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AACE Clinical Practice Guidelines for the Prevention and Treatment of Postmenopausal Osteoporosis

AACE Clinical Practice Guidelines for the Prevention and Treatment of Postmenopausal Osteoporosis

Introduction

In this era of constrained health-care resources, a critical need exists for efficient, measurable systems of disease management that strike a balance between social responsibility and patient welfare. Clinical guidelines have become an important component of these systems because they address those elements of care that have proved to be efficacious and reduce the high degree of variability in physicians' approaches to disease management.

These guidelines address the prevention, diagnosis, and management of postmenopausal osteoporosis, a disorder that is recognized as a major public health issue because of its profound physical and socioeconomic effects. Each year, approximately 1.3 million fractures which now cost the US health-care system more than $10 billion annually occur as the result of osteoporosis.

With these guidelines, we hope to simplify medical decision making but do not intend to be inclusive or restrictive because, ultimately, the physician must assume the responsibility for integrating the needs of the patient with those of society. The specific goals of these guidelines are as follows:

To reduce the incidence of fracture
To encourage the highest quality of life possible for individual patients
These guidelines address the controversies that exist within the subject of postmenopausal osteoporosis but do not debate them. In the absence of concrete cost-effectiveness data, they rely on contemporary consensus whenever possible. Physicians are encouraged to assess the recent, relevant reviews and studies listed in the "Recommended Reading" section for more detailed information and to continue following the literature.

The American Association of Clinical Endocrinologists (AACE) also recognizes the physician's prerogative to refer the patient for consultation by qualified experts, as a basic principle of medical decision making. Osteoporosis is a complex endocrinologic disorder of bone and mineral metabolism, and formal training in the science and management of metabolic bone disease is required in the academic realm of endocrinology. The clinical endocrinologist is a reliable source of referral expertise.

Finally, these guidelines will be continually updated to reflect the latest advances in the prevention, diagnosis, and treatment of postmenopausal osteoporosis. Because these changes often exceed the capability of our printed medium, these guidelines will be updated first on the AACE home page on the Internet. Please visit our Web site at / for the most recent version of these guidelines.

Osteoporosis Task Force
Co-Chairmen
Stephen F. Hodgson, M.D., F.A.C.E.
C. Conrad Johnston, Jr., M.D., F.A.C.E.

Committee Members
Louis V. Avioli, M.D., F.A.C.E.
H.Hunter Heath, III, M.D.
Sundeep Khosla, M.D.
Michael Kleerekoper, M.D., F.A.C.E.
Robert Lindsay, M.D., F.A.C.E.
Edward G. Lufkin, M.D.
B. Lawrence Riggs, M.D., F.A.C.E.
Nelson B. Watts, M.D., F.A.C.E.

 

Definition
Postmenopausal osteoporosis is a condition characterized by the following features:

  • Low bone mass
  • Microarchitectural deterioration of bone tissue leading to bone fragility
  • A consequent susceptibility to fracture

In the third or fourth decade of a woman's life, bone mass begins to decline in the hip because of an imbalance between the volume of mineral and matrix removed and that reincorporated during the remodeling process. When menopause occurs, the rate of bone loss accelerates and is particularly rapid in the first postmenopausal decade. This accelerated bone loss is caused by estrogen deficiency, which not only induces an enhanced, focal imbalance at remodeling sites but also may increase the overall rate of remodeling. Certain nutritional and lifestyle factors, such as inadequate intake of calcium, may contribute to low bone mass independent of estrogen level, and this can further increase a woman's risk of developing postmenopausal osteoporosis.

Postmenopausal osteoporosis affects the entire skeleton. In the early postmenopausal years, bone loss averages 2% per year but can vary from <1% to >5% (1). In the early phase of postmenopausal bone loss, the rate of trabecular (cancellous) bone loss exceeds that of cortical bone, and by the end of the first postmenopausal decade, most white women have osteopenia or osteoporosis (2). Postmenopausal osteoporosis is more prevalent in white and Asian women than in women of other races.

 

[figure 1]

Fig. 1. Mean bone mineral density (BMD) of the lumbar spine in women from the third through ninth decades of life. Note that BMD decreases with advancing age, beginning in third or fourth decade of life. Dark curved line = mean; upper curve = +2 SD; lower curve = -2 SD; light shaded area = consider preventive intervention; dark shaded area = consider therapeutic intervention. Diagram is intended to resemble a densitometry report. Sample T score for a 76-year-old woman = -3.68 SD, or approximately 63% of young adult mean BMD (each 10% increment above or below the mean represents one SD).

 

Fig 2. Estimated skeletal status (based on World Health Organization definitions) of white women in the United States, 1990, shown by age distribution. (Reproduced from Melton LJ III. Perspectives: how many women have osteoporosis now? J Bone Miner Res. 1995; 10:176. by permission of Blackwell Science, Inc.)

[figure 2]

 

Clinical Features and Complications
Low Bone Mass
Low bone mass is a major feature of postmenopausal osteoporosis and the primary determinant of fracture. The relationship between bone mass and fracture risk is more powerful than that between serum cholesterol concentration and coronary artery disease (3). Fortunately, bone mass can be readily measured, preserved, and increased with therapeutic intervention.

Fracture
Fracture is the most clinically significant complication of postmenopausal osteoporosis. The following are some of the clinical complications of fracture:

  • Pain
  • Deformity
  • Postural changes (spinal fractures)
  • Disability
  • Physical deconditioning due to inactivity
  • Changes in self-image

Hip fractures are costly and clinically serious. Among patients with hip fracture, 12 to 20% die within 1 year after the fracture, and more than 50% of the survivors are unable to return to independent living (4). Spinal injuries, in particular, may also lead to other adverse effects:

  • Loss of height
  • Kyphosis (Dowager's hump)
  • Back pain (acute and chronic)

Osteoporotic fractures often occur at a site of low bone mass and are usually induced by trauma.

Risk Factor Assessment
Assessment of risk factors can help the physician:

  • Identify women who are susceptible to fracture
  • Formulate clinical suspicion
  • Develop an osteoporosis prevention program

Several factors associated with osteoporosis are environmental and can be altered by the patient. A knowledge of all existing risk factors, when considered in conjunction with the bone mineral density (BMD) measurement, may also provide direction for intervention with a therapeutic agent (see "The Decision to Intervene").

Risk factors for osteoporotic fractures can be broadly categorized into two groups: (1) those that increase risk by increasing the likelihood of developing low bone mass and (2) those that increase risk independently of low bone mass for example, through increasing the risk of falling or by altering bone strength through mechanisms other than bone mass.

Risk factors that increase the likelihood that a patient may have low bone mass have limited utility. Although in the absence of bone mass measurements they convey information about risk, these factors offer no additional information once a bone mass measurement has been obtained. Moreover, their use as a prescreening device that is, to select patients for bone mass measurements and further clinical assessment has been shown to be inefficient and to result in failure to identify a substantial proportion of patients with low bone mass.

The following risk factors are in this first group:

  • Age
  • Caucasian or Asian race
  • Sedentary lifestyle
  • Smoking
  • Low body weight
  • Family history of osteoporosis
  • Excessive alcohol intake
  • Prolonged calcium-deficient diet
  • Nulliparity
  • Long-term use of certain medications (for example, glucocorticoids, phenytoin, excessive thyroxine)
  • Estrogen-deficient states

These risk factors may not contribute independently to the risk of having low bone mass. Low body weight, cigarette smoking, and excessive alcohol consumption, for example, may be found in the same person, but these factors may not separately increase the risk for low bone mass.

Once bone mass is known, several variables further influence the risk of subsequent fractures. Primary among these factors is a history of having suffered a fracture after age 40 years. Numerous investigators have observed that those persons with a history of fracture in adulthood have, independent of bone mass, roughly a doubled risk of sustaining another fracture. In addition to this risk, the Study of Osteoporotic Fractures has identified certain factors that have been shown to increase the risk of hip fractures (5), although no data suggest that these factors influence the risk of other osteoporotic fractures. The presence of any of the following factors should be considered to indicate an increased susceptibility to hip fracture beyond that attributable to low bone mass:

  • Maternal history of hip fracture
  • Greater height
  • Increased likelihood of falling

Each of these elements may be thought to reflect more general characteristics affecting hip fracture risk. Greater frailty, generalized weakness, poor visual function, and certain medications (such as long-acting benzodiazepines) increase the risk of suffering an injurious fall, by both increasing the probability of occurrence of a fall and decreasing the patient's ability to use protective reflexes. In fact, other studies have shown that both the direction of a fall (toward the side) and the absence of protective reflexes increase fracture risk independently of bone mass. Both maternal history of hip fracture and greater height may be associated with non-BMD structural characteristics of the proximal femur. Although not yet available in most clinical settings, scan data have shown that a longer hip axis confers an increased risk of fracture. Longer hip axes are associated with greater height and may be genetically determined; thus, some basis is provided for the observations about maternal history of hip fracture and greater height.

Prevention
Physicians should emphasize prevention of osteoporosis whenever possible. Any prevention program should have two primary goals:

  • To optimize bone mass
  • To preserve skeletal integrity

As part of any general osteoporosis prevention program, the physician should incorporate the following principles.

Promote a diet with adequate calcium content, particularly for growing children and adolescents. The recommended daily calcium intake for various populations is outlined in Table 1, and a guide to calcium-rich foods is provided in Table 2. Adequate calcium intake is a fundamental element of any osteoporosis prevention or treatment program, and calcium and vitamin D supplementation should be prescribed whenever needed to achieve the recommended daily intake levels (see "Intervention Agents").

Encourage good general nutrition, with adequate intake of vitamin D--especially in elderly patients.

Advocate regular weight-bearing exercise. Weight-bearing exercise enhances development of bone in children and adolescents and may slow bone loss attributable to disuse in elderly persons. In addition, regular exercise promotes mobility, agility, and muscle strength that may help prevent falls.

Strongly discourage use of tobacco. In general in comparison with nonsmokers, cigarette smokers are thinner, have an earlier natural menopause, may catabolize exogenous estrogen more rapidly, and have more fractures.

Consider additional preventive measures, including estrogen replacement therapy or estrogen + progestin replacement therapy (hormone replacement therapy) with calcium and vitamin D supplementation, for perimenopausal and postmenopausal women at high risk of developing osteoporosis. These additional measures, listed in Table 3, should be personalized to the needs of each patient (see "Intervention Estrogen Replacement Therapy").

The Decision to Intervene
When intervention with an agent is being considered whether for prevention or for treatment of postmenopausal osteoporosis and the patient is willing to accept available therapy, a thorough medical evaluation and BMD measurement are indicated.

Medical Evaluation
The medical evaluation includes elicitation of a family and a medical history and performance of a complete physical and gynecologic examination. Many patients with osteoporosis take medications or have coexisting diseases that cause or aggravate bone loss, and primary postmenopausal osteoporosis cannot be diagnosed or appropriately treated until these possibilities are eliminated.

The following laboratory tests are appropriate for excluding secondary causes of osteoporosis:

  • Complete blood cell count
  • Serum chemistry group (calcium, phosphate, liver enzymes, total alkaline phosphatase,
  • creatinine, electrolytes)
  • Urinalysis, including pH

If the physician has reason to suspect other causes for bone loss, additional laboratory evaluations are warranted and may include the following:

  • Thyrotropin
  • 24-hour urinary calcium excretion
  • Erythrocyte sedimentation rate
  • Parathyroid hormone concentration
  • 25-hydroxyvitamin D concentration
  • Dexamethasone suppression and other tests for hyperadrenocorticism
  • Acid-base studies
  • Serum or urine protein electrophoresis
  • Bone marrow examination or bone biopsy
  • Undecalcified iliac bone biopsy with double tetracycline labeling (consider only when osteoporosis is diagnosed and there is either no apparent cause for the condition or no response to therapy)


The causes of generalized secondary osteoporosis in adults are listed in Table 4. In the symptomatic patient, x-ray studies of the thoracic and lumbar spine can help the clinician assess the extent of osteoporotic damage. Generally, however, these x-ray films show bone loss only when it exceeds 30% or more (1).

Currently, no well-defined role has been established for biochemical markers of bone turnover in the management of the individual patient. In clinical trials, these serum markers such as collagen cross-links, bone-specific alkaline phosphatase, osteocalcin, and hydroxyproline have indicated early response to therapy. Preliminary evidence also suggests that high turnover may be an independent risk factor for fracture, but this relationship requires confirmation.

Bone Mineral Density Measurement
BMD measurement is indicated whenever a clinical decision to intervene with an agent will be directly influenced by the outcome of the test. When osteoporosis is suspected, BMD measurement is the single best diagnostic tool because it helps the physician determine fracture risk and identify patients who are candidates for intervention. For every decrease in bone mass of 1 standard deviation (SD), the relative risk of fracture increases 1.5- to 3-fold (6).

BMD measurements should be performed in the following settings:

  • For risk assessment in perimenopausal or post-menopausal women who are concerned about osteoporosis and willing to accept available interventions
  • In women with x-ray findings that suggest the presence of osteoporosis
  • In women beginning or receiving long-term glucocorticoid therapy, provided intervention is an option
  • For perimenopausal or postmenopausal women with asymptomatic primary hyperparathyroidism in whom evidence of skeletal loss would result in parathyroidectomy
  • In women undergoing treatment for osteoporosis, as a tool for monitoring the therapeutic response
  • Some women who have had several low-trauma fractures and a radiographic diagnosis of osteoporosis can be diagnosed without BMD measurement; however, the only effective way to monitor therapy objectively is by comparison with a baseline BMD measurement. BMD measurement is not indicated in women who are receiving estrogen therapy for nonskeletal indications and who do not have fragility fractures.


Available Techniques
Several techniques are available for bone mass measurement:

  • Single-energy x-ray absorptiometry, which
  • effectively has replaced single-energy photon
  • absorptiometry
  • Dual-energy x-ray absorptiometry (DEXA), which has largely superseded dual-energy photon absorptiometry
  • Quantitative computed tomography
  • Ultrasonography

The advantages and disadvantages of these techniques for BMD measurement are outlined in Table 5. It is important to note that results vary depending on the device used. Currently, DEXA is the preferred technique for the baseline and follow-up measurements because it provides reproducible results.

[figure 3]

Fig. 3.Bone mineral density (BMD) as a function of age. The proportion of patients with osteoporosis (BMD < or = 2.5 SD) increases exponentially with age. (Reproduced from Kanis J, Melton LJ III, Christiansen C, Johnston C, Khaltev N. Perspective: the diagnosis of osteoporosis. J Bone Miner Res. 1994;9:1139. By permission of Blackwell Science, Inc.)

 

Measurement Sites
BMD measurement at any axial (that is, hip, vertebra) or peripheral (that is, radius, calcaneus) site is useful for a one-time assessment of fracture risk. Currently, however, AACE recommends performing the first measurement at the hip. The hip is also a good site for the baseline and follow-up measurements when therapeutic intervention is planned. Vertebral compression and the presence of spinal implants, degenerative arthritis, or other spinal conditions can falsify the BMD measurement. Ideally, if resources allow, measurements should be taken at both sites for baseline and follow-up because the trabecular bone of the spine produces the quickest therapeutic response.

Diagnostic Criteria
The World Health Organization has established the following BMD-based diagnostic criteria for women who have experienced no fragility fractures. These criteria provide the physician with a basic diagnostic framework and should not serve as a precept for the therapeutic decision.

  • Normal: a value for BMD greater than 1 SD of the young adult mean
  • Osteopenia: a value for BMD more than 1 SD but less than 2.5 SD below the
  • young adult mean value
  • Osteoporosis: a BMD value 2.5 SD or greater below the young adult mean (1)
  • The patient with one or more low-trauma fractures is considered to have osteoporosis, regardless of the BMD value.


Most bone densitometry reports designate the SDs from the normal young adult mean in the form of "T" scores. Diagnostic criteria are commonly stated as T scores because fracture risk is derived from epidemiologic studies that use this designation as a reference. The densitometry reports also provide "Z" scores, which represent the SDs from age- and sex-matched control subjects. The Z score can provide useful diagnostic information because a Z score of 2 or greater below the age- and sex-matched control may suggest a secondary cause of osteoporosis. For each 10% decrease in BMD, the fracture risk approximately doubles.

The Decision-Making Process
Although bone mass is clearly correlated to fracture risk in populations, other factors have an important role in the individual patient's fracture risk. Osteoporosis exerts its pathologic effects over a continuum of bone density values. Even at the lowest bone mass measurement, some patients will remain free of fractures. For this reason, the decision to intervene with estrogen, calcitonin, or a bisphosphonate must involve clinical judgment that is based on a global patient profile and should not be based solely on BMD measurement.

The following are components of the global patient profile:


BMD values. Therapeutic efficacy and cost-effectiveness have not been linked to specific levels of bone density. A BMD measurement of 2.5 SD below the young adult mean (T score) is commonly used as an arbitrary cutoff point for defining the disease state, although several organizations have recently recommended a T score of 2 SD as a threshold for therapy. The proportion of patients with a BMD measurement of 2.5 SD or less than the young adult mean increases exponentially with age (Fig. 3) (6), and the number of women with osteoporosis who currently have a T score in this range totals approximately 6 to 7 million (7).

Until epidemiologic studies clarify these issues, the physician may consult the following guidelines when factoring the patient's bone density into the therapeutic decision:

  • Consider preventive intervention when the T score ranges from 1.5 to 2.5
  • Consider therapeutic intervention when (1) the T score is 2.5 or lower or (2) preventive intervention is ineffective (bone loss continues)

Patient acceptance of proposed treatment. The physician should inform the patient of all risks and benefits associated with intervention, and the patient should make a decision based on known information.

Menopausal status and age. If estrogen deficiency exists, estrogen replacement therapy (ERT) should be considered.

The patient's usual activity level.

Patient expectations. Some patients have higher functional needs and expectations than others, depending on their personalities, professions, and general life interests.

Likelihood of compliance to treatment and follow-up.

Lifestyle and other risk factors. Consider other risk factors, such as smoking, previous fractures of any type after age 50 years, and maternal history of hip fracture.

 

Intervention
Treatment Goals
Therapeutic intervention should have specific goals:

  • Prevent fractures
  • Stabilize, or achieve a moderate increase in, bone mass
  • Relieve symptoms of fractures and skeletal deformity
  • Maximize physical function (for example, halt progressive deformity)

The ability to achieve these goals depends on the patient's and the physician's commitment to therapy and the potential for the chosen therapeutic program to produce results.

Agents
AACE and the American College of Endocrinology recommend only the following agents:

  • Those that have been approved explicitly by the Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis
  • Those that do not require FDA approval, such as calcium and vitamin D supplementation
  • Agents approved by the FDA for osteoporosis prevention or treatment (or both) include estrogen therapy (with or without medroxyprogesterone acetate), alendronate sodium, and calcitonin. These agents suppress bone resorption and commonly result in bone mineral content increases that range from 2% to 10%. Even small increases in bone mass can substantially reduce the incidence of fracture.


A slow release form of sodium fluoride has received a preliminary recommendation by an FDA advisory committee and will likely receive final approval in the near future. Unlike the antiresorptive agents, sodium fluoride stimulates bone formation through a direct effect on osteoblasts.

Calcium and Vitamin D Supplementation
Role in Clinical Practice. Adequate calcium intake of 1,000 to 1,500 mg/day (see Table 1) and sufficient vitamin D intake are fundamental to all prevention and treatment programs for postmenopausal osteoporosis. Calcium and vitamin D supplementation is recommended whenever dietary intake is inadequate or restricted to less than the recommended amount. Supplementation should also be prescribed as part of any prevention or treatment program when needed to ensure sufficient daily calcium intake.

Available Forms and Recommended Dosing.The available forms and recommended dosages of calcium supplements are outlined in Table 6. When prescribing calcium, the physician should consider the individual patient's dietary habits and prescribe the dosage necessary to raise the daily calcium intake to the recommended level. The typical patient does not need concomitant magnesium supplementation.

To minimize gastrointestinal side effects and enhance absorption, patients should take calcium with meals and with a bedtime snack. The bedtime dosage may also counteract the parathyroid hormone-mediated calcium mobilization and excretion that occur during the overnight fast.

Efficacy. Calcium (0.5-2 g/day) and vitamin D (400 IU/day) supplementation can reduce the rate of bone loss in older women (>5 years postmenopausal). Fracture reduction efficacy of calcium and vitamin D supplementation, administered independently, has been demonstrated in women older than 75 years of age.

Side Effects. The most common side effect is constipation. Hypercalciuria is unusual at dosages of < OR = 1.5 g/day.

Contraindications. Patients with hypercalciuria should not receive calcium supplementation.

Duration of Treatment. Calcium and vitamin D supplementation can be administered safely to most women for an entire lifetime.

Estrogen Replacement Therapy
Role in Clinical Practice. In the United States, ERT is the standard of care for preventing and treating postmenopausal bone loss and should be considered for all estrogen-deficient women without contraindications. Progestin should be administered concomitantly in women who have not undergone hysterectomy.

Available Forms and Recommended Dosing. A continuous daily estrogen regimen is recommended to prevent estrogen-deficiency symptoms and to promote compliance. The available dosages of estrogens indicated for preventing or treating osteoporosis are outlined in Table 7, and the available progestins and combined progestin-estrogen preparations are summarized in Table 8.

For maximal skeletal protection, therapy should begin at the time of menopause or oophorectomy, although therapy can be initiated at any time after menopause. Studies indicate that correction of estrogen deficiency at any age prevents or slows bone loss in postmenopausal women with osteoporosis (8,9). The effect of estrogen therapy during a 2-year period in postmenopausal women (mean duration since menopause = 14.6 years) with 1,500-mg daily intake of calcium ensured by diet and supplementation is shown in Figure 4 (8).

Fig.4. Mean changes in bone mineral density of the lumbar spine in postmenopausal women with daily calcium intake of 1,500 mg for a 2 year period. Open triangle = with conjugated estrogens, 0.625 mg/day (N = 22; mean age = 62.3 years). Closed Circles = without estrogens (N = 18; mean age = 61.4 years). (Reproduced from Lindsay R, Tohme J. estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol. 1990;76:292. By permission of the American College of Obstetricians and Gynecologists).

[figure 4]

 

 

Efficacy. Epidemiologic evidence indicates that most women exposed to estrogen therapy for 7 to 10 years or longer have a 50% or greater reduction in the incidence of osteoporotic fractures (1,10). Long-term estrogen users may still experience senile bone loss, and continued estrogen therapy may be less likely to arrest bone loss or prevent fractures in women after age 75 years (11,12). A pooled estimate of the relative risk of hip fracture comparing estrogen users with nonusers is 0.7 (95% confidence interval) (1).

ERT also can confer nonskeletal benefits. For example, the lipoprotein profile can be altered beneficially. A significant increase in serum high-density lipoprotein and significant decreases in serum total cholesterol and low-density lipoproteins are associated with conjugated estrogen therapy (13,14). Similar changes also occur with continuous combined and cyclic conjugated estrogens + medroxyprogesterone acetate therapies (13,14).

ERT is associated with a decreased incidence of cardiovascular disease. The incidence of and mortality associated with cardiovascular disease are reduced by one-third to one-half in women receiving ERT, according to retrospective studies (15-26). In addition, estrogen therapy helps to maintain normal vaginal mucosa and to reduce menopausal symptoms, such as hot flushes.

Side Effects. Among the adverse effects of estrogen therapy is an increased risk of endometrial hyperplasia. Women who have not undergone hysterectomy who receive unopposed ERT have a 20% chance of developing endometrial hyperplasia after 1 year of therapy and a 61% chance after 3 years of therapy (14). When appropriate dosages of progestin are added to the regimen, this risk diminishes and is comparable to that of women who are not taking hormone therapy (13,14).

Irregular vaginal bleeding can occur in women who have not undergone hysterectomy and who are taking a combined estrogen-progestin regimen. This risk diminishes with time, and up to 80% of women receiving a continuous combined regimen consisting of 0.625 mg of conjugated estrogens daily plus an appropriate dose of medroxyprogesterone acetate become amenorrheic within 1 year after initiation of treatment (27).

The risk of cholelithiasis is increased twofold from ERT. Moreover, fluid retention, mastalgia, abdominal pain, and headache may occur but may be ameliorated with an appropriate lowering of the dosage.

The potential for estrogen use to increase the risk of breast cancer is controversial, although some studies suggest that a slightly increased risk of breast cancer is associated with prolonged estrogen use (in excess of 5 to 15 years) and older age (28,29). There is no longer a need to administer estrogen cyclically in order to minimize this risk, and the addition of progestin does not seem to increase the risk of breast cancer, although long-term breast cancer data on combined estrogen + progestin therapy are limited (29).

Contraindications. The following factors are contraindications to estrogen or combination estrogen-progestin therapy:

  • Known or suspected pregnancy
  • Known or suspected cancer of the breast
  • Known or suspected estrogen-dependent neoplasia
  • Undiagnosed, abnormal genital bleeding
  • Active thrombophlebitis or thromboembolic disorders or a history of thrombotic disease
  • Hypersensitivity to the hormones

Side effects not tolerated by the patient, as well as a substantial and uncontrollable increase in serum triglycerides, are valid reasons for discontinuing estrogen or estrogen + progestin therapy.

Duration of Treatment. Estrogen therapy may be continued for the duration of the patient's life. Direct evidence suggests that bone loss recurs after estrogen treatment is discontinued.

 

Bisphosphonates
Role in Clinical Practice. Alendronate sodium, an aminobisphosphonate, has been approved by the FDA for the treatment of osteoporosis in postmenopausal women. Etidronate disodium is marketed in Canada and Europe, and has been used "off-label" in the United States, for the treatment of postmenopausal osteoporosis, although it has not received FDA approval for that purpose.

Alendronate sodium is an effective alternative to ERT for treating postmenopausal osteoporosis in women who cannot or will not take estrogen therapy. Its efficacy as a preventive agent is not yet known, but it may be considered for use as part of an osteoporosis prevention program in high-risk women when therapy is desired and when estrogen is not a viable alternative.

Available Forms and Recommended Dosing. Alendronate sodium is supplied in 10-mg tablets, and daily dosing of 10 mg is recommended. Alendronate sodium should be taken with plain water on an empty stomach, at least 1/2 hour before the first food, beverage, or oral medication of the day. Ingestion with food, any beverage other than plain water, or certain medications, or ingestion within 2 hours after a meal, may considerably reduce absorption.

Small, asymptomatic decreases in serum calcium and phosphate may occur with alendronate sodium therapy. Patients who received therapy experienced 48% fewer new vertebral fractures than those taking placebo new vertebral fractures occurred in 6.2% of patients who received placebo and in 3.2% of patients who received alendronate (30).

Side Effects. Side effects of alendronate are generally mild and may include gastrointestinal discomfort and headache. Safety data for longer than 3 years of treatment are not yet available.

Contraindications. Contraindications to alendronate therapy include hypersensitivity to alendronate and hypocalcemia. Hypocalcemia must be corrected before therapy is initiated, as should other disturbances of mineral metabolism. No dose adjustment is necessary for patients with mild to moderate renal insufficiency (creatinine clearance of 35 to 60 mL/min). Alendronate sodium should not be used in patients with more severe renal insufficiency.

Duration of Treatment. The therapeutic efficacy of alendronate has been demonstrated for a 3-year period. The efficacy and safety beyond 3 years have not yet been established, and it is not known how termination of treatment affects the rate of bone loss.

Calcitonin
Role in Clinical Practice. Calcitonin may produce an analgesic effect (31) and is useful during the immediate postfracture period. It is an alternative to ERT and bisphosphonate therapy for postmenopausal osteoporosis in women who cannot or will not take estrogens or a bisphosphonate. Parenteral administration is inconvenient, and tolerance and compliance are relatively poor. A need for clear clinical substantiation of the long-term effect of calcitonin on BMD and fracture reduction efficacy still exists.

Available Forms and Recommended Dosing. Calcitonin is available in sterile solution for subcutaneous or intramuscular injection as well as glass bottles for nasal administration. For induction of maximal response, 100 IU/day administered subcutaneously or intramuscularly is the commonly used injection dosage. Lower dosages of 50 IU/day or 50 IU 3 times/week, or cyclic therapy in which the standard dosage is administered in 3-month intervals (3 months on, then 3 months off), may be used to prevent vertebral bone loss. A dosage of 200 IU/day of the nasal spray is recommended to produce the same response as 100 IU/day of the parenterally administered calcitonin, although it is not known whether certain conditions such as nasal polyps affect absorption of calcitonin.

Efficacy. Parenterally administered calcitonin increases total body calcium at 1 year, followed by a trend to decreasing total body calcium at 2 years. Treatment with 50 IU on alternate days has resulted in a significant increase in vertebral BMD after 1 year in postmenopausal women with high-turnover osteoporosis (32). The therapy had no effect on femoral BMD in these patients, but patients with normal bone turnover osteoporosis experienced a significant mean decrease in femoral BMD. The effect of injection of salmon calcitonin on fracture incidence is currently unknown.

Nasal spray calcitonin is a safe and cost-effective alternative to the parenteral form. In one clinical study, 100 IU of nasal spray calcitonin increased lumbar vertebral BMD in early postmenopausal women after 1 year, and BMD remained increased over the response to placebo for up to 2 years of observation (33). No difference in BMD between the treatment and placebo groups was noted on the cortical bone of the forearm or hip after 2 years (33). Although preliminary studies reveal that the nasal spray does decrease fracture incidence (33), this response requires further documentation from a five year fracture prevention trial study currently ongoing in the United States.

Side Effects.
Common side effects of parenterally administered calcitonin, which occur in up to 10% of patients, include nausea, with or without vomiting, and local inflammatory reactions at the injection site and vascular symptoms, including flushing and tingling of the hands.

The gastrointestinal side effects noted with the parenteral form are much less common with the nasal spray form. The major side effect of the nasal spray is nasal discomfort, including rhinitis and irritation of the nasal mucosa.

Contraindications. The main contraindication to both forms of calcitonin is hypersensitivity. For patients with suspected sensitivity to the drug, skin testing is recommended before treatment.

Duration of Treatment. The optimal duration of treatment with parenteral or nasal spray calcitonin is unknown.

Concomitant Use of Therapeutic Agents
No data firmly establish an additive effect on BMD or reduced fracture risk resulting from concomitant use of estrogen-progestin, alendronate, or calcitonin. Until these data are available, AACE does not recommend concomitant use of these agents for the purpose of preventing or treating postmenopausal osteoporosis.

In clinical trials, a small number of postmenopausal women received concomitant ERT and alendronate therapy, with no related adverse experiences. These two therapies can be used concurrently for different indications.

AACE recommendations for the use of various available agents in clinical practice are summarized in Table 9.

Posture Training and Exercise
Physical therapy can help prevent falls and reduce fracture risk in patients with established osteoporosis. A qualified physiatrist can develop a program for decreasing kyphotic posture and improving overall muscle strength. Refer to the Recommended Reading section for further information.

Follow-Up
The physician should perform annual follow-up assessments of all high-risk patients and patients who are part of any osteoporosis prevention or treatment program. Follow-up assessment should include the following:

  • Interim history
  • Complete medical examination, including
  • breast and pelvic examinations mammography,
  • and Papanicolaou smear if indicated
  • Assessment of compliance and activity level
  • Assessment of stature
  • Reinforcement of the therapeutic program and evaluation of the patient's level of
  • understanding and concern

BMD Measurement
The physician should use follow-up BMD measurements to monitor changes in bone mass. With DEXA technique, a change of 5% is considered clinically significant and is usually not observed in less than 2 years. Until specific data concerning the most efficient use of DEXA become available, the following guidelines provide a basic schedule for performing follow-up BMD measurements.

For patients with normal baseline BMD (T score more than 1.5), perform a follow-up measurement every 2 to 3 years. Patients who have BMD measurements well above the minimal desirable level may not need a repeat measurement.

For patients in an osteoporosis prevention program, perform a follow-up measurement every 1 to 2 years until bone mass stabilizes. When bone mass stabilizes, perform a follow-up measurement every 2 to 3 years.

For patients on a therapeutic program, perform a follow-up measurement annually for 3 consecutive years. If bone mass has stabilized after 3 years, perform a follow-up measurement every 2 years. Otherwise, continue with annual follow-up measurements until stability is achieved.

If the patient is taking glucocorticoids or has other conditions that may affect bone mass (Table 4),annual BMD measurements may be justified until bone mass stabilizes. A more rapid rate of bone loss may be anticipated in these patients.

Medical Evaluation
An annual follow-up medical evaluation is essential for all patients. (The evaluation must include a pelvic examination, breast examination, mammography, and, if indicated, a Papanicolaou smear.) For all patients who continue estrogen therapy, endometrial biopsy, transvaginal ultrasonography, or dilation and curettage are indicated to rule out neoplastic disorders whenever prolonged (>10 days) or persistent, irregular uterine bleeding occurs.

Acknowledgment
Wyeth-Ayerst Laboratories, Merck & Co., Inc., and Procter & Gamble are gratefully acknowledged for providing financial support for these guidelines, and Herrin Communications, Brandamore, Pennsylvania, prepared the manuscript.

 

Table 1
Recommended Daily Calcium Intake for Various Populations

Population

US RDA (mg)*

Consensus Development Conference(mg)**

NIH Consensus Development Conference (mg)***

Children 800 Not provided 800-1,200
Adolescents
and young adults
1,200 1,200 1,200-1,500
Adults 800 1,000 1,000
Postmenopausal
women
800 1,500 <65 yr: With ERT/HRT-1,000
Without ERT/HRT-1,500
>65 yr: All women-1,500

*RDA = recommended dietary allowance. Divided doses are advised.
**Sponsored by the European Foundation for Osteoporosis and Bone Disease, the National Osteoporosis Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, April 1-2, 1993. Recommendations are for white women only.
***Convened by the National Institute of Arthritis and Musculoskeletal and Skin Diseases with the Office of Medical Applications of Research of the National Institutes of Health, June 6-8, 1994. Cosponsored by the Office of Research on Women s Health; Office of the Director, National Institute on Aging; National Cancer Institute; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; and National Institute of Dental Research. ERT = estrogen replacement therapy; HRT = hormone replacement therapy.

 

Table 2
Calcium Content of Various Calcium-Rich Foods

Food

Serving size

Calcium per serving (mg)*

Dairy products:    
Milk* 1 cup 290-300
Swiss cheese 1 oz (slice) 250-270
Yogurt 1 cup 240-400
American cheese 1 oz (slice) 165-200
Ice cream or frozen dessert 1/2 cup 90-100
Cottage cheese 1/2 cup 80-100
Parmesan cheese 1 Tb 70
Powdered nonfat milk 1 tsp 50
Other:    
Sardines in oil (with bones) 3 oz 370
Canned salmon (with bones) 3 oz 170-210
Broccoli 1 cup 160-180
Soybean curd (tofu) 4 oz 145-155
Turnip greens 1/2 cup, cooked 100-125
Kale 1/2 cup, cooked 90-100
Corn bread 2 1/2-inch square 80-90
Egg 1 medium 55
Calcium-fortified food
(bread, cereals, fruit juices)***
1 serving 160

*A simple formula for calculating dietary calcium assigns 300 mg for the dairy-free diet, 300 mg for each serving of a dairy product (cup or slice), and 160 mg for each serving of calcium-fortified food.
**All milks (skim, 1%, 2%, and whole) have the same calcium content.
***Breads and cereals, unless fortified with calcium, are relatively low sources of calcium but still contribute substantially to calcium intake because these foods constitute such a large part of the diet.


Table 3
Preventive Measures for Decreasing the Risk of Osteoporosis in High-Risk Women

Premenopausal or perimenopausal

Postmenopausal

Elderly
Same as for postmenopausal group plus:
Identify estrogen-deficient women with low bonemass and institute therapy to preserve bone mass Identify and treat those with very low bone mass Anchor rugs
Adjust thyroid dose if needed to avoid over- replacement Identify and treat sensory defects, neurologic disease, and arthritis, which can contribute to frequency of falls

Minimize clutter
Recommend appropriate lifestyle changes, including smoking cessation, increase in weight-bearing activities, and dietary improvements Adjust dosage of drugs with sedative effects, which could slow reflexes or decrease coordination and impair patient s ability to break impact of a fall Remove loose wires
  Recommend appropriate lifestyle changes, including smoking cessation, increase in weight-bearing activities, and dietary improvements Use nonskid mats
  Minimize risk of falls and injuries with gait and balance training Install handrails in bathrooms, halls, and along stairways
    Light hallways, stairwells, and entrances
    Encourage patient to wear sturdy, low-heeled shoes

Table 4
Causes of Generalized Secondary Osteoporosis in Adults

Endocrine Disease
or
metabolic causes

Nutritional
Conditions

Drugs

Collagen
Metabolism
Disorders

Other

Hypogonadism
Hyperadrenocortism
Thyrotoxicosis
Anorexia Nervosa
Hyperprolactinemia
Systemic Mastocytosis
Porphyria
Hypophosphotasia in adults
Diabetes Mellitus, type 1
Thalassemia
Pregnancy
Hyperparathyroidism
Acromegaly
Malabsorption syndromes and Malnutrition
Chronic Liver Disease
Gastric Operations
Vitamin D Deficiency
Calcium Deficiency
Alcoholism
 
 
 
 
Vitamin D toxicity
Mephenytonin therapy
Glucocorticoids
Phenobarbital therapy
Excessive thyroid medication
 
 
 
 
 
Osteogenesis imperfecta
Homocystinuria due to cystathionine deficiency
Ehlers-Danlos syndrome
Marfan syndrome
 
 
 
 
 
Rheumatoid Arthritis
Myeloma and some cancers
Immobilization
Renal tubular acidosis
Hypercalciuria
 
 
 
 
 

Table 5
Overview of Bone Mineral Density Measurement Techniques*

Technique Precision
error (%)
Accuracy
error (%)**
Radiation effective
dose equivalent
(uSv)
Advantages and
disadvantages
Single-energy photon
absorptiometry***
Forearm
Calcaneus
1-2
2-5
<1
Very low radiation dose
Good accuracy and precision
Limited to peripheral skeleton
10-15 min scan time
Short isotope half-life, requiring regular replacement
Dual-energy x-ray
absorptiometry
Spine
Lateral lumbar spine
Proximal femur
Total body
1
2-3
1-2
1
5-8
5-10
5-8
1-2
1
5
1
3
Well-documented correlation to fracture risk
Scan time <5 min
Measures all areas
Good overall accuracy and precision (short- and long-term)
High resolution
No replacement of radioactive source
Low radiation dose
High cost
Influenced by aortic calcification and osteoarthritis at lumbar sites
Quantitative CT
Single-energy (spine)
Dual-energy (spine)
Peripheral (radius)
2-4
4-6
0.5-1
5-10
3-6
0.5-1
60
90
<2
Distinguishes between cancellous and cortical bone in spine
Good precision in radius
Relatively low precision in spine
Complex
High cost
Radiation exposure
Not well documented
Ultrasonography
Broad-band (calcaneus)
Speed of sound (calcaneus)
Speed of sound (patella)
1.6-3.8
0.3-1.9
<2
---
---
---
0
0
0
No radiation exposure
Inexpensive
Not validated as acceptable technique; precision and accuracy are uncertain
Limited to peripheral skeleton
*CT = computed tomography.
**A measure of the agreement between a test result and the true value.
***Currently being replaced by single-energy x-ray absorptiometry (SEXA). Preliminary reports suggest that this technique produces improved precision and accuracy, is more cost-effective, and emits a very low radiation dose. SEXA does not require replacement of a radiation source. SEXA requires submersion of forearm in water.

Table 6
Commercially Available Calcium Salts

Product
(% elemental Ca++)
Weight in mg
(elemental Ca++)
Tablets/day to
supply 1,000 mg
elemental Ca++
Comment
Calcium carbonate (40%)
Generic, chewable
500 (200)
600 (240)
650 (260)
1,260 (500)
1,500 (600)
5
4
4
2
2
Nonprescription
Most commonly used calcium preparation for osteoporosis
Gastrointestinal acid converts calcium carbonate to soluble calcium salts, food improves absorption in achlorhydric patients in fasting state
Caltrate 600 1,500 (600) 2 ---
Equilet, chewable 500 (200) 5 ---
Os-Cal 500, chewable 1,250 (500) 2 ---
Titralac Chewable
Extra-strength
420 (168)
750 (300)
6
4
---
Tums Chewable E-X 500 500 (200)
750 (300)
1,250 (500)
5
4
2
---
Calcium citrate (21.2%)
Citracal 950
Citracal Liquitab
Nutravescent
950 (200)
2,376 (500)
1,000
5
2
2
Nonprescription
Better absorption in fasting state than calcium carbonate
Calcium lactate (13%)
Generic
Plain
325 (42.2)
650 (84.5)
24
12
Nonprescription
Impractical because of large number of tablets required
Calcium phosphate (38%)
Posture
1,565.2 (600) 2 Nonprescription

Table 7
Available Estrogens Indicated for Prevention and Treatment of Osteoporosis

Preparation Osteoporosis indication Recommended dosing (mg/day) Available strengths (mg)
Conjugated estrogens:
Premarin tablets
Prevention and treatment 0.625* 0.3, 0.625, 0.9, 1.25, 2.5
Estradiol, micronized:
Estrace tablets
Prevention 0.5* 0.5, 1, 2
17-Estradiol:
Estraderm
transdermal patch
Prevention 0.05 0.05, 0.1
Estropipate:
Ogen tablets
Prevention 0.75* 0.75, 1.5, 3
*Although product labeling recommends cyclic therapy for osteoporosis, continuous administration is preferable when treating the perimenopausal or postmenopausal woman, to prevent cyclic recurrence of vasomotor symptoms.

Table 8
Available Progestins and Estrogen-Progestin Preparations*

Preparation FDA-cleared indications Dosage and administration
Estrogen-progestin combinations:
PremPro
PremPhase
Both preparations
Prevention of osteoporosis
Treatment of osteoporosis
Prevention and treatment of moderate to severe vasomotor symptoms
PremPro: 0.625 mg CE + 2.5 mg MPA/day for full 28-day cycle
PremPhase: 0.625 mg CE/day for full 28-day cycle + 5.0 mg MPA days 15-28 of each cycle
MPA:
Cycrin
Provera
Amen
All preparations:
Abnormal uterine bleeding due to hormonal imbalance in absence of organic pathology
All preparations:
5-10 mg/day for 5-10 days, beginning on day 16 or 21 of each cycle or
mg/day for 10 days beginning on day 16
Norethindrone acetate:
Aygestin
Norlutate
Norlutin
All preparations:
Abnormal uterine bleeding due to hormonal imbalance in absence of organic pathology
All preparations:
2.5-10 mg/day for 5-10 days during second half of "menstrual cycle" or
2.5-20 mg/day for days 5-25 of "menstrual cycle"
*CE = conjugated estrogens; FDA = Food and Drug Administration; MPA = medroxyprogesterone acetate.

Table 9
Summary of AACE Recommendations for the Use of Available Agents in Clinical Practice

Agent

Role

Calcium and vitamin D supplementation An essential component of all preventive and therapeutic programs when dietary intake is inadequate or an agent is prescribed.
Estrogen replacement therapy The first choice for preventing and treating postmenopausal osteoporosis in estrogen-deficient women. (Used with progestin in women who have not undergone hysterectomy).
Alendronate sodium An effective alternative to estrogen replacement therapy for treating postmenopausal osteoporosis in women who cannot or will not take estrogen therapy. (Should only be used as a preventive agent when therapy is indicated and estrogen replacement therapy is not a viable alternative).
Calcitonin (parenteral and nasal administration) Useful during immediate postfracture period because of analgesic effect
Recommended as an alternative to estrogen replacement and alendronate therapies for treating postmenopausal osteoporosis.

References

References
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