Current perspectives on bisphosphonate treatment in Paget’s disease of bone

Figures & data

Table 1 Summary of the studies comparing the efficacy of different bisphosphonates in treatment of active Paget’s disease of bone

References	Drugs	Duration	Study	Endpoint	Results
Miller et al^Citation32 1999	RIS 30 mg daily for 2 months (n=62) versus ETI 400 mg daily for 6 months (n=61)	12–18 months	Prospective, randomized, double-blind study	Normalized serum ALP at 12 months and 18 months	1) Serum ALP normalized at 12 months in 73% of RIS group and 15% in ETI group (P<0.001); 2) Median time to normalization: 91 days for RIS group, >360 days in ETI group (P<0.001); 3) At month 18, 53% of RIS group and 14% of ETI group remained in biochemical remission; 4) Reduction in pain posttreatment was statistically significant in RIS group, but not in ETI group
Siris et al^Citation33 1996	6 months of ALN 40 mg daily versus ETI 400 mg daily in 89 patients	6 months	Controlled study	Percentage change in serum ALP, changes in urinary DPD excretion, pain, functional impairment scores, and radiological osteolysis	1) The ALN-treated group had significantly greater reduction in both serum ALP (79% versus 44%) and urinary DPD (75% versus 51%) than the ETI-treated group (P<0.001) in both cases; 2) Normalization of serum ALP occurred more in ALN group than in ETI group (63.4% versus 17.0%; P<0.001)
Walsh et al^Citation35 2004	ALN 40 mg daily in 3-month blocks versus PAM 60 mg iv 3 monthly, continued until biochemical remission; At 1 year, nonresponders to PAM were crossed over to ALN treatment	2 years	Randomized, open-label trial	Biochemical remission as both ALP and urine DPD/creatinine ratios are normal; or a clear plateau effect was observed	1) At 1 year, biochemical remission occurs in 31/36 (86%) in ALN group and 21/36 (56%) in PAM group (P=0.017); 2) In previously untreated patients, remission was achieved in 20/22 (91%) in ALN group and 19/22 (86%) in PAM group (P>0.05); 3) In previously treated patients, remission was achieved in 11/14 (79%) ALN-treated subjects and 2/14 (14%) for PAM (P<0.001); 4) Of subjects crossed over to ALN, 10/14 (71%) achieved remission, including 9/11 (82%) previously treated patients
Merlotti et al^Citation36 2007	ZOL 4 mg iv (n=30) versus PAM 30 mg iv for 2 consecutive days every 3 months (n=60); After 6 months, nonresponders to PAM were crossed over to ZOL 4 mg iv once or NER 100 mg iv for 2 days	15 months	Randomized study; follow-up crossover study	Therapeutic response defined as normalization of ALP or a reduction of at least 75% in total ALP excess	1) At 6 months, 97% in ZOL group and 45% in PAM group had a therapeutic response; 2) At 6 months, normalization of ALP was achieved in 93% of ZOL group and 35% of PAM group; 3) ALP normalization was maintained in 79% and 65% of ZOL-treated patients after 12 and 15 months, respectively; loss of therapeutic response in two of 30 (6%) at 12 and 15 months; 4) At 6 months, PAM nonresponders crossed over to NER (n=15) or ZOL (n=18); therapeutic response was achieved in 14 of 15 (93%) in NER group and 17 of 18 (94%) in ZOL group. Similar normalization rates for NER- (80%) and ZOL-(83%) treated subjects. Normalization and clinical response were maintained at 9 month posttreatment in both groups
Reid et al^Citation37 2005	ZOL 5 mg iv once versus RIS 30 mg/day for 60 days	6 months	Randomized control trial	Therapeutic response defined as normalization of ALP or a reduction of at least 75% in total ALP excess	1) 96% (169 of 176) patients given ZOL versus 74.3% (127 of 171) given RIS (P<0.001) reached endpoint at 6 months; 2) ALP levels normalized in 88.6% ZOL-treated patients versus 57.9% for RIS (P<0.001); 3) Median time to endpoint (64 in ZOL group versus 89 days in RIS group, P<0.001); 4) Quality of life (SF 36 score) increased significantly from baseline at both 3 and 6 months in ZOL group and differed significantly from those in RIS group at 3 months
Hosking et al^Citation38 2007	ZOL 5 mg in 15-min iv infusion versus RIS 30 mg daily for 60 days (n=296)	Posttreatment 6–24 months without intervention	Follow-up study	Normalization or a >75% reduction in the total ALP excess above the midpoint of the reference range	1) At 6 months posttreatment, mean total ALP in ZOL-treated group maintained at the middle reference range, but increased in RIS group; 2) At 24 months posttreatment, serum total ALP in the RIS group increased compared with 6 months posttreatment, but remained unchanged in the ZOL-treated group
Reid et al^Citation39 2010	ZOL 5 mg iv once versus RIS 30 mg/day for 60 days	6.5 years without further intervention	Cohort follow-up	Times to relapse (serum total ALP level returns to within 20% of the pretreatment value); Loss of a response (response: normalization of ALP or ≥75% reduction in its excess)	1) Relapse rate is 0.7% (1/152) in ZOL group and 20% (23/115) in RIS group (P<0.001); 2) Loss of response rate is 12.5% (19/152) in ZOL group and 62% (71/115) in RIS group (P<0.0001); 3) Changes from baseline in quality of life, were more positive in ZOL group across the follow-up period (P=0.01)
Woitge et al^Citation40 2000	Ibandronate 2 mg iv bolus or infusion (n=20)	12 months	Prospective cohort study	Relapse defined as total ALP ≥25% increase above nadir	1) At 3 months, serum total ALP was normalized in 45% (9/20) patients; 2) At 12 months, relapse occurred in all patients

Abbreviations: ALN, alendronate; ALP, alkaline phosphatase; DPD, deoxypyridinoline; ETI, etidronate; iv, intravenously; NER, neridronate; PAM, pamidronate; RIS, risedronate; ZOL, zoledronic acid.

Table 2 The bisphosphonate regimes for Paget’s disease of bone, osteoporosis, and hypercalcemia in malignancy

Drug name	Regimen for Paget’s disease of bone	Regimen for osteoporosis	Regime for malignancy related hypercalcemia
Oral
Etidronate	400 mg/day ×3–6 months	400 mg/day ×2 weeks, followed by elemental calcium 500 mg/day ×10 weeks	n/a
Alendronate	40 mg/day ×6 months	10 mg/day	n/a
Risedronate	30 mg/day ×2 months	5 mg/day	n/a
Intravenous
Pamidronate	60 mg/day ×3 days	n/a	90 mg/3–4 weeks
Ibandronate	6 mg/day ×2 days	3 mg/3 months	n/a
Zoledronic acid	5 mg one dose	5 mg/year	4 mg/3–4 weeks

Abbreviation: n/a, not available.

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ReidIRMillerPLylesKComparison of a single infusion of zoledronic acid with risedronate for Paget’s diseaseN Engl J Med2005353989890816135834

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HoskingDLylesKBrownJPLong-term control of bone turnover in Paget’s disease with zoledronic acid and risedronateJ Bone Miner Res200722114214817032148

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