Osteoporosis Treatment at Home

Seven Secrets To Reverse Your Osteoporosis Or Osteopenia

This easy- to-read book will reveal quick, inexpensive ways to eat and exercise to prevent or reverse osteoporosis and enrich your life. In just a few months see an amazing difference in your bone quality and your life. Replace the fear of doing nothing or the excessive expense of harmful medications.

Seven Secrets To Reverse Your Osteoporosis Or Osteopenia Summary

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Regional Migratory Osteoporosis

Regional migratory osteoporosis (RMO) is also known as idiopathic regional osteoporosis, transient osteoporosis, and migratory algodystrophy. It was first described in 1967 (88) and its etiology remains unknown. It appears to be closely related to the disorder known as transient osteoporosis of the hip.3 RMO occurs in middle-aged men. It begins as gradually increasing joint pain in the lower extremities with no prior history of trauma. Pain generally reaches a maximum level after 2 months. Symptoms subside after 3 to 9 months but may recur at the same or another joint. X rays of the affected joint generally reveal preservation of the articular space with periarticular demineralization. The affected joint will be hot on radionuclide scans. Trevisan and Ortolani (89) reported bone density findings in three Caucasian men who experienced 13 acute episodes of RMO during the study period. The men were 43, 44, and 54 years of age at presentation. Of the episodes, 46 involved the foot. The...

National Osteoporosis Foundation Guidelines

The first guidelines or indications for bone mass measurements from a national organization were released in 1988 by the National Osteoporosis Foundation (NOF). These guidelines or clinical indications were developed in response to a report from the Office of Health Technology Assessment (OHTA) of the Public Health Service that had been submitted to the Health Care Finance Administration (HCFA). The report from OHTA To diagnose spinal osteoporosis in patients with vertebral abnormalities or roentgeno-graphic osteopenia in order to make decisions about further diagnostic evaluation and therapy. The NOF indications also noted the specific skeletal sites and techniques that should be used in these different circumstances. For an assessment of fracture risk in a postmenopausal woman, the NOF suggested that any site by any technique was appropriate. For the confirmation of spinal demineralization or the diagnosis of spinal osteoporosis, measuring the spine with DPA, DXA, or QCT was...

Guidelines from the European Foundation for Osteoporosis and Bone Disease

The European Foundation for Osteoporosis and Bone Disease (EFFO) published in 1996 some of the most practical guidelines yet for the clinical application of bone density measurements (12). Some of the clinical circumstances in which the EFFO believed that bone mass measurements should be considered are shown in Table 7-4. Like AACE, the EFFO was careful to emphasize that bone mass measurements should not be done if the result would not affect the clinical decision-making process. e. Conditions associated with osteoporosis 2. Radiographic evidence of osteopenia and or vertebral deformity a. Hormone replacement treatment in patients with secondary osteoporosis 2. Radiographic evidence of osteopenia and or vertebral deformity a. Hormone replacement treatment in patients with secondary osteoporosis The EFFO guidelines noted that the interval between BMD measurements for the detection of bone loss over time would vary with the anticipated rate of loss from the disease process. In some...

ACOG Recommendations for Bone Density Screening for Osteoporosis

In a press release (13) on February 28, 2002, the American College of Obstetricians and Gynecologists (ACOG) announced long-awaited recommendations for the use of bone densitometry. ACOG, like the NOF and AACE, recommended that all postmenopausal women 65 years of age and older be screened for osteoporosis. Similarly, they ACOG 2001 Recommendations for Bone Density Screening for Osteoporosis. Diseases and Conditions Associated with an Increased Risk for Osteoporosis in Which BMD Testing May Be Useful in Both Pre- and Postmenopausal Women ACOG 2001 Recommendations for Bone Density Screening for Osteoporosis. Diseases and Conditions Associated with an Increased Risk for Osteoporosis in Which BMD Testing May Be Useful in Both Pre- and Postmenopausal Women

Osteoporosis risk assessment instrument

The Osteoporosis Risk Assessment Instrument (ORAI) questionnaire was developed by Cadarette et al. (7) using information obtained at the baseline visit for women participating in the Canadian Multicentre Osteoporosis Study4 (CaMos). There were 926 par- 4 CaMos is a population-based cohort study in which risk factors for osteoporosis, BMD, and osteoporotic fracture are being evaluated over a 5-year period.

Diagnosing Osteoporosis

Guidelines of the Study Group of the WHO for the Diagnosis OF OSTEOPOROSIS The 1999 WHO and 2000 IOF Recommendations The Clinical Dilemma Diagnosing Osteoporosis in Men Many disease processes can affect skeletal mass. As the use of densitometry has become more widespread, an increasing number of diseases2 have been recognized as causing a decline in bone density. Nevertheless, the use of densitometry to diagnose osteoporosis remains the most common application of densitometry to disease states. In 1991 (1) and again in 1993 (2), Consensus Development Conferences attempted to clarify the clinical definition of osteoporosis. The NOF, the National Institutes of Health (NIH), and the European Foundation for Osteoporosis and Bone Disease sponsored these conferences. The definition of osteoporosis from the 1993 conference reflected only minor modifications from the 1991 conference. At the 1993 Consensus Development Conference (2) it was agreed that osteoporosis was The 1993 definition...

Guidelines of the study group of the who for the diagnosis of osteoporosis

In an extensive report published in 1994 (3), a WHO study group composed of 16 internationally known experts in the field of osteoporosis proposed criteria for the diagnosis of osteoporosis based on a specific level of bone density. The focus of the WHO study group was the study of world populations rather than the diagnosis of osteoporosis in individuals. While endorsing the prior 1991 and 1993 Consensus Development Conferences' definition of osteoporosis, the WHO recognized that their proposed criteria did not include any assessment of microarchitectural deterioration. The WHO attempted to reconcile the prevalence of the disease that would be created depending on the level of bone density chosen with published lifetime fracture risk estimates. The study group noted that a cut-off value of 2.5 SD or more below the average value for healthy young women for bone density at the PA spine or proximal femur or for bone mineral content at the midradius would result in 30 of all...

Changing the Definition of Osteoporosis

There has been considerable debate as to whether T-scores and the WHO Criteria should be retained or whether entirely new approaches to quantitatively defining osteoporosis should be pursued. The 1991 and 1993 Consensus Conferences' (1,2) definition of osteoporosis and even the 2000 Consensus Conference (23) definition2 ultimately define osteoporosis as a state of increased risk for fracture. It would be preferable for the diagnostic threshold for osteoporosis to coincide with the level of bone density that constitutes an unacceptable level of fracture risk, no matter what skeletal site or technique might be used for the measurement. Lu et al. (24) compared the diagnostic agreement for osteoporosis between two normal reference population approaches and a risk-based approach in 7671 women from the Study of Osteoporotic Fractures (SOF). Bone density was measured at eight different regions of interest using a combination of DXA and SPA the PA lumbar spine, total femur, femoral neck,...

Diagnosing osteoporosis in men

The issues surrounding the appropriate criteria for the diagnosis of osteoporosis in men are not substantially different than those for women. The WHO Criteria were 2At this NIH Consensus Conference osteoporosis was defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.

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.

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.

Medical guidelines for the prevention and management of postmenopausal osteoporosis

In women who have X-ray findings that suggest osteoporosis. 5. For establishing skeletal stability and monitoring therapeutic response in women receiving treatment for osteoporosis (baseline measurements should be made before intervention). (From Osteoporosis Task Force. American Association of Clinical Endocrinologists 2001 medical guidelines for clinical practice for the prevention and management of postmenopausal osteoporosis. Endocr Pract 2001 7 293-312.)

Inulin and Bone Health

For this is probably enhanced passive and active mineral transport across the intestinal epithelium, mediated by increased levels of butyrate and other short-chain fatty acids and decreased pH (ScholzAhrens and Schrezenmeir, 2002). Improvements in calcium and iron absorption may help prevent osteoporosis and anemia, respectively (Ohta et al., 1998 Weaver and Liebman, 2002). Fructooli-gosaccharide ingestion enabled rats, for instance, to recover from experimentally induced anemia and to increase levels of minerals in their bones (Ohta et al., 1998 Oda et al., 1994). Osteoporosis is a condition characterized by a decrease in bone mass and density that causes the bones, especially in postmenopausal women, to become fragile and vulnerable to fracture. It is a growing global problem, which can be alleviated by dietary approaches. Calcium is a key factor in bone strength. By optimizing peak bone mass in early adulthood and by minimizing bone loss during the postmenopausal period, the risk,...

The osteoporosis selfassessment tool

Koh and colleagues (11) developed the original Osteoporosis Self-Assessment Tool for Asians (OSTA) based on a study of 860 non-Caucasian, postmenopausal women from eight Asian countries. Risk factors were captured from a self-administered questionnaire and bone density was measured by DXA in the proximal femur. Proximal femur T-scores were based on the manufacturer's reference data for Asian women. Statistical analysis was performed to determine which risk factors were independent predictors of BMD. The risk factors that were captured are listed in Table 8-9. These independent predictors were combined in a multivariable model from which risk factors were dropped one at a time until only statistically significant variables remained in the model. An index was developed from the variables in the final model to identify those women with a high probability of having a femoral neck T-score of -2.5 or less. Adapted with permission of the publisher from Koh LKH, Sedrine WB, Torralba TP, et...

Osteoporosis

Osteoporosis is a disease that weakens our bones through the loss of bone density. Bones become weaker and weaker as bone density is lost, and osteoporosis is diagnosed when the bone density drops two or more standard deviation below normal, indicating loss of 25 or more of the total bone mass. Osteoporosis is manifested in fractures that result from any minor trauma. Every year in the United States, more than 1.4 million fractures that happen to people over 45 years old are attributed to osteoporosis. In recent years, considerable effort has been taken in the research of osteoporosis. Investigators have been focusing on developing quantitative techniques to assess a human skeleton. The trabecular bone has a high surface-to-volume ratio, and a presumed turnover rate approximately eight times higher than that of the cortical bone. Therefore, the trabecular bone is highly sensitive to various stimuli. In keeping with these data, the clinical and epidemiological observations show that...

Estimated Time To Complete

We are pleased to award category 1 credit(s) toward the AMA Physician's Recognition Award. By completing the Review in the CD-ROM Companion in Appendix XIV, you are eligible for up to 30 hours of category 1 credit. After answering all of the questions correctly, complete the review evaluation and enter the required identifying information on the certificate of course completion. This certificate is not valid until signed with authorized signature at the Foundation for Osteoporosis Research. The certificate may be printed one time only. Send the certificate and the required fee to the Foundation for Osteoporosis Research and Education for awarding of continuing education credits. This activity is offered by the Foundation for Osteoporosis Research and Education, a CMA accredited provider. Physicians completing this course may report up to 30 hours of category 1 credits toward the California Medical Association's Certification in Continuing Education and the American Medical...

Bone Growth Modeling and Remodeling

Under normal circumstances in the mature skeleton, bone resorption and bone formation are coupled. At any given remodeling site, bone formation predictably follows bone resorption such that resorbed bone is replaced with an equal amount of new bone. This predictable sequence of events in both cortical and trabecular bone remodeling is called ARF, an acronym for activation, resorption, and formation (50). In disease states like osteoporosis, even though the ARF sequence remains, resorption and formation may be uncoupled, leading to an imbalance in resorption and formation and a net bone loss. The rate at which BMUs are activated, initiating bone resorption, is called the activation frequency. In some disease states, the activation frequency may increase or decrease producing changes in bone mass.

Physiological Functions Of Cas

Sickness and for gastric and duodenal ulcers, neurological disorders, or osteoporosis. The development of more specific agents is required because of the high number of isozymes present in the human body as well as the isolation of many new representatives of CAs from all kingdoms. This is possible only by understanding in detail the catalytic and inhibition mechanisms of these enzymes. These enzymes and their inhibitors are indeed remarkable after many years of intense research in this field, they continue to offer interesting opportunities to develop novel drugs and new diagnostic tools or to understanding in greater depth the fundamental processes of the life sciences.

Qualitative or Categorical Data

If data are classified as belonging to categories, the data are considered qualitative data. Such data are discrete and generally consist of counts or the number of individuals belonging to each category. This type of data is also called categorical data. Categorical data can be ordinal or nominal, depending on whether there is a logical order to the categories. For example, individuals might be placed into height categories of tall, medium or short (remember that the actual measurement of height is a continuous quantitative variable, which is different from the current example). This is clearly qualitative or categorical data. There also is a logical order to these categories, with medium in between tall and short. This is an example of ordinal data. Nominal data has no obvious order. Hair color, for example, cannot be ordered. Qualitative count data of the number of individuals with brown, blond, or black hair can be obtained, but the categories of brown, blond, or black hair have...

Late Effects In Survivors

As noted earlier, patients who survive the first five years after HCT are likely to survive long-term with mortality rates eventually approaching that of the general population (5). However, some survivors experience late complications of HCT. Baker et al. (67) studied the long-term risks and benefits of HCT for CML. Two hundred forty-eight recipient of HCT for CML who had survived at least two years post-HCT were compared to 317 normal siblings. Subjects completed a 238-item survey on medical late effects. When compared with sibling controls, survivors had higher risks of ocular, oral health, endocrine, gastrointestinal, musculo-skeletal, neurosensory, and neuromotor impairments. Multivariate analysis of the allograft recipients identified chronic GVHD as a major risk factor for hypothyroid-ism, osteoporosis, cardiopulmonary, neurosensory, and neuromotor impairments. These data show the need for continued monitoring and medical intervention in these patients. The CIBMTR and EBMT...

Rationale for the Use of Antiestrogens in Cancer Treatment

Droloxifene, toremifene and idoxifene has been developed but these compounds were not superior to tamoxifen 143 . Even raloxifene was not further evaluated as a breast cancer treatment when early clinical trials showed less activity than tamoxifen in therapy of advanced breast cancer. Nevertheless, raloxifene was more effective in prevention of osteoporosis and was successfully developed as the first SERM for this indication. Only later was a reduction of the incidence of breast cancer observed as a beneficial side effect in the placebo-controlled raloxifene trials 144 .

Sensitivity and Specificity

Sensitivity and specificity are easily illustrated by considering a population of 1000 women in whom the spine bone density has been measured. A cut point can be chosen, most simply by picking a T-score such as -2.5 to determine the exact percentages of women with spine T-scores of -2.5 or poorer and spine T-scores better than -2.5. The women with T-scores of -2.5 or poorer are considered diseased. Based on World Health Organization (WHO) criteria,2 they have osteoporosis. The women with T-scores better than -2.5 are considered nondiseased in this example. They do not have osteoporosis, although many of them may be osteopenic. By using the T-score to pick a cut point that defines the categories of diseased and nondiseased, quantitative continuous bone density data has been converted into two qualitative nominal data categories. 2 See Chapter 9 for a discussion of the WHO criteria for the diagnosis of osteoporosis.

Pharmacology of Antiestrogens

Genic, which results in a different side-effect profile. While lipid levels were similar, the proliferative effects on the endometrium were reduced and the osteoporosis protection was less effective under toremifene treatment 160 . Although droloxifene was more potent in pre-clinical assays, it was significantly less active than tamoxifen in a randomised phase III trial in advanced breast cancer 161 . Levormeloxifene and idoxifene were noted to increase uterine prolapse and incontinence during phase III trials and therefore the trials were terminated prematurely 162 . Raloxifene was successfully approved for osteoporosis prevention after initial failure in breast cancer studies 144 . In the randomised, double-blind MORE study (Multiple Outcomes of Raloxifene) a 72 decrease in the incidence of invasive breast cancer was found after 4 years of raloxifene therapy, besides the prevention of osteoporosis 144 . A CORE (Continuing Outcomes Relevant to Evista) trial was conducted to examine...

Shewhart Rules And Cusum Charts

Although much has been written about quality control procedures in densitometry, much of this literature has been concerned with data collection in clinical research rather than patient data collected as part of medical care. Quality control, although absolutely necessary in clinical research, is no less necessary in clinical practice. The original indications for bone mass measurements from the National Osteoporosis Foundation published in 1988 and the guidelines for the clinical applications of bone densitometry from the International Society for Clinical Densitometry published in 1996 called for strict quality control procedures at clinical sites performing densitometry (1,2). The Canadian Panel2 of the International Society for Clinical Densitometry published specific guidelines for quality control procedures in 2002 (3). Such procedures are crucial to the generation of accurate and precise bone density data. When quality control is poor or absent, the bone density data may be...

Predicting rate of bone loss

If bone turnover markers could reliably predict the rate of bone loss, they would provide a cheap and easy way of screening women at high risk of developing osteoporosis. Unfortunately, there are major methodological problems that arise when trying to examine the association of bone markers with bone mineral density (BMD) in longitudinal studies 8 . For example, the magnitude of the error associated with BMD measurements over time (in the region of a few per cent) is similar to the annual changes that are seen in BMD. Therefore, it is difficult to make a valid assessment of the relationship between the rate of bone turnover and the subsequent rate of bone loss in individual postmenopausal women. Studies have previously given conflicting results 8-11 , but two recent studies suggest that bone markers cannot be used to predict the rate of bone loss. Yoshimura et al. 12 examined eight bone markers and their relationship with BMD change at the hip and femoral neck over 3 years in 400...

Replacing a densitometer

Johnston CC, Melton LJ, Lindsay R, Eddy DM. Clinical indications for bone mass measurements a report from the scientific advisory board of the National Osteoporosis Foundation. J Bone Miner Res 1989 4 S1-S28. 7. Pearson J, Dequeker J, Henley M, et al. European semi-anthropomorphic spine phantom for the calibration of bone densitometers assessment of precision, stability and accuracy. The European Quantitation of Osteoporosis Study group. Osteoporos Int 1995 5 174-184. 8. Pearson D. Standardization and pre-trial quality control. In Pearson D, Miller CG, eds. Clinical trials in osteoporosis. London, England Springer, 2002 43-65.

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.

Knockout experiments and human genetic diseases

Knock-out experiments have elucidated the role of proteins as markers of bone formation. Since type I collagen is essential for life, it is not possible to generate knockout mice with a total lack of type I collagen. However, mice missing the a2-chain of type I collagen are available. These animals produce a variant form of type I collagen, called a1-homotrimer collagen 1 . Homozygous oim oim mice have skeletal fractures, limb deformities and generalized osteopenia. In humans, the disease osteogenesis imperfecta is caused by genetic defects in type I collagen and many different mutations usually lead to this brittle bone disease. Knock-out of the tissue-nonspecific alkaline phosphatase (TNAP) gene leads to several abnormalities both in soft tissues and bones. The latter include impaired growth, abnormal

Tamoxifens Legacy A Menu of Medicines

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

Standardization of Forearm DXA Results

One hundred and one women, aged 20 to 80 years, with 13 to 19 subjects per decade were studied on each of the six devices. Women were excluded if they were pregnant, had a history of distal radial fracture, or had any bone diseases other than osteoporosis. Seventy-four percent of the women were white.

General Overdose Management

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.

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...

Pyridinium crosslinks

In both healthy individuals and in patient groups with osteoporosis, thyroid disorders, hyperparathyroidism and arthritic diseases. These observations paved the way for the development of direct immunoassays that initially measured both Pyd and Dpd along with small molecular weight substances (Mr < 1000). This was followed by the commercial development of specific monoclonal antibody-based assays that measure the more bone-specific crosslink, Dpd 9 . More recently, immunoassays for free urinary Dpd have become widely available on several types of automated immunoassay analyzers in reference laboratories and clinical laboratories.

Rational Design Of Mimetic Surfaces

Blood clotting, would healing, inflammation, osteoporosis, and cancer (27,34,35). Integrins interact with cell binding domains on ECM proteins, such as the ubiquitous arginine-glycine-aspartic acid (RGD) tripeptide sequence, through a binding site created by the dimeric, noncovalent interaction between a and b subunits (34,36,37). In contrast to integrin binding, cell surface proteoglycans (e.g., heparan sulfate) bind to ligands via purely electrostatic interactions. This binding is highly dependent on the spacial location of the charges within the ligand. For example, the negatively charged carboxyl and sulfate groups present in heparin interact with the positively charged heparin binding domains present in ECM proteins through consensus amino acid sequences such as X-B-B-X-B-X (X, hydrophobic B, positive basic residue) (6,38,39).

Bone markers and fracture risk

With the emergence of effective - but rather expensive - treatments, it is essential to detect those women at higher risk of fracture. Several prospective studies have shown that a standard deviation (SD) decrease of bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) or heel ultrasound is associated with a 2-4-fold increase in relative fracture risk including of the hip, spine and forearm. In this context, the question arises as to what extent bone markers can add to bone mass measurements in order to improve the assessment of fracture risk. The markers with the best performance characteristics in osteoporosis are in italics. Table 12.2. Combined use of bone mineral density (BMD) and of bone resorption marker (urinary CTx or free deoxypyridinoline Dpd ) to improve hip fracture risk in elderly women the EPIDOS study. Table 12.2. Combined use of bone mineral density (BMD) and of bone resorption marker (urinary CTx or free deoxypyridinoline Dpd ) to improve hip...

Ankylosing Spondylitis

Low bone density has been frequently observed in ankylosing spondylitis although its etiology remains uncertain. For 2 years Maillefert et al (23) followed 54 patients with ankylosing spondylitis to determine the prevalence of osteopenia and osteoporosis and the relationship of any observed bone loss to therapy, physical impairment, or inflammation. There were 35 men and 19 women in the study with an average age of 37.3 years and average disease duration of 12.4 years. In 23 patients, the disease duration was less than 10 years. Bone density was measured at baseline and 2 years with DXA at the PA lumbar spine and proximal femur (Hologic QDR 2000). The mean PA lumbar spine baseline T-score and z-score for the group was -1.24 and -0.98, respectively. At the proximal femur, the baseline T-score and z-score was -1.07 and 0.46, respectively. Seventeen percent had T-scores at the PA lumbar spine of -2.5 or poorer and 39 had T-scores between -1 and -2.5. At the femoral neck, 11 had T-scores...

Bone markers to monitor antiresorptive therapy

Monitoring the efficacy of treatment of osteoporosis is a challenge. The goal of treatment is to reduce the occurrence of fragility fractures. Measurement of BMD by DXA is a surrogate marker of treatment efficacy that has been widely used in clinical trials. Its use in the monitoring of treatment efficacy in the individual patient, however, has not been validated. Given a short-term precision error of 1-1.5 of BMD measurement at the spine and hip, the individual change must be greater than 3-5 to be seen as significant. With bisphosphonates such as alendronate, repeating BMD 2 years after initiating therapy will determine if a patient is responding to therapy, i.e. shows a significant increase in BMD - at least at the lumbar spine which is the most responsive site. With treatments such as raloxifene or nasal calcitonin that induce much smaller increases in BMD, DXA is not appropriate to monitor therapy and, with any treatment, DXA does not allow the identification of all responders...

Genome scans and candidate genes

A first step in the dissection of the genetic factors in osteoporosis is the 'genomics' of osteoporosis, i.e. the identification, mapping and characterization of the set of genes responsible for contributing to the genetic susceptibility to different aspects of osteoporosis. Finding the gene responsible for monogenic disorders has now become almost a routine exercise for specialized laboratories. However, the complex character of osteoporosis makes it quite resistant to standard methods of analysis which, in the past, have worked so well for the monogenic diseases. Therefore, different and often more cumbersome approaches have to be applied (see, for example, reference 5 ). In a top-down approach, large-scale genome searches are initially performed to identify which chromosomal areas might contain osteoporosis genes. In an optimal setting, such searches are performed in hundreds of relatives (sibs, pedigrees, etc.) with hundreds of DNA markers (mostly microsatellites) evenly spread...

Gluten Sensitive Enteropathy

In a study from Argentina, Gonzalez et al. (46) evaluated 127 consecutive postmenopausal women with osteoporosis, who had a mean age of 68. Osteoporosis was defined as at least one nontraumatic fracture and an L2-L4 and or femoral neck T-score below -2.5. Bone density was measured using a Lunar DPX. The Buenos Aires reference population was used to calculate T- and z-scores for the study populations. This reference database is reported as similar to the reference database for Caucasian women in the United States. The mean T-score for the osteoporotic population was -3.2 and -3.0 for spine and femoral neck, respectively. The prevalence of celiac disease in these osteoporotic women was compared to 747 women, with a mean age of 29, recruited for a population-based study. Screening for celiac disease was done using IgA and IgG antigliadin antibodies (AGA) in all patients. This was followed by antiendomysial antibodies (EmA) and total IgA in the patients testing positive for AGA....

Pregnancy and Lactation

Controversy exists as to whether a separate entity of pregnancy-induced osteoporosis exists or whether pregnancy is an incidental or precipitating factor in persons who already have osteoporosis. The syndrome is considered rare with about 80 cases documented in the literature. The women who are affected often present with vertebral fractures in the third trimester or shortly after delivery. Densitometry has demonstrated markedly low bone density in both the spine and proximal femur (81). Five cases of postpregnancy osteoporosis have been reported by Yamamoto et al. (82). These women ranged in age from 24 to 37 years. Of the five women, four were diagnosed after their first pregnancy. The fifth was diagnosed after her second pregnancy. All of the women presented with back pain and vertebral compression fractures, most within 1 month of delivery. BMD measurements were made at the 33 radial site with SPA (Norland-Cameron) and at the spine by either QCT or DXA (Hologic QDR-1000)....

Use in Prevention and Therapy

Fluoride can stimulate osteo-blastic activity and new bone formation, but its role in osteoporosis remains unclear.6,14 Although one study found a decrease in vertebral fractures with intermittent fluoride and calcium therapy,12 another found that skeletal fragility and fracture rates were increased by daily supplementation with fluoride and cal-cium.13 Overall, it appears fluoride has little beneficial effect in osteoporosis.14

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).

Small Leucine Rich Repeat Proteoglycans

Studies in knockout mice demonstrate that depletion in SLRP production can influence tissue properties. Absence of decorin results in lax, fragile skin, in which collagen fibril morphology is irregular (104). Absence of biglycan results in an osteoporosis-like phenotype, with a reduced growth rate and a decreased bone mass (105). Absence of lumican produces both skin laxity and corneal opacity, with an increased proportion of abnormally thick collagen fibrils (106). Absence of fibromodulin results in an abnormal collagen fibril organization in tendons (107). Thus, collagen fibril architecture is impaired in tissues in which SLRPs are deficient, but currently there is no information on how the intervertebral disks may be affected in these mice. Of these SLRP, only decorin has currently been linked to a human disorder, with a frameshift mutation being reported in congenital stromal dystrophy of the cornea (108). Impaired GAG synthesis can also have detrimental consequences, as...

Guidelines of the International Society for Clinical Densitometry

The guidelines from the International Society for Clinical Densitometry (ISCD) (5) were initially developed in 1994 during a meeting of an international panel of experts in bone densitometry and published in 1996. On the panel were 22 members from eight countries. The guidelines addressed both the use and interpretation of bone mass measurements in the prevention, detection, and management of all diseases characterized by low bone mass with an emphasis on osteoporosis. The guidelines provided a broad overview of how bone mass measurements should be used regardless of specific clinical circumstances in which they were employed. Although they did not specifically deal with patient selection, a review of the ISCD guidelines is included here because of their importance and their influence on the patient selection guidelines that followed. There were six major points on which the panel reached a consensus. Those points are summarized in Table 7-3. Diseases Associated with an Increased Risk...

Calcium and Vitamin D

Osteoporosis is increasingly being recognised as a leading extra-intestinal complication of inflammatory bowel disease. Calcium is absorbed in the proximal small intestine by a vitamin D-depend-ent Ca2+-binding protein, and vitamin D is absorbed in the duodenum and jejunum. Therefore, in Crohn's disease patients with extended inflammation or resection of the small intestine, osteoporosis results from impaired absorption of calcium and vitamin D. However, there are also some conflicting data suggesting that many factors, other than calcium or vitamin D deficiency, contribute to the pathogenesis of osteoporosis in Crohn's disease 23, 24 . These factors include cytokines, such as TNF-a, that disproportionately stimulate osteoclast activity, or corticosteroid usage 25, 26 . Overt vitamin D deficiency disease may occur in Crohn's disease patients and patients often present with bone pain and mild myopathy. Other symptoms at presentation include bone pain and mild myopathy.

Organization of Sport Groups

Slowly, the fact that exercise and physical activity can have positive aspects particularly for their age group has increased in the consciousness of elderly people for example, cardiovascular diseases and osteoporosis can be prevented, and the risk for diabetes and obesity reduced.

American Association of Clinical Endocrinologists Guidelines

In 1996, the American Association of Clinical Endocrinologists (AACE) developed guidelines for the prevention and treatment of osteoporosis (10). As part of these guidelines, BMD measurements were discussed. The specific clinical circumstances in which AACE believed that bone mass measurements were appropriate were virtually identical to the original guidelines from the NOF published in 1988, although they were clearly Risk assessment in perimenopausal or postmenopausal women who are concerned about osteoporosis and willing to accept available intervention. In women with X-ray findings that suggest the presence of osteoporosis. In women undergoing treatment for osteoporosis, as a tool for monitoring the therapeutic response. These guidelines reflect the increase in available therapeutic options beyond HRT for the prevention or treatment of osteoporosis. With the availability of nasal spray calcitonin and alendronate sodium, a woman's choices for the prevention or treatment of this...

North American Menopause Society Recommendations

The North American Menopause Society (NAMS) published a comprehensive review of postmenopausal osteoporosis in the journal Menopause in 2002 (14). Included in the review were recommendations for bone density testing in the specific context of osteoporosis prevention and management. NAMS noted that measurement of BMD is the preferred method for diagnosing osteoporosis and that DXA is the technological standard for measuring BMD. NAMS stated that the total hip was the preferred region of interest to evaluate, particularly when measuring bone density in women over 60 because of the increased likelihood of degenerative calcification in the spine that would affect spine measurements.3 Nevertheless, spine measurements were described as useful in early postmenopausal women because of the faster rate of bone loss at that site compared to the rate seen at the proximal femur. Citing a report from the International Osteoporosis Foundation (IOF) published in 2000 (15), NAMS stated that they...

US Preventive Services Task Force Recommendations

In September 2002, the US Preventive Services Task Force (USPSTF) issued recommendations for bone density testing when screening for postmenopausal osteoporosis (16). Like the recent guidelines from the NOF, AACE, NAMS, and ACOG that preceded the release of these recommendations, the USPSTF recommended that women age 65 and older be routinely screened for osteoporosis. Unlike previous guidelines that also recommended testing for postmenopausal women younger than age 65 who had risk factors for osteoporosis, the USPSTF limited their recommended for screening in younger postmenopausal women to those women ages 60 to 64 who were at high risk for osteoporosis. They made no comment on screening for postmenopausal women younger than age 60. The USPSTF also noted that there was no data to determine an upper age limit for screening. The recommendations to screen women age 65 and older and women 60 to 64 at high risk for osteoporosis were classified by the USPSTF as grade B recommendations. A...

Guidelines for Bone Density Testing in

Determining when testing is appropriate in men has become increasingly important with the advent of prescription pharmacologic therapy for the treatment of osteoporosis in men. The prevalence of osteoporosis in men, although not as great as that in women, is high. In one study (19), the prevalence of osteoporosis in a population-based sample of 348 men was 19 when osteoporosis was defined as 2.5 SD or more below the average peak BMD for men. The major risk factors for osteoporosis in men are not dissimilar from those seen in women cigarette smoking, advancing age, risk of falls, and the presence of diseases or the use of medications known to affect bone metabolism (20-22). Heavy alcohol consumption is considered a major risk factor in men, more so than in women. Other risk factors include a sedentary lifestyle, lifelong low calcium intake, and low body weight. Men with radiographic evidence of osteopenia. A Comparison of Major Guidelines for Bone Density Testing for the Detection of...

Biglycan and Tissue Organization

Of the biglycan gene leads most obviously to defects in skeletal development and bone formation (59) but the skin and other soft connective tissues are involved because collagen fibril abnormalities are seen there also (60). Deletion of both decorin and biglycan causes much more severe osteopenia and soft tissue abnormalities than deletion of either gene alone (60). The skin in these double mutant mice is especially fragile and is reminiscent of the rare human progeroid variant of Ehlers-Danlos syndrome (61,62). Type VI collagen is found in skin as thin beaded filaments and as hexagonal networks whose formation can be promoted in vitro by biglycan (31). This activity of biglycan is ascribed to the two GAG chains that are present on each protein monomer.

World Health Organization Task Force Recommendations for Men and Women

An interim report (25) from the WHO Task Force for Osteoporosis was published in 1999 in which recommendations for bone density testing for both men and women were made. Bone density measurements were recommended if there was the following Radiographic evidence of osteopenia or vertebral deformity. Chronic disorders associated with osteoporosis.

Alterations in Body Composition

Besides this significant loss of lean tissue, CHF patients also have a lower fat tissue mass (i.e. energy reserves) and decreased bone mineral density (i.e. osteoporosis) 21, 22 (Table 1). Other studies confirmed these findings and found significantly correlated plasma levels of inflammatory cytokines and catabolic hormones 23 , which might represent a mechanism for these changes in body composition. Bone mineral density (g cm2)

Bone Tissue Changes in Osteoarthritis

Using quantitative microfocal radiography, they demonstrated that thickening of the subchondral cortical plate is the earliest anatomic change in OA joints. It precedes changes in articular cartilage thickness, evaluated radiographically as joint space narrowing. Using labeled bisphosphonate in a scintigraphic study, Dieppe et al 56 demonstrated elevated bone cell activity in patients who had progressed to severe OA. The same investigators also showed that an increased bone scintigraphic signal at the affected knee was predictive of OA progression in the 5 years to follow. Similar results were reported for OA of the hand 201 . More recently, the same group of investigators has shown that in the OA knee, the scintigraphic abnormalities correlated with osteocalcin concentration in the synovial fluid, osteocalcin being a marker of bone formation 215 . Because increased subchondral bone turnover appears to parallel progression of OA, the level of urinary N-terminal...

Ehlers Danlos and Progeroid Syndromes

In 1987, Kresse et al. (119) described a young male patient of pronounced proger-oid appearance and signs of Ehlers-Danlos syndrome, whose fibroblasts secreted reduced amounts of the intact (proteoglycan form) of decorin, together with dec-orin protein core lacking a GAG chain. This patient suffered from developmental and connective tissue abnormalities, including osteopenia, hypermobile joints, loose skin, and impaired wound healing. The primary defect was subsequently shown to be a deficiency of galactosyltransferase I, the enzyme that catalyzes the second glycosylation step in the biosynthesis of GAG chains (120). Specific point

Muscle Mass Changes Sarcopenia

Similar to body mass index (BMI), a common definition of sarcopenia accounts for body size by dividing the ASMM by the height squared 44, 50, 51 . In the New Mexico Aging Process Study 45 , sex-specific cut-off points for kg m2 in the ASMM index were set as two standard deviations below the mean for a healthy young-adult population, similar to the definition of osteoporosis. These cut-off points were 7.26 kg m2 in men and 5.45 kg m2 in women. According to this definition, the prevalence of sarcopenia increases from 13-24 among people under 70 to more than 50 among those over 80 (Table 1). Other authors classified their patients as sarcopenic if their ASMM index fell into the sex-specific lowest 20 of the distribution of the index this definition resulted in very similar cut-off values (7.23 kg m2 in men and 5.67 kg m2 in women) 52 . The same authors also measured sarcopenia using the ALM, adjusted for FM and height 52 . The prevalence of sarcopenia according to the first method was...

Weight selection criteria

The use of weight alone as a criterion for selecting women for bone mass measurements was proposed in 1996 by Michaelsson et al. (16). In this study reported in Osteoporosis International, only anthropomorphic measures were considered in predicting which individuals were likely to have a low bone density. The measures included height, weight, BMI, waist-to-hip ratio, lean tissue mass, and fat tissue mass. Bone density was measured by DXA at the PA lumbar spine and femoral neck. Lean and fat tissue mass were determined using DXA total body studies. T-scores were calculated using the manufacturer's reference database for US Caucasian women. Osteopenia and osteoporosis were defined using WHO criteria for diagnosis. One hundred seventy-five women were studied, of whom 106 were postmenopausal. Their average weight was 148.6 lb (67.4 kg). The women were divided into tertiles based on weight. The sensitivity, specificity, and positive and negative predictive values for osteopenia and...

Comparing the performance of selfassessment questionnaires

SCORE, ORAI, SOFSURF, and OST were compared by Hochberg et al. (22) in a study of 17,572 Caucasian women ranging in age from 45 to 93 years who were initially screened for participation in FIT (23). Twenty-one percent of these women had osteoporosis at the femoral neck using the WHO criteria of a T-score of -2.5 or poorer and the NHANES III proximal femur database. At approximately 90 sensitivity, both OST and SOFSURF had an acceptable 46 specificity for the prediction of an osteo-porotic T-score at the femoral neck. The cutpoints, sensitivities, specificities, and LRs are shown in Table 8-14. The cutpoints for OST used in this study have been shifted up by one unit compared to those used in the original OSTA index for Asian women. The shift in the cutpoint for SCORE represents the effect of using the NHANES III reference database for the calculation of proximal femur T-scores and the prediction of a lower T-score than called for in the development of the SCORE index.

Implication of Biomechanical Processes in Osteoarthritis

Integrity of the overlying articular cartilage depends on the mechanical properties of its bony bed. The sclerosis of subchondral bone in OA may result from an increased stiffness of the tissue and not from an increase in bone mineral density 134 . Indeed, there is no direct relationship between BMD and accumulation of microdamage in bone tissue, whereas the accumulation of microdamage to bone is directly related to OA 65 . Moreover, although subchondral bone sclerosis in OA has been explained as a response to overloading, the morphologic changes observed in underloading are similar and overloading cannot therefore be the cause of subchondral bone sclerosis 112 . The association between osteophytes and femoral bone mineral density also indicates that aspects of bone formation may underlie the pathophysiology of OA 96 . Nonetheless, bone mass of OA patients is better preserved 36,165,205 than that of normal individuals 72 primary OA and osteoporosis rarely coexist 52,196,233 .

The 1999 who and 2000 iof recommendations

The 1994 WHO Criteria did not direct physicians to measure bone density at a specific site for the diagnosis of osteoporosis. An interim report (5) from the WHO Task-Force for Osteoporosis was published in 1999 in which it was stated that DXA of the proximal femur was preferred for diagnostic bone density measurements, particularly in elderly individuals. Physicians were not directed in this report, however, to limit the application of the WHO Criteria for diagnosis to BMD measurements made at the proximal femur. In 2000, the IOF (6) recommended that only bone density measured at the total femur be used for the diagnosis of osteoporosis based on the WHO Criteria. In 2002 however, the ISCD (7) stated that the WHO Criteria could be utilized with bone density measurements at the PA spine, total femur, femoral neck, or trochanter. They also stated that the WHO Criteria should not be applied to measurements of bone density made at any peripheral site (8). These positions strongly suggest...

What are the risks of longterm inhaled steroid use

Local side effects such as oral candidiasis and hoarseness are quite frequent, and systemic side effects are perhaps not as infrequent as is often believed in asthma. In EUROSCOP, an excess 6 developed bruises on the forearms > 5 cm in diameter at least once during the trial 14 , and although it was firmly stated that no other systemic side effects were seen, bruises are markers of systemic effects and it is likely that the study was underpowered to detect more deleterious effects. In a subsample in EUROSCOP, no effects of treatment with ICS were seen on bone mineral density, but as long-term treatment will often be offered to patients with an unfavourable osteoporosis profile (smoking, minimal physical activity and inappropriate nutrition), this potential problem has not been solved. In fact, in LHSII an increased loss of bone mineral density was found in the femoral neck, but not in the lumbar spine, and this should indicate a need for caution. Wisniewski et al. 30 showed an...

Role of Bone Tissue in Osteoarthritis Progression or Initiation

The concept of a role for bone tissue in OA is based on the observation that this tissue is sclerotic and that OA patients show increased bone mineral density (BMD) upon dual x-ray measures. Even though OA patients are said to have higher BMD and increased osteoid matrix, mineralization of the subchondral bone tissue is reduced 144 . This could result from an alteration in bone tissue remodeling or a change in bone turnover 8,17,68,90,145,197 and would also increase bone stiffness 32 . To increase the density of subchondral bone means bone formation exceeds bone resorption, 49,153, 217 . On the other hand, studies of changes in structure and metabolism of subchondral bone in the early phases of OA have, in general, indicated that bone resorption has increased more than bone formation 19,20,38,49,106,224,226 . A report by Bettica et al 13 has clearly shown that bone resorption is increased in patients with progressive knee OA. These changes are associated with an increase in the number...

Postpartum Depression

Fig. 4.8 Calcium supplementation increases bone density during lactation and weaning. Effects of calcium supplementation and lactation in 389 women on the change in bone mineral density of the lumbar spine during the first 6 months postpartum and postweaning. Significant differences were found between the calcium and placebo groups in the nonlactating women during the first 6 months, and forthe calcium and placebo groups in both the lactating and nonlactating women after weaning. (Adapted from Kalkwarf HJ, et al. N Engl J Med. 1997 337 523) Fig. 4.8 Calcium supplementation increases bone density during lactation and weaning. Effects of calcium supplementation and lactation in 389 women on the change in bone mineral density of the lumbar spine during the first 6 months postpartum and postweaning. Significant differences were found between the calcium and placebo groups in the nonlactating women during the first 6 months, and forthe calcium and placebo groups in both the lactating and...

Calcium Minerals and Skeleton Health

Ample calcium and mineral intake is particularly important for teenage females. Bone growth is rapid during adolescence, when about half of the total skeleton is formed. The amount of bone mineral that has accumulated in the skeleton during this period is a major determinant of risk of osteoporosis in later life. More calcium deposited into the skeleton during childhood and adolescence means a greater calcium bank to draw from during aging. seven have intakes near 1200 mg day.4 Milk and other dairy products are the primary source of calcium in the teenage diet, yet many adolescents regularly substitute soft drinks, iced tea, or other sweetened beverages for milk. Insufficient dietary calcium during adolescence can have lasting consequences. Poor intakes of calcium (and other minerals, such as zinc19) can compromise bone health and may increase incidence of bony fractures both during adolescence and later in life. Calcium supplements can help children and teenagers reach adequate...

Remaining Lifetime Fracture Probability

The fracture incidence and bone loss rate data on which the RLFP model was originally based were derived from the Kuakini Osteoporosis Study. The original implementation of RLFP was based on measurements of bone mass at the calcaneus. Bone density measurements performed at other sites had to be converted to an equivalent calcaneal measurement. Using nomograms, the physician could find the calcaneal BMC on one scale and the patient's age on a second scale (19). By connecting the two values, the physician could find the RLFP on a third scale. RLFP predictions have now been recalculated for DXA measurements of the axial and appendicular skeleton and are available on the internet at www.medsurf.com. After entering the patient's age, menopausal age, skeletal site measured, type of equipment used, and BMD, the RLFP calculation is presented as shown in Fig. 10-4. In this RLFP analysis, the RLFP was

The Fracture Threshold

Ross et al. (22) proposed that the fracture threshold be defined as the BMC or BMD at which the risk of fracture doubled in comparison to premenopausal women. This recommendation was based on a prospective study of 1098 women who participated in the Kuakini Osteoporosis Study beginning in 1981. These women underwent BMC and BMD measurements at the proximal and distal radius and os calcis yearly with SPA and, beginning in 1984, lumbar spine BMD measurements with DPA. Four hundred eight women had spine films at baseline and were used to calculate spine fracture incidence during 4 years of follow-up. Spine fracture prevalence was calculated based on data from subjects who had fractures prior to the first bone density measurement. The authors looked at a variety of ways to define the fracture threshold and the BMC or BMD levels at the various sites that resulted. These considerations are shown in Table 10-10. They observed that the levels of BMC and BMD that corresponded to the 10th...

Qualitative Risk Assessments

Qualitative fracture risk assessments are descriptions of risk as being low, moderate, or high or as not increased, increased, or markedly increased. At its most basic, a qualitative assessment of fracture risk may be a statement of not at risk versus at risk. This is an assessment of current fracture risk. In 2002, the Canadian Panel of the ISCD recommended that bone density reports contain a qualitative assessment of fracture risk (24). Thresholds for moderate and high fracture risk or increased and markedly increased fracture risk are generally the same as the WHO diagnostic categories of osteopenia and osteoporosis. These types of qualitative assessments of risk are commonly seen on computer-generated printouts of bone density data. Caution must be used however as such assessments are inappropriate in individuals under age 50. In deciding whether a quantitative or qualitative assessment of risk is necessary or sufficient, the physician must decide what difference such an...

Predicting fracture risk in men

The number of studies reporting fracture risk in men based on the decline in bone density has increased in recent years. As in so many of the studies on women, the increase in fracture risk is generally reported as the relative risk for fracture per SD decline in bone density. Other studies have reported absolute risk. The findings from these studies have led to two apparently contradictory conclusions women have a greater increase in relative risk for fracture per SD decline in BMD than do men but the absolute risk for fracture at any given level of BMD is the same in women and men (25). In Table 10-11, the age-adjusted relative risk values for fracture in men and women age 35 years and older from a population-based case-control study in Rochester, Minnesota are shown (26). The relative risks differ depending on the reference population used. Note that the relative risk for any type of fracture in men was 1.1 per SD decline in femoral neck BMD when the reference population was 20- to...

Clinical Features

The disease presents a few weeks after birth with feeding difficulties, lethargy, hypotonia, hypothermia, and seizures. Psychomotor development is markedly delayed, and death usually occurs within 1 to 2 years of onset. Somatic, vascular, and bony changes are characteristic. The infant's hair is short, stringy, wiry, often white, and, under the microscope, appears twisted. The skin is pale and thick or pasty. The blood vessels, as revealed by angiogram or at autopsy, are elongated, tortuous, and display focal luminal narrowing and dilations resulting from disruption and fragmentation of the elastic layer. The bone shows osteoporosis and an irregular lucent trabecular pattern on radiographs.

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...

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...

The Morphologic Diagnosis Of Multiple Myeloma

The growth pattern of myeloma on trephine is also predictive of the type of skeletal defects and correlates strongly with magnetic resonance imaging findings. Nodules of plasma cells are associated with osteolytic lesions, whereas interstitial and sarcomatous types are associated with osteoporosis.7

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

Magnetic Resonance Imaging

Renal insufficiency (serum creatinine > 2 mg dl) Anemia (hemoglobin < 10 g dl or 2 g dl < normal) Bone disease lytic lesions or osteoporosis Others symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 2 episodes in 12 months) For patients with a solitary bone lesion or osteoporosis without fracture as the sole defining criteria, > 30 bone marrow plasmacytosis is required for the diagnosis of systemic myeloma. For monoclonal protein, no specific level is required and it is absent in non-secretory myeloma.

Reporting the diagnosis

This patient has osteoporosis according to World Health Organization Criteria based this man has osteoporosis based the T-score of -2.6 at the femoral neck. In utilizing the WHO Criteria, it is important to note that modifiers such as mild, moderate, or severe are not used to describe the diagnostic category of osteopenia or low bone mass. In addition, severe osteoporosis should be used to describe only those individuals with a bone density 2.5 or more SD below the young-adult mean value and who have a presumed fragility fracture. One of the limitations of the WHO Criteria is that the WHO Criteria do not allow for an individual with an osteopenic bone density T-score and presumed fragility fracture to be called osteoporotic. In such a case, it would be reasonable to point out that this individual certainly meets the conceptual definition of osteoporosis as proposed by the Although this patient does not meet the quantitative definition of osteoporosis established by the World Health...

Reporting fracture risk

The previous discussion highlights the clinical dilemma of the densitometrist in explaining what these numbers mean, because the level of bone density that constitutes a diagnosis of osteoporosis is not necessarily the same level of bone density that constitutes an unacceptable level of risk for fracture. The prediction of fracture risk is therefore a separate statement. 1 See Chapter 9 for a discussion of the 1991 and 1993 Consensus Conferences' definition of osteoporosis.

Recommending evaluations for secondary causes of bone loss

More detailed and aggressive recommendations can be made based on published findings from studies of patients with osteoporosis such as those from Johnson et al. (9) and Tannenbaum et al. (10). In 1989, Johnson et al. (9) evaluated 180 individuals (173 women, 7 men) with osteoporosis. In this study, osteoporosis was defined as two atraumatic spinal compression fractures or as a PA lumbar spine bone density 10 or more below the age-matched predicted value. After a thorough medical evaluation, 83 of the 180 individuals were found to have additional diagnoses that could potentially contribute to the development of osteoporosis. These diagnoses are shown in Table 12-1. A total of 128 diagnoses were identified in the 83 patients. In 11 of the 180 patients, the diagnosis was previously unknown. In the study from Tannenbaum et al. (10), 173 postmenopausal women with osteoporosis at the PA lumbar spine, proximal femur, and or forearm based on WHO Criteria were evaluated for secondary causes...

Management Of Skeletal Disease

Bone disease in the form of lytic lesions, pathological fractures, or osteoporosis are present at diagnosis over three-quarters of the time,130 ultimately leading to significant morbidity in many patients with MM. While external beam radiation therapy is remarkably effective palliation for pain relief from existing lesions, it is the localized therapy without the potential to reduce the risk of skeletal complications outside of the radiation port. Bone resorption in MM results occurs due to stimulation of osteoclasts, which in turn results predominantly from receptor activator of NF-kB (RANK) signaling by RANK-ligand.131' 132 Bisphosphonates are synthetic pyrophosphate analogues that inhibit osteo-clast function directly though disruption of intracellu-lar biochemical pathways133, 134 or induction of apopto-sis,135 or indirectly by stimulating production of the inhibitory RANK decoy molecule, osteoprotegerin.136 The two bisphosphonates currently approved for use in treating MM-related...

Body Structure and Function

Musculoskeletal impairments are also prevalent. Osteopenia is a common complication of cancer therapy. Contributing factors include high-dose cortico-steroids and possibly reduced activity during times of illness 11 . Treatment with corticosteroids can result also in myopathy of the proximal musculature 3, 12 . Lack of activity due to bed rest, malaise, fatigue, or nausea also contribute to muscle weakness. Loss of range of motion, leading potentially to contracture, is a secondary impairment resulting from weakness and immobility. Vincristine-induced neuropathy can contribute to this problem. Skeletal impairments such as amputation, deformity resulting from limb-sparing procedures, and scoliosis can occur due to tumors and their treatment.

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...

Treatment recommendations

There are two aspects to treatment recommendations whom to treat and how to treat them. The NOF Guidelines (11) for the treatment of postmenopausal osteoporosis are extremely useful as well as clear. In 1998, the NOF recommended that prescription medications be considered for women with a bone density T-score of less than -1.5 in the presence of other risk factors and in women with a bone density T-score less than -2, regardless of other risk factors. It is relatively straightforward then, to make a statement such as The patient meets (or does not meet) National Osteoporosis Foundation guidelines for prescription intervention to prevent or treat osteoporosis. To recommend specific treatments is a more difficult undertaking. The Canadian Panel (4) did not recommend the inclusion of such recommendations in a densitometry report. It is clear, however, that primary care physicians want suggestions in this regard (2). Given the diverse specialties of physicians involved in densitometry,...

Intervention for the Acutely Ill Isolated or Hospitalized Patient

Rehabilitation and exercise are very important for hospitalized patients. Goals for acutely ill patients will be focused on comfort and prevention of unnecessary secondary complications. Bed rest and immobility combined with cancer treatments can result in rapid loss of muscle strength, contracture, pulmonary complications, skin damage, and osteoporosis. Interventions to prevent these problems may include positioning, frequent change of position, active bed exercises, and breathing exercises and airway clearance techniques if respiratory function is compromised 32 . Patients should get out of bed for weight-bearing activities as soon as possible. Patients in isolation, such as recipients of bone marrow transplants, require encouragement and activity opportunities to remain mobile, maintain the ability to perform activities of daily living, and avoid boredom 32 . Stationary bicycles, ergometers, treadmills, or light weights can be used if appropriate disinfection protocols are...

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....

Musculoskeletal and Related Tissues

Most clinically significant problems involve avascular necrosis (AVN), and osteoporosis (bone density > 2.5 SD below mean) osteopenia (bone density 1-2.5 SD below mean). Probably because most patients have already achieved their maximum growth at the time of diagnosis, leg length discrepancy does not appear to be a significant problem in Ewing sarcoma, in which the entire bone may receive as much as 70 Gy 116 . Young adult cancer survivors may also have reduced bone density, as measured by dual energy x-ray absorptiometry (DEXA) scans 117-119 . Although several studies have demonstrated decreased bone density at diagnosis in patients with ALL 120 , osteopenia and osteoporosis are well-recognized to progress following exposure to corticosteroids or radiation therapy in doses used in patients with soft-tissue sarcomas or Ewing sarcoma 116 . Osteopenia in ALL survivors, as documented by quantitative computed tomographic scans, has also been related to cranial...

Skeletal Complications

The skeletal complications of MM are the most distressing of all the end-organ complications encountered in this disease. Osteopenia and lytic bone lesions are a cause of disabling pain and pathologic fractures. Spinal cord compression may result as well. Thirty percent of patients will present with nonvertebral fractures and more than 50 will present with back pain or vertebral fractures.44,45 Approximately 80 of patients will have radiographic evidence of osteoporosis, lytic lesions, or fractures at the time of diagnosis.2 Osteoporosis, focal lysis, and hypercalcemia all result from increased osteoclastic activity. The molecular mechanism causing this enhanced activity is incompletely understood, but continues to be an area of intense investigation. The current paradigm proposes that an imbalance in osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) are central to bone resorption.46 OPGL is known to activate osteoclastic cells via the receptor activator of NF-kB (RANK).46 Ex...

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...

Src Kinase Genetics and Signal Transduction

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help understand its role in signal transduc-tion pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss 28-38 . In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as malignant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,

Diet and Physical activity

Investigations of dietary practices in childhood cancer survivors have been largely limited to small cohort studies evaluating the relationship of caloric intake with energy expenditure 31-33 , nutrient intake with bone mineral density 34-36 , or choles- terol intake with cardiovascular disease risk factors 37 . Results show concerning trends, with energy intake exceeding energy expenditure, suboptimal dietary calcium correlating with osteopenia, and dietary fat intake in levels that will not reduce cholesterol. These findings suggest that childhood cancer survivors would benefit from dietary interventions that match caloric intake with physical activity, optimize calcium and other nutrients needed for bone accretion, and reduce dietary fat. In contrast to the dearth of information about physical activity after treatment for childhood cancer, abundant literature is available documenting an increased incidence of health concerns that are influenced directly by these health behaviors,...

Role Of Cas In The Skin

Models that receive particular attention in providing further evidence and helping explain the evolving concepts of CAs physiology are those that report the clinical effects and systemic adverse events from the use of CAIs. Such interesting pharmacological agents, sulfonamide CAIs, have a firm place in medicine and are mainly useful as diuretics or to treat and prevent a variety of diseases such as glaucoma, epilepsy, congestive heart failure, mountain sickness, gastric and duodenal ulcers, neurological disorders and osteoporosis (Supuran and Scozzafava 2000a Supuran et al. 2003). Cases of olygohydrosis, a potentially serious adverse event characterized by deficient production and secretion of sweat, were reported in six children treated with zonisamide, an antiepileptic drug chemically classified as a sulfonamide and first marketed in Japan in 1989 (Knudsen et al. 2003). The apparent increased risk of oligohydrosis in the pediatric age group might be related to the dose and resulting...

Pyrrolopyrimidine Template Based Inhibitors CGP76030 and CGP76775

CGP-76030 (10) and CGP-76775 (11) 109-112 were first described as potent and selective inhibitors of Src tyrosine kinase in vitro and in vivo relative to animal models of osteoporosis, and subsequently in cancer cell lines (e.g., pancreatic and leukemia). In osteoclasts, CGP-77675 was selective for Src versus Cdc2, EGFR, Abl, and FAK, and it was an effective inhibitor of bone resorption in vitro and in vivo. Specifically, CGP-77675 inhibited osteoclasts (i.e., parathyroid hormone-induced bone resorption in rat fetal long bone cultures). It also dose-dependently reduced the hypercalcemia induced in mice by interleukin-1 as well as effected partial prevention of bone loss and micro-architectural changes in young ovariectomized rats. In PC3 prostate cancer cells, CGP-76030 has been determined to reduce growth, adhesion, motility, and invasion. In Bcr-Abl-driven chronic myelogenous leukemia cell lines, CGP-76030 has been shown to be an effective inhibitor of Bcr-Abl tyrosine kinase and...

American college of obstetricians and gynecologists guidelines for bone density measurements

Pre- or postmenopausal women with diseases or conditions associated with an increased risk of osteoporosis. (From ACOG releases recommendations for bone density screening for osteoporosis. Washington, DC American College of Obstetricians and Gynecologists, 2002. Accessed March 26, 2002, at

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,...

Structure and Development of the Bone

Osteoclast cells, originally described in 1973,73 are hematopoietic in origin, deriving from monocyte-macrophage lineage, which degrades the mineralized matrix produced during normal bone formation.55 73-76 Osteoclastic bone resorption characteristically occurs on the bone surfaces during bone remodeling and modeling following osteoblast bone production.77 Bone homeostasis is dependent on a balanced synchronism between bone formation and bone resorption, which is the reason why several bone pathologies, such as osteoporosis, focus on the regulation of osteo-clastogenesis.78 Active osteoclasts exhibit a characteristic phenotype resulting from two different plasma membrane specializations a clear zone and a ruffled border.50 Bone resorption occurs by

Management of posttransplantation bone disease

Management of post-transplantation bone disease consists of measures to optimize BMD preoperatively and prophylaxis of bone loss during and after transplantation. Known risk factors for osteoporosis should be avoided where possible, vitamin D deficiency corrected and hormone replacement therapy advised for hypogonadal patients, both men and women. Transdermal preparations are preferable since they avoid first pass hepatic metabolism and both oestrogen and testosterone can be administered by this route. In those patients who receive glucocorticoids for their underlying disease, treatment with a bisphosphonate should be advised. In nonglucocorticoid-treated patients with evidence of osteoporosis prior to transplantation, appropriate treatment should be given according to age, gender and clinical circumstances. At present, there are no adequately powered randomized controlled trials in transplant cohorts with fracture as the primary end-point that have been reported. Because of the...

Damage to the Eyes by Drugs Administered Systemically

Certain antipsychotic drugs can also cause fundus pigmentation in excessive doses melleril and chlorpromazine have been incriminated in this respect in the past. Recently, a number of cases of uveitis have been reported in patients using bisphosphonates for the treatment and prevention of osteoporosis. Interestingly, sudden visual loss has been reported in a number of patients taking the oral antiinflammatory COX-2 inhibitors (celecoxib and rofecoxib). The vision has returned to normal upon cessation of treatment.

Bart L Clarke md and Sundeep Khosla md

Further evaluation showed that she had forearm osteopenia with a one-third distal radius bone mineral density (BMD) of 0.873 gm cm2 (T-score -1.8, Z-score -2.0), vertebral osteoporosis with an L2-L4 lumbar spine BMD of 0.650 gm cm2 (T-score -2.5, Z-score -2.0), and left femoral neck osteopenia with BMD of 0.755 gm cm2 (T-score -1.9, Z-score -1.5). An X-ray of the kidneys, ureters, and bladder with tomograms showed no calcium-containing kidney stones. She denied any complaint of abdominal pain, esophageal reflux, heartburn, or history of peptic ulcer disease. She complained of mild fatigue and difficulty maintaining concentration, and wondered whether her mild hypercalcemia was contributing to her lack of energy or declining mental acuity. Family history was unremarkable for known hypercalcemia, hypercalciuria, calcium-containing kidney stones, osteoporosis, or other metabolic bone disease. She stopped smoking cigarettes 20 yr ago after 12 pack-years, and denied any history of alcohol...