Linda French, MD

Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.

Bacterial vaginosis

The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).^1,2

Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).³ Single-dose therapy may improve adherence (SOR: C).

Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).^4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.⁶ Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).⁸ A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).⁹

Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).^4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).^8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).¹²

Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).¹³ Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).¹⁴ Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).

BV and pregnancy

A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).^7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).⁷ Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).¹⁵

Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.

Candidiasis

Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).¹⁶ No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).

Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview¹⁶ identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study¹⁷ comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.

Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).^18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).²² Gastrointestinal side effects occur in up to 15% of women.²³

TABLE

Antifungal medications used to treat vulvovaginal candidiasis

Treating complicated VVC

About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.²⁴ Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).²⁴ Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).²⁵

Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.^24,26

Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).^27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).²⁴ If imidazole therapy fails to control symptoms, suspect resistance.

Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.³⁰ There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).³¹ Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).²⁴

Candida in pregnancy

Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.

Trichomoniasis

Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).³² Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.^33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).³² A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).³⁵

The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.³⁶ In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).³⁷ Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).³⁸ Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).³⁹ A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).⁴⁰ Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).⁴¹

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.

Bacterial vaginosis

The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).^1,2

Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).³ Single-dose therapy may improve adherence (SOR: C).

Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).^4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.⁶ Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).⁸ A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).⁹

Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).^4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).^8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).¹²

Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).¹³ Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).¹⁴ Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).

BV and pregnancy

A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).^7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).⁷ Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).¹⁵

Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.

Candidiasis

Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).¹⁶ No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).

Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview¹⁶ identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study¹⁷ comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.

Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).^18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).²² Gastrointestinal side effects occur in up to 15% of women.²³

TABLE

Antifungal medications used to treat vulvovaginal candidiasis

Treating complicated VVC

About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.²⁴ Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).²⁴ Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).²⁵

Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.^24,26

Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).^27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).²⁴ If imidazole therapy fails to control symptoms, suspect resistance.

Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.³⁰ There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).³¹ Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).²⁴

Candida in pregnancy

Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.

Trichomoniasis

Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).³² Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.^33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).³² A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).³⁵

The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.³⁶ In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).³⁷ Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).³⁸ Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).³⁹ A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).⁴⁰ Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).⁴¹

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.

Bacterial vaginosis

The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).^1,2

Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).³ Single-dose therapy may improve adherence (SOR: C).

Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).^4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.⁶ Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).⁸ A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).⁹

Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).^4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).^8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).¹²

Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).¹³ Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).¹⁴ Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).

BV and pregnancy

A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).^7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).⁷ Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).¹⁵

Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.

Candidiasis

Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).¹⁶ No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).

Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview¹⁶ identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study¹⁷ comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.

Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).^18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).²² Gastrointestinal side effects occur in up to 15% of women.²³

TABLE

Antifungal medications used to treat vulvovaginal candidiasis

Treating complicated VVC

About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.²⁴ Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).²⁴ Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).²⁵

Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.^24,26

Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).^27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).²⁴ If imidazole therapy fails to control symptoms, suspect resistance.

Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.³⁰ There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).³¹ Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).²⁴

Candida in pregnancy

Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.

Trichomoniasis

Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).³² Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.^33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).³² A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).³⁵

The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.³⁶ In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).³⁷ Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).³⁸ Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).³⁹ A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).⁴⁰ Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).⁴¹

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

In primary care practice, abnormal vaginal discharge is a common complaint. Signs and symptoms of vaginitis—the most common gynecologic diagnosis in primary care¹ —are not specific for any single underlying cause.² Officebased diagnostic testing, which is underused,³ must be employed to ensure accurate diagnosis and effective treatment. (An article on treatment by the same authors will appear in next month’s issue of The journal of family practice.)

In a primary-care study,⁴ vulvovaginal symptoms including vaginal discharge were due to vulvovaginal candidiasis (VVC) in 27% of patients, bacterial vaginosis (BV) in 21%, trichomoniasis in 8%, Chlamydia trachomatis in 2%, Neisseria gonorrhea (GC) in 1%, and no infection in 34%. Several pathogens may coexist.² VVC, BV, and trichomoniasis account for at least 90% of infectious vaginitis.⁵ This review will therefore focus heavily on these causes of vaginal discharge among women of reproductive age, including pregnant women.

Cervicitis and physiologic cervical discharge

Some women may interpret a physiologic increase in cervical mucous production as abnormal. It occurs cyclically prior to ovulation, is typically transparent and colorless, and may be more pronounced in women with an everted cervix.

Chlamydial infection

In the clinical examination of the cervix, 3 characteristics have been associated with chlamydial infection: yellow endocervical discharge, easily induced cervical bleeding, and opaque cervical discharge.⁶ All 3 findings are statistically significant and independently associated with chlamydial infection (odds ratios 2.8, 2.3, and 2.9, respectively). In the primary care study cited above, purulent cervical discharge was found in 6% of women, most commonly testing positive for Chlamydia, less often for GC.⁴

Trichomonas vaginalis may cause cervicitis as well as vaginitis. Mycoplasma genitalium has been proposed as an additional possible pathogen. It was identified in 7% of more than 700 women with mucopurulent cervical discharge seen in a STD clinic with otherwise negative cultures.⁷ With cervical discharge that appears to be purulent, testing is warranted as a minimum for Chlamydia and GC (SOR: B). Screening of asymptomatic women less than 26 years of age for Chlamydia is recommended by the US Preventive Services Task Force (SOR: A).

Bacterial Vaginosis

Bacterial vaginosis (BV) is neither an inflammatory condition nor an STD, but is a shift in vaginal flora from the normal condition in which lactobacilli predominate, to a polymicrobial flora in which gram-positive anaerobes predominate. In addition to annoying vaginal symptoms, BV is associated with increased risks of more serious conditions such as pelvic inflammatory disease (PID), postoperative infections, and pregnancyrelated complications including prematurity. It also increases the likelihood of acquiring HIV in women exposed to the virus.^8,9

Two principal factors put women at risk for acquiring BV: douching and exposure to a new sexual partner, both of which are thought to disrupt the vaginal ecosystem.¹⁰

Relative benefits of diagnostic tests

A gold standard test has not been established for BV. In about 50% of asymptomatic women, culture results are positive for flora such as Gardnerella vaginalis.⁵ While Amsel’s criteria are often used as a reference and generally suffice for the evaluation of symptomatic women, the best candidate for a gold standard test is probably Gram stain assessment using Nugent’s criteria (described in this section).¹¹ Lack of leukocytes in the vaginal fluid supports a diagnosis of BV. A finding of white blood cells in excess of the number of vaginal epithelial cells suggests an inflammatory process (SOR: C).¹²

Amsel’s criteria with wet mount. The diagnostic approach most commonly used in the office is Amsel’s criteria—homogenous discharge, positive whiff-amine test, pH >4.5, and clue cells found on wet-mount microscopy (see How to perform a wet mount ).¹³ Three of 4 criteria deemed positive is considered diagnostic. If Gram stain is used as the reference standard, then Amsel’s criteria have 70% sensitivity and 94% specificity for diagnosing BV.¹⁴ An analysis of the individual criteria follows. The positive and negative predictive values of each compared with the whole group as reference standard is displayed in Table 1 .

Homogenous discharge. A thin, homogenous, grayish discharge is traditionally associated with BV. However, it is not specific to BV, being found commonly also in women with culture results positive for VVC or no diagnosis of vaginitis.^2,15 It is the criterion least likely to be consistent with the whole group, seen in about half of women BVpositive and over one third of women BV-negative using Amsel’s criteria as the reference standard. ¹⁵

Whiff test. The whiff test is performed by adding drops of 10% potassium hydroxide solution to the vaginal fluid. A positive result is a “fishy” amine odor. In a study¹⁶ of 100 women complaining of malodorous discharge, a positive whiff test was predictive of positive culture results for anaerobic flora such as Bacteroides sp. with sensitivity 67%, specificity 94%, and a positive predictive value of 95%. The whiff test was not positive in any of the 5 cases with positive culture results for G vaginalis in the absence of anaerobes. There were also 12 cases positive for anaerobes without G vaginalis.

pH >4.5. Since the abnormal flora of BV is consistently associated with a vaginal pH >4.5, a normal pH excludes a diagnosis of BV.^17,18 The determination of pH in the narrow range around 4.5 is not accurate using standard nitrazine paper. Narrower-range test paper is available and more accurate. Examples include pH paper for 4.5 to 5.5 (Micro Essential Laboratory), FemExam pH and Amines Test Card (Litmus Concepts), pHem-ALERT: pH paper on a stick (Imagyn Gynecology). Cervical mucous, semen, and blood are alkaline and can interfere with pH testing. Estrogen production is also necessary to maintain an acidic environment. A pH of 3.8 to 4.5 is consistent with normal vaginal flora in premenopausal women with normal estrogen production.¹⁷

Clue cells. Clue cells are vaginal epithelial cells coated with coccobacilli giving an appearance as if coated with ground black pepper. Clue cells on wet mount preparation is considered the most accurate of Amsel’s diagnostic criteria for BV.¹⁹ On the other hand, office evaluation of the wet mount is considered by some authors to be unreliable due to dependence on the clinician’s microscopy skills and lack of a durable record of the patient sample.

Gram stain a more objective test. A Gram stain evaluation using Nugent’s criteria has been adopted as the gold standard test for research purposes, including studies of prematurity. The Gram-stained vaginal specimen is scored from 0 to 10 based on semi-quantitative assessment of 3 classes of morphotypes ( Table 2 ): large gram-positive rods (Lactobacilli), small gram-negative rods (Gardnerella and Bacteroides spp.), and small curved gram-variable rods (Mobiluncus spp.).¹¹

Diagnosis of BV is typically made when the Nugent score is 7 or more, which appears qualitatively as dominant morphotypes other than Lactobacilli. Gram staining is more objective and reproducible compared with wet-mount examination, with a sensitivity of 93% and specificity of 70% if Amsel’s criteria are used as the gold standard.¹⁴ It is useful for the evaluation of asymptomatic women. It also provides a durable record of the patient specimen. Compared with Gram stain, Amsel’s criteria tend to underdiagnose cases. We can expect that if screening for BV in pregnancy becomes a recommendation, Gram staining in a clinical laboratory will be the recommended method of diagnosis.

Other diagnostic tests for BV. DNA testing for Gardnerella is accurate for detection, but it is not synonymous with a diagnosis of BV, as described.²⁰ DNA testing is further described under “Differential Diagnosis.” Gram staining is more reliable than gas-liquid chromatography²¹ and an assay for proline aminopeptidase (a metabolic product of some of the bacteria associated with BV).²² Latex agglutination testing for vaginal lactoferrin is a nonspecific marker for leukocytes, and thus inflammation. It is of little clinical utility in the diagnosis of vaginal discharge.²³

TABLE 1
Predictive values of Amsel’s criteria (using 3 of 4 positive as diagnostic reference standard)

TABLE 2
How to use Nugent’s Gram stain criteria to diagnose bacterial vaginosis

Vulvovaginal Candidiasis

Candidiasis is the second most commonly diagnosed vaginitis in the United States. Some experts estimate that 75% of women will have a yeast infection at some point in life and 5% will have recurrent infections.²⁴ However, 10% to 30% of asymptomatic women with normal flora have positive culture results for Candida.^25-29 The proportion of symptomatic women with positive culture results is 20% to 40%.^4,30,31 Complications of VVC are rare,³² though vulvar vestibulitis³³ and chorioamnionitis in pregnancy³² have been reported.

Risk factors. Symptomatic yeast vaginitis has been associated with condom and diaphragm use, recent antibiotic use, receptive oral sex, oral contraceptive use, spermicide use, diabetes, and immunosuppression including AIDS.^31,34-37 The associations with antibiotic use and oral contraceptives are not consistent.^30,38 Although pregnancy has been postulated as a risk factor for symptomatic VVC, prevalence of yeast on culture in pregnant women is similar to that of nonpregnant women.³⁰

Suggestive symptoms. Among women with a culture result positive for Candida, the most common symptom is pruritus or burning.²⁸ Abnormal discharge is a complaint for most symptomatic women with VVC confirmed by culture.² In addition, women may complain of a thick, odorless, cottage cheese–like discharge.³⁹ A thick, curdled-appearing discharge points to a diagnosis of Candida because it is rarely present with BV or trichomoniasis. In one study,²⁸ a thick curdled discharge had a positive predictive value of 84% for diagnosis of VVC by culture (SOR: B). However, a thin discharge does not rule out VVC; in another study, clinicians described discharge as thin in about half of women ultimately diagnosed with VVC by culture in another study (SOR: B).² On exam, vulvar and vaginal erythema are often present but are not specific findings. The accuracy of the clinical exam for VVC is poor compared with culture (SOR: A).^2,30

Pathogens. Candida albicans is present in 80% to 90% of patients with VVC.^5,40 remainder have non-albicans species, including C glabrata and others.²⁸ An increase to almost 20% of non-Candida species in a vaginitis clinic by the mid-1990’s may be related to increased use of imidazoles available over-the-counter.^40,41 Wet mount results are typically negative in the presence of non-Candida VVC.²⁸

Diagnosis of VVC

The gold standard test for diagnosis of VVC is culture. The potassium hydroxide (KOH) wet mount is only 40% to 75% sensitive.^28,29,42,43 False-positive results are also observed with variable frequency.⁴⁴ The pH of the discharge is usually not more than 5.0 with Candida albicans, but may be higher with non-albicans species such as C glabrata.⁴⁵ Culture is recommended for patients with recurrent or persistent symptoms and a negative wet mount result (SOR: B).^5,28,46 Rapid slide latex agglutination testing is not better than microscopy (SOR: B).⁴²

Trichomoniasis

Trichomonas, a motile protozoan with 4 flagella, causes the third most common form of vaginitis in the United States and is more common in some developing countries. Trichomoniasis accounts for no more than 10% of all cases of vaginitis, and it appears to be decreasing since the introduction of metronidazole.^47,48 It is classified as an STD, although transmission is possible by other means if the organism is protected from desiccation—for example, in dirty washcloths or towels and contaminated water. Nonsexual transmission is thought to be uncommon.

Trichomoniasis is associated with GC and Chlamydia infections, and, like them, has been associated with seroconversion to HIV-positive status.⁴⁹ Trichomonads are identified in 30% to 80% of male sexual partners of infected women. In men, trichomoniasis most often is an asymptomatic carrier state.⁵⁰ However, it is the cause of about 10% of cases of nongonococcal urethritis in men.⁵¹

Clinical presentations. Women with trichomoniasis have variable presentations ranging from an asymptomatic carrier state to a malodorous, purulent discharge with vulvovaginal erythema. Punctate hemorrhagic cervical lesions are considered pathognomonic of trichomoniasis, but are seen in only about 2% of cases (SOR: B).⁵²

Diagnosis. Culture for trichomoniasis is the gold standard. Several culture media have been used, most commonly the Diamond medium. Recently introduced is a transport and culture medium for detection of Trichomonas (InPouch TV), which performs as well as Diamond medium (SOR: A).^53-55 A DNA probe is also available and accurate (SOR: A).

Motile trichomonads are seen on wet preparation in only 50% to 80% of culture-positive cases (SOR: B).^50,54,56 Polymorphonuclear leukocytes can be dominant on wet mount, making visualization of trichomonads more difficult. The pH of the vaginal fluid is usually basic.

Trichomonas reported with cervical cytology

Trichomonas may also be reported on Pap smears. A meta-analysis⁵⁷ comparing the pooled sensitivities and specificities of wet mounts and cytology demonstrated low sensitivities of 68% and 58%, respectively, and high specificities, 99.9% and 97%, respectively (SOR: A).

However, since cytology carries a 3% false-positive rate, its results are not diagnostic of trichomoniasis in low-risk, asymptomatic women.^50,57 Treatment may be prescribed empirically based on positive cytology results. However, if an asymptomatic woman were concerned about whether she really has an STD, a positive wet prep would confirm the diagnosis. A negative wet prep should be followed up with culture to reliably rule out disease (SOR: B).

Trichomoniasis in pregnancy

Screening for asymptomatic trichomoniasis in pregnancy has not been recommended. In fact, some evidence suggests that treatment of trichomoniasis in pregnancy is associated with poorer pregnancy outcomes including lower birth weight and more prematurity (SOR: B).^58,59

Aerobic vaginitis

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with predominance of abnormal aerobic flora.⁶⁰ Aerobic vaginitis, which may be severe, has been reported as the cause of 5% of cases in a series from a specialty vaginitis clinic.⁶¹ The usual predominant microorganisms are group B streptococci, Escherichia coli, and Staphylococcus aureus. It is likely that less severe cases of aerobic vaginitis are not recognized in the primary care setting and are treated as BV or resolve spontaneously (SOR: C). The case series referred to above also reported good therapeutic response to 2% topical clindamycin (SOR: C).⁶¹

Noninfectious Vaginitis

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic, cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease, and idiopathic vaginitis.

Irritant and allergic vaginitis may result from sensitivities to topical medications, the active or base ingredients of spermicidal products, douching solutions, and the latex of condoms or diaphragms. If a woman with persistent symptoms has been using such intravaginal products, she should stop (SOR: C).

Cytolytic vaginitis is characterized by overgrowth of lactobacilli and cytolysis of squamous cells, including presence of cytoplasmic fragments and intact cells with naked nuclei.⁶² The cause is uncertain but may include a reaction to intravaginal medications or other products such as tampons. It can be found in up to 5% of women with symptoms and signs of vaginitis.^62,63 Symptoms often mimic VVC and may include a white, cheesy discharge. Vaginal pH ranges from 3.5 to 5.5. Recurrences during luteal phase of the menstrual cycle have been described.⁶⁴ Intravaginal antifungals should be discontinued. Baking soda sitz baths or douches are often used, but clinical trial data to support this practice are lacking (SOR: C).

Noninfectious desquamative inflammatory vaginitis (DIV) has also been described.⁶⁵ DIV is an uncommon vaginitis characterized by profuse purulent discharge with epithelial cell exfoliation. It may occur at any time during the reproductive years or after menopause. There is probably a heterogeneous group of causes of DIV. Some cases may correspond to a disorder within the spectrum of lichen planus.⁶⁶ Treatment is usually difficult, though there may be some response to local or systemic corticosteroid therapy (SOR: C).⁶⁵

Differential diagnosis

A comparison of physical examination findings an diagnostic test results for various etiologies of vaginitis is summarized in Table 3 . An algorithmic approach to the differential diagnosis of abnormal vaginal discharge is presented in the Figure . Diagnosis is complicated in that signs and symptoms do little to help differentiate among BV, VVC, and trichomoniasis. A study² of 22 genitourinary symptoms and signs showed that none differentiated among the 3 infections. This lack of clear-cut differences in symptoms also makes self-diagnosis and telephone triage inaccurate.^67,68

A DNA probe testing system (Affirm VP III Microbial ID Test) for differential diagnosis is available but expensive. It identifies Gardnerella, Trichomonas, and Candida albicans with a sensitivity of 90% to 95%.^54,66 The analyzer costs approximately $10,000 and would typically be purchased by a laboratory. Individual test kits cost about $27.

TABLE 3
Comparative findings among causes of vaginitis

FIGURE
Sequence of office tests to evaluate abnormal vaginal discharge

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

In primary care practice, abnormal vaginal discharge is a common complaint. Signs and symptoms of vaginitis—the most common gynecologic diagnosis in primary care¹ —are not specific for any single underlying cause.² Officebased diagnostic testing, which is underused,³ must be employed to ensure accurate diagnosis and effective treatment. (An article on treatment by the same authors will appear in next month’s issue of The journal of family practice.)

In a primary-care study,⁴ vulvovaginal symptoms including vaginal discharge were due to vulvovaginal candidiasis (VVC) in 27% of patients, bacterial vaginosis (BV) in 21%, trichomoniasis in 8%, Chlamydia trachomatis in 2%, Neisseria gonorrhea (GC) in 1%, and no infection in 34%. Several pathogens may coexist.² VVC, BV, and trichomoniasis account for at least 90% of infectious vaginitis.⁵ This review will therefore focus heavily on these causes of vaginal discharge among women of reproductive age, including pregnant women.

Cervicitis and physiologic cervical discharge

Some women may interpret a physiologic increase in cervical mucous production as abnormal. It occurs cyclically prior to ovulation, is typically transparent and colorless, and may be more pronounced in women with an everted cervix.

Chlamydial infection

In the clinical examination of the cervix, 3 characteristics have been associated with chlamydial infection: yellow endocervical discharge, easily induced cervical bleeding, and opaque cervical discharge.⁶ All 3 findings are statistically significant and independently associated with chlamydial infection (odds ratios 2.8, 2.3, and 2.9, respectively). In the primary care study cited above, purulent cervical discharge was found in 6% of women, most commonly testing positive for Chlamydia, less often for GC.⁴

Trichomonas vaginalis may cause cervicitis as well as vaginitis. Mycoplasma genitalium has been proposed as an additional possible pathogen. It was identified in 7% of more than 700 women with mucopurulent cervical discharge seen in a STD clinic with otherwise negative cultures.⁷ With cervical discharge that appears to be purulent, testing is warranted as a minimum for Chlamydia and GC (SOR: B). Screening of asymptomatic women less than 26 years of age for Chlamydia is recommended by the US Preventive Services Task Force (SOR: A).

Bacterial Vaginosis

Bacterial vaginosis (BV) is neither an inflammatory condition nor an STD, but is a shift in vaginal flora from the normal condition in which lactobacilli predominate, to a polymicrobial flora in which gram-positive anaerobes predominate. In addition to annoying vaginal symptoms, BV is associated with increased risks of more serious conditions such as pelvic inflammatory disease (PID), postoperative infections, and pregnancyrelated complications including prematurity. It also increases the likelihood of acquiring HIV in women exposed to the virus.^8,9

Two principal factors put women at risk for acquiring BV: douching and exposure to a new sexual partner, both of which are thought to disrupt the vaginal ecosystem.¹⁰

Relative benefits of diagnostic tests

A gold standard test has not been established for BV. In about 50% of asymptomatic women, culture results are positive for flora such as Gardnerella vaginalis.⁵ While Amsel’s criteria are often used as a reference and generally suffice for the evaluation of symptomatic women, the best candidate for a gold standard test is probably Gram stain assessment using Nugent’s criteria (described in this section).¹¹ Lack of leukocytes in the vaginal fluid supports a diagnosis of BV. A finding of white blood cells in excess of the number of vaginal epithelial cells suggests an inflammatory process (SOR: C).¹²

Amsel’s criteria with wet mount. The diagnostic approach most commonly used in the office is Amsel’s criteria—homogenous discharge, positive whiff-amine test, pH >4.5, and clue cells found on wet-mount microscopy (see How to perform a wet mount ).¹³ Three of 4 criteria deemed positive is considered diagnostic. If Gram stain is used as the reference standard, then Amsel’s criteria have 70% sensitivity and 94% specificity for diagnosing BV.¹⁴ An analysis of the individual criteria follows. The positive and negative predictive values of each compared with the whole group as reference standard is displayed in Table 1 .

Homogenous discharge. A thin, homogenous, grayish discharge is traditionally associated with BV. However, it is not specific to BV, being found commonly also in women with culture results positive for VVC or no diagnosis of vaginitis.^2,15 It is the criterion least likely to be consistent with the whole group, seen in about half of women BVpositive and over one third of women BV-negative using Amsel’s criteria as the reference standard. ¹⁵

Whiff test. The whiff test is performed by adding drops of 10% potassium hydroxide solution to the vaginal fluid. A positive result is a “fishy” amine odor. In a study¹⁶ of 100 women complaining of malodorous discharge, a positive whiff test was predictive of positive culture results for anaerobic flora such as Bacteroides sp. with sensitivity 67%, specificity 94%, and a positive predictive value of 95%. The whiff test was not positive in any of the 5 cases with positive culture results for G vaginalis in the absence of anaerobes. There were also 12 cases positive for anaerobes without G vaginalis.

pH >4.5. Since the abnormal flora of BV is consistently associated with a vaginal pH >4.5, a normal pH excludes a diagnosis of BV.^17,18 The determination of pH in the narrow range around 4.5 is not accurate using standard nitrazine paper. Narrower-range test paper is available and more accurate. Examples include pH paper for 4.5 to 5.5 (Micro Essential Laboratory), FemExam pH and Amines Test Card (Litmus Concepts), pHem-ALERT: pH paper on a stick (Imagyn Gynecology). Cervical mucous, semen, and blood are alkaline and can interfere with pH testing. Estrogen production is also necessary to maintain an acidic environment. A pH of 3.8 to 4.5 is consistent with normal vaginal flora in premenopausal women with normal estrogen production.¹⁷

Clue cells. Clue cells are vaginal epithelial cells coated with coccobacilli giving an appearance as if coated with ground black pepper. Clue cells on wet mount preparation is considered the most accurate of Amsel’s diagnostic criteria for BV.¹⁹ On the other hand, office evaluation of the wet mount is considered by some authors to be unreliable due to dependence on the clinician’s microscopy skills and lack of a durable record of the patient sample.

Gram stain a more objective test. A Gram stain evaluation using Nugent’s criteria has been adopted as the gold standard test for research purposes, including studies of prematurity. The Gram-stained vaginal specimen is scored from 0 to 10 based on semi-quantitative assessment of 3 classes of morphotypes ( Table 2 ): large gram-positive rods (Lactobacilli), small gram-negative rods (Gardnerella and Bacteroides spp.), and small curved gram-variable rods (Mobiluncus spp.).¹¹

Diagnosis of BV is typically made when the Nugent score is 7 or more, which appears qualitatively as dominant morphotypes other than Lactobacilli. Gram staining is more objective and reproducible compared with wet-mount examination, with a sensitivity of 93% and specificity of 70% if Amsel’s criteria are used as the gold standard.¹⁴ It is useful for the evaluation of asymptomatic women. It also provides a durable record of the patient specimen. Compared with Gram stain, Amsel’s criteria tend to underdiagnose cases. We can expect that if screening for BV in pregnancy becomes a recommendation, Gram staining in a clinical laboratory will be the recommended method of diagnosis.

Other diagnostic tests for BV. DNA testing for Gardnerella is accurate for detection, but it is not synonymous with a diagnosis of BV, as described.²⁰ DNA testing is further described under “Differential Diagnosis.” Gram staining is more reliable than gas-liquid chromatography²¹ and an assay for proline aminopeptidase (a metabolic product of some of the bacteria associated with BV).²² Latex agglutination testing for vaginal lactoferrin is a nonspecific marker for leukocytes, and thus inflammation. It is of little clinical utility in the diagnosis of vaginal discharge.²³

TABLE 1
Predictive values of Amsel’s criteria (using 3 of 4 positive as diagnostic reference standard)

TABLE 2
How to use Nugent’s Gram stain criteria to diagnose bacterial vaginosis

Vulvovaginal Candidiasis

Candidiasis is the second most commonly diagnosed vaginitis in the United States. Some experts estimate that 75% of women will have a yeast infection at some point in life and 5% will have recurrent infections.²⁴ However, 10% to 30% of asymptomatic women with normal flora have positive culture results for Candida.^25-29 The proportion of symptomatic women with positive culture results is 20% to 40%.^4,30,31 Complications of VVC are rare,³² though vulvar vestibulitis³³ and chorioamnionitis in pregnancy³² have been reported.

Risk factors. Symptomatic yeast vaginitis has been associated with condom and diaphragm use, recent antibiotic use, receptive oral sex, oral contraceptive use, spermicide use, diabetes, and immunosuppression including AIDS.^31,34-37 The associations with antibiotic use and oral contraceptives are not consistent.^30,38 Although pregnancy has been postulated as a risk factor for symptomatic VVC, prevalence of yeast on culture in pregnant women is similar to that of nonpregnant women.³⁰

Suggestive symptoms. Among women with a culture result positive for Candida, the most common symptom is pruritus or burning.²⁸ Abnormal discharge is a complaint for most symptomatic women with VVC confirmed by culture.² In addition, women may complain of a thick, odorless, cottage cheese–like discharge.³⁹ A thick, curdled-appearing discharge points to a diagnosis of Candida because it is rarely present with BV or trichomoniasis. In one study,²⁸ a thick curdled discharge had a positive predictive value of 84% for diagnosis of VVC by culture (SOR: B). However, a thin discharge does not rule out VVC; in another study, clinicians described discharge as thin in about half of women ultimately diagnosed with VVC by culture in another study (SOR: B).² On exam, vulvar and vaginal erythema are often present but are not specific findings. The accuracy of the clinical exam for VVC is poor compared with culture (SOR: A).^2,30

Pathogens. Candida albicans is present in 80% to 90% of patients with VVC.^5,40 remainder have non-albicans species, including C glabrata and others.²⁸ An increase to almost 20% of non-Candida species in a vaginitis clinic by the mid-1990’s may be related to increased use of imidazoles available over-the-counter.^40,41 Wet mount results are typically negative in the presence of non-Candida VVC.²⁸

Diagnosis of VVC

The gold standard test for diagnosis of VVC is culture. The potassium hydroxide (KOH) wet mount is only 40% to 75% sensitive.^28,29,42,43 False-positive results are also observed with variable frequency.⁴⁴ The pH of the discharge is usually not more than 5.0 with Candida albicans, but may be higher with non-albicans species such as C glabrata.⁴⁵ Culture is recommended for patients with recurrent or persistent symptoms and a negative wet mount result (SOR: B).^5,28,46 Rapid slide latex agglutination testing is not better than microscopy (SOR: B).⁴²

Trichomoniasis

Trichomonas, a motile protozoan with 4 flagella, causes the third most common form of vaginitis in the United States and is more common in some developing countries. Trichomoniasis accounts for no more than 10% of all cases of vaginitis, and it appears to be decreasing since the introduction of metronidazole.^47,48 It is classified as an STD, although transmission is possible by other means if the organism is protected from desiccation—for example, in dirty washcloths or towels and contaminated water. Nonsexual transmission is thought to be uncommon.

Trichomoniasis is associated with GC and Chlamydia infections, and, like them, has been associated with seroconversion to HIV-positive status.⁴⁹ Trichomonads are identified in 30% to 80% of male sexual partners of infected women. In men, trichomoniasis most often is an asymptomatic carrier state.⁵⁰ However, it is the cause of about 10% of cases of nongonococcal urethritis in men.⁵¹

Clinical presentations. Women with trichomoniasis have variable presentations ranging from an asymptomatic carrier state to a malodorous, purulent discharge with vulvovaginal erythema. Punctate hemorrhagic cervical lesions are considered pathognomonic of trichomoniasis, but are seen in only about 2% of cases (SOR: B).⁵²

Diagnosis. Culture for trichomoniasis is the gold standard. Several culture media have been used, most commonly the Diamond medium. Recently introduced is a transport and culture medium for detection of Trichomonas (InPouch TV), which performs as well as Diamond medium (SOR: A).^53-55 A DNA probe is also available and accurate (SOR: A).

Motile trichomonads are seen on wet preparation in only 50% to 80% of culture-positive cases (SOR: B).^50,54,56 Polymorphonuclear leukocytes can be dominant on wet mount, making visualization of trichomonads more difficult. The pH of the vaginal fluid is usually basic.

Trichomonas reported with cervical cytology

Trichomonas may also be reported on Pap smears. A meta-analysis⁵⁷ comparing the pooled sensitivities and specificities of wet mounts and cytology demonstrated low sensitivities of 68% and 58%, respectively, and high specificities, 99.9% and 97%, respectively (SOR: A).

However, since cytology carries a 3% false-positive rate, its results are not diagnostic of trichomoniasis in low-risk, asymptomatic women.^50,57 Treatment may be prescribed empirically based on positive cytology results. However, if an asymptomatic woman were concerned about whether she really has an STD, a positive wet prep would confirm the diagnosis. A negative wet prep should be followed up with culture to reliably rule out disease (SOR: B).

Trichomoniasis in pregnancy

Screening for asymptomatic trichomoniasis in pregnancy has not been recommended. In fact, some evidence suggests that treatment of trichomoniasis in pregnancy is associated with poorer pregnancy outcomes including lower birth weight and more prematurity (SOR: B).^58,59

Aerobic vaginitis

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with predominance of abnormal aerobic flora.⁶⁰ Aerobic vaginitis, which may be severe, has been reported as the cause of 5% of cases in a series from a specialty vaginitis clinic.⁶¹ The usual predominant microorganisms are group B streptococci, Escherichia coli, and Staphylococcus aureus. It is likely that less severe cases of aerobic vaginitis are not recognized in the primary care setting and are treated as BV or resolve spontaneously (SOR: C). The case series referred to above also reported good therapeutic response to 2% topical clindamycin (SOR: C).⁶¹

Noninfectious Vaginitis

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic, cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease, and idiopathic vaginitis.

Irritant and allergic vaginitis may result from sensitivities to topical medications, the active or base ingredients of spermicidal products, douching solutions, and the latex of condoms or diaphragms. If a woman with persistent symptoms has been using such intravaginal products, she should stop (SOR: C).

Cytolytic vaginitis is characterized by overgrowth of lactobacilli and cytolysis of squamous cells, including presence of cytoplasmic fragments and intact cells with naked nuclei.⁶² The cause is uncertain but may include a reaction to intravaginal medications or other products such as tampons. It can be found in up to 5% of women with symptoms and signs of vaginitis.^62,63 Symptoms often mimic VVC and may include a white, cheesy discharge. Vaginal pH ranges from 3.5 to 5.5. Recurrences during luteal phase of the menstrual cycle have been described.⁶⁴ Intravaginal antifungals should be discontinued. Baking soda sitz baths or douches are often used, but clinical trial data to support this practice are lacking (SOR: C).

Noninfectious desquamative inflammatory vaginitis (DIV) has also been described.⁶⁵ DIV is an uncommon vaginitis characterized by profuse purulent discharge with epithelial cell exfoliation. It may occur at any time during the reproductive years or after menopause. There is probably a heterogeneous group of causes of DIV. Some cases may correspond to a disorder within the spectrum of lichen planus.⁶⁶ Treatment is usually difficult, though there may be some response to local or systemic corticosteroid therapy (SOR: C).⁶⁵

Differential diagnosis

A comparison of physical examination findings an diagnostic test results for various etiologies of vaginitis is summarized in Table 3 . An algorithmic approach to the differential diagnosis of abnormal vaginal discharge is presented in the Figure . Diagnosis is complicated in that signs and symptoms do little to help differentiate among BV, VVC, and trichomoniasis. A study² of 22 genitourinary symptoms and signs showed that none differentiated among the 3 infections. This lack of clear-cut differences in symptoms also makes self-diagnosis and telephone triage inaccurate.^67,68

A DNA probe testing system (Affirm VP III Microbial ID Test) for differential diagnosis is available but expensive. It identifies Gardnerella, Trichomonas, and Candida albicans with a sensitivity of 90% to 95%.^54,66 The analyzer costs approximately $10,000 and would typically be purchased by a laboratory. Individual test kits cost about $27.

TABLE 3
Comparative findings among causes of vaginitis

FIGURE
Sequence of office tests to evaluate abnormal vaginal discharge

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

In primary care practice, abnormal vaginal discharge is a common complaint. Signs and symptoms of vaginitis—the most common gynecologic diagnosis in primary care¹ —are not specific for any single underlying cause.² Officebased diagnostic testing, which is underused,³ must be employed to ensure accurate diagnosis and effective treatment. (An article on treatment by the same authors will appear in next month’s issue of The journal of family practice.)

In a primary-care study,⁴ vulvovaginal symptoms including vaginal discharge were due to vulvovaginal candidiasis (VVC) in 27% of patients, bacterial vaginosis (BV) in 21%, trichomoniasis in 8%, Chlamydia trachomatis in 2%, Neisseria gonorrhea (GC) in 1%, and no infection in 34%. Several pathogens may coexist.² VVC, BV, and trichomoniasis account for at least 90% of infectious vaginitis.⁵ This review will therefore focus heavily on these causes of vaginal discharge among women of reproductive age, including pregnant women.

Cervicitis and physiologic cervical discharge

Some women may interpret a physiologic increase in cervical mucous production as abnormal. It occurs cyclically prior to ovulation, is typically transparent and colorless, and may be more pronounced in women with an everted cervix.

Chlamydial infection

In the clinical examination of the cervix, 3 characteristics have been associated with chlamydial infection: yellow endocervical discharge, easily induced cervical bleeding, and opaque cervical discharge.⁶ All 3 findings are statistically significant and independently associated with chlamydial infection (odds ratios 2.8, 2.3, and 2.9, respectively). In the primary care study cited above, purulent cervical discharge was found in 6% of women, most commonly testing positive for Chlamydia, less often for GC.⁴

Trichomonas vaginalis may cause cervicitis as well as vaginitis. Mycoplasma genitalium has been proposed as an additional possible pathogen. It was identified in 7% of more than 700 women with mucopurulent cervical discharge seen in a STD clinic with otherwise negative cultures.⁷ With cervical discharge that appears to be purulent, testing is warranted as a minimum for Chlamydia and GC (SOR: B). Screening of asymptomatic women less than 26 years of age for Chlamydia is recommended by the US Preventive Services Task Force (SOR: A).

Bacterial Vaginosis

Bacterial vaginosis (BV) is neither an inflammatory condition nor an STD, but is a shift in vaginal flora from the normal condition in which lactobacilli predominate, to a polymicrobial flora in which gram-positive anaerobes predominate. In addition to annoying vaginal symptoms, BV is associated with increased risks of more serious conditions such as pelvic inflammatory disease (PID), postoperative infections, and pregnancyrelated complications including prematurity. It also increases the likelihood of acquiring HIV in women exposed to the virus.^8,9

Two principal factors put women at risk for acquiring BV: douching and exposure to a new sexual partner, both of which are thought to disrupt the vaginal ecosystem.¹⁰

Relative benefits of diagnostic tests

A gold standard test has not been established for BV. In about 50% of asymptomatic women, culture results are positive for flora such as Gardnerella vaginalis.⁵ While Amsel’s criteria are often used as a reference and generally suffice for the evaluation of symptomatic women, the best candidate for a gold standard test is probably Gram stain assessment using Nugent’s criteria (described in this section).¹¹ Lack of leukocytes in the vaginal fluid supports a diagnosis of BV. A finding of white blood cells in excess of the number of vaginal epithelial cells suggests an inflammatory process (SOR: C).¹²

Amsel’s criteria with wet mount. The diagnostic approach most commonly used in the office is Amsel’s criteria—homogenous discharge, positive whiff-amine test, pH >4.5, and clue cells found on wet-mount microscopy (see How to perform a wet mount ).¹³ Three of 4 criteria deemed positive is considered diagnostic. If Gram stain is used as the reference standard, then Amsel’s criteria have 70% sensitivity and 94% specificity for diagnosing BV.¹⁴ An analysis of the individual criteria follows. The positive and negative predictive values of each compared with the whole group as reference standard is displayed in Table 1 .

Homogenous discharge. A thin, homogenous, grayish discharge is traditionally associated with BV. However, it is not specific to BV, being found commonly also in women with culture results positive for VVC or no diagnosis of vaginitis.^2,15 It is the criterion least likely to be consistent with the whole group, seen in about half of women BVpositive and over one third of women BV-negative using Amsel’s criteria as the reference standard. ¹⁵

Whiff test. The whiff test is performed by adding drops of 10% potassium hydroxide solution to the vaginal fluid. A positive result is a “fishy” amine odor. In a study¹⁶ of 100 women complaining of malodorous discharge, a positive whiff test was predictive of positive culture results for anaerobic flora such as Bacteroides sp. with sensitivity 67%, specificity 94%, and a positive predictive value of 95%. The whiff test was not positive in any of the 5 cases with positive culture results for G vaginalis in the absence of anaerobes. There were also 12 cases positive for anaerobes without G vaginalis.

pH >4.5. Since the abnormal flora of BV is consistently associated with a vaginal pH >4.5, a normal pH excludes a diagnosis of BV.^17,18 The determination of pH in the narrow range around 4.5 is not accurate using standard nitrazine paper. Narrower-range test paper is available and more accurate. Examples include pH paper for 4.5 to 5.5 (Micro Essential Laboratory), FemExam pH and Amines Test Card (Litmus Concepts), pHem-ALERT: pH paper on a stick (Imagyn Gynecology). Cervical mucous, semen, and blood are alkaline and can interfere with pH testing. Estrogen production is also necessary to maintain an acidic environment. A pH of 3.8 to 4.5 is consistent with normal vaginal flora in premenopausal women with normal estrogen production.¹⁷

Clue cells. Clue cells are vaginal epithelial cells coated with coccobacilli giving an appearance as if coated with ground black pepper. Clue cells on wet mount preparation is considered the most accurate of Amsel’s diagnostic criteria for BV.¹⁹ On the other hand, office evaluation of the wet mount is considered by some authors to be unreliable due to dependence on the clinician’s microscopy skills and lack of a durable record of the patient sample.

Gram stain a more objective test. A Gram stain evaluation using Nugent’s criteria has been adopted as the gold standard test for research purposes, including studies of prematurity. The Gram-stained vaginal specimen is scored from 0 to 10 based on semi-quantitative assessment of 3 classes of morphotypes ( Table 2 ): large gram-positive rods (Lactobacilli), small gram-negative rods (Gardnerella and Bacteroides spp.), and small curved gram-variable rods (Mobiluncus spp.).¹¹

Diagnosis of BV is typically made when the Nugent score is 7 or more, which appears qualitatively as dominant morphotypes other than Lactobacilli. Gram staining is more objective and reproducible compared with wet-mount examination, with a sensitivity of 93% and specificity of 70% if Amsel’s criteria are used as the gold standard.¹⁴ It is useful for the evaluation of asymptomatic women. It also provides a durable record of the patient specimen. Compared with Gram stain, Amsel’s criteria tend to underdiagnose cases. We can expect that if screening for BV in pregnancy becomes a recommendation, Gram staining in a clinical laboratory will be the recommended method of diagnosis.

Other diagnostic tests for BV. DNA testing for Gardnerella is accurate for detection, but it is not synonymous with a diagnosis of BV, as described.²⁰ DNA testing is further described under “Differential Diagnosis.” Gram staining is more reliable than gas-liquid chromatography²¹ and an assay for proline aminopeptidase (a metabolic product of some of the bacteria associated with BV).²² Latex agglutination testing for vaginal lactoferrin is a nonspecific marker for leukocytes, and thus inflammation. It is of little clinical utility in the diagnosis of vaginal discharge.²³

TABLE 1
Predictive values of Amsel’s criteria (using 3 of 4 positive as diagnostic reference standard)

TABLE 2
How to use Nugent’s Gram stain criteria to diagnose bacterial vaginosis

Vulvovaginal Candidiasis

Candidiasis is the second most commonly diagnosed vaginitis in the United States. Some experts estimate that 75% of women will have a yeast infection at some point in life and 5% will have recurrent infections.²⁴ However, 10% to 30% of asymptomatic women with normal flora have positive culture results for Candida.^25-29 The proportion of symptomatic women with positive culture results is 20% to 40%.^4,30,31 Complications of VVC are rare,³² though vulvar vestibulitis³³ and chorioamnionitis in pregnancy³² have been reported.

Risk factors. Symptomatic yeast vaginitis has been associated with condom and diaphragm use, recent antibiotic use, receptive oral sex, oral contraceptive use, spermicide use, diabetes, and immunosuppression including AIDS.^31,34-37 The associations with antibiotic use and oral contraceptives are not consistent.^30,38 Although pregnancy has been postulated as a risk factor for symptomatic VVC, prevalence of yeast on culture in pregnant women is similar to that of nonpregnant women.³⁰

Suggestive symptoms. Among women with a culture result positive for Candida, the most common symptom is pruritus or burning.²⁸ Abnormal discharge is a complaint for most symptomatic women with VVC confirmed by culture.² In addition, women may complain of a thick, odorless, cottage cheese–like discharge.³⁹ A thick, curdled-appearing discharge points to a diagnosis of Candida because it is rarely present with BV or trichomoniasis. In one study,²⁸ a thick curdled discharge had a positive predictive value of 84% for diagnosis of VVC by culture (SOR: B). However, a thin discharge does not rule out VVC; in another study, clinicians described discharge as thin in about half of women ultimately diagnosed with VVC by culture in another study (SOR: B).² On exam, vulvar and vaginal erythema are often present but are not specific findings. The accuracy of the clinical exam for VVC is poor compared with culture (SOR: A).^2,30

Pathogens. Candida albicans is present in 80% to 90% of patients with VVC.^5,40 remainder have non-albicans species, including C glabrata and others.²⁸ An increase to almost 20% of non-Candida species in a vaginitis clinic by the mid-1990’s may be related to increased use of imidazoles available over-the-counter.^40,41 Wet mount results are typically negative in the presence of non-Candida VVC.²⁸

Diagnosis of VVC

The gold standard test for diagnosis of VVC is culture. The potassium hydroxide (KOH) wet mount is only 40% to 75% sensitive.^28,29,42,43 False-positive results are also observed with variable frequency.⁴⁴ The pH of the discharge is usually not more than 5.0 with Candida albicans, but may be higher with non-albicans species such as C glabrata.⁴⁵ Culture is recommended for patients with recurrent or persistent symptoms and a negative wet mount result (SOR: B).^5,28,46 Rapid slide latex agglutination testing is not better than microscopy (SOR: B).⁴²

Trichomoniasis

Trichomonas, a motile protozoan with 4 flagella, causes the third most common form of vaginitis in the United States and is more common in some developing countries. Trichomoniasis accounts for no more than 10% of all cases of vaginitis, and it appears to be decreasing since the introduction of metronidazole.^47,48 It is classified as an STD, although transmission is possible by other means if the organism is protected from desiccation—for example, in dirty washcloths or towels and contaminated water. Nonsexual transmission is thought to be uncommon.

Trichomoniasis is associated with GC and Chlamydia infections, and, like them, has been associated with seroconversion to HIV-positive status.⁴⁹ Trichomonads are identified in 30% to 80% of male sexual partners of infected women. In men, trichomoniasis most often is an asymptomatic carrier state.⁵⁰ However, it is the cause of about 10% of cases of nongonococcal urethritis in men.⁵¹

Clinical presentations. Women with trichomoniasis have variable presentations ranging from an asymptomatic carrier state to a malodorous, purulent discharge with vulvovaginal erythema. Punctate hemorrhagic cervical lesions are considered pathognomonic of trichomoniasis, but are seen in only about 2% of cases (SOR: B).⁵²

Diagnosis. Culture for trichomoniasis is the gold standard. Several culture media have been used, most commonly the Diamond medium. Recently introduced is a transport and culture medium for detection of Trichomonas (InPouch TV), which performs as well as Diamond medium (SOR: A).^53-55 A DNA probe is also available and accurate (SOR: A).

Motile trichomonads are seen on wet preparation in only 50% to 80% of culture-positive cases (SOR: B).^50,54,56 Polymorphonuclear leukocytes can be dominant on wet mount, making visualization of trichomonads more difficult. The pH of the vaginal fluid is usually basic.

Trichomonas reported with cervical cytology

Trichomonas may also be reported on Pap smears. A meta-analysis⁵⁷ comparing the pooled sensitivities and specificities of wet mounts and cytology demonstrated low sensitivities of 68% and 58%, respectively, and high specificities, 99.9% and 97%, respectively (SOR: A).

However, since cytology carries a 3% false-positive rate, its results are not diagnostic of trichomoniasis in low-risk, asymptomatic women.^50,57 Treatment may be prescribed empirically based on positive cytology results. However, if an asymptomatic woman were concerned about whether she really has an STD, a positive wet prep would confirm the diagnosis. A negative wet prep should be followed up with culture to reliably rule out disease (SOR: B).

Trichomoniasis in pregnancy

Screening for asymptomatic trichomoniasis in pregnancy has not been recommended. In fact, some evidence suggests that treatment of trichomoniasis in pregnancy is associated with poorer pregnancy outcomes including lower birth weight and more prematurity (SOR: B).^58,59

Aerobic vaginitis

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with predominance of abnormal aerobic flora.⁶⁰ Aerobic vaginitis, which may be severe, has been reported as the cause of 5% of cases in a series from a specialty vaginitis clinic.⁶¹ The usual predominant microorganisms are group B streptococci, Escherichia coli, and Staphylococcus aureus. It is likely that less severe cases of aerobic vaginitis are not recognized in the primary care setting and are treated as BV or resolve spontaneously (SOR: C). The case series referred to above also reported good therapeutic response to 2% topical clindamycin (SOR: C).⁶¹

Noninfectious Vaginitis

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic, cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease, and idiopathic vaginitis.

Irritant and allergic vaginitis may result from sensitivities to topical medications, the active or base ingredients of spermicidal products, douching solutions, and the latex of condoms or diaphragms. If a woman with persistent symptoms has been using such intravaginal products, she should stop (SOR: C).

Cytolytic vaginitis is characterized by overgrowth of lactobacilli and cytolysis of squamous cells, including presence of cytoplasmic fragments and intact cells with naked nuclei.⁶² The cause is uncertain but may include a reaction to intravaginal medications or other products such as tampons. It can be found in up to 5% of women with symptoms and signs of vaginitis.^62,63 Symptoms often mimic VVC and may include a white, cheesy discharge. Vaginal pH ranges from 3.5 to 5.5. Recurrences during luteal phase of the menstrual cycle have been described.⁶⁴ Intravaginal antifungals should be discontinued. Baking soda sitz baths or douches are often used, but clinical trial data to support this practice are lacking (SOR: C).

Noninfectious desquamative inflammatory vaginitis (DIV) has also been described.⁶⁵ DIV is an uncommon vaginitis characterized by profuse purulent discharge with epithelial cell exfoliation. It may occur at any time during the reproductive years or after menopause. There is probably a heterogeneous group of causes of DIV. Some cases may correspond to a disorder within the spectrum of lichen planus.⁶⁶ Treatment is usually difficult, though there may be some response to local or systemic corticosteroid therapy (SOR: C).⁶⁵

Differential diagnosis

A comparison of physical examination findings an diagnostic test results for various etiologies of vaginitis is summarized in Table 3 . An algorithmic approach to the differential diagnosis of abnormal vaginal discharge is presented in the Figure . Diagnosis is complicated in that signs and symptoms do little to help differentiate among BV, VVC, and trichomoniasis. A study² of 22 genitourinary symptoms and signs showed that none differentiated among the 3 infections. This lack of clear-cut differences in symptoms also makes self-diagnosis and telephone triage inaccurate.^67,68

A DNA probe testing system (Affirm VP III Microbial ID Test) for differential diagnosis is available but expensive. It identifies Gardnerella, Trichomonas, and Candida albicans with a sensitivity of 90% to 95%.^54,66 The analyzer costs approximately $10,000 and would typically be purchased by a laboratory. Individual test kits cost about $27.

TABLE 3
Comparative findings among causes of vaginitis

FIGURE
Sequence of office tests to evaluate abnormal vaginal discharge

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

Evidence summary

The term “dietary fiber” refers to a heterogeneous group of substances that may vary in their biologic effects. Fiber is thought to reduce the risk of colon cancer through the following proposed mechanisms—decreased gastrointestinal transit time, increased stool bulk, and fermentation of volatile fatty acids. Other aspects of diet such as fat content, red meat, and micronutrients may also play a role in the development of colon cancer.

Additional proposed risk factors include sedentary lifestyle, obesity, tobacco use, and alcohol consumption¹ ; while the commonly accepted high-risk groups for colon cancer are those aged >60 years, those with a positive family history of colorectal cancer, and those with familial polyposis syndrome. In summary, it appears that the cause of colon cancer is complex and multifactorial.

No randomized controlled trials of interventions test whether increase dietary fiber affects the development of colon cancer. Recent randomized controlled trials of interventions have used colon polyps as a surrogate endpoint, since it is believed that polyps are precursors to cancer. A Cochrane meta-analysis² of 5 trials (including 4349 subjects) of increased dietary fiber to prevent recurrence of colon adenomas found no difference between intervention and control groups for development of at least 1 adenoma (relative risk [RR]=1.04; 95% confidence interval [CI], 0.95–1.13). In a trial³ of ispaghula husk fiber, the intervention group actually had significantly more recurrent adenomas after 3 years (29.3% vs 20.2%; RR=1.67; 95% CI, 1.01–2.76; P=.04).

Other evidence comes from epidemiological studies, which have limited ability to demonstrate causation. Immigrants to Westernized countries from ethnic groups with lower risk of colon cancer develop colon cancer rates similar to the host country over time. Such data support environmental factors in the risk for colon cancer.

Dietary fiber is 1 of several possible factors, yet epidemiological evidence has not been consistent. A systematic review⁴ of dietary fiber and colorectal neoplasia (which included case-control and cohort studies as well as randomized controlled trials) showed that 13 of 24 case-control studies found an association with high dietary fiber as a possible protective factor, while only 3 of 13 longitudinal studies found such an association.

Recommendations from others

The American Gastroenterological Association states that “currently available evidence from epidemiological, animal, and intervention studies does not unequivocally support the protective role of fiber against development of colorectal cancer.”⁵ They recommend dietary fiber consumption of at least 30–35 g/d from a variety of sources. The intake level of most studies that demonstrate protective effects are in that range, and it is not certain what the best source(s) may be. They state that a high-fiber diet should begin before age 30, because the impact of dietary change may require decades; they also note that a high-fiber diet has other established health benefits.

The American Dietetic Association recommends a diet rich in dietary fiber through consumption of a variety of fruits, vegetables, whole and high-fiber grain products, and legumes for a daily intake of 20–35 g/d for healthy adults and, for children, a daily intake of 5 plus the child’s age in grams.⁶ They cite the epidemiological association of a high-fiber diet and lower colorectal cancer risk as well as many other health benefits.

Evidence summary

The term “dietary fiber” refers to a heterogeneous group of substances that may vary in their biologic effects. Fiber is thought to reduce the risk of colon cancer through the following proposed mechanisms—decreased gastrointestinal transit time, increased stool bulk, and fermentation of volatile fatty acids. Other aspects of diet such as fat content, red meat, and micronutrients may also play a role in the development of colon cancer.

Additional proposed risk factors include sedentary lifestyle, obesity, tobacco use, and alcohol consumption¹ ; while the commonly accepted high-risk groups for colon cancer are those aged >60 years, those with a positive family history of colorectal cancer, and those with familial polyposis syndrome. In summary, it appears that the cause of colon cancer is complex and multifactorial.

No randomized controlled trials of interventions test whether increase dietary fiber affects the development of colon cancer. Recent randomized controlled trials of interventions have used colon polyps as a surrogate endpoint, since it is believed that polyps are precursors to cancer. A Cochrane meta-analysis² of 5 trials (including 4349 subjects) of increased dietary fiber to prevent recurrence of colon adenomas found no difference between intervention and control groups for development of at least 1 adenoma (relative risk [RR]=1.04; 95% confidence interval [CI], 0.95–1.13). In a trial³ of ispaghula husk fiber, the intervention group actually had significantly more recurrent adenomas after 3 years (29.3% vs 20.2%; RR=1.67; 95% CI, 1.01–2.76; P=.04).

Other evidence comes from epidemiological studies, which have limited ability to demonstrate causation. Immigrants to Westernized countries from ethnic groups with lower risk of colon cancer develop colon cancer rates similar to the host country over time. Such data support environmental factors in the risk for colon cancer.

Dietary fiber is 1 of several possible factors, yet epidemiological evidence has not been consistent. A systematic review⁴ of dietary fiber and colorectal neoplasia (which included case-control and cohort studies as well as randomized controlled trials) showed that 13 of 24 case-control studies found an association with high dietary fiber as a possible protective factor, while only 3 of 13 longitudinal studies found such an association.

Recommendations from others

The American Gastroenterological Association states that “currently available evidence from epidemiological, animal, and intervention studies does not unequivocally support the protective role of fiber against development of colorectal cancer.”⁵ They recommend dietary fiber consumption of at least 30–35 g/d from a variety of sources. The intake level of most studies that demonstrate protective effects are in that range, and it is not certain what the best source(s) may be. They state that a high-fiber diet should begin before age 30, because the impact of dietary change may require decades; they also note that a high-fiber diet has other established health benefits.

The American Dietetic Association recommends a diet rich in dietary fiber through consumption of a variety of fruits, vegetables, whole and high-fiber grain products, and legumes for a daily intake of 20–35 g/d for healthy adults and, for children, a daily intake of 5 plus the child’s age in grams.⁶ They cite the epidemiological association of a high-fiber diet and lower colorectal cancer risk as well as many other health benefits.

Evidence summary

The term “dietary fiber” refers to a heterogeneous group of substances that may vary in their biologic effects. Fiber is thought to reduce the risk of colon cancer through the following proposed mechanisms—decreased gastrointestinal transit time, increased stool bulk, and fermentation of volatile fatty acids. Other aspects of diet such as fat content, red meat, and micronutrients may also play a role in the development of colon cancer.

Additional proposed risk factors include sedentary lifestyle, obesity, tobacco use, and alcohol consumption¹ ; while the commonly accepted high-risk groups for colon cancer are those aged >60 years, those with a positive family history of colorectal cancer, and those with familial polyposis syndrome. In summary, it appears that the cause of colon cancer is complex and multifactorial.

No randomized controlled trials of interventions test whether increase dietary fiber affects the development of colon cancer. Recent randomized controlled trials of interventions have used colon polyps as a surrogate endpoint, since it is believed that polyps are precursors to cancer. A Cochrane meta-analysis² of 5 trials (including 4349 subjects) of increased dietary fiber to prevent recurrence of colon adenomas found no difference between intervention and control groups for development of at least 1 adenoma (relative risk [RR]=1.04; 95% confidence interval [CI], 0.95–1.13). In a trial³ of ispaghula husk fiber, the intervention group actually had significantly more recurrent adenomas after 3 years (29.3% vs 20.2%; RR=1.67; 95% CI, 1.01–2.76; P=.04).

Other evidence comes from epidemiological studies, which have limited ability to demonstrate causation. Immigrants to Westernized countries from ethnic groups with lower risk of colon cancer develop colon cancer rates similar to the host country over time. Such data support environmental factors in the risk for colon cancer.

Dietary fiber is 1 of several possible factors, yet epidemiological evidence has not been consistent. A systematic review⁴ of dietary fiber and colorectal neoplasia (which included case-control and cohort studies as well as randomized controlled trials) showed that 13 of 24 case-control studies found an association with high dietary fiber as a possible protective factor, while only 3 of 13 longitudinal studies found such an association.

Recommendations from others

The American Gastroenterological Association states that “currently available evidence from epidemiological, animal, and intervention studies does not unequivocally support the protective role of fiber against development of colorectal cancer.”⁵ They recommend dietary fiber consumption of at least 30–35 g/d from a variety of sources. The intake level of most studies that demonstrate protective effects are in that range, and it is not certain what the best source(s) may be. They state that a high-fiber diet should begin before age 30, because the impact of dietary change may require decades; they also note that a high-fiber diet has other established health benefits.

The American Dietetic Association recommends a diet rich in dietary fiber through consumption of a variety of fruits, vegetables, whole and high-fiber grain products, and legumes for a daily intake of 20–35 g/d for healthy adults and, for children, a daily intake of 5 plus the child’s age in grams.⁶ They cite the epidemiological association of a high-fiber diet and lower colorectal cancer risk as well as many other health benefits.

The last decade has witnessed important technological advances in the diagnosis of osteoporosis and an increase in therapeutic options. However, there is still considerable uncertainty about optimal strategies for screening and primary preventive treatment.

In 1994, a World Health Organization working group proposed that the diagnosis of osteoporosis be made when BMD, assessed by a dual-energy x-ray absorptiometry (DXA), is at least 2.5 standard deviations below the mean for young adult women (T-score) at the spine, hip, or wrist, or when a history of a traumatic fracture is present.² A T-score between −1 and −2.5 is designated as osteopenia.

These facts underscore the importance of osteoporotic fractures:

• Only one third of patients regain their prior level of functioning after hip fracture, and one third are discharged to nursing homes.³
• About 1 in 5 patients dies within a year after a hip fracture.
• Vertebral fracture may result in chronic back pain and disability.⁴
• Existence of fracture greatly increases risk of subsequent fracture.⁵
• Direct medical costs for osteoporotic fractures are estimated at $13.8 billion in 1995 dollars.⁶

Prevalence of osteoporosis and fractures

Of American women over age 50 of all races, an estimated 15%, or 5 million, have osteoporosis (based on DXA T-score at the femoral neck) and an additional 40%, or 14 million, have osteopenia.⁷ In African Americans, the prevalence is about half that of whites.⁸ The prevalence of osteoporosis assessed by BMD testing increases with age—from 4% of white women aged 50 to 59 to 48% of women aged 80 to 89.⁹

At least 1 vertebral fracture, as indicated by radiographic criteria, has occurred in 5% of white women aged 50 to 59, and in 25% at age 80.³ The lifetime risk of hip fracture for 50-year-old white women and men is 14% and 5%, respectively; for African American women and men, 6% and 3%, respectively.³ Hip and symptomatic vertebral fractures occur mainly in women over 75,^3,10 and the risk for wrist fractures increases starting in the late 50s.¹¹

Age is a particularly important risk factor for hip fractures, reflecting deterioration in bone strength beyond that detectable with BMD testing. The National Osteoporosis Foundation¹² observed that the 5-year risk of hip fracture for women with the same T-score (−3) increases dramatically with advancing age (Figure): from 2.4% at age 50 to 9.7% at age 90, with the steepest increase occurring during the 10 years between ages 70 (5.5%) and 80 (9%).

FIGURE
Five-year risk for hip fracture for women with T-score of −3 by age¹²

Bone mineral density testing

Screening recommendations

The clinical value of different screening strategies is not established, although recommendations have been made within guidelines and consensus statements that discuss prevention and treatment of osteoporosis. Guidelines are consistent in recommending that BMD screening be done only if results will influence treatment decisions. The US Preventive Services Task Force,¹³ The National Osteoporosis Foundation,¹⁴ and American Association of Clinical Endocrinologists¹⁵ recommend screening all women over 65, as well as younger women with risk factors for osteoporosis. The National Institutes of Health³ and the North American Menopause Society¹⁶ recommend an individualized decision-making approach to screening. The National Osteoporosis Foundation developed nomograms that integrate risk factors into decision-making for testing and treatment,¹² which seem promising and merit testing in prospective studies.

Diagnostic testing

DXA. Although several technologies are available, DXA of the hip is considered the best predictor of hip fracture and an equivalent predictor of other fractures.¹⁰ The likelihood of making a diagnosis of osteoporosis based on BMD, however, varies and is related to type of test, equipment, anatomic site tested, number of sites tested, technique, and relevance of the reference range to the local population. For example, when the same group of people is tested with DXA equipment from different manufacturers, the proportion diagnosed with osteoporosis varies by as much as 15%.¹¹

Quantitative ultrasound (QUS) and radiographic absorptiometry (RA). Testing by QUS of the heel and RA of the hand are less expensive than DXA and have become popular. While QUS of the heel has been shown to predict hip fracture and all nonvertebral fractures nearly as well as DXA,^3,10 it does not highly correlate with DXA and appears to reflect other aspects of bone quality.¹⁰ Since QUS and DXA results frequently disagree and can cause confusion, DXA is the most appropriate test of BMD at present. If QUS and RA are used for screening, confirmation with DXA is recommended before therapy is initiated.

Calculations based on risk factors. In a comparison of strategies using risk factors to predict low BMD in postmenopausal women, 2 decision rules performed well: the Osteoporosis Risk Assessment Instrument, which is based on age and weight (Table 1),¹⁷ and the Simple Calculated Osteoporosis Risk Estimation (SCORE).¹⁷ Research to test these instruments with fracture rather than BMD as outcome is needed.¹⁸

Biochemical markers. Levels of markers in serum and/or urine reflect bone turnover and have potential use in diagnosing and monitoring therapy of osteoporosis. They are not yet widely available and have not been consistently associated with identifying patients at risk for fracture.¹⁰ They are not recommended at this time.

TABLE 1
Osteoporosis risk assessment instrument¹⁷

Importance of primary prevention

At least half of bone strength is attributable to genetic factors¹²; modifiable factors may contribute almost equally as a group, and therefore warrant attention. Genetic risk factors include age, family history, female sex, low weight, small frame, and white or Asian race. Primary prevention efforts should begin in childhood and continue throughout the life span to maximize bone mass.³

Prevention efforts that target the modifiable factors described below should be a routine part of the health-maintenance visit.

Fall reduction

Falls are the direct cause of more than 90% of osteoporotic hip fractures,¹⁹ and the tendency to fall increases with age. Some studies have shown that, for women over age 70, the most important predictors of hip fractures are fall-related factors^20,21 such as poor cognitive function, slow gait and otherwise impaired mobility, poor vision, drugs that impair alertness or balance, and history of falls. In women over 75, age and slow gait are equal to low BMD of the femoral neck as predictors of hip fracture.²² Unfortunately, labeling women as osteopenic or osteoporotic can cause fear of falling and lack of activity, leading to further acceleration of bone loss.¹⁰

Medications that interfere with balance or alertness should be avoided if possible. Environmental hazards such as loose rugs and uneven or slippery surfaces are also well-recognized modifiable risks for falls^23,24 that should be eliminated. Hip protectors effectively reduce fractures in the frail elderly²⁵ and can boost confidence for beneficial increases in physical activity levels,²⁶ but they are often poorly accepted by patients.^25,27 Other options include referral for gait training, home visits by a physician or nurse to identify problems in the home that increase the risk of falls, or providing information on home modification (such as installing bathtub rails, removing throw rugs, etc.).

Improvement of nutritional intake

Adequate consumption of calcium is essential for bone health. Calcium balance also can be adversely affected by dietary habits, including high intake of protein, phosphorus, and sodium, although these effects appear to be less important when dietary calcium is sufficient.³ The recommended calcium intake for postmenopausal women (1200–1500 mg/day)²⁸ can be met with food sources, but supplements should be added if needed. Most postmenopausal women in the United States consume only about 600 mg/day.²⁸ High-calcium foods include milk (290–300 mg/cup), sardines in oil, with bones (370 mg/3 oz), yogurt (300–500 mg depending on container size), cheese (165–270 mg/slice), canned salmon, with bones (170–210 mg/3 oz), broccoli (160–180 mg/cup), and tofu (144–155 mg/4 oz).¹⁵

Vitamin D is essential for intestinal absorption of calcium. The recommended intake for women is 400 IU/day for ages 51 to 70, 600 IU/day over age 70, and 800 IU/day for all high-risk women, including those who are homebound, institutionalized, on chronic glucocorticoids, or who live in northern latitudes and therefore have limited exposure to sunlight.²⁹ Sources of vitamin D include sunlight, vitamin D–fortified foods, fish oils, and supplements. Multivitamins typically contain 400 IU of vitamin D.

Phytoestrogens, particularly in the form of soy products, have received attention for bone health. Overall, studies do not support the use of soy foods to prevent osteoporosis.³ A well-designed trial in postmenopausal women found that ipriflavone, a synthetic phytoestrogen, did not decrease bone loss.³⁰ Furthermore, use was associated with subclinical lymphocytopenia.

Regular exercise

Weight-bearing physical activity such as walking or running in early life contributes to higher peak bone mass. Limited data suggest weight-bearing exercise in postmenopausal women produces small increases in bone density at the hip³¹ and improvement in balance and strength.³² For women with established osteoporosis, activities that place an anterior load on the vertebral bodies, such as forward flexion exercises, are associated with an increased incidence of new vertebral deformities, and patients should be advised to avoid them.³³

Avoidance of adverse health habits

Current smoking, compared with never smoking, doubles the risk of hip fracture.³⁴ Consumption of more than 1 alcoholic drink/day or more than 7/week is associated with osteoporosis and fracture, while moderate consumption of 1 drink/day or less is associated with decreased risk.³⁵ Excessive caffeine intake is also associated with increased osteoporosis risk and should be avoided. This effect appears to result from substitution of calcium-containing beverages such as milk or fortified orange juice with caffeinated, non–calcium-containing beverages such as colas.

Treatment for fracture prevention and pain relief

The goals of therapy for osteoporosis are fracture prevention and pain relief to maximize physical function.¹⁵ Prior fracture is associated with a fivefold risk of future fractures.⁵ About 20% of women who experience a vertebral fracture have another fracture within 1 year.³⁶ Currently available therapies (Table 2) are antiresorptive: they slow bone turnover and allow bone formation to exceed resorption. Trials of antiresorptive agents in elderly women with osteoporosis and baseline vertebral fracture demonstrate that 1 new vertebral fracture is prevented for each 12 to 35 women treated for 2 to 3 years.^14,37Table 3 summarizes the results of key treatment studies and provides information on the number of women that need to be treated (NNT) for the study period to prevent 1 fracture.

TABLE 2
Drug therapy for prevention and treatment of postmenopausal osteoporosis

TABLE 3
Clinical trials of drug therapy for the prevention of fracture in postmenopausal women with osteoporosis

Calcium and vitamin D

Calcium with or without vitamin D has been reported to positively affect fracture incidence.¹⁴ Vitamin D alone does not decrease the incidence of hip fractures.³⁸ Calcium, 1200 to 1500 mg/day, and vitamin D, 800 IU/day, should be used concurrently with other forms of pharmacologic treatment. Calcium supplements are best absorbed with meals; for maximum absorption, calcium should be taken in doses of 500 mg or less.^29,39

Minor gastrointestinal adverse effects may occur (most often constipation, 10%),¹⁴ which is often resolved by switching to a different preparation.⁴⁰ Calcium in doses up to 1500 mg/day does not increase the risk for renal calculi and may, in fact, decrease risk.^40,41 Calcium interferes with the absorption of certain medications, including tetracycline and quinolone antibiotics, which should be taken several hours apart from calcium. Calcium carbonate requires an acidic environment to dissolve. Patients taking stomach acid–suppressant therapy should use calcium citrate because it does not require an acidic environment for dissolution or should take their calcium supplement with meals. Traces of lead may be present in natural sources of calcium (bone meal, oyster shell, limestone, and dolomite), but can be avoided by use of over-the-counter calcium carbonate tablets (Tums).

Estrogen

Data from the Women’s Health Initiative (WHI) demonstrated that hormone replacement therapy (HRT) combining an estrogen and a progestin reduced hip and vertebral fractures by 1 in 2000 women per year and reduced all fractures by 1 in 333 women per year.⁴² Estrogen has a positive effect on BMD whether given in early or late postmenopause.⁴³ Rapid bone loss as assessed by BMD does not occur after stopping HRT.⁴⁴ However, in elderly women who have never used HRT, BMD is similar to those who have used it for 10 years and then stopped for at least 10 years.⁴³ The effect of short-term (< 5 years) HRT during perimenopause on lifetime risk of osteoporotic fracture is unknown.

Common side effects (Table 2) can often be addressed by altering dosages, specific products, or regimens. The risk for breast cancer increases with duration of treatment and with combination HRT, compared with estrogen-only preparations.^42,45,46 Combination HRT products are, however, essential for endometrial protection in women who have a uterus. The WHI reported an increase in breast cancer cases of 1 in 1250 women per year during an average 5-year follow-up.⁴² An increased risk for venous thromboembolism of 1 in 555 women per year was also observed with HRT use. Both the Heart and Estrogen/Progestin Study⁴⁷ and the WHI studies found that venous thromboembolism occurred more frequently in the first 2 years of HRT use. An increased risk of myocardial infarction in the first 2 years of use was also noted among women with coronary heart disease⁴⁷ and those without heart disease (1 in 1429 women per year).⁴² A small increase in stroke risk has also been documented.^42,48-50 Contraindications to estrogen use include active thromboembolism, estrogen-related cancers, and liver disease.

Bisphosphonates

Two bisphosphonates, alendronate and risedronate, are approved in the United States for both prevention and treatment of postmenopausal osteoporosis. Clinical trials have demonstrated that both rapidly reduce the risk for symptomatic fractures in women with previous fracture and osteoporosis.^37,51,52 The extent of fracture reduction is significant: Recent studies have shown that, over 3 years, the number of patients who would need to be treated with risedronate to prevent a vertebral fracture is 15, with alendronate, 34.^53,54 Prevention of fractures among women without a prior vertebral fracture is less well established. No published data demonstrate that one bisphosphonate is more effective than another at preventing clinical fractures. A bisphosphonate is, therefore, the drug of choice for severe osteoporosis.

Bisphosphonates are generally well tolerated.^55,56 However, postmarketing surveillance has demonstrated esophagitis and esophageal ulcer associated with alendronate.⁵⁵ A pooled analysis of trials of risedronate found no increase in upper gastrointestinal (GI) adverse events even in patients with history of peptic ulcers, heartburn, and esophagitis, or among those taking nonsteroidal anti-inflammatory drugs, including aspirin.⁵⁷

Oral bisphosphonates are not well absorbed (less than 1% of each dose).^55,56 Therefore, to maximize absorption and to decrease the likelihood of adverse GI effects, the manufacturers of both bisphosphonates recommend that patients take the medication with a full glass of water, remain upright (sitting or standing) for at least 30 minutes following the dose, and not recline until food is consumed. Both bisphosphonates should be used with caution in patients with active GI disorders. Bisphosphonates are eliminated via the kidney and are not recommended for patients with a creatinine clearance below 30 mL/min.

Selective estrogen receptor modulators (SERMs)

Raloxifene is currently the only selective estrogen receptor modulator approved in the United States for prevention and treatment of osteoporosis. It has been shown to significantly decrease new vertebral fractures in women with a previous history of fracture and osteoporosis.⁵⁸ The magnitude of fracture reduction is similar to that of bisphosphonates, although improvement in BMD is less marked.⁵⁹ Raloxifene may confer other benefits. It has been shown to reduce the risk of breast cancer^60,61 except in women with low estradiol levels,⁶⁰ and may reduce the risk of myocardial infarction in women at high risk.⁶⁰ Raloxifene does not increase the risk for endometrial cancer.⁶⁰

Hot flashes and leg cramps are relatively common side effects of raloxifene.⁶⁰ The observed risk of venous thromboembolism, 1 in 465 women per year during 3 years of treatment, is similar to that observed with HRT.⁶⁰ Raloxifene is teratogenic and should not be used in premenopausal women.

Salmon calcitonin

Salmon calcitonin has demonstrated an analgesic effect for osteoporotic fracture.^63,64 A large trial of salmon calcitonin at dosages of 100, 200, and 400 IU/day versus placebo found that salmon calcitonin at 200 IU/day decreased new vertebral fractures among women with a previous osteoporotic vertebral fracture based on radiographic assessment.⁶⁵ No benefit was observed at the 100 and 400 IU/day dosages. The effect of calcitonin on clinical (symptomatic) fractures has not been reported. Calcitonin is approved for use in treatment, but not prevention, of osteoporosis.

Nasal calcitonin can cause minor rhinitis symptoms.³⁰ Saline nasal solution may be useful to prevent or resolve irritation and dryness. Administration using alternate nostrils helps minimize local side effects. Unopened bottles (14 doses) must be stored in the refrigerator. Open bottles are stable at room temperature for up to 30 days.

Monitoring therapy

The value of serial densitometry to monitor the therapy of individual patients has not been established by randomized trials comparing different monitoring intervals or monitoring versus no monitoring.^10,66 One important limitation is the relative imprecision of BMD testing: it takes almost a year to detect a 3% change in BMD.¹⁰ Disconcerting decreases in BMD scores are seen in yearly testing and may be offset by larger increases later, without a change in therapy. In studies of alendronate and raloxifene, disproportionately large fracture reductions cannot be explained by improvement in BMD alone.^66,68 Bone densitometry is therefore not recommended until the patient has been treated for 2 years, and is of uncertain value beyond that point.

The last decade has witnessed important technological advances in the diagnosis of osteoporosis and an increase in therapeutic options. However, there is still considerable uncertainty about optimal strategies for screening and primary preventive treatment.

In 1994, a World Health Organization working group proposed that the diagnosis of osteoporosis be made when BMD, assessed by a dual-energy x-ray absorptiometry (DXA), is at least 2.5 standard deviations below the mean for young adult women (T-score) at the spine, hip, or wrist, or when a history of a traumatic fracture is present.² A T-score between −1 and −2.5 is designated as osteopenia.

These facts underscore the importance of osteoporotic fractures:

• Only one third of patients regain their prior level of functioning after hip fracture, and one third are discharged to nursing homes.³
• About 1 in 5 patients dies within a year after a hip fracture.
• Vertebral fracture may result in chronic back pain and disability.⁴
• Existence of fracture greatly increases risk of subsequent fracture.⁵
• Direct medical costs for osteoporotic fractures are estimated at $13.8 billion in 1995 dollars.⁶

Prevalence of osteoporosis and fractures

Of American women over age 50 of all races, an estimated 15%, or 5 million, have osteoporosis (based on DXA T-score at the femoral neck) and an additional 40%, or 14 million, have osteopenia.⁷ In African Americans, the prevalence is about half that of whites.⁸ The prevalence of osteoporosis assessed by BMD testing increases with age—from 4% of white women aged 50 to 59 to 48% of women aged 80 to 89.⁹

At least 1 vertebral fracture, as indicated by radiographic criteria, has occurred in 5% of white women aged 50 to 59, and in 25% at age 80.³ The lifetime risk of hip fracture for 50-year-old white women and men is 14% and 5%, respectively; for African American women and men, 6% and 3%, respectively.³ Hip and symptomatic vertebral fractures occur mainly in women over 75,^3,10 and the risk for wrist fractures increases starting in the late 50s.¹¹

Age is a particularly important risk factor for hip fractures, reflecting deterioration in bone strength beyond that detectable with BMD testing. The National Osteoporosis Foundation¹² observed that the 5-year risk of hip fracture for women with the same T-score (−3) increases dramatically with advancing age (Figure): from 2.4% at age 50 to 9.7% at age 90, with the steepest increase occurring during the 10 years between ages 70 (5.5%) and 80 (9%).

FIGURE
Five-year risk for hip fracture for women with T-score of −3 by age¹²

Bone mineral density testing

Screening recommendations

The clinical value of different screening strategies is not established, although recommendations have been made within guidelines and consensus statements that discuss prevention and treatment of osteoporosis. Guidelines are consistent in recommending that BMD screening be done only if results will influence treatment decisions. The US Preventive Services Task Force,¹³ The National Osteoporosis Foundation,¹⁴ and American Association of Clinical Endocrinologists¹⁵ recommend screening all women over 65, as well as younger women with risk factors for osteoporosis. The National Institutes of Health³ and the North American Menopause Society¹⁶ recommend an individualized decision-making approach to screening. The National Osteoporosis Foundation developed nomograms that integrate risk factors into decision-making for testing and treatment,¹² which seem promising and merit testing in prospective studies.

Diagnostic testing

DXA. Although several technologies are available, DXA of the hip is considered the best predictor of hip fracture and an equivalent predictor of other fractures.¹⁰ The likelihood of making a diagnosis of osteoporosis based on BMD, however, varies and is related to type of test, equipment, anatomic site tested, number of sites tested, technique, and relevance of the reference range to the local population. For example, when the same group of people is tested with DXA equipment from different manufacturers, the proportion diagnosed with osteoporosis varies by as much as 15%.¹¹

Quantitative ultrasound (QUS) and radiographic absorptiometry (RA). Testing by QUS of the heel and RA of the hand are less expensive than DXA and have become popular. While QUS of the heel has been shown to predict hip fracture and all nonvertebral fractures nearly as well as DXA,^3,10 it does not highly correlate with DXA and appears to reflect other aspects of bone quality.¹⁰ Since QUS and DXA results frequently disagree and can cause confusion, DXA is the most appropriate test of BMD at present. If QUS and RA are used for screening, confirmation with DXA is recommended before therapy is initiated.

Calculations based on risk factors. In a comparison of strategies using risk factors to predict low BMD in postmenopausal women, 2 decision rules performed well: the Osteoporosis Risk Assessment Instrument, which is based on age and weight (Table 1),¹⁷ and the Simple Calculated Osteoporosis Risk Estimation (SCORE).¹⁷ Research to test these instruments with fracture rather than BMD as outcome is needed.¹⁸

Biochemical markers. Levels of markers in serum and/or urine reflect bone turnover and have potential use in diagnosing and monitoring therapy of osteoporosis. They are not yet widely available and have not been consistently associated with identifying patients at risk for fracture.¹⁰ They are not recommended at this time.

TABLE 1
Osteoporosis risk assessment instrument¹⁷

Importance of primary prevention

At least half of bone strength is attributable to genetic factors¹²; modifiable factors may contribute almost equally as a group, and therefore warrant attention. Genetic risk factors include age, family history, female sex, low weight, small frame, and white or Asian race. Primary prevention efforts should begin in childhood and continue throughout the life span to maximize bone mass.³

Prevention efforts that target the modifiable factors described below should be a routine part of the health-maintenance visit.

Fall reduction

Falls are the direct cause of more than 90% of osteoporotic hip fractures,¹⁹ and the tendency to fall increases with age. Some studies have shown that, for women over age 70, the most important predictors of hip fractures are fall-related factors^20,21 such as poor cognitive function, slow gait and otherwise impaired mobility, poor vision, drugs that impair alertness or balance, and history of falls. In women over 75, age and slow gait are equal to low BMD of the femoral neck as predictors of hip fracture.²² Unfortunately, labeling women as osteopenic or osteoporotic can cause fear of falling and lack of activity, leading to further acceleration of bone loss.¹⁰

Medications that interfere with balance or alertness should be avoided if possible. Environmental hazards such as loose rugs and uneven or slippery surfaces are also well-recognized modifiable risks for falls^23,24 that should be eliminated. Hip protectors effectively reduce fractures in the frail elderly²⁵ and can boost confidence for beneficial increases in physical activity levels,²⁶ but they are often poorly accepted by patients.^25,27 Other options include referral for gait training, home visits by a physician or nurse to identify problems in the home that increase the risk of falls, or providing information on home modification (such as installing bathtub rails, removing throw rugs, etc.).

Improvement of nutritional intake

Adequate consumption of calcium is essential for bone health. Calcium balance also can be adversely affected by dietary habits, including high intake of protein, phosphorus, and sodium, although these effects appear to be less important when dietary calcium is sufficient.³ The recommended calcium intake for postmenopausal women (1200–1500 mg/day)²⁸ can be met with food sources, but supplements should be added if needed. Most postmenopausal women in the United States consume only about 600 mg/day.²⁸ High-calcium foods include milk (290–300 mg/cup), sardines in oil, with bones (370 mg/3 oz), yogurt (300–500 mg depending on container size), cheese (165–270 mg/slice), canned salmon, with bones (170–210 mg/3 oz), broccoli (160–180 mg/cup), and tofu (144–155 mg/4 oz).¹⁵

Vitamin D is essential for intestinal absorption of calcium. The recommended intake for women is 400 IU/day for ages 51 to 70, 600 IU/day over age 70, and 800 IU/day for all high-risk women, including those who are homebound, institutionalized, on chronic glucocorticoids, or who live in northern latitudes and therefore have limited exposure to sunlight.²⁹ Sources of vitamin D include sunlight, vitamin D–fortified foods, fish oils, and supplements. Multivitamins typically contain 400 IU of vitamin D.

Phytoestrogens, particularly in the form of soy products, have received attention for bone health. Overall, studies do not support the use of soy foods to prevent osteoporosis.³ A well-designed trial in postmenopausal women found that ipriflavone, a synthetic phytoestrogen, did not decrease bone loss.³⁰ Furthermore, use was associated with subclinical lymphocytopenia.

Regular exercise

Weight-bearing physical activity such as walking or running in early life contributes to higher peak bone mass. Limited data suggest weight-bearing exercise in postmenopausal women produces small increases in bone density at the hip³¹ and improvement in balance and strength.³² For women with established osteoporosis, activities that place an anterior load on the vertebral bodies, such as forward flexion exercises, are associated with an increased incidence of new vertebral deformities, and patients should be advised to avoid them.³³

Avoidance of adverse health habits

Current smoking, compared with never smoking, doubles the risk of hip fracture.³⁴ Consumption of more than 1 alcoholic drink/day or more than 7/week is associated with osteoporosis and fracture, while moderate consumption of 1 drink/day or less is associated with decreased risk.³⁵ Excessive caffeine intake is also associated with increased osteoporosis risk and should be avoided. This effect appears to result from substitution of calcium-containing beverages such as milk or fortified orange juice with caffeinated, non–calcium-containing beverages such as colas.

Treatment for fracture prevention and pain relief

The goals of therapy for osteoporosis are fracture prevention and pain relief to maximize physical function.¹⁵ Prior fracture is associated with a fivefold risk of future fractures.⁵ About 20% of women who experience a vertebral fracture have another fracture within 1 year.³⁶ Currently available therapies (Table 2) are antiresorptive: they slow bone turnover and allow bone formation to exceed resorption. Trials of antiresorptive agents in elderly women with osteoporosis and baseline vertebral fracture demonstrate that 1 new vertebral fracture is prevented for each 12 to 35 women treated for 2 to 3 years.^14,37Table 3 summarizes the results of key treatment studies and provides information on the number of women that need to be treated (NNT) for the study period to prevent 1 fracture.

TABLE 2
Drug therapy for prevention and treatment of postmenopausal osteoporosis

TABLE 3
Clinical trials of drug therapy for the prevention of fracture in postmenopausal women with osteoporosis

Calcium and vitamin D

Calcium with or without vitamin D has been reported to positively affect fracture incidence.¹⁴ Vitamin D alone does not decrease the incidence of hip fractures.³⁸ Calcium, 1200 to 1500 mg/day, and vitamin D, 800 IU/day, should be used concurrently with other forms of pharmacologic treatment. Calcium supplements are best absorbed with meals; for maximum absorption, calcium should be taken in doses of 500 mg or less.^29,39

Minor gastrointestinal adverse effects may occur (most often constipation, 10%),¹⁴ which is often resolved by switching to a different preparation.⁴⁰ Calcium in doses up to 1500 mg/day does not increase the risk for renal calculi and may, in fact, decrease risk.^40,41 Calcium interferes with the absorption of certain medications, including tetracycline and quinolone antibiotics, which should be taken several hours apart from calcium. Calcium carbonate requires an acidic environment to dissolve. Patients taking stomach acid–suppressant therapy should use calcium citrate because it does not require an acidic environment for dissolution or should take their calcium supplement with meals. Traces of lead may be present in natural sources of calcium (bone meal, oyster shell, limestone, and dolomite), but can be avoided by use of over-the-counter calcium carbonate tablets (Tums).

Estrogen

Data from the Women’s Health Initiative (WHI) demonstrated that hormone replacement therapy (HRT) combining an estrogen and a progestin reduced hip and vertebral fractures by 1 in 2000 women per year and reduced all fractures by 1 in 333 women per year.⁴² Estrogen has a positive effect on BMD whether given in early or late postmenopause.⁴³ Rapid bone loss as assessed by BMD does not occur after stopping HRT.⁴⁴ However, in elderly women who have never used HRT, BMD is similar to those who have used it for 10 years and then stopped for at least 10 years.⁴³ The effect of short-term (< 5 years) HRT during perimenopause on lifetime risk of osteoporotic fracture is unknown.

Common side effects (Table 2) can often be addressed by altering dosages, specific products, or regimens. The risk for breast cancer increases with duration of treatment and with combination HRT, compared with estrogen-only preparations.^42,45,46 Combination HRT products are, however, essential for endometrial protection in women who have a uterus. The WHI reported an increase in breast cancer cases of 1 in 1250 women per year during an average 5-year follow-up.⁴² An increased risk for venous thromboembolism of 1 in 555 women per year was also observed with HRT use. Both the Heart and Estrogen/Progestin Study⁴⁷ and the WHI studies found that venous thromboembolism occurred more frequently in the first 2 years of HRT use. An increased risk of myocardial infarction in the first 2 years of use was also noted among women with coronary heart disease⁴⁷ and those without heart disease (1 in 1429 women per year).⁴² A small increase in stroke risk has also been documented.^42,48-50 Contraindications to estrogen use include active thromboembolism, estrogen-related cancers, and liver disease.

Bisphosphonates

Two bisphosphonates, alendronate and risedronate, are approved in the United States for both prevention and treatment of postmenopausal osteoporosis. Clinical trials have demonstrated that both rapidly reduce the risk for symptomatic fractures in women with previous fracture and osteoporosis.^37,51,52 The extent of fracture reduction is significant: Recent studies have shown that, over 3 years, the number of patients who would need to be treated with risedronate to prevent a vertebral fracture is 15, with alendronate, 34.^53,54 Prevention of fractures among women without a prior vertebral fracture is less well established. No published data demonstrate that one bisphosphonate is more effective than another at preventing clinical fractures. A bisphosphonate is, therefore, the drug of choice for severe osteoporosis.

Bisphosphonates are generally well tolerated.^55,56 However, postmarketing surveillance has demonstrated esophagitis and esophageal ulcer associated with alendronate.⁵⁵ A pooled analysis of trials of risedronate found no increase in upper gastrointestinal (GI) adverse events even in patients with history of peptic ulcers, heartburn, and esophagitis, or among those taking nonsteroidal anti-inflammatory drugs, including aspirin.⁵⁷

Oral bisphosphonates are not well absorbed (less than 1% of each dose).^55,56 Therefore, to maximize absorption and to decrease the likelihood of adverse GI effects, the manufacturers of both bisphosphonates recommend that patients take the medication with a full glass of water, remain upright (sitting or standing) for at least 30 minutes following the dose, and not recline until food is consumed. Both bisphosphonates should be used with caution in patients with active GI disorders. Bisphosphonates are eliminated via the kidney and are not recommended for patients with a creatinine clearance below 30 mL/min.

Selective estrogen receptor modulators (SERMs)

Raloxifene is currently the only selective estrogen receptor modulator approved in the United States for prevention and treatment of osteoporosis. It has been shown to significantly decrease new vertebral fractures in women with a previous history of fracture and osteoporosis.⁵⁸ The magnitude of fracture reduction is similar to that of bisphosphonates, although improvement in BMD is less marked.⁵⁹ Raloxifene may confer other benefits. It has been shown to reduce the risk of breast cancer^60,61 except in women with low estradiol levels,⁶⁰ and may reduce the risk of myocardial infarction in women at high risk.⁶⁰ Raloxifene does not increase the risk for endometrial cancer.⁶⁰

Hot flashes and leg cramps are relatively common side effects of raloxifene.⁶⁰ The observed risk of venous thromboembolism, 1 in 465 women per year during 3 years of treatment, is similar to that observed with HRT.⁶⁰ Raloxifene is teratogenic and should not be used in premenopausal women.

Salmon calcitonin

Salmon calcitonin has demonstrated an analgesic effect for osteoporotic fracture.^63,64 A large trial of salmon calcitonin at dosages of 100, 200, and 400 IU/day versus placebo found that salmon calcitonin at 200 IU/day decreased new vertebral fractures among women with a previous osteoporotic vertebral fracture based on radiographic assessment.⁶⁵ No benefit was observed at the 100 and 400 IU/day dosages. The effect of calcitonin on clinical (symptomatic) fractures has not been reported. Calcitonin is approved for use in treatment, but not prevention, of osteoporosis.

Nasal calcitonin can cause minor rhinitis symptoms.³⁰ Saline nasal solution may be useful to prevent or resolve irritation and dryness. Administration using alternate nostrils helps minimize local side effects. Unopened bottles (14 doses) must be stored in the refrigerator. Open bottles are stable at room temperature for up to 30 days.

Monitoring therapy

The value of serial densitometry to monitor the therapy of individual patients has not been established by randomized trials comparing different monitoring intervals or monitoring versus no monitoring.^10,66 One important limitation is the relative imprecision of BMD testing: it takes almost a year to detect a 3% change in BMD.¹⁰ Disconcerting decreases in BMD scores are seen in yearly testing and may be offset by larger increases later, without a change in therapy. In studies of alendronate and raloxifene, disproportionately large fracture reductions cannot be explained by improvement in BMD alone.^66,68 Bone densitometry is therefore not recommended until the patient has been treated for 2 years, and is of uncertain value beyond that point.

The last decade has witnessed important technological advances in the diagnosis of osteoporosis and an increase in therapeutic options. However, there is still considerable uncertainty about optimal strategies for screening and primary preventive treatment.

In 1994, a World Health Organization working group proposed that the diagnosis of osteoporosis be made when BMD, assessed by a dual-energy x-ray absorptiometry (DXA), is at least 2.5 standard deviations below the mean for young adult women (T-score) at the spine, hip, or wrist, or when a history of a traumatic fracture is present.² A T-score between −1 and −2.5 is designated as osteopenia.

These facts underscore the importance of osteoporotic fractures:

• Only one third of patients regain their prior level of functioning after hip fracture, and one third are discharged to nursing homes.³
• About 1 in 5 patients dies within a year after a hip fracture.
• Vertebral fracture may result in chronic back pain and disability.⁴
• Existence of fracture greatly increases risk of subsequent fracture.⁵
• Direct medical costs for osteoporotic fractures are estimated at $13.8 billion in 1995 dollars.⁶

Prevalence of osteoporosis and fractures

Of American women over age 50 of all races, an estimated 15%, or 5 million, have osteoporosis (based on DXA T-score at the femoral neck) and an additional 40%, or 14 million, have osteopenia.⁷ In African Americans, the prevalence is about half that of whites.⁸ The prevalence of osteoporosis assessed by BMD testing increases with age—from 4% of white women aged 50 to 59 to 48% of women aged 80 to 89.⁹

At least 1 vertebral fracture, as indicated by radiographic criteria, has occurred in 5% of white women aged 50 to 59, and in 25% at age 80.³ The lifetime risk of hip fracture for 50-year-old white women and men is 14% and 5%, respectively; for African American women and men, 6% and 3%, respectively.³ Hip and symptomatic vertebral fractures occur mainly in women over 75,^3,10 and the risk for wrist fractures increases starting in the late 50s.¹¹

Age is a particularly important risk factor for hip fractures, reflecting deterioration in bone strength beyond that detectable with BMD testing. The National Osteoporosis Foundation¹² observed that the 5-year risk of hip fracture for women with the same T-score (−3) increases dramatically with advancing age (Figure): from 2.4% at age 50 to 9.7% at age 90, with the steepest increase occurring during the 10 years between ages 70 (5.5%) and 80 (9%).

FIGURE
Five-year risk for hip fracture for women with T-score of −3 by age¹²

Bone mineral density testing

Screening recommendations

The clinical value of different screening strategies is not established, although recommendations have been made within guidelines and consensus statements that discuss prevention and treatment of osteoporosis. Guidelines are consistent in recommending that BMD screening be done only if results will influence treatment decisions. The US Preventive Services Task Force,¹³ The National Osteoporosis Foundation,¹⁴ and American Association of Clinical Endocrinologists¹⁵ recommend screening all women over 65, as well as younger women with risk factors for osteoporosis. The National Institutes of Health³ and the North American Menopause Society¹⁶ recommend an individualized decision-making approach to screening. The National Osteoporosis Foundation developed nomograms that integrate risk factors into decision-making for testing and treatment,¹² which seem promising and merit testing in prospective studies.

Diagnostic testing

DXA. Although several technologies are available, DXA of the hip is considered the best predictor of hip fracture and an equivalent predictor of other fractures.¹⁰ The likelihood of making a diagnosis of osteoporosis based on BMD, however, varies and is related to type of test, equipment, anatomic site tested, number of sites tested, technique, and relevance of the reference range to the local population. For example, when the same group of people is tested with DXA equipment from different manufacturers, the proportion diagnosed with osteoporosis varies by as much as 15%.¹¹

Quantitative ultrasound (QUS) and radiographic absorptiometry (RA). Testing by QUS of the heel and RA of the hand are less expensive than DXA and have become popular. While QUS of the heel has been shown to predict hip fracture and all nonvertebral fractures nearly as well as DXA,^3,10 it does not highly correlate with DXA and appears to reflect other aspects of bone quality.¹⁰ Since QUS and DXA results frequently disagree and can cause confusion, DXA is the most appropriate test of BMD at present. If QUS and RA are used for screening, confirmation with DXA is recommended before therapy is initiated.

Calculations based on risk factors. In a comparison of strategies using risk factors to predict low BMD in postmenopausal women, 2 decision rules performed well: the Osteoporosis Risk Assessment Instrument, which is based on age and weight (Table 1),¹⁷ and the Simple Calculated Osteoporosis Risk Estimation (SCORE).¹⁷ Research to test these instruments with fracture rather than BMD as outcome is needed.¹⁸

Biochemical markers. Levels of markers in serum and/or urine reflect bone turnover and have potential use in diagnosing and monitoring therapy of osteoporosis. They are not yet widely available and have not been consistently associated with identifying patients at risk for fracture.¹⁰ They are not recommended at this time.

TABLE 1
Osteoporosis risk assessment instrument¹⁷

Importance of primary prevention

At least half of bone strength is attributable to genetic factors¹²; modifiable factors may contribute almost equally as a group, and therefore warrant attention. Genetic risk factors include age, family history, female sex, low weight, small frame, and white or Asian race. Primary prevention efforts should begin in childhood and continue throughout the life span to maximize bone mass.³

Prevention efforts that target the modifiable factors described below should be a routine part of the health-maintenance visit.

Fall reduction

Falls are the direct cause of more than 90% of osteoporotic hip fractures,¹⁹ and the tendency to fall increases with age. Some studies have shown that, for women over age 70, the most important predictors of hip fractures are fall-related factors^20,21 such as poor cognitive function, slow gait and otherwise impaired mobility, poor vision, drugs that impair alertness or balance, and history of falls. In women over 75, age and slow gait are equal to low BMD of the femoral neck as predictors of hip fracture.²² Unfortunately, labeling women as osteopenic or osteoporotic can cause fear of falling and lack of activity, leading to further acceleration of bone loss.¹⁰

Medications that interfere with balance or alertness should be avoided if possible. Environmental hazards such as loose rugs and uneven or slippery surfaces are also well-recognized modifiable risks for falls^23,24 that should be eliminated. Hip protectors effectively reduce fractures in the frail elderly²⁵ and can boost confidence for beneficial increases in physical activity levels,²⁶ but they are often poorly accepted by patients.^25,27 Other options include referral for gait training, home visits by a physician or nurse to identify problems in the home that increase the risk of falls, or providing information on home modification (such as installing bathtub rails, removing throw rugs, etc.).

Improvement of nutritional intake

Adequate consumption of calcium is essential for bone health. Calcium balance also can be adversely affected by dietary habits, including high intake of protein, phosphorus, and sodium, although these effects appear to be less important when dietary calcium is sufficient.³ The recommended calcium intake for postmenopausal women (1200–1500 mg/day)²⁸ can be met with food sources, but supplements should be added if needed. Most postmenopausal women in the United States consume only about 600 mg/day.²⁸ High-calcium foods include milk (290–300 mg/cup), sardines in oil, with bones (370 mg/3 oz), yogurt (300–500 mg depending on container size), cheese (165–270 mg/slice), canned salmon, with bones (170–210 mg/3 oz), broccoli (160–180 mg/cup), and tofu (144–155 mg/4 oz).¹⁵

Vitamin D is essential for intestinal absorption of calcium. The recommended intake for women is 400 IU/day for ages 51 to 70, 600 IU/day over age 70, and 800 IU/day for all high-risk women, including those who are homebound, institutionalized, on chronic glucocorticoids, or who live in northern latitudes and therefore have limited exposure to sunlight.²⁹ Sources of vitamin D include sunlight, vitamin D–fortified foods, fish oils, and supplements. Multivitamins typically contain 400 IU of vitamin D.

Phytoestrogens, particularly in the form of soy products, have received attention for bone health. Overall, studies do not support the use of soy foods to prevent osteoporosis.³ A well-designed trial in postmenopausal women found that ipriflavone, a synthetic phytoestrogen, did not decrease bone loss.³⁰ Furthermore, use was associated with subclinical lymphocytopenia.

Regular exercise

Weight-bearing physical activity such as walking or running in early life contributes to higher peak bone mass. Limited data suggest weight-bearing exercise in postmenopausal women produces small increases in bone density at the hip³¹ and improvement in balance and strength.³² For women with established osteoporosis, activities that place an anterior load on the vertebral bodies, such as forward flexion exercises, are associated with an increased incidence of new vertebral deformities, and patients should be advised to avoid them.³³

Avoidance of adverse health habits

Current smoking, compared with never smoking, doubles the risk of hip fracture.³⁴ Consumption of more than 1 alcoholic drink/day or more than 7/week is associated with osteoporosis and fracture, while moderate consumption of 1 drink/day or less is associated with decreased risk.³⁵ Excessive caffeine intake is also associated with increased osteoporosis risk and should be avoided. This effect appears to result from substitution of calcium-containing beverages such as milk or fortified orange juice with caffeinated, non–calcium-containing beverages such as colas.

Treatment for fracture prevention and pain relief

The goals of therapy for osteoporosis are fracture prevention and pain relief to maximize physical function.¹⁵ Prior fracture is associated with a fivefold risk of future fractures.⁵ About 20% of women who experience a vertebral fracture have another fracture within 1 year.³⁶ Currently available therapies (Table 2) are antiresorptive: they slow bone turnover and allow bone formation to exceed resorption. Trials of antiresorptive agents in elderly women with osteoporosis and baseline vertebral fracture demonstrate that 1 new vertebral fracture is prevented for each 12 to 35 women treated for 2 to 3 years.^14,37Table 3 summarizes the results of key treatment studies and provides information on the number of women that need to be treated (NNT) for the study period to prevent 1 fracture.

TABLE 2
Drug therapy for prevention and treatment of postmenopausal osteoporosis

TABLE 3
Clinical trials of drug therapy for the prevention of fracture in postmenopausal women with osteoporosis

Calcium and vitamin D

Calcium with or without vitamin D has been reported to positively affect fracture incidence.¹⁴ Vitamin D alone does not decrease the incidence of hip fractures.³⁸ Calcium, 1200 to 1500 mg/day, and vitamin D, 800 IU/day, should be used concurrently with other forms of pharmacologic treatment. Calcium supplements are best absorbed with meals; for maximum absorption, calcium should be taken in doses of 500 mg or less.^29,39

Minor gastrointestinal adverse effects may occur (most often constipation, 10%),¹⁴ which is often resolved by switching to a different preparation.⁴⁰ Calcium in doses up to 1500 mg/day does not increase the risk for renal calculi and may, in fact, decrease risk.^40,41 Calcium interferes with the absorption of certain medications, including tetracycline and quinolone antibiotics, which should be taken several hours apart from calcium. Calcium carbonate requires an acidic environment to dissolve. Patients taking stomach acid–suppressant therapy should use calcium citrate because it does not require an acidic environment for dissolution or should take their calcium supplement with meals. Traces of lead may be present in natural sources of calcium (bone meal, oyster shell, limestone, and dolomite), but can be avoided by use of over-the-counter calcium carbonate tablets (Tums).

Estrogen

Data from the Women’s Health Initiative (WHI) demonstrated that hormone replacement therapy (HRT) combining an estrogen and a progestin reduced hip and vertebral fractures by 1 in 2000 women per year and reduced all fractures by 1 in 333 women per year.⁴² Estrogen has a positive effect on BMD whether given in early or late postmenopause.⁴³ Rapid bone loss as assessed by BMD does not occur after stopping HRT.⁴⁴ However, in elderly women who have never used HRT, BMD is similar to those who have used it for 10 years and then stopped for at least 10 years.⁴³ The effect of short-term (< 5 years) HRT during perimenopause on lifetime risk of osteoporotic fracture is unknown.

Common side effects (Table 2) can often be addressed by altering dosages, specific products, or regimens. The risk for breast cancer increases with duration of treatment and with combination HRT, compared with estrogen-only preparations.^42,45,46 Combination HRT products are, however, essential for endometrial protection in women who have a uterus. The WHI reported an increase in breast cancer cases of 1 in 1250 women per year during an average 5-year follow-up.⁴² An increased risk for venous thromboembolism of 1 in 555 women per year was also observed with HRT use. Both the Heart and Estrogen/Progestin Study⁴⁷ and the WHI studies found that venous thromboembolism occurred more frequently in the first 2 years of HRT use. An increased risk of myocardial infarction in the first 2 years of use was also noted among women with coronary heart disease⁴⁷ and those without heart disease (1 in 1429 women per year).⁴² A small increase in stroke risk has also been documented.^42,48-50 Contraindications to estrogen use include active thromboembolism, estrogen-related cancers, and liver disease.

Bisphosphonates

Two bisphosphonates, alendronate and risedronate, are approved in the United States for both prevention and treatment of postmenopausal osteoporosis. Clinical trials have demonstrated that both rapidly reduce the risk for symptomatic fractures in women with previous fracture and osteoporosis.^37,51,52 The extent of fracture reduction is significant: Recent studies have shown that, over 3 years, the number of patients who would need to be treated with risedronate to prevent a vertebral fracture is 15, with alendronate, 34.^53,54 Prevention of fractures among women without a prior vertebral fracture is less well established. No published data demonstrate that one bisphosphonate is more effective than another at preventing clinical fractures. A bisphosphonate is, therefore, the drug of choice for severe osteoporosis.

Bisphosphonates are generally well tolerated.^55,56 However, postmarketing surveillance has demonstrated esophagitis and esophageal ulcer associated with alendronate.⁵⁵ A pooled analysis of trials of risedronate found no increase in upper gastrointestinal (GI) adverse events even in patients with history of peptic ulcers, heartburn, and esophagitis, or among those taking nonsteroidal anti-inflammatory drugs, including aspirin.⁵⁷

Oral bisphosphonates are not well absorbed (less than 1% of each dose).^55,56 Therefore, to maximize absorption and to decrease the likelihood of adverse GI effects, the manufacturers of both bisphosphonates recommend that patients take the medication with a full glass of water, remain upright (sitting or standing) for at least 30 minutes following the dose, and not recline until food is consumed. Both bisphosphonates should be used with caution in patients with active GI disorders. Bisphosphonates are eliminated via the kidney and are not recommended for patients with a creatinine clearance below 30 mL/min.

Selective estrogen receptor modulators (SERMs)

Raloxifene is currently the only selective estrogen receptor modulator approved in the United States for prevention and treatment of osteoporosis. It has been shown to significantly decrease new vertebral fractures in women with a previous history of fracture and osteoporosis.⁵⁸ The magnitude of fracture reduction is similar to that of bisphosphonates, although improvement in BMD is less marked.⁵⁹ Raloxifene may confer other benefits. It has been shown to reduce the risk of breast cancer^60,61 except in women with low estradiol levels,⁶⁰ and may reduce the risk of myocardial infarction in women at high risk.⁶⁰ Raloxifene does not increase the risk for endometrial cancer.⁶⁰

Hot flashes and leg cramps are relatively common side effects of raloxifene.⁶⁰ The observed risk of venous thromboembolism, 1 in 465 women per year during 3 years of treatment, is similar to that observed with HRT.⁶⁰ Raloxifene is teratogenic and should not be used in premenopausal women.

Salmon calcitonin

Salmon calcitonin has demonstrated an analgesic effect for osteoporotic fracture.^63,64 A large trial of salmon calcitonin at dosages of 100, 200, and 400 IU/day versus placebo found that salmon calcitonin at 200 IU/day decreased new vertebral fractures among women with a previous osteoporotic vertebral fracture based on radiographic assessment.⁶⁵ No benefit was observed at the 100 and 400 IU/day dosages. The effect of calcitonin on clinical (symptomatic) fractures has not been reported. Calcitonin is approved for use in treatment, but not prevention, of osteoporosis.

Nasal calcitonin can cause minor rhinitis symptoms.³⁰ Saline nasal solution may be useful to prevent or resolve irritation and dryness. Administration using alternate nostrils helps minimize local side effects. Unopened bottles (14 doses) must be stored in the refrigerator. Open bottles are stable at room temperature for up to 30 days.

Monitoring therapy

The value of serial densitometry to monitor the therapy of individual patients has not been established by randomized trials comparing different monitoring intervals or monitoring versus no monitoring.^10,66 One important limitation is the relative imprecision of BMD testing: it takes almost a year to detect a 3% change in BMD.¹⁰ Disconcerting decreases in BMD scores are seen in yearly testing and may be offset by larger increases later, without a change in therapy. In studies of alendronate and raloxifene, disproportionately large fracture reductions cannot be explained by improvement in BMD alone.^66,68 Bone densitometry is therefore not recommended until the patient has been treated for 2 years, and is of uncertain value beyond that point.

Evidence summary

Nonsurgical treatments that are beneficial in eradicating genital warts are podofilox (Condylox) (8 randomized controlled trials [RCTs] with 1035 participants), imiquimod (Aldara) (2 RCTs with 968 participants), and intralesional interferon (8 RCTs). Cryotherapy is equivalent to trichloroacetic acid^1,2 and electrosurgery.³ Although surgical treatments have not been compared with placebo or no treatment, both electrosurgery and surgical excision are superior to podophyllin in clinical trials.^4,5 Laser surgery is as effective as surgical excision.⁶ Studies of topical interferon show conflicting results.⁷ Systemic interferon is not beneficial.⁷ Topical 5-FU has not been studied with RCTs. Wart clearance rates are summarized in the Table. Treatment duration for nonsurgical options is 4 to 8 weeks. Treatment of genital warts has not been shown to reduce transmission to sex partners.⁷

Two RCTs^4,5 showed more frequent recurrence with podophyllin (60% to 65%) than with surgical excision (19% to 20%). Another trial¹ showed recurrence in 22% of participants receiving electrosurgery, in 21% of those receiving cryotherapy, and in 44% of those receiving podophyllin treatment. Data are lacking on recurrence rates with imiquimod, podofilox, and intralesional interferon.

Pain occurs in less than 20% of people with imiquimod, cryotherapy, podophyllin, and electrosurgery; 39% with topical interferon; 44% with electrosurgery; 75% with podofilox; and 100% with surgical excision or laser surgery.⁷ However, pain has been measured using methods that are unlikely to be comparable across studies. Flulike symptoms, leukopenia, thrombocytopenia, and elevated aspartate transaminase levels are associated with intralesional interferon.⁷ Topical medications have not been studied in pregnant patients. Cryotherapy is safe in pregnancy based on case series, if only 3 or 4 treatments are given.⁷

Direct comparisons between home therapies (imiquimod, podofilox) and other treatments are needed. Products for home use are relatively expensive: a 1-month supply of imiquimod costs approximately $150; a 1-month supply of podofilox, $110 to $130. These are average wholesale prices, rounded to the nearest $10, as of Feb. 15, 2002.

TABLE
CLEARANCE RATES REPORTED IN CLINICAL TRIALS

Recommendations from others

The CDC endorses podophyllin, bi- and trichloroacetic acid, podofilox, imiquimod, cryotherapy, intralesional interferon, electrosurgery, laser surgery, and surgical excision.⁸ A United Kingdom guideline on anogenital warts recommends physical ablative methods such as cryotherapy and surgical options for keratinized lesions and topical medications for soft lesions. The guideline also recommends ablative therapy for persons with a small number of warts regardless of type. Interferon and 5-FU are not recommended.⁹

Clinical Commentary by David White, MD, at http://www.fpin.org.

Evidence summary

Nonsurgical treatments that are beneficial in eradicating genital warts are podofilox (Condylox) (8 randomized controlled trials [RCTs] with 1035 participants), imiquimod (Aldara) (2 RCTs with 968 participants), and intralesional interferon (8 RCTs). Cryotherapy is equivalent to trichloroacetic acid^1,2 and electrosurgery.³ Although surgical treatments have not been compared with placebo or no treatment, both electrosurgery and surgical excision are superior to podophyllin in clinical trials.^4,5 Laser surgery is as effective as surgical excision.⁶ Studies of topical interferon show conflicting results.⁷ Systemic interferon is not beneficial.⁷ Topical 5-FU has not been studied with RCTs. Wart clearance rates are summarized in the Table. Treatment duration for nonsurgical options is 4 to 8 weeks. Treatment of genital warts has not been shown to reduce transmission to sex partners.⁷

Two RCTs^4,5 showed more frequent recurrence with podophyllin (60% to 65%) than with surgical excision (19% to 20%). Another trial¹ showed recurrence in 22% of participants receiving electrosurgery, in 21% of those receiving cryotherapy, and in 44% of those receiving podophyllin treatment. Data are lacking on recurrence rates with imiquimod, podofilox, and intralesional interferon.

Pain occurs in less than 20% of people with imiquimod, cryotherapy, podophyllin, and electrosurgery; 39% with topical interferon; 44% with electrosurgery; 75% with podofilox; and 100% with surgical excision or laser surgery.⁷ However, pain has been measured using methods that are unlikely to be comparable across studies. Flulike symptoms, leukopenia, thrombocytopenia, and elevated aspartate transaminase levels are associated with intralesional interferon.⁷ Topical medications have not been studied in pregnant patients. Cryotherapy is safe in pregnancy based on case series, if only 3 or 4 treatments are given.⁷

Direct comparisons between home therapies (imiquimod, podofilox) and other treatments are needed. Products for home use are relatively expensive: a 1-month supply of imiquimod costs approximately $150; a 1-month supply of podofilox, $110 to $130. These are average wholesale prices, rounded to the nearest $10, as of Feb. 15, 2002.

TABLE
CLEARANCE RATES REPORTED IN CLINICAL TRIALS

Recommendations from others

The CDC endorses podophyllin, bi- and trichloroacetic acid, podofilox, imiquimod, cryotherapy, intralesional interferon, electrosurgery, laser surgery, and surgical excision.⁸ A United Kingdom guideline on anogenital warts recommends physical ablative methods such as cryotherapy and surgical options for keratinized lesions and topical medications for soft lesions. The guideline also recommends ablative therapy for persons with a small number of warts regardless of type. Interferon and 5-FU are not recommended.⁹

Clinical Commentary by David White, MD, at http://www.fpin.org.

Evidence summary

Nonsurgical treatments that are beneficial in eradicating genital warts are podofilox (Condylox) (8 randomized controlled trials [RCTs] with 1035 participants), imiquimod (Aldara) (2 RCTs with 968 participants), and intralesional interferon (8 RCTs). Cryotherapy is equivalent to trichloroacetic acid^1,2 and electrosurgery.³ Although surgical treatments have not been compared with placebo or no treatment, both electrosurgery and surgical excision are superior to podophyllin in clinical trials.^4,5 Laser surgery is as effective as surgical excision.⁶ Studies of topical interferon show conflicting results.⁷ Systemic interferon is not beneficial.⁷ Topical 5-FU has not been studied with RCTs. Wart clearance rates are summarized in the Table. Treatment duration for nonsurgical options is 4 to 8 weeks. Treatment of genital warts has not been shown to reduce transmission to sex partners.⁷

Two RCTs^4,5 showed more frequent recurrence with podophyllin (60% to 65%) than with surgical excision (19% to 20%). Another trial¹ showed recurrence in 22% of participants receiving electrosurgery, in 21% of those receiving cryotherapy, and in 44% of those receiving podophyllin treatment. Data are lacking on recurrence rates with imiquimod, podofilox, and intralesional interferon.

Pain occurs in less than 20% of people with imiquimod, cryotherapy, podophyllin, and electrosurgery; 39% with topical interferon; 44% with electrosurgery; 75% with podofilox; and 100% with surgical excision or laser surgery.⁷ However, pain has been measured using methods that are unlikely to be comparable across studies. Flulike symptoms, leukopenia, thrombocytopenia, and elevated aspartate transaminase levels are associated with intralesional interferon.⁷ Topical medications have not been studied in pregnant patients. Cryotherapy is safe in pregnancy based on case series, if only 3 or 4 treatments are given.⁷

Direct comparisons between home therapies (imiquimod, podofilox) and other treatments are needed. Products for home use are relatively expensive: a 1-month supply of imiquimod costs approximately $150; a 1-month supply of podofilox, $110 to $130. These are average wholesale prices, rounded to the nearest $10, as of Feb. 15, 2002.

TABLE
CLEARANCE RATES REPORTED IN CLINICAL TRIALS

Recommendations from others

The CDC endorses podophyllin, bi- and trichloroacetic acid, podofilox, imiquimod, cryotherapy, intralesional interferon, electrosurgery, laser surgery, and surgical excision.⁸ A United Kingdom guideline on anogenital warts recommends physical ablative methods such as cryotherapy and surgical options for keratinized lesions and topical medications for soft lesions. The guideline also recommends ablative therapy for persons with a small number of warts regardless of type. Interferon and 5-FU are not recommended.⁹

Clinical Commentary by David White, MD, at http://www.fpin.org.

Menopause has been successfully promoted as an estrogen-deficient state. Prescriptions in the United States for noncontraceptive estrogen formulations increased from 16 million to 39 million between 1982 and 1992; progestin sales reached 4.7 million by 1992 after their introduction in 1986.¹ A condition for which half of the population becomes eligible for pharmacologic treatment for 30 years or more of their life spans is worthy of family physicians’ attention. Counseling of women regarding menopause has also been incorporated into the Health Employer Data Information Set (HEDIS) for measuring the quality of care provided by health care plans.

The women of the generation born from 1946 to 1965 are now 36 to 55 years old. About half will at some time seek medical attention for relief of symptoms believed to be related to the menopausal transition.² The clinical picture, however, can be confusing: women at midlife are susceptible to diseases that may affect or be affected by the menopausal transition. Life cycle changes can also provoke dysphoric symptoms similar to those of menopause or aggravate symptoms that already exist.

Natural history

A woman’s hormonal rhythm changes gradually, usually in the early to middle forties. Ovarian mass decreases progressively; production of ovarian hormones decreases as well. The menstrual cycles tend to be somewhat shorter. Follicle-stimulating hormone (FSH) and estrogen levels fluctuate. Estrogen levels may be transiently higher than in former years in response to higher FSH levels, recruiting more ovarian follicles. Anovulatory cycles are more frequent. Perimenopausal menstrual irregularity typically lasts for approximately 4 years; the large majority of women experience such irregularity for 1 to 7 years.² For 10% of women, menses simply cease without prior menstrual irregularity.

The best estimate of mean age at menopause in the United States, based on a cohort of primarily Caucasian women, is 51.3 years.² Smokers experience menopause 1.8 years earlier than nonsmokers (50.2 versus 52.0 years). Less than 10% of women reach menopause before age 46, while approximately 30% do so before age 50.² A recent review³ concluded that the lifetime number of ovulatory cycles is predictive of age at menopause: earlier for women with shorter cycles and nulliparous women, later for multigravid women and those with a history of oral contraceptive use. A familial tendency toward similarity in age at menopause has been noted.

Premature menopause or premature ovarian failure is defined as cessation of menstrual periods before 40 years of age. The prevalence of premature ovarian failure is approximately 1% by age 40 and 0.1% by 30 years of age.⁴ Premature ovarian failure is frequently an autoimmune disorder.⁵

Diagnosis of menopause

The gold standard for diagnosing menopause is to do so retrospectively, 1 year after the last menstrual period. In general, a diagnosis of menopause based on menstrual history or hormone levels is not considered necessary to begin treatment for perimenopausal symptoms, which often begin several years before the onset of menopause.

Laboratory diagnosis

The extent to which FSH or other serologic markers can be used to diagnose menopause is controversial. The most important clinical reason to do so is to discontinue contraceptive methods safely. Some consider an FSH level greater than 40 mIU/mL to be diagnostic. This value was chosen because it is about 2 standard deviations above the periovulatory peak in FSH levels in regularly cycling women. However, longitudinal studies^6,7 during the perimenopausal years have demonstrated that hormonal patterns that include FSH values greater than 40 mIU/mL often abruptly revert to premenopausal patterns and are accompanied by ovulatory cycles. For the individual patient, hormone levels do not appear to rule out fertility reliably.⁸ Studies defining test characteristics (sensitivity, specificity, likelihood ratios) of hormone assays for the diagnosis of menopause are needed.

History and physical examination

A large population-based survey of Swedish women⁹ found that the most common climacteric symptoms are, in order of frequency, vasomotor symptoms (hot flashes), mood disturbances, sleep disturbances, decreased libido, and vaginal dryness. Several observational studies^10-13 have shown that vasomotor symptoms have the clearest temporal association with the menstrual cycle changes of the climacteric. These symptoms result from a sudden change in the hypothalamic control of temperature regulation,¹⁴ although the precise triggers have not been elucidated. Hot flashes occur commonly among women in their late thirties and forties who have regular menstrual cycles.¹⁵ Several studies^2,10,13,16 have shown that the prevalence of hot flashes peaks in the year immediately following the final menstrual period. A typical pattern prevalence of hot flashes is 25% in premenopausal women, 69% in perimenopausal women, and 39% in late-postmenopausal women (more than 4.5 years).¹⁷ Fifteen years after menopause, 10% of women may continue to have moderate to severe hot flashes,¹⁸ which can be lifelong.

Irritability and mood swings are common climacteric complaints. Women often compare them with their earlier premenstrual symptoms. Studies of depressive symptoms in menopausal women indicate that menopause is not associated with increased rates of major depression.¹⁹ Stressful life context and poor health status appear to be more important risk factors for depression than symptoms of menopause in climacteric women.²⁰

Many perimenopausal women complain of poor sleep, often attributed to nocturnal hot flashes. Subjective impairment of sleep quality that is associated with climacteric vasomotor symptoms does not manifest as abnormalities in polysomnographic sleep recordings.²¹ It does not appear to be related to sleep apnea.

Sexual dysfunction is common in women at midlife and beyond. Dyspareunia, associated with vaginal dryness, increases in frequency with increasing time after menopause.⁹ The other complaint is decreased libido. Multiple factors may contribute to lack of sexual interest. Both aging and the menopause are independently associated with decreases in sexual responsiveness.²² The roles of declining endogenous sex steroid hormones in this process have not been elucidated.

Treatment

Vasomotor symptoms

Table 1 summarizes treatment options for vasomotor symptoms. Numerous well-designed clinical trials have demonstrated the effectiveness of oral or transdermal estrogen replacement therapy (ERT) for hot flashes.^18,23-25 Low-dose oral contraceptive formulations are approved until 50 years of age for nonsmoking women.²⁶ In a well-designed randomized controlled trial (RCT) of 93 women, low-dose estrogen (0.625 mg conjugated equine estrogens daily) plus 1.25 mg methyltestosterone daily was shown to be more effective than low-dose estrogen only and as effective as high-dose estrogen (1.25 mg conjugated estrogens daily).²⁷

Phytoestrogens may be helpful, but have not yet been studied extensively. One RCT²⁸ of 104 postmenopausal women comparing ingestion of 60 g soy protein daily with that of 60 g casein (placebo) daily showed a 45% relative reduction of hot flashes at 12 weeks in the group taking soy versus the control group. A second RCT²⁹ of 51 women comparing soy protein with carbohydrate placebo showed a decrease in severity, but not frequency, of hot flashes. Another well-designed RCT³⁰ including 69 women treated with 40 g soy daily versus whey protein for 24 weeks showed no difference between treatment groups and improvement in symptom scores over time in both groups. It is difficult to include a 40-g to 60-g protein supplement in the daily diet because of the accompanying caloric intake required. Recent reports of randomized placebo-controlled trials of black cohosh³¹ and dong quai³² and a systematic review³³ of controlled trials of red clover have found no benefit.

Alternatives to estrogen for treatment of hot flashes include methyldopa, clonidine, transdermal progesterone, and megestrol acetate. Megestrol, which reduces symptoms by 70%, appears to be the most effective of these.³⁴ Although long-term use of megestrol acetate by cancer survivors for the treatment of hot flashes has been demonstrated to be effective and well tolerated,³⁵ it is not customarily used at menopause. A 20% reduction in hot flashes can be expected with clonidine at a dose of 0.1 to 0.2 mg daily,^34,36 although this regimen may cause an increase in difficulty sleeping³⁷ as well as dry mouth, constipation, and low blood pressure. Transdermal progesterone cream alone has been shown to improve vasomotor symptoms, although without protective effect regarding bone loss.³⁸ One small study³⁹ of behavioral approaches showed symptom reduction with deep-breathing relaxation techniques. Pilot studies of sertraline,⁴⁰ venlafaxine,⁴¹ and paroxetine⁴² show promise in the treatment of hot flashes.

The remainder of this article focuses on hormonal treatment effects and risks for menopausal women. A summary appears in Table 2.

TABLE 1
TREATMENT OF VASOMOTOR SYMPTOMS