The Active Female: Health Issues Throughout the Lifespan 2008th Edition

19. Osteoporosis and Current Therapeutic Management

Kellie F. Flood-Shaffer 

(1)

Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, University of Cincinnati, Cincinnati, OH, USA

Kellie F. Flood-Shaffer

Email: floodskf@uc.edu

Abstract

Osteoporosis which means “porous bones” is one of the most common skeletal disorders faced by women and their health care providers today. It occurs when there is a change in the balance of bone renewal. As estrogen levels diminish with the onset of menopause, there is excessive bone resorption which is not fully compensated for by an increase in bone formation. The most rapid bone loss in a woman’s life cycle appears to occur during the first 5 years after menopause. The World Health Organization (WHO) criteria for diagnosing osteoporosis and osteopenia (decreased bone mineral content) are based on a comparison of an individual’s bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DEXA) with that of a young adult reference group. BMD is expressed using a T-score that represents the difference in a number of standard deviations relative to the average peak bone mass of same gender, young, healthy adults. The WHO classifies osteoporosis as a T-score lower than −2.5 (World Health Organization (WHO) Scientific group on the assessment of osteoporosis at the primary health care level: report of WHO study group summary meeting report. Brussels, Belgium, 5–7 May, 2004; Kanis and Gluer. Osteoporosis Int. 11:192–202, 2009) and osteopenia as a T-score between −1 and −2.5. The primary goal of treatment is to reduce the risk of fractures. Although numerous effective therapies for the treatment of osteoporosis are readily available in a variety of forms, maintaining a healthy lifestyle with proper, balanced nutrition and sufficient, regular physical activity should be paramount for all women.

Keywords

OsteoporosisMenopauseOsteopeniaBone loss

19.1 Learning Objectives

After completing this chapter, you should have an understanding of:

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19.2 Introduction

Osteoporosis which means “porous bones” is one of the most common skeletal disorders faced by women and their health care providers today. It occurs when there is a change in the balance of bone renewal. The process of bone resorption and renewal requires three elements: (a) the regular supply of protein, calcium, and vitamins; (b) the regular use of the bones (exercise); and (c) requisite hormones which harmonize and direct the breakdown and removal of old bone and the creation of new bone.

Osteoporosis is characterized by low bone mass, compromised bone strength, and structural deterioration of the bone tissue which leads to bone fragility and an increased susceptibility to fractures, most commonly of the wrist (distal radius), hip (femoral neck) and spine (especially in the lumbar vertebrae). These fragility fractures lead to a decreased quality of life and a staggering economic burden. There are an estimated 2.8 million physician visits annually, 1.7 million fractures annually, and over 450,000 hospital admissions all at a cost of over $20 billion in the USA alone. The primary goal of treatment is to reduce the risk of fractures. Current estimates are that there are over 57 million Americans affected by low bone mineral density including 9 million with osteoporosis and 48 million with osteopenia.

19.3 Research Findings

19.3.1 The Definition of Osteoporosis

Osteoporosis is a progressive, skeletal disease characterized by low bone density and deterioration of the microarchitecture of the bone tissue; the consequences of this are bone fragility and increased susceptibility to fracture [1]. The World Health Organization (WHO) criteria for diagnosing osteoporosis and osteopenia (decreased bone mineral content) are based on a comparison of an individual’s bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DEXA) with that of a young adult reference group. BMD is expressed using a T-score that represents the difference in a number of standard deviations relative to the average peak bone mass of same gender, young, healthy adults. The WHO classifies osteoporosis as a T-score lower than −2.5 [12] and osteopenia as a T-score between −1 and −2.5. The National Institutes of Health have expanded the definition of osteoporosis to include compromised bone strength, independent of bone density.

19.3.2 The Pathophysiology of Osteoporosis

The process of bone remodeling occurs throughout the life cycle. The activity of osteoclasts (bone breakdown or resorption) in normal adults is balanced by the activity of osteoblasts (bone formation). Estrogen deficiency leads to over-expression of osteoclasts. As estrogen levels diminish with the onset of menopause, there is excessive bone resorption which is not fully compensated for by an increase in bone formation. Thus, osteoporosis results from an imbalance in the two processes of bone remodeling. The result is a net loss of bone tissue with associated changes in the microarchitecture of the bone. The most rapid bone loss in a woman’s life cycle appears to occur during the first 5 years after menopause. Osteoclastic activity increases with aging in all humans. Bone loss can be measured in the hip and spine years prior to the last menstrual period (menopause) [34]. BMD is reduced by approximately 50 % between peak bone mass at age 30 and age 90, when bone loss seems to end.

19.3.3 Classifications of Osteoporosis

Riggs and Melton have classified osteoporosis as either primary, which has 2 subtypes, or secondary [5]. Primary Osteoporosis is the more common form of the disease and refers to an inadequate bone remodeling process. Type 1primary osteoporosis is characterized primarily by trabecular bone loss, although some measurable cortical bone loss may also occur. It is more common in women and is often termed postmenopausal osteoporosis. It results primarily from estrogen deficiency. The skeleton is more sensitive to parathyroid hormone (PTH) and this causes increased calcium resorption from the bone. Type 2 primary osteoporosis is characterized by both trabecular and cortical bone loss. It is often called osteoporosis of aging. It occurs in adults over the age of 70 and is associated with decreased availability of vitamin D and decreased bone formation. Hallmarks are a decline in calcium absorption, increased PTH levels and bone resorption.

Secondary osteoporosis is caused by genetic, calcium balance, endocrine, gastrointestinal, neoplastic, renal, or rheumatologic disorders or as a result of medication therapies or use of other drugs. Glucocorticoid-induced osteoporosis is the most common secondary form of the disease. Glucocorticoids suppress the osteoblast function, inhibit intestinal calcium absorption, and increase osteoclastic activity. These drugs may also increase renal excretion of calcium. BMD may be increased by as much as 60 % in patients who are on glucocorticoid therapy.

Other important drugs associated with secondary bone loss include but are not limited to: alcohol, tobacco, heparin and other anticoagulants, lithium, anticonvulsants, cytotoxic drugs, gonadotropin-releasing hormone agonists, vitamin A, and Tamoxifen [6]. Chronic medical conditions which may contribute to secondary bone loss include but are not limited to: hemophilia, thalassemia, Cushing’s syndrome, hypothyroidism, Type 1 diabetes mellitus, chronic liver disease, malabsorption syndromes (celiac disease), lymphoma, leukemia, disordered eating (anorexia nervosa), rheumatoid arthritis, and primary hyperparathyroidism [6].

19.3.4 Risk Factors in the Development of Osteoporosis

Osteoporosis is associated with a number of risk factors, some modifiable and some nonmodifiable. Nonmodifiable factors are genetic factors such as Asian or white race, female gender, family history of fragility fractures, ethnicity, and thin body habitus. These also include advanced age and a personal history of fracture [78]. Modifiable factors include poor nutrition or malnutrition, estrogen deficiency, sedentary lifestyle, smoking, and excessive alcohol intake among others.

Nonmodifiable factors require that the patient receive education on these risk factors and avoid exacerbating their risk of fracture by adopting and/or not modifying any of the modifiable risk factors. Perhaps the most difficult most difficult task that a health care provider may deal with is encouraging and being successful with changing behaviors which predispose patients to osteoporosis. Sedentary lifestyle, smoking, excess use of alcohol, inadequate intake of vitamin D and calcium, and the epidemic of heavy consumption of carbonated and caffeinated drinks in the USA continues to place younger and younger women at risk of not reaching their genetically determined peak bone mass [9].

19.4 Contemporary Understanding of the Issues

19.4.1 The Diagnosis of Osteoporosis

The gold standard for the diagnosis of osteopenia and osteoporosis of the hip and spine remains Dual-energy X-ray absorptiometry (DEXA). Dual-energy X-ray absorptiometry machine standard error is small and it has the best normative database available. For trabecular bone measurements, lateral spine DEXA may be superior to anterior-posterior views. There are clinical assessments, radiographic studies, and biochemical measurements which can be used to assist in the diagnosis as well. All women should have their risk factors for osteoporosis assessed at the time of annual physical. A thorough medical history should include review of hormone status, nutritional status (specifically to include vitamin D, calcium, and protein intake), personal history of low trauma fracture, lifestyle factors (to include smoking, alcohol intake, and physical activity level). Family history should also be reviewed with respect to height loss with age, compression or hip fractures. Height should be measured and compared to self-reported maximum height. Repeat measurements of height should be done annually. Radiographic studies of the lateral spine should be included in the evaluation if a compression fracture is suspected or spinal deformity is present. Biochemical tests may be incorporated into the diagnostic evaluation particularly if a secondary cause of osteoporosis is suspected. Labs should include: serum chemistries, complete blood count, thyroid function tests, and a 24-h urine collection for calcium excretion. Further testing may include: intact PTH, urinary free cortisol, erythrocyte sedimentation rate, serum protein electrophoresis, serum 25-hydroxyvitamin D concentration, and other biochemical markers of bone turnover.

A recent study by Pickhardt et al. found that abdominal computed tomography (CT) images obtained for other reasons that include the lumbar spine can be used to identify patients with osteoporosis or normal bone mineral density (BMD) without additional radiation exposure or cost. This study was based upon the data that shows nearly half of all female Medicare beneficiaries have never undergone BMD testing and more than 80 % of all persons with a major osteoporosis related fracture do not have BMD testing or receive pharmacologic agents to reduce fracture risk. In 2011, there were more than 80 million CT scans performed in the USA all of which may carry potentially useful information about BMD. In this study, CT scan was 90 % sensitive and more than 90 % specific for distinguishing osteoporosis from osteopenia and normal BMD. The greatest limitation of the study was that it did not assess potential benefits and costs of using CT primarily to evaluate BMD [10].

19.4.2 Recommendations for Bone Mineral Density Measurements

The National Osteoporosis Foundation (NOF) recommends BMD testing be performed on: (a) all women age ≥65 years of age; (b) all postmenopausal women <65 years of age if they have any additional risk factors other than being white, postmenopausal and female; and (c) postmenopausal women who have suffered a fragility fracture (to confirm diagnosis and determine disease severity) [11]. In women aged 65 or greater, if BMD is measured as normal, repeat BMD measurements can be delayed up to 15 years.

As previously mentioned, the T-score is used to determine the presence or absence of bone loss. However, the Z-score may be of more use in younger women and in identifying women who may need to undergo a workup for secondary causes of osteoporosis. The Z-score represents the difference in number of standard deviations between an individual’s BMD and the BMD of a population adjusted for age, gender, and race. One should suspect secondary causes of osteoporosis if the Z-score is >1.5 SD below the mean [12].

The American College of Rheumatology has recommended that patients undergo a baseline lumbar spine or hip BMD before initiating long-term glucocorticoid therapy or other drug therapy associated with bone loss.

Conditions which may falsely elevate BMD measurements especially in the elderly patient include osteophytes, arthritis, and spinal compression fractures. In these cases, a hip or femoral neck BMD is recommended. Another alternative site which has shown to be a good predictor of hip fracture is the calcaneus, which is rich in trabecular bone. A peripheral measurement, such as the calcaneus, is performed using single absorptiometry.

19.4.3 The Management of Osteoporosis

19.4.3.1 Prevention

Maximizing peak bone mass begins early in life with adequate nutrition and exercise [1315]. Other lifestyle factors, such as limiting caffeine, alcohol, and carbonated drinks, and avoiding tobacco use play an important role in the prevention of osteoporosis. Caffeine, tobacco, and excess alcohol consumption all play a role in altering calcium absorption and estrogen metabolism and have been directly linked to an increase in hip, wrist and spine fractures.

Regular physical activity with weight bearing exercises should be encouraged. Weight-bearing exercise such as walking, jogging, aerobics, Tai Chi, or weight lifting helps to stimulate osteoblastic activity, thus helping to maintain the balance in bone remodeling after age 30. Physical exercise also increases muscle strength as well as core strength, coordination, agility, and balance which serve to reduce the risk of falls and thereby reduce the risk of fracture.

19.4.3.2 Vitamins and Minerals

Calcium

The daily recommended dose of calcium for premenopausal women is 1,200 mg/day to maintain bone mass. As calcium absorption decreases with age, the requirement for postmenopausal women increases to 1,500 mg/day [16]. A diet rich in calcium would include any or all of the following calcium-rich foods: dairy products such as skim milk, low-fat or nonfat yogurt, cheese, cottage cheese, and ice cream; dark green vegetables such as broccoli, kale, turnip greens; calcium fortified foods such as orange juice, breads, and cereals; and certain types of fish and shellfish. Sardines and salmon are a good source of calcium especially if the bones are consumed with the fish. Homemade chicken or turkey soup can provide another excellent source of calcium, if the poultry is boiled with the bones in place, thus allowing the calcium to leach out of the bones and into the broth.

Some dairy sources are also rich in fat therefore low calorie sources of calcium must be considered. Diet alone commonly fails to provide the daily recommended dose of calcium for most women in which case supplements are required. The two most common commercially available calcium supplements are in the form calcium carbonate and calcium citrate. Calcium citrate is generally better tolerated than calcium carbonate, which often causes gas and constipation. Daily doses of calcium exceeding 2,000 mg have been associated with increased cardiovascular disease and are not advised [17]. Vitamin D is an important requirement for adequate intestinal calcium absorption.

Vitamin D

The daily recommended dose of vitamin D in premenopausal women is 400–600 IU/day and for the postmenopausal woman, the range is 800–1,000 IU/day. The elderly, chronically ill, homebound or institutionalized patient is at greatest risk for vitamin D deficiency and therefore benefits the most from supplementation. Most calcium supplement products on the market, as well as multivitamin formulations are fortified with vitamin D. Women should be made aware that “more does not necessarily mean better” when taking multivitamins. Due to the association of excess vitamin A intake and increased risk of hip fracture, one should not take two multivitamins in order to get additional vitamin D. In a large trial of elderly women, (mean age, 84), long-term calcium and vitamin D supplementation was associated with a 44 % reduction in hip fracture incidence [18]. Exposure to just 15 min of sunshine daily will provide the vast majority of the daily recommended dose of vitamin D; however, sun-exposed skin creates the additional risk of sunburn and skin cancer.

19.4.3.3 Pharmacologic Therapy

Fracture prevention is the primary goal of pharmacologic therapy for osteoporosis. Secondary goals include: stabilizing and increasing BMD, relief of symptoms of fracture and skeletal deformity (ies), and improvement of the patient’s mobility and functional status. Organizations such as the North American Menopause Society (NAMS), the American Association of Clinical Endocrinologists (AACE) and NOF all offer guidelines for intervening with pharmacologic therapy. Each organization bases its therapeutic recommendations on T-scores, risk factors, and prior fracture history [311].

Many factors influence the use of pharmacologic therapy including but not limited to: length of time to realize benefit, impact on quality of life, impact on breast tissue, cardiovascular status, and potential side effects. Cost of therapy is always an issue as many of these therapies are quite expensive.

Prevention and treatment therapeutic options include: bisphosphonates, and selective estrogen receptor modulators (SERMs). Prevention-only therapy consists of hormone therapy (HT). Treatment-only therapy includes calcitonin and recombinant human PTH. There are several major clinical trials which have demonstrated the efficacy of each of these therapies in the reduction of fracture risk. Hormone therapy, raloxifene (a SERM), and the bisphosphonates have been shown to reduce risk of vertebral fracture over 3–7 years. The bisphosphonates and HT have been shown to reduce hip fracture risk.

Bisphosphonates

The bisphosphonates, of which there are currently several available on the US market, are antiresorptive agents which bind preferentially to hydroxyapatite crystals in the mineralized bone matrix to inhibit osteoclastic activity, thus reducing bone turnover. In addition to arresting bone loss and decreasing fracture risk, the bisphosphonates have been shown to increase BMD in postmenopausal women with osteoporosis by up to 8 % in the spine and up to 4 % in the hip. In micro CT-scans of human bone the bisphosphonates have preserved horizontal trabecular bone, thus additionally maintaining bone strength. Due to the poor bioavailability of bisphosphonates of less than 1 %, there are specific and important dosing instructions and precautions. The oral medications (both tablets and liquid forms) must be taken on an empty stomach with at least 8 oz of water to properly dissolve and absorb the drug from the stomach. The patient must remain upright (sitting or standing) for a minimum of 30 min after administration of the medication. No other food or drink is to be ingested during those 30–60 min. Careful evaluation of candidates for bisphosphonates is required and should include questions concerning any history of difficulty with swallowing, or any history of gastrointestinal disorders which cause esophageal irritation (i.e., gastroesophageal reflux disorder). There are also injectable forms of the bisphosphonates. Not all women are good candidates for bisphosphonates.

Alendronate

In the Fracture Intervention Trial (FIT), postmenopausal women with low bone mass were randomized to two groups on the basis of whether or not they had vertebral fractures at baseline. Alendronate showed reduction of vertebral fractures of 47 % at year 3 and reduced incidence of hip fractures up to 56 % [19]. The recommended dose of alendronate for prevention of postmenopausal osteoporosis is 5 mg/day or 35 mg/week; for treatment, the dosage is increased to 10 mg/day or 70 mg/week in either a tablet or liquid solution. Both dosage regimens are equally effective. Alendronate is also indicated for the treatment of glucocorticoid-induced osteoporosis. Importantly, newer data demonstrates that alendronate 10 mg/day can increase or maintain BMD after discontinuation of HT [20].

Risedronate

Risedronate has the same treatment and prevention indications as alendronate as well as the glucocorticoid-induced osteoporosis prevention and treatment indication. The approved dosage of risedronate is 5 mg/day, 35 mg/week, or 150 mg/month. Risedronate has been shown to decrease both vertebral and nonvertebral fractures in postmenopausal women. At 3 years of use, risedronate was associated with a 70–75 % reduction in first vertebral fracture [21]. This reduction appears to be sustained over at least 5 years [22].

Ibandronate

Ibandronate was approved by the FDA in May 2003; it inhibits osteoclast-mediated bone resorption. The oral dose is 150 mg once a month and the injectable form is administered intravenously in a dose of 3 mg over 15–30 s every 3 months for the prevention and treatment of osteoporosis in postmenopausal women [23]. A contraindication to Ibandronate is known hypersensitivity to Ibandronate injections or to any of its excipients. Hypersensitivity may cause anaphylaxis; fatal events have been reported.

Zoledronic Acid

Zoledronic Acid is strictly an injectable bisphosphonates which inhibits osteoclastic bone resorption. It is usually reserved for patients who are good candidates for bisphosphonates but either cannot tolerate or have failed oral therapy. For prevention, the dose is 5 mg every 2 years and for treatment 5 mg is infused intravenously once a year. The patient must be hydrated with intravenous fluid prior to infusion of the drug, and the intravenous line must be flushed with saline solution after infusion as well. The drug is administered over no less than 15 min.

Selective Estrogen Receptor Modulators (SERMs)

SERMs are nonhormonal agents that bind to the estrogen receptor but induce different estrogenic responses in various tissues. Raloxifene is currently the only SERM which is FDA approved for the prevention and treatment of osteoporosis.

Raloxifene

Raloxifene has the unique property of activating estrogen receptors in the bone while not activating estrogen receptors in the breast or uterus. The recommended dose of raloxifene is 60 mg/day for both prevention and treatment of osteoporosis. Unlike the bisphosphonates, raloxifene can be taken at any time of day, with or without food. Also, unlike the bisphosphonates, raloxifene has shown an increased risk of hot flashes, leg cramps and thromboembolic events among users [2425]. In the Multiple Outcomes of Raloxifene Evaluation (MORE), raloxifene was associated with a 30 % reduction in vertebral fractures in postmenopausal women with at least one vertebral fracture and a 55 % reduction in postmenopausal women with no vertebral fracture over 3 years. BMD improved 2.6 % and 2.7 % at the spine and hip respectively [26]. Raloxifene was shown to have extra skeletal effects which are quite important to the overall health of women. In the MORE study, raloxifene was associated with a 65 % relative risk reduction in all breast cancers with a 90 % reduction in estrogen receptor-positive breast cancers, a 12 % reduction in estrogen receptor-negative breast cancer, and a 76 % relative risk reduction in cardiovascular events in a subgroup of at-risk women in the study group [27].

RANK Ligand Inhibitor

The RANK ligand is a new member of the tumor necrosis factor superfamily which acts as an osteoblast-expressed ligand that stimulates osteoclastic differentiation. Inhibition of the RANK ligand has proven to b a successful method of treating osteoporosis.

Denosumab

This medication is a RANK-ligand inhibitor and the only one currently approved in the USA for the treatment of osteoporosis. Denosumab slows the formation, action and survival of osteoclasts. Patients receive a 60 mg injection every 6 months. Common side effects include rash as well as back, bone, joint, and muscle pain.

19.5 Current and Future Directions

19.5.1 Hormone Therapy

19.5.1.1 Estrogen

Bone tissue is exquisitely sensitive to estrogen. The rationale for estrogen therapy was based on the observation that the bone remodeling rate increased as estrogen levels declined resulting in greater bone resorption than bone formation. Estrogen’s beneficial effect on bone is due to several factors including its ability to increase circulating calcitonin levels which leads to decreased bone resorption. Estrogen receptors are also present on osteoblastic cells, which respond to the hormone by increasing collagen production. There are over 50 randomized, placebo-controlled studies which have demonstrated that HT reduces the rate of bone resorption and loss and promotes an increase in BMD [3]. The benefits of HT on BMD are independent of estrogen preparation but are dose dependent. However, estrogen therapy even in doses as low as 0.3 mg of conjugated equine estrogen have been shown to have a beneficial effect on hip and spine BMD [28]. Low-dose birth control pills may be used for perimenopausal women at risk for bone loss, if no contraindications to that therapy exist.

Prior to the publication of the Heart and Estrogen/Progestin Replacement Study (HERS) [29] and the Women’s Health Initiative (WHI) [30], most of the data available on the effects of HT in fracture prevention was based on observational and epidemiologic studies [31]. In the HERS trial, the primary evaluation endpoint was postmenopausal women and cardiovascular disease; fracture was a secondary endpoint. Study participants were not selected on the basis of osteoporosis risk. HERS concluded that fracture risk following 4 years of HT (0.625 mg/day of conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone acetate was not reduced.

The WHI Estrogen plus Progestin trial was conducted in postmenopausal women aged 50–79 (average age 63 years) with an intact uterus. The women were randomized to HT using the same preparation as the HERS trial versus placebo. The HT group showed a 34 % lower relative risk of hip and a 34 % lower relative risk of spine fracture as well as a 24 % lower risk of fracture at all sites.

In a study done in 2002, Greenspan et al. showed that once HT is withdrawn, accelerated bone loss occurs. The reduction of BMD was as much as 4.5 % in the spine and as much as 2.4 % in the hip after just 1 year off of HT [32].

The WHI created a paradigm shift which has nearly entirely changed the way estrogens are prescribed in the USA today, not due to the bone data, but rather due to the other risks which were identified. Women randomized to the HT arm of the study also showed a 29 % increased risk of coronary heart disease and a 41 % higher risk of cerebral vascular accident (stroke). The WHI also found another risk identified in HERS which was an increased risk of venous thromboembolism. Unlike HERS, which found no significant increased risk of breast cancer, the WHI reported a very significant increased risk in invasive breast cancer in women treated with HT. One other positive finding of the WHI in addition to reduced fracture risk was the data which showed a significantly decreased risk of colon cancer development in women taking HT. Following the release of the WHI both the NAMS and the US Preventive Services Task Force have recommended against the uses of estrogen for the primary treatment of osteoporosis, recommending instead, alternative therapies. Both the NAMS and the NOF do still endorse estrogen, when prescribed appropriately, as beneficial to bone health.

19.5.1.2 Androgen

Androgens in women have been studied, with regard to BMD, to a limited degree. Results of two studies which employed testosterone implants and oral methyltestosterone in addition to HT indicated significant beneficial effects on BMD [3334]. However, the degree to which these effects were due to aromatization, thus representing estrogen rather than androgen effects, is unclear. The small number of participants in these studies and the lack of long-term, well-controlled trials prevent proper evaluation of the effects of testosterone treatment on BMD.

Currently the use of testosterone or its derivatives for the treatment of bone loss is only recommended in male patients.

19.5.1.3 Progesterone

To date, there is no reliable evidence that topical progesterone creams offer protection against bone loss. In a 1999 study, women were randomized to a progesterone cream 20 mg or placebo cream, to be applied once daily. BMD was assessed every 4 months for 1 year and no significant difference was found between the treatment and control groups with respect to BMD of the hip and spine [35]. There is some evidence that norethindrone acetate may maintain BMD in women receiving gonadotropin releasing hormone agonists for conditions such as endometriosis or uterine leiomyomata. Norethindrone acetate or combination estrogen progestin regimens are used for “add-back” therapy in these women primarily to control vasomotor symptoms such as hot flashes.

19.5.1.4 Calcitonin

Calcitonin is a polypeptide hormone which decreases the rate of bone absorption by inhibiting resorptive activity in osteoclasts. It is available as a subcutaneous injection (100 IU/day) or as a nasal spray (200 IU/day). It is indicated for the treatment of postmenopausal osteoporosis in females more than 5 years post menopause with low bone mass relative to healthy premenopausal females. It stabilizes or increases vertebral and nonvertebral BMD, predominantly at the forearm and lumbar spine. The Prevent Recurrence of Osteoporosis Fractures (PROOF) Study showed that the intranasal dose of calcitonin was associated with a 36 % risk reduction in vertebral fracture and only a 20 % risk reduction in nonvertebral fracture in women with low bone mass and history of vertebral compression fractures. The study had a high dropout rate and failed to show any effect on hip fractures [36].

19.5.1.5 Teriparatide

Teriparatide is a synthetic form of human recombinant parathyroid hormone (PTH). PTH is the primary regulator of calcium and phosphate metabolism in bones. Teriparatide 20 mcg/day injected subcutaneously once a day in the thigh or abdomen is indicated for the treatment of osteoporosis in postmenopausal women at high risk of fracture. It is the first approved treatment for osteoporosis that stimulates both cortical and trabecular bone formation. In a randomized, double-blind trial, involving nearly 1,700 postmenopausal women with prior vertebral fracture, teriparatide 20 mcg/day reduced new vertebral fractures by 65 % and nonvertebral fractures by 35 % [37]. Prior to Teriparatide administration, laboratory tests should be done including BMD by DEXA (spine and hip), total serum calcium, total serum alkaline phosphatase, 25-hydroxyvitamin D, PTH, and creatinine clearance. Use of teriparatide is contraindicated in patients with hypercalcemia, Paget’s disease, elevated bone-specific alkaline phosphatase, osteogenic sarcoma, history of skeletal radiation, pregnancy and lactation, unfused epiphyses, bone cancer or metastatic cancer to the bone. Therapy with teriparatide is not recommended for more than 2 years in humans due to the development of osteosarcomas in animal studies.

19.5.1.6 Combination Therapy

Several studies have examined the effect of combining two antiresorptive agents on bone mass and have found that at the spine and total hip, the combination resulted in a greater increase than with one agent alone. A recent randomized trial by Greenspan et al., showed that in women aged 65–90 combination therapy with HT and alendronate was more effective in increasing bone mass than either therapy alone [32]. Currently, combination therapy remains controversial; however, a new study may help to resolve the controversy. In a randomized controlled trial in which patients were assigned in a 1:1:1 ratio to receive 20 μg teriparatide daily, denosumab 60 mg every 6 months, or both the data appear quite promising in favor of combination therapy. BMD was measured at 0, 3, 6, and 12 months in all groups. At 12 months, overall BMD showed a greater improvement in the combination group than in the single therapy groups. Additionally, femoral neck and total hip BMD also increased more in the combination therapy group. The authors concluded that combination therapy might therefore be useful to treat patients at high risk of fracture [38].

19.5.2 Complementary and Alternative Therapy

Phytoestrogens are found in various plants and foods, these substances are similar in action to estrogen. There are conflicting data on phytoestrogens and their effects on BMD Some studies report that phytoestrogens are beneficial for bone resorption and BMD in postmenopausal women, while other studies have reported no effect [39]. Much conflicting information exists with respect to the use of soy (bean) isoflavones in the treatment of patients with osteoporosis. While it seems likely that soy isoflavones have many health benefits, the evidence for using soy as an alternative treatment in osteoporosis remains largely inconclusive. Zhang, in his study, showed that postmenopausal women who ate an average of 11 g of soy protein daily had a lower risk of fracture than those who did not ingest that level of soy [40]. One cup of soy milk contains 7–11 g of soy protein.

One 12 week trial of postmenopausal women revealed that black cohosh extract increased levels of bone-specific alkaline phosphatase, a metabolic marker for bone formation, compared to women on HT or placebo. However, no BMD measurements were done. This study may suggest that black cohosh is beneficial but the data are insufficient to be conclusive. Red clover has undergone similar evaluations and the results may be promising, but are as yet insufficient [41]. Wild yam has not been studied in a controlled trial for the treatment of osteoporosis; however, it has been marketed for that indication in the USA. All herbal remedies and alternative or complementary forms of therapy must be used with caution as little to no data from controlled trials is available. Currently herbals are sold as nutritional supplements and are therefore not regulated by the FDA. Many herbal remedies have interactions with prescription medications, ranging from annoying to life-threatening. No herbal remedy should be initiated without a thorough review and discussion of all other medications that a patient is taking.

19.6 Concluding Remarks

Early prevention of bone loss is the key to reducing a woman’s lifetime risk of developing osteoporosis and fracture. Women should be encouraged to educate themselves with information on healthy habits and be aware of their personal risk factors both modifiable and non-modifiable. Changing one’s modifiable risks by avoiding or discontinuing personal habits which are known to damage bone is vitally important to bone health. Although numerous effective therapies for the treatment of osteoporosis are readily available in a variety of forms, maintaining a healthy lifestyle with proper, balanced nutrition and sufficient, regular physical activity should be paramount for all women. Therapeutic regimens for osteoporosis are safe and beneficial and should be employed as soon as the need is identified.

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