Paget's disease: Acquired resistance to one aminobisphosphonate with retained response to another

Twenty-five years after the first paper on etidronate in Paget's disease, t here are few published papers that address bisphosphonate resistance as a s pecific clinical phenomenon. We report our data from two studies, Study 1 i s a retrospective study of 20 patients,vith moderate to severe disease who were treated with intravenous (iv) pamidronate (221 +/- 18 mg [SEM]; range 60-360 mg), and after biochemical remission and relapse were retreated with generally larger iv dosage (293 +/- 28 mg; range 180-600 mg), The nadir bo ne turnover values were similar: plasma alkaline phosphatase (pAP) in 20 pa tients was 243 +/- 40 IU/l (mean +/- SEM) after the first course, and 267 /- 44 IU/l after the second (reference range [RR] 35-135 IU/l). Likewise, f asting urinary hydroxyproline excretion (Hyp,) in 14 of the 20 patients was 4.5 +/- 1.1 mu mol/LGF and 4.1 +/- 0.9 mu mol/LGF, respectively (RR 0.40-1 .92 mu mol/LGF). However the minimum duration of biochemical remission was significantly shorter after the second course-10.9 +/- 1.7 months (first) a nd 5.6 +/- 0.9 months (second) (p < 0.03; Friedman's ANOVA n = 17). A subgr oup of 10 patients who were followed for three courses showed a significant ly higher pAP nadir in the third course. Study 2 is a prospective study of 40 patients, 23 previously untreated (NILPREV) and 17 previously treated wi th iv pamidronate (PAMPREV) and in biochemical relapse, who were randomly a llocated to either oral alendronate 40 mg daily in 3 month units, or iv pam idronate 60 mg every 3 months. Treatment was continued until PAP and fastin g urinary deoxypyridinoline/creatinine (Dpy/Cr) ratios (RR 5-27 mu mol/mol) were both in the reference range, or a clear plateau in each marker develo ped. At baseline, there were no significant differences in either marker be tween the two NILPREV groups and between the two PAMPREV groups. Using log- transformed data, in NILPREV the PAP reductions were significant and simila r over the first 6 months, However, although each Dpy/Cr reduction was also significant, the difference in responses favored alendronate (p < 0.015). In PAMPREV both markers showed no significant response to pamidronate; comp arison showed a significantly greater response to alendronate (pAP p < 0.02 ; Dpy/Cr p < 0.002). Using two-way ANOVA, the pAP responses to alendronate in NILPREV and PAMPREV were similar and those to pamidronate were different (p = 0.034). The percentage of patients with both markers in the RR at 6 m onths or earlier were identical in NILPREV patients: alendronate 87% and pa midronate 87%, However in PAMPREV they were different: alendronate 83% and pamidronate 0% (p = 0.003). These data indicate: 1) patients treated with t he same aminobisphosphonates for two courses show similar nadir values of b one turnover markers but a shorter remission time after the second course. In a third course the nadirs are significantly higher; and 2) in the alendr onate/pamidronate comparison, NILPREV and PAMPREV patients showed similar P AP responses to alendronate, but significantly different responses to pamid ronate. Thus, patients showing acquired partial resistance to one aminobisp hosphonate (usually after two or more previous courses) are still capable o f remission after exposure to another compound of the same class.