POSTMENOPAUSAL OSTEOPOROSIS About the diseasePostmenopausal Osteoporosis becomes a serious health threat for aging postmenopausal women by predisposing

them to an increased risk of fracture. Osteoporotic fractures are associated with substantial morbidity and mortality in postmenopausal women, especially older women.1 The World Health Organization (WHO) defines osteoporosis as a systemic skeletal disease characterized by low bone density and micro architectural deterioration of bone tissue, leading to increased bone fragility and fracture risk. Osteoporosis is called the silent epidemic for good reason; there are no symptoms to alert women to the progressive weakening of their bones.2 Despite these caveats, the current consensus is that approximately 1.66 million hip fractures occur each year world-wide, that the incidence is set to increase 4-fold by the year 2050. In countries with a high fracture incidence, rates are greater amongst women by 34-fold.3 What causes Osteoporosis in Postmenopausal Women? Osteoporosis is caused when more bone is lost over a period of time than is deposited. However the reasons for this imbalance are quite complex. During and after the menopause there is a marked fall in the production of sex hormones, oestrogen.Without oestrogen, bones gradually become brittle and prone to breakage. Research has shown that oestrogen is very beneficial in preventing bone loss and preventing the development of brittle bones. Bone loss may also accelerates in the elderly of both sex and in association with some diseases and certain kind of treatments.

Figure-Annual incidence of osteoporotic fractures in females by site 4

Role of Estrogen Estrogen has three fundamental effects on bone metabolism: (1) It inhibits the activation of bone remodeling and the initiation of new basic multicellular units (BMUs); (2) it inhibits differentiation and promotes apoptosis of osteoclasts, thereby reducing bone resorption; and (3) while estrogen suppresses self-renewal of early mesenchymal progenitors, it promotes the commitment and differentiation and prevents apoptosis of osteoblastic cells, thereby maintaining bone formation at the cellular level This explains why the lifespan of osteoblasts is shortened by the loss of estrogen after menopause,a factor known to be important in menopausal osteoporosis.5 Multiple Clinical Risk Factors Low bone mass is only one of several risk factors for osteoporotic fracture and these include both skeletal and non-skeletal factors. Of those that act independently of low bone mass, physical frailty, propensity to fall and a history of fracture appear to be strong predictors. In addition, the risk of fracture at a given BMC or BMD is strongly influenced by age. Skeletal factors that may act independently of bone mass include skeletal geometry and aspects of bone quality such as turnover, trabecular connectedness, osteocyte viability and osteonal distribution. Of those risk factors that are associated with a low bone mass, and may be acting through this pathway, family history and genetic susceptibility are especially important. Indeed, heritability studies have indicated that 6070% of the variation in BMD within a population has a genetic origin. Environmental factors, other than nutritional status and diet, are important determinants of fracture risk. These include cigarette smoking, alcohol abuse, physical inactivity, dependency and use of certain medications. In epidemiological studies, therefore, exploration of the influence of diet or specific nutrients on bone mass or fracture risk is likely to be confounded by the coexistence of other risk factors, especially where there is the potential for clustering of potentially adverse environmental factors. Nutritional Factors Genetic Factors

Oestrogen level

Ethnic origin

POST MENOPAUSAL OSTEOPOROSIS

Vitamin D

Bodily Build Environamental Nutritional Factors factors

Figure- Factors which affect the risk of Postmenopusal osteoporosis (Target osteoporosis, ABPI, 1996,pp7) Bone biology systemic and local regulation of bone turnover Current pharmacological treatments for osteoporosis were developed on the basis of existing knowledge of basic bone biology, while the development of novel therapies will rely on the exploration of fundamental regulatory mechanisms. The balance between bone resorption and bone formation is maintained through a complex regulatory system of systemic and local factors that act on bone cells, such as calcium-regulating hormones, sex hormones, growth factors, and cytokines. The competence of bone cells and the number of active cells determines the production of bone matrix proteins, while other incompletely understood intrinsic mechanisms determine mineralization and microstructure formation. Resorption of bone at a specific site may be induced by microdamage, but the initiating event in the process of osteo clastic activation is not understood. After activation, osteoclasts cause a local decrease in pH, which precipitates the dissolution of mineral. Exposure of the matrix permits enzymatic degradation of the collagenous structure. The signals responsible for termination of bone resorption and initiation of bone formation (coupling) are not well understood; however, evidence suggests that the liberation of components of the matrixembedded, insulin-like growth factor (IGF) system - IGF-I, IGF-II, and their binding proteins may induce this shift. Tight coupling between resorption and formation is needed to maintain bone mass and preserve the structural integrity of the bone. Incomplete filling of resorptive cavities results in the net loss of bone that is characteristic of osteoporosis.6

Figure - Controlling bone mineral balance DIAGNOSIS Peak bone mass is achieved by a womans third decade of life. The process of bone loss begins at that time and accelerates at menopause. By age 80, many women have lost, on average, approximately 30% of their peak bone mass. However; osteoporosis is not always the result of bone loss. A woman who does not achieve an adequate peak bone mass as a young adult may have low bone density without substantial bone loss as she ages. Osteoporosis has no warning signs. Often, the first indication of the disease is a fracture. Nearly all nonvertebral fractures are caused by a fall; however, vertebral fractures often occur without a fall, and need not necessarily be painful. Only roughly one third of vertebral fractures are painful, and two thirds are painless. Marked height loss over the years may be a sign of underlying vertebral compression fractures, even without significant associated back pain. Wrist or other fractures may occur at a younger age than vertebral or hip fractures and may also be early clinical expressions of osteoporosis. Osteoporosis is categorized as either primary or secondary. Primary osteoporosis is usually due to bone loss that occurs with aging. Secondary

osteoporosis is a result of medications (eg, glucocorticoids) or diseases (eg, malabsorption) that adversely affect skeletal health.7 A T-score is useful to express BMD in a postmenopausal population and is calculated by comparing current BMD to the mean peak BMD of a normal, young adult population of the same gender.

T score according to World Health Organization Definition

PREVENTION AND TREATMENT It is now widely agreed that osteoporosis is for the most part a safely preventable and treatable condition. The main aim of any therapy for osteoporosis is to prevent fractures. Primary prevention attempts to increase peak bone mass by diet and exercise. Secondary prevention aims to prevent bone loss after the menopause by use of drugs. Non Pharmacological Management Options1. Calcium - Adequate calcium h the diet is essential for normal bone growth and attainment of peak bone mass. However, a high calcium intake will not prevent accelerated bone loss after the menopause. Calcium supplements are used to support other therapies. 2. Vitamin D -It plays a major role in calcium absorption and incorporation into bone. Patients require supplements where there may be deficiency e.g. the housebound and elderly. 3. Physical exercise - Weight bearing exercise like walking (rather than swimming) contributes to the development and maintenance of bone mass. Exercise in the elderly is beneficial in in supply to muscle, bone and neural tissue. This improves muscular function and agility, thereby reducing the likelihood of falls.

4. Fall prevention- Fall prevention is another important content in health care for women with osteoporosis.Fractures are the most concerning outcomes of osteoporosis and one of the strongest risk factor for a fracture is history of a fall.Sleep,psychotropic and cardiac medications are of particular concern and gradually withdrawing them when reasonable can reduse the risk of falls. Current Pharmacological Management Options Regarding the selection criteria of proper osteoporosis pharmacological therapies, an ideal medication needs to have good efficacy to increase bone mass as well as to improve the bone quality as well. Basically, such medication should show its effect to correct bone remodeling and/or modeling defects, bone structural and material abnormalities, etc. Current FDA-approved pharmacologic agents for osteoporosis prevention and/or treatment include antiresorptive agents including bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate), calcitonin, estrogens and/or hormone therapy, selective estrogen receptor modulator (raloxifene), and one anabolic agent, i.e., parathyroid hormone [PTH (1-34), teriparatide]. On the other hand, strontium ranelate is also available in Europe in addition to aforementioned drugs. The meta-analysis studies on the effects of showed that most antiresorptive agents are effective in increasing BMD, with the teriparatide and bisphosphonates having a greater increase in BMD. 1. Bisphosphonates Category: BPs is a group of synthetic analogues of P-C-P compound. The nitrogen-containing bisphosphonates (NBPs) are the main currently used medications. Brand name and FDA approval indications for postmenopausal osteoporosis: (1) Alendronate (Brand name: Fosamax or Fosamax Plus): for the prevention of postmenopausal osteoporosis (5 mg daily, or 35 mg weekly); for treatment (10 mg daily, or 70 mg weekly, or 70 mg weekly with 2,800 IU and 5600 IU of vitamin D3) (2) Risedronate (Brand name: Actonel or Actonel with Calcium): for the prevention and treatment of postmenopausal osteoporosis (5 mg daily; 35 mg weekly; 35 mg weekly with 6 tablets of 500 mg calcium carbonate, or 75 mg on two consecutive days every month) (3) Ibandronate (Brand name: Boniva): for the prevention and treatment of postmenopausal osteoporosis (2.5 mg daily orally, 150 mg monthly orally, and 3 mg every 3 months intravenous injection) . The oral ibandronate is also approved for the prevention. Serum creatinine should be checked before each injection (4) Zoledronate (Brand name: Reclast): for treatment of postmenopausal osteoporosis: (5 mg by intravenous infusion over at least 15 minutes once yearly) Adverse events: All oral N-BPs have similar adverse events, including upper gastrointestinal disorders (such as dysphagia, esophagitis, esophageal ulcer, gastric ulcer, etc.), musculoskeletal

pain, etc. The side effects of intravenous NBPs include a transient acute phase flu-like reaction, visual disturbances, headache, atrial fibrillation, bone and muscle ach that may be improved by pre-treatment with acetoaminophen. Osteonecrosis of the jaw is rare in patients undergoing either oral or intravenous N-BPs treatment for osteoporosis. 2. Estrogen/Harmone Replacement Therapy Category: Estrogen is a biological agent (endogenous steroidal hormone) (Brand name: Estrogen therapy (ET) brand names:Climara, Estrace, Estraderm, Estratab, Ogen, Ortho-Est, Premarin, Vivelle; Hormone therapy (HT) brand names: e.g. Activella, Femhrt, Premphase, Prempro). FDA approval indications for postmenopausal osteoporosis: for the prevention of osteoporosis, relief of menopause-associated symptoms, such as vasomotor symptoms and vulvovaginal atrophy, etc. Progestin is recommended to protect the uterine lining in women having uterus and undergoing HT. Regarding the potential side effects of ET/HT, FDA recommends that other approved non-estrogen treatments should first be carefully considered before use ET/HT solely for the prevention of osteoporosis Adverse events: ET/HT with premarin and medroxyprogesterone treatment increased the risks of coronary heart disease (CHD) (29%), breast cancer (26%), stroke (40%), venous thrombo embolism (11%), deep vein thrumbosis, and a slight increase in the risk of dementia. The colorectal cancer and hip fractures were decreased. Subsequent analysis showed no increase in cardiovascular disorders in women starting treatment within 10 years of menopause and no increase in breast cancer incidence over 7.1 years of treatment in the estrogen. Furthermore, women not previously exposed to HT have a much less increase in breast cancer risk [56]. FDA recommends that the use ET/HT to relieve menopausal symptoms should be reduced to lowest doses possible for the shortest period of; and considers all available medications prior to selecting ET/HT for prevention of osteoporosis