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

Abstract

Twenty-five years after the first paper on etidronate in Paget's disease, there are few published papers that address bisphosphonate resistance as a specific clinical phenomenon. We report our data from two studies. Study 1 is a retrospective study of 20 patients with moderate to severe disease who were treated with intravenous (iv) However the minimum duration of biochemical remission was significantly shorter after the second course-10.9 i 1.7 months (first) and 5.6 f 0.9 months (second) (p c 0.03; Friedman's ANOVA n = 17). A subgroup of 10 patients who were followed for three courses showed a significantly higher PAP nadir in the third 'course. Study 2 is a prospective study of 40 patients, 23 previously untreated (NILPREV) and 17 previously treated with iv pamidronate (PAMPREV) and in biochemical relapse, who were randomly allocated to either oral alendronate 40 mg daily in 3 month units, or iv pamidronate 60 mg every 3 months. Treatment was continued until PAP and fasting urinary deoxypyridinolindcreatinine @py/Cr) ratios (RR 5-27 pmoYmo1) were both in the reference range, or a dear plateau in each marker developed. At baseline, there were no significant differences in either marker between the two NILPREV groups and between the two PAMPREV groups. Using log-transformed data, in NILPREV the PAP reductions were significant and similar over the first 6 months. However, although each Dpy/Cr reduction was also significant, the difference in responses favored alendronate (p c 0.015). In PAMPREV both markers showed no significant response to pamidronate; comparison showed a significantly greater response to alendronate (PAP p < 0.02; Dpy/Cr p c 0.002). Using two-way ANOVA, the PAP responses to alendronate in NILPREV and PAMPREV were similar and thaw to pamidronate were different (p = 0.034). The percentage of patients with both markers in the RR at 6 months or earlier were identical in NILPREV patients: alendronate 87% and pamidronate 87%. However in PAMPREV they were different: alendronate 83% and pamidronate 0% (p = 0.003). These data indicate: 1) patients treated with the same aminobisphosphonates for two courses show similar nadir values of bone turnover markers but a shorter remission time after the second course. In a third course the nadirs are significantly higher; and 2) in the alendronabdpamidronate comparison, NILPREV and PAMPREV

Overcoming resistance to bisphosphonates through the administration of alfacalcidol: results of a 1-year, open follow-up study

“…In Paget's disease, by contrast, where therapy is aimed at achieving complete biochemical remission, resistance to bisphosphonates has been demonstrated by several researchers. The lack of a complete biochemical remission is regarded by some as the criterion for bisphosphonate resistance [10], whereas according to others [11], the latter is established by a lower than 50-per-cent decrease in serum alkaline phosphatase (AP) level. Notwithstanding the criteria, the prevalence of resistance varies with different bisphosphonates in the range between 83% (etidronate [10]) and 11% (zolendronate [12]).…”

Comparison of intravenous and intramuscular neridronate regimens for the treatment of paget disease of bone

“…As a counterpart, acquired resistance to the intravenous infusion of some amino-bisphosphonates such as pamidronate has been reported in different studies. (9,15,18,19) In one of these studies, we demonstrated that intravenous infusions with either zoledronate or neridronate are effective in achieving therapeutic response at 6 months in up to 90% of patient nonresponders to multiple courses of pamidronate. (15) Results from this study confirm and extend these observations and indicate that a single course with neridronate 200 mg is effective and normalizes bone turnover in up to 85% of patients with PDB within the first year of treatment and in up to 55% after the second year.…”

“…Subjects were evaluated at baseline and after 3,6,12,18,24,30 The primary efficacy endpoint was the rate of therapeutic response assessed at 6, 12, 24, and 36 months and defined as the normalization of ALP levels or a reduction of at least 75% in total ALP excess (the difference from the midpoint of the reference range). Secondary endpoints were the reduction of bone pain, time of nadir of ALP (defined as the number of days from the beginning of the treatment to the time when the lowest value was observed), time to a therapeutic response (defined as the number of days between the onset of treatment and the visit at which a response was observed), and the average percent decrease in ALP or the other bone turnover markers at each time point compared with baseline levels.…”

Medical Management of Paget's Disease of Bone: Indications for Treatment and Review of Current Therapies

“…Use of acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) is very helpful in ameliorating the self-limited flu-like symptoms. Finally, physicians should be aware that acquired or secondary resistance to both etidronate and pamidronate (16,23,24) have been described, with less robust decreases in bone turnover markers or reductions in the duration of biochemical remissions or both with repeated courses of therapy. It seems that switching to a different bisphosphonate is effective in restoring a better treatment response.…”

“…It seems that switching to a different bisphosphonate is effective in restoring a better treatment response. (24) It is unclear at this time whether acquired resistance occurs with the other approved agents.…”