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1-Year Controlled Randomised Trial of Prevention of Early Postmenopausal Bone Loss by Intranasal Calcitonin

79 women who had been menopausal for less than 36 months and who had not received any form of treatment to prevent bone loss were randomly assigned to a 12-month regimen of calcium 500 mg/day or calcium 500 mg plus intranasal salmon calcitonin 50 IU/day for 5 days per week. After 12 months of treatment bone mineral density had decreased in the calcium-only group by a mean of 3.16 (SEM 0.6)% (p less than 0.01) but had increased in the calcium plus calcitonin group by 1.38 (0.8)% (NS). The difference in response between the two treatment groups was also highly significant (p less than 0.01), as was the difference between values for hydroxyprolinuria/creatininuria (p less than 0.01). Endogenous calcitonin levels rose significantly in the calcium group but remained unchanged in calcitonin-treated patients. Treatment by calcitonin and calcium was not followed by increased secretion of parathyroid hormone. The findings suggest that intranasal calcitonin can counteract early postmenopausal bone loss.

PREVENTION OF POSTMENOPAUSAL BONE LOSS BY TILUDRONATE

76 healthy women, who had been menopausal for less than 96 months and who had never received any form of treatment to prevent bone loss, were entered into a randomised double-blind study. For the first 6 months, half the patients received tiludronate 100 mg daily, while the others received placebo. During the second 6 months, all patients received placebo. Bone mineral density of the lumbar spine decreased significantly by 2.1% (SE 0.8%) in the placebo group and did not significantly change in the tiludronate group (+1.33 [0.8]%). The difference in response between the groups was significant, as were the differences between values for corrected urinary hydroxyproline and calcium. Treatment with tiludronate was not followed by increased secretion of parathyroid hormone. A 6 month course of oral tiludronate may counteract postmenopausal bone loss for at least a year by decreasing bone resorption.

Relationship between whole plasma calcitonin levels, calcitonin secretory capacity, and plasma levels of estrone in healthy women and postmenopausal osteoporotics.

The exact role of calcitonin (CT) in the pathogenesis of postmenopausal osteoporosis remains unknown. Whole plasma calcitonin (iCT) basal levels, metabolic clearance rate (MCR), and production rate (PR) of CT were measured in 9 premenopausal and 16 postmenopausal women, including 11 osteoporotics (OP). Basal iCT levels were statistically lower in postmenopausal women than in the premenopausal group (P less than 0.01) and strongly correlated (r = 0.72; P less than 0.001) with estrone circulating levels (E1). MCR were similar in all groups. PR were similar in eugonadal women between 22 (mean +/- SD = 30.9 +/- 9.9 micrograms/d) and 37 yr (mean +/- SD = 25.5 +/- 11.1 micrograms/d) premenopausal women. In healthy postmenopausal women PR were reduced, but not significantly (mean +/- SD = 19.5 +/- 6.95 micrograms/d), whereas osteoporotic patients presented a highly significant reduction of CT PR (mean +/- SD = 9.8 +/- 4 micrograms/d) (P less than 0.01). Because there is a strong relationship between E1 and PR (r = 0.64; P less than 0.001), CT secretory capacity appears to be modulated by estrogen circulating levels. This modulation leads to a menopause-related decrease in iCT. In osteoporotics, an independent impairment of CT production drastically lowers PR and basal iCT levels. CT might be one of the determining factors in the pathogenesis of postmenopausal osteoporosis.

Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl)thiomethylene bisphosphonate, in the treatment of Paget's disease of bone

Several Biophosphonates have been used as therapeutic agents for Pagets bone disease. (Chloro-4 phenyl)thiomethylene-bisphosphonate (CIPsMBP) has recently been shown to have significant antiosteoclastic activity while an affect of CIPsMBP on mineralization was only observed at high doses. We tested this drug for 6 months in 23 pagetic patients distributed in three groups. Gr 1 (n = 5) receiving 200 mg/day showed a decrease of serum alkaline phosphatase (SAP) to 42 +/- 4% (p less than 0.01) of initial value (100%) while hydroxyprolinuria/creatinuria ratio (OH/Cr) dropped to 69 +/- 8% of baseline. In 4 patients receiving 400 mg/day, SAP improved to 48 +/- 9% of initial value (p less than 0.01) and OH/Cr to 40 +/- 3% (p less than 0.01). In the last group (n = 14) receiving 200 mg/day for 3 months, and 400 mg/day thereafter up to the 6th month SAP decreased to 53 +/- 4% and OH/Cr to 62 +/- 6% of initial value (p less than 0.01). Clinical improvement was significant from the first month of treatment. No resistance (mean decrease of SAP lower than 30%) was recorded and no radiological or clinical evidence of mineralization defect appeared. The clinical and biological tolerance was excellent throughout the study.

Strontium ranelate: a new paradigm in the treatment of osteoporosis

In vitro, strontium ranelate increases collagen and non-collagenic protein synthesis by mature osteoblast-enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. The drug was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomised study. At the conclusion of the study, the percentage variation of lumbar bone mineral density (BMD) from baseline was significantly different in the group receiving strontium ranelate 1000 mg/day as compared with placebo (+5.53 versus -0.75%, respectively). Increase in total hip and neck BMD averages were 3.2 and 2.5%, respectively. The effect of strontium ranelate in postmenopausal women with established osteoporosis was assessed during a multinational, prospective, double-blind, randomised, placebo-controlled trial. Strontium ranelate (500, 1000, 2000 mg/day) or placebo were given to 353 Caucasian women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving strontium ranelate 2000 mg was 7.3% (p < 0.001). A significant increase in bone alkaline phophatase (p = 0.002) over a 6-month period and a significant decrease in N-telopeptide crosslinks (p = 0.004) throughout the 2-year period were seen in the group receiving 2000 mg of strontium ranelate. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralisation defects. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patients experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture was also demonstrated in the patients treated for ≥ 18 months.

Efficacy and safety of drugs for Paget's disease of bone.

Pagets disease of bone is characterized by an anarchic bone turnover starting with excessive resorption caused by structural and functional abnormalities involving osteoclasts. Calcitonin and bisphosphonates are now considered as the main therapeutic approaches for this disease. Daily parenteral administration of calcitonin to patients with Pagets disease of bone results in a significant fall in serum alkaline phosphatase and urinary hydroxyproline levels. This treatment has also been reported to be effective in relieving clinical symptoms of the disease, mainly bone pain. The drawbacks of injectable calcitonin have stimulated interest in alternative routes of delivery. Substantial evidence of calcitonin bioavailability and bioefficacy equivalent to those of parenteral administration is currently available for only two alternative routes: nasal spray and rectal suppository. Since many results have been published showing a dramatic effect of several bisphosphonates in Pagets disease of bone, nasal and rectal calcitonin are no longer considered as the treatments of choice in this condition. A major advantage of the use of bisphosphonates over calcitonin in Pagets disease is that biochemical and histologic suppression of disease activity may persist for many years after the cessation of treatment. Oral etidronate and intravenous pamidronate have been extensively used and have provided satisfactory benefits to the patient. Since the risk/benefit ratio of alendronate does not appear to be completely positive, it is likely that the future of treatment of Pagets disease of bone will be based on the oral formulation of the new bisphosphonates, including tiludronate, risedronate or dimethyl-pamidronate.

Influence of Specific Anti-Salmon Calcitonin Antibodies on Biological Effectiveness of Nasal Salmon Calcitonin in Paget's Disease of Bone

(1990). Influence of Specific Anti-Salmon Calcitonin Antibodies on Biological Effectiveness of Nasal Salmon Calcitonin in Pagets Disease of Bone. Scandinavian Journal of Rheumatology: Vol. 19, No. 1, pp. 83-86.

Naturocetic (glucosamine and chondroitin sulfate) compounds as structure-modifying drugs in the treatment of osteoarthritis.

Purpose of reviewSeveral entities have been investigated carefully for the symptomatic and structural management of osteoarthritis. This review reports recent findings suggesting that such compounds may delay the structural progression of osteoarthritis.Recent findingsThe most compelling evidence of

Fractures in osteoporosis: the challenge for the new millennium

Osteoporosis is the most common form of metabolic bone disease affecting the skeletal system as a whole. It is characterized by bone fragility due to low bone mass and modifications of the internal bone structure with alterations of its microarchitecture. Bone fragility results in an increase in susceptibility to fractures occurring after minor trauma, and is the clinical end point of this disease. During adulthood, bone tissue undergoes continuous remodeling, with a balance between formation by osteoblasts and resorption by osteoclasts. After the age of 30, resorption starts to outstrip formation and bone mineral density (BMD) begins to decline gradually. Osteoporosis occurs when the resorption phase of bone remodeling predominates, leading to bone loss. Fifty-five percent of people aged 50 years and over have a low bone mass, which puts them at high risk of having osteoporosis and related fractures. Among those suffering from osteoporosis, 80% are women and most of them are postmenopausal. Indeed, estrogen deficiency at the menopause increases osteoclast activity, so that the rate of bone resorption exceeds that of bone formation. Because of the accelerated bone loss, women can lose up to 20% of their bone mass during the 5–7 years that follow the menopause, making them more susceptible to fractures [1]. With the general aging of the world’s population, the prevalence and incidence of osteoporosis are increasing and the burden of its associated morbidity and mortality constitutes a major health concern in the world. The World Health Organization (WHO) estimates that over the next 25 years the population aged 65 years and over will increase by 88%, while the working population will concomitantly grow by only 45% [2]. The most striking changes during the next 50 years will be observed in the oldest age group (80 years and above), which is the one most affected by osteoporotic fractures [3]. By 2020, the very elderly will make up 20% of the population in Germany, 21% in France and Spain, and 22% in Italy and Greece. As the incidence of bone fracture rises with age, the increasing life expectancy will obviously have an impact on osteoporotic fractures. Women are the most affected, with a higher age-adjusted prevalence of osteoporosis than men (29.1% versus 12.1%; mean age 68.3 versus 67.5 years, respectively) [4]. Women are also more affected than men by all types of fracture, with the female-male ratio of the incidence of vertebral and non-vertebral fractures being 2:1 [5] and 2.5:1 [4,6], respectively. About 40% of women aged 50 years are predicted to sustain at least one fracture in the remainder of their lifetime, of whom 20% are expected to suffer from multiple fractures [7]. The earliest fractures reported in women are those affecting the wrist, with the peak incidence during the perimenopausal period. They are followed by vertebral fractures, while hip fractures occur in older people, aged 70 and over. Women are particularly prone to wrist fractures, with an age-adjusted female-male ratio of 4:1. While no increase in incidence with age has been documented in men [5], the incidence does increase markedly in women aged 45–65 years. According to some studies, it stabilizes after the age of 70 [4,5]; nevertheless, this pattern was not found in the European Prospective Osteoporosis Study (EPOS) [6], where the incidence rose progressively with age, including the oldest age. Forearm fractures almost always result from a fall on the outstretched arm and usually occur outdoors during icy weather [3]. Osteoporos Int (2005) 16: S1–S3 DOI 10.1007/s00198-004-1752-9

Current options for the management of postmenopausal osteoporosis.

Introduction: Osteoporosis is a well-recognized disease with severe consequences if left untreated. The prevention of osteoporosis-associated fractures should include fall prevention, calcium supplementation and life-style advice, as well as pharmacological therapy using agents with proven antifracture efficacy. Areas covered: This manuscript offers an evidence-based critical assessment of the currently available efficacy data on all new chemical entities that have been granted a marketing authorization for the management of primary osteoporosis in women. Expert opinion: The availability of new therapeutic agents makes clinical decision making in osteoporosis more complex. Therapeutic decisions should be based on a balance between the benefits and risks of treatment, which must be carefully considered in each particular case, both by the physician and the patient. Indeed, no single agent is appropriate for all patients. Therefore, treatment decisions should be made on a tailor-made basis, taking into account all measures of treatment effect and risk, before making informed judgments about the best individual treatment option.