Curing Your Osteoporosis Permanently

The Osteoporosis Reversing Breakthrough

eres just a few things youll learn about how to get back into health. and conquer Osteoporosis. Those not-so innocent yet everyday substances that are currently attacking your body, perpetuating and aggravating your Osteoporosis. What to do and what Not to do to overcome your Osteoporosis effectively and permanently. How to create the energy you need to be able to work full time and feel confident you will be able to take care of your loved ones. How the pharmaceutical and food industry are conspiring to poison you and make you sick (Hint: American medical system is now the leading cause of death in the US). Which food industries use advertising to encourage doctors to tell you that their food is good for you just like those cigarette ads in the 1950s! The single most effective fruits and vegetables in cleaning up excess acidic waste and how to cleanse your inner terrain completely from systemic acidosis. Why, what your Doctor has told you is wrong, and why many medications actually increase the side effects and complications of Osteoporosis (primarily by depleting vital vitamins, minerals and nutrients from your body). Which supplements every patient must take to stop the symptoms and boost your body's ability to reverse Osteoporosis. How to naturally reduce your cravings for toxic foods. Lifestyle and food choices to reverse your Osteoporosis fast, naturally, and for good. Why treating the symptoms of disease is like using an umbrella inside your house instead of fixing the roof. The most powerful creator of health (Hint: its not a food or vitamin!) The best way to simplify the task of making a health-conscious lifestyle adjustment. A miraculous scientific discovery that jump-starts your body to do its natural work, which is to heal itself and restore your Health.

The Osteoporosis Reversing Breakthrough Summary

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Author: Matt Traverso
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Screening for osteoporosis and osteopenia

Normal bone density is defined as a bone mineral density (BMD) value within one standard deviation of the mean value in young adults of the same sex and race. B. Osteopenia is defined as a BMD between 1 and 2.5 standard deviations below the mean. C. Osteoporosis is defined as a value more than 2.5 standard deviations below the mean this level is the fracture threshold. These values are referred to as T-scores (number of standard deviations above or below the mean value).

Of the National Osteoporosis Foundation

All women should be counseled about the risk factors for osteoporosis, especially smoking cessation and limiting alcohol. All women should be encouraged to participate in regular weight-bearing and exercise. B. Measurement of BMD is recommended for all women 65 years and older regardless of risk factors. BMD should also be measured in all women under the age of 65 years who have one or more risk factors for osteoporosis (in addition to menopause). The hip is the recommended site of measurement. C. All adults should be advised to consume at least 1,200 mg of calcium per day and 400 to 800 IU of vitamin D per day. A daily multivitamin (which provides 400 IU) is recommended. In patients with documented vitamin D deficiency, osteoporosis, or previous fracture, two multivitamins may be reasonable, particularly if dietary intake is inadequate and access to sunlight is poor.

Osteoporosis and Fracture Risk

Osteoporosis is a reduction in bone mass and bone microarchitecture leading to increased bone fragility and fracture risk. The most common cause of osteoporosis is increased bone turnover with excessive bone resorption (destruction) that exceeds bone formation. Among women, this is often caused by estrogen deficiency following menopause. A second large and independent contributor is glucocorticoid use. Later in life, a combination of vitamin D insufficiency, reduced 1,25(OH)2-vitamin D3 production and inadequate calcium nutrition contribute to bone loss in both men and women. Both menopause and glucocorticoid use cause an imbalance between the processes of bone resorption (removal) and formation, leading to bone loss. A woman can experience a loss of up to 5 of her bone mass per year during the first half decade postmenopause. There exists a correlation between the reduction in bone mineral density1-4 and or increased bone turnover5-7 with increased fracture risk.

Metabolic Bone Diseases and Drug Induced Osteoporosis

Metabolic Bone Disease Cats

Bone scintigraphy has traditionally been considered to be not as useful as radiography in the study of metabolic bone diseases including senile or postmenopausal osteoporosis, osteo-dystrophy, drug-induced osteoporosis, and rickets and osteomalacia. However, aided by the pinhole technique, 99mTc-MDP bone scin-tigraphy has been shown to be able to portray characteristic features in systemic and local osteoporosis or osteopenia, which is defined as a state of reduced bone mass with increased cavity. Rickets and osteomalacia, a state of deficient formation of inadequately mineralized osteoid, can also be efficiently diagnosed by bone scintigraphy. Indeed, it is well known that bone scintigraphy is highly sensitive and reli- Fig. 15.1 Usefulness of whole-body bone scintigraphy in the study of systemic osteoporosis. Anterior (left) and Fig. 15.1 Usefulness of whole-body bone scintigraphy in the study of systemic osteoporosis. Anterior (left) and able for detecting fractures and infractions...

Issues in Preclinical and Clinical Development for Drugs to Treat Osteoporosis

The clinical development of drugs for the treatment of osteoporosis is required to satisfy specific regulatory guidelines prior to approval for marketing. In 1994, the US FDA released draft guidelines covering preclinical and clinical development of osteoporosis drugs of postmenopausal osteoporosis.52 The World Health Organization has developed similar guidelines53 and these are available on its website. The FDA guidelines are under current review and variations may be expected. In addition, as these guidelines have continuing draft status, particular requirements could be open to negotiation, as shown by the recent approval of teriparatide (PTH 1-34), with phase III data of approximately 2 years' duration rather than the 3 years described in the guidelines.

Transient Osteoporosis with Bone Marrow Edema

Can Marrow Edema Painful

This condition has been proposed as a syndrome that is associated with osteoporosis (Wilson et al. 1988). These authors reported ten patients with hip or knee pain whose radiographs were either normal or minimally os-teopenic at the diseased site. Bone scintigraphy showed increased tracer uptake, and MRI demonstrated decreased signal intensity on T1- weighted images and increased signal intensity on T2-weighted images, denoting hyperemia and edema. Clinical symptoms slowly resolved over a period of months and did not recur. In one case, intense uptake in the right femoral head returned to a near-normal state after 8 months. Marrow edema might be a coincidental process, but its association with regional osteoporosis cannot be denied. In essence, edema is a nonspecific response of marrow tissue to a variety of physical stresses or injuries (Moore et al. 1991), and is associated with an increased amount of extracellular water as a result of hyperperfusion (Wilson et al. 1988)....

Transient Regional Osteoporosis

Radiographic Pictures Osteoporosis

Two closely related types of transient regional osteoporosis have been described transient osteoporosis of the hip and regional migratory osteoporosis. Classically, these two conditions have been dealt with as separate entities because of the difference between the involved Clinically, both diseases show rapidly developing, painful osteoporosis in periarticular bones, without definite precipitating causes such as trauma or immobilization. The disease is self-limited and resolves spontaneously over a period from months to a year. Transient osteoporosis of the hip is usually unilateral, affecting men and women equally, with a predilection for the young and middle-aged. The onset is either abrupt or gradual, and pain becomes worse on weight bearing. On the other hand, regional migratory osteoporosis occurs in the periarticular bones of the knee, ankle, and foot and the humerus. As the term indicates, the painful lesions move from bone to bone. More than one bone may be involved at one...

Involutional Osteoporosis

Compression Fracture Vertebrae

Involutional osteoporosis includes senile osteoporosis and postmenopausal osteoporosis. The reported incidences vary according to the diagnostic method used and the population studied. One radiographic study of spinal osteoporosis in a series of ambulatory women aged between 45 and 79 years recorded an incidence of 29 (Smith et al. 1960). Most recent studies have indicated a prevalence of 50 in women and 20 in men in their late seventies (Fujiwara 2004) and 11.4 in women of 50 years or older and 1.6 in men of the same age group (Yang et al. 2006). Osteoporosis reflects the state of bone mass reduction that makes the bone brittle and fragile. Postmenopausal osteoporosis typically affects women in the sixth and seventh decades of life. In addition to reduced estrogen level, lowered physical activity and nutritional state are related to this condition. Histologically, involutional osteoporosis is characterized by a disproportionate reduction of the trabecular Fig. 15.5A, B Involutional...

Osteoporosis

Over 1.3 million osteoporotic fractures occur each year in the United States. The risk of all fractures increases with age among persons who survive until age 90, 33 percent of women will have a hip fracture. The lifetime risk of hip fracture for white women at age 50 is 16 percent. Osteoporosis is characterized by low bone mass, microarchitectural disruption, and increased skeletal fragility.

Primary Nursing Diagnosis

The treatment prescribed is based on the acuity and severity of the symptoms. Some patients are treated pharmacologically with corticosteroids to relieve edema and analgesics to manage joint and GI discomfort. Allergy testing to identify the provocative allergen is usually performed. If the allergen is a food or medication, the patient needs to avoid ingesting the allergen for the rest of his or her life. Patients who are placed on corticosteroids or immunosuppressive therapy need an environment that protects them as much as possible from secondary infection. If the patient is on corticosteroids, monitor her or him for signs of Cushing's syndrome and the complications of corticosteroids, such as labile emotions, fluid retention, hyperglycemia, and osteoporosis.

Role of Bone Compliance

Detailed identification of the role of vertebral compliance in joint biomechanics is essential in areas such as prosthetic replacement of segmental elements, in vitro experimental studies, and in vivo measurements of joint displacements through bony posterior elements. Changes in bone material properties are also known to occur with aging, remodeling, and osteoporosis 75-77 . The joint biomechanics, as well as degenerative processes, therefore, could be affected by changes in the structure and density of the bony vertebrae. Moreover, rigid simulation of bony elements, if found reliable in yielding accurate results, Alteration in the relative stiffness of bony elements noticeably affects the joint biomechanical response in terms of both the gross response and the state of stress and strain in various components. The extent of change depends on the magnitude and type of applied loads. The results of this investigation suggest that changes in bone properties associated with the aging,...

Histology and Physiology of Bone

Living bone is continuously renewed by production and resorption that are mediated through the bioactivities of the osteoblasts and osteoclasts, respectively. The bone turnover is well balanced and in a state of equilibrium unless disturbed by disease and or disuse. When bone production is out-balanced by bone resorption or destruction, as in acute osteomyelitis, tumor, or immobilization, osteolysis or osteopenia may ensue. In a reverse condition, osteoblastic reaction predominates, resulting in osteosclerosis or increased bone density.

Selective Estrogen Receptor Modulation

In the 1960s and 1970s, antiestrogenicity was correlated with antitumor activity. However, the finding that nonsteroidal antiestrogens expressed increased estrogenic properties, i.e., vaginal cornification and increased uterine weight in the mouse, raised questions about the reasons for the species specificity. One obvious possibility was species-specific metabolism, i.e., the mouse converts antiestrogens to estrogens via novel metabolic pathways. However, no species-specific metabolic routes to known estrogens were identified but knowledge of the mouse model created a new dimension for study that ultimately led to the recognition of the target site-specific actions of antiestrogens. This concept was subsequently referred to as selective estrogen receptor modulation (SERM) to describe the target site-specific effects of raloxifene (see 8.09 Raloxifene), an antiestrogen originally targeted for an application in breast cancer but now used, paradoxically, as a preventive for...

Current Chemoprevention

The promise of the chemoprevention for breast cancer is becoming a reality. However, there are many challenges. Tamoxifen, the pioneering medicine, is considered by many to be too controversial to be widely used as a chemopreventive. However, there are no alternatives for the premenopausal woman at high risk for breast cancer and the good news is that this risk group has the best risk-benefit ratio.214 For postmenopausal women, where the side effects are well defined, the future depends on the results of current clinical trials with raloxifene or aromatase inhibitors. Unfortunately, there are no comparisons of a SERM with an aromatase inhibitor so the choice of a chemopreventive strategy will need to be made on a patient-by-patient basis. In other words, the options are the use of raloxifene or an aromatase inhibitor with bone monitoring and a bisphosphonate to avoid osteoporosis.

Background and Introduction

The female sex hormone estrogen plays an essential role in reproduction and is important for the overall maintenance of physiologic homeostasis in a woman's body.1'2 During menopause, which occurs in women at an average age of 51, the amount of estrogen produced by the ovaries decreases and this estrogen deficiency causes menstrual periods to become less frequent and then stop.3-5 The loss of estrogen is responsible for many of the uncomfortable symptoms associated with menopause, including hot flashes, mood swings or depression, sleep disorders, vaginal dryness, and urinary dysfunction.6 Osteoporosis or bone loss is another consequence of reduced estrogen levels after menopause.7-11 In women, bone density increases until ages 30-35,12 but slowly declines after menopause.13 Postmenopausal women are also at increased risk for coronary heart disease (CHD)14,15 and Alzheimer's disease,16-18 as a result of estrogen deficiency. The realization that the symptoms reported by postmenopausal...

Raloxifene and Breast Cancer Prevention

The rationale for the use of SERMs, including raloxifene, as breast cancer preventives is based on a strategic hypothesis formulated when SERM action was first recognized in the late 1980s. The evidence to support the use of raloxifene in this paradigm stems from observations made in the laboratory91,96 and the clinic165 along with close monitoring of ongoing osteoporosis placebo-controlled trials. Previous studies have shown that raloxifene inhibits the growth of dimethylbenzanthracene-induced rat mammary carcinoma94 but it prevents mammary cancer by reducing the incidence of N-nitrosomethylurea-induced tumors91'92 if given after the carcinogen but before the appearance of palpable tumors. However, as would be anticipated with a drug that has a short biological half-life, raloxifene is not superior to tamoxifen at equivalent doses.91 Studies have shown that raloxifene, when administered orally, is rapidly absorbed from the gastrointestinal tract and undergoes extensive phase II...

Rank order of hazards from food components

In general, in developed countries food safety is adequate. However, it should be noted that the information on the (chronic) toxicity of natural food components is insufficient. Further, a number of important health problems such as cardiovascular disorders, diabetes, osteoporosis, obesity, allergy, and cancer are believed to be related to nutrition. Nutritional interventions could drastically reduce the incidence of these diseases.

Musculoskeletal System

The development of osteoporosis in middle-age men is uncommon except in male alcoholics, where decreased bone mass has been documented (Turner, 2000). In women, improvement in bone mass has been shown with moderate alcohol use, especially in postmenopausal women (Laitinen et al., 1993).

Glucocorticoid Therapy

With short-term use, glucocorticoids are practically free of adverse effects, even at the highest dosage. Long-term use is likely to cause changes mimicking the signs of Cushing's syndrome (endogenous overproduction of cortisol). Sequelae of the anti-inflammatory action lowered resistance to infection, delayed wound healing, impaired healing of peptic ulcers. Sequelae of exaggerated glucocor-ticoid action a) increased gluconeogen-esis and release of glucose insulin-dependent conversion of glucose to triglycerides (adiposity mainly noticeable in the face, neck, and trunk) steroid-diabetes if insulin release is insufficient b) increased protein catabolism with atrophy of skeletal musculature (thin extremities), osteoporosis, growth retardation in infants, skin atrophy. Sequelae of the intrinsically weak, but now manifest, mineralocorticoid action of cortisol salt and fluid retention, hypertension, edema KCl loss with danger of hypokalemia.

Selective estrogen receptor modulators

Raloxifene (Evista) (5 mg daily or a once-a-week preparation) is a selective estrogen receptor modulator (SERM) for prevention and treatment of osteoporosis. It increases bone mineral density and reduces serum total and low-density-lipoprotein (LDL) cholesterol. It also appears to reduce the incidence of vertebral fractures and is one of the first-line drugs for prevention of osteoporosis. ment of osteoporosis. Venous thromboembolism is a risk.

Sources of Estrogens in Women

A new synthetic steroid tibolone with a combination of weak estrogenic, progestoge-nic, and androgenic activity is also available for HRT (14). Additionally, selective estrogen receptor modulators (SERMS), such as raloxifene are used for the treatment of osteoporosis and it is likely that vascular-specific SERMS will also soon be available (15). Furthermore, phytoestrogens, a diverse group of compounds found in various plant-derived foods and beverages, can have both estrogenic and antiestrogenic effects (16).

Synovitis in Renal Transplantation and Prolonged Hemodialysis

Soft-tissue radiography shows distension of the articular capsule and periarticular soft-tissue swelling when the process has run a chronic course or in the presence of infection (Fig. 8.7A) and bone technique radiography demonstrates articular narrowing with diffuse periarticular osteopenia (Fig. 8.7B).

Gender Ethnicracial And Life Span Considerations

Hypocalcemia can occur at any age, in both sexes, and in all races and ethnicities, but infants, children, and the elderly are at high risk. In infants, it occurs when cow's milk formula with a high concentration of phosphate is given. The large bone turnover during growth spurts accounts for hypocalcemia in children, especially if their calcium intake is deficient. Osteoporosis in the elderly is associated with a lifetime low intake of calcium, which leads to a total body calcium deficit.

Disorders of the Small Intestine

Treatment for celiac disease is to follow a strict gluten-free diet. You will need to avoid wheat, rye, barley, and other grains that contain gluten. You also will need to watch for hidden gluten in foods such as pasta and beer. Rice and corn are safe to eat, and gluten-free flour and other food products also are available. Symptoms will begin to improve within a few days of beginning the diet, though full recovery may take up to 2 years. If left untreated, celiac disease can lead to intestinal cancer, osteoporosis (see page 301), and seizures.

Alternative Therapies to Hormone Replacement Therapy

SERMs are nonsteroidal estrogenic compounds with both estrogenic agonist (on bone and lipoproteins) and estrogenic-antagonist (on breast and endometrium) effects in use for the treatment of osteoporosis. Although SERMs have shown beneficial effects on some surrogate markers of CVD it is not known whether this will translate into clinical benefit. The recent secondary analysis of the osteoporosis prevention study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, suggested that there were no significant differences between raloxifene and placebo group regarding combined CHD and CVD events. Interestingly, however, in the subset with increased cardiovascular risk, the raloxifene group had a significantly lower risk of CVD events compared with placebo (99). The Raloxifene Use for the Heart Studyis currently testing the impact of raloxifene on cardiovascular endpoints in postmenopausal women. The results of this trial will provide information on the net clinical cardiovascular...

Disorders of the Bones

Osteoporosis Osteoporosis is a disease in which the bones become thin, porous, weak, and more susceptible to fractures. Although osteoporosis is generally regarded as a women's health concern, the disease also can develop in men. Because men have larger, denser skeletons, they usually experience bone loss later in life than women. However, older men are at increased risk for hip fracture and other joint fractures as a result of osteoporosis. Men and women lose bone mass at an increased rate after age 65, and calcium absorption decreases with age in both sexes. About a third of men over age 75 have been diagnosed with osteoporosis, and one of every eight men over age 50 will experience a bone fracture as a result of osteoporosis. Therefore all men need to take steps to prevent osteoporosis (see following page). Bone mass increases throughout childhood and young adulthood, reaching its peak at about age 20. After age 35, bone tissue breaks down faster than new bone is formed. Bone...

The Plumbing Of Long Bones

Bone Lamellae Lacunae And Trabeculae

Blood and interstitial fluid have many functions in bone. They transport nutrients to, and carry waste from, the bone cells (osteocytes) buried in the bony matrix. They are involved in the transport of minerals to the bone tissue for storage and the retrieval of those minerals when the body needs them. Interstitial flow is thought to have a role in bone's mechanosensory system. Bone deformation causes the interstitial flow over the bone cell membrane the shear stress of the flowing fluid is sensed by the cell 1,2,3 . A full physiological understanding of this mechanosensory system will provide insight into the following three important clinical problems (a) how to maintain the long term stability of bone implants, (b) the physiological mechanism underlying osteoporosis, and (c) how to maintain bone in long-duration space flights and long-term bed rest.

Follicular Growth and Ovulation Estrogen and Progestin Production

Estrogen Follicular Growth

Ethinylestradiol (EE) is more stable metaboli-cally, passes largely unchanged through the liver after oral intake and mimics estradiol at estrogen receptors. Mestranol itself is inactive however, cleavage of the C-3 methoxy group again yields EE. In oral contraceptives, one of the two agents forms the estrogen component (p. 256). (Sulfate-)conjugated estrogens can be extracted from equine urine and are used for the prevention of post-menopausal osteoporosis and in the therapy of climacteric complaints. Because of their high polarity (sulfate, glu-curonide), they would hardly appear suitable for this route of administration. For transdermal delivery, an adhesive patch is available that releases estradiol transcutaneously into the body. Indications for estrogens and progestins include hormonal contraception (p. 256), hormone replacement, as in postmenopausal women for prophylaxis of osteoporosis bleeding anomalies, menstrual complaints. Concerning adverse...

Osteomyelitis of the Spine

What Vertebral Endplate

Fig. 6.30 (Uni)concave and biconcave endplate deformities in spinal compression fractures. Posterior pinhole scan of the lumbar spine in an elderly woman with marked osteoporosis shows biconcave deformity in the L2 vertebra (open arrows) and (uni)concave deformity in L4 due to compression fractures (arrow). The former fractures were older than the latter, and hence show less intense tracer uptake. Note that the disk spaces are not narrowed Fig. 6.30 (Uni)concave and biconcave endplate deformities in spinal compression fractures. Posterior pinhole scan of the lumbar spine in an elderly woman with marked osteoporosis shows biconcave deformity in the L2 vertebra (open arrows) and (uni)concave deformity in L4 due to compression fractures (arrow). The former fractures were older than the latter, and hence show less intense tracer uptake. Note that the disk spaces are not narrowed

Regulation of osteoblasts

Wnt proteins signal through b-catenin and are important in bone metabolism, as absence of Wnt signaling induces osteopenia and constitutive activation of the Wnt pathway produces a high-bone-mass phenotype in human patients. Wnts appear to have an important role in osteoblast lineage commitment and in providing autocrine signals vital for full osteoblast differentiation. The human high-bone-mass phenotype in particular has provided strong validation for the concept that a Wnt pathway agonist could have bone anabolic actions.21

Diseases of Bone Epidemiology and Diagnosis

6.21.3.1 Metabolic Bone Diseases 6.21.3.1.1 Osteoporosis Osteoporosis is defined as a chronic skeletal disorder characterized by compromised bone strength. The latter is caused by, or associated with, low bone mass and changes in bone size and geometry, bone turnover, and microarchitecture. Compromised bone strength leads to enhanced bone fragility, which predisposes to an increased risk of fracture. 'Minimal-trauma fractures' are the hallmark and major complication of osteoporosis, causing substantial morbidity, excess mortality, and high cost. Amongst the metabolic bone diseases, osteoporosis is by far the most frequent one. The World Health Organization defines osteoporosis as a BMD of 2.5 standard deviations (SD) or more below the mean for young healthy individuals. According to this definition, approximately 30 of all postmenopausal women and 20 of all men older than 60 years of age have osteoporosis. The incidence of osteoporosis and of osteoporotic fractures increases with age...

Preclinical Study Requirements

In addition to the normal toxicological and pharmacological studies required, there is a specific requirement for pharmacology studies in two different recognized animal models of osteoporosis. One of these studies should be conducted in an oophorectomized rat model and be of 12 months' duration. A second study should be in a large-animal model that shows full skeletal remodeling (sheep, pigs, and primates are given as good examples, but the validity of dog models is questioned). The large-animal study should be of 16 months' duration. The purpose of these studies is to demonstrate that the new chemical entity (NCE) tested does not have deleterious effects on bone quality, despite positive effects on bone mass. This requirement reflects a concern initially raised about fluoride, which increases BMD but can reduce bone strength. Reflecting the concerns regarding bone quality, these two pharmacology studies must include evaluation of bone quality as endpoints. This can be achieved,...

Clinical Study Requirements

Phase II studies extend safety data, confirm biological activity of the NCE in humans, and define dose and dosing frequency for phase III trials. For osteoporosis NCEs, phase II trials are typically 1 year in duration and utilize BMD measurement as the primary clinical endpoint. Surrogate markers of bone remodeling can also be used as these give excellent information to assess dose responses, maintenance of pharmacological action, and mechanism of action. Bone biopsy and histomorphometry provide information regarding NCE mechanism of action and maintenance or improvement in bone quality. However, given the competitive market for osteoporosis drugs that already show fracture benefit, commercial considerations likely make the generation of data demonstrating fracture benefit an imperative. It is possible that shorter trials showing fracture benefit will be accepted, as was the case with teriparatide. All subjects should receive calcium and vitamin D supplementation, with a total calcium...

Clinical Use of Alendronate Fosamax

Alendronate (ALN) has had the most extensive clinical use to date in terms of the number of patients, over 4 million, and duration of monitored treatment, over 10 years. Its ability to reduce hip and other fractures is documented in large randomized placebo-controlled clinical trials, and 10 years of follow-up data are available from the extension of phase III ALN clinical trials.8 ALN is widely used for the treatment and prevention of osteoporosis in postmenopausal women and glucocorticoid-treated patients of both genders.9-16 ALN has been proven effective in significantly reducing the incidence of both vertebral and nonvertebral fractures, including those of the hip. The reduced risk of vertebral fracture is also associated with less height loss,17 as well as a significant reduction in the number of days where patients experience disability.18 Because ALN acts via a nonhormonal pathway, it has also been effectively used to increase bone mass associated with a number of different...

Mean LOS 49 days Description Medical Bone Diseases and Specific Arthropathies with CC

(Osteoporosis is an age-related metabolic disease that is defined as low bone mass with a normal ratio of mineral to osteoid, the organic matrix of bone. Approximately 10 million Americans have osteoporosis and another 14 million have low bone mass, or osteopenia. With the aging of the U.S. population, osteoporosis is expected to increase and hip fractures are expected to rise to 750,000 per year by the year 2050. Bone demineralization results in decreased density and subsequent fractures as bone resorption occurs faster than bone formation. The general reduction in skeletal bone mass occurs as bones lose calcium and phosphate, become brittle and porous, and develop an increased susceptibility to fractures. Common sites for fractures are the wrist, hip, and vertebral column. Osteoporosis can be classified as primary or secondary. Primary osteoporosis is more common and is not associated with an underlying medical condition. Secondary osteoporosis results from an associated underlying...

Goals Of Clinical Trials

The objective of this study is to evaluate the efficacy and safety of the test drug under investigation with a placebo in the treatment of postmenopausal women with osteoporosis. 1. This trial is a randomized, double-blind, placebo-controlled trial conducted in x centers to evaluate the efficacy based on bone mineral density (BMD) of the test drug under investigation at dose y, frequency z, compared to a placebo, in the treatment of postmenopausal women with osteoporosis. 2. This trial is a randomized, double-blind, placebo-controlled trial conducted in x centers to evaluate the safety of the test drug under investigation at dose y, frequency z, compared to a placebo, in the treatment of postmenopausal women with osteoporosis.

Discharge And Home Healthcare Guidelines

Reinforce the medication, exercise, and diet plan. Provide a hazard-free environment to prevent falls. Apply orthotic devices correctly. Remove scatter rugs, provide good lighting, and install handrails in the bathroom. Be sure the patient understands all medications, including the dosage, route, action, and side effects. If the patient is placed on estrogen therapy, she needs routine gynecologic checkups to detect early signs of cervical cancer. Consider placement in a nursing home if a patient cannot return home. Communicate the special needs of the patient on the transfer chart. The need for physical or occupational therapy, social work, and homemaking personnel is determined by the home care nurse. Facilitate the procurement of needed orthotic devices or ambulation aids before the patient goes home. The Osteoporosis Foundation provides information to clients regarding the disease and its treatment.

New Research Areas

Large, long-term clinical trials are needed in males over the age of 50 years to determine the benefits and risks of androgen replacement therapy. These studies could determine if cardiovascular risk, prostate cancer, frailty, fractures, osteoporosis, cognitive function, and life expectancy are influenced by androgen replacement therapy. A critical area of uncertainty is what testosterone concentration is needed to provide adequate androgenic effects. This is an important question because it relates to the concentration of testosterone where benefits might or might not be expected. Should free, bioavailable, or total testosterone concentrations be used

Mechanism of Action at the Tissue Level

Osteoporosis and other types of bone loss are associated with increased bone turnover and elevated levels of bone resorption. Osteoclastic bone resorption is a 2-week process that begins the bone remodeling process. Resorption itself can be effectively slowed or controlled by inhibiting osteoclast generation, reducing osteoclast activity, or both. ALN is one of the most effective inhibitors of bone resorption. ALN improvement of mechanical strength, reflected in a reduction in fracture risk, is caused by an increase in bone mass and mineralization (discussed above) as well as by an improvement in architecture, attributable to a reduction in bone turnover. A higher number of bone remodeling sites, where excessive osteoclastic destruction of bone takes place, leads to loss of bone tissue, formation of areas of stress concentration, and increased fracture risk. By reducing turnover, bisphosphonates reverse this condition. Effects on bone turnover can be estimated by measuring either...

Vitamins and Minerals Interact with Each Other

Vitamin and mineral supplements have several other significant features that must be taken into account. First, complex interactions occur between vitamins and minerals. As a result, high doses of a single vitamin or mineral may be harmful or ineffective. For example, excessive vitamin C intake may affect the body's ability to absorb copper, and high doses of vitamin B-may produce deficiencies of vitamins B2 and Bg. Also, calcium cannot be utilized for bone health without adequate levels of vitamin D.

Experimental Disease Models

One of the most significant current clinical trials involving the endocrine modulation of breast cancer is the Study of Raloxifene and Tamoxifen, or STAR. This is a large phase III, double-blind trial in which postmenopausal women are assigned to take tamoxifen (20mgday_ or raloxifene (60mgday_ for 5 years. The primary aim of this trial is to compare these two selective estrogen receptor modulators (SERMs) directly for efficacy and safety parameters with respect to breast cancer, coronary heart disease, and osteoporosis. In particular, the effects of long-term raloxifene therapy on preventing the occurrence of invasive breast cancer in postmenopausal women who are identified as being at risk for the disease will be investigated. The interaction of the estrogen receptor with its natural ligand, 17 -estradiol (E2), mediates a number of fundamental physiological processes, including regulation of the female reproductive system and the maintenance of skeletal and cardiovascular health....

Vitamin D and Calcium

Vitamin D is well recognized for its role in maintaining the health of bones. Vitamin D and calcium work together to make dense, strong bones. Low levels of vitamin D may lead to severely decreased bone density, a condition known as osteoporosis. A less severe form of decreased bone density is referred to as osteopenia. Although studies of osteoporosis often focus on elderly women, it is increasingly recognized that osteoporosis affects many other population groups. Among people with MS, several possible risk factors exist for osteoporosis and low vitamin D levels People with MS are more likely to be women and to be less physically active than the general population women and inactive people are at increased risk for osteoporosis. Steroids, which are sometimes used to treat MS attacks, may cause osteoporosis. The significance of this steroid effect is unclear in people with MS. Given these multiple factors, one would expect an increased prevalence of osteoporosis in people with MS. In...

Prevention of dementia II

Selective prevention strategies are directed towards individuals at high risk with established risk factors for a disease. Common examples include weight reduction in overweight people to reduce the risk of coronary artery disease and diabetes, smoking cessation to reduce the risk of lung, heart and blood vessel disease, and increased calcium intake in people with osteoporosis to reduce the risk of fractures. Some dementia prevention strategies in this category may be useful for everybody, not just those with risk factors for dementia, and I indicate those which are most promising. Not all established dementia risk factors currently have effective preventive strategies.

Design of Inhibitors Binding to SH2 Domains

Src is the prototype of a nonreceptor protein tyrosine kinase. Its activation in human tumors such as breast cancer has been reported.130 In addition, Src-deficient mice exhibit osteoporosis or hypertrophy of bones, indicating disturbed osteoclast function.131'132 Thus, inhibiting Src function in vivo may inhibit tumor growth and be useful for treatment of osteoporosis. Nonreceptor tyrosine kinases generally require SH2 domains for efficient substrate phosphorylation.129 Therefore SH2 inhibition is likely to suppress phosphorylation and downstream signaling. Src kinase is normally held in an inactive conformation via an intramolecular interaction between its SH2 domain and a tyrosine-phosphorylated C-terminal residue, pTyr527. This is shown in Figure 20a, which shows the 3D structure of src kinase as a ribbon plot, including the interaction of the phosphorylated tyrosine pTyr527 with the SH2 domain.133 The disruption of this interaction leads to an activation of the kinase. Tyr527...

Surgical Other Kidney and Urinary Tract Operating Room Procedures

All individuals with CRF experience similar physiological changes, regardless of the initial cause of the disease. The kidneys are unable to perform their normal functions of excretion of wastes, concentration of urine, regulation of blood pressure, regulation of acid-base balance, and production of erythropoietin (the hormone needed for red blood cell production and survival). Complications of CRF include uremia (accumulation of metabolic waste products in the blood and body tissues), anemia, peripheral neuropathy, sexual dysfunction, osteopenia (reduction of bone tissue), pathological fractures, fluid overload, congestive heart failure, hypertension, pericarditis, electrolyte imbalances (hypocalcemia, hyperkalemia, hyperphosphatemia), metabolic acidosis, esophagitis, and gastritis.

Example The Estrogen Receptor

This section describes examples of usage of the methods that were introduced above. Molecular dynamics simulations have proven useful for drug design purposes on many different targets.88-103 Here, we will focus on the ligand-binding domain of the estrogen receptor. The estrogen receptor is a member of the nuclear hormone receptors and plays a key role in the growth, development, and maintenance of a diverse range of tissues. It consists of an N-terminal DNA-binding domain, a ligand-binding domain, and a C-terminal activation domain. Upon binding of an agonist to the ligand-binding domain a conformational change in the estrogen receptor takes place, allowing it to homodimerize and subsequently to translocate to the nucleus. Here, the DNA-binding domain directly interacts with response elements on the DNA, thereby activating or repressing transcription.104 Apart from the physiological effects, the estrogen receptor is involved in a range of diseases such as breast cancer, osteoporosis,...

Biosynthesis Of Hypericin

Arabidopsis Transformation

Dietary supplements of ephedrine plus caffeine for weight loss (weight loss being the current first-line recommendation of physicians for osteoporosis) show some promise, but are not sufficient in number of study subjects. Ephedrine is a sympathomimetic amine with effects similar to those of adrenaline it is produced by Ephedra (or ma huang), which has been used by the Chinese for at least 5,000 years. Ephedrine has resulted in deaths and hence is worrisome as an over-the-counter dietary supplement (Fillmore et al., 1999). Ephedrine has been described as a causative factor of vasculitis but myocarditis has not yet been associated with either ephedrine or its plant derivative ephedra (Zaacks et al, 1999). The content of ephedra alkaloids in herbal dietary supplements containing Ephedra (ma huang) has been studied by Gurley and co 2003 Taylor & Francis Ltd

Standard rate method See standardisation

For example, hormone replacement therapy in menopausal women seeks to reduce the risk of fracture in this population, notably due to osteoporosis. To judge the efficacy of a new treatment using the robust criterion of a lessening of the risk of compression fractures would require a follow-up of more than 10 years. It is permissible, at least at the beginning, to judge this efficacy by the comparative evolution of the bone mineral density, which allows for a considerably shorter study.

Unmet Medical Needs and New Research Areas

The advent of endocrine therapy has led to significant advances in the treatment of cancer. In particular, modulation of the estrogen receptor and the proteins that regulate estrogen synthesis have led to improved treatments for breast cancer. The clinical manifestation of tissue-selective compounds such as tamoxifen has led to the identification of SERMs as viable treatments for therapies ranging from breast cancer to osteoporosis. Moreover, this discovery has laid the groundwork for the identification of tissue-selective agents for other steroid receptors such as the androgen, glucocorticoid, and progesterone receptors, i.e., SARMs, SGRMs, and SPRMs, respectively. Future research will lie in obtaining the appropriate tissue selectivity for the disease state in question. An in depth understanding of ligand-protein interactions, including co-regulators, will be important for fine-tuning tissue-selective pharmacology. In the area of the regulation of estrogen synthesis, small-molecule,...

Vascular Bone Disorders

Vascularity-related bone disorders of scinti-graphic interest include avascular necrosis, infarction, dysbaric necrosis, hyperemic or congestive osteoporosis, congestive periostitis, and periostitis in Burger's disease. 99mTc-MDP bone scintigraphy augmented with nuclear angiography and pinhole scanning appears to be the method of choice for dynamic biochemical study of these vascularity-related bone disorders because it is not only sensitive and often specific but also noninvasive, holistic, and easily repeatable in a day or two if necessary. In particular, pinhole bone scanning is highly valued for its ability to detect avascularity before radiography, and to subsequently assess the clinical course to revascularization (Fig. 14.1). On the other hand, nuclear angiography can diagnose regional osteoporosis or osteopenia that is related to hyperperfusion, hypoxia periostitis in Burger's disease, and chronic venous congestion.

Possibly Effective CAM Therapies

During conventional medical visits, osteoporosis and osteopenia are not always strongly considered in people with MS. Also, the use of vitamin D and calcium may not be seriously considered for people with osteopenia (a mild form of bone tissue loss) or for those with normal bone tissue and risk factors for osteoporosis. For these reasons, recognition and treatment or prevention of decreased bone density may conceivably be considered alternative. Simple approaches that are effective, inexpensive, and safe are

Dehydroepiandrosterone

The androgen dehydroepiandrosterone (DHEA) belongs to the group of steroid hormones that are produced by the adrenal cortex. In vitro, T lymphocytes, on exposure with DHEA, have been shown to produce increased amounts of Th1 cytokines such as IFN-y and IL-2, whereas the production of Th2 cytokines such as IL-4 was decreased (Daynes et al. 1990). Moreover, DHEA and DHEA-sulphate serum levels were found to be decreased in patients with SLE unrelated to disease activity or treatment (Jungers et al. 1982). In an animal model of lupus (female NZB NZW mice), treatment with androgens resulted in an improvement in disease activity. The ability of androgens to promote an immunodeviation toward Th1 as well as their efficacy in lupus mice prompted studies in humans (Melez et al. 1980). Accordingly, patients with lupus nephritis or severe cytopenias were treated with DHEA, 200 mg d. As a result of this treatment, no difference in SLE disease indices compared with placebo was noted. Only the loss...

Osteodystrophy Associated with Hyperparathyroidism and Brown Tumor

Typical Bone Resorbption

Fig. 15.11A-C Acrolysis and subperiosteal bone resorption in hyperparathyroidism. A Dorsopalmar radiograph of the right hand in a 56-year-old man with parathyroid adenoma shows generalized osteopenia with acrolysis (white arrows) and lacy subperiosteal bone resorption (black arrows). B High-resolution planar scintigraph of the hands demonstrates prominent tracer uptake in lysed tufts (arrows) and diffusely increased granular bone uptake in the phalangeal shafts. C Dorsal pinhole scinti-graph shows diffuse granular uptake in phalangeal bones with peculiar uptake in the tufts (arrowheads) and sub-periosteums (arrows). The tufts are clubbed giving rise to a drumstick appearance (ds) Fig. 15.11A-C Acrolysis and subperiosteal bone resorption in hyperparathyroidism. A Dorsopalmar radiograph of the right hand in a 56-year-old man with parathyroid adenoma shows generalized osteopenia with acrolysis (white arrows) and lacy subperiosteal bone resorption (black arrows). B High-resolution planar...

Reflex Sympathetic Dystrophy

Reflex Sympathetic Nerve Dystrophy

It is a rheumatic disorder of clinical importance and academic interest. Involvement is usually regional and diffuse, but can be segmental and small in rare cases (Helms et al. 1980). The condition is also referred to as causalgia, Sudeck's atrophy, posttraumatic osteoporosis and angiospasm, reflex neurovascular dystrophy, and the shoulder-hand syndrome. Common symptoms include pain, swelling, stiffness, tenderness, vasomotor and sensory disturbances, hyperesthesia, disability, and skin atrophy, and other trophic skin alterations such as hypertrichosis and hyperhidrosis. The pathogenesis is yet not clarified, although the theory of internuncial pool proposed by Lorente (1938) is widely supported. The theory assumes that painful impulses created by a peripheral injury travel via the afferent pathways to the spinal cord, where a series of reflexes originate. Reflex- The diagnosis of RSD largely depends upon symptoms and radiographic and scintigraphic findings....

Sterile Traumatic Synovitis

Periarticular Osteopenia

Rupture of the anterior cruciate ligament, meniscal tear, or impingement of reparative tissue (Comin and Rodriguez-Merchan 1997 Huh et al. 2004). The traumatic synovitis produces sterile effusion of various amounts, which occasionally may result in fibrosis. Radiographic features include capsular distension and osteopenia of regional bones, and the signs of traumatic injuries such as fracture. Scintig-raphy shows widening of the joint space when effusion is profuse. Characteristically, however, unlike in transient synovitis and reactive syno-vitis, the subchondral uptake is mild or absent unless infection supervenes (Fig. 8.6).

Evolution of Antiestrogens to Raloxifene

The recognition of SERM activity (see 8.08 Tamoxifen) and the possibility of developing multifunctional medicines eventually resulted in the successful reinvention of keoxifene as raloxifene to treat and prevent osteoporosis. This was a direct result of the finding that tamoxifen and keoxifene can maintain bone density96,97 but reduce mammary cancer incidence in rats.91 The concept of using SERMs to treat or prevent multiple diseases in women was clearly outlined in 1990.143 We have obtained valuable clinical information about this group of drugs that can be applied in other disease states. Research does not travel in straight lines and observations in one field of science often become major discoveries in another. Important clues have been garnered about the effects of tamoxifen on bone and lipids so it is possible that derivatives could find targeted applications to retard osteoporosis or atherosclerosis. The ubiquitous application of novel compounds to prevent diseases associated...

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

It has been established that HRT is beneficial in reducing osteoporosis and alleviating climacteric symptoms. HRT has also been shown to have beneficial effects on risk factors for CVD. However, data from recent clinical trials indicate that HRT, in the form of continuous combined CEE with MPA, has no cardioprotective effects and is not recommended for primary or secondary prevention of CVD in postmenopausal women.

Current Treatment

Although mild disease can be treated successfully with 5-ASAs, many patients eventually require corticosteroids to control symptoms. Oral glucocorticoids (e.g., prednisolone) are some of the most effective therapies for inducing clinical remission in patients with active CD and UC. However, the adverse effects (including obesity, osteoporosis, hypertension, and adrenal suppression) of chronic corticosteroid treatment are both extremely undesirable and invariably culminate in the development of clinically challenging, steroid-refractory disease. Budesonide (2) is a highly effective second-generation oral corticosteroid, but was engineered with metabolic vulnerability, to enable a topical mode of action coupled with extensive first-pass metabolism and low systemic exposure. Despite this potential improvement in safety burden for this class of agents, approximately 30 of patients will also be unable to discontinue steroid therapy without disease exacerbation, and approximately 20 will...

Hormonal regulation of bone remodeling

The synthesis of calcitriol is usually induced through low serum calcium or inorganic phosphate levels. However, changes in active vitamin D levels occur slower than those in PTH as the 'storage form' of vitamin D, 25-hydroxyvitamin D (calcidiol), needs to be converted into the biologically active form of the hormone, i.e., 1, 25-dihydroxyvitamin D. This conversion activation is achieved through the hydroxylation of 25-hydroxyvitamin D in its C1 position by CYP27B (a-hydroxylase). The activity of the latter enzyme, which is predominantly found in kidney parenchymal cells, is upregulated by PTH, and downregulated by plasma HPO4 levels. Conversely, calcitriol inhibits the secretion of PTH from the parathyroid glands.9 Measurement of serum 25 and 1,25 vitamin D levels may be useful in patients with osteoporosis, vitamin D deficiency, renal disease, hypercalcemia, and sarcoidosis. Glucocorticoids seem to have different effects on bone, depending on the dose and duration of exposure....

Anorexia Nervosa DRG Categr 428

Weight is lost three ways in this condition by restricting food intake, by excessive exercise, or by purging either with laxatives or by vomiting. Initially, patients receive attention and praise for their extreme self-control over food intake, but as the illness progresses, this attention is replaced by worry and efforts to monitor the patient's food intake. The increased negative attention and attempts at control of the patient serve to reinforce the patient's need for control and contribute to the progression of the illness. Adverse consequences of anorexia nervosa include possible atrophy of the cardiac muscle and cardiac dysrhythmias, alteration in thyroid metabolism, and estrogen deficiencies (those with long-standing estrogen deficiencies may develop osteoporosis). Refeeding may lead to slowed peristalsis, constipation, bloating, and fluid retention. Mortality rates are as high as 10 to 20 , and only half of people with anorexia nervosa recover completely.

Tamoxifens Legacy A Menu of Medicines

Gnrh Tumour Removal

Tamoxifen is the first SERM and without the developing pharmaceutical database during the 1980s, raloxifene, originally a failed breast cancer drug called keoxifene (see 8.09 Raloxifene), would not have been reinvented as a treatment and preventive for osteoporosis with breast and endometrial safety.225,226

Schmorls Cartilaginous Node

Schmorl's node is the dislocation of the denatured nucleus pulposus into vertebral cancel-lous bone through the weakened annulus fi-brosus and diskovertebral junction, creating an intravertebral defect surrounded by eburna-tion. Nodes are often seen in association with diskovertebral osteochondrosis, trauma, osteoporosis, or Scheuermann's disease.

Medications for High Cholesterol

Sometimes, despite making changes to their diet, some people continue to have excessive serum cholesterol concentrations. This situation occurs in patients with the nephrotic syndrome, and in those diabetics who have relatively high rates of protein excretion. These high serum cholesterol levels usually can be treated readily in patients with and without renal failure, including people with diabetes, by the administration of a statin drug. These drugs are just as effective in renal disease as in its absence, and no more toxic. They are being used more and more widely, and seem to have other beneficial effects some may reduce the incidence of Alzheimer's disease, and some may reduce the incidence of osteoporosis.

Normal Variants

Navicular Bone Normal Varient

The appearance and intensity of tracer uptake within the skull vary because the count rate is comparatively low and radioactivity distribution is usually uneven. A higher count rate is commonly observed in the peripheries of the skull due to curvature and perpendicular or tangential aligning of the scan detector. Accordingly, calvarial uptake may be diffusely or locally not uniform even in the absence of hyperostosis. Diffuse increased calvarial uptake related to postmenopausal osteoporosis is a rather common finding in elderly women (Senda and Itoh 1987) (Fig. 5.1A, b). Experience dictates that radiographic correlation is a necessity to accurately distinguish increased tracer uptake of simple cranial hyperostosis from pathological uptake of polycythemic cranial hyperostosis, iatrogenic osteoporosis, Paget's disease and renal osteodystrophy with osteomalacia (Fig. 5.1C, D). Fig. 5.1A-D Diffuse calvarial uptake in postmenopausal porosis and renal osteodystrophy. A Lateral scintigraph...

Medical treatment

These agents (eg, leuprolide Lupron , goserelin Zoladex ) inhibit the secretion of gonadotropin. GnRH agonists are contraindicated in pregnancy and have hypoestrogenic side effects. They produce a mild degree of bone loss. Because of concerns about osteopenia, add-back therapy with low-dose estrogen has been recommended. The dosage of leuprolide is a single monthly 3.75-mg depot injection given intramuscularly. Goserelin, in a dosage of 3.6 mg, is administered subcutane-ously every 28 days. A nasal spray (nafarelin Synarel ) may be used twice daily. The response rate is similar to that with danazol about 90 percent of patients experience pain relief.

MetaboliteY

Finally there were sincere concerns about the side effects of adjuvant therapy and the ethical issues of treating patients who might never have recurrent disease. Although this argument primarily focused on chemotherapy and node-negative patients, it is fair to say that few women in the 1970s had received extended therapy with tamoxifen therefore, long-term side effects were largely unknown. Most tamoxifen-treated patients had only received about 2 years of treatment for advanced disease before drug resistance developed. Potential side effects such as thrombosis and osteoporosis were only of secondary importance. The evaluation of tamoxifen as a chemopreventive in the 1990s would, however, change that perspective.

Treatment

Functional hypothalamic amenorrhea can usually be reversed by weight gain, reduction in the intensity of exercise, or resolution of illness or emotional stress. For women who want to continue to exercise, estrogen-progestin replacement therapy should be given to those not seeking fertility to prevent osteoporosis. Women who want to become pregnant can be treated with gonado-tropins or pulsatile GnRH.

Alendronate sodium

D Action Kinetics Alendronate inhibits osteoclast activity, thereby preventing bone resorption. It appears to reduce fracture risk and reverse the progression of osteoporosis. Alendronate does not inhibit bone mineralization. It is well absorbed orally and is initially distributed to soft tissues, but then quickly redistributed to bone. The drug is not metabolized and is excreted through the urine. However, the tV2, terminal is believed to be more than 10 years, due to slow release from the skeleton. Uses Prevention and treatment of osteoporosis in postmenopausal women (concomitant estrogen therapy is not recommended due to lack of experience). Prevention of fractures in postmenopausal women with osteoporosis. Paget's disease of bone. Contraindications In hypocalce-mia. Those with severe renal insufficiency (creatinine clearance less than 35 mL min). Lactation. Special Concerns Use with caution in those with upper GI problems, such as dysphagia, symptomatic esophageal diseases,...

Toxicities

Gastrointestinal Increased gastric acidity leads to peptic ulcer, nausea and vomiting. Central nervous system (CNS) Agitation, restlessness, tremors, seizures. Metabolic Reduced serum K and Ca (chronic osteoporosis 2 cups day, 100 mg day). Muscle Increased contractility, high creatine phosphokinse (CPK), rhabdomyolysis.

Bisphosphonates

Alendronate (Fosamax) has effects comparable to those of estrogen for both the treatment of osteoporosis (10 mg day or 70 mg once a week) and for its prevention (5 mg day). Alendronate (in a dose of 5 mg day or 35 mg week) can also prevent osteoporosis in postmenopausal women. 2. Risedronate (Actonel), a bisphosphonate, has been approved for prevention and treatment of osteoporosis at doses of 5 mg day or 35 mg once per week. Its efficacy and side effect profile are similar to those of alendronate. C. Raloxifene (Evista) is a selective estrogen receptor modulator. It is available for prevention and treatment of osteoporosis. At a dose of 60 mg day, bone density increases by 2.4 percent in the lumbar spine and hip over a two year period. This effect is slightly less than with bisphosphonates.

Complex Patenting

Although it is not relevant to consider all the subsequent patents awarded to Eli Lilly and Company, it is perhaps pertinent to observe that these are often patents for formulations of numerous oral preparations. These patents are illustrated by patent numbers 5,811,120 (September 22, 1998), 5,972,383 (October 26, 1999), US 6,458,811 B1 (October 1, 2002), US 6,797,719 B2 (September 28, 2004), and US 6,894,064 B2 (May 17, 2005). Each of these is a new invention for raloxifene-like analogs ''optionally containing estrogen or progestin for alleviating the symptoms of osteoporosis, lowering lipid levels, and inhibiting endometriosis, uterine fibroids, and breast cancer.''

Prevalent fractures

Figure 6 The effect of raloxifene on (a) bone mineral density and vertebral fracture in postmenopausal women with osteoporoisis79 and (b) breast cancer incidence168 in the MORE trial. At 36 months of the evaluable radiographs in 6828 women, risk of vertebral fracture was reduced in both study groups receiving raloxifene (60mgday -1 group RR, 0.62 95 CI, 0.5-0.8 120 mg day-1 group RR, 0.5 95 CI, 0.4-0.7). The cumulative incidence of breast cancer among subjects in the placebo group and those in the combined raloxifene group are represented as a percentage of all patients randomized to either group. Statistical significance of the difference between the groups was tested by a log-rank test (P < 0.001). 60 mg day1 reduced the risk of vertebral fractures by 30 (RR, 0.7 95 CI 0.5-0.8) and by 50 (RR, 0.5 95 CI 0.4-0.7) at 120mgday-1, compared to placebo (Figure 6a). The risk of nonvertebral fracture for raloxifene versus placebo, however, did not differ significantly.79 Compared with...

Bazedoxifene

Bazedoxifene (TSE-424 Figure 10) is a novel SERM developed by Wyeth Pharmaceuticals that is currently in phase III clinical trials for the prevention and treatment of postmenopausal osteoporosis. It is an indole-based estrogen receptor ligand that has been stringently selected to ensure an improved profile over its predecessor raloxifene. It was developed using preclinical selection parameters, which included favorable effects on the skeleton and lipid metabolism, demonstrable mammary and uterine safety, and neutral effects on hot flashes.192 Bazedoxifene treatment maintains bone mineral density, preserves normal bone histology, increases bone compressive strength, and reduces total cholesterol levels in animal models.192-194 It lacks uterotropic activity194 and it blocks raloxifene-induced increases in uterine weight192 and inhibits E2-induced proliferation in MCF-7 breast cancer cells.192 Based on the favorable preclinical evaluation, it is suggested that bazedoxifene has the...

Ligand

No significant association between concentrations of TH and a polymorphism in the D3 gene have been described and there have been no descriptions of deficiencies of deiodinases neither in humans nor in animals 67 . The present conclusion of studies over the recent years have clarified that genetic variation by polymorphisms plays an important role in the serum concentrations of thyroid function variables, and that deiodination of the iodothyronines are crucial players in this unique set-point. In adults it is becoming increasingly clear also, that only minor modifications from this set-point resulting in mild (or subclinical) hypo- or hyperthyroidism, may induce alterations in thyroid hormone bioactivity with consequences for clinical end-points such as bone mineral density, atherosclerosis and heart rate, with increased morbidity and even increased mortality 68, 69 . How frequent such alterations are in children has not been investigated, and therefore it is unknown if, e.g.,...

Theophylline

Oral corticosteroids decrease symptoms and may prevent an early relapse. Chronic use of oral corticosteroids can cause glucose intolerance, weight gain, increased blood pressure, osteoporosis, cataracts, immunosuppression and decreased growth in children. Alternate-day use of corticosteroids can decrease the incidence of adverse effects, but not of osteoporosis.

Corticosteroids

Their effects are often transient. Further, frequent use of corticosteroids is associated with long-term adverse effects, such as osteoporosis, and their use has to be carefully managed. On the other hand, individual pulses of corticosteroids are relatively free from adverse effects.

Cadmium

Cadmium has been shown to interfere with the metabolism of vitamin D, calcium, and collagen. These effects manifest themselves as osteoporosis and osteomalacia in humans as well as in animals. An illustrative example is the Itai Itai bone disease (ouch ouch disease). This disease occurred as an epidemic among the inhabitants of the Fuchu area in Japan, who for a long time ingested rice that was highly contaminated with Cd (300 to 2000 g Cd per day). The etiology of this disease points to a combination of factors. Not only the exposure to Cd, but also a deficient diet (low in protein, calcium, and vitamin D) were found to be responsible for the development of this disease in that particular area.

Hyperprolactinemia

Hyperprolactinemia in women leads to amenorrhea, galactorrhea, and osteoporosis, while in men it may result in diminished sexual drive and impotence, or may be asymptomatic. The degree of hyperprolactinemia is directly related to the functionality of the prolactin-secreting tumor. Serum prolactin levels over 200 ng mL correlate well with the presence of a prolactinoma. Normal prolactin levels are in the ranges of 1 -20ng mL in men, and 1-25 ng mL in women.

Proteins

A twofold increase in protein intake (30 energy ) (see Figure 12.3e) resulted in acceleration of the processes that lead to renal glomerular sclerosis. Further, it has been suggested that habitual high protein intake contributes to osteoporosis. However, protein intakes slightly higher than the physiological need are generally believed to be safe, because excess nitrogen is efficiently eliminated. This occurs mainly in the liver, where amino acids are metabolized to urea. Based on these findings, official committees recommend an upper limit of twice the RDA for protein. Oxidation of sulfur-containing amino acids has both nutritional and safety implications.

With diabetes

Pause on lipid profile and bone mineral density, and there is evidence that estrogen may also improve carbohydrate metabolism and body fat distribution in healthy postmeno-pausal women (124-126). The role of HRT in preventing CVD in postmenopausal women, as discussed in detail in the first part of this chapter, remains highly controversial, but there is strong evidence that it may be beneficial in the early postmenopausal period and early stages of atherosclerosis.

Geriatrics

Normal changes in elderly slightly impaired immune response, visual (presbyopia) and hearing (presbycusis) impairment, decreased muscle mass, increased fat deposits, osteoporosis, brain changes (decreased weight, enlarged ventricles and sulci), and slightly decreased ability to learn new material.

Bone Remodeling

Figure 2 Cancellous bone remodeling. (a) Normal bone is remodeled by teams of osteoclasts and osteoblasts, forming a bone multicellular unit that progresses across the bone surface with osteoclasts eroding a pit, which is subsequently refilled by osteoblasts. (b) In osteoporosis, bone removed by each cycle is greater than that replaced, so that the trabeculae become thinner and can be perforated and lost. (c) Antiresorptive treatment inhibits osteoclasts so that numbers and size of pits are reduced, resulting in a coupled reduction in bone formation. Bone volume is increased as existing holes are filled and then maintained through the reduction in remodeling cycles. (d) Anabolic factors like teriparatide induce osteoblasts to form more bone during each remodeling cycle. Bone volume increases until osteoclast activity increases, apparently to compensate for the increased bone formation. Teriparatide action depends on the presence of remodeling cycles, as concurrent treatment with an...

Sex hormones

Sex hormones are major regulators of bone turnover and remodeling in both genders. Estrogens reduce bone loss by inhibiting the generation of new osteoclasts, reducing the activation frequency of the BMU and promoting apoptosis of mature osteoclasts via mechanisms that are not well understood. Some of the effects of estrogen seem to be mediated via the modulation of growth factors and cytokines, while others are associated with binding to at least two different estrogen receptors (ERa, ERb). A reduction in circulating endogenous estrogen levels, as occurs during and after menopause, has been shown to prolong osteoclast survival and stimulate the recruitment and hence generation of osteoclasts. The result is an increase in the activation frequency of the BMU, reflected in a high bone turnover state.14 While there is no doubt that androgens (i.e., testosterone, dihydrotestosterone) play a dominant role in male bone health, it also appears that circulating estradiol levels are important...

Metastatic Disease

Hematogenous metastases are most common in the axial skeleton. Currently, the mainstay for the detection of bone metastases is a radionuclide bone scan. However, it is well known that bone scans can yield false-negative findings, especially in cases of very aggressive metastases. Furthermore, the technique has a high false-positive rate, mainly due to degenerative disease, healing fractures and various metabolic disorders and their complications (e.g., osteoporosis and osteomalacia). It has been demonstrated that bone scintigraphy is unnecessary in the evaluation of newly diagnosed, untreated prostate cancer with no clinical signs of bone pathology and serum PSA levels of less than 10 ng ml 36 . In patients with an elevated PSA (> 10 ng ml) or with locally advanced tumours, bone scans are considered worthwhile for detecting both asymptomatic and symptomatic metastasis. MR imaging is more sensitive in detecting bone marrow metastases compared to ra-dionuclide bone scanning 37 ....

Lasofoxifene

Lasofoxifene (Figure 10) is a novel nonsteroidal SERM that is in clinical trials for the prevention and treatment of osteoporosis in postmenopausal women.195 It is a diaryltetrahydronaphthalene derivative referred to as CP336156. The structure of CP336156 is reminiscent of nafoxidine (Figure 3) if it were to be demethylated in vivo. There are two diastereometric salts. CP336156 is the L enantiomer that has 20 times the binding affinity of the D enantiomer. Studies with human MCF-7 breast cancer cells and blocks N-nitrosomethylurea-induced mammary carcinomas in rats.198 In a phase III clinical trial conducted by Pfizer199 involving 410 postmenopausal women randomly assigned to CP336156 (0.25 or 1 mgday _ 1), raloxifene (60 mgday_ 1), or a placebo, CP336156 increased bone mineral density at the lumbar spine by about 2 after 2 years of treatment, compared to no increase with raloxifene and a 2 decrease in the placebo group. Changes in bone turnover markers were also greater with CP336156...

Disease Basis1

Most studies indicate that taking estrogen for more than 10 years may lead to a slight increase in risk for developing breast cancer. However, these studies indicate that, depending on the patient, the positive benefits of taking estrogen as far as reducing the risk for osteoporosis and colon cancer may outweigh the increase in risk that may be associated with estrogen replacement therapy.

Calcium

Calcium supplements are sometimes recommended for MS, often for unstated reasons. Calcium supplements should be taken by people with inadequate dietary intakes of calcium. Also, calcium and vitamin D supplements are indicated for people with MS who have osteoporosis or risk factors for osteoporosis (see Vitamin D and Calcium in this chapter). No other clear uses are apparent for calcium supplements in MS. It should be noted that calcium interferes with iron absorption consequently, calcium and iron supplements should not be taken together.

Skeletal Involvement

Administration of retinoids induces bone toxicities similar to those of chronic hyper-vitaminosis A (remodeling of long bones, cortical hyperostosis, decalcification, premature epiphyseal closure, periosteal thickening, and osteoporosis). In general, synthetic retinoids produce bony changes such as diffuse idiopathic skeletal hyperos-tosis, including anterior spinal ligament calcification, osteophytes, and bony bridges, but without narrowing of the disk space. Calcification of the anterior spinal ligament with bony bridging of vertebrae has been observed with long-term, high-dose (2 mg kg per day) isotretinoin therapy, and minimal spinal hyperostosis has been reported in 10 of patients treated with short-term, low-dose isotretinoin. Ossification of the spinal posterior longitudinal ligament is rare. Extraspinal involvement (extraspinal tendon and ligament calcification) is significantly increased in patients receiving long-term etretinate therapy at an average dose of 0.8 mg kg per...

Raloxifene and Bone

The 1995 patent and the December 10, 1997 FDA approval of raloxifene for the treatment and prevention of osteoporosis were based, in part, on earlier studies performed in 1987 by Jordan and coworkers96 which showed that raloxifene preserved bone density in ovariectomized rats (Figure 4a) and prevented rat mammary carcinogenesis (Figure 4b).91 The discovery that raloxifene and related compounds might prevent osteoporosis96 laid the foundation for subsequent confirmation of bone data in animals.97-99,163 These discoveries also led to clinical trials that demonstrated maintenance of bone density in postmenopausal women at risk for osteoporosis.78 These data were remarkably similar to those observed with tamoxifen.144 However, the actual proof that raloxifene could be useful to treat osteoporosis was obtained in the MORE trial (Figure 5), which was a multicenter, randomized, blinded, placebo-controlled osteoporosis treatment trial. A total of 7705 women aged 31-80 years in 25 countries...