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

Aminobisphosphonates actually represent the most common treatment for Paget disease of bone (PDB). In a previous study we demonstrated that either zoledronic acid (4 mg) or neridronate (200 mg) given as a single intravenous infusion showed a similar short-term efficacy in achieving biochemical remission in up to 90% of patient nonresponders to pamidronate. In this study we compared the long-term (36 months) effects of a same neridronate dose (200 mg) given as an intravenous (100-mg infusion for 2 consecutive days) or intramuscular (25-mg injection weekly for 2 months) regimen in 56 patients with active PDB. All patients were advised to receive calcium plus vitamin D supplementation throughout the study period. At 6 months, 92.6% and 96.5% of patients receiving intravenous and intramuscular neridronate, respectively, achieved a therapeutic response [defined as normalization of alkaline phosphatase (ALP) levels or a reduction of at least 75% in total ALP excess]. The response to treatment was significantly correlated with baseline ALP and 25-hydroxyvitamin D [25(OH)D] levels at 6 months. The decrease in ALP levels was highest in patients with higher baseline total or bone-specific ALP levels and with higher 25(OH)D levels at 6 months. Response rates were maintained at 12 months but decreased progressively at 24 and 36 months without significant differences between the two neridronate regimens. Both regimens were well tolerated. The only relevant side effect was an acute-phase response occurring in 14% of the patients. In conclusion, these results indicate that a 200-mg intramuscular neridronate course has a similar efficacy as an intravenous infusion of the same dose for the treatment of PDB and might be of particular value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusions.

The effects of recombinant TSH on bone turnover markers and serum osteoprotegerin and RANKL levels.

OBJECTIVE: Recently it was found that thyrotropin (TSH) receptors are present both in osteoclast and osteoblast and that TSH can modulate bone remodeling independent of thyroid hormones. The aim of this study was, firstly, to evaluate the effects of acute administration of TSH on bone remodeling markers both in men and in women and, secondly, to evaluate if these effects are mediated by variations in serum osteoprotegerin (OPG) and receptor activator of nuclear factor-KB ligand (RANKL). DESIGN: We studied 30 thyroidectomized patients (10 premenopausal and 10 postmenopausal women, 10 men) affected by thyroid carcinoma on l-thyroxine therapy. Eighty age- and sex-matched subjects were used as controls. A blood sample was drawn from each patient at baseline and 3 and 5 days after recombinant human TSH (rhTSH) administration, in preparation for (131)I whole body scan, to assess serum bone markers and serum OPG and RANKL levels. MAIN OUTCOME: At baseline, postmenopausal women and men had significantly higher values of bone turnover markers and serum OPG compared to control subjects. In all thyroidectomized patients serum RANKL was lower than in controls. After rhTSH administration, serum N-terminal propeptide of type-I procollagen (PINP), a marker of bone formation, increased significantly in postmenopausal women, while serum RANKL significantly increased after 3 days in postmenopausal patients and men returning to baseline values at day 5. Serum OPG levels did not change significantly. CONCLUSIONS: The low serum TSH observed in thyroidectomized patients on l-thyroxine therapy is associated with an increase of bone turnover in postmenopausal women and men that is associated with an increase of OPG and a decrease of serum RANKL levels. The acute TSH administration results in an increase of PINP, an index of osteoblastic activity, associated with an increase of serum RANKL. The lack of this response in premenopausal women suggests an influence of estrogen status on bone reactivity to TSH.

The effects of zoledronic acid on serum lipids in multiple myeloma patients.

Nitrogen-containing bisphosphonates (N-BPs) inhibit osteoclast-mediated bone resorption and are widely used for tumor-associated osteolysis. The mechanism of action of these drugs has not been completely clarified, but it has been observed that N-BPs may inhibit squalene synthase or farnesyl pyrophosphate synthase. Zoledronic acid (ZA) represents a novel N-BP which also has antitumor activity. To explore the effects of ZA on serum lipids, we studied 26 patients with smoldering myeloma at diagnosis. Sixteen patients were treated with ZA (4 mg) at baseline and at months 1, 2, 4, and 6. The remaining 10 served as controls. In all subjects, total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and C-terminal telopeptide of type I collagen (CTX) were measured at baseline and after 1, 3, and 6 months. In treated patients, we observed a progressive and significant reduction of TC, with a maximum decrease of 13% at 6 months. Moreover LDL-C decreased by 21% at 6 months, while no significant difference was appreciated in HDL-C and TGs. Also, the indexes of cardiovascular risk improved after ZA administration: TC/HDL-C ratio progressively decreased by 17% and HDL-C/LDL-C ratio increased by 36%, showing an effect that appears to be cumulative. In conclusion, ZA given intravenously at high doses in patients with smoldering myeloma seems to be able to modify the lipid profile with an improvement of atherosclerotic risk index.

Comparison of different intravenous bisphosphonate regimens for Paget's disease of bone.

UNLABELLED: This randomized study compared different intravenous bisphosphonates in PDB. Zoledronate was superior with respect to pamidronate in achieving biochemical remission, with therapeutic response maintained in most patients at 15 mo. Single neridronate and zoledronate infusion showed a similar efficacy in up to 90% of patients nonresponders to pamidronate. INTRODUCTION: Intravenous bisphosphonates represent a common therapy for Paget's disease of bone (PDB). However, there have been few head to head randomized trials comparing intravenous bisphosphonates. MATERIALS AND METHODS: We performed a 15-mo, randomized study comparing different intravenous bisphosphonates in 90 subjects with active PDB. At baseline, patients were randomly assigned to receive pamidronate (30 mg, i.v., for 2 consecutive days every 3 mo; n = 60) or zoledronate (4 mg, i.v.; n = 30). After 6 mo, nonresponders to pamidronate were crossed over to zoledronate or neridronate (100 mg, i.v., for 2 consecutive days). The primary efficacy endpoint was therapeutic response at 6 mo, defined as normalization of alkaline phosphatase (ALP) or a reduction of at least 75% in total ALP excess. RESULTS: At 6 mo, 97% of patients receiving zoledronate had a therapeutic response compared with 45% of patients receiving pamidronate. Normalization of ALP was achieved in 93% of patients in the zoledronate group and in 35% of patients in the pamidronate group. ALP normalization was maintained in 79% and 65% of zoledronate-treated patients after 12 and 15 mo, respectively; loss of therapeutic response was observed in 2 of 30 (6%) at 12 and 15 mo. At 6 mo, 27 patients showing therapeutic response to pamidronate continued the treatment, whereas nonresponders were crossed-over to neridronate (n = 15) or zoledronate (n = 18). Among these subjects, 14 of 15 (93%) in the neridronate group and 17 of 18 (94%) in the zoledronate group achieved a therapeutic response. Similar normalization rates were observed between neridronate- (80%) and zoledronate- (83%) treated subjects. Normalization and therapeutic response were maintained at 9 mo from treatment (corresponding to 15 mo from the baseline visit) in either neridronate or zoledronate groups. CONCLUSIONS: Single neridronate and zoledronate infusion showed a similar efficacy in achieving biochemical remission in up to 90% of patients nonresponders to pamidronate. Therapeutic response to zoledronate seems to be maintained in most patients at 15 mo.

The effect of zoledronic acid on serum osteoprotegerin in early stage multiple myeloma.

We evaluated the effect of zoledronic acid (ZA) on serum levels of osteoprotegerin (OPG) and the ligand for receptor activator of nuclear factor kappaB (RANKL) in patients with smoldering myeloma. In treated subjects we found an increase of OPG accounting for an effect of ZA on osteoblast and/or bone marrow stromal cells together with the direct effect on osteoclasts.

Prevalence of Paget's disease of bone in Italy.

UNLABELLED: We examined the prevalence of PDB in Italy from radiological, scintigraphic, and biochemical surveys in two Italian towns. Prevalence rates varied from 0.7% to 2.4%, were higher in males than in females, and slightly differed between the two towns. Unlike previous studies in populations of British descent, no secular trend for a decreasing prevalence emerged. INTRODUCTION: Clinical, radiological, and necropsy data from different countries suggested pronounced geographical variations in the prevalence of Paget's disease of bone (PDB). Despite the impact of the disease on the population, there are limited data on the prevalence of PDB in Italy. MATERIALS AND METHODS: The objective of this study was to estimate the prevalence of PDB in the district of Siena (Central Italy) and Turin (Northern Italy) from radiological, biochemical, and scintigraphic surveys. We examined a sample of 1778 consecutive pelvic radiographs performed between 1999 and 2000 at the Hospital Radiology Unit in Siena and 6609 pelvic radiographs performed in 1986-1987, 1992-1993, and 1999-2002 from the Radiology Department of Molinette Hospital in Turin. In Siena, 7906 consecutive (99m)TC-MDP bone scans performed over a 4-year period (January 2000 to May 2004) were also screened for the presence of PDB, and the prevalence of elevated alkaline phosphatase (ALP) levels (>300 UI/liter) was estimated from 7449 computerized medical records over a 3-year period (January 2000 to February 2003). The finding of PDB on the pelvic radiograph and bone scan was based on standardized radiological criteria. RESULTS: At the end of the radiological surveys, 16/1778 pelvic PDB cases (8 males and 8 females) were observed in Siena and 41/6609 (27 males and 14 females) in Turin. The crude prevalence of the disease was 0.89% in Siena and 0.62% in Turin. Given that pelvic involvement is commonly described in 60-90% of PDB patients, the estimated overall prevalence of PDB ranged from 1.0% to 1.5% in Siena and from 0.7% to 1.0% in Turin. No decrease in the prevalence of PDB was evident after comparison of prevalence rates from different periods. Biochemical analyses showed 296/7449 subjects with elevated ALP levels and normal liver enzymes, 87 of whom had confirmed diagnosis of PDB. The estimated prevalence of biochemical PDB was 1.5%. The scintigraphic survey showed a PDB prevalence of 194/7906 (2.4%), which was significantly higher than the radiological and biochemical estimates. CONCLUSIONS: Our surveys suggest that PDB in Italy has an estimated prevalence of at least 1%, comparable with that observed in United States and other European countries, but lower than that described in Britain and New Zealand. No secular trend for a decreasing prevalence of PDB was observed.

Characteristics and familial aggregation of Paget's disease of bone in Italy.

UNLABELLED: This study examined the characteristics of 147 PDB cases from Italy. Our data showed a reduced clinical severity of PDB with respect to other populations and provided further support of the importance of environmental factors (rural area of residence and animal contact) in the pathogenesis of PDB. Familial aggregation was observed in 15% of cases. INTRODUCTION: The etiology of Paget's disease of bone (PDB) remains unknown. Current evidence suggests that interactions among genetic or exogenous factors seem to be necessary for disease expression. Major epidemiological studies were performed in the United Kingdom and in other populations of British descent. To date, there are no reliable data on PDB characteristics among the Italian population, and its frequency in different areas of the country remains unknown. MATERIALS AND METHODS: In an attempt to evaluate clinical characteristics, the proportion of familial cases and the influence of environmental features on the occurrence of the disease, we studied 147 consecutive PDB patients. For all subjects, a detailed medical history was obtained, and constitutional features were recorded. Characteristics of PDB patients were compared with those obtained from 323 consecutive non-Pagetic outpatient control subjects. RESULTS AND CONCLUSIONS: Of the 147 PDB patients, 22 (15%) had at least one other family member affected, 19 (13%) reported one family member with suspected features of PDB, and 106 (72%) were classified as sporadic PDB. Even though we observed a reduced clinical severity of PDB with respect to other populations (mean number of affected sites, 2.2 +/- 1.6), we did not find any evidence of a decreased severity of the disease over time. We also found an association of PDB with animal contact (odds ratio [OR], 2.22; p < 0.0005) and a significant prevalence of PDB in rural versus urban districts (OR, 2.42; p < 0.0005). Osteoarthritis (45%), fractures (14%), hearing loss (14%), and valvular calcifications (15%) were the most observed complications. Interestingly, the geographical distribution of PDB showed a concentration of cases in rural areas of Campania and Tuscany. These areas may indicate local clustering of PDB cases in Italy, similar to that observed in other countries.

Vitamin D status and bone turnover in women with acute hip fracture.

Hypovitaminosis D is common in elderly women. Few data are available on vitamin D status and bone turnover in women with acute hip fracture. The aims of this study were to determine whether elderly Italian women with an acute hip fracture also had low vitamin D levels and an increase of bone turnover compared with elderly women with osteoporosis but without fractures. Seventy-four women with acute osteoporotic hip fracture and 73 women with postmenopausal osteoporosis were studied. All women were self-sufficient and had adequate sunlight exposure. To exclude the effect of trauma on serum 25-hydroxycolecalciferol levels and bone markers (bone alkaline phosphatase and C-terminal telopeptides of Type I collagen as indices of bone formation and bone resorption), blood samples were drawn within 24 hours of the fracture. Current data indicated that in our patients the prevalence of hypovitaminosis D is common although to a lesser extent than in women who are housebound. Women with acute hip fractures had a higher prevalence of vitamin deficiency defined as serum 25-hydroxycolecalciferol lower than 12 ng/mL, compared with women with osteoporosis. Moreover, the presence of fracture did not influence the rate of bone formation, whereas the increase in bone resorption could be attributed to an older age of women with acute hip fracture because of similar values of parathyroid hormone levels in the two groups.