Wednesday, November 21, 2012

Osteoporosis

Osteoporosis is defined as a condition of thinning of bone and bone tissues as a result of  the loss of bone density over a long period of time.

I. Symptoms
1. Back pain, as a result of fractured or collapsed vertebra
In the study to investigate the prevalence and factors associated with low back pain among adults in Taiwan. Methods: The National Health Interview Survey, a cross-sectional study, was conducted from October 2002 to March 2003 to gather data from 24,435 adults aged 20 years and older selected randomly from Taiwan's general population, showed that patients with osteoporosis were more likely than those without osteoporosis to have low back pain (OR = 2.55, 95% CI = 2.33-2.78) or frequent low back pain (OR = 4.15, 95% CI = 3.66-4.70). The ORs of frequent low back pain in association with osteoporosis in men and women were 5.77 (95% CI = 4.66-7.15) and 3.49 (95% CI = 2.99-4.07), respectively(1).

2. Loss of height over time
In a study of 231 men and women over the age of 65 underwent DXA scan of their spine and hip (including bone mineral density and Vertebral Fracture Assessment), measurement of their height, and a questionnaire, showed that height loss was significantly associated with a vertebral fracture (p=0.0160). The magnitude of the association translates to a 19% increase in odds for 1/2 in. and 177% for 3 in. Although 45% had osteoporosis by either bone mineral density or fracture criteria, 30% would have been misclassified if bone mineral density criteria were used alone(2).
Others showed that Osteoporosis is a recognised co-morbidity in patients with chronic obstructive pulmonary disease (COPD) and may cause excessive height loss resulting in the 'normal' values and disease progression being under-estimated(3).

3. A stooped posture
Postural deformity might represent another risk factor for postural instability and falls. In the study to investigate the influence of spinal curvature on postural instability in patients with osteoporosis, showed that no significant correlations were observed between any parameters of postural balance and angle of thoracic kyphosis. However, all parameters showed significant positive correlations with angle of lumbar kyphosis (r = 0.251-0.334; p < 0.05-0.001). Moreover, lumbar kyphosis, but not thoracic kyphosis, showed a positive correlation with spinal inclination (r = 0.692, p < 0.001), and all parameters of postural balance showed significant positive correlations with spinal inclination (r = 0.417-0.551, p < 0.001)(4).

4. Easy bone fracture
In a multicenter, double-blind, placebo-controlled trial of randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months, found that Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis(5).

5. Neck and low back pain
In the study to determine the 1-year prevalence of neck pain and low back pain in the Spanish population and their association with sociodemographic and lifestyle habits, self-reported health status and comorbidity with other chronic disorders, found that neck and low back pain are prevalent and highly associated between them, more frequent in female (particularly neck pain) and associated to worse self-reported health status. Individuals with neck and low back pain were more likely than those without pain to have depression and other painful conditions, including headache and osteoporosis(6)

6.  Depression
Researchers showed there is  negative associations between depression and BMD variables in the three assessed areas. There were negative correlations between anxiety, stress and spine BMD, as well as a tendency towards negative relations in the right and left hip BMD. Concurrent hierarchical regressions showed that the addition of the three psychological variables increased the explained variance by 6-8 %. In addition, depression was found to have a unique significant contribution to the explained variance in right and left hip BMD(7). 
 
7. Other symptoms
In the study to study compare symptoms at midlife, menopause attitudes, and depression among three groups of late peri- or postmenopausal women, namely, women with cardiovascular disease (CVD group), women with osteoporosis (Os group), and women in generally good health (Co group), showed that the CVD group reported significantly more severe symptoms at midlife than did the Co group; significantly more severe "psychosomatic symptoms" than did the Co group; and significantly more severe "gastrointestinal symptoms and swelling" and "vasomotor symptoms" than did either the Os group or the Co group. The CVD group also reported significantly greater depressive symptoms than did the Os group(8).

8. Etc.

II. Causes and Risk factors 
A. Causes
1. SPRY1 gene 
In the study to determine whether genetic variation in the human SPRY1 gene is associated with obesity-related phenotypes and/or osteoporosis in humans, found that the four single nucleotide polymorphisms (SNPs) were significantly associated with either obesity-related traits or osteoporosis. The TGCC haplotype in the SRPY1 gene showed simultaneous association with an increased risk for obesity-related traits, percentage body fat (p=0.0087) and percentage abdominal fat (p=0.047), and osteoporosis (odds ratio=1.50; p=0.025) in the recessive genetic model(9).

2. Other causes
According to the study by Dr. Fitzpatrick LA at the Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine, Rochester, in some studies, 20% to 30% of postmenopausal women and more than 50% of men with osteoporosis have a secondary cause. There are numerous causes of secondary bone loss, including adverse effects of drug therapy, endocrine disorders, eating disorders, immobilization, marrow-related disorders, disorders of the gastrointestinal or biliary tract, renal disease, and cancer(10).
Other study suggested that Secondary osteoporosis occurs in almost two-thirds of men, more than half of premenopausal and perimenopausal women, and about one-fifth of postmenopausal women. Its causes are vast, and they include hypogonadism, medications, hyperthyroidism, vitamin D deficiency, primary hyperparathyroidism, solid organ transplantation, gastrointestinal diseases, hematologic diseases, Cushing's syndrome, and idiopathic hypercalciuria(11).

4. Etc.

B. Risk factors
1. Young Age at Diagnosis, Male Sex, and Decreased Lean Mass
In the study to investigate the prevalence and identify the risk factors of osteoporosis. METHODS:: Forty long-term survivors of osteosarcoma and 55 controls were enrolled. The mean age of the survivors was 21.8±5.2 years. They were diagnosed at younger than 23 years of age (mean, 14.9+5.0 y). Bone mineral densities (BMD) and body compositions were measured by dual-energy x-ray absorptiometry, showed that nineteen (47.5%) subjects had osteoporosis and 12 (30.0%) had osteopenia. The regions affected by osteoporosis were: femur neck of osteosarcoma site (47.5%), unaffected femur neck (12.5%), lumbar spine (12.5%), and total body (15.0%). Twelve subjects (30.0%) had 14 episodes of fractures. The identified risk factors of osteoporosis were young age at diagnosis, male sex, and low lean mass. Subjects diagnosed before attainment of puberty (male≤16 y, female≤14 y) were found to have a higher prevalence of osteoporosis (37.5% vs. 10.0%, P<0.01). Males had a higher prevalence of osteopenia or osteoporosis than females (86.4% vs. 66.7%, P<0.01). Total lean mass was positively correlated with unaffected femur neck BMD. Regional lean mass in affected limb was significantly reduced along with affected femur neck BMD(12).

2. Male sex, a low lean mass, and adult growth hormone replacement
There was the high prevalence of osteoporosis and osteopenia, 25.0% and 42.9%, respectively, and three additional risk factors, male sex, a low lean mass, and adult growth hormone replacement, were identified, according to the study by Seoul National University College of Medicine(13).


3. Aging
Bone loss occurs during the normal aging process. The term "primary" osteoporosis refers to osteoporosis that results from the involutional losses associated with aging and, in women, additional losses related to natural menopause, according to the study by Department of Medicine, College of Physicians and Surgeons, Columbia University(14).

4. Chlamydia pneumoniae
there is an association between the presence of Chlamydia pneumoniae DNA both in osteoporotic bone tissue and peripheral blood mononuclear cells (PBMCs) and the increase in circulating resorptive cytokines(15).

5. Race
Research on ethnically diverse populations is necessary to better understand how lactose maldigestion influences the risk for osteoporosis. Low calcium intakes, a greater than previously thought potential for low bone density and extensive lactose maldigestion among Hispanic-American and Asian-American populations may create an elevated risk for osteoporosis(16).

6. Family history
In the study to assess the relationship between the prevalence of reported physician-diagnosed osteoporosis and family history in a representative sample of U.S. women, examine whether osteoporosis risk factors account for this relationship, and evaluate the likelihood that women at high risk of osteoporosis due to family history report preventive behaviors, showed that family history is a significant, independent risk factor for osteoporosis in U.S. women aged>or=35 years. Further studies are warranted to evaluate family history as a convenient and inexpensive tool for identifying women at risk of osteoporosis and for promoting the adoption of preventive behaviors(17).

7. Skin color and body size
In the comparison of skin color, body size and bone mineral density (BMD) among three groups of postmenopausal women: 104 healthy black women, 45 healthy white women, and 52 osteoporotic white women with vertebral fractures. The osteoporotics are above the ideal body mass index recommended by the National Institutes of Health, researchers found that fair skin is not a risk factor for osteoporosis and that large body size is not protective against the development of osteoporosis, although it may have a salutary effect on BMD in both blacks and whites(18).
  
8.  Diet and lifestyle
In the study of total of 632 women age > or =60 years were enrolled in this study. Subjects were interviewed about their lifestyle by means of a questionnaire regarding the consumption pattern of dietary items, showed that the BMD was higher in subjects with the habits of alcohol drinking, green tea drinking, and physical activity and lower in those with the habits of smoking and cheese consumption. Multiple regression analysis showed that factors associated with BMD were smoking, alcohol consumption, green tea drinking, and physical activity after adjusting for age and body mass index (BMI)(19).

9. Heavy alcohol intake or alcoholism
Heavy alcohol intake or alcoholism, however, frequently disrupts calcium and bone homeostasis, which leads to reduce bone mineral density and increase the incidence of fragility fracture, according to the studyby Department of Endocrinology and Metabolism, Saitama Medical School(20).

10. Smoking and lower serum IGF-I levels
In the study of age, body mass index, current smoking history, and serum insulin-like growth factor-I levels associated with bone mineral density in middle-aged Korean men, suggest that higher age, a lower BMI, current smoking history, and lower serum IGF-I levels are risk factors for lower BMD in middle-aged Korean men; however, serum testosterone levels and GH secretory capacity were not found to be correlated with BMD(21).

11. Other risk factors
The frequency of decreased bone mineral density, vitamin and calcium diet content and sufficiency with vitamins evaluated by means of blood serum level determination among patients suffering from chronic diseases (of cardiovascular system, gastrointestinal tract, osteopenia and osteoporosis)(22).

III. Diagnosis
According to the Clinical practice guidelines for the diagnosis and management of osteoporosis. Scientific Advisory Board, Osteoporosis Society of Canada, Screening and diagnostic methods: risk-factor assessment, clinical evaluation, measurement of bone mineral density, laboratory investigations.

If you are experience certain symptom of osteoporosis, the tests which your doctor order include
1. Blood and urinary tests
The aim of the tests are to check for the bone metabolism and the progression of bone (loss) diseases.

2. Dual energy X-ray absorptiometry (DXA)
Dual energy X-ray absorptiometry (DXA) is one most common test to measure the total bone density of including spine, hip, wrist etc. with accurate result.

3. Quantitative Ultrasound and computed tomography (QCT)
The evaluation of bone density at the lumbar spine and hip.using a standard X-ray Computed Tomography (CT) scanner. Quantitative ultrasound (QUS), a technology
for measuring properties of bone at peripheral skeletal sites, is more portable and less expensive than DXA, without the use of ionizing radiation(23).

Dr. Riggs BL and the research team in the study of Better tools for assessing osteoporosis indicated that a whole new field of research into the determinants of bone loss and fractures in the axial skeleton and set the stage for subsequent development of dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT), which are now the standard methods for assessing osteoporosis severity and treatment efficacy(24), but other study found that in cross-sectional study of males with glucocorticoid-induced osteoporosis (GIO, quantitative computed tomography (QCT), High-resolution quantitative computed tomography (HRQCT)-based measurements and finite element analysis (FEA) variables were superior to DXA in discriminating between patients of differing prevalent vertebral fracture status(25).

4. Etc.

IV. Complication associated with Osteoporosis 
Pain, Fractures, Vertebral, Wrist, Rib fractures are associated with Osteoporosis, according to the study of New advances in imaging osteoporosis and its complications, said "We, as clinicians, should aim to increase awareness of this fracture type both as a frequent and varied source of pain in patients with osteoporosis and as the ultimate marker of severely impaired bone strength."(26)

IV. Preventions
Generalized partial linear model (GPLM) is found to be effective in determining nonlinear effects of an important continuous-scale risk factor. The final GPLM model shows that TCM symptoms play an important role in assessing the risk of osteoporosis. The GPLM also reveals a nonlinear effect of the important risk factor, menopause years, which might be missed by the generalized linear model.
A. Foods and Phytochemicals to prevent Osteoporosis
1. Green tea
In the study to investigate whether black tea polyphenol, theaflavin-3,3'-digallate (TFDG) and green tea, epigallocatechin-3-gallate (EGCG)affect MMP activity and osteoclast formation and differentiation in vitro, showed that TFDG and EGCG inhibited the formation and differentiation of osteoclasts via inhibition of MMPs. TFDG may suppress actin ring formation more effectively than EGCG. Thus, TFDG and EGCG may be suitable agents or lead compounds for the treatment of bone resorption diseases(27).

2. Soy
In the study to clarify the effect of ingesting soy isoflavone extracts (not soy protein or foods containing isoflavones) on bone mineral density (BMD) in menopausal women, found that  the varying effects of isoflavones on spine BMD across trials might be associated with study characteristics of intervention duration (6 vs. 12 months), region of participant (Asian vs. Western), and basal BMD (normal bone mass vs. osteopenia or osteoporosis). No significant effects on femoral neck, hip total, and trochanter BMD were found. Soy isoflavone extract supplements increased lumbar spine BMD in menopausal women(28).

3. Orange juice
In the study to evaluate the possible variations in antioxidant enzymes, lipid peroxidation and erythrocyte deformability in experimentally induced osteoporosis in female rats and to assess the effects of vitamin C supplementation on those variations, indicated that BMD was significantly lower in the group O than in the group C (p = 0.015), whereas it was significantly higher in the group OVC than in the group O (p = 0.003). MDA activity was significantly higher in the group O than in the group C (p = 0.032), whereas it was significantly lower in the group OVC than in the group O (p = 0.025). SOD activity was significantly higher in the group O than in the group C (p = 0.032). Erythrocyte deformability was significantly higher in the group O than in the group C and OVC (p = 0.008, p = 0.021, respectively)(29).

4. Milk thistle seeds
In the study to investigate that silibinin had bone-forming and osteoprotective effects in in vitro cell systems of murine osteoblastic MC3T3-E1 cells and RAW 264.7 murine macrophages, found that that silibinin retarded tartrate-resistant acid phosphatase and cathepsin K induction and matrix metalloproteinase-9 activity elevated by RANKL through disturbing TRAF6-c-Src signaling pathways. These results demonstrate that silibinin was a potential therapeutic agent promoting bone-forming osteoblastogenesis and encumbering osteoclastic bone resorption(30).

5. Skin and seed of grape
In the study to investigate the molecular mechanism of how resveratrol can modulate the lineage commitment of human mesenchymal stem cells to osteogenesis other than adipogenesis, showed that
resveratrol promoted spontaneous osteogenesis but prevented adipogenesis in human embryonic stem cell-derived mesenchymal progenitors. Resveratrol upregulated the expression of osteo-lineage genes RUNX2 and osteocalcin while suppressing adipo-lineage genes PPARγ2 and LEPTIN in adipogenic medium. Furthermore,  the osteogenic effect of resveratrol was mediated mainly through SIRT1/FOXO3A with a smaller contribution from the estrogenic pathway(31).

6. Etc.

B. Antioxidant vitamins and minerals to prevent Osteoporosis
1. In the study to evaluate whether antioxidant defenses are decreased in elderly osteoporotic women and, if this is the case, to understand whether osteoporosis is a condition characterized by increased oxidative stress, researchers at the Gerontology and Geriatrics, University of Perugia, found that dietary and endogenous antioxidants were consistently lower in osteoporotic than in control subjects. On the other hand, plasma levels of malondialdehyde, a byproduct of lipid peroxidation, did not differ between groups. Our results reveal that antioxidant defenses are markedly decreased in osteoporotic women. The mechanisms underlying antioxidant depletion and its relevance to the pathogenesis of osteoporosis deserve further investigation(32).

2. Selenium plus vitamins E and C
In the study to to investigate the effect of heparin on osteoporosis initiation, and the effect of selenium plus vitamins E and C, and the sole combination of vitamins E and C on the progress of osteoporosis induced by heparin through histologic means, showed that the combination of vitamins E and C given to the experimental rabbits partially prevented this bone tissue destruction. When sodium selenite was given together with vitamins E and C to the osteoporosis model rabbits, the long bone tissue had almost the same structure as in normal rabbits, for example the development of numerous bone trabeculae(33).

3. Vitamin C
According to the study epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. In the study of Vitamin C prevents hypogonadal bone loss by School of Stomatology, Wuhan University, Wuhan indicated that the ingestion of vitamin C prevents the low-turnover bone loss following ovariectomy in mice. This prevention in areal bone mineral density and micro-CT parameters results from the stimulation of bone formation, demonstrable in vivo by histomorphometry, bone marker measurements, and quantitative PCR. Notably, the reductions in the bone formation rate, plasma osteocalcin levels, and ex vivo osteoblast gene expression 8 weeks post-ovariectomy are all returned to levels of sham-operated controls(34).


4. Calcium and vitamin D 
Calcium supplements reduce the rate of bone loss in osteoporotic patients. Some recent studies have reported a significant positive effect of calcium treatment not only on bone mass but also on fracture incidence. The SENECA study, has also shown that vitamin D insufficiency is frequent in elderly populations in Europe. There are a number of studies on the effects of vitamin D supplementation on bone loss in the elderly, showing that supplementations with daily doses of 400-800 IU of vitamin D, given alone or in combination with calcium, are able to reverse vitamin D insufficiency, to prevent bone loss and to improve bone density in the elderly, according to the Dr. Gennari C. by Institute of Internal Medicine, University of Siena(35)

5. Etc.

V. Treatments
A. In conventional medicine perspective
A.1. Bisphosphonates
1. Including Alendronate (Fosamax), Risedronate (Actonel, Atelvia), Ibandronate (Boniva), Zoledronic acid (Reclast, Zometa), etc.. Bisphosphonates are antiresorptive medications widely prescribed for treating osteoporosis. In placebo-controlled clinical trials they have been shown to significantly reduce the risk of osteoporotic fractures(36).
Others suggested that Because bisphosphonate accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time(37).
    2. Side effects
    a. Nausea
    b. Abdominal pain
    c. Difficulty swallowing
    d. Rrisk of an inflamed esophagus or esophageal ulcers(38)
    e. Risk of scleritis and a variety of ocular side effects(39)
    f. Etc. 
     
    2. Hormone-related therapy
    Hormone replacement therapy can help to maintain bone density for menopause women, but it increases
    a, The risk of breast cancer and heart disease(40) 
    b. The risk for venous thromboembolism(41)
    c. The risk of (Nonmelanoma Skin Cancers) NMSC.(42)
    d. The risk of stroke(43)
    e. etc.

    B. In herbal medicine perspective
    1. Red clover
    In the study to test the combined effect of a quality-controlled red clover extract (RCE) standardized to contain 40% isoflavones by weight (genistein, daidzein, biochanin A, and formononetin present as hydrolyzed aglycones) together with a modified alkaline supplementation on bone metabolic and biomechanical parameters in an experimental model of surgically-induced menopause, showed that red clover preparation in dosages amenable to clinical practice do improve OVX-induced osteoporosis while a mild metabolic alkalosis might further synergize some therapeutic aspects(44).

    2. Soy
    In the study to to examine whether soybean protein isolate prevents bone loss induced by ovarian hormone deficiency, researchers at the Department of Human Nutrition and Dietetics, University of Illinois at Chicago, indicated that despite the higher rate of bone turnover in the soybean-fed animals, the vertebral and femoral bone densities of these rats were significantly greater than those of rats in the ovx group, suggesting that formation exceeded resorption(45).

    3. Soybeans, clover and alfalfa sprouts, and oilseeds (such as flaxseed)
    Studies in humans, animals, and cell culture systems suggest that dietary phytoestrogens found in Soybeans, clover and alfalfa sprouts, and oilseeds (such as flaxseed) play an important role in prevention of menopausal symptoms, osteoporosis, cancer, and heart disease(46).

    4. Etc.


    C. In traditional Chinese medicine perspective
    Osteoporosis in elder is defined as one of the conditions of the drop of Kidney Jing to certain level. As we age, our kidney doesn’t have the energy to nourish the bones, and they become weak and brittle, leading to the symptoms of earaches, ringing in the ears, hearing loss, hair loss, teeth problems, knee pain and lower back pain, loss of sex drive, including osteoporosis. 

    1. Du-Huo-Ji-Sheng-Tang and Du Zhong (Cortex Eucommiae) 
    Du-Huo-Ji-Sheng-Tang and Du Zhong (Cortex Eucommiae) were the most frequently prescribed herbal formula and single herb, respectively, for the treatment of osteoporosis, according to the study by the
    Department for Traditional Chinese Medicine, Chang Gung Memorial Hospital(47)

    2.  Zuogui Pill
    In the study to reveal the mechanism of Zuogui Pill (see text) in treatment of glucocorticoid-induced osteoporosis from the angle of the Wnt signal transduction pathway and to provide further experimental evidence for expounding the scientific connotation of "the kidney dominating the bones" in TCM, found that Zuogui Pill can prevent and treat glucocorticoid-induced osteoporosis in rats by up-regulating the expression of the key signal molecules Wnt1, LRP-5 and beta-catenin in Wnt signal transduction pathway(48).

    3. Embedding thread at Shenshu (BL 23)
    In the study to observe the clinical effect of embedding thread at Shenshu (BL 23) for preventing and treating primary osteoporosis, found that BMDs of hip and lumbar vertebrae were both increased in the embedding thread group, and the BMDs of femoral neck and femoral trochanter in this group were significantly higher than those in the medication group (both P < 0.05). The rate of bone fracture during 5 years after treatment was 2.1% (1/48) in the embedding thread group, which was significantly lower than 18.2% (4/22) in the medication group (P < 0 05)(49).

    4. Shaoyang Meridians 
    In the review to explore the theory of "Shaoyang Meridians being in charge of the bone" in Huangdi's Internal Classic, which has been buried for long time, indicated that the theory of "Shaoyang Meridians being in charge of the bone" possibly first in the world recognizes osteoporosis being a general bony disease, and articulates that the Foot-Shaoyang Meradians can modulate bony strength under physiological and pathological conditions, and treat osteoporosis which mainly manifests as ostealgia and easy fracture(50).

    5. Kidney-replenishing herbs (KRH)
    In the study to investigate the effect of Kidney-replenishing herbs (KRH) on ovarian function of experimental rats with dexamethasone-induced osteoporosis (OP), showed that KRH could elevate the level of GH, LH, FSH, E2 and P, increase the weight and improve the histomorphologic features of ovary and uterus in OP rats(51).



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