Paget's disease of bone treated in five days with AHPrBP (APD) per Os

Amino-hydroxypropylidene bisphosphonic acid (AHPrBP, previously APD) is a potent inhibitor of bone resorption. Since it remains in bone for a long time, and since it was not found to impair bone mineralization, it could be administered at high dose over a short period of time. Therefore, 11 patients with symptomatic Paget's disease received AHPrBP orally at 1200 mg/day over 5 consecutive days. Controls were performed after 1 month in all patients, 6 months in 8 patients, and one year in 4 patients. Clinical improvement and biochemical remission was observed in all patients, except one with severe disease. Side effects were negligible. Disease activity at bone scintigram decreased over 6 months. Plasma alkaline phosphatase activity fell progressively and significantly from 210 +/- 26 U/l (means +/- SEM) to 103 +/- 10 U/l after 6 months (nl less than 120 U/l). Urinary excretion of hydroxyproline decreased immediately and became normal (nl less than 2.3 mumol/lGF) as a mean at day 5 (from 4.6 +/- 0.4 mumol/lGF to 2.1 +/- 0.3 mumol/lGF). Thereafter it remained within the normal range (2.0 +/- 0.2 mumol/l at day 180). Plasma calcium and phosphate concentrations fell transiently between day 4 and 15, whereas plasma PTH levels increased over this period of time. In conclusion, a short course of AHPrBP given per os at high dose induces a rapid decline in activity and remission of moderate Paget's disease, without significant side effects.     

Efficacious management with aminobisphosphonate (APD) in Paget's disease of bone

The effects of treatment with aminobisphosphonate (APD) have been studied in a large and well-defined group of patients with Paget's disease over a period of seven years. Particular attention is given to the pharmacology of the drug, to methods of assessment of efficacy, and to the quality and the long-term persistence of the treatment results. These studies are compared to previously reported studies on bisphosphonates (P-C-Ps). The data suggest that the efficacy of P-C-Ps in Paget's disease results from a physiologic adaptation of all cellular processes involved in bone metabolism to a primary inhibition of bone resorption. The prolonged persistence of remissions may indicate that this is associated with disappearance rather than suppression of pathogenic material. If the low specific toxicity of the new generations of P-C-Ps is confirmed, it will be possible to induce complete and prolonged remissions through short oral or parenteral treatment courses that are associated with minimal side effects. Early institution of treatment in selected patients may prevent the development of deformity, fracture, and pain.     

Intravenous aminopropylidene bisphosphonate (APD) in the treatment of Paget's bone disease

We studied the effect of the intravenous administration of the bisphosphonate APD in 9 patients with Paget's bone disease. The medication was given in a daily dose of 25 mg for 7 days in 0.9% saline infusion over 2 hours. At the end of treatment a significant fall of serum calcium and phosphate was observed. The urinary excretion of calcium decreased markedly and the serum levels of the mid-molecule PTH fragment increased from (mean +/- SE) 85 +/- 11 to 122 +/- 16 pg/ml (p less than 0.05). A marked and rapid decline in the hydroxyprolinuria was observed from 297 +/- 61 mg/24 h to 194 +/- 51 mg/24 h (p less than 0.01); meanwhile the serum alkaline phosphatase decreased from 102 +/- 22 to 84 +/- 21 KAU (p less than 0.05). The effect of ADP on suppression of hydroxyprolinuria varied markedly from +1 to -81% and was negatively related to the basal hydroxyprolinuria (r = -0.90; p less than 0.001). The duration of the bone turnover suppression was short. A relapse greater than 30% in hydroxyprolinuria was observed in 6 of 8 patients 2 to 3 months after APD withdrawal. The short-term intravenous administration of ADP is a useful means to rapidly suppress the activity of Paget's bone disease. However, further studies should determine the optimum dose, the length of treatment, and the need to associate oral therapy to induce a prolonged remission.     

Long-term measurement of skeletal and lean body mass in Paget's disease of bone treated with synthetic human calcitonin

Summary Total body calcium (an index of skeletal mass), ulnar bone density, and total body potassium (lean body mass) were followed for up to 5 years in 38 patients with Paget's disease during treatment with synthetic human calcitonin. Calcium was measured by neutron activation, ulnar density by X-ray photodensitometry, and potassium by counting its natural⁴⁰K radioactivity. There was a significant rise in total skeletal mass in a group of 8 patients in the 12 months following the start of therapy, but overall, total bone mass and ulnar density remained constant during treatment. Small mean losses of body potassium were observed (∼4%) after several years elapsed on treatment. Over an average period of 12 months after discontinuation of therapy in 21 patients there was no significant mean change in calcium or potassium. The means of the ratios of total body calcium divided by predicted normal calcium (over the whole period of measurement) were 1.08 (males) and 0.99 (females) and were not significantly different. Comparison of the ulnar densities of patients and normal subjects gave similar results. The average ratio of measured to predicted normal potassium was 1.13 (both males and females). Thus there was no indication of depletion in skeletal mass below normal either in the untreated disease or resulting from treatment.     

Long-term measurement of skeletal and lean body mass in Paget's disease of bone treated with synthetic human calcitonin

Total body calcium (an index of skeletal mass), ulnar bone density, and total body potassium (lean body mass) were followed for up to 5 years in 38 patients with Paget's disease during treatment with synthetic human calcitonin. Calcium was measured by neutron activation, ulnar density by X-ray photodensitometry, and potassium by counting its natural 40K radioactivity. There was a significant rise in total skeletal mass in a group of 8 patients in the 12 months following the start of therapy, but overall, total bone mass and ulnar density remained constant during treatment. Small mean losses of body potassium were observed (approximately 4%) after several years elapsed on treatment. Over an average period of 12 months after discontinuation of therapy in 21 patients there was no significant mean change in calcium or potassium. The means of the ratios of total body calcium divided by predicted normal calcium (over the whole period of measurement) were 1.08 (males) and 0.99 (females) and were not significantly different. Comparison of the ulnar densities of patients and normal subjects gave similar results. The average ratio of measured to predicted normal potassium was 1.13 (both males and females). Thus there was no indication of depletion in skeletal mass below normal either in the untreated disease or resulting from treatment.     

Hypercalcaemia in Paget's disease of bone.

Albright in 1944 described a syndrome of hypercalcaemia in patients immobilized following fractures through bones affected with Paget's disease. This paper reports a further two cases in which this syndrome was considered the cause of hypercalcaemia with fatal outcome. Both patients had parathyroid adenomata. The literature is reviewed, and it is argued that no firm evidence for the existence of this syndrome has ever been put forward. The finding of hypercalcaemia in Paget's disease of bone should prompt an exhaustive search for its cause.     

Treatment of Paget's disease of bone with mithramycin.

The hypothesis that Paget's disease of bone is a low grade neoplastic process led us to use the cytotoxic antibiotic mithramycin in its treatment. The dramatic effects observed on the serum calcium and alkaline phosphatase, and urinary hydroxyproline are compatible with the concept that mithramycin is primarily toxic to osteoclasts. Subjective and objective clinical effects establish this agent as useful in the treatment of Paget's disease despite its observed toxicity to other organ systems.     

Paget's disease of bone

Paget's disease of bone is defined as a process of increased bone remodeling; the primary event is increased resorption (osteoclastic activity) followed by subsequent reactive bone formation (osteoblastic activity). It is usually asymmetric and may be asymptomatic. The etiology is unknown, but recent evidence appears to support the theory that a virus is an important etiologic factor. It may present with a wide variation in the clinical and radiographic picture. The most frequent sites of involvement include the spine, femora, cranium, pelvis, and sternum. The most common complaints are pain, skeletal deformity, and change in skin temperature. Pathologic fractures may be the presenting manifestations or complications in a patient with known Paget's disease. They occur most frequently in the long weight-bearing bones of the lower extremities such as the femoral neck and subtrochanteric and tibial regions. The two major therapeutic agents available for treatment are calcitonins (porcine, salmon, or human) and diphosphonates. The aim of such therapy is to control the metabolic activity of the disease, to normalize the biochemical parameters, and to improve the symptoms. Fortunately, tumors are rare; early diagnosis may give rise to more effective palliation, if not a significant cure rate.     

Changes in serum HDL and LDL cholesterol in patients with Paget's bone disease treated with pamidronate

Amino bisphosphonates represent one of the most important advances in the management of Paget's and other metabolic bone diseases. Although their mechanism of action has not yet been completely clarified, they seem to inhibit the mevalonate pathway and so they could interfere with cholesterol synthesis. The present study aimed to evaluate cholesterol and lipoprotein serum levels in patients with Paget's bone disease treated with intravenous pamidronate. The study included 20 consecutive patients (mean age, 67.6 +/- 11.0 years) with Paget's bone disease for at least 1 year, who needed intravenous amino bisphosphonate treatment; 12 patients with inactive Paget's bone disease served as controls. The patients with active Paget's bone disease underwent three cycles (every 3 months) of treatment with 60 mg of intravenous pamidronate. Controls were given a saline infusion following the same administration schedule. In all subjects total alkaline phosphatase (total ALP), bone alkaline phosphatase (bone ALP), total cholesterol (TC), tryglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) were measured before infusions (pamidronate or saline) at baseline and at 3-month intervals up to 9 months. In the control group no significant changes were observed through the study period for any of the biochemical parameters. In the pamidronate-treated patients, both bone ALP and total ALP significantly fell at the end of the study. In patients with active treatment, at the end of the study period HDL-C significantly (P < 0.05) increased by 10.3%, whereas LDL-C significantly (P < 0.05) decreased by 5.5%. In these patients TC showed a negative trend without reaching statistical significance, whereas the HDL-C/LDL-C ratio rose 16.2% above the basal value and TC/HDL-C decreased by 12.5%. In conclusion, pamidronate given intravenously seems to be able to induce a prolonged shifting in circulating cholesterol from the LDL-C to the HDL-C from associated with a weak decrease in total cholesterol, thus producing a possible improvement in the atherosclerotic risk index.     

Prevalence of Paget's disease of bone in Italy.

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.     

The diagnosis of Paget's disease of bone.

Paget's disease of the bone is a common disorder and usually presents no diagnostic difficulty. However, atypical cases may cause problems in diagnosis, particularly in younger patients, and this paper describes some of the more unusual modes of presentation mainly related to the osteolytic phase and to accentuation of normal anatomical features. The role of various imaging techniques is discussed, emphasizing that recognition of the plain radiographic changes of Paget's disease remains the key to diagnosis in most cases.     

Treatment of Paget's disease with intermittent low-dose infusions of disodium pamidronate (APD)

Disodium pamidronate (APD) is a potent inhibitor of bone resorption, with less risk of defective mineralization than earlier bisphosphonates. We assessed the response to six spaced low-dose intravenous infusions of APD given at intervals of approximately 6 weeks followed by weekly infusions if bone turnover remained abnormal. Three groups of 10 patients were studied, each group receiving infusions of 15, 30, or 45 mg. Hydroxyproline excretion fell by 62% and alkaline phosphatase was reduced by 72%, with no difference between the dose levels. A total of 21 patients (70%) achieved normal levels of bone turnover, indicating that low-dose infusions of APD are a safe and effective treatment for Paget's disease.     

Short-term therapy with oral olpadronate in active Paget's disease of bone.

One of the aims of the treatment of Paget's disease with bisphosphonates should be the normalization of the activity of the disease with the shortest possible exposure to the drug. Olpadronate (OPD) is a new bisphosphonate characterized by the dimethylation of the amino group, its potency is near to alendronate, and more soluble in the digestive media than other aminobisphosphonates. We treated 46 patients (28 men and 18 women, mean age 70 years) with active Paget's disease with oral OPD, 200 mg/day for 12 +/- 2 days, except 2 patients who received 400 mg/day. Eight patients had never been treated before, and 38 had previously received antiosteolytic drugs. The period without treatment prior to OPD was (X +/- 1 SD) 14 +/- 12 months. Baseline bone alkaline phosphatase (BALP) (levels fell from (X +/- 1 SD) 54.0 +/- 62.7 IU/ml (range 22-396) to a lowest mean value of 16.2 +/- 6.4 IU/ml (range 8-45) (normal range 5-21 IU/ml). Forty patients normalized BALP values, in most of the cases within the first 3 months after OPD treatment. Two patients showed partial response (> 50% decrease from baseline), three patients presented poor response (< 50% decrease from baseline), and one patient did not respond at all. Two patients complained of gastric discomfort, and one patient had diarrhea, which disappeared after discontinuation of the drug. Follow-up was carried out on 36 patients; 22 patients are still in remission, with an average length of 9.0 +/- 2.6 months. Fourteen patients experienced relapse after 9 +/- 2 months remission. In conclusion, a 12-day treatment with 200 mg/day of OPD proved to be a very effective and well tolerated therapy of Paget's disease and induced biochemical remissions in the vast majority of patients, even in those with very active disease.