Nathalie Sarlet

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.

A double-blind, placebo-controlled, dose-finding trial of intermittent nasal salmon calcitonin for prevention of postmenopausal lumbar spine bone loss

PURPOSE Nasal administration of salmon calcitonin (SCT) has been suggested for preventing trabecular bone loss during the first years following the menopause, but no conclusive evidence has appeared about the minimal effective dose. Since nasal calcitonin is highly expensive, it makes sense to define this dose. PATIENTS AND METHODS We performed a double-blind, placebo-controlled, randomized, single-center study with a 3-arm parallel-group design. The subjects were 251 healthy women who had experienced natural menopause within the past 6 to 72 months and were not affected by any diseases or treatments that interfere with calcium metabolism. They were randomly allocated in groups of 6 to receive intranasal SCT 50 IU (n = 84), SCT 200 IU (n = 84), or placebo (n = 83). All treatments were given on 5 consecutive days per week. Statistical analysis was based on two populations: intention-to-treat (IT) and valid completers (VC). The main assessments performed were bone mineral density of the lumbar spine (LSBMD) and biochemical parameters reflecting bone turnover (serum alkaline phosphatase, urinary calcium/creatinine, and hydroxyproline/creatinine ratios). RESULTS Changes over the treatment period were comparable in the IT and VC populations. In the group receiving the placebo, LSBMD decreased from baseline to end point by a mean of 6.28% (95% confidence interval [CI] -7.69 to -4.89) in the IT population and 6.98% (95% CI -8.86 to -5.11) in the VC population (P = 0.0001, end LSBMD versus baseline LSBMD). LSBMD increased slightly with the 50-IU/d dose of SCT, by 0.82% (95% CI -0.26 to 1.89) in the IT population, and 0.51% (95% CI -0.69 to 1.72) in the VC (P = NS, versus baseline). Subjects who received SCT 200 IU/d experienced significant increases of 2.03% (95% CI 0.92 to 3.15) in the IT population and 2.26% (95% CI 1.01 to 3.51) in the VC (both P = 0.001). The difference between the evolution of the combined groups receiving nasal SCT and the group treated with the placebo was highly significant (P = 0.0001). No significant changes were recorded in biochemical parameters reflecting bone turnover. CONCLUSIONS SCT 50 IU/d administered nasally and intermittently appears to prevent lumbar bone loss in nonobese early postmenopausal women.

Minimal levels of serum estradiol prevent postmenopausal bone loss

SummaryBiochemical parameters reflecting bone resorption [urinary calcium/creatinine (Ca/Cr) and hydroxyproline/ creatinine (OH/Cr)] were related to serum estrogens [estrone (E1) and estradiol (E2)] in 262 healthy women including 158 patients receiving estrogen replacement therapy (ERT) for at least 6 months, 49 eugonadal women, and 55 untreated postmenopausal women. A significant (P<0.001) correlation exists between serum E2 and Ca/Cr: Ca/Cr (mg/dl)=-0.00044 E2 (pg/ml)+0.129 (n=262; r=-0.37), serum E2 and OH/Cr: (OH/Cr (mg/g)=-0.049 E2 (pg/ml)+18.76 (n=262; r=-0.36), serum E1 and Ca/Cr: Ca/Cr (mg/dl)=-0.0003 E1 (pg/ml)+0.127 (n=261; r=-0.28) but not between serum E1 and OH/Cr. Women with circulating levels of E2 between 60 and 90 pg/ml have a significant (P< 0.01) reduction of Ca/Cr and OH/Cr when compared with those with lower levels of E2. Higher values of E2 do not provide additional benefit. We conclude that in postmenopausal women receiving an estrogen replacement therapy (ERT), a significant reduction of bone resorption is achieved when circulating levels of estradiol reach a value (60 pg/ml) corresponding to the one measured, in eugonadal women, during the last days of the early follicular phase of the menstrual cycle. We suggest that oral or percutaneous ERT should induce a minimal value of 60 pg/ml to prevent postmenopausal bone loss.

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

Alphacalcidol in Prevention of Glucocorticoid-Induced Osteoporosis

Abstract. One of the major drawbacks of glucocorticoids long-term therapy is the occurrence of a severe osteoporosis characterized by fractures occurring at different sites, mainly at the level of trabecular bone. One of the major determinants of glucocorticoid-induced osteoporosis is a decrease in the intestinal absorption of calcium (Ca) leading to a secondary hyperparathyroidism. D-hormones have been shown to significantly improve Ca absorption in the gut and subsequently to decrease parathyroid hormone circulating levels, hence normalizing bone turnover. In a recent study evaluating 145 patients suffering from diseases requiring long-term treatment with high doses of corticosteroids, we have demonstrated a significant benefit of alphacalcidol (1 μg/day) over placebo in terms of changes in bone mineral density of the lumbar spine. These results are in accordance with studies showing better prevention of bone loss and vertebral fractures in cardiac transplant patients treated with alphacalcidol than those treated with etidronate. There is now a convergent body of evidence to suggest that alphacalcidol is a reasonable, safe, and effective option for the prevention of glucocorticoid-induced osteoporosis, provided that serum Ca is monitored on a regular basis.

Dual photon absorptiometry of lumbar spine in West European (Belgian) postmenopausal females: normal range and fracture threshold

SummaryBone mineral content (BMC) and bone mineral density (BMD) of lumbar spine have been measured in 695 healthy postmenopausal and 64 type I osteoporotic Belgian, Caucasian females. Bone loss is strongly correlated to time elapse from menopause (Tm) with a maximum rate of bone loss during the first five years of menopause. BMC (gHA)=41.6+0.662 ln Tm −0.481 (ln Tm)2 and BMD (gHA/cm2)=0.91+0.00711 in Tm −0.00846 (ln Tm)2 (in both cases p<0.001 and Tm expressed in months of menopause). After 20 years of menopause, 50 to 60% of normal women have vertebral BMC and BMD values below the 90th percentile of women with vertebral fractures and, thus, might be considered to have asymptomatic osteoporosis. We conclude that prevention of postmenopausal osteoporosis should be initiated as soon as possible after the onset of menopause and that bone density screening should be extended in elderly in order to detect and allow treatment of asymptomatic “densitometric” osteoporosis.

Is there any place for salmon calcitonin in prevention of postmenopausal bone loss

Introduction Postmenopausal bone loss and subsequent osteoporosis (OP) are consequences of a change in bone turnover leading to an imbalance between resorption and formation1. One of the most effective ways of preventing postmenopausal bone loss, or at least of slowing its rate, is to use estrogen replacement therapy (ERT), either alone or in combination with a progestogen2,3. However, the dose of estrogen required to produce a net gain of bone is much higher than that required to control other postmenopausal symptoms4, hence the risk of adverse effects is greater, which makes ERT unsuitable for many postmenopausal women. For a large subset of postmenopausal women there is thus an urgent need for an alternative to ERT in order to prevent excessive bone loss.

The treatment of severe postmenopausal osteoporosis : a review of current and emerging therapeutic options.

Several chemical entities have shown their ability to reduce axial and/or appendicular fractures in patients with osteoporosis. Since patients who have experienced a previous fracture are at high risk for subsequent vertebral or hip fracture, it is of prime importance to treat such patients with medications that have unequivocally demonstrated their ability to reduce fracture rates in patients with prevalent fractures. Results obtained with calcium and vitamin D, in this particular population, are not fully satisfactory and these medications are probably better used in conjunction with other therapeutic regimens. Bisphosphonates have shown their ability to reduce vertebral (alendronate, risedronate, ibandronate) and non-vertebral (alendronate, risedronate) fractures in patients with established osteoporosis. Raloxifene has also shown similar properties, notwithstanding its effect on non-vertebral fractures, which has only been derived from a post hoc analysis limited to patients with prevalent severe vertebral fractures at baseline. This compound also has interesting non-skeletal benefits, including effects on the breast and heart. Teriparatide, a bone-forming agent, promptly reduces the rate of vertebral and all non-vertebral fractures, without significant adverse effects. Strontium ranelate, the first agent shown to concomitantly decrease bone resorption and stimulate bone formation, has also shown its ability to reduce rates of vertebral and non-vertebral fractures in patients with established osteoporosis. It significantly reduces hip fractures in elderly individuals at high risk for such events. Its safety profile is also excellent.

Comprehensive Therapy in Osteoporosis Using a Single Drug: From ADFR to Strontium Ranelate

In vitro, strontium ranelate increases collagen and non-collagenic proteins 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 rat 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. In a phase II dose ranging trial Strontium ranelate (500 mg, 1000 mg, 2000 mg/day) or placebo were given to 353 postmenopausal women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving 2000 mg of strontium ranelate was + 7.3%, a significant increase in bone alkaline phosphatase, over a 6-month period and a significant decrease in N-telopeptide crosslinks throughout the 2-year period were seen. 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. 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 patient 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 by 16% in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture by 36% was also demonstrated in the patients at high risk of hip fracture (age > or =74 years and Femoral Neck T score < or = -2.4 according to NHANES normative value). All these results suggest that strontium ranelate is a new, effective and safe treatment of vertebral and non-vertebral osteoporosis, with a unique mode of action.

Calcitonin and Postmenopausal Bone Loss

In order to establish the role of calcitonin (CT) in postmenopausal bone loss, we studied CT metabolism in 25 pre- and postmenopausal women. Postmenopausal women presented a highly significant reduction of CT basal levels compared to premenopausal females (p less than 0.01). Also, production rates of CT in osteoporotics were significantly lower than in either young premenopausal (18-25 years old), older premenopausal (35-40 years old), or postmenopausal healthy subjects. In a study in rabbits, we found that injection of CT, along with equimolar amounts of anti-SCT antibodies extracted from serum of pagetic patients, did not inhibit the hypocalcemic response to the hormone, thus demonstrating that resistance to CT treatment cannot be accounted for by antibody production. In a subsequent clinical study in patients with Pagets disease of bone, we found that 200 IU/day of salmon CT (SCT), given by nasal spray, improved both clinically and biochemically the activity of the disease, as demonstrated by 37 +/- 4% decrease of serum alkaline phosphatase and 35 +/- 5% fall of urinary excretion of hydroxyproline after six months of therapy. The effectiveness of CT as nasal spray was further tested in healthy women at an early stage of menopause. A 12-month course of intranasal SCT counteracted early postmenopausal bone loss, presumably by inhibiting bone resorption. In conclusion, intranasal CT seems to be a very attractive alternative to be considered for the prevention of postmenopausal osteoporosis.