Acquired Resistance to Bisphosphonates in Paget's Disease of Bone (2006)

Bisphosphonates are the treatment of choice of patients with Paget's disease of bone. They suppress the abnormally increased rate of bone remodeling, and they induce clinical and biochemical remission in the majority of patients, associated with arrest of the radiological progression of the disease and normalization of bone histology.1, 2 Short treatment courses with bisphosphonates induce remissions that can last long after discontinuation of treatment, but recurrences occur frequently. Recurrences of the disease respond adequately to a new bisphosphonate course,3-5 but reduced responsiveness has also been reported.6-8 This impaired response to consecutive treatments is usually referred to as acquired resistance,9 and should be distinguished from intrinsic resistance to a particular bisphosphonate.10 Acquired resistance has been reported for etidronate and pamidronate, but there are limited data with more potent nitrogen-containing bisphosphonates (N-BPs). In this article, we review briefly the current evidence of acquired resistance to N-BPs and discuss possible mechanisms for its development. Before characterizing a patient unresponsive to bisphosphonate treatment, certain issues regarding the assessment of the response need to be considered. First, some patients may not respond to oral bisphosphonates but may show a prompt response to the same compound given intravenously.11 In this case, factors interfering with the already low intestinal absorption of the drug are most likely responsible for the apparent impaired response to oral treatment. Second, patients retreated with the same bisphosphonate during a recurrence of their disease may show a reduced fractional decrease in biochemical indices of bone remodeling compared with previous treatment, a response that may be considered compatible with development of resistance to therapy. However, it has been shown in studies with clodronate and pamidronate12, 13 that the actual level of biochemical indices of bone remodeling, rather than their fractional decrease after every treatment, should be compared with those obtained after the initial course of therapy. This is because of the fact that patients who are offered a new treatment course of bisphosphonate generally have a lower rate of bone turnover compared with the one at the start of the first treatment. Finally, in patients with Paget's disease and concurrent hyperparathyroidism, response is generally less complete and recurrences occur quicker than in similar patients without hyperparathyroidism. Therefore, for optimal responses of patients with Paget's disease and autonomous hyperparathyroidism to bisphosphonates, parathyroidectomy should be considered.14 Resistance to bisphosphonates in patients with Paget's disease can be defined in different ways. These include a progressive increase in nadir serum alkaline phosphatase (ALP) activity with every consecutive treatment; use of a higher dose of the same bisphosphonate to achieve the same response; shortening of the period of remission after a new course with the same bisphosphonate; and a difference in the slope of increase in serum ALP activity between consecutive treatments. These are depicted in Fig. 1. Serum ALP activity of a patient with Paget's disease followed for 7 years and treated three times with oral olpadronate 200 mg/day for 30 days (arrows). Solid horizontal line represents the upper limit of the reference range. Interrupted lines represent different ways of defining resistance. (A) Nadir value of serum ALP activity; (B) duration of remission; and (C) slope of increase in serum ALP activity after remission. As discussed above, in early studies with pamidronate, there was no evidence of resistance, assessed as nadir values of biochemical indices of bone remodeling, in a large cohort of patients with Paget's disease.2, 3 In a recent detailed analysis of data of patients with Paget's disease treated with pamidronate, we found a progressive reduction in responsiveness, assessed as the duration of remission to consecutive treatments with pamidronate (Fig. 2). This impaired response to consecutive treatments was related to the extent of skeletal involvement but not to the dose of pamidronate or to the biochemical activity of the disease (unpublished data). For example, only patients with three or more affected bones were likely to develop resistance to pamidronate. These observations are in agreement with an earlier report by Gutteridge et al.7 These authors treated 20 patients with Paget's disease (17 with polyostotic disease) with intravenous pamidronate (mean dose, 221 mg). All patients went into biochemical remission, and they were followed until biochemical relapse. They were treated again with intravenous pamidronate (mean dose, 293 mg). In line with previous studies, nadir serum ALP activity did not differ between the first and the second treatment course (median, 150 and 180 IU/liter, respectively). However, the duration of remission after the second pamidronate course was significantly shorter than that after the first course (10.9 versus 5.6 months, respectively), indicating relative resistance to the same bisphosphonate. Similarly, Trombetti et al.8 reported that 14% of 76 patients with Paget's disease developed resistance to consecutive treatments with intravenous pamidronate. All had extensive disease. Duration of remission (mean ± SE) in patients with Paget's disease who received three consecutive courses with pamidronate (white bars) or olpadronate (gray bars). Results were adjusted for bisphosphonate dose and pretreatment serum ALP activity. Test for trend: pamidronate (p = 0.22) and olpadronate (p = 0.80). There is, therefore, sufficient evidence to support development of acquired resistance to pamidronate in patients with extensive Paget's disease. These observations raise the following questions: first, is acquired resistance restricted to pamidronate or does it also occur with other N-BPs, and second, does impaired response to pamidronate represent a more general phenomenon of bisphosphonate pharmacology in Paget's disease or can it be resolved by treatment with another N-BP? Regarding the first question, there are limited data on acquired resistance to N-BPs other than pamidronate. In earlier studies with olpadronate, we showed that the induction and duration of biochemical remission did not differ between patients receiving this bisphosphonate for the first time or for a recurrence of their disease.4 In addition, we showed that induction of remission by olpadronate was independent of previous treatment with this bisphosphonate and was the same in bisphosphonate-naïve patients and in those treated for a recurrence of the disease.15 Finally, because, as mentioned above, resistance in some studies could not be detected by nadir serum ALP activity but could be detected by differences in duration of remission, we analyzed in this way patients who received three consecutive courses of olpadronate. As shown in Fig. 2, there was no difference in duration of remission among treatments contrasting the findings with pamidronate. Furthermore, responses were the same even when data of patients with extensive disease were analyzed separately. At present, there are no systematic analyses of data from patients treated with other N-BPs but the olpadronate results indicate that development of resistance to N-BPs is not a general phenomenon in Paget's disease and may be confined only to pamidronate. The second question, namely the response of patients resistant to pamidronate to another N-BP, has been addressed by Gutteridge et al.7 These investigators treated a small group of patients with Paget's disease who were bisphosphonate naïve with intravenous pamidronate or oral alendronate. Both groups responded adequately to bisphosphonate treatment and reached comparable levels of nadir serum ALP activity after 6 months. However, when they treated in the same way two groups of patients who had previously received pamidronate, during a recurrence of their disease, a different picture emerged. In patients who were given a new pamidronate course, there was hardly any change in serum ALP activity, whereas those who were given alendronate showed an adequate response. Within the experimental limitations of the study, these data strongly suggest that acquired resistance is specific to pamidronate and is not observed after treatment with another N-BP. Similar results were previously reported for patients resistant to etidronate who were shown to respond to other BPs.(16,17) A study by Joshua et al.18 can help in better understanding the responses of patients with Paget's disease to BPs. These authors treated 100 patients with intravenous pamidronate. This treatment induced biochemical remission, defined as normalization of serum ALP activity in 84, a result consistent with the known efficacy of pamidronate in Paget's disease. However, 16 patients failed to normalize serum ALP activity even after a total dose of 1 g pamidronate. In the past, these patients may have been classified as resistant to bisphosphonate therapy. Fifteen patients were further treated with oral alendronate, and in nine, serum ALP normalized. Of the remaining six patients, two discontinued treatment because of gastrointestinal intolerance to alendronate, whereas in four, alendronate treatment failed to induce biochemical remission. Three of these four patients were treated with non-N-BPs (clodronate and/or tiludronate), and one responded, leaving two patients from the whole group showing an inadequate response to treatment. Does this 2% represent the true occurrence of primary resistance to bisphosphonates? This cannot be confidently concluded from these observations in which unresponsiveness may not be only related to the bisphosphonates used but also to dosing and tolerability limitations. For example, previous studies have shown an adequate response to very high doses of pamidronate in patients thought to be resistant to treatment.19-21 Furthermore, alendronate cannot be given at doses >40 mg/day because of the limitations of its oral tolerability. Existing studies with oral risedronate do not help address this issue, which might be definitely resolved with the use of zoledronic acid, the most potent N-BP currently available. In a large randomized clinical trial of patients with Paget's disease, daily oral risedronate 30 mg/day for 2 months was compared to a single intravenous infusion of 5 mg zoledronic acid.22 Zoledronic acid treatment induced a significantly better response, leading to normalization of serum ALP activity in 89% of patients. Of interest was the fact that 31.2% of patients in the zoledronic acid cohort had previously received N-BP treatment (alendronate, pamidronate, or risedronate) and were treated for a recurrence of their disease. Unfortunately, in the publication, there was no separate mention of the response of this subgroup. However, judging from the overall effect, one may conclude that the majority, at least, responded adequately to zoledronic acid. The mechanism underlying the development of resistance to BPs in Paget's disease is currently unknown. Theoretically, for pagetic osteoclasts to become unresponsive to bisphosphonate treatment with time, either the intracellular uptake of bisphosphonate should be reduced or its interaction with its molecular target should be altered. There are no known mechanisms that can impair the uptake of the bisphosphonate by the osteoclasts with time. Moreover, studies with statins that target the same intracellular biochemical route upstream of farnesyl pyrophosphate synthase (FPPS), the molecular target of N-BPs, showed no evidence of development of resistance to their action.23, 24 It is more likely that resistance to the action of bisphosphonate in Paget's disease is caused by disease-related factors rather than decreased responsiveness of the molecular target. This is supported by the findings that the response to pamidronate could be impaired exclusively in patients with extensive Paget's disease. The question that arises is why the same pattern of response was not observed during treatment with olpadronate. It may be that pamidronate, because of its lower potency, should be given to patients with extensive bone disease at doses higher than those currently used. Reports of development of resistance to etidronate, which is a weak inhibitor of resorption, as well as successful treatment of patients characterized resistant to treatment, with very high doses of pamidronate, support this notion. However, this approach is not feasible because of safety and tolerability concerns with such doses. Alternatively, it was recently shown that a significant part of the antiresorptive activity of pamidronate is caused by its effect on intracellular targets other than FPPS,25 and it may be that altered interaction of pamidronate with these, currently unknown targets, contribute to the impaired response with time. This hypothesis needs, however, confirmation, and studies with other potent N-BPs may help to clarify the exact mechanism of diminished responsiveness. Within the limitations of existing studies, available data suggest that acquired resistance is specific for pamidronate and is limited to patients with extensive Paget's disease. This resistance does not seem to extend to other N-BPs, but the evidence is very weak at present. Furthermore, conclusions about acquired resistance to bisphosphonates cannot be extrapolated to patients with potential intrinsic impaired responsiveness to some bisphosphonates. With the availability of very potent bisphosphonates, such patients, if they exist, can now be studied in detail. Identification and characterization of such individuals can help to better understand the clinical pharmacology of bisphosphonates, which can be of significance not only for the management of Paget's disease but also for the numerous other bone diseases currently treated with bisphosphonates. Over the years, Paget's disease has been a great model of bone disease for the study of the pharmacology of BPs, and in the future, it may also offer clues about potential development of resistance to N-BPs.