 10 mg daily for an additional 5 yr. On entry into FLEX, these women had a mean duration of 5 yr of prior therapy with alendronate. At the end of the 5-yr FLEX Study in the women who discontinued alendronate 5 yr earlier, total-hip bone mineral density (BMD) declined 3.4%, which was only 0.16% greater than that at the FIT baseline, some 10 yr earlier. In the women who continued alendronate, the total-hip BMD declined by 1.02%. The 2.4% difference in decline between the groups was statistically significant. At the lumbar spine, the women who discontinued alendronate had a 1.52% increase over the 5 yr of the FLEX Trial compared with an increase of 5.26% in the women who had continued alendronate, for a statistically significant 3.7% difference. Discontinuation of alendronate resulted in a gradual increase in bone turnover markers, which was statistically significantly different from the markers in the group continuing alendronate. At the end of FLEX, both serum C-telopeptide and bone-specific alkaline phosphatase were only 7% lower than those at FIT baseline in the group that discontinued alendronate. There was no statistically significant difference in the incidences of nonvertebral (19% placebo vs 18.9% alendronate) or morphometric vertebral fractures (11.3% placebo vs 9.8% alendronate) between the 2 groups in FLEX. There was, however, a statistically significant 55% reduction in the relative risk of clinical spine fractures in the women who continued alendronate for an additional 5 yr compared with those who discontinued it for 5 yr after 5 yr of therapy (5.3% placebo vs 2.4% alendronate). In a post Journal of Clinical Densitometry: Assessment of Skeletal Health
Bonnick hoc analysis of the FLEX Trial (6), women without a vertebral fracture at FLEX baseline but with a femoral neck T-score of 2.5 or lesser who continued alendronate had a significantly reduced incidence of nonvertebral fractures compared with those who discontinued alendronate, but those with a femoral neck T-score greater than 2.5 did not. No difference in morphometric spine fracture risks was seen in this subgroup, regardless of femoral neck T-score. In an earlier phase III study (7) in which women received either 5 or 10 mg of alendronate daily for 10 yr or 20 mg of alendronate in years 1 and 2 followed by 5 mg daily in years 3e5 and then placebo for 5 yr, changes in bone density and bone turnover markers with discontinuation of alendronate were similar to those seen in FLEX. In this trial, fracture incidence was assessed as a measure of safety rather than efficacy. No statistically significant differences in morphometric spine fracture incidence or nonvertebral incidence were seen between the groups. The effects of discontinuation of risedronate after 3 yr of therapy have been evaluated in 1 study (8). Women who previously participated in the phase III North American Risedronate Fracture Trial (2) were eligible to participate in a 1-yr extension of that trial, in which all the participants continued to receive calcium and vitamin D but no active study drug. Thus, participants had received either 3 yr of 5 mg risedronate daily or placebo before entering the 1-yr extension. There was no group that continued risedronate for a fourth year in this study. At the end of the 1-yr extension, BMD in the lumbar spine, femoral neck, and trochanter declined significantly in the former risedronate-treated women although the bone densities at all 3 sites were still significantly higher than those in the former placebo group. Bone turnover markers increased over the course of the year in the former risedronate-treated women and were not significantly different from those of the placebo group by the end of the year. In spite of these changes in the intermediate endpoints, the relative risk of new morphometric vertebral fractures was reduced 46% in the former risedronate-treated women compared with that in the placebo group. Nonvertebral fracture incidence was not an efficacy endpoint in this study but, as an adverse event, was not different between the 2 groups. From this study, one would reasonably conclude that a year after stopping therapy it is still better to have taken risedronate for 3 yr than to have not taken it, in terms of vertebral fracture risk reduction efficacy. Because of the lack of a group that continued on risedronate for an additional year with Volume 14, 2011
Drug Holiday which to compare, one cannot draw any conclusions as to how much, if any, efficacy is lost by discontinuing the drug as opposed to continuing it. The data from the 3-yr extension of the original phase III fracture trial (4) in PMO of zoledronic acid have not yet been published, but preliminary data have been presented (9). At the end of the original 3-yr trial, the women who received zoledronic acid intravenously once a year during the original trial were re-randomized in a blinded fashion to continue to receive once-yearly zoledronic acid for an additional 3 yr or a placebo infusion. The placebo group from the original phase III trial received once-yearly zoledronic acid during the 3-yr extension. The primary endpoint in the extension, as in the FLEX Trial, was the change in femoral neck bone density, although changes in bone density at other skeletal sites and fracture incidence were evaluated as well. In the women who received zoledronic acid for 6 yr, femoral neck bone density remained stable during years 3e6, whereas in the women who received zoledronic acid for 3 yr followed by 3 yr of placebo, femoral neck bone density declined 1.04%. Although this was a statistically significant decline in the extension placebo group, the femoral neck bone density remained well greater than the baseline values obtained 6 yr earlier. Results for the lumbar spine and total-hip BMD were similar. Bone turnover markers remained reduced and stable in the women who continued zoledronic acid for a total of 6 yr, and although they rose significantly in the extension-placebo group, the markers were still significantly less than the baseline values obtained 6 yr earlier. The relative risk of new morphometric spine fractures was significantly reduced by 52% in the women who continued zoledronic acid for 6 yr compared with those who received it for 3 yr followed by a placebo infusion for 3 yr. There was no difference in nonvertebral or clinical spine fractures between the 2 groups. There are no data available at present to assess the effects of discontinuation of ibandronate after any period of use. In reviewing the available data for alendronate, risedronate, and zoledronic acid, it would seem clear that the data are unique to each bisphosphonate and for the specific time period of use and time period of discontinuation studied. As a consequence, if we are to make reasonable clinical decisions based on the data that we have, we must consider not only the specific needs and wants of the individual patient but also the evidence that we have for the specific bisphosphonate that they Journal of Clinical Densitometry: Assessment of Skeletal Health
379 are taking. There is no all-encompassing single statement that can be made regarding the sustained efficacy of the various bisphosphonates after the same period of use and the same period of discontinuation.
If Efficacy is Lost After a Certain Period of Use . If the effectiveness of a bisphosphonate in reducing fracture risk was lost after a certain period of use, then there would clearly be no reason to continue it past that time, but there are simply no data to suggest that this is true for any of the bisphosphonates. This observation is limited, of course, by the duration of the studies evaluating efficacy in fracture risk. Alendronate therapy has been evaluated in studies (5e7) spanning a 10-yr period and risedronate therapy (11,12) over a period of 7 yr. In neither case is a loss of efficacy suggested during the time periods studied, based on either the effects on the intermediate endpoints of bone density and bone turnover or on the ultimate evidence of efficacy, reduction in fracture risk. Preliminary data (9) from the 3-yr extension of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) do not suggest any loss of efficacy over 6 yr of treatment. No extension trials beyond the original 3-yr phase III fracture trial of ibandronate have been performed.
If the Risk/Benefit Ratio Favors Risk After a Certain Period of Use . In recent years, the specter of osteonecrosis of the jaw (ONJ), atrial fibrillation, renal failure, esophageal cancer, and atypical femoral shaft fractures have individually and in combination impugned the safety of the bisphosphonates and the feasibility of their use in the prevention and/or treatment of PMO. The simple listing of these safety concerns is sufficient to give most physicians pause. However, although none of these safety issues should be minimized in any way, the attention they have received and continue to receive would seem to be out of proportion to the risk that these entities pose to any individual after any period of bisphosphonate use. The confounding effect of value judgmentsdjudgments of worth or importance made on the basis of personal beliefs or opinions about specific risks and benefitsd in perpetuating this attention must be recognized. The identification of most, but not all, of these issues in the postmarketing phase for these drugs rather than Volume 14, 2011
380 during pre-approval clinical trials is also a source of consternation for physicians and alarm for the public, which may contribute to both the continued attention and nature of the value judgments being made. Osteonecrosis of the Jaw The association between ONJ and bisphosphonate use is very strong, although the specific pathophysiological mechanisms involved remain elusive (13). The clinical implications of this association, however, are most relevant to the oncologic use of vastly higher and more frequent doses of intravenous bisphosphonates than those used in the treatment of PMO. The oncologic use of intravenous bisphosphonates results in a prevalence of ONJ that is estimated to be 1e10 per 100 patients (14). This prevalence would be described as common using the Council for International Organizations of Medical Sciences (CIOMS) terminology (15). Increasing risk with increasing duration of intravenous bisphosphonate use in oncology has also been described (16,17). In spite of this, there has been no great outcry about the use of these agents in oncology, unlike in PMO, where ONJ, with a risk of 1 per 10,000 to less than 1 per 100,000 patienttreatment years (14), is more appropriately described in CIOMS terminology as rare to very rare, and a relationship between increasing duration of use and increasing risk has generally not been found (9,18). The most likely explanation for this is the value judgments that are being made. Our patients make value judgments and we, as health care professionals, make value judgments. There is nothing wrong with that as long as we are aware that we are doing so. The substantial risk of ONJ in the oncology patient who needs the intravenous bisphosphonate pales against the risk of death. And yet, the incredibly small risk of ONJ for the PMO patient may underlie decisions to stop therapy or never begin, even in patients at high risk for fracture. The broken bone with its attendant morbidity and mortality may be farther removed from the osteoporosis patient’s reality than death from cancer for the oncology patient. This is a value judgment that is understandable, both in the context of oncology specifically and oncology and PMO comparatively. It is questionable, however, in the specific context of PMO. Atrial Fibrillation Atrial fibrillation came to the fore with the publication of clinical trial data from the phase III HORIZON-PFT of zoledronic acid (4). Although Journal of Clinical Densitometry: Assessment of Skeletal Health
Bonnick the overall incidence of atrial fibrillation was not different between the zoledronic acid- and placebotreated women, the incidence of serious adverse events involving atrial fibrillation was. The numbers were small, 1.4% in the zoledronic acid-treated women vs 0.4% in the placebo group, but the difference was statistically significant. This finding, however, has not been replicated in any other clinical trial of zoledronic acid in the treatment of osteoporosis (19e21) and has not been clearly seen in any prospective trial in the prevention or treatment of osteoporosis with other bisphosphonates (1e3,22,23). In 2008, after careful review, the FDA concluded (24) that no clear association between bisphosphonate use and the risk of atrial fibrillation could be found and that health care providers should not alter their prescribing practices based on this particular issue. Renal Impairment All bisphosphonates are excreted unchanged by the kidneys. Attention to renal function is mandatory for their safe use. Oral bisphosphonates for the prevention or treatment of PMO have not been linked to adverse effects on renal function, but early studies suggested that rapid intravenous infusions of bisphosphonates were associated with renal failure, perhaps because of the nephrotoxic effects of high systemic drug concentrations on renal tubular cells (25). In 2009, a report (26) from the FDA described 24 cases of renal impairment and acute renal failure associated with the use of zoledronic acid in the formulation known as Reclast. It was noted in the report that most of the patients responded to hydration and that, in several cases, acute renal failure, dialysis, and death occurred in patients with preexisting renal insufficiency or in the presence of other risk factors, such as nephrotoxic medications, severe dehydration, or concomitant diuretic therapy. The FDA appropriately reminded physicians to avoid using Reclast in patients with a creatinine clearance less than 35 mL/min, to monitor the serum creatinine before each dose, to ensure that patients were adequately hydrated before the infusion, and to infuse Reclast for a minimum of 15 min. All of these recommendations can be found in the FDA-approved prescribing information for this bisphosphonate. In an extensive analysis (27) of a renal safety substudy performed in the HORIZON-PFT that included 5035 participants, there were no long-term changes in renal function in the zoledronic acid-treated women that were statistically different from those Volume 14, 2011
Drug Holiday of the controls. Women enrolled in the HORIZONPFT were required to have an estimated creatinine clearance greater than or equal to 30 mL/min (4). In a pooled analysis of more than 3000 women with PMO who received intravenous ibandronate, there were no cases of renal failure or other significant renal adverse effects (23). Guidelines exist for adjustments in dosage and/or frequency of administration based on renal function for the use of zoledronic acid and pamidronate in oncology, but no such adjustment guidelines exist for the use of any oral or intravenous bisphosphonate in the prevention or treatment of PMO. Instead, there are cut points for renal function, which are 30 or 35 mL/min, depending on the particular bisphosphonate, based on the Cockcroft-Gault calculation of estimated creatinine clearance. As long as these FDA-approved cutpoints and administration guidelines are followed, the risk of renal damage in patients receiving an oral bisphosphonate appears to be nil and with intravenous bisphosphonates, extremely small. Esophageal Cancer In 2009 in a letter to the editor in the New England Journal of Medicine, 23 cases from the United States and 31 cases from Europe and Japan of esophageal cancer associated with oral bisphosphonate use were briefly described. The author went so far as to recommend that oral bisphosphonates were not be prescribed to anyone with a history of Barrett’s esophagus and to state that oral bisphosphonates should be considered a risk factor for esophageal cancer. This report was criticized by multiple authors in letters (28) to the editor of the same journal. Two publications (29,30) appeared in 2010 addressing the issue of oral bisphosphonate use and esophageal cancer, both using the UK General Practice Research Database but different statistical approaches. In the study from Cardwell et al (29), the authors concluded that there was no difference in the risk of esophageal cancer between users and nonusers of bisphosphonates and no difference in the risk of esophageal cancer among bisphosphonate users by type or duration of bisphosphonate use. Green et al (30), however, concluded that after 5 yr of bisphosphonate use, the risk for esophageal cancer doubled. The authors pointed out that this would mean that the baseline risk in women for esophageal cancer would increase from 0.5 per 1000 to 1 per 1000. In CIOMS terminology (15), the rare event of esophageal cancer in women would now be called uncommon. Journal of Clinical Densitometry: Assessment of Skeletal Health
381 Atypical Subtrochanteric and Femoral Shaft Fractures Atypical subtrochanteric and femoral shaft fractures have also been considered a possible consequence of bisphosphonate therapy. Bisphosphonates given for the treatment of PMO are to reduce fracture risk. The irony of possibly causing fractures with these drugs has made this issue a particularly ‘‘hot topic’’ and in no small way; concern regarding atypical fractures was one of the driving force behind FDA’s recent addition of the limitationof-use statement in the prescribing information for all bisphosphonates approved for the treatment of PMO. Subtrochanteric and femoral shaft fractures are known to occur as a result of underlying skeletal fragility, although they are considered the least common types of hip fracture. Nieves et al (31) estimated that about 3% of femoral fractures were subtrochanteric in location and 5% were femoral shaft or lower femur in location. It is not the location alone, however, that is the subject of concern here. It is a low-trauma fracture in this location that on X-ray has a transverse or short oblique configuration and is noncomminuted (32). After an exhaustive review of the published literature, a task force of the American Society for Bone and Mineral Research (ASBMR) identified 291 cases associated with bisphosphonate use. They noted that if bisphosphonates were prescribed for women at high risk of fracture, 700e1000 nonvertebral fractures per 100,000 person-years and 1000e2300 clinical spine fractures per 100,000 person-years would be prevented, compared with the reported incidence of atypical femoral fractures from bisphosphonate use of 78e100 per 100,000. A recent report (33) from Sweden concluded that the relative risk of atypical fracture with the use of bisphosphonates was significantly increased at 47.3% and that the risk increased with increasing duration of use, particularly after 2 yr. Although this sounded alarming, the authors noted that this equated to a difference of 5 cases per 10,000 patient-years between bisphosphonate users and nonusers. Much as the ASBMR task force had concluded, the authors observed that the absolute risk to any 1 individual was small and that the benefits of fracture prevention would greatly outweigh the risk of atypical fractures if bisphosphonates were appropriately prescribed. It is reasonable then to look at these specific issues and conclude that the risk of any of these to any Volume 14, 2011
382 1 individual, no matter how long they continue treatment, does not outweigh the benefit of the medication, assuming that the initiation of bisphosphonate therapy in the particular patient was appropriate in the first place. Nevertheless, the patient may conclude that they would prefer to risk having a fracture than risk developing any of these entities. That is a value judgment with which a physician might not agree based on the evidence, but it is a value judgment that must be honored.
So About That Drug Holiday . As our knowledge stands today, there is no reason to routinely plan a drug holiday or cessation of therapy after a fixed period of use in a patient who is appropriately prescribed a bisphosphonate to reduce fracture risk. In the few studies designed to evaluate the persistence of fracture risk reduction benefit after cessation of therapy, it appears that there is some persistence of fracture risk reduction benefit after cessation of therapy for alendronate, risedronate, and zoledronic acid. However, the data for each bisphosphonate are quite specific for a given period of use and a given period of discontinuation. It is not the same for all 3. In the case of alendronate and zoledronic acid, although it appears that there is a persistence of fracture risk reduction in some categories of fracture risk after cessation of the drug, there is risk reduction in additional categories if the drug is continued. Because of the design of the risedronate trial, one simply cannot say whether risk reduction in any category is better if the drug is continued after any particular duration of therapy as opposed to being stopped. In the absence of data, one can only speculate about any persistence of effect with ibandronate. There are no data to suggest that the fracture risk reduction benefit stops after a certain period of use for any of the bisphosphonates over the time periods that they have been studied. Finally, in terms of safety, the occurrence of such things as ONJ and atypical fractures are rare, even after 3 yr or more of use. If the individual truly needs the drug, the risk of any of these entities, as we understand it now, is not likely to exceed the potential benefit. In January 2011, a ‘‘limitations of use’’ statement was added to the FDA-approved prescribing information for all bisphosphonates approved for the treatment of osteoporosis. The statement reads as follows: Journal of Clinical Densitometry: Assessment of Skeletal Health
Bonnick The safety and effectiveness of [insert bisphosphonate name] for the treatment of osteoporosis is based on clinical data of 3-yr duration. The optimal duration of use has not been determined. All patients on bisphosphonate treatment should have the need for continued therapy re-evaluated on a periodic basis.
This statement is both factually and philosophically correct. The trials submitted to the FDA for registration of bisphosphonates for the treatment of PMO were 3 yr in duration. There are trials of longer duration for some of the bisphosphonates, as noted here, but the FDA assessment of each drug was originally based on 3-yr trial data. Hence, although the clinician has data available from which efficacy and safety for a period longer than 3 yr could be evaluated, statements made by the FDA are overwhelmingly based on 3-yr data. It is also true that the ‘‘optimal’’ duration of use for any of these bisphosphonates is not known. In any case, all patients on any treatment for any chronic disease should have the need for continued therapy reevaluated on a periodic basis. That is not the easy answer to whether a patient should have a drug holiday or how long a patient should be treated, but it is the right answer. Given our current knowledge, there should not be a blanket recommendation for an automatic drug holiday or cessation of therapy in all patients treated with any of the bisphosphonates. Each patient, as the individual that he or she is, should have that need reevaluated on a periodic basis, keeping in mind the wishes of the patient and the ever-changing scope of our knowledge.
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