Natural Osteoporosis Cure and Treatment

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

Rating:

4.6 stars out of 11 votes

Contents: EBook
Author: Matt Traverso
Price: $47.00

My The Osteoporosis Reversing Breakthrough Review

Highly Recommended

The author has done a thorough research even about the obscure and minor details related to the subject area. And also facts weren’t just dumped, but presented in an interesting manner.

Purchasing this e-book was one of the best decisions I have made, since it is worth every penny I invested on it. I highly recommend this to everyone out there.

Download Now

Role of Estrogen Hydroxylation in Bone Density and Osteoporosis

The importance of estrogen metabolism in the pathogenesis of hormone-related diseases has come primarily from studies on breast cancer. For example, a lower circulating 2OHE1 16aOHE1 ratio is associated with an increased risk of breast cancer 67-70 , whereas high serum 16aOHE1 is a strong predictor of breast cancer risk 67 . In vitro studies showed that breast tissues obtained from women with breast cancer have increased 16-hydroxyl-ation. Furthermore, the addition of E2 to MCF-7 cell lines upregulates 16-hydroxylation with 2-hydroxylation unchanged. The ability of estrogen hydroxylation to alter hormonal status even among women in the reproductive age is likewise suggested by observation of frequent menstrual irregularities in young women with high 2-hydroxylated estrogens 71, 72 . What's more, estrogen metabolism may also be an important regulator of male hormonal status as well since high levels of 16aOHE1 and low 2OHE1 16aOHE1 ratio were associated with an increased risk of...

Osteoporosis Treatment Marine Algal Compounds

Treatment for Osteoporosis 418 IV. Marine Compound for Osteoporosis 420 A. Bone mineral density 420 D. Osteoclast differentiation in osteoporosis 422 Abstract Osteoporosis is one of the most common bone diseases that occur due to imbalance during bone formation and bone resorption. About half of all women over the age of 50 will have a fracture on the hip, wrist, or vertebra. Research and treatment of osteoporosis are challenging for researchers and physicians. There are several types of treatments for osteoporosis including most famous bisphospho-nates, estrogen agonists antagonists, parathyroid hormone, estrogen therapy, hormone therapy, and recently developed RANKL inhibition. In the recent days, much attention has been paid for marine algal extracts and compounds for osteoporosis treatment. In this chapter, we extensively deal with marine algae compounds and their rich mineral constituents for osteoporosis treatment.

Osteoporosis Prevention And Treatment104106

Epiandrosterone Pathway

Osteoporosis is an enormous public health problem, responsible for approximately 1.5 million fractures in the United States each year. Because of the prevalence of osteoporosis, especially in older women, the prevention and treatment of this condition have received much attention. Prior to menopause, a good diet and exercise are essential for young women, to decrease the risk of osteoporosis later in life. After menopause, supplemental estrogens can have a positive effect relative to osteoporosis. Estrogens mainly act by decreasing bone resorption, so estrogens are better at preventing bone loss than restoring bone mass. Estrogens taken after menopause (often with a supplemental progestin) have been unequivocally shown to greatly decrease the incidence and severity of osteoporosis, especially when combined with good nutrition and exercise. The long-term use of estrogens plus a progestin for preventing osteoporosis, however, should be carefully evaluated in light of the WHI studies...

Treatment For Osteoporosis

The goals of osteoporosis treatment are to control pain from the disease, reduce bone loss, and prevent bone fractures with medicines or hormone therapies. There are several types of treatments for osteoporosis including most famous bisphosphonates, estrogen agonists antagonists, parathyroid hormone, hormone therapy, and recently developed receptor activator of nuclear factor-kB ligand (RANKL) inhibition. Estrogen agonists antagonists in combination with estrogen for prevention and treatment of osteoporosis have also been studied (Stovall and Pinkerton, 2008). Bazedoxifene for the prevention of postmenopausal osteoporosis (Gennari et al., 2008), parathyroid hormone (Black et al., 2003 Finkelstein et al., 2003 Horwitz etal., 2010 Neer et al., 2001), estrogen therapy (Eskridge et al., 2010 Genant et al., 1997 Lindsay, 1987 Lindsay and Tohme, 1990), hormone therapy (Engel et al., 2011 Pentti et al., 2009), and recently developed RANKL inhibitory (McClung, 2006, 2007) treatment options...

Osteoporosis

Osteoporosis is the major underlying cause of bone fractures in postmeno-pausal women and in the elderly. It is clear and not disputed that calcium deficiency caused by very low intake is the cause of bone loss and osteoporosis. Since maintenance of serum calcium is of vital importance for the body homeo-stasis, when the dietary intake is reduced, the calcium needed is taken from the bone stores. However, epidemiological data are conflicting in finding a relationship between calcium intake and bone health, although racial and other confounding factors may complicate the picture. A weak but positive relation between calcium intake and bone mass was found in a study conducted in the USA.15 There is strong evidence for the importance of an adequate calcium intake in the prevention of bone loss associated with aging and or menopause, in the reduction of risk fracture16 and of a close positive relation between calcium intake and bone mass.17 Absorption efficiency for calcium at the...

Functional Foods And Disease Prevention

Further, soy protein inclusions are getting highly recognized by women population due to their ability to reduce the risk of heart diseases by lowering blood cholesterol levels, promoting bone health, and easing symptoms of menopause. Further, there is an increasing demand for products targeting children. Active ingredients are added in these products and are capable of supporting brain development of infants, immunity enhancement, and acting against allergy reactions in the body. Also some of these products are aiming at promoting healthier eating habits and active life styles among children to prevent the unprecedented growth of obesity and related complications. Functional protein, peptides, and amino acids from different food sources are also renowned, and among them, soy protein concentrates are gaining much popularity attributed to the functional properties specifically toward women population. Other than that, there are products that are becoming popular for...

Definitions And Applications

Markers that reflect a response to therapy or drug treatment are called drug activity markers. They are used to demonstrate proof of concept, to establish dose regimens, and for optimizing combination therapies. They are used to measure the pharmacodynamic response, where the magnitude of the change defines the potency of the candidate drug. Examples include biochemical markers for bone resorption and deposition in studies on osteoporosis, such as osteocalcin, bone-specific alkaline phosphatase, and type I collagen propeptides and telopeptides 4 and viral load (hepatitis or human immunodeficiency virus) for measuring response to antiviral therapy 3 .

Present Situation And Potential Of Seaweeds For Novel Functional Food Product Developments

Isotonic drinks, bakery, and hypoallergenic baby foods. Further, ever-concerning chronic disease-related conditions such as cancer, high cholesterol, coronary heart diseases, atherosclerosis, stroke, hypertension, diabetes (type II), gastrointestinal disorders, osteoporosis, intestinal complications, and immune disorders including allergy have been used as prime focuses when developing these functional food products. When analyzing the supply structure of these functional foods, the main types of successful actors in the commercial functional food segment are multinational food companies with a broad product range and pharmaceutical or dietary products producing companies. Therefore, the combination of consumer acceptance, advances in science and technology, and scientifically backed evidence linking consumption of biochemical compounds in seaweed to disease and disease prevention can be taken as unprecedented opportunity for these food marketers to develop seaweed-based functional...

Selecting The Right Imaging Technique For The Purpose At Hand

Patient-selection markers fall into three basic categories (1) those that identify a disease process (e.g., MRI markers of synovitis), (2) those that identity specific tissue or patient characteristics (e.g., tumor estrogen receptors), and (3) those that establish the severity and extent of disease, or the disease burden (e.g., bone mineral density, tumor stage, Sharp score). These markers are usually also useful for monitoring treatment response, but not always. The critical criterion for a marker to be useful for monitoring treatment is that the marker change with the disease and or therapy. This is not necessarily the case with markers that identify specific tissue or patient characteristics, or for markers of disease features upstream from the site of action of the therapy being tested (Fig. 14). In addition to whether the maker actually changes with disease and or therapy, the rate at which it changes and how precisely this change can be measured are important considerations....

Assessment of sympathetic activity

Sympathetic hyperactivity may be present in some peripheral neuropathic pain states as part of complex regional pain syndrome (CRPS formerly known as cau-salgia or reflex sympathetic dystrophy see Chapter 27, Complex regional pain syndromes). The clinical aspects of sympathetic hyperactivity include a perception of burning-type pain soon (hours or days) after injury together with the demonstration of swelling, smooth glossy skin, and vasomotor instability. A characteristic localized osteoporosis may be observed in the extremities (Sudeck's atrophy) later on. These features may exist alone or in combination. Sweating may be affected, producing either wet or dry skin. Similarly, the skin may be cooler or warmer, depending on the degree of cutaneous vasoconstriction. In patients suspected of sympathetic dysfunction, tests can be useful to document the degree of sympathetic involvement. These include sweat testing, galvanic skin resistance, plethysmography, skin blood flow measurement...

Potential Health Benefits of Dietary Estrogens

Both clinical and epidemiological data suggest that dietary estrogens may have a beneficial effect on the human endocrine system. Breast cancer, prostate cancer, colon cancer, menopausal symptoms, heart disease, and osteoporosis share a common epidemiology in that they are rare in Far Eastern populations eating traditional diets containing soybean products compared with Western populations. However, with Westernization and loss of traditional eating patterns, the pattern of disease incidence is also changing in these countries. Cross-sectional studies have shown higher phytoestrogen levels in the urine and plasma of populations at lower risk of these diseases 28, 91 . This section will focus on the beneficial role which phytoestrogens may play in breast cancer, prostate cancer, colon cancer, endogenous hormones, the menstrual cycle, menopausal symptoms, cardiovascular disease, and osteoporosis.

Local tender spot injection

Injection of local anesthetic and corticosteroid is a common procedure in pain and rheumatological practice. This can be into a tender muscle, inflamed joint, tendon, ligament, or bursa, for example. Use of these drugs in this fashion is tried and tested, but not without real and potential drawbacks. Lipoatrophy and the creation of localized telangectasia are not uncommon in the short term, while the worry of tendon weakening or osteoporosis inhibits repeated treatment. This can be most frustrating as these injections are often particularly effective. Clinical reports and experience suggest that use of a 5HT3 antagonist in place of a corticosteroid can be rewarded by pain relief of a similar magnitude and duration, but devoid of the short- and long-term potential risks of corticosteroid injection. For example, in clinical practice Achilles tendinitis can be a very troubling condition. A significant worry associated with corticosteroid injection would be tendon weakening which may...

Case study a SAR investigation to discover potent geminal bisphosphonates

Bisphosphonates, or diphosphonates as they were originally known, are derivatives of bisphosphonic acid (Fig. 3.6), which is an analogue of the naturally occurring pyrophosphoric acid. They were synthesised in the nineteenth century for use as antiscalers and anticorrosive agents. However, it was not until the late 1960s that they were recognised as potential sources of drugs. Bisphosphonates are now used to treat diseases such as osteoporosis, Paget's disease and myeloma, which involve a loss of calcium and other minerals from the bone.

Flavonoids and Chronic Disease

Research with cell cultures and animal models suggests flavonoids may play a role in promoting human health and reducing the risk of some chronic diseases. Flavonoids have been purported to have a beneficial effect on cardiovascular disease, cancer, neurodegenerative diseases, diabetes, and osteoporosis as well as having antibacterial, anticarcinogenic, antiinflammatory, diuretic, and immunostimulatory actions. Observational studies have associated

Green Chemistry Considerations in PeptideI ike API Manufacture

Peptide-based drug molecules are prevalent in drug discovery studies that target receptors or enzymes 4 . Some native or modified peptides are used as therapeutic agents, such as the osteoporosis drug teriparatide (recombinant human parathyroid hormone 1-34 ) '5a and the anti-cancer drug leuprorelin '5b (Figure 9.1). In most cases, however, the peptide is converted into a low-molecular-weight peptide mimetic compound by reducing the number of peptide bonds and by

Beclomethasone Dipropionate

Daily doses of inhaled BDP up to 1 mg proved to be effective in chronic asthma without causing significant systemic glucocorticoid actions. The greater doses used to control more severe asthma do, however, cause modest, but significant suppression of hypophysial-pituitary-adrenal function and perhaps a degree of osteoporosis after prolonged use (43). This is why a more selectively acting topical steroid was sought and found in fluticasone propionate, and also why the effectiveness of concurrent treatment with low-dose BDP and salmeterol is important (see Section IV).

Regional Anesthesia and Other Interventions

In addition to NSAIDs and opioids, which are first-line treatments for acute nocicep-tive bone pain, several other treatment options exist. Vertebroplasty and kyphoplasty may be useful in patients with vertebral fractures secondary to osteoporosis and malignancy, but are generally less beneficial in young patients with traumatic fractures. Contraindications to both techniques include bleeding disorders, unstable fractures with posterior element involvement, and definitive neurological symptoms. Whereas multiple uncontrolled studies have demonstrated efficacy for both vertebroplasty and kyphoplasty, a recent double-blind, placebo-controlled study failed to show benefit for vertebroplasty (Kallmes et al. 2009).

Nontumorinduced hypercalcemia

An increase in calcium flux from bone, following accelerated bone destruction, is by far the most common mechanism. Examples are hyperparathyroidism, the most frequent cause, thyrotoxicosis, and certain cases of acute osteoporosis, as during immobilization. Increased intestinal calcium absorption is a less frequent cause of hypercalcemia. It occurs, for example, in vitamin D intoxication or in sarcoidosis, in which macrophages produce l,25(OH)2 D. An increase in tubular reabsorption of calcium is usually due to abnormally high levels of parathyroid hormone as encountered in primary hyperparathyroidism. In familial hypocalciuric hypercalcemia the recently discovered Ca2+-sensing receptor appears to be involved.

Conclusions and Future Research Considerations

In addition to food safety, a growing area of interest is the development of therapeutic products specifically designed to interact with synaptic transmission of the GluRs in the CNS (Cunningham et al., 1994 Michaelis, 1998 Dingledine et al., 1999 Moghaddam, 1999 Gallo and Ghiani, 2000). It is established that a myriad of pre- and postsynaptic mechanisms exist by which iGluRs and mGluRs could modulate cell functions in the CNS. Selective agonists and antagonists could be used to modulate glutamatergic neuronal transmissions in very select areas of the CNS (Moroni et al., 1986). For example, it has been suggested that NMDAR 1 antagonists may be useful in preventing tolerance to opiate analgesia and helping control withdrawal symptoms from addictive drugs. Also, the overactivation of NMDAR 1 has been suggested as one of the factors to cause chronic diseases such as Huntington's, Alzheimer's, Parkinson's, HIV-related neuronal injury, and amyotrophic lateral sclerosis. Therefore,...

O Future Directions

A monoclonal antibody target for the treatment of osteoporosis is the RANKL, which is the essential mediator of os-teoclasts. As pointed out in the osteoporosis discussion, the loss of calcium by increased osteoclastic activity and decreased osteoclast apoptosis is opposed by a RANKL inhibitor, osteoprotegerin a 401-amino acid glycoprotein, and a member of the TNF superfamily. Rather than develop a pharmaceutically acceptable osteoprotegerin, a fully human monoclonal antibody, denosumab, that binds to the RANKL preventing its binding to RANK is being evaluated for the treatment of osteoporosis. The reported result is inhibition of all stages of osteoclast activity.17 It is important to keep a perspective when administering drugs that interfere with the immune system over long periods of time. RANKL is part of the normal bone remodeling process as well as with pathological bone loss. The key is balance, and this will require long-term studies in patients with post-menopausal...

Acute and Chronic Transplant Rejection

Other indications in which animal experimental proof of principle studies have been performed include chronic inflammatory bowel disease, i.e. different mouse models of colitis in which NF-kB decoy ODNs were successfully administered intrarectally, either encapsulated in a viral envelope52 or as naked DNA, albeit fully phosphorothioate-modified,53 osteoporosis in rats (NF-kB decoy ODN),54 diabetic nephropathy in rats (AP-1 decoy ODN55 or ring-Sp-1 decoy ODN56), experimental autoimmune myocarditis in rats (NF-kB decoy

Case Study 4 Clinical Semimechanistic and Mechanistic Population PKPD Model for Biomarker Response to Ibandronate

Biomarkers of bone turnover provide a rapid and accessible means of evaluating physiological responses to antiresorptive therapies. Recent evidence also suggests an association between the magnitude of biomarker suppression and the likely response in terms of bone mineral density (BMD) change and fracture risk reduction. This association suggests that these biomarkers are on the causal pathway for prevention of fracture following administration of bisphosphonates. As such, biochemical markers of bone turnover can offer a timely indication of the likely efficacy associated with nominal dosing regimens. The aim of this project was to develop and validate a pharmacological model for ibandronate, a new bisphosphonate for the treatment of osteoporosis, capable of describing its PK in serum and urine, and the urinary excretion of the C-telopeptide of the a chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate 28 . A classical PK PD model was developed that...

Outlook and Perspectives

To address questions on the function of the GR in the central nervous system, a GR mutant was generated by the use of a nestin-Cre mouse (unpublished data). In these mice the GR is ablated in most of the cells in the CNS. First studies suggest impaired feedback regulation of the HPA axis along with increased corticosterone levels, which mimics to some extent the human Cushing's syndrome. As in those patients, abnormal fat distribution, signs of osteoporosis, and growth defects were observed in CNS-specific GR-mutants (GRflox flox nestin-Cre).

Physical examination

Infection (urinary tract, pulmonary, skin, etc.) Recent significant trauma, fall, or lift, or trivial trauma in someone at risk for osteoporosis, disabling symptoms of sudden onset, or pain located in the sacrum instead of the usual low back location (sacral insufficiency fractures) Younger ages (20s and 30s), prolonged morning stiffness > 30 minutes, symptoms improved with exercise but not rest, significant inability to bend well, also possible lower extremity large joint involvement

Physical therapy rest versus exercise

Available evidence suggests that range of motion, strengthening, and aerobic conditioning exercises are safe for patients with RA and improve muscle strength, cardiovascular fitness, and probably physical function. They do not seem to exacerbate joint symptoms. Preliminary evidence also suggests aerobic weight-bearing exercise may help prevent corticosteroid-associated osteoporosis.76 III , 77 III , 78 III

Division of Bone and Mineral Diseases Washington University School of Medicine St Louis Missouri

Estrogen is metabolized predominantly via two competing pathways, the 2-hydroxyl (nonestrogenic) and the 16a-hydroxyl (estrogenic) pathways. Studies have indicated that these pathways are important determinants of bone mineral density (BMD) in postmenopausal women. Women with predominant metabolism through the 2-hydroxyl pathway have accelerated postmenopausal bone loss and lower BMD compared to those with predominant 16a-hydroxylation who are protected from bone loss. Increased 2-hydroxylation has been observed in women with a positive family history of osteoporosis suggesting that the increased risk of osteoporosis in those with family history may, in part, be related to inherited differences in estrogen metabolism. Polymorphisms in the cytochrome P450 (CYP450) enzymes that metabolize estrogen are believed to result in alteration in the activity of these enzymes leading to differences in estrogen hydroxylation. It is the resulting estrogen tone'' generated from the variable...

Other Potential Untoward Effects

Osteoporosis Osteoporosis is associated with the loss of bone mass and an increased incidence of fractures. Estrogen therapy clearly is efficacious in decreasing the incidence of fractures, although bone loss resumes when treatment is discontinued. However, because of potential risks associated with estrogen use, first-line use of other drugs should be carefully considered (see Chapter 61). Estrogens are more effective at preventing than restoring bone loss and are most effective if initiated before significant bone loss occurs. Tibolone (LIVIAL) is widely used in Europe for treatment of vasomotor symptoms and prevention of osteoporosis but is not approved in the U.S. The parent compound is metabolized in a tissue-selective manner to metabolites that have predominantly estrogenic, progestogenic, and androgenic activities. The drug increases bone mineral density and decreases vasomotor symptoms without stimulating the endometrium, but its effects on fractures, breast cancer, and...

Other medicinal benefits

Fucoidan extracted from the marine brown sea vegetable Undaria pinna-tifida has significantly induced osteoblastic cell differentiation and has potential in use as a functional food ingredient in bone health supplements (Cho et al., 2009). Moreover, fucoidan from C. okamuranus (Phaeo-phyceae) protects gastric mucosa against acid and pepsin. Therefore, fucoidan can be developed as a potential antiulcer ingredient in functional foods (Nagaoka et al., 2000 Shibata et al., 2000).

Factors Influencing Estrogen Hydroxylation

There are several factors that have been found to modulate estrogen metabolism. Foodstuffs containing high levels of phytochemicals and indole 3-carbinol found in vegetables like cabbage, cauliflower, Brussels sprouts, broccoli, and kale, increased urinary excretion of 2OHE1 relative to 16aOHE1, through induction of CYP450 2-hydroxylase activity 55 . Exposure to polycyclic aromatic hydrocarbons from cigarette smoking also causes an increase in 2-hydroxylation and this may partly explain the higher risk for osteoporosis in smokers 56 . Medications such as phenobarbital 57 and thyroid hormones may induce 2-hydroxylation 58 , while cimetidine may reduce overall rate of estrogen metabolism 59 . Use of oral contraceptives 60 and increased body weight may significantly lower 2OHE1 16aOHE1 ratio 61 . The lower ratio in overweight individuals is mostly related to a decrease in C-2 hydroxylation, without a change in 16a-hydroxylation 61 . This proestrogenic ratio created by excess body weight...

The Calcium Sensing Receptor GPCR Variability in the Population

If any of these variants are genetic determinants of the extracellular calcium concentration (15), they may also confer risk for disease states such as familial hypercalcemia. In some genetic backgrounds, the CASR variants may in turn be risk factors for a number of common disorders, such as hypertension and cancer. The Ala986Ser variant, for example, has been associated with bone mineral density (18), primary hyperparathyroidism (19), and Paget disease (20). The Ala986Ser variant is, however, a relatively mild inactivating variant that may predispose to hypercalcemia without being fully predictive of hypocalciuria. By contrast, the Arg990Gly variant appears to be better associated with activation of the renal CASR. This results in the increased calcium excretion that characterizes idiopathic hypercalciuria and is predictive of nephrolithiasis (21). Thus, the study of the different human phenotypes that result from the variable penetrance of polymorphisms of CASR (22) may result in a...

The intracellular ClC6 and ClC7 proteins

Bone degradation is carried out by a specialized osteoclast plasma membrane domain, the ruffled border, through acidification of the resorption lacuna. In fact, the ruffled border is formed by the exocytotic insertion of vesicles of late endosomal lysosomal origin, containing the H+-ATPase. ClC-7 colocalizes with the proton pump in this membrane and was suggested to function as a shunt for the efficient acidification (Jentsch et al. 2005a). This hypothesis is in agreement with the finding that ClC-7 knockout osteoclasts still attach to ivory but fail to acidify the resorption lacuna and are unable to degrade the bone surrogate (Kornak et al. 2001). Moreover, polymorphisms in the gene coding for ClC-7 have been associated with alterations in bone mineral density and bone resorption markers in post-menopausal women and have been found to modulate the phenotypes of patients affected by autosomal dominant osteopetrosis type II (Kornak et al. 2006). Given the essential role of ClC-7 for...

Reasons For Failure Of A Biomarker

There are several examples of biomarker failure. One of the most recent examples is the approval of gefitinib for non-small cell lung cancer (NSCLC). Gefitinib was originally approved based on tumor response as opposed to overall survival. In a postmarketing survival trial that included approximately 1700 patients, there was no benefit over placebo on overall survival. Other examples include bone mineral density (BMD) in osteoporosis for fluoride treatment. However, the Cardiac Arrhytmia Suppression Trial (CAST) provides the best known example of a failure of a biomarker. This study was based on the hypothesis (supported by statistical association and a plausible biological mechanism) that suppression of arrythmias would prevent sudden death after myocardial infarction. The study demonstrated a worse outcome on mortality for patients receiving active treatments compared to those receiving placebo. The theoretical background for biomarker failure is given by Frank and Hargreaves...

Physiological Influences

Investigated, but the findings to date in the elderly suggest genetic factors are not important. A study looking at the development of neck pain in the elderly failed to demonstrate a significant influence of genetic factors.11 IV Similar work on back pain in the over 70 age group suggests a small genetic effect in men but not women. Significant predictors for back pain found in this latter study included previous or current diagnosis of osteoporosis, arthritic or lumbar disk disease, as well as environmental effects.12 IV

Clinical Management of Hyperprolactinaemia

The next step should be to measure PRL levels routinely, on initiating antipsychotic treatment and during the stabilisation period as part of patients physical health screen. This should be followed by training in recognition and follow-up of the longer-term systemic and metabolic side effects of the medication including establishment of osteoporosis and breast problems as early as possible. Medical management and psychiatrists should make the case for financial resources when necessary. There are several guidelines on the monitoring and management of PRL in schizophrenia, but few offer practical advice 55 . Peveler et al. 56 put together some clinical recommendations on antipsychotic-associated HPRL based on a critical appraisal of the current literature. Their main recommendation was that PRL elevation appeared to be of greatest concern in people under the age of 25 years as they are at greatest risk of subsequent osteoporosis. HPRL should be avoided in those with a history of...

Vertebral fracture pain

Vertebral fracture can result from trauma and is more likely if the vertebral bone is abnormally soft either because of osteoporosis or malignant infiltration. In general the resultant pain is similar whether it is produced by a malignant or non-malignant process. Where vertebral infiltration by tumor occurs, radiotherapeutical treatment is often of benefit. The treatment outlined here is only of the pharmacological variety.

Marine algal diet with calcium supplement

The well-known correlation between diet and health demonstrates the great possibilities of food to maintain or even improve our health (Plaza et al., 2008). Dietary factors are very important for osteoporosis, and Ca2+ is the most important cationic mineral in the bone (Aslam et al., 2010).

Brand Differentiation

During the past few years we have seen the traditional vitamin supplement companies offer customized products for men, women, smokers, joggers, osteoporosis, menopause and children. Look for the food industry to follow suit. The nutraceutical functional foods market will mature offering foods and beverages not only for improved lifestyle and performance, but also for those with risk factors for the major diseases and those afflicted with chronic conditions.

Beneficial and Adverse Effects of Dietary Estrogens on the Human Endocrine System Clinical and Epidemiological Data

Dietary estrogens, also known as phytoestrogens, represent a family of plant compounds which are of biological interest because they exhibit both in vivo and in vitro weak estrogenic and anti-estrogenic properties. Phytoestrogens appear to exert their physiological effects through a variety of possible mechanisms, such as their ability to bind to estrogen receptors and their actions on tyrosine kinases and growth factors. Phytoestrogens can be classified into three main categories consisting of isoflavones, lignans, and coumestans. A variety of commonly consumed foods contains appreciable amounts of these plant compounds which have been identified in various human body fluids, such as plasma, urine, bile, saliva, feces, breast milk, prostatic fluid and semen. Accumulating evidence from both clinical and epidemiologi-cal studies has suggested that dietary estrogens may potentially affect the human endocrine system. The existing evidence reviewed here will identify the current research...

Therapeutic Potential Of Marine Algae

Marine algae consist of numerous bioactive substances for known and unknown applications in medical and pharmacological fields. Natural products from marine algae can be used as pharmacological ingredients materials for bone health or as functional foods for bone-strengthening applications. Marine algae have contributed numerous therapeutic compounds for the treatment of multiple disease categories such as antitumor (Fuller et al., 1994, Guardia et al., 1999), anticancer (Gerwick et al., 1994), antibacterial (Ali et al., 2002, Bennamara et al., 1999, Smyrniotopoulos et al., 2003), anti-inflammatory (Awad, 2000, Wiemer et al., 1991), antiviral (Barbosa et al., 2004, Wang et al., 2007), antimicrobial (Barreto and Meyer, 2006), antimalarial (Lane et al., 2007, Topcu et al., 2003). In contrast, several investigations about compounds derived from marine algae effect on bone health as well as osteoblast differentiation processing were reported. Marine algae are also known as favorite food...

Role of Hippocampus and Amygdala in Glucocorticoid Negative Feedback

Glucocorticoid feedback inhibition of ACTH release protects the organism against the deleterious effects of hypercortisolemia (Munck et al., 1984). Whether due to endogenous causes such as Cushing's Syndrome or extrinsic causes such as trauma or chronic stress, hypercortisolemia has at least two major deleterious effects. First, it suppresses the immune-inflammatory defence system and so incapacitates the animal's ability to respond to infection by pathogenic microorganisms (Dallman, 1993 Thompson, 1994). Second, persistent hypercortisolemia will have major adverse effects on intermediary metabolism, resulting eventually in all the features of Cushing's Syndrome, viz., android obesity, diabetes mellitus, hyperlipidemia, hypertension, and osteoporosis.

Symptoms Of Deficiency

Evidence indicates a role for vitamin K in adult skeletal maintenance and osteoporosis. Low concentrations of the vitamin are associated with deficits in bone mineral density and fractures vitamin K supplementation increases the carboxylation state of osteocalcin and also improves bone mineral density, but the relationship of these two effects is unclear. Bone mineral density in adults is not changed by therapeutic use of oral anticoagulants, but new bone formation may be impaired.

Common Side Effects Associated with Antipsychotic Induced Hyperprolactinaemia

Decreased Bone Mineral Density and Osteoporosis Osteoporosis is defined by the WHO as at least a fall of 2.5 SDs below the mean peak bone density for young adults and osteopenia is defined as bone density between < 2.5 and > 1.0 SD. Prior to the introduction of antipsychotics, there were not many reports of fractures or osteopenia osteoporosis in patients with schizophrenia, except for a few case reports of hip fractures in patients undergoing unmodified electroconvulsive therapy. A great deal of our current knowledge and understanding about the risks of developing osteopenia osteoporosis or fractures associated with HPRL comes from animal studies and reports of patients with pituitary tumours. Little is known about the putative role of PRL on bone cells and bone formation in humans 36 . Adler et al. 37 investigated the effects of PRL excess and estrogen deficiency on bone in rats and concluded that HPRL with osteoporosis is likely to be due to PRL-induced hypogonadism rather than...

Zoanthamines Antiosteoporotic Alkaloids

Norzoanthamine and norzoanthamine hydrochloride inhibit IL-6 induction in preosteoblastic MC3T3-E1 cells stimulated by parathyroid hormone at concentrations of 13 and 4.7 g ml, respectively 5 . IL-6 is known to stimulate osteoclast formation, and therefore suppression of IL-6 secretion would prevent osteoporosis. Osteoporosis is caused by an imbalance between bone resorption and bone formation, which results in bone loss and fractures after mineral flux. The frequency of fracture is significantly increased in osteoporosis hip fracture in senile patients is a very serious problem, because it often limits their quality of life. Therefore, in addition to prevention of losing bone mass, the maintenance of bone mechanical strength is very important 8 . To discover candidates for new antiosteoporotic drugs, simple and sensitive in vitro assay systems are essential. Although a variety of in vitro screening systems for antiosteoporotic drugs have been developed, the results of in vitro...

Antiandrogen Therapy In Prostate Cancer

Common side effects of all forms of antiandrogen hormonal therapy include vasomotor flushing, loss of libido, gynecomastia, increased weight, decreased bone mineral density (BMD), and loss of muscle mass. There is variability to these side effects. For example, AR blockers cause more gynecomastia compared with GnRH agonists but less vasomotor flushing and loss of BMD. Importantly, the increased cardiovascular toxicity observed with high doses of estrogen is not observed with other forms of ADT.

O Diseases Of Bone Tissue Utilizing Approved Drug Therapies

Bisphosphonate Binding

Osteoporosis Osteoporosis is the most common of the bone diseases. It is a pathological condition characterized by decreased bone mass and structural deterioration of bone tissue.2 The result is bone fragility leading to increased risk of fractures of the hip, spine, and wrist. Many times the broken hip is considered the result of the patient falling when, in actuality, the broken hip was the initial event causing the fall. The economic impact of this disease is tremendous. Osteoporosis is responsible for more than 1.5 million fractures annually distributed among 300,000 hips, 700,000 vertebrae, 250,000 wrists, and 300,000 other sites. It is more common in women than men because women, on average, have a smaller bone mass than men. Diagnosis, prior to an actual fracture, is done by bone density measurements. Osteoporosis has been considered a disease of aging, but inflammation may be an important variable. Calcium flux favors bone mineralization through adolescence. Bone resorption...

Serm And Antiestrogen Products

Raloxifene, ethoxy phenyl methanone (Evista), is a benzothiophene derivative that differs slightly from the triphenylethylene SERMs. A key structural difference is the carbonyl hinge that connects the modified phenolic side chain to the ben-zothiophene ring system. This hinge is the key structural element that leads to the differing actions at the ERs.55 Raloxifene, unlike tamoxifen and toremifene, has antagonist properties on the endometrium and breast tissue and agonist properties on bone and the cardiovascular system. The lack of agonist action on endometrial tissue has been suggested as a reason for the lack of endometrial cancer associated with raloxifene use. Raloxifene is approved for the prevention and treatment of osteoporosis in postmenopausal women. It has also been investigated for preventing breast cancer in comparison with tamoxifen. Recent studies indicates that it has similar effectiveness to tamoxifen, but has a preferable side effect profile.63...

Eicosanoid Catabolism

There are as yet no potent selective antagonists of prostanoid receptors in clinical use. TP antagonists are under evaluation in cardiovascular disease, whereas EP agonists and antagonists are under evaluation in the treatment of bone fracture and osteoporosis. Orally active antagonists of LTC4 and D4 have been approved for the treatment of asthma (see Chapter 27). These agents act by binding to the CysLT1 receptor and include montelukast and zafirlukast. In patients with mild-to-moderately severe asthma, they cause bronchodilation, reduce the bronchoconstriction caused by

Selecting and Qualifying Imaging Sites

The degree to which imaging equipment across the multiple sites included in a clinical trial must be standardized depends on the type of measurements that will be made, and the ability of the central radiology service to deal with multivendor image data. Ideally, all equipment, software platforms, and upgrade schedules at all of the sites throughout the duration of the study should be identical, but this is rarely feasible. Knowing what deviations from this ideal can be tolerated without compromise to the scientific integrity of the study requires considerable sophistication and experience. In almost all cases, however, the imaging modality (plain radiography, CT, MRI, ultrasound, etc,) used to measure the particular morphological, compositional, or process-related feature of interest must be the same across all sites in the study. Additionally, the same specific instrument should be used for all serial examinations of an individual subject. Sometimes, however, equipment changes...

Selective Estrogen Receptor Modulators And Antiestrogens

Whereas estrogens have been very important in chemical contraception and HRT, compounds that can antagonize the ER have been of great interest for the treatment of estrogen-dependent breast cancers. Tumor biopsies have shown ER to be present in about 60 of primary breast cancers, and most are responsive to estrogen blockade. Unfortunately, most of these ER-related breast cancers also develop resistance to antiestrogen therapy within 5 years. In contrast, only about 6 of nonmalignant breast tissues have significant ER present. Three compounds that are used clinically for estrogen antagonist action in the treatment of breast cancer are tamoxifen, toremifene, and fulvestrant (Fig. 25.15). Two additional agents that can antagonize ERs are clomiphene, which is used as an ovulation stimulant, and raloxifene, which is used for the prevention and treatment of osteoporosis.

Phytoestrogens And Carcinogenesis

Despite the adverse effects of naturally occurring phytoestrogens, these compounds also exhibit beneficial effects.146 Both epidemiological and experimental studies have shown that the consumption of phytoestrogen-rich diets may reduced the risk of cardiovascular diseases, menopausal disorder, osteoporosis, as well as breast and prostate cancers,146152-15 suggesting that their use may be worthwhile.155 There are two principal categories of phytoestrogens, isoflavones and lignanes. Isoflavones and flavones, represented by genistein, luteolin, and daidzein, are produced by leguminous plants (soybean, alfalfa), while lignanes are found in high concentration in linseed.146 The commonly available lignanes are enterolactone and enterodiol. These phytoestrogens

Extracts of Marine Algae Show Inhibitory Activity Against Osteoclast Differentiation

The imbalance between bone resorption and bone formation results in osteoporosis. Therefore, substances that can suppress osteoclast formation are potential candidate materials for drug development or functional foods. There have been reports that extracts or purified compounds from marine micro- and macroalgae can suppress osteoclast differentiation. Symbioimine, isolated from the cultured dinoflagellate Symbiodinium sp., had suppressive effects against osteoclast differentiation in osteoclast-like cells. Norzoanthamine, isolated from the colonial zoanthid Zoanthas sp., has been shown to have antiosteoporosis activity in ovariectomized mice. With regard to marine extracts, the fucoxan-thin-rich component from brown algae has been shown to have suppressive effects against osteoclast differentiation. An extract of Sargassum fusiforme has recently been shown to have antiosteo-porosis activity. This extract suppressed both osteoclast differentiation and accelerated osteoblast...

Testosterone Testosterone

Testosterone deficiency in men can result from inadequate function either of the testes (primary hypogonadism), or of the hypothalamus and pituitary (secondary hypogonadism). Testosterone levels in men generally decrease with age. Although administration of testosterone to elderly men produces beneficial results, such as increased muscle mass, bone mineral density, and mental function, its use is limited due to the possible promotion of prostatic malignancy.2

Treatment of specific fractures

In the fit and healthy, considerable force is required to fracture a vertebra (Table 20.1). In the patient with osteoporosis this can happen with forces that would otherwise be inconsequential. As with any fracture, immediate pain is normal after the fracture. What is more problematical is that pain can be a long-term consequence of such a fracture. When a vertebral body is traumatized to the extent that fracture occurs, its physical shape is often altered. A vertebral body exists in a dynamic structure function relationship to its surrounding structures and so with a change in shape, its architectural relationships change as well. The list of alterations that can occur is long (Figure 20.2).

Molecular Mechanisms Of Cancer Chemotherapy

Biological agents The designation 'biological agents' is sometimes used as a summary designation for a diverse group of compounds that do not directly interfere with basic cellular functions, such as DNA replication and mitosis. Rather, they act on signaling pathways controlling cell proliferation and differentiation. By activating or inhibiting receptor molecules, they redirect cancer cells in a more subtle fashion towards normal behavior. Hormones and antihormones used in the treatment of breast cancer ( 18.4) and of prostate cancer ( 19.2) as well as inducers of differentiation such as retinoic acid used in the therapy of acute promyelocytic leukemia ( 10.5) can be assigned to this category. They act selectively on certain cancers since they activate or inhibit receptor proteins that are specifically required for their growth and survival. This does not automatically imply that such compounds do not have adverse side effects. However, these are typically not caused by toxicity....

Imaging

Sequential images of the scanned area. These images can be viewed in a number of different dimensions axial, sagittal, and frontal, with three-dimensional reconstructions available. CT scans provide an assessment of bony and joint abnormalities, readily detecting fractures, subluxations, cystic bone lesions, and assessing bone mineral density. Additionally, CT scans produce images of soft tissue pathology.

Miscellaneous

The effect of oral magnesium supplementation has been studied in osteoporosis. In fact, significant reductions in serum and bone magnesium have been described in several studies on post-menopausal women with osteoporosis. Recently, dietary magnesium has been observed to be positively associated with bone mineral density (BMD) in a community-based study in elderly men and women.89 Despite this, epidemiological studies relating magnesium intake

Magnesium

Magnesium plays many important roles in structure, function, and metabolism and is involved in numerous essential physiologic reactions in the human body. Supplemental magnesium has been used extensively by patients for cardiovascular disease, diabetes, osteoporosis, asthma, and migraines, although most individuals consume adequate levels in their diet (Institute of Medicine 2001). Patients with a history of these illnesses may be supplementing with magnesium and therefore should be questioned.

Vitamin D

Individuals with osteoporosis frequently have a deficiency in vitamin D (Mezquita-Raya et al. 2001). With increasing age, vitamin D and calcium metabolism increase the risk of deficiency. Studies show a clear benefit of vitamin D and calcium supplementation in older postmenopausal women. Supplementation results in increased bone density, decreased bone turnover, and decreased non-vertebral fractures as well as decreases in fall risk and body sway (Malabanan and Holick 2003).

Glucocorticosteroids

The continued use of glucocorticosteroids at supraphysiological doses will lead to several side-effects, some of them potentially life-threatening. These include increased susceptibility to infections, osteoporosis, hyperglycaemia, myopathy, behavioural disturbances and hypertension 122 . The severity of these side-effects limits the use of glucocorticosteroids, but would also justify a drug targeting approach. Beneficial effects of targeted glucocorticosteroids that inhibit many of the harmful mediators of the fibrotic process are therefore anticipated.

Menopausal Symptoms

HRT has been seen as a specific treatment for symptoms in the short-term and preventative therapy in the long-term 167 . Postmenopausal hormone therapy has both benefits and hazards, including a decreased risk of osteoporosis and cardiovascular disease and an increased risk of breast and endometrial cancer 168,169 . In a prospective study conducted by Grodstein et al. 170 , the relation between postmenopausal hormones and mortality was examined to provide a balanced assessment of the risks and benefits of hormone use. On average, mortality among women who use postmenopausal hormones is lower than among non-users. However, the survival benefit diminishes with longer duration of use and is lower for women at low risk for coronary disease. In a systematic review of scientific and lay literature, the strongest controlled study data of alternative treatment for menopausal symptoms supports phytoestro-gens for their role in diminishing menopausal symptoms related to estrogen deficiency and...

Conclusions

Our understanding of dietary estrogens and their physiological impact on the human endocrine system is broadening as research in this area is expanding with both clinical and epidemiological studies. These dietary estrogens are not only structurally similar to endogenous hormones, but have demonstrated their ability to bind to ERs and have both estrogenic and anti-estrogenic effects. The growing interest in this area suggests that these dietary estrogens may confer significant health benefits related to hormonally-related diseases and conditions such as breast, prostate and colon cancer, menopausal symptoms, the menstrual cycle, osteoporosis, and coronary heart disease. These compounds may play a significant role in the molecular processes concerned with the pathogenesis of these diseases with a real possibility that they can exercise a restraining influence on their development. The possibility still exists that the association between risk of disease and phytoestrogen intake is not...

Calcitriol Rocaltrol

Year of discovery 1968 Year of introduction 1978 (Roche) Drug category Hormone, responsible for the regulation of calcium and phosphate metabolism Main uses Treatment of hypocalcemia, rickets, and osteoporosis Other brand names. Calcijex. Vitamin D deficiency can cause rickets and osteoporosis. When the amount of vitamin D3 produced in the body is insufficient, it needs to be obtained from food sources such as fatty fish or from dietary supplements. Another member of the vitamin D family, vitamin D2, which is derived from fungal and plant sources, is often used instead of vitamin D3, although it is less effective. Calcitriol is a useful treatment for osteoporosis in older patients with an impaired capacity to make it from vitamin D3.

Corticosteroids

Are responsible for inflammatory pains they also produce reduced ectopic firing of neurons (e.g., after amputation), producing phantom limb pain. Corticosteroids inhibit activity of C fibers but not of other sensory fibers (e.g., AP fibers). Each of the corticosteroids produces equivalent analgesia (Bruera et al. 1985 Ettinger and Portenoy 1988). Selection of one corticosteroid over another may be based on the tolerability and the desire to avoid serious miner-alocorticoid effects (e.g., such as those seen with dexamethasone). Patients in whom steroid use might be contraindicated include those with severe cardiac compromise, a predisposition to congestive heart failure, severe osteoporosis, diabetes mellitus, or electrolyte disturbances.

Metabolic Acidosis

GCs lead to a dramatic decrease in bone mineral density, either when endogenously in excess or when administered exogenously 218 . The mechanism by which GCs decrease bone density is multifactorial. The osteopenia appears due to a complex combination of direct effects on bone formation 219-222 and resorption 219, 220, 223 , and indirect effects on calcium homeostasis, including decreased intestinal calcium absorption 223 . Animal and human studies suggest that metabolic acidosis stimulates an increase in cortisol production 214-216 . CMA can increase cortisol production and both acidosis and cortisol induce osteopenia. in muscle, acidosis is known to stimulate protein and essential amino acid breakdown through the ubiquitin-proteasome proteolytic pathway, a mechanism that requires GCs 214 . A very mild Western diet-induced CMA (a degree of acidosis that would not be recognized by applying diagnostic acid-base criteria found in textbooks) results in a state of...

Investigations

The laboratory features in RA reflect the acute-phase response and chronic inflammation of the joints and are listed in Box 38.2. Anemia, thrombocytopenia, leukope-nia, or abnormal liver function tests may also be caused by drug toxicity.The earliest radiographic changes are seen in the hands in the form of soft-tissue swelling and periarticular osteopenia, but these are nonspecific signs. Erosions typical of RA develop in bare areas of bone

Enzymatic Activity

The importance of cathepsin K is evident in the genetic disorder pycnodysostosis. The mutation occurs at residue 212 (Y212C), and it abolishes the interaction between ChS-A and the protein, thus eliminating the enzyme's ability to degrade the collagen substrates but not gelatin substrates 52 . This leads to decreased bone resorption and the formation of denser bone, which during development causes a drastic decrease in stature. On the other hand, overproduction of the enzyme can lead to disorders such as osteoporosis. Consequently, research is under way to find mechanisms to interfere with the enzyme's activity, which include interfering with complex formation of ChS-A and cathepsin K, masking the collagen binding site and blocking attachment of ChS-A to collagen 55 . The appeal to using these mechanisms of inhibition is that they will interfere with the degradation of collagen while at the same time allowing the enzyme to execute other functions such as degradation of gelatinised...

Contraindications

Another open question is whether bisphosphonates can be given during fracture healing or during stabilization of orthopedic implants such as hip prostheses. Recent data indicate that at least alendronate in the dog and man, clodronate and pamidronate in the rat, and ibandronate in the dog do not significantly hamper fracture healing. In fact the callus can be thicker, contain more calcium, and have greater mechanical strength, but it is remodeled at a later stage to normal bone size. Furthermore bisphosphonates can prevent bone loss under plates or around hip prostheses. It would appear, therefore, that there is no contraindication with the low doses such as those used in osteoporosis which do not inhibit mineralization. In contrast, large doses of etidronate, which are likely to inhibit mineralization, should be avoided. The same applies to patients with vertebral fractures.

Opportunities

Reassuring patients and their physicians that specific interventions are active. This is particularly important in the setting of chronic therapies, where the clinical outcome is temporally remote or otherwise difficult to monitor. Examples of drug activity markers include measures of viral load to assess therapeutic intervention in hepatitis or HIV infection, and measures of bone mineral density or biochemical markers of bone turnover following treatment for osteoporosis. Biological activity markers also are useful in setting an individualized dose. Hemoglobin A1c is a commonly employed example used to optimize the dose of insulin for management of diabetes mellitus. Biological activity markers can also be used to assess combined dosing of two or more agents as is common with chemotherapeutics cocktails for treatment of neoplasia. As with natural history markers, there are nonclinical correlates of biological activity markers and the latter typically serve as experimental endpoints.

Heparin

Pregnancy Heparins are used for the management of venous thromboembolism in pregnancy because they do not cross the placenta. Low molecular weight hepar-ins are preferred because they have a lower risk of osteoporosis and of heparin-induced thrombocytopenia. Low molecular weight heparins are eliminated more rapidly in pregnancy, requiring alteration of the dosage regimen for drugs such as dalteparin, enoxaparin, and tinzaparin see also under individual drugs. Treatment should be stopped at the onset of labour and advice sought from a specialist on continuing therapy after birth.

Neurotensin

Teriparatide is a recombinant form of parathyroid hormone, which is used for the treatment of osteoporosis in men and postmenopausal women. The N-terminal region possesses 34 amino acids, which are identical to the biologically active region of the 84-amino acid sequence of human parathyroid hormone. It has been shown to act on osteoblasts to stimulate new bone growth and improve bone density.

Fractures

Several studies have found a 1.5- to twofold increase in the risk of bone fractures in elderly patients taking TCAs or SSRIs. In a cohort study of more than 8,000 community-dwelling older women followed for almost 5 years, the risk of nonspinal fractures increased by a factor of 1.7 for those taking TCAs or SSRIs (Ensrud et al. 2003). More recently, a randomized cohort of 5,008 community-dwelling adults older than 50 years followed for a 5-year period found a 2.1-fold increase in the rate of fractures for those taking SSRIs (Richards et al. 2007). In this study, SSRI use was also associated with increased risk of falls, lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine in a dose- dependent fashion.

Chapter Overview

The use of vitamins, especially as multivitamins, has increased significantly as a result of a move toward the practice of healthier lifestyles. There are two approaches to the use of vitamins that are not always clearly distinct. The first is in the treatment of known or suspected deficiencies, or to prevent deficiencies as bodily needs change as seen during pregnancy, disease, or aging. In this approach, health consequences are caused by vitamin deficiency, and the vitamins restore health by resolving the deficiency. There are numerous studies that prove the efficacy of using vitamins to treat their known deficiency syndromes or to prevent deficiencies. However, there is evidence that vitamin deficiencies may cause more health problems than are currently known. The role of vitamin deficiencies in cancer, cardiovascular disease, bone health, and immune disorders, among others, continue to be examined although the results are often conflicting. Certainly, the maintenance of adequate...

Calcitonin

Measurement of serum calcitonin is used diagnostically to detect medullary thyroid cancer, especially in the setting of multiple endocrine neoplasia, type 2. Therapeutically, it is used in the acute management of hypercalcemia. It also is approved for Paget's disease, generally by subcutaneous injection because of limited bioavailability of the intranasal form, and for the therapy of osteoporosis. After initial therapy at 100 units day, the dose typically is reduced to 50 units three times a week. Side effects include allergic reactions, nausea, hand swelling, urticaria, and rarely intestinal cramping.

Parathyroid Hormone

Continuous administration of PTH or high circulating PTH levels achieved in primary hyperthyroidism causes bone demineralization and osteopenia. Paradoxically, intermittent PTH administration promotes bone growth. The FDA has approved human recombinant PTH (1-34) for treating severe osteoporosis, and full-length PTH is also undergoing clinical trials.

Clinical Effects

In postmenopausal women with osteoporosis, teriparatide increases bone mineral density and reduces the risk of vertebral and nonvertebral fractures. The precise role of this agent relative to other agents used for osteoporosis, alone or in combination, remains to be determined. Candidates for teriparatide therapy at this time are women with a history of an osteoporotic fracture who have multiple risk factors for fracture and who are intolerant or have failed other therapies. The drug is also approved to increase bone mass in men with idiopathic or hypogonadal osteoporosis who are at high risk for fracture.

Therapeutic Uses

Phytonadione, or other vitamin K products, should not be administered to patients receiving coumarin anticoagulants, such as warfarin, during routine therapy as these can antagonize their effects. However, phytonadione is indicated in the treatment of overdoses of vitamin K-epoxide reductase inhibitors, such as warfarin, or other drugs that can interfere with vitamin K utilization in the clotting process. Of particular note is the requirement in this one use for an active form of vitamin K. Specifically, the only marketed product is phytonadione. Inactive forms, such as menadiol, are not bioactivated with sufficient rapidity to be used as antidotes in this situation. Finally, vitamin K may also have some utility in preventing bone loss as is seen in osteoporosis.125

Synthesis

Ideally, drugs approved for medical treatment are intended to achieve predictable therapeutic responses, but physicians as well as their recipients know that for a drug to be safe and effective for everyone is rare. Because responses to standard doses of a drug can vary so much from one person to another, drug therapy is still regarded as a medical art. Adverse drug reactions of a serious nature are likely to occur more frequently than is generally recognized, costing far more than U.S. 100 billion annually and ranking among the leading causes of hospitalization and death. A recent epidemiological study that measured the effectiveness of major drugs commonly used for a variety of diseases found, for instance, that for COX2 inhibitors used to treat pain, the highest percentage of patients who responded was 80 , while responses to drugs used to treat cancer ranked lowest at 25 . Successful drugs employed in the treatment of major diseases, such as diabetes, cardiovascular disease,...

SIRT1 and T2D

Other sirtuins might also play an important role for the regulation of aging and longevity. For example, SIRT3 has been linked to human longevity (Rose et al. 2003 Schapira 2011). Sirt6-deficient mice display the phenotype of premature senescence such as severe lymphopenia, loss of subcutaneous fat, osteopenia, and metabolic disorders, dying at around 4 weeks of age (Mostoslavsky et al. 2006). SIRT6 modulates telomeric chromatin by deacetylating lysine 9 of histone H3, preventing telomere dysfunction and cellular senescence (Michishita et al. 2008). Moreover, SIRT6 attenuates NF-kB signaling by deacetylating lysine 9 of histone H3 at chromatin, inhibiting apoptosis and cellular senescence (Kawahara et al. 2009 Mahajan et al. 2011). These findings provide the idea that increasing SIRT6 might prevent against age-induced physiological changes, thus possibly extend lifespan. It has been recently reported that SIRT1 is involved in maintaining SIRT6 expression under nutrient deprivation in...

Macroalgae

Uchiyama et al. (2004) investigated the effect of the water-soluble extract from marine algae Sargassum horneri on osteoclastic bone resorption and osteoblastic bone formation in vitro. They found two components in the crude extract heat-labile component with a molecular weight of 1000 and heat-stable component with a molecular weight of 50,000. The former component increased the calcium content in rat femoral-diaphy-seal tissues at 25 mg ml (Uchiyama and Yamaguchi, 2003 Yamaguchi et al., 2001), and the latter suppressed 1,25(OH)2VD3-induced osteoclast-like cell formation. Their research group also reported that the S. horneri extract helped to prevent bone loss in streptozotocin-induced diabetic rats in vivo (Uchiyama and Yamaguchi, 2003). Interestingly, these two active components in S. horneri extract were thought to regulate bone metabolism to prevent osteoporosis. The effect of SME on bone resorption in vivo was examined in ovariec-tomized mice, an experimental model of...

Menkes Disease

Menkes Syndrome Models

Lysyl oxidase (LOX) is a secreted enzyme that catalyzes crosslinking of elastin and collagen, and it is found extracellularly attached to its substrates. A deficiency of LOX will virtually affect all organs containing connective tissue. In Menkes disease, skin, bones, and blood vessels are profoundly affected, leading to symptoms like loose skin and joints, osteoporosis, abnormal facies, hernias, bladder diverticula, arterial aneurysms, petechial hemorrhage. Apart from its role in the connective tissue disturbance, LOX deficiency also has an indirect contribution to the CNS degeneration through arterial changes (2). Decreased LOX activity has been demonstrated in cultured skin fibroblasts of MD patients by several researchers (34-41).

Humans

Poor manganese status has been implicated in a variety of disease states and metabolic disorders, including osteoporosis, congenital malformations, TPN, Perthes' disease (necrosis of femur head), senile cataracts, epilepsy, amyo-trophic lateral sclerosis (degenerative disease of motor neurons), acromegaly (pituitary disorder of excess growth of extremities and face), hip abnormalities, multiple sclerosis,23 phenylketonuria (congenital defect causing mental retardation) and maple syrup urine disease (neurodegenerative disease of amino acids in urine).8 One exacerbating factor is the iron intake and status of an individual, as both iron and manganese share a common transport protein in the blood (transferrin) and cell (divalent metal transporter DMT1). In young women, a supplement of 60 mg Fe day for 4 months decreased activity of leukocyte manganese.24 Also, manganese absorption was lowered in women with high ferritin, the iron storage protein.25

Microalgae

The zoanthamine alkaloids are a structurally unique family of natural products that exhibit antiosteoporotic, antibiotic, anti-inflammatory, and cytotoxic biological activities. Although they are isolated from soft coral of the order zoantharia, symbiotic algae may play an important role in their biosynthesis. Norzoanthamine (Fig. 34.2) was isolated along with some analogs from a Zoanthus species collected off the Ayamaru coast of the Amami Islands in Japan (Fukuzawa et al., 1995). Norzoanthamine and its hydrochloride salt have been shown to prevent bone loss in ovariecto-mized mice, a pharmaceutical model for postmenopausal osteoporosis (Kuramoto et al., 1996). As ovariectomized mice do not produce sufficient estrogen, they quickly lose bone mass and strength within a few weeks. However, oral treatment of mice with norzoanthamine HCl at doses of

Eb1053

Estrogen replacement, osteoporosis prevention, 130-132 Etidronate treatment, 105-106, 109-110 osteoporosis treatment, 138, 145, 150151 treatment, 106-110 osteoporosis treatment, 140, 151 iVlarvil 10, see Alendronate Matrix, composition, 4-5 Menopause, osteoporosis relationship, 125-127, 140-142, 146 Mevalonate pathway, bisphosphonate effects, 42, 44-45 Mineralization, see also Bone mineral density Ossification inhibition, preclinical biology, 48-50 ectopic mineralization, 48 normal mineralization, 49, 56 Minerals, see also Bone mineral density osteoporosis compared, 124 Osteoporosis, 123-152 additive effects, 148-149 bone mineral density, 123, 137143

F650f657

Glucocorticoid-induced osteoporosis. Curr Opin Nephrol Hypertens 2001 10 589-595. Canalis E. Mechanisms of glucocorticoid action in bone Implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 1996 81 3441-3447. Cooper MS, Hewiston M, Stewart PM. Glucocorticoid activity, inactivity and the osteoblast. J Endocrinol 1999 163 159-164. Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res 1999 14 1061-1066. Lane NE. An update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 2001 27 235-253. Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells Potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinol 1999 140 4382-4389. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis Pathogenesis and...

Cerezyme

Type 1 Gaucher disease is a hereditary condition occurring in about 1 40,000 individuals. It is characterized by a functional deficiency in j-glucocerebrosidase enzyme activity and the resulting accumulation of lipid glucocerebroside in tissue macrophages, which become engorged and are termed Gaucher cells. Gaucher cells typically accumulate in the liver, spleen, and bone marrow and, occasionally, in lung, kidney, and intestine. Secondary hematological sequelae include severe anemia and thrombocytopenia in addition to characteristic progressive hepatosplenomegaly. Skeletal complications are common and are frequently the most debilitating and disabling feature of Gaucher disease. Possible skeletal complications are osteonecrosis, osteopenia with secondary pathological fractures, remodeling failure, os-teosclerosis, and bone crises.

Adverse events

In clinical studies, alendronate was very well tolerated up to a daily oral dose of 20 mg with an overall profile comparable to placebo. This was also the case for the digestive tract. Signs of upper gastrointestinal intolerance occurred in some postmenopausal patients with osteoporosis treated with 40 mg. However, this dose was well tolerated in patients with Paget's disease. Nevertheless, in clinical practice, it seems that alendronate administration is occasionally accompanied by gastrointestinal disturbances in some patients. Furthermore a postmarketing analysis performed by the manufacturer reported that about 0.1 o of patients who had received 10 mg of alendronate daily per os displayed serious or severe adverse esophageal effects. These included symptoms related to esopha- q effects i geal dysfunction, and structural alterations like esophagitis, erosions, and animals ulcerations. p'64 Fractures have occurred in children treated for fibrodysplasia ossificans progressiva, and...

Teriparatide Forteo

Year of discovery 1970s Year of introduction 2002 (Eli Lilly) Drug category Anabolic agent Main uses Treatment of osteoporosis for patients with high risk of fractures Drug category First drug in its class, directly affecting osteoblasts and causing bone growth. Teriparatide is a synthetic parathyroid hormone segment containing the first 34 amino acid of the natural protein. This drug, developed by Eli Lilly and marketed under the name Forteo, was approved in 2002 for the treatment of osteoporosis. It is the first parathyroid hormone derivative on the market and also the first agent to act by affecting osteoblasts, thereby directly causing bone growth and an increase of bone density.2 Teriparatide is used as second-line therapy mainly in cases involving individuals with a history of osteoporosis-related fracture, or intolerant of other therapies. Since teriparatide is not orally absorbed, it is administered by injection.

Pagets disease

Beethoven Paget Disease

It is a fairly common disease, actually the second most common metabolic bone disease after osteoporosis in some countries. It has been estimated that in the countries where the ailment is prevalent, up to 3 of the population over the age of 50, more in later years, is affected. A recent study suggests a decrease in the prevalence of the disease in the last 20 years. The disease is frequent in Europe, with the exception of the Scandinavian countries, and is frequent in regions inhabited by European immigrants, such as North America and Australia. In contrast, it is rare in the Arab countries, as well as among blacks and Asians. It is almost always diagnosed in patients over the age of 40 and is probably somewhat more common in men than in women. Recent work shows that there is a genetic predisposition, as a family history is often present. Possibly a gene abnormality on chromosome 18q causes Paget's disease in some families.

Glucocorticoids

Toxicity and monitoring Most side effects are dose-dependent. Long-term use is associated with a number of complications, including psychiatric problems, cataracts, myopathy, osteoporosis, avascular bone necrosis, glucose intolerance or overt diabetes mellitus, and hypertension. In addition, psoriatic patients treated with parenteral or topical glucocorticoids may have a pustular flare, particularly if the steroid is tapered rapidly.

Conclusion

Much of the discussion in this chapter on glutamate receptor antagonists has dealt with negative side effects. It was not our intention to necessarily portray glutamate receptor compounds in a negative light, but to indicate potential sources of problems in the development of therapeutics in peripheral tissues. A potentially key strength of the voluminous work already performed in the CNS field is application of the libraries of compounds already developed by pharmaceutical companies to peripheral disorders. Groundwork research on the numerous organs and peripheral systems that have been shown to possess functional glutamate receptors described throughout this book strongly suggest that glutamate receptor agonists and antagonists will have therapeutic value in the periphery. Numerous possibilities already exist for the therapeutic use of glutamate-receptor-based compounds in diabetes, asthma, and osteoporosis by virtue of the receptors shown in the pancreas, lung, and bone in both...

Bisphosphonates

Bisphosphonates are pyrophosphate analogs (Figure 61-8) they contain 2 phosphonate groups attached to a germinal (central) carbon that replaces the oxygen in pyrophosphate. They have a strong affinity for bone, especially areas undergoing remodeling. They are used extensively in conditions characterized by osteoclast-mediated bone resorption, including osteoporosis, steroid-induced osteoporosis, Paget's disease, tumor-associated osteolysis, breast and prostate cancer, and hypercalcemia.

Raloxifene Evista

Year of discovery 1982 Year of introduction 1997 (Eli Lilly) Drug category Selective estrogen receptor modulator (SERM) Main uses Prevention and treatment of osteoporosis. A reduced level of estrogen in postmenopausal women is a major risk factor for osteoporosis. Unfortunately, the use of natural estrogens for the treatment and prevention of osteoporosis is accompanied by an increased risk of uterine and breast cancer. Although the combination of estrogen with progestin in hormone replacement therapy (HRT) is protective against uterine cancer, it leads to an increased risk of coronary heart disease, invasive breast cancer, stroke and pulmonary embolism. were found to produce a tissue-specific response upon binding to estrogen receptors. This discovery stimulated the search for substances that have beneficial estrogenic effects in certain tissues (e.g., bone, brain, liver), but antagonistic or no activity in other tissues (e.g., breast and endometrium), where estrogenic action is...