VITAMIN D

Age considerations in nutrient needs for bone health: Older adults

Journal of the American College of Nutrition (USA), 1996, 15/6 (575-578)

Current knowledge of the relation between nutrition and bone health in the elderly is sufficient, if applied, to lead to a reduction in fractures in the aged of from 30-60%. The critical nutrients are calcium and vitamin D, and possibly phosphate as well. Additionally, nutritional measures, especially protein repletion, dramatically improve outcomes from hip fracture. Fortunately the indicated interventions have a favorable cost- benefit relationship, especially when skim milk is used as the source of the needed nutrients.

Osteoporosis in lung transplantation candidates with end-stage pulmonary disease

American Journal of Medicine (USA), 1996, 101/3 (262-269)

PURPOSE: Fractures, a common complication of cardiac and liver transplantation, have not been reported in association with lung transplantation. However, many patients with end-stage pulmonary disease have multiple risk factors for osteoporosis, and several studies have suggested that osteoporosis before transplantation may increase the risk of fracture after transplantation. Therefore, we evaluated a group of patients with end-stage pulmonary disease who were awaiting lung transplantation to determine the prevalence of osteoporosis. METHODS: Seventy patients (aged 18-70 years) were evaluated consecutively with bone densitometry by dual-energy x-ray absorptiometry. The patients were predominantly Caucasian (96%). Bone mass was expressed as bone mineral density (BMD; g/cm2), as the number of standard deviations (SD) below peak bone mass (T score), and as bone mineral apparent density (BMAD; g/cm3), a measurement that minimizes the effects of bone size on BMD. Spine radiographs were obtained in a subset of 50 consecutive patients to detect vertebral compression fractures. Vitamin 0 status was assessed with serum concentrations of 25-hydroxyvitamin D. The patients were sorted into groups by pulmonary diagnosis: chronic obstructive pulmonary disease (COPD; n = 28); cystic fibrosis (n = 11); idiopathic pulmonary fibrosis; and other lung diseases (Other; n = 31). RESULTS: In the group as a whole, osteoporosis (T score below -2.5) was present in 30% of the patients at the lumbar spine and 49% at the femoral neck. Osteopenia (T score between -1 and -2.5) was present in an additional 35% at the lumbar spine and 31% at the femoral neck. The average femoral neck T score of patients with COPD and cystic fibrosis fell into the osteoporotic range (-2.7+or-0.3 and 2.6+or-0.3, respectively), significantly (P < 0.01) below that of the patients in the Other category (-1.5 +or-0.3). The average lumbar spine T score fell into the osteopenic range in all three groups. Low BMAD in patients with cystic fibrosis confirmed that their low BMD was not due to their smaller body size. The prevalence rate of vertebral fractures was 29% in patients with COPD and 25% in those with cystic fibrosis. Vitamin D deficiency (25- hydroxyvitamin D levels less than or equal to10 ng/ml) was present in 36% of patients with cystic fibrosis and 20% with COPD and Other lung diseases. Lumbar spine BMD tended to be lower in cystic fibrosis patients with vitamin D deficiency. Patients with exposure to glucocorticoids (n = 46) had significantly more vertebral fractures (P < 0.05) and duration of exposure correlated negatively with lumbar spine BMD (r = -0.398; P = 0.008). COPD and Other patients not on glucocorticoids had mild lumbar spine osteopenia (0.972 + or - 0.06 g/cm2; T = - 1.2 + or - 0.6). Very few of the patients on glucocorticoids were on any regimen to prevent osteoporosis. CONCLUSIONS: Osteoporosis and vitamin D deficiency are extremely common in patients with end-stage pulmonary disease. Only 34% of patients had normal lumbar spine BMD and only 22% had normal BMD at the hip. Patients with cystic fibrosis and glucocorticoid-treated patients with COPD were most severely affected. Therapies to prevent bone loss and treat established osteoporosis are uncommonly utilized in glucocorticoid-treated patients with end-stage pulmonary disease. Candidates for lung transplantation should be evaluated for osteoporosis and vitamin D deficiency at the time of acceptance to the transplant waiting list.

Development of clinical practice guidelines for prevention and treatment of osteoporosis

1 (S30-S33) Calcified Tissue International (USA), 1996, 59/SUPPL.

Clinical practice guidelines should be written for the physician who sees patients who already have or are at high risk for osteoporosis. They should also guide the physician in distinguishing between those at high and low risk and provide general guidelines for prevention of osteoporosis for the low-risk patient. Patients at high risk may require intervention to prevent further bone loss. The guidelines should be based on the strongest evidence available and be easy to comprehend and apply. Methods to identify individuals at high risk for osteoporosis must be described. Effective interventions also should be described, as should their benefits and risks. Elderly individuals who have a poor diet and little sun exposure may be vitamin D deficient unless a supplement is given. Factors that may be deleterious to the skeleton should be avoided. Weight-bearing exercise is important throughout life. Assessment of fracture risk is important in choosing candidates for intervention, especially interventions aimed at preventing osteoporosis. Measuring bone mass at any skeletal site is the necessary initial step for most individuals; measurement at the hip may best assess the risk of hip fracture. Some risk factors independent of bone mass may also aid in patient selection. The WHO has defined osteoporosis as a bone mass at least 2.5 standard deviations (SDs) below the mean of young normal. Such individuals and those with bone mass from 1to2.5 SDs below the mean of young normal may also be considered for intervention. The decision will depend on assessments of the risks, the costs of treatment, the desire of the patient, and the presence of other independent risk factors. The patient with an acute fracture may require an orthopedic intervention and should receive adequate analgesia. Physical therapy is an important adjunct that AIDS recovery. A number of therapeutic interventions, including adequate calcium intake throughout life and an adequate vitamin D intake, are available to high-risk individuals. These interventions my be recommended generally and do not require a diagnosis of osteoporosis. Similarly, a safe weight-bearing exercise program that helps to maintain muscle strength can be recommended to older patients.Other forms of therapy include hormone replacement, bisphosphonates, and calcitonin. Vitamin D analogs and selective estrogen receptor modulators may be helpful in the future. The risks and costs of each therapy should be weighed against its benefit in slowing bone loss or increasing bone mass and reducing fractures.

Harmonization of clinical practice guidelines for the prevention and treatment of osteoporosis and osteopenia in Europe: A difficult challenge

Calcified Tissue International (USA), 1996, 59/SUPPL. 1 (S24-S29)

Europe is a patchwork of various medical cultures and financial resources. Variations abound with respect to financing accessibility to public health systems, health expenditures, drug registration and reimbursement, the prescription of drugs, and clinical applications, as well as the perception of osteoporosis itself. However, there are possibilities for the harmonization of medical services among the various countries within Europe. The European Agency for the Evaluation of Medicinal Products (EAEMP) is attending to the centralized or decentralized procedures for the registration of drugs. The Group for the Respect of Ethics and Excellence in Science (GREES) is investigating guidelines for drug registration as well as gathering and making available medical references. The European Foundation for Osteoporosis and Bone Diseases (EFFO) is increasing awareness of the prevalence of the disease and the need for prevention and treatment. Finally, the International Federation of Societies on Skeletal Diseases (IFSSD) is coordinating epidemiologic, clinical, and social research. There is a need for increased awareness of osteoporosis throughout Europe. Health authorities are in need of cost/benefit reports leading to the registration and reimbursement of agents. Primary care physicians need information about osteoporosis and need to become involved in the diagnosis and science of the disease. Awareness needs to be generated among specialists: they need to be educated in the latest techniques for diagnosis and treatment. Finally, the general population needs to become aware of osteoporosis and to be encouraged to participate in the prevention and treatment of this disease. Current screening and detection in Europe is being done by densitometry. However, other techniques on the horizon include ultrasound and biochemical markers. Primary prevention, i.e., maximizing peak bone mass, includes examining the genetics of osteoporosis to determine the high-risk population and promoting reasonable physical exercise and dietary/lie-style habits (e.g., increased calcium and avoidance of tobacco). Secondary prevention includes the identification of high-risk groups through risk factors, biochemical markers, and densitometry and adherence to the World Health Organization definition of osteopenia-osteoporosis (adapted to financial concerns by GREES guidelines). Other therapies include hormone replacement agents (although there are risks for cancer and concerns about durability), calcium and other inhibitors of bone resorption, physical activity, and vitamin D prophylaxis in the elderly. Treatment of established or severe osteoporosis includes drugs upon availability (inhibitors of bone resorption and stimulators of bone formation), surgery, and experimental approaches.

Clinical practice guidelines for the diagnosis and management of osteoporosis

Canadian Medical Association Journal (Canada), 1996, 155/8 (1113-1129)

Objective: To recommend clinical practice guidelines for the assessment of people at risk for osteoporosis, and for effective diagnosis and management of the condition. Options: Screening and diagnostic methods: risk-factor assessment, clinical evaluation, measurement of bone mineral density, laboratory investigations. Prophylactic and corrective therapies: calcium and vitamin D nutritional supplementation, physical activity and fall-avoidance techniques, ovarian hormone therapy, bisphosphonate drugs, other drug therapies. Pain-management medications and techniques. Outcomes: Prevention of loss of bone mineral density and fracture; increased bone mass; and improved quality of life. Evidence: Epidemiologic and clinical studies and reports were examined, with emphasis on recent randomized controlled trials. Clinical practice in Canada and elsewhere was surveyed. Availability of treatment products and diagnostic equipment in Canada was considered. Values: Cost-effective methods and products that can be adopted across Canada were considered. A high value was given to accurate assessment of fracture risk and osteoporosis, and to increasing bone mineral density, reducing fractures: and fracture risk and minimizing side effects of diagnosis and treatment. Benefits, harms and costs: Proper diagnosis and management of osteoporosis minimize injury and disability, improve quality of life for patients and reduce costs to society. Rationally targeted methods of screening and diagnosis are safe and cost effective. Harmful side effects and costs of recommended therapies are minimal compared with the harms and costs of untreated osteoporosis. Alternative therapies provide a range of choices for physicians and patients. Recommendations: Population sets at high risk should be identified and then the diagnosis confirmed through bone densitometry. Dual-energy x-ray absorptiometry is the preferred measurement technique. Radiography can be an adjunct when indicated. Calcium and vitamin D nutritional supplementation should be at currenly recommended levels. Patients should be counselled in fall-avoidance techniques and exercises. Immobilization should be avoided. Guidelines for management of acute pain are listed. Ovarian hormone therapy is the therapy of choice for osteoporosis prevention and treatment in post menopausal women. Bisphosphonates are an alternative therapy for women with established osteoporosis who cannot or prefer not to take ovarian hormone therapy. Validation: These guidelines were reviewed and approved by the Scientific Advisory Board of the Osteoporosis Society of Canada, in consultation with individual family and general practitioners.

Current and potential future drug treatments for osteoporosis

Annals of the Rheumatic Diseases (United Kingdom), 1996, 55/10 (700-714)

There has been a major interest in the drug treatment of osteoporosis and an increase in the number of drugs available in most countries. The ideal drug (one which increases or restores bone density and trabecular connectivity) is still not available. However, in patients with relatively preserved trabecular connectivity and moderately reduced bone density, several agents have shown substantial clinical benefit. Oestrogens are still the mainstay of drug treatment, but the risks of breast cancer versus the cardiovascular and skeletal benefits with long term use have to be assessed in the individual. Newer tissue specific oestrogens show some promise in this respect. The bisphosphonates and possibly fluoride are likely to be the major alternatives to oestrogens in the medium term. The newer bisphosphonates, alendronate and in the future risedronate, are likely to supersede etidronate. Calcitriol probably has a limited role, confined to those patients in whom HRT or bisphosphonates are not appropriate. Calcium supplementation, or an increase in dietary intake if deficient, irrespective of which agent is used, is also of benefit. In older patients there is considerable support for using a combination of calcium and vitamin D. Whether combination treatment, for example oestrogens, bisphosphonates, and calcium together, will result in greater efficacy remains to be conclusively shown, but may be an attractive option in younger patients with higher bone turnover. Apart from fluoride, bone formation stimulators are unlikely to have a major role until the next century, although it may be possible to use growth factors as part of an ADFR regimen (A = activate remodelling, D depress resorption, F = free formation, and R = repeat). This is still an important theoretical approach and needs further work with newer agents to see if increased efficacy can be found. In addition sequential treatment may be necessary in view of the limited time periods over which particular agents, such as intermittent fluoride (four years), have ben examined, and this will have to be individually tailored.

Osteoporosis of the lumbar spine

Schweizerische Rundschau fur Medizin/Praxis (Switzerland), 1996, 85/43 (1354-1359)

The brief review demonstrates a positive influence of the treatment modalities established today on postmenopausal, age-related or glucocorticoid-induced bone loss. Measures developing direct anabolic effects are, however, rare. In other words prevention of osteoporosis is more important than therapy. Prevention means above all to change life cycle, to prevent excessive post-menopausal mineral lossers and to treat patients with long-term steroid regimens in higher doses (over 7.5 mg/day). Preventive measures include adequate intake of calcium, reduced intake of salt, encouraging physical activities as well as avoiding excessive alcohol- and nicotine consumption. From the osteoporotic point of view estrogen substitution is indicated in postmenopausal women. However, an individual evaluation of the indication is mandatory in view of the above discussed aspects. A densitometry-guided follow-up may contribute by valuable data to this decision. Only if these measures fail may further therapeutic and secondary-preventive measures be taken into consideration. Such secondary-preventive measures comprise antiresorptive drugs (calcitonin, higher doses of vitamin D, bisphosphonates) as well as fluoride which stimulates bone remodeling.

Common polymorphism of the vitamin D receptor gene is associated with variation of peak bone mass in young Finns

Calcified Tissue International (USA), 1996, 59/4 (231-234)

Previous studies suggested a relation between polymorphism of the vitamin D receptor (VDR) gene and bone mineral density (BMD) at perimenopausal age. To enlighten the possible association of the VDR gene polymorphism and BMD, we studied young (20-29 years) adults whose BMD provides a measure of their maximal bone mass. After sequencing the DNA regions flanking the polymorphic BsmI site, we set up a specific solid-phase minisequencing technique to assay this allelic variation. BMD values were adjusted for age, sex, weight, physical activity, smoking, and calcium intake. Young subjects homozygous for the b allele (BsmI site present) had a significantly higher BMD in lumbar spine and femoral neck than those homozygous for the B allele (BsmI site absent). This data shows that the BsmI polymorphism of the VDR gene is associated with peak bone mass. The implication of this result regarding the prevention of osteoporosis deserves further attention.

Diminished effect of etidronate in vitamin D deficient osteopenic postmenopausal women

European Journal of Clinical Pharmacology (Germany), 1996, 51/2 (145-147)

Objective: The effects of vitamin D deficiency in osteopenic postmenopausal women treated with intermittent cyclical etidronate have been studied. Bone mass and biochemical parameters as bone markers were measured before and after one year of therapy with intermittent cyclical etidronate. Results: In 30 patients without vitamin D deficiency, bone mass in the lumbal spine and femoral neck was significantly increased compared to 28 vitamin D deficient patients. after cyclical intermittent etidronate therapy, serum osteocalcin and PTH were significantly increased in the vitamin D deficient patients, whereas in non-vitamin D deficient patients they did not change. Conclusion: It is worthwhile measuring serum vitamin D before starting etidronate therapy and, in case of deficiency, to give vitamin D.

Vitamin D metabolites and analogs in the treatment of osteoporosis

Canadian Medical Association Journal (Canada), 1996, 155/7 (955-961)

Objective: To review recent findings on the skeletal actions of vitamin D and to examine results of the latest clinical trials of vitamin D in the treatment of osteoporosis. Options: The vitamin D analog 1-alpha hydroxycholecalciferol (1alpha-OH-D3); the vitamin D metabolite calcitriol. Outcomes: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with vitamin D therapies. Evidence: Relevant laboratory and clinical studies and reports were examined. Greatest reliance was placed on recent large-scale, randomized, controlled trials; others were noted and their methods critiqued. Clinical practice in Japan was also considered. Values: Reducing fractures, increasing bone mineral density and minimizing side effects of treatment were given a high value. Benefits, harms and costs: Vitamin D maintains the dynamic nature of bone and so presumably helps to keep it healthy. Calcitriol and 1alpha-OH-D3 may be effective in increasing bone mass and preventing fractures in osteoporosis. Calcitriol may be an alternative treatment in the prevention and management of corticosteroid-induced osteoporosis. Possible side effects of vitamin D analogs and metabolites are hypercalcemia, hypercalciuria, renal calcification and renal stones. Recommendations: The use of 1alpha-OH-D3 for the treatment of osteoporosis in Canada cannot be supported without larger and longer randomized, controlled clinical trials. Calcitriol appears to prevent vertebral fractures in patients with osteoporosis. More information is needed on its mechanism of action and efficacy in preventing hip fractures. Future studies should focus on comparisons with other effective therapies and on determining whether its effect on fractures is greater than that achieved through improved vitamin D nutrition. Patients taking calcitriol at dose levels required for antifracture effects should be monitored for serum and urine calcium response to the drug. Calcitriol should not be given to atients whose calcium intake is at current generally recommended levels. At present, prescription of calcitriol for the treatment of osteoporosis should be reserved for physicians with a special interest in the treatment of metabolic bone disease. Validation: These recommendations were developed by the Scientific Advisory Board of the Osteoporosis Society of Canada at its 1995 Consensus Conference.

Calcium nutrition and osteoporosis

Canadian Medical Association Journal (Canada), 1996, 155/7 (935-939)

Objective: To recommend appropriate levels of calcium intake in light of the most recent studies. Options: Dietary calcium intake, calcium supplementation, calcium and vitamin D supplementation; ovarian hormone therapy in postmenopausal women. Outcomes: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with osteoporosis prevention. Evidence: Relevant clinical studies and reports were examined, in particular those published since the 1988 Osteoporosis Society of Canada position paper on calcium nutrition. Only studies in humans were considered, including controlled, randomized trials and prospective studies, using bone mass and fractures as end-points. Studies in early and later phases of skeletal growth were noted. The analysis was designed to eliminate menopause as a confounding variable. Values: Preventing osteoporosis and maximizing quality of life were given a high value. Benefits, harms and costs: Adequate calcium nutrition increases bone mineral density during skeletal growth and prevents bone loss and osteoporotic fractures in the elderly. Risks associated with high dietary calcium intake are low, and a recent study extends this conclusion to the risk of kidney stones. Lactase-deficient patients may substitute yogurt and lactase-treated milk for cow's milk. True milk allergy is probably rare; its promotion of diabetes mellitus in susceptible people is being studied. Recommendations: Current recommended intakes of calcium are too low. Revised intake guidelines designed to reduce bone loss and protect against osteoporotic fractures are suggested. Canadians should attempt to meet their calcium requirements principally through food sources. Pharmaceutical calcium supplements and a dietician's advice should be considered where dietary preferences or lactase deficiency restrict consumption of dairy foods. Further research is necessary before recommending the general use of calcium supplements by adolescents. Calcium suplementation cannot substitute for hormone therapy in the prevention of postmenopausal bone loss and fractures. Adequate amounts of vitamin D are necessary for optimal calcium absorption and bone health. Elderly people and those who use heavy sun screens should have a dietary intake of 400 to 800 IU of vitamin D per day.

Osteoporosis of Crohn's disease: A critical review

Canadian Journal of Gastroenterology (Canada), 1996, 10/5 (317-321)

Osteoporosis has long been a recognized complication of Crohn's disease (CD), with a documented incidence ranging from 31% to 65%. The cause of osteoporosis in Crohn's patients is likely multifactorial; corticosteroids, inflammatory cytokines, small bowel resection and the resultant calcium and vitamin D deficiencies, hypogonadism, malnutrition and the cachexia of inflammation all play a role. However, the mechanism responsible for osteoporosis associated with CD remains unclear. Treatment of decreased bone density in CD patients has been limited to calcium and vitamin D replacement. The present understanding of the pathophysiology, mechanism and treatment of osteoporosis in CD is reviewed, with the focus on the role of steroid-induced osteoporosis and the use of bisphosphonates.

Effect of Vitamin D receptor gene polymorphism on vitamin D therapy for postmenopausal bone loss

Acta Obstetrica et Gynaecologica Japonica (Japan), 1996, 48/9 (799-805)

In order to assess the effect of vitamin D receptor (VDR) gene polymorphisms on vitamin D3 therapy for postmenopausal bone loss. Thirty-four Japanese postmenopausal women, administer ed vitamin D3 (Alfarol(R)1.0microg/day) and Ca(2.0g/day) for 18 months, were analyzed by RFLP Bone mineral density (BMI) at the lumbar spine (L2-4) and Os-calcis were measured every 6 months by dual energy X-ray absorptiometry (DXA) and single energy X-ray absorptiometry (SXA) VDR gene allelic polymorphisms were assessed by Bsm 1 endonuclease restriction after specific PCR amplification. Genotypic polymorphism was defined as BB, bb and Bb. The genotypes were BB in 1 (3.1%) Bb in 13 (40.6%) and bb in 18 (56.3%). The women in these two major VDR genotype groups (Bb and bb) were similar in their backgrounds (interms of age, menopausal age, body mass index, and BMD in premedication), but the VDR genotype was associated the percent of change in BMD after treatment. In Group-Bb, the mean percent increases in L2-4 BMD were 3.2%, 4.9% and 4.1% at 6, 12 and 18 months. In contrast, in Group-bb they were 0.8%, 1.8% and 4.2% at the same points. Analysis of VDR alleles may prove useful in selecting the vitamin D therapy for osteopenia before treatment.

Immunosuppression: Tightrope walk between iatrogenic side effects and therapy

Schweizerische Medizinische Wochenschrift (Switzerland), 1996, 126/38 (1603-1609)

The therapeutic effect of most immunosuppressive agents is inspecific and therefore often limited by an increased risk of infection by viral, bacterial or fungal organisms as well as by an increased incidence of malignant neoplasms. This short review includes the most commonly used immunosuppressants such as corticosteroids, azathioprine, methotrexate, cyclophosphamide and cyclosporine. The most common risks of long-term corticosteroids treatment are Cushing-like changes, decreased glucose tolerance and the usually benign steroid diabetes. Also clinically important is osteoporosis, since it can be prevented by physical training, calcium supplementation and treatment with vitamin D if necessary. Although there is still no proof of a significantly increased risk of peptic ulcer during steroid therapy, patients may develop gastrointestinal hemorrhage and even perforation without producing pain while being treated with corticosteroids. Mineralocorticoid effects, such as salt and water retention, are seen only with hydrocortisone and prednisone, whereas with synthetic steroids such as dexamethasone, sodium retention is absent despite their strong antiphlogistic activity. The most important side effect of the cytotoxic agents azathioprine, methotrexate and cyclophosphamide is marrow suppression. Due to the high turnover of neutrophils, patients most frequently suffer neutropenia rather than thrombocytopenia or anemia. Neutropenia, as well as impaired humoral and cellular immune mechanisms, are responsible for increased susceptibility to bacterial, viral or parasitic diseases during immunosuppressive therapy. Hepatotoxicity has been reported among patients receiving azathioprine (cholestatic hepatitis) and methotrexate (elevated AST levels and, rarely, liver fibrosis or cirrhosis). Cyclophosphamide causes hemorrhagic cystitis in a substantial proportion of patients, as well as an increased incidence of urothelial neoplasms. Both these side effects may be prevented by Mesna. The most important side effects of cyclosporin are acute and chronic nephrotoxicity usually associated with significantly elevated plasma levels of the drug. It must be borne in mind that severe nephrotoxicity may occur in patients receiving cyclosporine and ketoconazole together, since the latter may inappropriately increase the plasma cyclosporine level.

Glucocorticoid-induced osteoporosis

Medecine et Hygiene (Switzerland), 1996, 54/2127 (1490-1495)

Corticosteroids induce mainly trabecular bone loss leading to osteoporosis responsible for fractures and a high rate of morbidity. Thus patients starting a long-term treatment with corticosteroids should be assessed for bone density and biochemical markers. All will benefit from preventive measures with calcium and vitamin D supplements as well as hormonal treatment if necessary. In patients with low bone mass and even more for those with fractures, remineralising treatments with fluoride or bisphosphonates will belp reduce the bone loss and may even increase bone mass.

Relation of common allelic variation at vitamin D receptor locus to bone mineral density and postmenopausal bone loss: Cross sectional and longitudinal population study

British Medical Journal (United Kingdom), 1996, 313/7057 (586-590)

Objective - To determine whether common allelic variation at the vitamin D receptor locus is related to bone mineral density and postmenopausal bone loss. Design - Cross sectional and longitudinal population study. Setting - Outpatient clinic in research centre. Subjects - 599 healthy women aged 27 to 72 and 125 women with low bone mass aged 55-77 had bone mineral density measured once in the cross sectional study. 136 women aged 45-54 were followed up for 18 years in the longitudinal study. Main outcome measures - Bone mineral density measured at the lumbar spine, hip, and forearm and rate of bone loss at different times over 18 years in relation to vitamin D receptor genotype as defined by the endonucleases ApaI, BsmI, and TaqI. Results - Vitamin D receptor genotype was not related to bone mineral density at any site. The maximum difference between homozygotes was 1.3%(P=0.33, n=723). Women with low bone mineral density had almost the same genotype frequencies as the women with normal bone mineral densities. Vitamin D receptor genotype was not related to early postmenopausal bone loss from age 51 to 53 (mean (SD) total loss at the lower forearm -3.6% (3.6%)), late postmenopausal bone loss from age 63 to 69 (at the hip -6.2% (8.7%)), or to long term postmenopausal loss from age 51 to 69(at the lower forearm -24.5% (11.4%)). Conclusion - Common allelic variation at the vitamin D receptor locus as defined by the endonucleases ApaI, BsmI, and TaqI is related neither to bone mineral density nor to the rate of bone loss in healthy postmenopausal Danish women.

Systemic osteoporosis in rheumatoid arthritis. Pathogenetic mechanisms and therapeutic approaches

Zeitschrift fur Rheumatologie (Germany), 1996, 55/3 (149-157)

Iuxtaarticular osteoporosis is a typical x-ray symptom of rheumatoid arthritis and is an early radiological criterion of the disease before destructive changes of joints can be seen. A systemic osteoporosis, independent from corticoid treatment, will develop significantly later. Nevertheless both conditions have some pathogenetic mechanisms in common. The risk of generalized osteoporosis in rheumatoid arthritis correlates with the degree of inflammatory activity. Different cytokines originating from the affected joints can be measured in plasma at increased levels and augment osteoclastic activity in bone tissue. During the early phase of disease the best prevention of osteoporosis is therefore adequate suppression of inflammation. Taking into account these mechanisms, corticoid treatment may be osteoprotective. Clinical manifestation of systemic osteoporosis in rheumatic patients depends on bone mass at onset of disease, on the activity of inflammation, and on additional negative effects on bone mass due to corticoids and immobility. The risk of development of osteoporosis in rheumatoid arthritis can be reduced at any time. Bone density should be measured very early after diagnosis. In cases with age-corresponding normal values calcium- and vitamin D-supplements will be sufficient for prevention. In postmenopausal women or men with androgen deficiency hormones should be replaced. If significant osteopenia is already present an antiresorptive therapy is indicated with, for example, calcitonins, bisphosphonates or active vitamin D-derivatives. The latter are of special interest in this condition. Besides ameliorating enteral calcium absorption and inhibition of osteoclastic bone resorption they may have an additional positive effect on bone mass by their antiinflammatory effect on the underlying disease. In cases with advanced osteopenia with or without fractures, little inflammatory activity and low or stopped corticoid medication, it can be tried to increase bone mass by fluoride-calcium therapy.

Treatments for oestoporosis

Revue Francaise de Gynecologie et d'Obstetrique (France), 1996, 91/6 (329-334)

Preventive therapy for osteoporosis should theoretically be recommended to women at cessation of menses and to elderly individuals of either sex. However, therapeutic decisions depend heavily on individual factors, primarily bone mass assessed using absorptiometry or other means. Hormone replacement therapy (HRT) with estrogen-progestogen combinations is the most effective treatment for women at menopause but is contraindicated in some patients; the results of some studies that found a small increase in the breast cancer risk in patients receiving HRT are open to criticism. Fluoride therapy has generated considerable controversy but can continue to be used according to reasonable rules. Prophylactic calcitonin therapy is expensive and requires treatment modalities that patients are reluctant to accept. Supplemental calcium and vitamin D therapy is undeniably effective, at least in very elderly subjects. Other treatments are also discussed. Current views held by patients, and perhaps by some physicians, regarding the value of preventive treatment for osteoporosis need to be changed.

A comparison of the effects of alfacalcidol treatment and vitamin D2 supplementation on calcium absorption in elderly women with vertebral fractures

Osteoporosis International (United Kingdom), 1996, 6/4 (284-290)

Although vitamin D supplementation in the frail elderly improves calcium absorption, suppresses parathyroid hormone, decreases bone loss and reduces the risk of fractures, such treatment may be ineffective in patients with vertebral osteoporosis, because of impaired vitamin D metabolism or resistance to the action of vitamin D metabolites on the bowel. We have therefore performed a randomized, single masked study comparing the effects of alfacalcidol treatment (0.25 microg twice daily) and vitamin D2 supplementation (500-1000 units daily) on calcium absorption and bone turnover in 46 elderly women (median age 69 years, range 64-79 years) with radiological evidence of vertebral fractures. Serum 25-hydroxyvitamin D increased significantly after 3 and 6 months of treatment with vitamin D2 (p < 0.001), but was unchanged in the group receiving alfacalcidol. Serum 1,25-dihydroxyvitamin D did not change significantly in either group over the study period. Fractional 45Ca absorption increased after 3 months of treatment with alfacalcidol (p < 0.05), but was unchanged with vitamin D2. There was also a reduction in plasma intact parathyroid hormone and serum alkaline phosphatase after 6 months of treatment with alfacalcidol (p < 0.05) which was not seen in the group receiving vitamin D2. Our study shows that vitamin D2 supplementation is ineffective in stimulating calcium absorption in elderly women with vertebral osteoporosis. By increasing calcium absorption in such patients, alfacalcidol may prove more effective than vitamin D in the management of vertebral osteoporosis.

Review: Treatment of primary biliary cirrhosis

Journal of Gastroenterology and Hepatology (Australia),1996, 11/7 (605-609)

Primary biliary cirrhosis (PBC) is a slowly progressive chronic cholestatic disease of the liver thought to be caused by immune destruction of the interlobular bile ducts. One-third of patients are asymptomatic and one-third of these develop symptoms within 5 years. Therapeutic regimens should be directed at the control of symptoms, prevention of complications and specific therapy aimed at controlling progression of the disease. Symptoms may be secondary to cholestasis or due to other associated diseases. The cause of pruritus secondary to cholestasis remains unknown; the anion exchange resin cholestyramine generally brings relief. In patients resistant or intolerant to this therapy, rifampin may be helpful, as well as ultraviolet light without sunblock. Liver transplantation may rarely be the only option for uncontrollable pruritus. Clinical manifestations of keratoconjunctivitis sicca and xerostomia need constant attention to prevent corneal ulcers and dental caries. Preventative therapy includes regular screening for thyroid dysfunction and replacement therapy when necessary and the administration of the fat soluble vitamins A, D and K once hyperbilirubinaemia is present. Osteoporosis is a complication of all cholestatic liver disease. There is no satisfactory preventative therapy. It may be appropriate to give hormone replacement therapy to all post- menopausal women with PBC to reduce osteoporosis. Liver transplantation is the best option for those with fractures. Oesophageal varices may develop early in the course of PBC, non selective beta-blocker therapy should be used as prophylaxis against variceal haemorrhage. The only specific therapy shown to cause both a biochemical and survival benefit in patients with PBC is ursodeoxycholic acid (UDCA). Treatment with UDCA delays progression, but does not result in a cure of this disease. Currently, liver transplantation is the only definitive treatment available for end-stage disease.

Osteoporosis

Physical Medicine and Rehabilitation Clinics of North America (USA), 1996, 7/3 (583-599)

The management of osteoporosis is challenging. Physicians can look forward to a growing number of medications for treatment and prevention. Rehabilitation management includes the amelioration of pain, prescription of physical activity, and exercise as well as the appropriate use of modalities and orthotics. It is also essential to counsel the patient on diet, including the needs for calcium and vitamin D. Assessment and treatment of emotional and psychosocial factors is also necessary. The prevention of disability with particular emphasis on fall prevention will help reduce the incidence of fractures. Rehabilitation intervention can help improve quality of life for the many patients with osteoporosis.

Nutritional and biochemical studies on vitamin D and its active derivatives

Yakugaku Zasshi (Japan), 1996, 116/6 (457-472)

We have performed nutritional and biochemical studies on vitamin D and its active derivatives and the following results are obtained. 1. Since recent studies have revealed that dietary supplement of vitamin D (D2 and D3) and calcium is effective for preventing osteoporosis, a simplified routine method for determination of vitamin D in foods is established and applied to the assay on the contents of vitamin D in various kinds of Japanese foods. 2. A simplified routine method for simultaneous determination of vitamin D and its metabolites in the plasma and milk is established and applied to nutritional and clinical studies. 3. Physiological activities of two kinds of novel vitamin D3 derivatives, 22-oxa-1alpha,25-dihydroxyvitamin D3 (22-oxa-1,25(OH)2D3, OCT) and 2beta-(3-hydroxypropoxy)-1,25(OH)2D3 (ED- 71) have been studied. OCT, which has less calcemic and stronger cell differentiation activities than 1,25(OH)2D3, is a candidate for curing leukemia and other cancers without hypercalcemia. We have clarified that the property is due to its weak binding affinity for vitamin D binding protein and rapid turn-over in the body and rapid excretion into bile. On the other hand, ED-71, which has stronger effects on intestinal calcium absorption and longer bone turn-over than 1,25(OH)2D3, is a candidate for curing osteoporosis. We have clarified that the properties are due to stronger binding affinity for DBP and longer half-life than 1,25(OH)2D3.

Lower serum 25-hydroxyvitamin D is associated with increased bone resorption markers and lower bone density at the proximal femur in normal females: A population-based study

Experimental and Clinical Endocrinology and Diabetes (Germany), 1996, 104/3 (289-292)

Subclinical vitamin D deficiency is considered to be a risk factor for osteoporosis. Therefore, we studied vitamin D status and bone mineral density (BMD) in an age- and sex-stratified population based sample (209 males and 206 females aged between 50 and 80 years). In addition, urinary excretion of pyridinium crosslinks of collagen was determined in order to monitor bone resorption. We found a seasonal variation of serum 25-hydroxyvitamin D (25(OH)D) levels with higher values detected in the summer (27 +/- 10 ng/ml) and lower values measured in the winter (17 +/- 9 ng/ml). Further analyses were performed separately for winter and summer, respectively. We also excluded subjects taking osteotropic medication. In men, we found no significant relationship between vitamin D status and bone density or pyridinium crosslinks. In women, we found significant positive correlations between 25(OH)D and proximal femur BMD in winter (r = 0.21, p < 0.05) and in summer (r = 0.36, p < 0.01). The association between 25(OH)D and proximal femur BMD persisted after correction for age and body mass index. Serum 25(OH)D and urinary pyridinium crosslinks were inversely correlated in females in winter (r = -0.24, p < 0.02) and in summer (r = -0.32, p < 0.02). Our data support the hypothesis that already moderately low serum levels of 25(OH)D within the 'normal' range lead to osteopenia via increased bone resorption.

Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: A 3 year followup

Journal of Rheumatology (Canada), 1996, 23/6 (995-1000)

Objective. To determine the efficacy and safety of vitamin D 50,000 units/week and calcium 1,000 mg/day in the prevention of corticosteroid induced osteoporosis. Methods. A minimized double blind, placebo controlled trial in corticosteroid treated subjects in a tertiary care university affiliated hospital. The sample was 62 subjects with polymyalgia rheumatica, temporal arteritis, asthma, vasculitis, or systemic lupus erythematosus. The primary outcome measure was the percentage change in bone mineral density (BMD) of the lumbar spine in the 2 treatment groups from baseline to 36 mo followup. Results. BMD of the lumbar spine in the vitamin D and calcium treated group decreased by a mean (SD) of 2.6% (4.1%) at 12 mo, 3.7% (4.5%) at 24 mo, and 2.2% (5.8%) at 36 mo. In the placebo group there was a decrease of 4.1% (4.1%) at 12 mo, 3.8% (5.6%) at 24 mo, and 1.5% (8.8%) at 36 mo. The observed differences between groups were not statistically significant. The difference at 36 mo was -0.693% (95% CI -5.34, 3.95). Conclusion. Vitamin D and calcium may help prevent the early loss of bone seen in the lumbar spine as measured by densitometry of the lumbar spine. Longterm vitamin D and calcium in those undergoing extended therapy with corticosteroids does not appear to be beneficial.

Novelties and issues in the drug market 1995

Ricerca e Pratica (Italy), 1996, 12/68 (63-71)

Undoubtly the most relevant data produced in this period regard the treatment of hypercholesterolemia. The S4 study has in fact conclusively demonstrated the efficacy of statins in the secondary prevention of coronary events. The West of Scotland Coronary Prevention Study Group has strongly shown a role for statins also in primary prevention, although with a less favourable benefit/risk and benfit/cost profile. Alendronate is the fourth drug shown effective in reducing bone fractures in post-menopausal women, after estrogens, calcitonin, and calcium plus Vitamin D. While estrogens remain first choice when therapy is considered in the immediate post-menopause-because of their higher protective effect and their added cardiovascular benefits - available data are not sufficient to chose among alternatives for older women or for those unwilling to take estrogens. Calcium plus Vitamin D remains the cheapest choice. Formoterol is the first long acting beta-2-agonist to come on the market after the success of salmeterol. Its quick onset of action has been considered a good reason to advise it also for the relief of asthma attacks. It is our opinion that the use of a short acting alternative (like salbutamol) is still to be preferred for safety reasons. Interferon beta has been studied in patients with relapsing-remitting multiple sclerosis. Although it seems able to reduce recurrences, the drug has no demonstrable effect on disability. Methodological issues, and strong vested interests, advise caution with reguard to an uncritical acceptance of this therapeutic option.

Roles of diet and physical activity in the prevention of osteoporosis

Scandinavian Journal of Rheumatology, Supplement (Norway), 1996, 25/103 (65-74)

In recent years, much attention has been directed toward the prevention of osteoporosis, since this disease has become a leading cause of morbidity and mortality in elderly women. Research has demonstrated that the prevention of osteoporosis and osteoporosis-related fractures may best be achieved by initiating sound health behaviors early in life and continuing them throughout life. Evidence suggests that osteoporosis is easier to prevent than to treat. In fact, healthy early life practices, including the adequate consumption of most nutrients, regular physical activity, and other healthy behaviors, contribute to greater bone mineral measurements and optimal peak bone mass by the fourth decade of life of females, and, perhaps, also of males. Several reports have shown that the adequate consumption of nutrients, calcium in particular, during the pre-pubertal and early post-pubertal years of females contribute to increased peak bone mass. Indeed, skeletal benefits from long-term calcium supplementation have been reported for females at practically every period of the life cycle. Vitamin D, which may be either consumed or produced endogenously through the action of sunlight, promotes calcium absorption and thereby enhances bone mineralization. Thus, the adequate consumption of calcium, in conjunction with vitamin D, in early life will likely optimize peak bone mass, and adequate intakes of these two nutrients should continue through the remainder of life to help maintain bone mass. On the other hand, excess phosphorus consumption may deter bone mineral accrual because of the resultant elevation of serum parathyroid hormone levels. Additionally, high intakes of protein, sodium, and caffeine may decrease bone mineral mass through increased urinary excretion of calcium. Vitamin K may also have an important positive effect on the development and maintenance of bone through its role in promoting carboxylations of the matrix protein, osteocalcin. In conclusion, the prevention of osteoporosis needs to begin during the pre-ubertal years and it should be continued throughout life. Bone mass can better be maintained later in life through adequate consumption of several nutrients with specific roles in calcium and bone metabolism, regular physical activity, and the practice of a healthy lifestyle. Mechanisms through which the nutrients and exercise affect bone mass will be explored.

Vitamin D in the treatment of osteoporosis revisited

Proceedings of the Society for Experimental Biology and Medicine (USA), 1996, 212/2 (110-115)

Interest in vitamin D treatment for osteoporosis has recently been revived because of the focus in various parts of the world on the elderly population, which is predominantly vitamin D deficient, in addition to postmenopausal osteoporosis due to estrogen withdrawal, which has been the central theme of osteoporosis research for many years. Combined use of other agents along with vitamin D has fortified the therapeutic armory against osteoporosis. The recent suggestion of a role of vitamin D receptor polymorphism in the development and progress of osteoporosis, possibly by interfering with its expected action, provoked intense discussions on the role of vitamin D in the pathogenesis and treatment of osteoporosis. Vitamin D receptor polymorphism may explain some of the racial differences in the incidence of osteoporosis and its complications. Responses to vitamin D treatment may also be predicted by vitamin D receptor allelic analysis, though the currently proposed allelic patterns are yet far from being widely accepted. The outlook for vitamin D treatment for osteoporosis may require insight into vitamin D receptor, not only for vitamin D's given form, but also for a possible future form designed to intervene at the genomic level.

Prevention of bone loss in cardiac transplant recipients: A comparison of biphosphonates and vitamin D

Transplantation (USA), 1996, 61/10 (1495-1499)

Bone mineral density is already abnormally reduced at the moment of cardiac transplantation and bone loss occurs at an impressive rate in the first postoperative year. The aim of the study was to compare two prophylactic medical regimens as to their efficacy in mitigating hone loss after transplantation. Forty-eight consecutive recipients were randomized to receive either alternating calcium carbonate and disodium etidronate (group A) or a daily supplement of calcium carbonate and alphacalcidol (group B). Bone mineral density measurements were performed immediately before hospital discharge and 6, 12, and 24 months after surgery using dual energy X-ray absorptiometry. Clinical events were recorded and roentgenograms of the spine were performed postoperatively and 1 and 2 years later. In both treatment groups bone loss remained significant at the level of the lumbar spine in the first postoperative year (P < 0.005) and at the level of the femoral neck in the first (P < 0.005) and the second (P < 0.05) year after transplantation. Six months after transplantation, however, patients receiving alphacalcidol had a significant reduction in bone loss at the level of the lumbar spine (P=0.047) and at the level of the femoral neck (P=0.043). At the level of the femoral neck this decrease in bone loss was even more pronounced in the second postoperative year (P < 0.001). In the group of patients treated with disodium etidronate, 4 recipients needed additional hospitalizations for treatment of symptomatic fractures at the level of the lumbar spine or the femoral neck. No such events happened in recipients receiving vitamin D supplements. Prophylactic administration of calcium carbonate and alphacalcidol after cardiac transplantation reduces bone loss and seems to decrease osteoporotic complications.

Osteoporotic fractures: Background and prevention strategies

Maturitas (Ireland), 1996, 23/2 (193-207)

Objectives: To review current knowledge of the epidemiology, pathogenesis, prevention and treatment of osteoporosis, with particular reference to issues related to the menopause. Methods: Peer-reviewed publications were assessed. Results: Much international variation exists in the prevalence of osteoporosis and the incidence of fracture. Risk fractures for oesteoporosis are numerous. The menopause and other causes of hypogonadism in both women and men strongly predispose to osteoporosis. Various endocrinopathies, especially glucocorticoid excess, also are important. The contribution of family history may be explained by one or more markers. Poor vitamin D and calcium nutrition, smoking, high alcohol consumption and inactivity increase risk. Reduced bone mass is a major risk factor for fracture, although the magnitude of that risk may vary between populations. In addition, bone fragility, length of the femoral neck (for hip fracture), history of prior fracture (for vertebral fracture) and falls affect fracture risk. Useful methods for measuring bone density are available for both epidemiologic surveillance and for clinical practice. Dual energy x-ray absorptiometry is the most desirable method in clinical care settings. Some risk factors can be modified for prevention of osteoporosis. Postmenopausal bone loss can be inhibited with estrogen or estrogen plus progestin therapy. Bone loss in the elderly may be moderated with calcium and vitamin D supplementation. Maintenance of muscle tone and strength through exercise may reduce falls.Conclusion: Osteoporosis is a large and growing health problem in many countries. Prevention of osteoporosis is a high priority, especially because treatment of the established disease remains sub-optimal. Prevention requires immediate, intermediate-term and long-term strategies. First line therapy for established osteoporosis in women in many countries is estrogen or estrogen plus progestin, calcium and vitamin D. Prospects for improved prevention of osteoporotic fractures are encouragng.

Current and future nonhormonal approaches to the treatment of osteoporosis

International Journal of Fertility and Menopausal Studies (USA), 1996, 41/2 (148-155)

Osteoporosis is the most important metabolic bone disease of women. Still, approaches to successful therapy are limited. The 'gold standard' for prevention of osteoporosis in the menopausal years is estrogen. None of the other agents should be regarded as true alternatives to estrogens. Current recommendations for dietary calcium and vitamin D will be given as well as the following therapies: bisphosphonates, fluoride, calcitonin, and parathyroid hormone.

Osteomalacia and osteoporosis in a woman with ankylosing spondylitis

Journal of Bone and Mineral Research (USA), 1996, 11/5 (697-703)

Three months postpartum, a 33-year-old woman with ankylosing spondylitis (AS) suffered multiple vertebral fractures. Bone mineral density was 61-67% of age-matched normal values at the lumbar spine and proximal femur, and an initial iliac crest bone biopsy revealed osteoporosis and osteomalacia. Secondary causes of bone disease were excluded, and the patient was treated with calcium, vitamin D, and nasal spray calcitonin (400 u/day). Over 4 years, she has shown partial recovery of bone mass and almost complete resolution of osteomalacia. Osteoporosis and fracture occur in patients with AS, yet this case represents a rare association between AS and both osteomalacia and postpregnancy spinal osteoporosis.

Calcium and vitamin D nutritional needs of elderly women

Journal of Nutrition (USA), 1996, 126/4 SUPPL. (1165S-1167S)

Because osteoporosis is irreversible, the most effective approach to reduce morbidity and mortality from this disease is to maximize peak bone mass and minimize bone loss. This presentation reviews the evidence that calcium and vitamin D influence rates of bone loss in postmenopausal women. In the first five or more years after menopause, women lose bone very rapidly. During this period, high dose calcium supplementation modestly reduces cortical loss from long bones but has minimal effect on more trabecular sites such as the spine. In addition, vitamin D appears to enhance the effectiveness of supplemental calcium. Late postmenopausal women are generally more responsive to added calcium, and those with the lowest dietary calcium intakes benefit the most. In calcium-replete women, supplementation with vitamin D reduces bone loss and fracture incidence. Available evidence indicates that postmenopausal women should consume 1000-1500 mg of calcium and 400 to 800 IU of vitamin D per day to minimize bone loss.

Vitamin D and bone health

Journal of Nutrition (USA), 1996, 126/4 SUPPL. (1159S-1164S)

Vitamin D plays an essential role in maintaining a healthy mineralized skeleton for most land vertebrates including humans. Sunlight causes the photoproduction of vitamin D3 in the skin. Once formed, vitamin D3 is metabolized sequentially in the liver and kidney to 1,25-dihydroxy vitamin D. The major biological function of 1,25-dihydroxyvitamin D is to keep the serum calcium and phosphorus concentrations within the normal range to maintain essential cellular functions and to promote mineralization of the skeleton. Most foods do not contain any vitamin D. Foods fortified with vitamin D have a variable amount present and cannot be depended on as a sole source of vitamin D nutrition. Exposure to sunlight provides most humans with their vitamin D requirement. Aging, sunscreen use and the change in the zenith angle of the sun can dramatically affect the cutaneous production of vitamin D3. Vitamin D insufficiency and vitamin D deficiency is now being recognized as a major cause of metabolic bone disease in the elderly. Vitamin D deficiency not only causes osteomalacia but can exacerbate osteoporosis. It is generally accepted that an increase in calcium intake to 1000-1500 mg/d along with an adequate source of vitamin D of at least 400 IU/d is important for maintaining good bone health.