Bisphosphonate resistance in Paget's disease of bone

Abstract

Objective. To determine whether resistance to one bisphosphonate predicts resistance to another bisphosphonate.Methods. One hundred patients with Paget's disease were treated with intravenous (IV) pamidronate. The initial dose was 120 mg, followed by further doses of 240 mg, until either biochemical remission was achieved or a total dose of 1 gm was given. Biochemical remission was defined as an alkaline phosphatase level within the reference range. Patients whose disease failed to respond to pamidronate were then treated with alendronate for 6 months. Patients whose disease failed to respond to alendronate were given either tiludronate for 3 months, or clodronate for 6 months.Results. Sixteen of the 100 patients treated with pamidronate failed to achieve a biochemical response despite a cumulative dose of 1 gm. Of the 16 nonresponders, 1 died of an unrelated cause, and the remaining 15 patients were treated with alendronate. In 2 of these patients, the treatment was changed to another bisphosphonate because of gastrointestinal intolerance to alendronate. Of the remaining 13 patients, 9 (69%) achieved full biochemical remission. In 4 other patients, both pamidronate and alendronate therapy were unsuccessful (1 patient responded to tiludronate, tiludronate therapy was unsuccessful in 1, clodronate was unsuccessful in 1, and 1 patient elected to receive no further treatment). Of the 2 patients who could not receive alendronate because of gastrointestinal intolerance, 1 achieved normalization with tiludronate, and a repeat course of pamidronate was unsuccessful in the other. In total, 73% of patients in whom initial treatment with IV pamidronate was unsuccessful responded to a change in bisphosphonate treatment.Conclusion. Failure to achieve biochemical normalization is likely to be specific to the individual drug rather than indicative of bisphosphonate class resistance.Paget's disease is a disorder of bone resulting from accelerated bone turnover (1). The prevalence of Paget's disease varies geographically. In England and Wales, the prevalence was recently estimated to be 0.3% among men and women ages 55 years or older (2). Estimates from the 1970s of the prevalence of Paget's disease in Great Britain and western Europe are 5% and 2-4%, respectively (3).The most widely used treatments for Paget's disease are bisphosphonates. The bisphosphonates used as inhibitors of bone resorption are structural analogs of naturally occurring pyrophosphate-containing compounds. They all contain 2 phosphonate groups attached to a single carbon atom, forming a P-C-P structure. All bisphosphonates have the 2 phosphonate side chains that allow binding to the bone surface, but the side chains (R1 and R2) attached to the central carbon atom differ among bisphosphonates. The R1 side chain can help further with bone surface binding because of the presence of a hydroxyl group in this position. The R2 side chain is where the variations in potency of the different bisphosphonates occur. Bisphosphonates have been broadly divided into the fo...

Paget’s disease of bone: a review of epidemiology, pathophysiology and management

“…This may be defined as an increase in the nadir SAP with subsequent treatments, requirement of a higher dose to get an equivalent response, and shortening of the length of time the patient remains in remission after a new course [Papapoulos et al 2006]. These patients may respond well to an alternate bisphosphonate [Gutteridge et al 1999b;Joshua et al 2003;Rendina et al 2004;Papapoulos et al 2006].…”

Acquired Resistance to Bisphosphonates in Paget's Disease of Bone

“…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.…”

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]).…”