Prevention and Treatment of Osteoporosis

Author: Cesar Libanati, MD, Associate Professor of Medicine, Pettis VAMC and Loma Linda University, Loma Linda, CA.

Peer Reviewers: Paul Miller, MD, Medical Director, Colorado Center for Bone Research, Lakewood, CO; Clifford J. Rosen, MD, Research Professor of Nutrition, University of Maine, Bangor, ME.

Editor’s Note—Recent improvements in diagnostic testing coupled with the rapidly expanding number of therapeutic options for the prevention and treatment of osteoporosis have resulted in growing recognition of this disease as a silent epidemic of major proportion. Primary care physicians are uniquely positioned to help prevent the occurrence of osteoporotic fractures in the aging population. This article summarizes recent developments in osteoporosis prevention and treatment. It is intended to assist primary care physicians in keeping up with this rapidly evolving field.

The clinical consequence of osteoporosis is the development of skeletal fractures after minimal or no trauma (i.e., after a fall from a standing height or less). Osteoporotic fractures occur primarily at the wrist, the spine, or the hip. Hip fractures, the most morbid complication of osteoporosis, occur at a rate of approximately 250,000 per year in the United States.1 Although we lack up-to-date estimates, based on 1995 data, the annual costs associated with the care of osteoporotic fractures likely exceeds $10 billion in the United States.2 These expenditures are expected to escalate to $40 billion by the year 2025.

Generally speaking, osteoporotic fractures are the result of reduced bone strength due to bone loss leading to low bone mass and microarchitectural deterioration of trabecular bone.3 Clinically speaking, that definition translates to a decrease in bone density (mass/unit volume of bone) that can now be measured with excellent precision and accuracy in the office setting. Thus, bone density testing provides the basis for the identification of patients with low bone density and for the implementation of therapeutic recommendations much like blood pressure measurements or cholesterol testing enable physicians and patients to recognize the need for intervention and tailor treatment for hypertension and hypercholesterolemia, respectively.

Osteoporosis Causes

The risk of developing an osteoporotic fracture primarily relates to the amount of bone present at any given moment. This, in turn, is the result of the maximum amount of bone achieved during early adulthood (peak bone mass) minus the accumulated bone loss. Two pathogenic mechanisms, alone or in combination, can result in osteoporosis: 1) conditions that result in reduced peak bone mass; and 2) accelerated or prolonged bone loss.

Osteoporosis is more prevalent in whites than in blacks, and in women than in men, reflecting the fact that blacks and males achieve higher peak bone mass than whites and females, respectively. Genetics appear to play a major role in the determination of peak bone mass as suggested by the fact that almost 98% of peak bone mass is achieved by the end of the second decade of life.4 The booming identification of candidate genes associated with bone density underscores the polygenic regulatory mechanisms of peak bone density.5-8 Undoubtedly, environmental factors such as calcium intake and weight bearing may also play a role in the attainment of peak bone density. Research into the mechanisms responsible for maximizing peak bone density is a logical approach to attempt to prevent osteoporosis. Unfortunately, while it is clear that reduced calcium intake or suboptimal exercise early in life can result in a deficit in peak bone mass and should be avoided. The opposite (i.e., supplemental calcium intake or increased exercise during adolescence) does not necessarily result in a sustained improvement in peak bone mass.

After peak bone mass has been attained, age-related bone loss occurs. This bone loss is universal but it accelerates in females during menopause due to the decrease in estrogen production.9,10 While menopause is the most common cause responsible for estrogen deficiency, other conditions associated with a diminished estrogen production, such as exercise-associated amenorrhea, surgical oophorectomy, anorexia nervosa, or hyperprolactinemia, will result in bone loss. Recent evidence also points to estrogen deficiency as a significant factor responsible for senile male osteoporosis.11 Later in life, in addition to estrogen deficiency, other physiological changes may contribute to bone loss: calcium malabsorption, leading to secondary hyperparathyroidism and a decline in growth factors at both the endocrine and the local tissue levels, further leads to a negative bone balance and a reduction in bone mass in both sexes.12 Accordingly, the incidence of osteoporosis increases with age; approximately 20% of women in their seventh decade of life, 30% of women in their eighth decade of life, and 70% of women older than 80 years suffer osteoporosis.1

Accelerated bone loss is common in conditions such as immobilization, malabsorption, hyperparathyroidism, hypo-gonadism, multiple myeloma, and glucocorticoid therapy. Patients suffering from those conditions may benefit from bone density determination. In general, a good history, a physical examination, and few appropriate laboratory evaluations enable physicians to rule out these secondary causes of osteoporosis.

Diagnosis

A number of clinical risk factors have historically been associated with the risk of developing osteoporosis. Among these we recognize: female gender, increasing age, family history, Caucasian or Asian race, estrogen deficient state, nulliparity, sedentarism, lifelong history of low calcium intake, smoking, excessive alcohol or caffeine consumption, and long term use of glucocorticoid drugs. However, these risk factors, used alone or in combination, have only a limited predictive value in clinical practice and cannot be relied upon to always identify patients with low bone density and increased risk for fracture. The presence of an osteoporotic fracture is a noteworthy exception and patients who have already sustained a fragility fracture have a markedly increased risk of sustaining further fractures independent of their bone density level or other risk factors.13,14 This observation can help identify osteoporotic patients in daily clinical practice. It also underscores the need to identify and treat patients before their first osteoporotic fracture has occurred. In this regard, it is well accepted that bone density is the strongest predictor of fracture risk (with roughly a doubling in the fracture risk for each unit of standard deviation decrease in bone density).15 Other factors such as propensity to fall14 and greater height16 increase fracture risk, while thiazide diuretics appear to reduce hip fracture risk in elderly subjects.17

Because bone density is such a strong predictor of fracture risk, bone density testing has become the cornerstone for osteoporosis diagnosis and also provides guidelines for pharmacologic intervention.

Bone Density Testing

With the advent and availability of bone density testing, we can now determine the risk for fracture in an individual patient much like we can determine the risk for stroke or heart disease from blood pressure or cholesterol measurements. In fact, the relationship between bone density and fracture risk is stronger than the widely accepted relationship between cholesterol and coronary artery disease. Bone density can be assessed by a number of different techniques such as dual X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and quantitative ultrasound (QUS). DXA and QCT allow bone density measurements at a central or peripheral skeletal location; QUS determinations are limited to peripheral skeletal sites. Evidence indicates that bone density measurements obtained with any of the available methods are intercorrelated and that bone density measured by any of those methods indicates fracture risk. Peripheral measurements rely on density evaluations at the forearm, calcaneus, phalanges, or tibia. Central measurements are those performed at the spine and hip, the two areas of clinical relevance in osteoporosis.18 Peripheral density measurements offer the advantage of being lower cost and portable, thus, potentially enabling the screening of a large number of patients. Their disadvantage is that a normal peripheral density measurement does not necessarily rule out osteoporosis or osteopenia in the hip or spine. Patients with risk factors for osteoporosis may benefit more from a central than a peripheral bone density measurement since a normal peripheral bone density test in those patients does not exclude osteopenia or osteoporosis at a central site. Recommendations are being developed to ensure the most cost-effective use of peripheral and central bone density technologies.18 (See Table 1.)

    Table 1. Indications for Bone Density Testing
    • Estrogen-deficient women at clinical risk for osteoporosis
    • Individuals with vertebral abnormalities
    • Individuals receiving, or planning to receive, long-term glucocorticoid (steroid) therapy
    • Individuals with primary hyperparathyroidism
    • Individuals being monitored to assess the response of an approved osteoporosis drug therapy
    ______________________________________________________________________________

Central DXA measurements are preferred and have become the standard for clinical testing20,21 largely due to the fact that this technique is highly reproducible and that adequate reference databases are available for spine and hip DXA measurements in clinical practice. This latter point is of major relevance since the diagnosis of normal, osteopenic, and osteoporotic densities relies on the comparison of the density of the individual studied, expressed in units of T-Score, to that of a normal young reference population. Although less than ideal, the standardization of bone density reporting in terms of T-Scores has facilitated interpretation of bone density. The World Health Organization’s proposed definition of normal, osteopenia and osteoporosis based on T-Score analysis is now widespread and has been incorporated into diagnostic and treatment algorithms. Simply stated, a T-Score is simply the absolute density level of the patient being measured expressed in terms of units of standard deviation from the "ideal" or peak bone density achieved during young adulthood (the T-Score is calculated using the following formula: T-score = [density of the individual - young normal bone density]/standard deviation of young normal). Although the cutoff points for the classification of osteopenic (a bone density resulting in a T-Score between –1 and –2.5) and osteoporotic (a bone density resulting in a T-Score inferior to –2.5) densities is somewhat arbitrary since the relationship between fracture risk and bone density is continuous, it provides a useful framework for test interpretation and patient evaluation and management.22 The lower the density in the osteopenic or osteoporotic range, the more negative the T-Score. Since the calculation of the T-Score involves density comparison to that of a normal young population, it is ideal that a young reference database common to all manufacturers and techniques be used for standardization.23,24 Such a common reference database is available for hip measurements with central densitometers (NHANES III database25). A Z-Score is also included in most density reports. The Z-Score is the absolute density level of the patient expressed in terms of units of standard deviation from the "expected" density for an age-, sex-, and race-matched individual. Although the use of the Z-Score is less well defined than that of the T-Score, a low Z-Score (i.e., inferior to –2.0) helps the ordering physician by alerting that the patient may have lost greater amount of bone than expected.

Another advantage of DXA over the other available techniques is that expected changes in density in response to different therapies are well documented both at the spine and hip and, thus, enable educated decisions regarding treatment response during follow-up of individual patients.

Both hip and spine need to be measured. The spine allows for precise follow-up of response to therapy and the hip density is necessary, in the elderly, to avoid false-negative diagnoses due to the presence of degenerative changes that may artifactually increase the bone density determination in the spine.

Patients with normal spine and hip densities may not need to worry about osteoporotic fractures and may not require any form of pharmacological intervention (estrogen replacement therapy [ERT] after menopause may still be advisable based on cardiovascular risk profile and menopausal symptoms). Subjects with osteopenia should be carefully counseled, treated, and followed such that, at least, no further bone loss develops. Finally, patients with osteoporosis require active intervention aimed at fall prevention and pharmacologic therapy to increase bone density and decrease fracture risk.

Biochemical Markers of Bone Formation and Bone Resorption

Bone balance is the result of bone formation minus bone resorption. Both bone formation and bone resorption may be assessed by means of chemical measurements of skeletal-specific proteins or byproducts of collagen breakdown in serum and urine. Bone formation markers (i.e., alkaline phosphatase, osteocalcin) are available but their use outside of research studies is hampered by poor precision, daily or seasonal variance, and the lack of FDA-approved therapeutic agents to increase bone formation. Bone resorption markers (urinary hydroxyproline and the newer collagen cross links such as pyridinoline, deoxypyridinoline, N-telopeptides, and C-telopeptides) have been proposed to assist in the identification of patients likely to sustain fractures (independent of bone density) in the identification of individuals with rapid bone loss and in the monitoring of antiresorptive therapeutic responses. The rationale behind these applications is simple: if bone resorption and bone loss are correlated and if antiresorptive therapies (such as estrogen, alendronate, raloxifene, and calcitonin) are effective at decreasing bone resorption and reducing fracture risk, then a marker of bone resorption could be used to identify patients more likely to benefit from therapeutic intervention and monitor the efficacy of the treatment.26-29 Although these strategies prove correct when applied to large number of study patients, the use of these markers for the identification or follow-up of individual subjects in clinical practice may be limited. The limitations arise, in part, from the large variance (15-30%) in marker measurements. While duplicate measurements would improve the variance, they would also result in greater expenditure. Recent reports further question the usefulness of these markers in day-to-day practice.30,31 To date, we cannot provide evidence-based guidelines for the use of these biochemical markers in the diagnosis or monitoring of osteoporotic patients with the possible exception of bone resorption marker decrease after three months of alendronate therapy—enabling some prediction of the bone density to increase later.32

Prevention and Treatment Strategies

The main objective in the prevention and treatment of osteoporosis is the maintenance of skeletal integrity by 1) achieving the highest possible peak bone density; 2) arresting bone loss; and 3) preventing falls.

More studies are needed to enable recommendations that will undeniably contribute to a higher peak bone density. Until then, it is important to encourage a balanced diet including at least 1300 mg of calcium during the adolescent years and 1000-1500 mg afterward, to promote weight bearing exercise, and to recommend avoidance of alcohol and tobacco products. Detailed information about calcium content in food products is widely available in food labels. As a rule of thumb, a cup of milk or 2 oz of cheese provide approximately 300 mg of calcium.

Daily calcium supplementation (1000-1500 mg) along with 400-800 IU vitamin D have been shown to reduce the rate of bone loss in women greater than five years postmenopause and should be given concomitantly with all other pharmacological interventions. While adequate calcium intake via food or supplementation may help achieve maximum peak bone density, slow bone loss and decrease (particularly when combined with vitamin D) fracture risk33 in some patients, it is now well accepted that calcium and vitamin D alone may not prevent the development of osteoporosis in large number of patients.

As previously mentioned, bone loss may begin after peak bone density is achieved and accelerates during menopause with the greatest bone loss occurring in the first 5-7 menopausal years.34,35 The perimenopausal years, therefore, constitute a unique window when primary care providers could have a major effect by discussing and instituting therapeutic plans to prevent bone loss. Bone density testing at this time of life can assist the female patient and her doctor to make a well-informed decision about the need to institute measures to prevent osteoporosis. Another advantage of bone density testing is that it increases acceptance of ERT.36 Females who are not willing or incapable of receiving ERT and have osteopenic densities may consider alternative agents such as alendronate and raloxifene, which are now FDA approved to prevent bone loss. After the age of 65, a bone density test should be performed, if not previously done, in that individual to decide if pharmacologic therapy should be considered to prevent or treat osteoporosis. (See Table 2.)

    Table 2. Available FDA Approved Drugs for the Managementof Osteoporosis 
    Drug Dosage Indication Comments
    Estrogen See text Prevention and Treatment OngoingWomen Health Initiative Study will hopefully allow evidence-based recommendationsregarding ideal onset, dosage and length of therapy
    Raloxifene 60mg PO QD Prevention No breast oruterine tissue stimulation; Decrease in cholesterol similar to estrogen
    Alendronate 5 mg PO QD Prevention Treatment Adherenceto strict instructions on how to 10 mg PO QD take the medicine essential.Well-documented reduction in spine and hip fracture risk.
    Calcitonin 200 IU QD (nasal) 
    50-100 IU QD SQ
    Treatment Modestanalgesic effect. Not indicated in the early post-menopausal years.
    Calcium See text Prevention/Treatment Calciumalone may not prevent the development of osteoporosis
    Vitamin D 400-800 IU QD Prevention/Treatment Mayhelp reduce hip fracture incidence in the elderly
    ____________________________________________________________________________________________________________________

Estrogen Replacement Therapy

Estrogen deficiency after menopause predictably leads to bone loss and osteoporosis. Accordingly, ERT is the accepted standard of practice for the prevention and for the treatment of osteoporosis. All postmenopausal women without contraindications should consider ERT. Contraindications to estrogen administration include family or individual history of breast cancer; estrogen dependent neoplasia; undiagnosed genital bleeding; and a history of or active thromboembolic disorder.

Because the greatest rate of bone loss occurs in the first years after cessation of ovarian function, ERT should be initiated at the onset of menopause to prevent bone loss accumulation. Recent placebo-controlled studies to evaluate the effect on alendronate37 or raloxifene38 in the prevention of osteoporosis in postmenopausal women included an estrogen-treated arm. Conjugated estrogens, at a dose of 0.625 mg per day, resulted in approximate increases in bone density at the spine and the hip of 5% and 3%, respectively, at 24 months.

Unfortunately, we lack well-controlled prospective studies to evaluate the ideal dose and the optimal duration of estrogen therapy to prevent osteoporosis. Accordingly, there are no clear recommendations regarding the optimal duration of ERT. From a skeletal standpoint, bone density assessment at regular intervals (possibly every 3-5 years) provides density data to help determine if continuation of ERT may be further recommended. Baseline and repeat bone density testing remains the sole test that allows documenting maintenance. The importance of repeat bone density testing is stressed by reports of development of osteoporosis despite compliance with ERT39 and of bone loss occurring in patients followed longitudinally while receiving ERT.40 If ERT is discontinued and no other therapies are instituted, serial bone density measurements should be continued to monitor for accelerated bone loss known to occur after ERT is stopped.41 Although ERT may be most beneficial if started early after cessation of menses, elderly patients also increase bone density and decrease fracture incidence if receiving ERT.42

Different estrogen preparations are currently available for the prevention and treatment of osteoporosis. The route of administration (oral or transdermal) does not seem to affect the efficacy of estrogen. Conjugated estrogens and transdermal estradiol are commonly prescribed at a dose of 0.625 mg and 0.05 mg, respectively, for the prevention of postmenopausal osteoporosis. For the treatment of postmenopausal osteoporosis conjugated estrogens doses of 0.625-1.25 mg daily are most commonly used.

Although we also lack good studies of estrogen’s effect on fracture, several small studies and epidemiological observations reveal a lower incidence of fractures in osteoporotic women treated with estrogen.41,43-45 Estimates of fracture risk reduction from ERT vary between 20% and 60% and the greatest fracture benefit from estrogen therapy may occur if estrogen is used for 10 years or longer.

The benefits of ERT are not limited to bone. Estrogens decrease total cholesterol and low-density lipoprotein levels and increase high-density lipoprotein (HDL) levels.46 Estrogens also cause vasodilatation and other direct benefits on the endothelium. Based on these actions and few well-controlled studies, we have widely accepted that estrogens reduce cardiovascular morbidity and mortality.47 While most beneficial effects of estrogen on the lipid profile are maintained if a progestin is added, this therapy tends to reduce the increase on HDL characteristic of estrogen’s action. The cardiovascular benefit of estrogen supplementation was recently questioned by the publication of the results of the Heart and Estrogen/Progestin Replacement Study.48 This research reported that treatment with oral conjugated estrogen and medroxyprogesterone, during a follow-up period of approximately four years, did not reduce the overall rate of coronary events in postmenopausal women with established atherosclerotic heart disease. Far from settling the issue, this study stresses the notion that estrogen therapeutic recommendations regarding dosage and length of therapy need to be individualized rather than generalized. The results of the ongoing Women’s Health Initiative Study will hopefully provide data to allow evidence-based recommendations regarding the ideal onset, dosage, and recommended length of ERT. Other major potential beneficial effects of ERT such as colon cancer and Alzheimer’s disease incidence reductions while exciting also remain to be formally studied.

Unfortunately, ERT has side effects. ERT results in endometrial hyperplasia and doubles the risk of endometrial cancer in women with an intact uterus. This increased risk can be easily eliminated by the addition of medroxyprogesterone acetate either cyclically (12-14 days/month) at a dose of 5-10 mg or continuously at a dose of 2.5-5 mg daily. Other adverse events related to ERT are breast tenderness, weight gain, headaches, and libido changes. Unfortunately, most women who receive prescriptions for ERT stop therapy within a few months. The side effects, together with concerns about increased breast cancer risk, account for the poor compliance observed with ERT. The breast cancer risk, if present, is likely related to the cumulative time on estrogen supplementation. Evidence suggests a small increase in breast cancer risk after 10-15 years of estrogen supplementation.49,50 Again, the Women’s Health Initiative Study may help clarify the relationship between ERT and breast cancer risk. Until that study is completed, the availability of selective estrogen receptors modulators, which result in positive effects on bone and lipid profile while avoiding breast or uterine tissue stimulation, offer an alternative to females concerned about the possible increase in breast cancer risk or those who have been on continuous ERT for more than a decade. Finally, ERT results in a small increase in thromboembolic events.51

Selective Estrogen Receptor Modulators

With the discovery and molecular understanding of the function and tissue distribution of two distinct estrogen receptors, a new group of drugs has emerged to potentially improve estrogen’s beneficial actions while reducing or avoiding altogether estrogen’s known side effects. These drugs have been termed selective estrogen receptor modulators (SERMs). SERMs act as either estrogen analogs or estrogen antagonists depending on the tissue and on the presence or absence of endogenous estrogen. The oldest of all SERMs is tamoxifen, which was recently approved for the prevention of breast cancer in selected populations. Tamoxifen prevented bone loss at the spine but not at the wrist in postmenopausal women.52

Raloxifene, a new SERM, was recently approved by the FDA for the prevention of osteoporosis based on the results of large, randomized, placebo-controlled, double-blind studies.38 When used at a dose of 60 mg per day, raloxifene demonstrated modest but statistically significant increases (1.5%-2% in 24 months) in bone density at the hip and spine compared to calcium supplemented groups. This increase in density was approximately half of that seen in those patients receiving ERT but raloxifene therapy was not associated with uterine stimulation. Raloxifene therapy was recently shown to be associated with a significant decrease in vertebral fracture risk compared to placebo53 and, thus, may also prove beneficial in the treatment of established osteoporosis in addition to the already approved use for osteoporosis prevention.

Raloxifene also results in a beneficial effect on the lipid profile similar to that seen with estrogen (raloxifene does not improve total HDL cholesterol but does not increase triglycerides either). It remains to be proven if this effect on lipids will positively affect cardiovascular morbidity and mortality. The results of a double-blind, placebo-controlled, five-year study initiated in 1998, the Raloxifene Use for the Heart, will in time hopefully address this important question.

Possibly, the most exciting aspect of raloxifene therapy is the lack of breast stimulation and the possibility that, like tamoxifen, it may provide a protective effect against certain types of breast cancer. Preliminary reports indicate that raloxifene therapy results in a 50-70% reduction in breast cancer risk.54 Again, ongoing studies will provide a more definite answer to the reduction in breast cancer risk reportedly associated with raloxifene administration.

Raloxifene may be taken at any time during the day and without regard to foods or medicines with the exception of cholestiramine, which prevents intestinal absorption of raloxifene. Raloxifene may be better tolerated than ERT and raloxifene administration resulted in fewer dropout rates than ERT as a result of side effects.55 Minor common side effects associated with raloxifene therapy include hot flashes and leg cramps. Serious side effects include an increased risk of venous thromboembolism (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis).38 Although rare and similar in incidence to patients receiving ERT, thromboembolic adverse events are serious enough to recommend stopping raloxifene and prompt evaluation in patients complaining of leg pain or swelling, unexplained shortness of breath or hemoptisis, or changes in vision while receiving raloxifene therapy. Raloxifene should not be used before menopause and should be discontinued in patients who become immobilized.

Bisphosphonates

Alendronate is an oral bisphosphonate approved for the treatment and prevention of osteoporosis in women. Alendronate exerts its effect on bone by inhibiting osteoclasts and thereby reducing bone resorption without negatively affecting mineralization. Large-scale, randomized, placebo-controlled, double-blind studies have demonstrated that alendronate, given at a dose of 5 mg and 10 mg per day, is effective at maintaining and increasing bone density, respectively.37,56

The recommended dose for prevention of osteoporosis is 5 mg per day. This dose resulted in significant increases in lumbar (3.5%) and hip (2%) densities when compared to placebo. These increases were slightly but not significantly different from those observed in the ERT arm of the trial. The recommended dose for the treatment of osteoporosis is 10 mg per day. With this dosing, bone density significantly increased at the spine and the hip by about 7% and 4%, respectively at 36 months. These increases in density were associated with an approximate 50% reduction in fracture risk at both skeletal sites. Subgroup analysis revealed similar reductions in fracture risk regardless of age, degree of baseline bone resorption, or absolute pretreatment bone density level.

Alendronate has also been documented to prevent and improve osteoporosis associated with prednisone therapy.57

The effect of combination therapy such as alendronate and estrogen is currently under evaluation. Preliminary reports indicate that an additive effect on bone density occurs when these two agents are used in combination.58

Regardless of the dosage used, patients should be instructed to take the alendronate pill in the morning with 2-3 glasses of water, at least 30 minutes before any food or beverages. Because bisphosphonates are poorly absorbed and because these groups of drugs bind tightly to other compounds, it is important that no other medication be taken at the same time, particularly calcium preparations. Patients should also be instructed against lying down after taking alendronate to avoid gastro-esophageal reflux. Esophagitis, a side effect rarely observed in the research trials but reported after the drug was approved and released for general use by the FDA, emphasizes the importance to adhering to the recommendations on how to take the drug. Alendronate is not recommended for use in patients with severe renal insufficiency or hypocalcemia.

Because alendronate exclusively exerts its effect on the skeletal system, follow-up bone density is a logical tool to monitor therapy. In the controlled trials, the majority of patients responded to therapy with maintenance or improvement in bone density. If this is proven the case in real practice, a follow-up of bone density may not be routinely required with this form of therapy, particularly in those patients who demonstrate a decrease in their bone resorption marker. As with any test, bone density testing while on alendronate should only be performed if the result will influence therapeutic recommendations.

Calcitonin

Calcitonin, a naturally occurring hormone, has long been used for the treatment of osteoporosis. Until recently, the only calcitonin available was an injectable form. Recently, a nasal spray form was approved for the treatment of postmenopausal osteoporosis. Presently available calcitonins include salmon calcitonin (injectable and nasal spray) and human calcitonin (injectable only). In the treatment of osteoporosis, calcitonin may be given as either 50 IU or 100 IU intramuscularly or subcutaneously daily or every other day59 or as 200 IU intranasally every day.60 The nasal spray, at a dose of 200 IU/d, alternating nares, results in a modest but not significant increase in bone density at the spine (2%) compared to placebo-treated subjects. For reasons still poorly understood, the increase in bone density associated with calcitonin administration may be transient. Although recent abstract reports regarding a reduction in fracture occurrence with nasal calcitonin therapy are encouraging, the effect of this therapy on hip fracture remains to be demonstrated. Patients who have suffered an acute osteoporotic fracture61 may benefit from the analgesic effect of calcitonin, a unique characteristic of this agent.

Calcitonin is an alternative to estrogen and alendronate therapy in women who cannot tolerate or refuse these therapies and may be useful in the management of painful acute osteoporotic fractures. It is generally well tolerated with minimal adverse effects. Because of the possible, albeit rare, allergic reaction to salmon, calcitonin skin testing should be done before initiation of parenteral therapy in patients with suspected allergy to calcitonin. Adverse effects occurring with parenteral therapy include nausea or vomiting and transient vasomotor symptoms. These side effects are self-limited and can be managed with a reduction in the administered dose. Nasal calcitonin side effects are primarily limited to rhinitis.

The Immediate Future

While the past decade resulted in major diagnostic and therapeutic developments leading to 1) improved recognition of patients at risk for fracture before fractures occur by means of bone density testing; and 2) an increased availability of agents to halt bone loss and reduce future fracture occurrence, the medical community is still lagging in the use of both the diagnostic tools and the therapeutic agents. As a result, many unrecognized patients with osteopenia continue to lose bone and many patients with osteoporosis continue to fracture. The immediate future calls for the recognition that osteopenia and osteoporosis need to be considered in the differential diagnosis in all women after the menopause. This goal can only be accomplished if primary care providers recognize the importance of this disease.

The More Distant Future

All currently approved therapeutic agents for the prevention and treatment of osteoporosis share one common mechanism of action: they inhibit or decrease bone resorption. While this group of agents is effective at maintaining or mildly increasing bone density, we now need agents that would result in ample gains in bone density to correct the large bone density deficits characteristic of severe osteoporosis. This can only be accomplished by agents that stimulate bone formation. Parathyroid hormone peptides, growth hormone, and growth factors are anabolic agents currently under different phases of development to treat osteoporosis. It is likely that one such agent will become available in the next 5-10 years.

Conclusion

The increasing availability of bone density testing to identify patients at risk for osteoporotic fractures, coupled with the FDA approval of alternatives to ERT for the prevention and treatment of osteoporosis, signals a turning point in our battle against this morbid condition. Calcium with or without vitamin D supplementation is encouraged but may not prevent osteoporosis. Bone density testing allows the accurate and rapid identification of patients at risk for osteoporotic fractures and provides the basis for pharmacologic intervention. ERT should be considered in all postmenopausal women without contraindications. Alternatives to estrogen for osteoporosis prevention include the new SERM raloxifene (60 mg/d) or the bisphosphonate alendronate (5 mg/d). For the treatment of osteoporosis, estrogen and alendronate (10 mg/d) result in significant increases in bone density. Alendronate therapy has been associated with proven reductions in fracture risk at both the spine and hip. Calcitonin offers a safe alternative although the effect on density is modest and the effect on fracture, particularly at the hip, is less well documented.

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