Optimisation of vitamin D status in global populations.

Vitamin D is important for musculoskeletal health. Concentrations of 25-hydroxyvitamin D, the most commonly measured metabolite, vary markedly around the world and are influenced by many factors including sun exposure, skin pigmentation, covering, season and supplement use. Whilst overt vitamin D deficiency with biochemical consequences presents an increased risk of severe sequelae such as rickets, osteomalacia or cardiomyopathy and usually warrants prompt replacement treatment, the role of vitamin D supplementation in the population presents a different set of considerations. Here the issue is to keep, on average, the population at a level whereby the risk of adverse health outcomes in the population is minimised. This position paper, which complements recently published work from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, addresses key considerations regarding vitamin D assessment and intervention from the population perspective. This position paper, on behalf of the International Osteoporosis Foundation Vitamin D Working Group, summarises the burden and possible amelioration of vitamin D deficiency in global populations. It addresses key issues including screening, supplementation and food fortification.

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

Taxonomy of rare genetic metabolic bone disorders.

UNLABELLED: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. INTRODUCTION: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. METHODS: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. RESULTS: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. CONCLUSIONS: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Treatment failure in osteoporosis.

UNLABELLED: Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided. INTRODUCTION: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture. METHODS: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making. RESULTS: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease. CONCLUSION: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.

A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis.

UNLABELLED: This paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18 years and over in whom oral glucocorticoid therapy is considered for 3 months or longer. INTRODUCTION: The need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010. METHODS AND RESULTS: The epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review. CONCLUSIONS: Guidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country.

Improved cardiac performance with human calcitonin gene related peptide in patients with congestive heart failure.

STUDY OBJECTIVE: The aim of the study was to assess the cardiovascular effects of human calcitonin gene related peptide (CGRP) in patients with congestive heart failure. DESIGN: The effects of CGRP II (or beta), 12.5 micrograms.h-1, given by intravenous infusion for 24 h to digitalised patients with congestive heart failure, were assessed by measurement of cardiac functional indices. PATIENTS: Five patients (four female) were studied. Age was 73-82 years. Three were in New York Heart Association phase III and two in phase IV. MEASUREMENTS AND MAIN RESULTS: The pre-ejection period to left ventricular ejection time ratio and the QT distance adjusted for heart rate were lowered by 21% and 4% respectively. The left ventricular shortening index was raised by 43%. The arterial pressure and heart rate did not change consistently. CONCLUSION: Calcitonin gene related peptide improves myocardial contractility in patients with congestive heart failure. This is the first time this has been shown.

Estrogen preserves a normal intestinal responsiveness to 1,25-dihydroxyvitamin D3 in oophorectomized women.

Estrogen treatment improves calcium malabsorption induced by surgical or natural menopause, but the mechanisms involved are still under debate, with both increased production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and improved peripheral responsiveness to the steroid having been proposed. To address this issue, we studied the effect of short term administration of 1,25-(OH)2D3 (1 microgram/day for 7 days) on intestinal fractional absorption of 47Ca (47Ca FA) and vertebral bone density, measured by dual photon absorptiometry, in 14 premenopausal women (aged 31-50 yr) before and 6 months after oophorectomy. After surgery, patients were randomly allocated to a 6-month treatment with either conjugated estrogens (0.625 mg/day; n = 7) or placebo (n = 7). Oophorectomy caused a decrease in both basal 47Ca FA (-40.8 +/- 23.4%; P = 0.004) and vertebral bone density (-7.21 +/- 1.20%; P less than 0.001) in the placebo group. Estrogen replacement prevented these changes and increased basal serum 1,25-(OH)2D3 (+10.3 +/- 10.9%; P = 0.047), whereas a detectable but not significant decrease was observed in the control group (-8.8 +/- 10.5%; P = 0.07). Assessment of 47Ca FA before and after 1,25-(OH)2D3 administration revealed a similar degree of responsiveness to the steroid in the estrogen-treated women before and at the end of the study period (45.8 +/- 6.9% vs. 42.9% +/- 14.9% from basal, respectively; P = 0.142), but a blunted response to 1,25-(OH)2D3 was observed in the placebo group at 6 months (27.9 +/- 17.7%) compared to the result obtained before surgery (36.7 +/- 9.1%; P = 0.032). Multifactor analysis of variance revealed that the effects of estrogen and 1,25-(OH)2D3 on 47Ca FA were independent of basal serum 1,25-(OH)2D3 levels. On the other hand, calcitriol administration increased serum 1,25-(OH)2D3 to a similar extent before and 6 months after surgery in the placebo group (24.2 +/- 18.3% vs. 34.7 +/- 16.7% from basal, respectively; P = 0.484) as well as in the estrogen-treated women (34.2 +/- 17.2% vs. 26.6 +/- 15.45%; P = 0.302). The significant impairment of 1,25-(OH)2D3 stimulation of 47Ca FA in spite of increased levels of circulating 1,25-(OH)2D3 in the untreated women is suggestive of an end-organ resistance to the vitamin D metabolite in a hypoestrogenic condition, which can be prevented by hormone replacement, and supports the hypothesis of a vitamin D-independent action of estrogen on intestinal calcium absorption.

Dose-response bioactivity and bioavailability of salmon calcitonin in premenopausal and postmenopausal women.

We investigated the acute, dose-response to three intranasal doses of salmon calcitonin (sCT) (50 IU, 100 IU, and 200 IU) and one im dose (50 IU) in eight premenopausal and eight early postmenopausal women. Total serum calcium and serum beta-endorphin revealed significant changes after all four administrations (P less than 0.05). After the two highest intranasal and the im doses cAMP increased 10% and 35%, respectively (P less than 0.05). All administrations except the 50 IU intranasal dose produced significant increases in plasma sCT (P less than 0.05). The areas under the concentration-time curves, calculated for the period with the maximal changes (i.e. 120-240 min), illustrated a significant dose-related response in total serum calcium, beta-endorphin, and sCT (P less than 0.01-0.001). cAMP showed a dose-related tendency, the response to the im injection being significantly higher than that to the two lowest doses of intranasal sCT (P less than 0.05). We conclude that the doses administered produce a dose-related biological response and bioavailability. In women with normal and high bone turnover, sCT 100 IU intranasally seems as optimal as 50 IU im. The response to sCT should, furthermore, be assessed on bioactivity rather than on bioavailability.

Androgens and osteocalcin during the menstrual cycle.

The relationship between physiological variations in female sex and androgenic hormones and calciotropic hormones was investigated during the menstrual cycle. Estradiol, progesterone, total and free testosterone, androstenedione, immunoreactive PTH, calcitonin, osteocalcin (OC), and ionized calcium serum levels were determined throughout the menstrual cycle in a population of healthy eumenorrhoic women (n = 12; age range: 20-29 yr; mean: 24.2 yr). The women were studied from the first day of a menstrual phase until the first day of the following menstrual phase. Cycle length was standardized on the preovulatory estradiol peak (day 0), and values were given for the first day of a menstrual phase, and days -12, -10, -8, -6, -4, -2, 0, 2, 4, 6, 8, 10, 12, and 14 of the menstrual cycle. All subjects had a regular ovulatory cycle, as indicated by the hormonal profile. No significant cycle phase-dependent changes in calciotropic hormones were present. Significant positive correlations between total testosterone (r = 0.32, P < 0.001), free testosterone (r = 0.26, P < 0.001), androstenedione (r = 0.35, P < 0.0001), and OC were observed. The significant relations between these variables were confirmed by a time series analysis. For the first time, these findings indicate a relationship between androgens and OC serum levels during the menstrual cycle. An important regulatory role of endogenous androgens in OC secretion, bone formation, and maintenance of normal bone mineral content in the healthy eumenorrhoic woman is hence suggested.

Selective estrogen receptor modulators (SERMs): effects on multiple organ systems.

SERMs represent a structurally diverse group of compounds which interact with the estrogen receptor but which elicit agonist or antagonist activity depending on the organ system and physiological context. Evaluation of the actions of these compounds has led researchers to a fuller understanding not only of the antiestrogens but also of steroid signaling in general. Based on their evolving clinical profiles, SERMs have the potential to address long-term health maintenance needs of women in their non-reproductive years.

Trends in the incidence of hip fracture in Siena, Italy, from 1980 to 1991.

There is general agreement that the crude incidence of proximal femur (hip) fractures is rising in conjunction with the ageing of the underlying population. To explore possible changes in hip fracture incidence over time we analysed all femoral fractures occurring in the county of Siena from 1980 to 1991. Data were collected from hospital record charts of the Department of Orthopaedics, recording all hip fractures occurring during the 12-year period. In this period, the mean resident population in Siena was 238,369 inhabitants (aged 0 to 90+ years) and the crude number of all femoral fractures was 2,238. However, in calculating incidence rates, only hip fractures occurring in the population aged over 50 years were considered. In this population, the number of hip fractures was 1,825 with a male/female ratio of 1:2.8. A time-series data analysis (temporal trend) of the incidence of hip fracture during the 12-year period revealed a linear and significant (p < 0.001) trend to increase, but only in males, with an annual increasing rate of 3.62 per 100,000 person-years. In the female population, the temporal analysis did not show any significant trend during the observation period.

Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk.

In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis, defined by low bone mineral density and/or prevalent vertebral fractures (VF), were randomized to placebo or raloxifene (60 or 120 mg/day). All women received daily calcium (500 mg) and vitamin D (400-600 IU) supplements. Our previous analyses found that changes in BMD and biochemical markers of bone turnover are poorly predictive of the reduction in VF risk observed with raloxifene. This present study evaluated the effects of raloxifene on type I procollagen N-terminal propeptide (PINP), a new marker of bone turnover. Logistic regression analysis models evaluated the relationships between the changes at 1 year in PINP, serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urinary excretion of type I collagen C-telopeptide fragments normalized to creatinine (CTx/Cr), and the risk of new VF at 3 years for placebo and pooled raloxifene. A subset of 967 women (mean age = 68 years) from the MORE cohort had PINP, OC, BSAP, and CTx evaluated at baseline. Both doses of raloxifene significantly decreased (P < 0.001) all biochemical markers of bone turnover from baseline. Compared to baseline, PINP levels were decreased by medians of 11.0% and 40.8% in the placebo and pooled raloxifene groups, respectively. In addition, the placebo and pooled raloxifene groups decreased serum OC by 8.5% and 31.8%, BSAP by 15.8% and 34.6%, and urinary CTx/Cr excretion by 5.6% and 46.5%, respectively, from baseline. In the pooled raloxifene group, the logistic regression relationship between 3-year VF risk and 1-year percentage change for each biochemical marker was statistically significant with PINP (slope estimate = 0.0085, P = 0.009), OC (slope estimate = 0.0068, P = 0.035), and BSAP (slope estimate = 0.0056, P = 0.039), but not with CTx/Cr (slope estimate = 0.0027, P = 0.192). Furthermore, the percent decrease in PINP at 1 year could account for 28% of the total reduction in vertebral fracture risk. In conclusion, a 1-year decrease in PINP, BSAP, or OC, but not CTx/Cr, may be predictive of the 3-year VF risk reduction with raloxifene therapy in this subset of postmenopausal women with osteoporosis.

The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro.

Raloxifene is a selective estrogen receptor modulator (SERM) that prevents bone loss. Although it is largely used for the treatment of osteoporosis, the mechanisms by which this compound modulates the activity of bone cells are still poorly understood. In this study we investigate whether raloxifene affects osteoclast and osteoblast activity in vitro. Bone marrow cultures were established from neonatal mice and treated with 1,25(OH)(2) vitamin D(3) (VitD(3), 10(-8) mol/L) to induce osteoclast generation. Similar to 17beta-estradiol, raloxifene significantly reduced the number of osteoclasts in a concentration-dependent manner, with maximal inhibition at 10(-11) mol/L (-48%). However, as for 17beta-estradiol, at a high concentration (10(-7) mol/L), the inhibitory effect of raloxifene was abolished. In a pit assay, raloxifene inhibited bone resorption. A maximal effect was observed at 10(-9) mol/L, and maintained at a high concentration, indicating that inhibition of osteoclast formation and inhibition of bone resorption may be due to activation of, at least in part, different pathways. Osteoblasts from neonatal mice calvariae were also exposed to raloxifene. In these cells, this compound induced a concentration-dependent increase of proliferation, which was blocked by the estrogen-receptor antagonist ICI 164,384. Raloxifene also increased the osteoblast-specific transcription factor Cbfa1/Runx2 and alpha2 procollagen type I chain mRNAs, with a pattern that only partially coincided with that of 17beta-estradiol. Consistent with decreased osteoclastogenesis, raloxifene inhibited the mRNA expression of interleukin (IL)-1beta and IL-6 at a low concentration, but not at a high concentration, whereas 17beta-estradiol had similar effects on IL-6 and inhibited IL-1beta at both concentrations. Furthermore, both compounds were able to inhibit tumor necrosis factor (TNF)-alpha-induced IL-1beta, but not IL-6, increase. In conclusion, these data show that raloxifene negatively modulates osteoclasts, and positively affects osteoblasts, suggesting not only an antiresorptive role, but also an osteoblast stimulatory role.

Biological activity of different calcitonins in men.

Calcitonin has been isolated and its structure defined from several species, including man. Synthetic preparations of several calcitonins are available for clinical use. Of these, porcine (pCT), human (hCT), and salmon (sCT) have been synthetized according to their natural sequences, while eel calcitonin (cCT) is available as amino-suberic acid derivative (ASU-eCT). The different molecular configuration results in different biological potency and tolerability. Currently, the potency of calcitonin in man is evaluated by its capacity of lowering serum calcium and stimulating cAMP plasma levels after acute infusion. In normal subjects, cAMP stimulation seems to be a more sensitive test, since plasma calcium in normal subjects is poorly affected by an acute treatment with calcitonin. On the other hand, the side effects are usually assessed by clinical observation, on the basis of duration and intensity of the symptoms. Our experience, emerging from several studies devoted to comparing the biological activity and tolerability of different calcitonin preparations in humans, indicates that the hypocalcemic effect and the increase of plasma cAMP are produced by all peptides, according to the potency order sCT greater than hCT greater than ASU-eCT. For all peptides, the most constant side effect is flushing, and the frequency order of side effects is hCT greater than sCT = ASU-eCT.

Effect of ipriflavone--a synthetic derivative of natural isoflavones--on bone mass loss in the early years after menopause.

OBJECTIVE: We studied whether oral administration of ipriflavone, a synthetic derivative of naturally occurring isoflavones, could prevent bone loss occurring shortly after menopause. DESIGN: Fifty-six women with low vertebral bone density and with postmenopausal age less than five years were randomly allocated to receive either ipriflavone, 200 mg three times daily, or placebo. All subjects also received 1,000 mg elemental calcium daily. RESULTS: Vertebral bone density declined after two years in women taking only calcium (4.9 +/- 1.1%, SEM, p = 0.001), but it did not change in those receiving ipriflavone (-0.4 +/- 1.1%, n.s.). A significant (p = 0.010) between-treatment difference was evidenced at both year 1 and year 2. At the end of the study, urine hydroxyproline/creatinine excretion was higher in the control group than in the ipriflavone group, as compared to no difference at baseline. Five patients taking ipriflavone and five taking placebo experienced gastrointestinal discomfort or other adverse reactions, but only one and four subjects, respectively, had to discontinue the study. CONCLUSIONS: Ipriflavone prevents the rapid bone loss following early menopause. This effect is associated with a reduction of bone turnover rate.

Acute cardiovascular and renal effects of human calcitonin gene-related peptide.

Acute cardiovascular and renal effects of 25 micrograms IV human calcitonin gene-related peptide (hCGRP) have been studied in four normotensive and untreated subjects, in the absence and the presence of indomethacin, a prostaglandin synthesis-blocking agent. Intravenous infusion of hCGRP, alone, caused a transient but significant increase in heart rate (HR), hypotension, and facial flushing. Along with these effects, a positive inotropic action of hCGRP was documented by a noninvasive poligraphy. Furthermore, a significant increase in the catecholamines (norepinephrine and epinephrine), in the cyclic nucleotide (cyclic AMP and cyclic GMP) plasma levels, and a small decrease in total calcium with no change in inorganic phosphorus serum levels, occurred. Also acute renal hCGRP induced effects were observed, as a significant increase in urinary volume and in the urinary calcium, sodium, potassium, and chloride excretion. Indomethacin did not affect all the cardiovascular, metabolic, and renal hCGRP-induced effects. These results are in agreement with the hypothesis that hCGRP acts on the heart, vessels, and kidney, directly or indirectly, by the mediation of other vasodilating agents or systems excluding the prostaglandin system.

Calcitonin, estrogens and the bone.

Estrogen deficiency following natural or surgical menopause, is thought to be the main factor leading to postmenopausal bone loss. Furthermore, after estrogen failure a significant reduction of intestinal calcium absorption and a negativization of calcium balance has been observed. The mechanism of estrogen effect on skeletal tissue is not yet fully elucidated. Recently, specific receptors for estrogens in osteoblastic cells have been described; however their low density does not give a full explanation about their functional role. Therefore estrogens act, at least in part, indirectly through calciotropic hormones. In order to further elucidate this issue, we performed some studies in postmenopausal osteoporotic patients and in fertile oophorectomized women. In the first double blind placebo controlled study, after a 1-year estrogen treatment period we observed an increase in bone mineral content in the hormone-treated patients. Furthermore, in all treated patients an improvement of intestinal calcium absorption was detected, while 1,25-dihydroxy-vitamin D serum levels did not show significant changes. To further analyse the relationship between estrogens (E) and calcitonin (CT) in postmenopausal osteoporosis, we performed a double blind placebo controlled study to evaluate the effects of 1-yr estro-progestative treatment on CT secretory reserve, evaluated by calcium infusion test. Blood levels of CT showed a progressive increase during the study period in the hormone-treated group, with a significant increase in the CT response to calcium stimulation test, suggesting a modulation of CT secretion by E. Recently, we performed two studies in fertile oophorectomized women. In the first, we followed longitudinally 24 fertile women for 1 yr. In these patients we measured, before and after oophorectomy, biochemical indexes of bone metabolism and bone mass. During the observation period a significant increase in bone resorption and a significant drop in intestinal calcium absorption was observed. In the second study, performed on 14 women before and 6 months after oophorectomy, a treatment with conjugated estrogens allowed the correction of the primary intestinal defect responsible for the reduced calcium absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Management of osteoporosis and Paget's disease. An appraisal of the risks and benefits of drug treatment.

Osteoporosis is a major public health problem occurring primarily among the postmenopausal population. Osteoporosis is a preventable disease, but despite several advances in its prevention, treatment of the established disease to date remains a major challenge to be managed by primary care physicians. Stabilisation of bone mass and prevention of falls are of paramount importance in any therapeutic programme for osteoporotic patients with established vertebral fractures. Drug therapy for osteoporosis can be divided operationally into 2 main categories: those that inhibit bone resorption, and thus reduce bone turnover, and those that stimulate bone formation, exerting an anabolic effect. Therapeutic agents that inhibit bone remodeling would appear to be best suited to those patients with high turnover osteoporosis (about 30%). Included in this category are calcium, vitamin D and its metabolites, gonadal steroids, calcitonin, ipriflavone and bisphosphonates. Although estrogen replacement therapy has been proven to be effective in older females, calcitonin appears to be the treatment of choice for this population since it stabilises or increases bone mass and also has reported analgesic properties. Drugs that stimulate bone remodeling or bone formation would be best suited to patients with low turnover osteoporosis (about 70%). The agent in this class that is widely used is sodium fluoride. New therapies include intermittent injections of synthetic parathyroid hormone, and cyclic bisphosphonates to activate then depress resorption and formation. Any attempts to stabilise the skeleton with any drug regimen must be accompanied by an adequate calcium supply, i.e. 1200 to 1500 mg/day). The theoretical basis of tailoring treatment for osteoporosis to the underlying histology has not yet been fully proven, but there is increasing experimental support to this approach. Drugs that inhibit bone turnover, such as calcitonin, appear to be effective in increasing bone mass for 1.5 to 2 years, about the time it would take to replenish the remodeling space in a patient with high turnover osteoporosis. In contrast, although bone mass appears to increase for as long as 5 years in patients treated with sodium fluoride, there has been no consistent reduction in occurrence of vertebral or hip fractures. Paget' disease of bone is a focal disorder of the skeleton characterised by excessive resorption and subsequently disorganised formation of bone. The aetiology of the disease is unknown. Paget's disease may be mono-ostotic or polyostotic; pain and bone deformities due to enlargement of skeletal segments represent the main clinical aspects. However, in many patients the disease may be asymptomatic.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of nandrolone decanoate therapy on bone mass and calcium metabolism in women with established post-menopausal osteoporosis: a double-blind placebo-controlled study.

In many patients with involutional osteoporosis anabolic steroids may produce a rapid subjective improvement and a pronounced reduction in the frequency of complaints. Animal experiments have demonstrated that anabolic steroids can also have an objective effect on bone tissue. Twenty (20) post-menopausal osteoporotic patients were randomly assigned to 2 different treatment regimens; 10 patients were treated with 50 mg i.m. of nandrolone decanoate (ND) every 3 wk for 12 mth and 10 patients were treated with a placebo. Both groups also received an oral calcium supplement (1 g/day). Bone mineral content (BMC) was measured by dual photon absorptiometry before and after 1, 3, 6 and 12 mth of treatment. Plasma alkaline phosphatase (ALP) and urinary hydroxyproline excretion were measured at the same time. Intestinal calcium absorption was measured by the 47Ca oral test before and after treatment. A transiliac bone biopsy was performed before and after treatment in 4 patients in each group. After 1 yr there was a significant increase in lumbar spine BMC in the group receiving calcium plus ND. A progressive increase in plasma ALP was also observed in the group treated with ND but this was not significant, whereas radiocalcium absorption did increase significantly in this group. Histomorphometric study of bone samples demonstrated a significant increase in trabecular bone volume (TBV) and in active osteoid surface area in the patients treated with ND. Because plasma ALP tends to increase when a small decrease in bone resorption occurs (as measured by urinary hydroxyproline excretion) and the active osteoid surfaces also significant augment, we concluded that ND therapy increases the bone formation rate through inhibition of bone resorption. This interpretation could explain the considerable increase in lumbar spine BMC and the significant increase in TBV observed in patients treated with ND.