Differential therapy of osteoporosis

In the past decade, we observed progress in the differential diagnosis of osteoporosis, mainly because of advanced radiological and laboratory procedures, including new bone markers. Loss of bone can also be related to primary and secondary forms of osteoporosis. Consequently, secondary osteoporosis (and osteomalacia) should be treated primarily according to the original disease. Although etiopathology of primary osteoporosis is still unclean differential therapy should be applied to the different subgroups (juvenile, postmenopausal, and senile osteoporosis). Furthermore, even patients of the same age and sex can be at risk for osteoporosis or have definite osteoporosis. This can be differentiated in "low or high turnover osteoporosis" and should be diagnosed and treated as described. Conjugated estrogens in combination with progesterone decrease the rate of endometrial carcinoma and have been established to be very effective in the treatment of high turnover osteoporosis and patients at high risk of developing manifest osteoporosis. In combination with calcium (1 g/day) total doses of estrogen can be reduced to 0.3 g/day. The same applies for the treatment of low turnover (mostly manifest) osteoporosis with fluoride. Daily doses of fluoride can be decreased from 80 mg sodium fluoride to 50g in combination with calcium. These reductions of daily fluoride doses decreases the rate of side effects and allows longer control periods, provided that bone measurements demonstrate a beneficial long-term effect. The control periods depend on the sensitivity of the bone density measurements. Special indications, modifications, alterations and additions of further drugs are discussed for the individual patient.     

Serum and urinary markers of bone remodeling: assessment of bone turnover

It appears that at present, serum BGP is the one bone protein that has the most promise for assisting in the diagnosis and management of high turnover metabolic bone disease states. If further studies confirm its usefulness in osteoporosis as a predictor of rapid bone loss without the need for bone biopsy, this serum marker will then not only allow early detection but also an appropriate choice of therapy in osteoporosis, i.e. the use of specific inhibitors of high turnover states such as estrogen, calcitonin, or bisphosphonates. In addition, it may also permit more accurate follow-up of patients suffering from diseases such as primary hyperparathyroidism after surgery. In low turnover osteoporosis, it may also serve a useful function to observe whether the osteoblast can be stimulated to enhance bone formation with therapies such as fluoride, anabolic steroids, PTH, etc. As yet, additional measurements, such as bone histomorphometry and other bone mineral markers, are required for definitive diagnosis. Hopefully, the availability of specific well-characterized antibodies against BGP may define its role more accurately. Recently, several other new bone proteins have been identified but at present they have very limited clinical application. Future studies into the structure-function relationship of these bone proteins may identify those markers which will be most relevant to the diagnosis and treatment of metabolic bone disease.     

Glucocorticoid Osteoporosis

Glucocorticoids act on calcium metabolism at many levels to produce osteoporosis, the major pathogenic effect probably being an inhibition of bone formation. In men, this is likely to be contributed to by a dose-related reduction in circulating testosterone concentrations. Bone density is reduced 10-20% at the commonly assessed sites, but deficits of twice this magnitude are found in trabe-cular bone. Dose and duration of steroid treatment influence the degree of osteopenia, but biochemical indexes of calcium metabolism are not predictive.

In managing a steroid-treated patient, bone den-sitometry is usually helpful. Those with low densities should optimize their calcium intake, and those with sex hormone deficiency should receive appropriate replacement therapy. If bone loss is severe or continues despite these measures, the addition of bisphosphonate, calcitonin, fluoride, or a vitamin D metabolite may be appropriate, according to local availability. Thiazide diuretics can be combined with all these regimens. If thiazide diuretics are combined with vitamin D or its metabolites, careful monitoring of serum calcium should be undertaken. Bone density should be monitored annually until it is stable.     

Therapies for symptomatic primary osteoporosis

There is no universally accepted pharmacologic treatment for primary symptomatic osteoporosis. However, three agents discussed in this review show varying degrees of promise. Calcitonin increases bone density and has the added benefit of analgesic properties. Etidronate disodium, a diphosphonate approved for symptomatic Paget's disease, has been shown to increase bone density and decrease fractures in osteoporosis. Sodium fluoride, although an effective stimulator of bone growth in low turnover osteoporosis, has been associated with toxicity and increased fractures.     

Prevention and Treatment of Postmenopausal Osteoporosis

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of the skeleton leading to enhanced bone fragility and an increased risk of fracture. Prior to fracture, diagnosis is established by documenting low bone mass. In the first section of this article we review the clinical use of bone mass measurements and biochemical markers of bone remodeling in selecting patients most in need of preventive therapy at menopause. Women with high bone turnover lose bone at menopause more rapidly than those with normal bone turnover and are more likely to derive benefit from the several preventive therapies available. The second section addresses the available technologies used to diagnose osteoporosis and/or establish fragility fracture risk using noninvasive bone mass measurement and biochemical markers of bone remodeling separately or in combination. In the third section we review the several treatment options available for patients with osteoporosis, including alendronate (alendronic acid), risendronate (risedronic acid), calcitonin, teriparatide, and raloxifene, and the approaches to monitoring the therapeutic response. The final section deals with fall protection--an often forgotten aspect of management of the patient at risk for sustaining and osteoporotic fragility fracture.     

The role of bone turnover markers and risk factors in the assessment of osteoporosis and fracture risk.

The clinical evaluation of osteoporosis in individual patients involves confirmation of the diagnosis, the investigation of secondary causes of osteoporosis and the evaluation of subsequent fracture risk. Optimum clinical assessment involves bone mineral densitometry with the treatment thresholds modified by clinical risk factors for individual patients. Bone turnover markers and clinical risk factors can be used to identify patients at risk of osteoporotic fracture and those who have secondary osteoporosis. Risk assessment should involve the evaluation of absolute rather than relative risk. Further work is required to improve the integration of clinical risk factors, bone turnover markers and bone densitometry into appropriate models to enable the assessment of the absolute risk of fracture for individual patients.     

Clinical relevance of changes in bone metabolism in inflammatory bowel disease

Low bone mineral density is an established, frequent, but often neglected complication in patients with inflammatory bowel disease (IBD). Data regarding the diagnosis, therapy and follow-up of low bone mass in IBD has been partially extrapolated from postmenopausal osteoporosis; however, the pathophysiology of bone loss is altered in young patients with IBD. Fracture, a disabling complication, is the most important clinical outcome of low bone mass. Estimation of fracture risk in IBD is difficult. Numerous ...     

Therapy-induced fluorosis--damage or goal?

Report on 3 female patients who, after treatment of an osteoporosis with sodium fluoride, have developed a skeletal fluorosis. The proof was performed radiologically, histologically and by means of fluoride analysis in the bone ash. The diagnosis was made accidentally. Complaints relating to this are not mentioned. Osteosclerosis after fluoride therapy is no iatrogenically damage for the patient, but the aim of the therapy for the prevention of osteopenic fractures.     

钙营养对氟的骨骼毒性的影响

用富钙平衡饲料和低钙偏食饲料分别饲养Ｗｉｓｔａｒ大鼠,并经饮水投予氟１００ｍｇ／Ｌ,为期４个月,以研究钙营养对氟的骨骼毒性的影响及其作用机理。     

Increase of bone mineral density with sodium fluoride in patients with Crohn's disease

BACKGROUND AND AIMS: Low bone density with an increased risk of vertebral fractures is a frequent complication in inflammatory bowel disease. Since the aetiology of osteopathia in these patients is different compared to postmenopausal or steroid-induced osteoporosis, no treatment strategy is established. Supplementation of calcium and vitamin D has been shown to prevent further bone loss, but no data are available showing the anabolic effect of sodium fluoride in Crohn's disease. METHODS: We carried out a one-year prospective clinical trial in 33 patients with chronic active Crohn's disease who were randomly assigned to receive either calcium (500 mg b.i.d.) and 1000 IU vitamin D3 only, or retarded-release sodium fluoride (25 mg t.i.d.) additionally. The diagnosis of Crohn's disease had been made at least two years ago, and all patients had received systemic high-dose steroid therapy during the previous year. Eleven of 15 patients who received calcium/vitamin D and 15 of 18 patients who additionally received sodium fluoride completed the study. The primary endpoint of the study was the increase of bone mineral density, measured by dual energy X-ray absorptiometry (DXA) after one year of treatment. Bone-specific alkaline phosphatase and osteocalcin were used as markers for bone turnover. RESULTS: In the calcium/vitamin D only group, bone density was not significantly changed after one year of treatment, whereas in the calcium/vitamin D/fluoride group, bone density of the lumbar spine increased from -1.39+/-0.3 (Z-score, mean +/- SEM) to -0.65+/-0.3 (P<0.05) after one year of treatment. Increase of bone density was positively correlated to the osteoblastic markers bone-specific alkaline phosphatase (r = 0.53) and osteocalcin (r = 0.43). CONCLUSIONS: Sodium fluoride in combination with vitamin D and calcium is an effective, well-tolerated and inexpensive treatment to increase lumbar bone density in patients with chronic active Crohn's disease and osteoporosis.     

Awareness, attitudes and opinions on osteoporosis of primary care physicians working in the metropolitan area of Rome: a brief report

Attitudes of primary care physicians towards prevention, diagnosis and treatment of osteoporosis have important implications in clinical practice; however, in Italy, this issue has been poorly investigated. This study aimed to determine whether the awareness and opinions of family physicians regarding the management of osteoporosis are in line with the suggestions of experts in the field. One hundred of 115 randomly selected family physicians from the area of Rome were asked to participate, and completed a survey on osteoporosis including ten close-ended questions. Response rates documented the degree of awareness about osteoporosis. Thirty-six percent of physicians make the diagnosis of osteoporosis based exclusively on bone densitometry (BD), while 17% never utilize BD. Fifty-three percent of doctors assess biochemical markers of bone turnover, but half of them are unaware of the existence of more sensitive and specific markers. Forty-four percent of physicians autonomously start therapy according to the suggestions of journal reports (38%), and/or pharmaceutical advertisements (18%). Regarding treatment follow-up, 60% of doctors gave inadequate answers, as 25% and 35% of them check bone markers after six months of therapy, and BD within one year of therapy initiation, respectively. In conclusion, experts on osteoporosis should give more attention to the education of primary care physicians regarding the management of the disease.     

Bisphosphonate-associated osteonecrosis of the jaw in rheumatology: a systematic review

Osteonecrosis of the jaw (ONJ) is a well-known devastating side effect of parenteral bisphosphonate therapy for cancer. Several ONJ cases have been reported in patients taking oral bisphosphonates for osteoporosis or Paget's disease. Even if the number of cases of ONJ in patients taking oral bisphosphonates are still rare compared to the total exposure, rheumatologists treating bone diseases with bisphosphonates must be aware of this new complication, allowing for prevention and early diagnosis. The patients must be informed on the benefit/risk of bisphosphonate therapy and, when necessary and possible, alternative therapy for postmenopausal osteoporosis should be considered. The need for the patient to be dentally fit and to maintain this state forever should be part of the informed consent for bisphosphonate treatment. It is uncommon for rheumatologists to ask about dental problems but this new bisphosphonate- associated complication highlights the need for this to change. In this paper we review the literature available on this newly described bisphosphonate-induced complication with particular emphasis on ONJ cases related to the use of oral bisphosphonates.     

Management of corticosteroid-induced osteoporosis

OBJECTIVES: To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS: This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS: Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. Conclusions: Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.     

Osteoporosis,estrogens, and bone metabolism. Implications for chronic renal insufficiency

The relationship between estrogens, bone metabolism and osteoporosis is well known. Chronic renal failure in women is associated with menstrual disorders, lower bone mineral density and increased risk of fractures. However, most studies on renal osteodystrophy have not taken into account the role of oestrogen deficiency, its interaction, and the possible benefits of hormone replacement therapy (HRT) in uremic women. According to these limitations and the actual evidence of benefits and risks of HRT, we conclude that: a) Osteoporosis must be evaluated as a part of renal osteodystrophy; b) HRT would be considered in women with climateric symptoms and osteoporosis, and should not be used for prevention of cardiovascular disease, and c) Clearly we need to do more studies related to osteoporosis and estrogens in CRF, but right now we have to try to optimize bone turnover in our uremic patients.     

Diagnostic procedure in osteoporosis

Osteoporosis is a very important differential diagnosis in chronic back pain. Early diagnosis of osteoporosis remains difficult, as an initial loss of skeletal mass cannot be recognized in X-ray pictures. A clear assessment can only be reached by the application of different non-invasive quantitative methods of bone mineral determination. So far as possible bone mineral content should be measured at an axial and a peripheral site of the skeleton. Crush fractures of vertebrae indicate an advanced calcipenic osteopathy. During the diagnostic procedure of osteoporosis other metabolic osteopathies (e.g. the different forms of hyperparathyroidism and osteomalacia) must be excluded by laboratory examinations or sometimes even by bone histology. If other generalised osteopathies can be excluded one has to look for etiological factors of a possible form of secondary osteoporosis because some of these allow a specific therapeutic approach. In about 80% no disturbances of calciumphosphorous metabolism can be detected, which means that a diagnosis of primary (idiopathic) osteoporosis must be made. In primary and secondary forms of osteoporosis the actual skeletal status and the activity of the osteoporotic process should be defined before beginning a differentiated treatment.     

New osteoformative agents for osteoporosis

PURPOSE: Antiresorptive therapy are usual treatment of osteoporosis, but they prevent no more than 40 or 60% of osteoporotic fracture. Thus, there is a need for osteoformative agents that can further augment bone mass and reduce risk fracture more substantially. CURRENT KNOWLEDGER AND KEYPOINTS: Daily injections of 1-34 aminoterminal fragment of PTH increase bone formation and bone mass. A randomized study recently demonstrated that PTH 1-34 decrease the risk of vertebral and non vertebral fracture, and the place of this treatment in the strategy of osteoporosis treatment is to demonstrate. Oral administration of strontium salt at low dosage level stimulate bone formation and decrease bone resorption. Preliminary data needs to be confirmed by a multicenter antifracture study. Retrospective results with statins in three international studies have not be confirmed by the only randomized clinical trial. Use of low dose intermittent fluoride therapy are still recommended by some authors. FUTURES PROSPECTS AND PROJECTS: Effects of insuline like growth factor I and other growing factor on bone turnover have to be confirmed in human, and pharmacological and tolerance problems have to be solved.     

Current and potential future drug treatments for osteoporosis.

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 been examined, and this will have to be individually tailored. Other approaches include trying to increase peak bone mineral density, although influencing the young to prevent a disease that may not manifest itself for half a century is daunting.     

Osteoporosis associated with rheumatoid arthritis: pathogenesis and management

Rheumatoid arthritis is associated with both localized and generalized osteoporosis. Localized osteoporosis can be considered to be caused by local disease mechanisms, including the generation of factors from activation of the cytokine pathway. The etiology of generalized osteoporosis has been difficult to elucidate, particularly because of the lack of sensitive techniques to measure bone mineral density. The introduction of single- and dual-photon absorptiometry and quantitative computed tomography has allowed more accurate assessment of bone mineral density. In general, bone mineral density loss at appendicular sites does not correlate well with axial bone density loss. Corticosteroid treatment exaggerates the development of osteoporosis in up to 40% of patients with rheumatoid arthritis. Sex hormone status, physical activity, disease duration, and functional class are all significant predictors for the development of osteoporosis. Current therapy for prevention and treatment is based largely on theoretical considerations. Physical activity should be encouraged once acute joint inflammation has settled. Postmenopausal women and amenorrheic premenopausal women will benefit from cyclical estrogen replacement. Patients with low serum 1,25-dihydroxy vitamin D3 levels, and males with low serum testosterone levels, are candidates for replacement therapy with the appropriate hormones. In patients who are receiving corticosteroids the dose should be limited, and oral calcium supplements are of benefit. The use of the newer corticosteroid deflazacort, and disease-modifying immunosuppressive drugs, are discussed. Other therapeutic options which should be considered, although published trials are scarce, are calcitonin and the diphosphonates. Further studies are awaited concerning the optimum prevention and treatment of osteoporosis associated with rheumatoid arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)     

双膦酸盐类药物治疗骨质疏松症药物假期的研究进展

骨质疏松症是绝经后妇女和老年男性的常见病。双膦酸盐是治疗骨质疏松症的一线药物,其具有残留作用,在用药结束后仍可发挥抑制破骨细胞功能的作用。尽管双膦酸盐类药物的用药安全性已被证实,但长期使用可出现一些潜在不良反应,包括非典型性股骨骨折及双膦酸盐性下颌骨坏死等,这已引起越来越多专家的注意。施行药物假期的目的是在尽可能保证骨质疏松患者骨量及骨密度的情况下减少使用双膦酸盐类药物的使用,以期将其长期使用可能带来的不利因素降到最低。在药物假期期间,应合理监测相关骨指标,如有骨密度值明显降低或者新发骨折,即应立刻开始重新治疗。     

Managing osteoporosis in ulcerative colitis: Something new?

The authors revise the latest evidence in the literature regarding managing of osteoporosis in ulcerative colitis(UC), paying particular attention to the latest tendency of the research concerning the management of bone damage in the patient affected by UC. It is wise to assess vitamin D status in ulcerative colitis patients to recognize who is predisposed to low levels of vitamin D, whose deficiency has to be treated with oral or parenteral vitamin D supplementation. An adequate dietary calcium intake or supplementation and physical activity, if possible, should be guaranteed. Osteoporotic risk factors, such as smoking and excessive alcohol intake, must be avoided. Steroid has to be prescribed at the lowest possible dosage and for the shortest possible time. Moreover, conditions favoring falling have to been minimized, like carpets, low illumination, sedatives assumption, vitamin D deficiency. It is advisable to assess the fracture risk in all UC patient by the fracture assessment risk tool(FRAX tool), that calculates the ten years risk of fracture for the population aged from 40 to 90 years in many countries of the world. A high risk value could indicate the necessity of treatment, whereas a low risk value suggests a followup only. An intermediate risk supports the decision to prescribe bone mineral density(BMD) assessment and a subsequent patient revaluation for treatment. Dual energy X-ray absorptiometry bone densitometry can be used not only for BMD measurement, but also to collect data about bone quality by the means of trabecular bone score and hip structural analysis assessment. These two indices could represent a method of interesting perspectives in evaluating bone status in patients affected by diseases like UC, which may present an impairment of bone quality as well as of bone quantity. In literature there is no strong evidence for instituting pharmacological therapy of bone impairment in UC patients for clinical indications other than those that are also applied to the patients with osteoporosis. Therefore, a reasonable advice is to consider pharmacological treatment for osteoporosis in those UC patients who already present fragility fractures, which bring a high risk of subsequent fractures. Therapy has also to be considered in patients with a high risk of fracture even if it did not yet happen, and particularly when they had long periods of corticosteroid therapy or cumulative high dosages. In patients without fragility fractures or steroid treatment, a medical decision about treatment could be guided by the FRAX tool to determine the intervention threshold. Among drugs for osteoporosis treatment, the bisphosphonates are the most studied ones, with the best and longest evidence of efficacy and safety. Despite this, several questions are still open, such as the duration of treatment, the necessity to discontinue it, the indication of therapy in young patients, particularly in those without previous fractures. Further, it has to be mentioned that a longterm bisphosphonates use in primary osteoporosis has been associated with an increased incidence of dramatic side-effects, even if uncommon, like osteonecrosis of the jaw and atypical sub-trochanteric anddiaphyseal femoral fractures.UC is a long-lasting disease and the majority of patients is relatively young.In this scenario primary prevention of fragility fracture is the best cost-effective strategy.Vitamin D supplementation,adequate calcium intake,suitable physical activity(when possible),removing of risk factors for osteoporosis like smoking,and avoiding falling are the best medical acts.