Rapid, divergent changes in spinal and forearm bone density following short-term intravenous treatment of paget's disease with pamidronate disodium

Abstract

Intravenous disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate (pamidronate disodium) was used to treat 39 patients (22 males and 17 females, age range 48–85 years) with symptomatic Paget's disease. Patients were stratified into three groups based on the biochemical severity of the disease as assessed by fasting urinary hydroxyproline excretion (Hyp_E, μmol/liter GF, glomerular filtrate): group I (n = 23), Hyp_E < 5.0, treated with 120 mg total dose over 2 or 4 days; group II (n = 6), 5.0 ≤ Hyp_E ≤ 10.0, 180 mg over 3 or 6 days; and group III (n = 10), Hyp_E > 10.0, 240 mg over 4 or 8 days. Bone mineral density (BMD) was measured before and 3 and 6 months following treatment in the spine (LI-4) using dual-energy x-ray absorptiometry and in the forearm at an ultradistal and a shaft site using single-photon absorptiometry. When groups I-III were combined, nonpagetic and pagetic lumbar spinal BMD had both risen significantly at 3 months compared with the pretreatment values (p < 0.001). In each group, lumbar spinal BMD in pagetic vertebrae rose markedly by 3 months, with no further significant change at 6 months. The percentage rises in the three groups were not different from each other at 3 or 6 months. Nonpagetic lumbar spinal BMD followed a similar and significant trend but with a significantly smaller rise than for pagetic bone. (For the combined groups, nonpagetic BMD rose 5.1 ± 1.1% SEM, above pretreatment at 6 months; pagetic BMD rose 17.8 ± 1.6%: significance of comparison = p < 0.0001). In contrast, forearm BMD in group III had fallen at 6 months by 8.3 ± 2.5% (p < 0.01) and 7.0 ± 1.2% (p < 0.001) in the ultradistal and shaft sites, respectively. There were no significant changes in forearm BMD in groups I and II. When groups I-III were combined, the maximum observed changes within each individual in ultradistal forearm BMD (seen posttreatment) were correlated inversely with maximum intraindividual changes (seen posttreatment) in intact parathyroid hormone (Spearman's Q = −0.53, p < 0.001). A group of 18 control subjects with untreated Paget's disease were studied for 3–6 months. No changes were seen in nonpagetic or pagetic lumbar spinal BMD or in forearm BMD. Three mechanisms are proposed to explain these findings: (1) in nonpagetic bone, persistence of bone formation following acute reduction in resorption, with a more marked effect in the axial than in the appendicular skeleton; (2) in pagetic bone, magnification of mechanism 1, caused by the presence of abnormally active osteoclasts, leading to a marked divergence between bone resorption and formation, and (3) in cancellous and cortical distal forearm bone, the onset of acute secondary hyperparathyroidism following treatment, leading to resorption. These findings have implications for treatment of Paget's disease using pamidronate or other bisphosphonates in patients with preexisting appendicular osteopenia, particularly if the treatment-induced appendicular deficit is sustained.