M.N.C. Beneton

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure

Abstract Objective: To determine whether alfacalcidol—used in management of overt renal bone disease—may safely prevent renal bone disease when used earlier in course of renal failure. Design: Double blind, prospective, randomised, placebo controlled study. Setting: 17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. Subjects: 176 patients aged 18–81 with mild to moderate chronic renal failure (creatinine clearance 15–50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. Interventions: Alfacalcidol 0.25 μg (titrated according to serum calcium concentration) or placebo given for two years. Main outcome measures: Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. Results: 132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P<0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P<0.001). There was no difference in rate of progression of renal failure between the two groups. Conclusion: Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure. Key messages Key messages Treating such patients with alfacalcidol (up to 1 μg/day for two years) significantly improved their osteomalacia and hyperparathyroid disease Treatment had no apparent adverse effect on renal function Hypercalcaemic episodes were uncommon and readily responded to decreases in drug dose Alfacalcidol might be used more widely for patients with moderate renal failure not yet needing dialysis

Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis

Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half‐life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half‐life of greater than 10 years (n = 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1 year.

Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption

Abstract:  We studied bone biopsies from 26 patients with myelomatosis with apparently normal skeletal metabolism. Quantitative histomorphometric measurements suggested that skeletal disease was progressive despite normocalcaemia and normal urinary excretion rates of calcium and hydroxyproline. When biopsies were divided according to the involvement of marrow by plasma cells, bone resorption — as judged by the eroded surface — increased significantly the greater plasma cell burden. Osteoclasts were frequent with moderate tumour burdens, but there was no further increase in the number of osteoclasts when plasma cell infiltration increased by more than 50% of bone marrow. Contrary to expectation, the numbers of osteoblasts and bone formation rates were increased with bone biopsies with moderate tumour burden, but were markedly lower when plasma cell infiltration occupied more than 50% of bone marrow, due to a decreased functional capacity of osteoblasts. We conclude that skeletal bone disease in myeloma is commonly progressive despite apparently stable bone disease as judged by biochemical measurements. The major mechanism of bone loss in myelomatosis is increased osteoclastic resorption but decreased bone formation contributes to bone loss with heavy plasma cell burdens. Urinary excretion of calcium and hydroxyproline provide insensitive indices of bone resorption in myelomatosis.

Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer

We studied bone biopsies from 65 normocalcaemic women with breast cancer and predominantly osteolytic bone metastases in order to examine the pathophysiology of bone destruction in metastatic bone disease. Quantitative histomorphometric measurements were made at sites of tumour involvement, at sites adjacent to tumour tissue and at sites distant from tumour tissue. There were no significant differences in bone volume or in indices of bone resorption or formation between biopsies taken from sites distant from tumour and the controls. Bone resorption, as judged by eroded surface, increased progressively from bone distant from tumour to tumour-laden bone. The number of osteoclasts was significantly increased in bone immediately adjacent to tumour and within metastases. There was no decrease in the ratio of osteoclast to eroded surface in breast cancer compared to controls suggesting that increased resorption in breast cancer was mainly osteoclast mediated and locally activated by the tumour. Two thirds of the biopsies taken from tumour involved regions showed osteosclerosis with woven bone formation. The volume of the pre-existing lamellar trabecular bone was lower than normal in 75% of these biopsies, suggesting that bone resorption must have been increased before the onset of woven bone formation. Since all patients were receiving hormonal treatment or chemotherapy, it is likely that osteosclerosis at sites of previous resorption mainly resulted from the basic cancer treatment as a sign of response to treatment. Osteoclastic bone resorption was, however, not completely inhibited by the active cancer treatment.

Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study.

A 3‐year prospective, randomized, placebo‐controlled trial of oral clodronate 800 mg showed that the incidence of clinical fractures was decreased by 20% in 5596 elderly women unselected for osteoporosis. The effect occurred in the absence of systematic calcium and vitamin D supplementation and was observed across a wide range of BMDs.

INTRAVENOUS CLODRONATE IN THE TREATMENT AND RETREATMENT OF PAGET'S DISEASE OF BONE

The effects of short courses (5 days) of intravenous clodronate 300 mg daily were studied in 31 patients with active Pagets disease of bone. The diphosphonate induced a striking reduction in biochemical indices of disease activity, which was sustained for at least 6 months after withdrawal of treatment. Apparent resistance to further treatment in patients previously treated for Pagets disease was an artefact due to incomplete relapse before retreatment. There was no significant difference in the degree of suppression of alkaline phosphatase activity between patients given intravenous clodronate and 45 patients given clodronate 1.6 g daily by mouth for 6 months. Short-term intravenous clodronate provides a useful alternative strategy for the treatment of patients with Pagets disease.

Clodronate Reduces Vertebral Fracture Risk in Women With Postmenopausal or Secondary Osteoporosis: Results of a Double-Blind, Placebo-Controlled 3-Year Study

The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis. The incidence of vertebral fractures was significantly reduced by 46%. The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density, QUS, weight, and smoking.

Vertebral Fracture Assessment (VFA) With a Densitometer Predicts Future Fractures in Elderly Women Unselected for Osteoporosis

Low radiation dose imaging of the lateral spine acquired with a bone densitometer for vertebral fracture assessment (VFA) has great potential for clinical use. We have undertaken an evaluation of VFA in a prospective population cohort of elderly women to examine the prevalence of vertebral fractures, their ability to predict incident fractures, and their use in targeting therapy. Women (n = 5157) ≥75 yr of age living in the general community in the United Kingdom underwent posteroanterior and lateral imaging of the spine (T4–L4) with a densitometer (Hologic QDR4500A) at entry to a randomized, double‐blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 yr. The women were identified from general practice registers and recruited by letter of invitation regardless of skeletal status. The proportion of vertebrae interpretable varied from 98.2% at T12 to 57.1% at T4, with >92% interpretable at levels between T8 and L3. As judged by BMD at the total hip, 19.6% of the women had osteoporosis, and the prevalence of vertebral fracture was 14.5%. Women with one or more vertebral fractures had a relative risk (RR) for incident osteoporotic fractures of 2.01 (95% CI, 1.64–2.47). The RR for hip fractures was 2.29 (95% CI, 1.63–3.21). After adjustment for age, femoral neck BMD, weight, and treatment, the RR was 1.50 (95% CI, 1.21–1.86) for osteoporotic fractures, with similar results for hip fractures (RR, 1.41; 95% CI, 0.99–2.02). For women with two or more vertebral fractures, the adjusted RRs were 1.97 (95% CI, 1.24–2.72) and 1.86 (95% CI, 1.14–3.03) for osteoporotic and hip fractures, respectively. We conclude that VFA can frequently detect vertebral fractures in a population cohort of elderly women. These fractures, like radiographic fractures, predict future clinical fractures independent of age, weight, and BMD. Having multiple vertebral fractures was associated with greater risk of incident osteoporotic fractures and hip fractures.

Effects of Intravenous Etidronate Disodium on Skeletal and Calcium Metabolism

The induction of hypercalcemia in malignant disease is almost invariably associated with increased bone resorption. However, tumor-induced changes in bone formation and renal tubular resorption of calcium are also important factors that induce hypercalcemia in some patients. In addition, alterations in calcium fluxes to and from the extracellular fluid secondary to hypercalcemia are important in maintaining or aggravating the hypercalcemic effects of increased bone resorption. These factors significantly affect the responses to treatment of hypercalcemia with inhibitors of bone resorption. This study examined the relative importance of these factors and the effects of intravenous etidronate disodium (etidronate) in neoplastic bone disease with and without hypercalcemia and in Pagets disease of bone. It is concluded that intravenous etidronate is an effective inhibitor of bone resorption, which accounts in large measure for its effects on serum calcium concentrations. These studies of etidronate in hypercalcemia suggest the response is sustained for several weeks.

Alendronate in the treatment of Paget's disease of bone

We studied four treatment regimens of oral alendronate in 60 patients with active Pagets disease. Two groups received an oral daily dose of either 40 or 80 mg of alendronate for 3 months, followed by placebo for a further 3 months: the other two groups received treatment with 40 or 80 mg per day for 6 months. Activity of alkaline phosphatase and urinary hydroxyproline excretion were measured before, during, and after treatment, at intervals for a total follow-up of 1 year. A transiliac bone biopsy was performed in 24 patients before and after the treatment. An additional 16 patients had a third biopsy more than a year after stopping treatment. Alendronate induced a marked suppression in the urinary excretion of hydroxyproline within 2 weeks (p < 0.01) followed by a fall in serum activity of alkaline phosphatase at 1 month (p < 0.01) in all treatment groups. Nine months after the start of treatment patients treated with 80 mg for 6 months had a significantly lower mean alkaline phosphatase activity compared to the other treatment groups (p < 0.02), which persisted at 1 year (p < 0.05). Alkaline phosphatase decreased to within the laboratory reference range in all patients given 80 mg for 6 months. In contrast, alkaline phosphatase decreased to within the laboratory reference range in 73-83% of patients given 80 mg for 3 months and the 40 mg dose. Histomorphometric assessment showed a decrease in indices of bone turnover in the pagetic biopsies. None of the biopsies taken after treatment showed evidence of impaired mineralization of bone. Gastrointestinal side effects occurred in 25% of patients of whom two withdrew from treatment. We conclude that oral alendronate is an effective agent for the treatment of Pagets disease of bone.