Clinical Review

The past year has seen continuing variety in pharmaceutical and nonpharmaceutical approaches to osteoporosis, which remains—and will remain—a significant source of morbidity and mortality as the Baby Boom generation ages. As more people who are less healthy live longer, the sequelae of fragility fractures, mainly of the hip and spine, will increase as well, unless we continue to make strides in the identification of risk and in the prevention, detection, and treatment of osteoporosis.

In this article, I highlight:

• two trials of the newly FDA-approved denosumab (Prolia) that demonstrate its benefits and risks
• a recent report on osteonecrosis of the jaw in bisphosphonate users, including low-risk women taking an oral formulation
• guidance from Canada on how to derive maximum benefit from vitamin D
• disappointing findings on the benefits of resistance training for women
• two studies detailing the benefits of another SERM, lasofoxifene.

Denosumab outperforms alendronate as well as placebo

Cummings SR, San Martin J, McClung MR, et al; for FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.

Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial [published online ahead of print December 14, 2009]. J Bone Miner Res. doi:10.1359/jbmr.080910.

In their report from the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), Cummings and colleagues describe this prospective, placebo-controlled study of 7,868 postmenopausal women, all with a T-score worse than –2.5. Participants were randomized to 60 mg of subcutaneous denosumab or placebo every 6 months for 3 years. Those taking denosumab experienced a 68% reduction in the rate of new vertebral fracture (P < .001), a 20% reduction in nonvertebral fracture (P =.02), and a 40% reduction in hip fracture (P =.04), compared with placebo.

Denosumab is a fully human monoclonal antibody against the receptor activator of RANKL, which is a cytokine essential for the formation, function, and survival of osteoclasts. By binding to RANKL, denosumab prevents the usual interaction between RANKL and its receptor on osteoclast precursors and osteoclasts. And by preventing this interaction, denosumab reversibly inhibits osteoclast-mediated bone resorption, thereby reducing bone turnover and increasing bone mineral density (BMD).

Denosumab received FDA approval in June 2010 for the treatment of osteoporosis in postmenopausal women who have a high risk of fracture (defined as a history of osteoporotic fracture, the presence of multiple risk factors for fracture, or the failure of or intolerance to another form of osteoporosis therapy).

Details of the FREEDOM trial

The average age of women in the trial was 72.3 years (range, 60 to 90 years). At baseline, 23% of participants had a preexisting vertebral fracture. The primary endpoint was new vertebral fracture, with nonvertebral fracture and hip fracture as secondary endpoints.

No significant differences were found between denosumab and placebo in:

• total incidence of adverse events
• serious adverse events
• discontinuation of treatment because of adverse events
• overall incidence of cancer
• overall incidence of cardiovascular events
• adverse or serious adverse events of infection
• local reactions at the site of injection.

No neutralizing antibodies developed in either group.

Four cases of opportunistic infection were reported in the denosumab group, and three were reported in the placebo group. Eczema was reported by 3% of women in the denosumab group, versus 1.7% in the placebo group (P < .001). Falls that were not associated with a fracture were reported by 4.5% of subjects taking denosumab, versus 5.7% of those taking placebo (P =.02). Flatulence was more common among women taking denosumab (2.2%) than among those taking placebo (1.4%) (P =.008). Twelve women (0.3%) in the denosumab group reported serious adverse events of cellulitis, compared with one woman taking placebo (<0.1%) (P =.002).

Seventy women (1.8%) died in the denosumab group, compared with 90 (2.3%) in the placebo group (P =.08).

Denosumab versus alendronate

Brown and associates compared denosumab and alendronate in a randomized, blinded trial of 1,189 postmenopausal women who had a T-score worse than –2.0 at the lumbar spine or total hip. At month 12, denosumab significantly increased BMD at the total hip, compared with alendronate (3.5% versus 2.6%) (P < .0001). Compared with alendronate, denosumab also increased BMD in the:

• femoral neck (0.6%)
• trochanter (1.0%)
• lumbar spine (1.1%)
• 1/3 radius (0.6%) (P ≤ .0002 for all sites).

Denosumab led to significantly greater reduction of bone turnover markers than did alendronate therapy. Unlike bisphosphonates, denosumab is not retained in bone.

Participants were randomized 1:1 to:

• 60 mg subcutaneous denosumab injection every 6 months plus oral placebo weekly (n=594)
• 70 mg of oral alendronate weekly plus subcutaneous placebo injections every 6 months (n=595).

BMD was assessed at 6 and 12 months, and bone turnover markers were assessed at 1, 3, 6, 9, and 12 months. Safety was evaluated by monitoring adverse events and laboratory values.

No significant difference between denosumab and alendronate was observed in the overall incidence of adverse events (80.9% versus 82.3%, respectively) (P =.60), including gastrointestinal disorders, infections, and neoplasms. Most adverse events were mild or moderate in severity. Treatment-related adverse events were similar between groups (17% and 18.3% for denosumab and alendronate, respectively). Similar numbers of women experienced serious adverse events (34 women [5.7%] taking denosumab versus 37 [6.3%] taking alendronate). The overall safety profile was similar for both drugs.

Is osteonecrosis of the jaw a concern with denosumab?

The package insert for Prolia mentions that osteonecrosis of the jaw (ONJ) can “occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has been reported in patients receiving Prolia.”

Although no cases of ONJ were reported in the FREEDOM trial, a letter by Kyrgidis and Toolis to Osteoporosis International makes the point that ONJ may not be related solely to bisphosphonate use.¹ Taylor and colleagues described a case of a cancer patient who had never taken a bisphosphonate but who was treated with denosumab and later developed ONJ.² Kyrgidis and Toolis refer to presentations in the European Journal of Cancer Supplements that reported on head-to-head trials of denosumab and intravenous zoledronic acid in the treatment of bone metastases in cancer patients.¹ In one trial, the incidence of ONJ with denosumab was 2.0%, compared with 1.4% for zoledronic acid (P =.31). In another trial, the incidence of ONJ was 1.1% for denosumab and 1.3% for zoledronic acid (P =1.0). Kyrgidis and Toolis concluded that the association between ONJ and denosumab appears to be somewhat dose-related, as it is with bisphosphonate-related ONJ.

Plausible mechanisms for denosumab-related and bisphosphonate-related ONJ include defective osteoclast differentiation, function, survival, and “fatigue.”

Because denosumab has a shorter clearance time than bisphosphonates do, it seems feasible that treatment of denosumab-related ONJ will be easier and healing earlier than with bisphosphonate-related ONJ.

Osteonecrosis of the jaw in bisphosphonate users

Otto S, Abu-Id MH, Fedele S, et al. Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence—a multi-centre study [published online ahead of print June 25, 2010]. J Craniomaxillofac Surg. doi:10.1016/j.jcms.2010.05.009.

ONJ is a serious side effect well known to practitioners of maxillofacial surgery.³ Most research into the condition has focused on patients who have bone metastasis who have received intravenous bisphosphonates. In this report, Otto and colleagues describe a large multicenter trial at 11 European centers from 2004 through 2008. ONJ occurred in 470 patients taking a bisphosphonate. Each case was clinically examined, and a detailed history was supplied.

Although more than 90% of these cases were associated with intravenous bisphosphonate use, mainly in cancer patients who had bony metastasis, 37 cases (7.8%) occurred in women taking an oral bisphosphonate for osteoporosis. Of these, only 43% had any of the risk factors defined by the American Association of Oral and Maxillofacial Surgery (such as duration of bisphosphonate use and previous dental procedures). That means that 57% of these cases would be considered low-risk.

In this group of oral bisphosphonate users, patients tended to be older and had been on bisphosphonate therapy longer than patients in the high-risk group. Overall, 78% of the oral users who developed ONJ had been taking a bisphosphonate longer than 3 years.

Vitamin D guidelines emphasize its importance and versatility

Hanley DA, Cranney A, Jones G, et al; for the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ. 2010;182(12):E610-E618.

The Institute of Medicine is expected to release a comprehensive report on Vitamin D late this fall. In the meantime, the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada has published its own set of guidelines that underscores the importance of adequate vitamin D intake to ensure bone health and help prevent osteoporosis.

Here are a few points taken from these guidelines:

• Vitamin D is an essential nutrient in the prevention of osteoporosis. It may reduce the risk of other medical disorders unrelated to bone and mineral metabolism.

• Vitamin D₃ may be better utilized in the body. After synthesis in the skin or dietary ingestion, vitamin D is removed from the bloodstream into various tissues, including the liver, adipose tissue, and muscle. Its biologic half-life is about 60 days, and it is eventually converted to 25-hydroxyvitamin D in the hepatocytes. Vitamin D₃ (cholecalciferol) is the molecule synthesized in the skin in response to ultraviolet B radiation, whereas vitamin D₂ (ergocalciferol) is derived from irradiation of certain fungi. Both vitamin D₂ and vitamin D₃ create 1,25-dihydroxyvitamin D, the active form, although there is some evidence that vitamin D₂ may not be used in the body as efficiently as vitamin D₃. Most vitamin D supplements consist of vitamin D₃, but high-dose preparations, available by prescription, are vitamin D₂.

• Vitamin D deficiency is a continuum. The term “deficiency” was previously used to describe the advanced clinical effects of chronically low vitamin D. “Insufficiency” described a milder form of deficiency in which reduced absorption of calcium and the resultant mild secondary hyperparathyroidism might increase bone loss.

• Don’t rely on sunlight. Ultraviolet B radiation (wavelength 290–315 nm) promotes synthesis of vitamin D. The amount of exposure needed to achieve adequate vitamin D status depends on latitude, altitude, time of year and day, weather, other environmental characteristics, age, skin pigmentation, clothing, activity, and the amount of skin irradiated. The influence of diet on vitamin D status is minimal, and most circulating vitamin D is derived from exposure to sunlight. Dermatologists recommend that the safest course is to avoid exposure to the sun and to take vitamin D supplements.

• Vitamin D insufficiency has been associated with malignancies (especially colorectal cancer), diabetes, multiple sclerosis, and impaired immune response. The benefits of vitamin D for these nontraditional roles are associated with 25-hydroxyvitamin D levels above 75 nmol/L.

• What is an optimal serum level? To most consistently improve clinical outcomes such as fracture risk, an optimal serum level of 25-hydroxyvitamin D is probably above 75 nmol/L; for most patients, supplementation is needed to achieve this level.

• The recommended vitamin D intake is 10 μg to 25 μg (400–1,000 IU) daily for low-risk adults younger than 50 years, and 20 μg to 50 μg (800–2,000 IU) for high-risk and older adults, with consideration of higher dosages.

• Consider monitoring vitamin D intake. A dosage as high as 50 μg (2,000 IU) requires no monitoring. If a higher dosage is needed, monitoring is appropriate.

Resistance training provides greater benefits for men than for women

Martyn-St. James M, Carroll S. Progressive high-intensity resistance training and bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects. Sports Med. 2006;36(8):683–704.

Most of our patients believe that weight-bearing exercise “builds bone.” Although the importance of maintaining adequate flexibility, agility, mobility, and strength is obvious in terms of fall prevention, its role in increasing bone mass has been unclear. As early as 2006, Martyn-St. James reported that a high-intensity progressive resistance training program in premenopausal women significantly increased absolute BMD at the lumbar spine, but not at the femoral neck.

Earlier this year Bemben and Bemben reported their findings in regard to 45 men and 79 women 55 to 74 years old who undertook either high-intensity or low-intensity resistance training either 2 or 3 days a week.⁴ Regardless of intensity and frequency, resistance training improved BMD of the proximal femur and lumbar spine but not the total body. Men and women responded similarly at the hip, but men had a greater response at the lumbar spine than women did.

Last, Almstedt and colleagues explored changes in BMD in response to 24 weeks of resistance training among college-aged men and women.⁵ Men had significantly greater increases in BMD at the lateral spine and femoral neck.

Overall, male exercisers experienced an increase in BMD of 2.7% to 7.7%, whereas women experienced an increase of 0.8% to 1.5%, depending on the bone site. In the control group, both men and women experienced an increase of approximately 1% at any bone site. These findings indicate that 24 weeks of resistance training, including squat and dead-lift exercises, is effective in increasing BMD in young, healthy men. Similar benefits were not obtained by women who followed the same protocol.

Lasofoxifene gets the nod—in Europe, not the United States

Cummings SR, Ensrud K, Delmas PD, et al; for PEARL Study Investigators. Lasofoxifene in post-menopausal women with osteoporosis. N Engl J Med. 2010;362(8):686–696.

Goldstein SR, Neven P, Cummings S, et al. Postmenopausal evaluation and risk reduction with lasofoxifene trial: 5-year gynecological outcomes [published online ahead of print August 3, 2010]. Menopause. doi:10.1097/gme.0b013e3181e84bb4.

On September 8, 2008, an FDA advisory panel voted 9–3 in support of this statement: “There is a population of postmenopausal women with osteoporosis in which the benefits of lasofoxifene likely outweigh the risks.” However, the FDA decided against approval of lasofoxifene, a new SERM developed for the treatment of osteoporosis in postmenopausal women. The drug has been approved outside the United States, most notably in the European Union.

The reasoning behind the FDA’s failure to approve the SERM is unclear. As Cummings and associates report in the PEARL trial (Postmenopausal Evaluation and Risk Reduction with Laxofoxifene), an international, randomized, placebo-controlled study of 8,556 postmenopausal women who had T-scores worse than –2.5, the drug had a favorable therapeutic profile.

In that study, participants were randomized to a daily dosage of 0.25 mg of lasofoxifene, 0.5 mg of lasofoxifene, or placebo. For the first 3 years of this trial, which took place at 113 sites in 32 countries, the primary endpoint was vertebral fracture. For the first 5 years of the trial, co-primary endpoints were nonvertebral fracture and breast cancer. Mean age of participants was 67 years (age range, 59 to 80 years), and 28% had at least one baseline vertebral fracture, as defined by radiograph.

At the 0.5-mg dosage (the one suggested to the FDA), lasofoxifene reduced the rate of nonvertebral fracture by 24% (P =.002). It reduced vertebral fracture by 42% (P < .001). And it reduced estrogen-receptor–positive breast cancer (P < .001) and all invasive breast cancer (P < .001) by 81% and 85%, respectively. As for major coronary heart disease events (P < .02) and stroke (P =.04), lasofoxifene reduced them by 32% and 36%, respectively.

Lasofoxifene is the first SERM to reduce nonvertebral fracture. Although no significant reduction in hip fracture was observed in this trial, the small number of cases may have been a factor (incidence <1%).

As it does with other SERMs and estrogen, the risk of thromboembolic events increased significantly (HR, 2.06), as did pulmonary embolism (HR, 4.49). Fatal stroke, for which raloxifene was given a boxed warning by the FDA, did not increase significantly with lasofoxifene.

The gynecologic effects of lasofoxifene (reported separately) did not include an increased risk of endometrial cancer or hyperplasia. Although the incidence of endometrial polyps did increase, the polyps were all inactive. Vaginal bleeding, secondary to atrophy, doubled in comparison with placebo.

All-cause mortality did not increase significantly among women taking a daily dosage of 0.5 mg of lasofoxifene, but it did among those taking a dosage of 0.25 mg (38%) (P =.05). And only with the 0.25-mg dosage was there a trend toward more overall deaths due to cancer (P =.06). A biologic reason for these differences in the rate of death is lacking, but the fact that there was no increased mortality at the higher dosage suggests that the difference might be due to chance.

We want to hear from you! Tell us what you think.

The past year has seen continuing variety in pharmaceutical and nonpharmaceutical approaches to osteoporosis, which remains—and will remain—a significant source of morbidity and mortality as the Baby Boom generation ages. As more people who are less healthy live longer, the sequelae of fragility fractures, mainly of the hip and spine, will increase as well, unless we continue to make strides in the identification of risk and in the prevention, detection, and treatment of osteoporosis.

In this article, I highlight:

• two trials of the newly FDA-approved denosumab (Prolia) that demonstrate its benefits and risks
• a recent report on osteonecrosis of the jaw in bisphosphonate users, including low-risk women taking an oral formulation
• guidance from Canada on how to derive maximum benefit from vitamin D
• disappointing findings on the benefits of resistance training for women
• two studies detailing the benefits of another SERM, lasofoxifene.

Denosumab outperforms alendronate as well as placebo

Cummings SR, San Martin J, McClung MR, et al; for FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.

Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial [published online ahead of print December 14, 2009]. J Bone Miner Res. doi:10.1359/jbmr.080910.

In their report from the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), Cummings and colleagues describe this prospective, placebo-controlled study of 7,868 postmenopausal women, all with a T-score worse than –2.5. Participants were randomized to 60 mg of subcutaneous denosumab or placebo every 6 months for 3 years. Those taking denosumab experienced a 68% reduction in the rate of new vertebral fracture (P < .001), a 20% reduction in nonvertebral fracture (P =.02), and a 40% reduction in hip fracture (P =.04), compared with placebo.

Denosumab is a fully human monoclonal antibody against the receptor activator of RANKL, which is a cytokine essential for the formation, function, and survival of osteoclasts. By binding to RANKL, denosumab prevents the usual interaction between RANKL and its receptor on osteoclast precursors and osteoclasts. And by preventing this interaction, denosumab reversibly inhibits osteoclast-mediated bone resorption, thereby reducing bone turnover and increasing bone mineral density (BMD).

Denosumab received FDA approval in June 2010 for the treatment of osteoporosis in postmenopausal women who have a high risk of fracture (defined as a history of osteoporotic fracture, the presence of multiple risk factors for fracture, or the failure of or intolerance to another form of osteoporosis therapy).

Details of the FREEDOM trial

The average age of women in the trial was 72.3 years (range, 60 to 90 years). At baseline, 23% of participants had a preexisting vertebral fracture. The primary endpoint was new vertebral fracture, with nonvertebral fracture and hip fracture as secondary endpoints.

No significant differences were found between denosumab and placebo in:

• total incidence of adverse events
• serious adverse events
• discontinuation of treatment because of adverse events
• overall incidence of cancer
• overall incidence of cardiovascular events
• adverse or serious adverse events of infection
• local reactions at the site of injection.

No neutralizing antibodies developed in either group.

Four cases of opportunistic infection were reported in the denosumab group, and three were reported in the placebo group. Eczema was reported by 3% of women in the denosumab group, versus 1.7% in the placebo group (P < .001). Falls that were not associated with a fracture were reported by 4.5% of subjects taking denosumab, versus 5.7% of those taking placebo (P =.02). Flatulence was more common among women taking denosumab (2.2%) than among those taking placebo (1.4%) (P =.008). Twelve women (0.3%) in the denosumab group reported serious adverse events of cellulitis, compared with one woman taking placebo (<0.1%) (P =.002).

Seventy women (1.8%) died in the denosumab group, compared with 90 (2.3%) in the placebo group (P =.08).

Denosumab versus alendronate

Brown and associates compared denosumab and alendronate in a randomized, blinded trial of 1,189 postmenopausal women who had a T-score worse than –2.0 at the lumbar spine or total hip. At month 12, denosumab significantly increased BMD at the total hip, compared with alendronate (3.5% versus 2.6%) (P < .0001). Compared with alendronate, denosumab also increased BMD in the:

• femoral neck (0.6%)
• trochanter (1.0%)
• lumbar spine (1.1%)
• 1/3 radius (0.6%) (P ≤ .0002 for all sites).

Denosumab led to significantly greater reduction of bone turnover markers than did alendronate therapy. Unlike bisphosphonates, denosumab is not retained in bone.

Participants were randomized 1:1 to:

• 60 mg subcutaneous denosumab injection every 6 months plus oral placebo weekly (n=594)
• 70 mg of oral alendronate weekly plus subcutaneous placebo injections every 6 months (n=595).

BMD was assessed at 6 and 12 months, and bone turnover markers were assessed at 1, 3, 6, 9, and 12 months. Safety was evaluated by monitoring adverse events and laboratory values.

No significant difference between denosumab and alendronate was observed in the overall incidence of adverse events (80.9% versus 82.3%, respectively) (P =.60), including gastrointestinal disorders, infections, and neoplasms. Most adverse events were mild or moderate in severity. Treatment-related adverse events were similar between groups (17% and 18.3% for denosumab and alendronate, respectively). Similar numbers of women experienced serious adverse events (34 women [5.7%] taking denosumab versus 37 [6.3%] taking alendronate). The overall safety profile was similar for both drugs.

Is osteonecrosis of the jaw a concern with denosumab?

The package insert for Prolia mentions that osteonecrosis of the jaw (ONJ) can “occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has been reported in patients receiving Prolia.”

Although no cases of ONJ were reported in the FREEDOM trial, a letter by Kyrgidis and Toolis to Osteoporosis International makes the point that ONJ may not be related solely to bisphosphonate use.¹ Taylor and colleagues described a case of a cancer patient who had never taken a bisphosphonate but who was treated with denosumab and later developed ONJ.² Kyrgidis and Toolis refer to presentations in the European Journal of Cancer Supplements that reported on head-to-head trials of denosumab and intravenous zoledronic acid in the treatment of bone metastases in cancer patients.¹ In one trial, the incidence of ONJ with denosumab was 2.0%, compared with 1.4% for zoledronic acid (P =.31). In another trial, the incidence of ONJ was 1.1% for denosumab and 1.3% for zoledronic acid (P =1.0). Kyrgidis and Toolis concluded that the association between ONJ and denosumab appears to be somewhat dose-related, as it is with bisphosphonate-related ONJ.

Plausible mechanisms for denosumab-related and bisphosphonate-related ONJ include defective osteoclast differentiation, function, survival, and “fatigue.”

Because denosumab has a shorter clearance time than bisphosphonates do, it seems feasible that treatment of denosumab-related ONJ will be easier and healing earlier than with bisphosphonate-related ONJ.

Osteonecrosis of the jaw in bisphosphonate users

Otto S, Abu-Id MH, Fedele S, et al. Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence—a multi-centre study [published online ahead of print June 25, 2010]. J Craniomaxillofac Surg. doi:10.1016/j.jcms.2010.05.009.

ONJ is a serious side effect well known to practitioners of maxillofacial surgery.³ Most research into the condition has focused on patients who have bone metastasis who have received intravenous bisphosphonates. In this report, Otto and colleagues describe a large multicenter trial at 11 European centers from 2004 through 2008. ONJ occurred in 470 patients taking a bisphosphonate. Each case was clinically examined, and a detailed history was supplied.

Although more than 90% of these cases were associated with intravenous bisphosphonate use, mainly in cancer patients who had bony metastasis, 37 cases (7.8%) occurred in women taking an oral bisphosphonate for osteoporosis. Of these, only 43% had any of the risk factors defined by the American Association of Oral and Maxillofacial Surgery (such as duration of bisphosphonate use and previous dental procedures). That means that 57% of these cases would be considered low-risk.

In this group of oral bisphosphonate users, patients tended to be older and had been on bisphosphonate therapy longer than patients in the high-risk group. Overall, 78% of the oral users who developed ONJ had been taking a bisphosphonate longer than 3 years.

Vitamin D guidelines emphasize its importance and versatility

Hanley DA, Cranney A, Jones G, et al; for the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ. 2010;182(12):E610-E618.

The Institute of Medicine is expected to release a comprehensive report on Vitamin D late this fall. In the meantime, the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada has published its own set of guidelines that underscores the importance of adequate vitamin D intake to ensure bone health and help prevent osteoporosis.

Here are a few points taken from these guidelines:

• Vitamin D is an essential nutrient in the prevention of osteoporosis. It may reduce the risk of other medical disorders unrelated to bone and mineral metabolism.

• Vitamin D₃ may be better utilized in the body. After synthesis in the skin or dietary ingestion, vitamin D is removed from the bloodstream into various tissues, including the liver, adipose tissue, and muscle. Its biologic half-life is about 60 days, and it is eventually converted to 25-hydroxyvitamin D in the hepatocytes. Vitamin D₃ (cholecalciferol) is the molecule synthesized in the skin in response to ultraviolet B radiation, whereas vitamin D₂ (ergocalciferol) is derived from irradiation of certain fungi. Both vitamin D₂ and vitamin D₃ create 1,25-dihydroxyvitamin D, the active form, although there is some evidence that vitamin D₂ may not be used in the body as efficiently as vitamin D₃. Most vitamin D supplements consist of vitamin D₃, but high-dose preparations, available by prescription, are vitamin D₂.

• Vitamin D deficiency is a continuum. The term “deficiency” was previously used to describe the advanced clinical effects of chronically low vitamin D. “Insufficiency” described a milder form of deficiency in which reduced absorption of calcium and the resultant mild secondary hyperparathyroidism might increase bone loss.

• Don’t rely on sunlight. Ultraviolet B radiation (wavelength 290–315 nm) promotes synthesis of vitamin D. The amount of exposure needed to achieve adequate vitamin D status depends on latitude, altitude, time of year and day, weather, other environmental characteristics, age, skin pigmentation, clothing, activity, and the amount of skin irradiated. The influence of diet on vitamin D status is minimal, and most circulating vitamin D is derived from exposure to sunlight. Dermatologists recommend that the safest course is to avoid exposure to the sun and to take vitamin D supplements.

• Vitamin D insufficiency has been associated with malignancies (especially colorectal cancer), diabetes, multiple sclerosis, and impaired immune response. The benefits of vitamin D for these nontraditional roles are associated with 25-hydroxyvitamin D levels above 75 nmol/L.

• What is an optimal serum level? To most consistently improve clinical outcomes such as fracture risk, an optimal serum level of 25-hydroxyvitamin D is probably above 75 nmol/L; for most patients, supplementation is needed to achieve this level.

• The recommended vitamin D intake is 10 μg to 25 μg (400–1,000 IU) daily for low-risk adults younger than 50 years, and 20 μg to 50 μg (800–2,000 IU) for high-risk and older adults, with consideration of higher dosages.

• Consider monitoring vitamin D intake. A dosage as high as 50 μg (2,000 IU) requires no monitoring. If a higher dosage is needed, monitoring is appropriate.

Resistance training provides greater benefits for men than for women

Martyn-St. James M, Carroll S. Progressive high-intensity resistance training and bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects. Sports Med. 2006;36(8):683–704.

Most of our patients believe that weight-bearing exercise “builds bone.” Although the importance of maintaining adequate flexibility, agility, mobility, and strength is obvious in terms of fall prevention, its role in increasing bone mass has been unclear. As early as 2006, Martyn-St. James reported that a high-intensity progressive resistance training program in premenopausal women significantly increased absolute BMD at the lumbar spine, but not at the femoral neck.

Earlier this year Bemben and Bemben reported their findings in regard to 45 men and 79 women 55 to 74 years old who undertook either high-intensity or low-intensity resistance training either 2 or 3 days a week.⁴ Regardless of intensity and frequency, resistance training improved BMD of the proximal femur and lumbar spine but not the total body. Men and women responded similarly at the hip, but men had a greater response at the lumbar spine than women did.

Last, Almstedt and colleagues explored changes in BMD in response to 24 weeks of resistance training among college-aged men and women.⁵ Men had significantly greater increases in BMD at the lateral spine and femoral neck.

Overall, male exercisers experienced an increase in BMD of 2.7% to 7.7%, whereas women experienced an increase of 0.8% to 1.5%, depending on the bone site. In the control group, both men and women experienced an increase of approximately 1% at any bone site. These findings indicate that 24 weeks of resistance training, including squat and dead-lift exercises, is effective in increasing BMD in young, healthy men. Similar benefits were not obtained by women who followed the same protocol.

Lasofoxifene gets the nod—in Europe, not the United States

Cummings SR, Ensrud K, Delmas PD, et al; for PEARL Study Investigators. Lasofoxifene in post-menopausal women with osteoporosis. N Engl J Med. 2010;362(8):686–696.

Goldstein SR, Neven P, Cummings S, et al. Postmenopausal evaluation and risk reduction with lasofoxifene trial: 5-year gynecological outcomes [published online ahead of print August 3, 2010]. Menopause. doi:10.1097/gme.0b013e3181e84bb4.

On September 8, 2008, an FDA advisory panel voted 9–3 in support of this statement: “There is a population of postmenopausal women with osteoporosis in which the benefits of lasofoxifene likely outweigh the risks.” However, the FDA decided against approval of lasofoxifene, a new SERM developed for the treatment of osteoporosis in postmenopausal women. The drug has been approved outside the United States, most notably in the European Union.

The reasoning behind the FDA’s failure to approve the SERM is unclear. As Cummings and associates report in the PEARL trial (Postmenopausal Evaluation and Risk Reduction with Laxofoxifene), an international, randomized, placebo-controlled study of 8,556 postmenopausal women who had T-scores worse than –2.5, the drug had a favorable therapeutic profile.

In that study, participants were randomized to a daily dosage of 0.25 mg of lasofoxifene, 0.5 mg of lasofoxifene, or placebo. For the first 3 years of this trial, which took place at 113 sites in 32 countries, the primary endpoint was vertebral fracture. For the first 5 years of the trial, co-primary endpoints were nonvertebral fracture and breast cancer. Mean age of participants was 67 years (age range, 59 to 80 years), and 28% had at least one baseline vertebral fracture, as defined by radiograph.

At the 0.5-mg dosage (the one suggested to the FDA), lasofoxifene reduced the rate of nonvertebral fracture by 24% (P =.002). It reduced vertebral fracture by 42% (P < .001). And it reduced estrogen-receptor–positive breast cancer (P < .001) and all invasive breast cancer (P < .001) by 81% and 85%, respectively. As for major coronary heart disease events (P < .02) and stroke (P =.04), lasofoxifene reduced them by 32% and 36%, respectively.

Lasofoxifene is the first SERM to reduce nonvertebral fracture. Although no significant reduction in hip fracture was observed in this trial, the small number of cases may have been a factor (incidence <1%).

As it does with other SERMs and estrogen, the risk of thromboembolic events increased significantly (HR, 2.06), as did pulmonary embolism (HR, 4.49). Fatal stroke, for which raloxifene was given a boxed warning by the FDA, did not increase significantly with lasofoxifene.

The gynecologic effects of lasofoxifene (reported separately) did not include an increased risk of endometrial cancer or hyperplasia. Although the incidence of endometrial polyps did increase, the polyps were all inactive. Vaginal bleeding, secondary to atrophy, doubled in comparison with placebo.

All-cause mortality did not increase significantly among women taking a daily dosage of 0.5 mg of lasofoxifene, but it did among those taking a dosage of 0.25 mg (38%) (P =.05). And only with the 0.25-mg dosage was there a trend toward more overall deaths due to cancer (P =.06). A biologic reason for these differences in the rate of death is lacking, but the fact that there was no increased mortality at the higher dosage suggests that the difference might be due to chance.

We want to hear from you! Tell us what you think.

The past year has seen continuing variety in pharmaceutical and nonpharmaceutical approaches to osteoporosis, which remains—and will remain—a significant source of morbidity and mortality as the Baby Boom generation ages. As more people who are less healthy live longer, the sequelae of fragility fractures, mainly of the hip and spine, will increase as well, unless we continue to make strides in the identification of risk and in the prevention, detection, and treatment of osteoporosis.

In this article, I highlight:

• two trials of the newly FDA-approved denosumab (Prolia) that demonstrate its benefits and risks
• a recent report on osteonecrosis of the jaw in bisphosphonate users, including low-risk women taking an oral formulation
• guidance from Canada on how to derive maximum benefit from vitamin D
• disappointing findings on the benefits of resistance training for women
• two studies detailing the benefits of another SERM, lasofoxifene.

Denosumab outperforms alendronate as well as placebo

Cummings SR, San Martin J, McClung MR, et al; for FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.

Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial [published online ahead of print December 14, 2009]. J Bone Miner Res. doi:10.1359/jbmr.080910.

In their report from the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), Cummings and colleagues describe this prospective, placebo-controlled study of 7,868 postmenopausal women, all with a T-score worse than –2.5. Participants were randomized to 60 mg of subcutaneous denosumab or placebo every 6 months for 3 years. Those taking denosumab experienced a 68% reduction in the rate of new vertebral fracture (P < .001), a 20% reduction in nonvertebral fracture (P =.02), and a 40% reduction in hip fracture (P =.04), compared with placebo.

Denosumab is a fully human monoclonal antibody against the receptor activator of RANKL, which is a cytokine essential for the formation, function, and survival of osteoclasts. By binding to RANKL, denosumab prevents the usual interaction between RANKL and its receptor on osteoclast precursors and osteoclasts. And by preventing this interaction, denosumab reversibly inhibits osteoclast-mediated bone resorption, thereby reducing bone turnover and increasing bone mineral density (BMD).

Denosumab received FDA approval in June 2010 for the treatment of osteoporosis in postmenopausal women who have a high risk of fracture (defined as a history of osteoporotic fracture, the presence of multiple risk factors for fracture, or the failure of or intolerance to another form of osteoporosis therapy).

Details of the FREEDOM trial

The average age of women in the trial was 72.3 years (range, 60 to 90 years). At baseline, 23% of participants had a preexisting vertebral fracture. The primary endpoint was new vertebral fracture, with nonvertebral fracture and hip fracture as secondary endpoints.

No significant differences were found between denosumab and placebo in:

• total incidence of adverse events
• serious adverse events
• discontinuation of treatment because of adverse events
• overall incidence of cancer
• overall incidence of cardiovascular events
• adverse or serious adverse events of infection
• local reactions at the site of injection.

No neutralizing antibodies developed in either group.

Four cases of opportunistic infection were reported in the denosumab group, and three were reported in the placebo group. Eczema was reported by 3% of women in the denosumab group, versus 1.7% in the placebo group (P < .001). Falls that were not associated with a fracture were reported by 4.5% of subjects taking denosumab, versus 5.7% of those taking placebo (P =.02). Flatulence was more common among women taking denosumab (2.2%) than among those taking placebo (1.4%) (P =.008). Twelve women (0.3%) in the denosumab group reported serious adverse events of cellulitis, compared with one woman taking placebo (<0.1%) (P =.002).

Seventy women (1.8%) died in the denosumab group, compared with 90 (2.3%) in the placebo group (P =.08).

Denosumab versus alendronate

Brown and associates compared denosumab and alendronate in a randomized, blinded trial of 1,189 postmenopausal women who had a T-score worse than –2.0 at the lumbar spine or total hip. At month 12, denosumab significantly increased BMD at the total hip, compared with alendronate (3.5% versus 2.6%) (P < .0001). Compared with alendronate, denosumab also increased BMD in the:

• femoral neck (0.6%)
• trochanter (1.0%)
• lumbar spine (1.1%)
• 1/3 radius (0.6%) (P ≤ .0002 for all sites).

Denosumab led to significantly greater reduction of bone turnover markers than did alendronate therapy. Unlike bisphosphonates, denosumab is not retained in bone.

Participants were randomized 1:1 to:

• 60 mg subcutaneous denosumab injection every 6 months plus oral placebo weekly (n=594)
• 70 mg of oral alendronate weekly plus subcutaneous placebo injections every 6 months (n=595).

BMD was assessed at 6 and 12 months, and bone turnover markers were assessed at 1, 3, 6, 9, and 12 months. Safety was evaluated by monitoring adverse events and laboratory values.

No significant difference between denosumab and alendronate was observed in the overall incidence of adverse events (80.9% versus 82.3%, respectively) (P =.60), including gastrointestinal disorders, infections, and neoplasms. Most adverse events were mild or moderate in severity. Treatment-related adverse events were similar between groups (17% and 18.3% for denosumab and alendronate, respectively). Similar numbers of women experienced serious adverse events (34 women [5.7%] taking denosumab versus 37 [6.3%] taking alendronate). The overall safety profile was similar for both drugs.

Is osteonecrosis of the jaw a concern with denosumab?

The package insert for Prolia mentions that osteonecrosis of the jaw (ONJ) can “occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has been reported in patients receiving Prolia.”

Although no cases of ONJ were reported in the FREEDOM trial, a letter by Kyrgidis and Toolis to Osteoporosis International makes the point that ONJ may not be related solely to bisphosphonate use.¹ Taylor and colleagues described a case of a cancer patient who had never taken a bisphosphonate but who was treated with denosumab and later developed ONJ.² Kyrgidis and Toolis refer to presentations in the European Journal of Cancer Supplements that reported on head-to-head trials of denosumab and intravenous zoledronic acid in the treatment of bone metastases in cancer patients.¹ In one trial, the incidence of ONJ with denosumab was 2.0%, compared with 1.4% for zoledronic acid (P =.31). In another trial, the incidence of ONJ was 1.1% for denosumab and 1.3% for zoledronic acid (P =1.0). Kyrgidis and Toolis concluded that the association between ONJ and denosumab appears to be somewhat dose-related, as it is with bisphosphonate-related ONJ.

Plausible mechanisms for denosumab-related and bisphosphonate-related ONJ include defective osteoclast differentiation, function, survival, and “fatigue.”

Because denosumab has a shorter clearance time than bisphosphonates do, it seems feasible that treatment of denosumab-related ONJ will be easier and healing earlier than with bisphosphonate-related ONJ.

Osteonecrosis of the jaw in bisphosphonate users

Otto S, Abu-Id MH, Fedele S, et al. Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence—a multi-centre study [published online ahead of print June 25, 2010]. J Craniomaxillofac Surg. doi:10.1016/j.jcms.2010.05.009.

ONJ is a serious side effect well known to practitioners of maxillofacial surgery.³ Most research into the condition has focused on patients who have bone metastasis who have received intravenous bisphosphonates. In this report, Otto and colleagues describe a large multicenter trial at 11 European centers from 2004 through 2008. ONJ occurred in 470 patients taking a bisphosphonate. Each case was clinically examined, and a detailed history was supplied.

Although more than 90% of these cases were associated with intravenous bisphosphonate use, mainly in cancer patients who had bony metastasis, 37 cases (7.8%) occurred in women taking an oral bisphosphonate for osteoporosis. Of these, only 43% had any of the risk factors defined by the American Association of Oral and Maxillofacial Surgery (such as duration of bisphosphonate use and previous dental procedures). That means that 57% of these cases would be considered low-risk.

In this group of oral bisphosphonate users, patients tended to be older and had been on bisphosphonate therapy longer than patients in the high-risk group. Overall, 78% of the oral users who developed ONJ had been taking a bisphosphonate longer than 3 years.

Vitamin D guidelines emphasize its importance and versatility

Hanley DA, Cranney A, Jones G, et al; for the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ. 2010;182(12):E610-E618.

The Institute of Medicine is expected to release a comprehensive report on Vitamin D late this fall. In the meantime, the Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada has published its own set of guidelines that underscores the importance of adequate vitamin D intake to ensure bone health and help prevent osteoporosis.

Here are a few points taken from these guidelines:

• Vitamin D is an essential nutrient in the prevention of osteoporosis. It may reduce the risk of other medical disorders unrelated to bone and mineral metabolism.

• Vitamin D₃ may be better utilized in the body. After synthesis in the skin or dietary ingestion, vitamin D is removed from the bloodstream into various tissues, including the liver, adipose tissue, and muscle. Its biologic half-life is about 60 days, and it is eventually converted to 25-hydroxyvitamin D in the hepatocytes. Vitamin D₃ (cholecalciferol) is the molecule synthesized in the skin in response to ultraviolet B radiation, whereas vitamin D₂ (ergocalciferol) is derived from irradiation of certain fungi. Both vitamin D₂ and vitamin D₃ create 1,25-dihydroxyvitamin D, the active form, although there is some evidence that vitamin D₂ may not be used in the body as efficiently as vitamin D₃. Most vitamin D supplements consist of vitamin D₃, but high-dose preparations, available by prescription, are vitamin D₂.

• Vitamin D deficiency is a continuum. The term “deficiency” was previously used to describe the advanced clinical effects of chronically low vitamin D. “Insufficiency” described a milder form of deficiency in which reduced absorption of calcium and the resultant mild secondary hyperparathyroidism might increase bone loss.

• Don’t rely on sunlight. Ultraviolet B radiation (wavelength 290–315 nm) promotes synthesis of vitamin D. The amount of exposure needed to achieve adequate vitamin D status depends on latitude, altitude, time of year and day, weather, other environmental characteristics, age, skin pigmentation, clothing, activity, and the amount of skin irradiated. The influence of diet on vitamin D status is minimal, and most circulating vitamin D is derived from exposure to sunlight. Dermatologists recommend that the safest course is to avoid exposure to the sun and to take vitamin D supplements.

• Vitamin D insufficiency has been associated with malignancies (especially colorectal cancer), diabetes, multiple sclerosis, and impaired immune response. The benefits of vitamin D for these nontraditional roles are associated with 25-hydroxyvitamin D levels above 75 nmol/L.

• What is an optimal serum level? To most consistently improve clinical outcomes such as fracture risk, an optimal serum level of 25-hydroxyvitamin D is probably above 75 nmol/L; for most patients, supplementation is needed to achieve this level.

• The recommended vitamin D intake is 10 μg to 25 μg (400–1,000 IU) daily for low-risk adults younger than 50 years, and 20 μg to 50 μg (800–2,000 IU) for high-risk and older adults, with consideration of higher dosages.

• Consider monitoring vitamin D intake. A dosage as high as 50 μg (2,000 IU) requires no monitoring. If a higher dosage is needed, monitoring is appropriate.

Resistance training provides greater benefits for men than for women

Martyn-St. James M, Carroll S. Progressive high-intensity resistance training and bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects. Sports Med. 2006;36(8):683–704.

Most of our patients believe that weight-bearing exercise “builds bone.” Although the importance of maintaining adequate flexibility, agility, mobility, and strength is obvious in terms of fall prevention, its role in increasing bone mass has been unclear. As early as 2006, Martyn-St. James reported that a high-intensity progressive resistance training program in premenopausal women significantly increased absolute BMD at the lumbar spine, but not at the femoral neck.

Earlier this year Bemben and Bemben reported their findings in regard to 45 men and 79 women 55 to 74 years old who undertook either high-intensity or low-intensity resistance training either 2 or 3 days a week.⁴ Regardless of intensity and frequency, resistance training improved BMD of the proximal femur and lumbar spine but not the total body. Men and women responded similarly at the hip, but men had a greater response at the lumbar spine than women did.

Last, Almstedt and colleagues explored changes in BMD in response to 24 weeks of resistance training among college-aged men and women.⁵ Men had significantly greater increases in BMD at the lateral spine and femoral neck.

Overall, male exercisers experienced an increase in BMD of 2.7% to 7.7%, whereas women experienced an increase of 0.8% to 1.5%, depending on the bone site. In the control group, both men and women experienced an increase of approximately 1% at any bone site. These findings indicate that 24 weeks of resistance training, including squat and dead-lift exercises, is effective in increasing BMD in young, healthy men. Similar benefits were not obtained by women who followed the same protocol.

Lasofoxifene gets the nod—in Europe, not the United States

Cummings SR, Ensrud K, Delmas PD, et al; for PEARL Study Investigators. Lasofoxifene in post-menopausal women with osteoporosis. N Engl J Med. 2010;362(8):686–696.

Goldstein SR, Neven P, Cummings S, et al. Postmenopausal evaluation and risk reduction with lasofoxifene trial: 5-year gynecological outcomes [published online ahead of print August 3, 2010]. Menopause. doi:10.1097/gme.0b013e3181e84bb4.

On September 8, 2008, an FDA advisory panel voted 9–3 in support of this statement: “There is a population of postmenopausal women with osteoporosis in which the benefits of lasofoxifene likely outweigh the risks.” However, the FDA decided against approval of lasofoxifene, a new SERM developed for the treatment of osteoporosis in postmenopausal women. The drug has been approved outside the United States, most notably in the European Union.

The reasoning behind the FDA’s failure to approve the SERM is unclear. As Cummings and associates report in the PEARL trial (Postmenopausal Evaluation and Risk Reduction with Laxofoxifene), an international, randomized, placebo-controlled study of 8,556 postmenopausal women who had T-scores worse than –2.5, the drug had a favorable therapeutic profile.

In that study, participants were randomized to a daily dosage of 0.25 mg of lasofoxifene, 0.5 mg of lasofoxifene, or placebo. For the first 3 years of this trial, which took place at 113 sites in 32 countries, the primary endpoint was vertebral fracture. For the first 5 years of the trial, co-primary endpoints were nonvertebral fracture and breast cancer. Mean age of participants was 67 years (age range, 59 to 80 years), and 28% had at least one baseline vertebral fracture, as defined by radiograph.

At the 0.5-mg dosage (the one suggested to the FDA), lasofoxifene reduced the rate of nonvertebral fracture by 24% (P =.002). It reduced vertebral fracture by 42% (P < .001). And it reduced estrogen-receptor–positive breast cancer (P < .001) and all invasive breast cancer (P < .001) by 81% and 85%, respectively. As for major coronary heart disease events (P < .02) and stroke (P =.04), lasofoxifene reduced them by 32% and 36%, respectively.

Lasofoxifene is the first SERM to reduce nonvertebral fracture. Although no significant reduction in hip fracture was observed in this trial, the small number of cases may have been a factor (incidence <1%).

As it does with other SERMs and estrogen, the risk of thromboembolic events increased significantly (HR, 2.06), as did pulmonary embolism (HR, 4.49). Fatal stroke, for which raloxifene was given a boxed warning by the FDA, did not increase significantly with lasofoxifene.

The gynecologic effects of lasofoxifene (reported separately) did not include an increased risk of endometrial cancer or hyperplasia. Although the incidence of endometrial polyps did increase, the polyps were all inactive. Vaginal bleeding, secondary to atrophy, doubled in comparison with placebo.

All-cause mortality did not increase significantly among women taking a daily dosage of 0.5 mg of lasofoxifene, but it did among those taking a dosage of 0.25 mg (38%) (P =.05). And only with the 0.25-mg dosage was there a trend toward more overall deaths due to cancer (P =.06). A biologic reason for these differences in the rate of death is lacking, but the fact that there was no increased mortality at the higher dosage suggests that the difference might be due to chance.

We want to hear from you! Tell us what you think.

Although roughly three quarters of ovarian neoplasms occur in premenopausal women, 87% of masses in this population are benign. The vast majority of malignant neoplasms—about 75%—are diagnosed in postmenopausal women.

These figures suggest that you have some discerning to do. Specifically, how do you identify the small percentage of masses in premenopausal women that are malignant—and winnow out the benign neoplasms in the postmenopausal population?

Now that we’ve equipped you with an understanding of the morphologic building blocks of adnexal masses, and how those masses are assessed using ultrasonography (US) (described in Part 2 of this four-part series), you can apply your skills of discernment to ovarian neoplasms. Specifically:

• teratoma (dermoid cyst)—one of the two most prevalent benign neoplasms of the ovary
• serous cystadenoma—the other most prevalent benign neoplasm
• hormone-secreting tumors
• malignant neoplasms.

Recall that Part 1 of this series offered a starting point for US imaging of the adnexae by describing (and showing) how basic pelvic structures appear in grayscale US and color and power Doppler. Part 2 focused on non-neoplastic ovarian masses. Part 4 will take as its subject tubal entities such as torsion, ectopic pregnancy, and cancer.

Teratomas present a variety of “faces”

Teratomas may appear to be solid, cystic, or both (FIGURE 1). At times, they have a bizarre or variable appearance. The overwhelming majority of teratomas can be recognized by shadowing, which may be extreme if the tumor contains a solid, echogenic central mass (FIGURE 1A). Such an echogenic core is sometimes called the “fried egg” sign when it is detected by transabdominal US.

FIGURE 1 Cystic and solid benign teratomas

A. Shadowing (small arrows) is apparent in a teratoma containing low-level echoic fluid. B. Several spherical “balls” floating in a cystic teratoma, with shadowing. C. Solid teratoma. D. A “typical” teratoma, with septation and multilocularity. E. Macroscopic view of an ovarian teratoma (arrow). F. Multiple sebaceous ball-shaped structures within a benign cystic teratoma (inset: macroscopic view).When the teratoma is cystic or partially cystic, it may contain a linear hyperechoic area consistent with sebaceous fluid and hair. Although magnetic resonance imaging (MRI) can confirm the fat content of a teratoma, US is very efficient in making the diagnosis, rendering MRI unnecessary.

As for blood vessels, teratomas are known to have scant or no apparent vascularity. A rule of thumb: If a bizarre adnexal structure with no vascularity is visible on US, and if it is cystic or solid in appearance (or both), benign teratoma should be included in the differential diagnosis.

Because an ovarian teratoma can assume almost any shape and form, three-dimensional (3D) US is almost useless in its evaluation.

Cystadenomas are relatively easy to identify on US

Benign cystadenomas—serous or mucinous—are extremely common. In at least 20% to 30% of cases, they are bilateral.

The US characteristics of these masses include:

• multilocularity, in many cases (although two thirds of simple unilocular cysts in postmenopausal women are serous cystadenomas)
• multiseptation, with the septae often fanning out from a central, apparently solid structure (FIGURE 2)
• anechoic nature when they contain fluid (in the serous variety) or with low-level echogenicity (in mucous cystadenomas).

FIGURE 2 Benign cystadenoma

A–C. Typical sonographic appearance of a benign cystadenoma, with septae fanning out from a solid area, creating an anechoic, fluid-filled, multilocular pattern. D. MRI appearance of the cyst (arrow points to solid area from which the septae fan out).As for vascularity, cystadenomas have a paucity of core vessels and have, if measured quantitatively, what we consider to be normal resistive and pulsatility indices and low peak systolic velocity. Histologically, they are benign. These neoplasms can be identified using US with relative ease and high confidence, rendering computed tomography (CT) and MRI (FIGURE 2D) virtually redundant.

When US characteristics overlap

Based on our 20 years of experience with US assessment of adnexal masses, and the potential overlap (on grayscale as well as color and power Doppler) between the US appearance of endometriomas, cystadenomas, and cystic teratomas, we recommend that, when a mass is not pathognomonic on US, this triad of entities be considered in the differential diagnosis. The entity that has the greatest number of relevant characteristics should be listed as the most likely and first possibility on the US report.

(For a description of the US appearance of endometriomas, see Part 2 of this series, which appeared in the October 2010 issue of OBG Management.)

Hormone-secreting tumors are small and symptomatic

Although hormone-secreting tumors are not malignant in the strict sense of the definition, they should be mentioned here because of the high probability that they can be diagnosed by transvaginal sonography (TVS). These tumors are small, hiding at times in an ovary of almost normal size. They are also vascular, featuring a characteristic ring-like pattern, much like that of the corpus luteum, on color or power Doppler. They also produce general and clear clinical symptoms and signs. For example, testosterone-like tumors cause male-pattern baldness, hirsutism, and voice changes.

Many providers suspect a hormone-secreting tumor based on its signs and symptoms, and seek US confirmation from us. In many of these cases, laboratory tests have been done and point to the possible diagnosis—e.g., a high testosterone level in the case of a Sertoli-Leydig cell tumor.

One typical estrogen-secreting tumor is the granulosa cell tumor (FIGURE 3). This tumor can usually be identified by the solid-appearing tissue surrounding multiple cysts of different sizes; it is typically richly supplied with blood vessels.

Another clue to the diagnosis is the state of the endometrium. Because a granulosa cell tumor secretes estrogen, it causes a thickened endometrial lining and, usually, abnormal uterine bleeding.

FIGURE 3 Granulosa cell tumor

A. Sagittal image of the uterus demonstrating a thick, hyperechoic endometrial echo under hormonal stimulation of the tumor. B. Multicystic and solid areas alternate in the enlarged uterus. Power Doppler demonstrates the typical increased vascularity. (The arrows point to the cystic area of the tumor.)

Malignant ovarian neoplasms are rare

As a rule, the larger the lesion, the more suspicious it is.

Malignant tumors usually have a complex appearance:

• thick walls (≥4 mm)
• heterogeneous texture
• multilocularity
• solid components
• papillary excrescences within the tumor as well as on the outer surface (FIGURE 4A and 4B).

FIGURE 4 Adenocarcinoma of the ovary

A. An enlarged right ovary containing several cystic structures. B. Right ovary and transverse section of the uterus. C, D. Power Doppler evaluation demonstrating rich vascularization. E. 3D orthogonal planes and volume calculation of the ovary (31.1 cc). F. 3D angiogram (lower right image) of the rich vascularization of the cancer. G. Relationship between the vascular right ovary and the uterus.Tumor vascularity is another marker suggestive of ovarian malignancy (FIGURE 4C and 4D). A fast-growing tumor requires a vascular “infrastructure,” a mesh of blood vessels that is laid down in expedited fashion and that is controlled by vascular growth factors. As explained in Part 2 of this series, the vessels in this vascular mesh lack the muscular layer of normal vessels. They frequently are intertwined, forming anastomoses and vascular lakes through which blood flows without much resistance. Look, therefore, for low resistance and high-velocity flow.

A new way to employ 3D US is to detect, measure, and quantify the blood supply to a tumor. FIGURE 4E shows how the vascularity and volume of an ovarian mass are calculated, with 3D angiographic display of the blood vessels contained within it demonstrated in FIGURE 4F. This vascular pattern can also be viewed in the context of the pelvic organs (FIGURE 4G), an approach that is useful in teaching.

Recently, Sladkevicus and colleagues used 3D US angiography to define tumor vascularity, identifying straight vessels, those that had changes in caliber, and bridging between vessels.¹ They studied 104 patients who had 77 benign tumors, 6 borderline tumors, and 21 cancers. The researchers concluded that dense vessel patterns in the tumor made malignancy five times more likely. Widely dispersed straight vessels without branching were the strongest predictors of benign status, reducing the likelihood of malignancy by a factor of 10.¹

We described the importance of a finding of blood vessels in an internal papillary structure as an accurate predictor of malignancy. We focused on a small volume of the mass, which was selected by a software program, and found that a preselected volume of 1 cc could reliably predict an increased, and pathological, vascular supply to an ovary containing cancer.^2,3

Stay tuned!

In the final installment of this series, coming next month, we discuss the use of US imaging to evaluate tubal anomalies, including torsion, ectopic pregnancy, and cancer.

We want to hear from you! Tell us what you think.

Although roughly three quarters of ovarian neoplasms occur in premenopausal women, 87% of masses in this population are benign. The vast majority of malignant neoplasms—about 75%—are diagnosed in postmenopausal women.

These figures suggest that you have some discerning to do. Specifically, how do you identify the small percentage of masses in premenopausal women that are malignant—and winnow out the benign neoplasms in the postmenopausal population?

Now that we’ve equipped you with an understanding of the morphologic building blocks of adnexal masses, and how those masses are assessed using ultrasonography (US) (described in Part 2 of this four-part series), you can apply your skills of discernment to ovarian neoplasms. Specifically:

• teratoma (dermoid cyst)—one of the two most prevalent benign neoplasms of the ovary
• serous cystadenoma—the other most prevalent benign neoplasm
• hormone-secreting tumors
• malignant neoplasms.

Recall that Part 1 of this series offered a starting point for US imaging of the adnexae by describing (and showing) how basic pelvic structures appear in grayscale US and color and power Doppler. Part 2 focused on non-neoplastic ovarian masses. Part 4 will take as its subject tubal entities such as torsion, ectopic pregnancy, and cancer.

Teratomas present a variety of “faces”

Teratomas may appear to be solid, cystic, or both (FIGURE 1). At times, they have a bizarre or variable appearance. The overwhelming majority of teratomas can be recognized by shadowing, which may be extreme if the tumor contains a solid, echogenic central mass (FIGURE 1A). Such an echogenic core is sometimes called the “fried egg” sign when it is detected by transabdominal US.

FIGURE 1 Cystic and solid benign teratomas

A. Shadowing (small arrows) is apparent in a teratoma containing low-level echoic fluid. B. Several spherical “balls” floating in a cystic teratoma, with shadowing. C. Solid teratoma. D. A “typical” teratoma, with septation and multilocularity. E. Macroscopic view of an ovarian teratoma (arrow). F. Multiple sebaceous ball-shaped structures within a benign cystic teratoma (inset: macroscopic view).When the teratoma is cystic or partially cystic, it may contain a linear hyperechoic area consistent with sebaceous fluid and hair. Although magnetic resonance imaging (MRI) can confirm the fat content of a teratoma, US is very efficient in making the diagnosis, rendering MRI unnecessary.

As for blood vessels, teratomas are known to have scant or no apparent vascularity. A rule of thumb: If a bizarre adnexal structure with no vascularity is visible on US, and if it is cystic or solid in appearance (or both), benign teratoma should be included in the differential diagnosis.

Because an ovarian teratoma can assume almost any shape and form, three-dimensional (3D) US is almost useless in its evaluation.

Cystadenomas are relatively easy to identify on US

Benign cystadenomas—serous or mucinous—are extremely common. In at least 20% to 30% of cases, they are bilateral.

The US characteristics of these masses include:

• multilocularity, in many cases (although two thirds of simple unilocular cysts in postmenopausal women are serous cystadenomas)
• multiseptation, with the septae often fanning out from a central, apparently solid structure (FIGURE 2)
• anechoic nature when they contain fluid (in the serous variety) or with low-level echogenicity (in mucous cystadenomas).

FIGURE 2 Benign cystadenoma

A–C. Typical sonographic appearance of a benign cystadenoma, with septae fanning out from a solid area, creating an anechoic, fluid-filled, multilocular pattern. D. MRI appearance of the cyst (arrow points to solid area from which the septae fan out).As for vascularity, cystadenomas have a paucity of core vessels and have, if measured quantitatively, what we consider to be normal resistive and pulsatility indices and low peak systolic velocity. Histologically, they are benign. These neoplasms can be identified using US with relative ease and high confidence, rendering computed tomography (CT) and MRI (FIGURE 2D) virtually redundant.

When US characteristics overlap

Based on our 20 years of experience with US assessment of adnexal masses, and the potential overlap (on grayscale as well as color and power Doppler) between the US appearance of endometriomas, cystadenomas, and cystic teratomas, we recommend that, when a mass is not pathognomonic on US, this triad of entities be considered in the differential diagnosis. The entity that has the greatest number of relevant characteristics should be listed as the most likely and first possibility on the US report.

(For a description of the US appearance of endometriomas, see Part 2 of this series, which appeared in the October 2010 issue of OBG Management.)

Hormone-secreting tumors are small and symptomatic

Although hormone-secreting tumors are not malignant in the strict sense of the definition, they should be mentioned here because of the high probability that they can be diagnosed by transvaginal sonography (TVS). These tumors are small, hiding at times in an ovary of almost normal size. They are also vascular, featuring a characteristic ring-like pattern, much like that of the corpus luteum, on color or power Doppler. They also produce general and clear clinical symptoms and signs. For example, testosterone-like tumors cause male-pattern baldness, hirsutism, and voice changes.

Many providers suspect a hormone-secreting tumor based on its signs and symptoms, and seek US confirmation from us. In many of these cases, laboratory tests have been done and point to the possible diagnosis—e.g., a high testosterone level in the case of a Sertoli-Leydig cell tumor.

One typical estrogen-secreting tumor is the granulosa cell tumor (FIGURE 3). This tumor can usually be identified by the solid-appearing tissue surrounding multiple cysts of different sizes; it is typically richly supplied with blood vessels.

Another clue to the diagnosis is the state of the endometrium. Because a granulosa cell tumor secretes estrogen, it causes a thickened endometrial lining and, usually, abnormal uterine bleeding.

FIGURE 3 Granulosa cell tumor

A. Sagittal image of the uterus demonstrating a thick, hyperechoic endometrial echo under hormonal stimulation of the tumor. B. Multicystic and solid areas alternate in the enlarged uterus. Power Doppler demonstrates the typical increased vascularity. (The arrows point to the cystic area of the tumor.)

Malignant ovarian neoplasms are rare

As a rule, the larger the lesion, the more suspicious it is.

Malignant tumors usually have a complex appearance:

• thick walls (≥4 mm)
• heterogeneous texture
• multilocularity
• solid components
• papillary excrescences within the tumor as well as on the outer surface (FIGURE 4A and 4B).

FIGURE 4 Adenocarcinoma of the ovary

A. An enlarged right ovary containing several cystic structures. B. Right ovary and transverse section of the uterus. C, D. Power Doppler evaluation demonstrating rich vascularization. E. 3D orthogonal planes and volume calculation of the ovary (31.1 cc). F. 3D angiogram (lower right image) of the rich vascularization of the cancer. G. Relationship between the vascular right ovary and the uterus.Tumor vascularity is another marker suggestive of ovarian malignancy (FIGURE 4C and 4D). A fast-growing tumor requires a vascular “infrastructure,” a mesh of blood vessels that is laid down in expedited fashion and that is controlled by vascular growth factors. As explained in Part 2 of this series, the vessels in this vascular mesh lack the muscular layer of normal vessels. They frequently are intertwined, forming anastomoses and vascular lakes through which blood flows without much resistance. Look, therefore, for low resistance and high-velocity flow.

A new way to employ 3D US is to detect, measure, and quantify the blood supply to a tumor. FIGURE 4E shows how the vascularity and volume of an ovarian mass are calculated, with 3D angiographic display of the blood vessels contained within it demonstrated in FIGURE 4F. This vascular pattern can also be viewed in the context of the pelvic organs (FIGURE 4G), an approach that is useful in teaching.

Recently, Sladkevicus and colleagues used 3D US angiography to define tumor vascularity, identifying straight vessels, those that had changes in caliber, and bridging between vessels.¹ They studied 104 patients who had 77 benign tumors, 6 borderline tumors, and 21 cancers. The researchers concluded that dense vessel patterns in the tumor made malignancy five times more likely. Widely dispersed straight vessels without branching were the strongest predictors of benign status, reducing the likelihood of malignancy by a factor of 10.¹

We described the importance of a finding of blood vessels in an internal papillary structure as an accurate predictor of malignancy. We focused on a small volume of the mass, which was selected by a software program, and found that a preselected volume of 1 cc could reliably predict an increased, and pathological, vascular supply to an ovary containing cancer.^2,3

Stay tuned!

In the final installment of this series, coming next month, we discuss the use of US imaging to evaluate tubal anomalies, including torsion, ectopic pregnancy, and cancer.

We want to hear from you! Tell us what you think.

Although roughly three quarters of ovarian neoplasms occur in premenopausal women, 87% of masses in this population are benign. The vast majority of malignant neoplasms—about 75%—are diagnosed in postmenopausal women.

These figures suggest that you have some discerning to do. Specifically, how do you identify the small percentage of masses in premenopausal women that are malignant—and winnow out the benign neoplasms in the postmenopausal population?

Now that we’ve equipped you with an understanding of the morphologic building blocks of adnexal masses, and how those masses are assessed using ultrasonography (US) (described in Part 2 of this four-part series), you can apply your skills of discernment to ovarian neoplasms. Specifically:

• teratoma (dermoid cyst)—one of the two most prevalent benign neoplasms of the ovary
• serous cystadenoma—the other most prevalent benign neoplasm
• hormone-secreting tumors
• malignant neoplasms.

Recall that Part 1 of this series offered a starting point for US imaging of the adnexae by describing (and showing) how basic pelvic structures appear in grayscale US and color and power Doppler. Part 2 focused on non-neoplastic ovarian masses. Part 4 will take as its subject tubal entities such as torsion, ectopic pregnancy, and cancer.

Teratomas present a variety of “faces”

Teratomas may appear to be solid, cystic, or both (FIGURE 1). At times, they have a bizarre or variable appearance. The overwhelming majority of teratomas can be recognized by shadowing, which may be extreme if the tumor contains a solid, echogenic central mass (FIGURE 1A). Such an echogenic core is sometimes called the “fried egg” sign when it is detected by transabdominal US.

FIGURE 1 Cystic and solid benign teratomas

A. Shadowing (small arrows) is apparent in a teratoma containing low-level echoic fluid. B. Several spherical “balls” floating in a cystic teratoma, with shadowing. C. Solid teratoma. D. A “typical” teratoma, with septation and multilocularity. E. Macroscopic view of an ovarian teratoma (arrow). F. Multiple sebaceous ball-shaped structures within a benign cystic teratoma (inset: macroscopic view).When the teratoma is cystic or partially cystic, it may contain a linear hyperechoic area consistent with sebaceous fluid and hair. Although magnetic resonance imaging (MRI) can confirm the fat content of a teratoma, US is very efficient in making the diagnosis, rendering MRI unnecessary.

As for blood vessels, teratomas are known to have scant or no apparent vascularity. A rule of thumb: If a bizarre adnexal structure with no vascularity is visible on US, and if it is cystic or solid in appearance (or both), benign teratoma should be included in the differential diagnosis.

Because an ovarian teratoma can assume almost any shape and form, three-dimensional (3D) US is almost useless in its evaluation.

Cystadenomas are relatively easy to identify on US

Benign cystadenomas—serous or mucinous—are extremely common. In at least 20% to 30% of cases, they are bilateral.

The US characteristics of these masses include:

• multilocularity, in many cases (although two thirds of simple unilocular cysts in postmenopausal women are serous cystadenomas)
• multiseptation, with the septae often fanning out from a central, apparently solid structure (FIGURE 2)
• anechoic nature when they contain fluid (in the serous variety) or with low-level echogenicity (in mucous cystadenomas).

FIGURE 2 Benign cystadenoma

A–C. Typical sonographic appearance of a benign cystadenoma, with septae fanning out from a solid area, creating an anechoic, fluid-filled, multilocular pattern. D. MRI appearance of the cyst (arrow points to solid area from which the septae fan out).As for vascularity, cystadenomas have a paucity of core vessels and have, if measured quantitatively, what we consider to be normal resistive and pulsatility indices and low peak systolic velocity. Histologically, they are benign. These neoplasms can be identified using US with relative ease and high confidence, rendering computed tomography (CT) and MRI (FIGURE 2D) virtually redundant.

When US characteristics overlap

Based on our 20 years of experience with US assessment of adnexal masses, and the potential overlap (on grayscale as well as color and power Doppler) between the US appearance of endometriomas, cystadenomas, and cystic teratomas, we recommend that, when a mass is not pathognomonic on US, this triad of entities be considered in the differential diagnosis. The entity that has the greatest number of relevant characteristics should be listed as the most likely and first possibility on the US report.

(For a description of the US appearance of endometriomas, see Part 2 of this series, which appeared in the October 2010 issue of OBG Management.)

Hormone-secreting tumors are small and symptomatic

Although hormone-secreting tumors are not malignant in the strict sense of the definition, they should be mentioned here because of the high probability that they can be diagnosed by transvaginal sonography (TVS). These tumors are small, hiding at times in an ovary of almost normal size. They are also vascular, featuring a characteristic ring-like pattern, much like that of the corpus luteum, on color or power Doppler. They also produce general and clear clinical symptoms and signs. For example, testosterone-like tumors cause male-pattern baldness, hirsutism, and voice changes.

Many providers suspect a hormone-secreting tumor based on its signs and symptoms, and seek US confirmation from us. In many of these cases, laboratory tests have been done and point to the possible diagnosis—e.g., a high testosterone level in the case of a Sertoli-Leydig cell tumor.

One typical estrogen-secreting tumor is the granulosa cell tumor (FIGURE 3). This tumor can usually be identified by the solid-appearing tissue surrounding multiple cysts of different sizes; it is typically richly supplied with blood vessels.

Another clue to the diagnosis is the state of the endometrium. Because a granulosa cell tumor secretes estrogen, it causes a thickened endometrial lining and, usually, abnormal uterine bleeding.

FIGURE 3 Granulosa cell tumor

A. Sagittal image of the uterus demonstrating a thick, hyperechoic endometrial echo under hormonal stimulation of the tumor. B. Multicystic and solid areas alternate in the enlarged uterus. Power Doppler demonstrates the typical increased vascularity. (The arrows point to the cystic area of the tumor.)

Malignant ovarian neoplasms are rare

As a rule, the larger the lesion, the more suspicious it is.

Malignant tumors usually have a complex appearance:

• thick walls (≥4 mm)
• heterogeneous texture
• multilocularity
• solid components
• papillary excrescences within the tumor as well as on the outer surface (FIGURE 4A and 4B).

FIGURE 4 Adenocarcinoma of the ovary

A. An enlarged right ovary containing several cystic structures. B. Right ovary and transverse section of the uterus. C, D. Power Doppler evaluation demonstrating rich vascularization. E. 3D orthogonal planes and volume calculation of the ovary (31.1 cc). F. 3D angiogram (lower right image) of the rich vascularization of the cancer. G. Relationship between the vascular right ovary and the uterus.Tumor vascularity is another marker suggestive of ovarian malignancy (FIGURE 4C and 4D). A fast-growing tumor requires a vascular “infrastructure,” a mesh of blood vessels that is laid down in expedited fashion and that is controlled by vascular growth factors. As explained in Part 2 of this series, the vessels in this vascular mesh lack the muscular layer of normal vessels. They frequently are intertwined, forming anastomoses and vascular lakes through which blood flows without much resistance. Look, therefore, for low resistance and high-velocity flow.

A new way to employ 3D US is to detect, measure, and quantify the blood supply to a tumor. FIGURE 4E shows how the vascularity and volume of an ovarian mass are calculated, with 3D angiographic display of the blood vessels contained within it demonstrated in FIGURE 4F. This vascular pattern can also be viewed in the context of the pelvic organs (FIGURE 4G), an approach that is useful in teaching.

Recently, Sladkevicus and colleagues used 3D US angiography to define tumor vascularity, identifying straight vessels, those that had changes in caliber, and bridging between vessels.¹ They studied 104 patients who had 77 benign tumors, 6 borderline tumors, and 21 cancers. The researchers concluded that dense vessel patterns in the tumor made malignancy five times more likely. Widely dispersed straight vessels without branching were the strongest predictors of benign status, reducing the likelihood of malignancy by a factor of 10.¹

We described the importance of a finding of blood vessels in an internal papillary structure as an accurate predictor of malignancy. We focused on a small volume of the mass, which was selected by a software program, and found that a preselected volume of 1 cc could reliably predict an increased, and pathological, vascular supply to an ovary containing cancer.^2,3

Stay tuned!

In the final installment of this series, coming next month, we discuss the use of US imaging to evaluate tubal anomalies, including torsion, ectopic pregnancy, and cancer.

We want to hear from you! Tell us what you think.

CASE: Is the vaginal route appropriate?

A 46-year-old woman (para 2 with 1 cesarean delivery) who has a history of benign menorrhagia comes to your office seeking definitive treatment after medical therapy fails to alleviate her bleeding. pelvic examination reveals a uterus of 14-weeks’ size that descends to the distal vagina, with good vaginal access. What options for hysterectomy do you offer to the patient?

There are few absolute contraindications to a vaginal approach to hysterectomy. Among them are advanced pelvic malignancy, severe endometriosis, and a suspicious adnexal mass. Contraindications do not include a history of pelvic surgery, cesarean delivery, or an enlarged uterus. Such circumstances may increase the challenges involved in performing vaginal hysterectomy, but data suggest that it is achievable in these settings.^1-7

Vaginal hysterectomy offers substantial benefits, making the challenges worthwhile in most cases. It is the original minimally invasive approach to hysterectomy. It yields outcomes, postoperative discomfort levels, and recovery times similar to those of laparoscopic-assisted vaginal hysterectomy, total laparoscopic hysterectomy, and robotic- assisted hysterectomy—but the vaginal approach is more cost-effective.^3,8-11

This article focuses on strategies and techniques for accomplishing the difficult vaginal hysterectomy, describing five keys to success:

• surgical experience
• adequate exposure
• entry into the anterior cul-de-sac
• uterine mobility (or the ability to create it)
• good morcellation technique.

For clarity throughout this article, we assume that hysterectomy is being performed for benign indications.

1. Surgical experience

Vaginal hysterectomy can be performed successfully in the setting of nulliparity, uterine enlargement, and a history of cesarean delivery, provided the surgeon has the appropriate skill set, assistance, and patience. Little is lost if the operation is attempted vaginally but needs to be converted to a laparoscopic or open approach. If the surgeon persists in attempting to complete each hysterectomy vaginally, he or she will gradually improve in skill and eventually gain the ability to complete tougher cases without the need to convert.

Chen and colleagues developed and validated the Vaginal Surgical Skills Index (VSSI), identifying 13 aspects of successful vaginal surgery:

• inspection
• incision
• maintenance of visibility
• use of assistance
• knowledge of instruments
• tissue and instrument handling
• electrosurgery
• knot-tying and ligation
• hemostasis
• procedure completion
• time and motion
• flow and forward planning
• knowledge of the procedure.¹²

Thirty-seven trainees from two institutions were evaluated during 76 surgical procedures. The trainees were supervised by five surgeons, who completed the evaluations immediately after each procedure. A sixth surgeon from a different institution watched videos of each procedure and acted as a blinded external reviewer.

Chen and colleagues found good inter-rater and intra-rater reliability and high internal consistency for the VSSI, one of the first tools to objectively assess vaginal surgery skills.

2. Obtaining adequate exposure

Good anesthesia, proper lighting, and fixed retraction are invaluable when operating vaginally. A weighted speculum with Deaver retractors at 3, 9, and 12 o’clock provide good visualization if assistants are available. Self- retaining retractors are also useful (FIGURE 1).

FIGURE 1 Fixed retraction

A Magrina-Bookwalter fixed vaginal retractor in place at the time of surgery.We prefer to empty the bladder before making the vaginal incision, although no data suggest that doing so helps to avoid inadvertent bladder injury.

3. Entry into the anterior cul-de-sac

We prefer to enter the anterior cul-de-sac first. The pertinent risk in vaginal hysterectomy is injury to the bladder. Because anatomic planes are undisturbed at this point, we feel entry into the anterior cul-de-sac gives the surgeon the best opportunity to avoid injury. If it is a struggle or lack of uterine descent makes it difficult, then start with entry into the posterior cul-de-sac (see “gaining mobility”).

FIGURE 2 Palpate the bladder reflection

A. Use the index finger to palpate the bladder reflection. B. Note it with a marking.In a patient who does not have a history of surgery, palpation of the bladder reflection on the anterior uterus can help determine the appropriate site for the initial incision (FIGURE 2). Place a Deaver retractor anteriorly to assist with retraction. It is important to make the first incision deep enough to set up entry into the anterior cul-de-sac (FIGURE 3).

FIGURE 3 Incise the vaginal epithelium

A sharp and deep incision aids in identification of the appropriate plane.With traction on the uterus, grasp the anterior vaginal epithelium and elevate it to allow sharp dissection and mobilization of the bladder (FIGURE 4). We prefer sharp dissection rather than blunt dissection because it maintains surgical planes and is more precise.

FIGURE 4 Dissect the bladder free of the uterus

We recommend sharp dissection to free the bladder from the uterus.Once the peritoneum is identified, grasp, elevate, and incise it (FIGURE 5). Insert scissors through the peritoneal defect, spread the tips widely, and place the anterior Deaver retractor intraperitoneally (FIGURE 6) so that bowel can be visualized (FIGURE 7).

FIGURE 5 Use traction and counter-traction

Sharp entry into the peritoneal cavity is enhanced through the use of traction and counter-traction.

FIGURE 6 Open the peritoneal defect

Place scissors into the peritoneal defect and spread the blades wide.

FIGURE 7 Visualize the bowel

Visualization of the bowel confirms an intraperitoneal location.

WATCH THE VIDEO: Vaginal hysterectomy with entry into the anterior cul-de-sac

If the patient has a history of cesarean delivery, entry into the anterior cul-de-sac can be more challenging. Several maneuvers can help avert bladder injury:

• Stay on the uterus during dissection into the vesicovaginal space. It is better to stay deep and cut into the uterus than to dissect superficially and end up with a cystotomy.
• Retrograde fill the bladder to identify the plane between the bladder and the uterus.
• Postpone entry into the anterior cul-desac until after posterior entry, ligation of the uterosacral ligaments, and the first “bite” of the cardinal ligaments.
• Use a uterine sound, bent into a “U” shape, passing it through the urethra into the bladder and allowing the point to come back toward the surgeon (while it is in the bladder). Manipulation of this sound through external palpation should make it possible to identify the bladder reflection.
• In the setting of a small uterus, after entering the posterior cul-de-sac, pass a finger along the back of the uterus, around the fundus, and back toward the surgeon. This maneuver identifies the optimal spot for dissection between the bladder and the uterus.

When cervical elongation is encountered during entry into the cul-de-sac, the peritoneal reflection will be higher (both anteriorly and posteriorly), and additional bites on the pedicles, as well as additional dissection, may be required before entry is accomplished (FIGURE 8).

FIGURE 8 When the cervix is elongated

When the cervix is elongated, the peritoneal reflection, both anteriorly and posteriorly, is much higher on the uterus (near the small myoma).

When cystotomy happens

If cystotomy occurs during an attempt to enter the anterior cul-de-sac, a number of steps can lead to successful repair. Rather than repair the defect immediately, mark it with a suture for later identification. Once the uterus is removed, inspect the bladder carefully to identify any additional injuries, then repair the cystotomy using absorbable 2-0 suture on a tapered needle (we prefer chromic suture).

Begin by taking a full-thickness bite of tissue, just lateral to the edge of the cystotomy. Then run the suture, incorporating the bladder epithelium into the closure. Place a second, imbricating layer of the same suture. Last, if possible, sew the peritoneum beneath the bladder over the repair for an additional layer of reinforcement.

WATCH THE VIDEO: Transvaginal cystotomy repair

Cystoscopy helps to visualize the repair and test for water-tightness, and assess ureteral patency.

Keep the bladder on catheter drainage for 10 to 14 days.

4. Gaining mobility

In the setting of nulliparity or a small, well-supported uterus, it may be necessary to create mobility to accomplish the hysterectomy vaginally. Begin by entering the posterior cul-de-sac and cutting and suture ligating the uterosacral ligaments. Then take the first bite of the cardinal pedicles bilaterally. This typically facilitates uterine descent, making it possible to enter the anterior culde-sac and accomplish the hysterectomy.

On occasion, once the uterine arteries have been secured, you can split (bi-valve) the uterus to gain access to the utero-ovarian pedicles and complete the hysterectomy.

5. Good morcellation technique

Morcellation facilitates removal of the large uterus. As experience with morcellation increases, the surgeon will be able to remove larger and larger uteri vaginally. However, it is critical to secure the uterine vessels before morcellation begins, and it is preferable to have entered both cul-de-sacs as well. Once those steps have been accomplished, bi-valve the cervix in the midline, following the endocervical canal to stay in the midline (FIGURES 9,10). Use a tenaculum to grasp bites of the uterus in an anterior and posterior fashion (FIGURE 11). This step reduces uterine size until the fundus can be inverted and the utero-ovarian pedicles secured. Be sure to excise uterine tissue under direct visualization to avoid inadvertent injury to the bowel and bladder.

FIGURE 9 Begin morcellation

Once the uterine vessels have been controlled, morcellation may begin.

FIGURE 10 Bi-valve the cervix

Bi-valve the cervix in the midline, following the endocervical canal.

FIGURE 11 Excise the fibroid

Fibroids may be excised sharply with the aid of a scalpel and traction supplied by a tenaculum.

WATCH THE VIDEO: Vaginal hysterectomy with morcellation for the enlarged uterus

We need to do more vaginal procedures

Of the roughly 600,000 hysterectomies performed each year in the United States, roughly 60% are performed abdominally.^13,14 More and more hysterectomies are being done laparoscopically or with robotic assistance, and fewer straight vaginal hysterectomies are performed.¹⁵ Recent graduates are less likely than their predecessors to be up-to-date on this important skill set—a fact that may lead to further decreases in the number of hysterectomies performed vaginally each year.¹⁶

We need to make every effort to increase the rate of vaginal hysterectomy. Not only is it better for the patient; it saves precious health-care dollars.

CASE: resolved

The vaginal approach was chosen for this patient. After ligation of the uterine vessels, morcellation allowed for a successful hysterectomy without complication.

We want to hear from you! Tell us what you think.

CASE: Is the vaginal route appropriate?

A 46-year-old woman (para 2 with 1 cesarean delivery) who has a history of benign menorrhagia comes to your office seeking definitive treatment after medical therapy fails to alleviate her bleeding. pelvic examination reveals a uterus of 14-weeks’ size that descends to the distal vagina, with good vaginal access. What options for hysterectomy do you offer to the patient?

There are few absolute contraindications to a vaginal approach to hysterectomy. Among them are advanced pelvic malignancy, severe endometriosis, and a suspicious adnexal mass. Contraindications do not include a history of pelvic surgery, cesarean delivery, or an enlarged uterus. Such circumstances may increase the challenges involved in performing vaginal hysterectomy, but data suggest that it is achievable in these settings.^1-7

Vaginal hysterectomy offers substantial benefits, making the challenges worthwhile in most cases. It is the original minimally invasive approach to hysterectomy. It yields outcomes, postoperative discomfort levels, and recovery times similar to those of laparoscopic-assisted vaginal hysterectomy, total laparoscopic hysterectomy, and robotic- assisted hysterectomy—but the vaginal approach is more cost-effective.^3,8-11

This article focuses on strategies and techniques for accomplishing the difficult vaginal hysterectomy, describing five keys to success:

• surgical experience
• adequate exposure
• entry into the anterior cul-de-sac
• uterine mobility (or the ability to create it)
• good morcellation technique.

For clarity throughout this article, we assume that hysterectomy is being performed for benign indications.

1. Surgical experience

Vaginal hysterectomy can be performed successfully in the setting of nulliparity, uterine enlargement, and a history of cesarean delivery, provided the surgeon has the appropriate skill set, assistance, and patience. Little is lost if the operation is attempted vaginally but needs to be converted to a laparoscopic or open approach. If the surgeon persists in attempting to complete each hysterectomy vaginally, he or she will gradually improve in skill and eventually gain the ability to complete tougher cases without the need to convert.

Chen and colleagues developed and validated the Vaginal Surgical Skills Index (VSSI), identifying 13 aspects of successful vaginal surgery:

• inspection
• incision
• maintenance of visibility
• use of assistance
• knowledge of instruments
• tissue and instrument handling
• electrosurgery
• knot-tying and ligation
• hemostasis
• procedure completion
• time and motion
• flow and forward planning
• knowledge of the procedure.¹²

Thirty-seven trainees from two institutions were evaluated during 76 surgical procedures. The trainees were supervised by five surgeons, who completed the evaluations immediately after each procedure. A sixth surgeon from a different institution watched videos of each procedure and acted as a blinded external reviewer.

Chen and colleagues found good inter-rater and intra-rater reliability and high internal consistency for the VSSI, one of the first tools to objectively assess vaginal surgery skills.

2. Obtaining adequate exposure

Good anesthesia, proper lighting, and fixed retraction are invaluable when operating vaginally. A weighted speculum with Deaver retractors at 3, 9, and 12 o’clock provide good visualization if assistants are available. Self- retaining retractors are also useful (FIGURE 1).

FIGURE 1 Fixed retraction

A Magrina-Bookwalter fixed vaginal retractor in place at the time of surgery.We prefer to empty the bladder before making the vaginal incision, although no data suggest that doing so helps to avoid inadvertent bladder injury.

3. Entry into the anterior cul-de-sac

We prefer to enter the anterior cul-de-sac first. The pertinent risk in vaginal hysterectomy is injury to the bladder. Because anatomic planes are undisturbed at this point, we feel entry into the anterior cul-de-sac gives the surgeon the best opportunity to avoid injury. If it is a struggle or lack of uterine descent makes it difficult, then start with entry into the posterior cul-de-sac (see “gaining mobility”).

FIGURE 2 Palpate the bladder reflection

A. Use the index finger to palpate the bladder reflection. B. Note it with a marking.In a patient who does not have a history of surgery, palpation of the bladder reflection on the anterior uterus can help determine the appropriate site for the initial incision (FIGURE 2). Place a Deaver retractor anteriorly to assist with retraction. It is important to make the first incision deep enough to set up entry into the anterior cul-de-sac (FIGURE 3).

FIGURE 3 Incise the vaginal epithelium

A sharp and deep incision aids in identification of the appropriate plane.With traction on the uterus, grasp the anterior vaginal epithelium and elevate it to allow sharp dissection and mobilization of the bladder (FIGURE 4). We prefer sharp dissection rather than blunt dissection because it maintains surgical planes and is more precise.

FIGURE 4 Dissect the bladder free of the uterus

We recommend sharp dissection to free the bladder from the uterus.Once the peritoneum is identified, grasp, elevate, and incise it (FIGURE 5). Insert scissors through the peritoneal defect, spread the tips widely, and place the anterior Deaver retractor intraperitoneally (FIGURE 6) so that bowel can be visualized (FIGURE 7).

FIGURE 5 Use traction and counter-traction

Sharp entry into the peritoneal cavity is enhanced through the use of traction and counter-traction.

FIGURE 6 Open the peritoneal defect

Place scissors into the peritoneal defect and spread the blades wide.

FIGURE 7 Visualize the bowel

Visualization of the bowel confirms an intraperitoneal location.

WATCH THE VIDEO: Vaginal hysterectomy with entry into the anterior cul-de-sac

If the patient has a history of cesarean delivery, entry into the anterior cul-de-sac can be more challenging. Several maneuvers can help avert bladder injury:

• Stay on the uterus during dissection into the vesicovaginal space. It is better to stay deep and cut into the uterus than to dissect superficially and end up with a cystotomy.
• Retrograde fill the bladder to identify the plane between the bladder and the uterus.
• Postpone entry into the anterior cul-desac until after posterior entry, ligation of the uterosacral ligaments, and the first “bite” of the cardinal ligaments.
• Use a uterine sound, bent into a “U” shape, passing it through the urethra into the bladder and allowing the point to come back toward the surgeon (while it is in the bladder). Manipulation of this sound through external palpation should make it possible to identify the bladder reflection.
• In the setting of a small uterus, after entering the posterior cul-de-sac, pass a finger along the back of the uterus, around the fundus, and back toward the surgeon. This maneuver identifies the optimal spot for dissection between the bladder and the uterus.

When cervical elongation is encountered during entry into the cul-de-sac, the peritoneal reflection will be higher (both anteriorly and posteriorly), and additional bites on the pedicles, as well as additional dissection, may be required before entry is accomplished (FIGURE 8).

FIGURE 8 When the cervix is elongated

When the cervix is elongated, the peritoneal reflection, both anteriorly and posteriorly, is much higher on the uterus (near the small myoma).

When cystotomy happens

If cystotomy occurs during an attempt to enter the anterior cul-de-sac, a number of steps can lead to successful repair. Rather than repair the defect immediately, mark it with a suture for later identification. Once the uterus is removed, inspect the bladder carefully to identify any additional injuries, then repair the cystotomy using absorbable 2-0 suture on a tapered needle (we prefer chromic suture).

Begin by taking a full-thickness bite of tissue, just lateral to the edge of the cystotomy. Then run the suture, incorporating the bladder epithelium into the closure. Place a second, imbricating layer of the same suture. Last, if possible, sew the peritoneum beneath the bladder over the repair for an additional layer of reinforcement.

WATCH THE VIDEO: Transvaginal cystotomy repair

Cystoscopy helps to visualize the repair and test for water-tightness, and assess ureteral patency.

Keep the bladder on catheter drainage for 10 to 14 days.

4. Gaining mobility

In the setting of nulliparity or a small, well-supported uterus, it may be necessary to create mobility to accomplish the hysterectomy vaginally. Begin by entering the posterior cul-de-sac and cutting and suture ligating the uterosacral ligaments. Then take the first bite of the cardinal pedicles bilaterally. This typically facilitates uterine descent, making it possible to enter the anterior culde-sac and accomplish the hysterectomy.

On occasion, once the uterine arteries have been secured, you can split (bi-valve) the uterus to gain access to the utero-ovarian pedicles and complete the hysterectomy.

5. Good morcellation technique

Morcellation facilitates removal of the large uterus. As experience with morcellation increases, the surgeon will be able to remove larger and larger uteri vaginally. However, it is critical to secure the uterine vessels before morcellation begins, and it is preferable to have entered both cul-de-sacs as well. Once those steps have been accomplished, bi-valve the cervix in the midline, following the endocervical canal to stay in the midline (FIGURES 9,10). Use a tenaculum to grasp bites of the uterus in an anterior and posterior fashion (FIGURE 11). This step reduces uterine size until the fundus can be inverted and the utero-ovarian pedicles secured. Be sure to excise uterine tissue under direct visualization to avoid inadvertent injury to the bowel and bladder.

FIGURE 9 Begin morcellation

Once the uterine vessels have been controlled, morcellation may begin.

FIGURE 10 Bi-valve the cervix

Bi-valve the cervix in the midline, following the endocervical canal.

FIGURE 11 Excise the fibroid

Fibroids may be excised sharply with the aid of a scalpel and traction supplied by a tenaculum.

WATCH THE VIDEO: Vaginal hysterectomy with morcellation for the enlarged uterus

We need to do more vaginal procedures

Of the roughly 600,000 hysterectomies performed each year in the United States, roughly 60% are performed abdominally.^13,14 More and more hysterectomies are being done laparoscopically or with robotic assistance, and fewer straight vaginal hysterectomies are performed.¹⁵ Recent graduates are less likely than their predecessors to be up-to-date on this important skill set—a fact that may lead to further decreases in the number of hysterectomies performed vaginally each year.¹⁶

We need to make every effort to increase the rate of vaginal hysterectomy. Not only is it better for the patient; it saves precious health-care dollars.

CASE: resolved

The vaginal approach was chosen for this patient. After ligation of the uterine vessels, morcellation allowed for a successful hysterectomy without complication.

We want to hear from you! Tell us what you think.

CASE: Is the vaginal route appropriate?

A 46-year-old woman (para 2 with 1 cesarean delivery) who has a history of benign menorrhagia comes to your office seeking definitive treatment after medical therapy fails to alleviate her bleeding. pelvic examination reveals a uterus of 14-weeks’ size that descends to the distal vagina, with good vaginal access. What options for hysterectomy do you offer to the patient?

There are few absolute contraindications to a vaginal approach to hysterectomy. Among them are advanced pelvic malignancy, severe endometriosis, and a suspicious adnexal mass. Contraindications do not include a history of pelvic surgery, cesarean delivery, or an enlarged uterus. Such circumstances may increase the challenges involved in performing vaginal hysterectomy, but data suggest that it is achievable in these settings.^1-7

Vaginal hysterectomy offers substantial benefits, making the challenges worthwhile in most cases. It is the original minimally invasive approach to hysterectomy. It yields outcomes, postoperative discomfort levels, and recovery times similar to those of laparoscopic-assisted vaginal hysterectomy, total laparoscopic hysterectomy, and robotic- assisted hysterectomy—but the vaginal approach is more cost-effective.^3,8-11

This article focuses on strategies and techniques for accomplishing the difficult vaginal hysterectomy, describing five keys to success:

• surgical experience
• adequate exposure
• entry into the anterior cul-de-sac
• uterine mobility (or the ability to create it)
• good morcellation technique.

For clarity throughout this article, we assume that hysterectomy is being performed for benign indications.

1. Surgical experience

Vaginal hysterectomy can be performed successfully in the setting of nulliparity, uterine enlargement, and a history of cesarean delivery, provided the surgeon has the appropriate skill set, assistance, and patience. Little is lost if the operation is attempted vaginally but needs to be converted to a laparoscopic or open approach. If the surgeon persists in attempting to complete each hysterectomy vaginally, he or she will gradually improve in skill and eventually gain the ability to complete tougher cases without the need to convert.

Chen and colleagues developed and validated the Vaginal Surgical Skills Index (VSSI), identifying 13 aspects of successful vaginal surgery:

• inspection
• incision
• maintenance of visibility
• use of assistance
• knowledge of instruments
• tissue and instrument handling
• electrosurgery
• knot-tying and ligation
• hemostasis
• procedure completion
• time and motion
• flow and forward planning
• knowledge of the procedure.¹²

Thirty-seven trainees from two institutions were evaluated during 76 surgical procedures. The trainees were supervised by five surgeons, who completed the evaluations immediately after each procedure. A sixth surgeon from a different institution watched videos of each procedure and acted as a blinded external reviewer.

Chen and colleagues found good inter-rater and intra-rater reliability and high internal consistency for the VSSI, one of the first tools to objectively assess vaginal surgery skills.

2. Obtaining adequate exposure

Good anesthesia, proper lighting, and fixed retraction are invaluable when operating vaginally. A weighted speculum with Deaver retractors at 3, 9, and 12 o’clock provide good visualization if assistants are available. Self- retaining retractors are also useful (FIGURE 1).

FIGURE 1 Fixed retraction

A Magrina-Bookwalter fixed vaginal retractor in place at the time of surgery.We prefer to empty the bladder before making the vaginal incision, although no data suggest that doing so helps to avoid inadvertent bladder injury.

3. Entry into the anterior cul-de-sac

We prefer to enter the anterior cul-de-sac first. The pertinent risk in vaginal hysterectomy is injury to the bladder. Because anatomic planes are undisturbed at this point, we feel entry into the anterior cul-de-sac gives the surgeon the best opportunity to avoid injury. If it is a struggle or lack of uterine descent makes it difficult, then start with entry into the posterior cul-de-sac (see “gaining mobility”).

FIGURE 2 Palpate the bladder reflection

A. Use the index finger to palpate the bladder reflection. B. Note it with a marking.In a patient who does not have a history of surgery, palpation of the bladder reflection on the anterior uterus can help determine the appropriate site for the initial incision (FIGURE 2). Place a Deaver retractor anteriorly to assist with retraction. It is important to make the first incision deep enough to set up entry into the anterior cul-de-sac (FIGURE 3).

FIGURE 3 Incise the vaginal epithelium

A sharp and deep incision aids in identification of the appropriate plane.With traction on the uterus, grasp the anterior vaginal epithelium and elevate it to allow sharp dissection and mobilization of the bladder (FIGURE 4). We prefer sharp dissection rather than blunt dissection because it maintains surgical planes and is more precise.

FIGURE 4 Dissect the bladder free of the uterus

We recommend sharp dissection to free the bladder from the uterus.Once the peritoneum is identified, grasp, elevate, and incise it (FIGURE 5). Insert scissors through the peritoneal defect, spread the tips widely, and place the anterior Deaver retractor intraperitoneally (FIGURE 6) so that bowel can be visualized (FIGURE 7).

FIGURE 5 Use traction and counter-traction

Sharp entry into the peritoneal cavity is enhanced through the use of traction and counter-traction.

FIGURE 6 Open the peritoneal defect

Place scissors into the peritoneal defect and spread the blades wide.

FIGURE 7 Visualize the bowel

Visualization of the bowel confirms an intraperitoneal location.

WATCH THE VIDEO: Vaginal hysterectomy with entry into the anterior cul-de-sac

If the patient has a history of cesarean delivery, entry into the anterior cul-de-sac can be more challenging. Several maneuvers can help avert bladder injury:

• Stay on the uterus during dissection into the vesicovaginal space. It is better to stay deep and cut into the uterus than to dissect superficially and end up with a cystotomy.
• Retrograde fill the bladder to identify the plane between the bladder and the uterus.
• Postpone entry into the anterior cul-desac until after posterior entry, ligation of the uterosacral ligaments, and the first “bite” of the cardinal ligaments.
• Use a uterine sound, bent into a “U” shape, passing it through the urethra into the bladder and allowing the point to come back toward the surgeon (while it is in the bladder). Manipulation of this sound through external palpation should make it possible to identify the bladder reflection.
• In the setting of a small uterus, after entering the posterior cul-de-sac, pass a finger along the back of the uterus, around the fundus, and back toward the surgeon. This maneuver identifies the optimal spot for dissection between the bladder and the uterus.

When cervical elongation is encountered during entry into the cul-de-sac, the peritoneal reflection will be higher (both anteriorly and posteriorly), and additional bites on the pedicles, as well as additional dissection, may be required before entry is accomplished (FIGURE 8).

FIGURE 8 When the cervix is elongated

When the cervix is elongated, the peritoneal reflection, both anteriorly and posteriorly, is much higher on the uterus (near the small myoma).

When cystotomy happens

If cystotomy occurs during an attempt to enter the anterior cul-de-sac, a number of steps can lead to successful repair. Rather than repair the defect immediately, mark it with a suture for later identification. Once the uterus is removed, inspect the bladder carefully to identify any additional injuries, then repair the cystotomy using absorbable 2-0 suture on a tapered needle (we prefer chromic suture).

Begin by taking a full-thickness bite of tissue, just lateral to the edge of the cystotomy. Then run the suture, incorporating the bladder epithelium into the closure. Place a second, imbricating layer of the same suture. Last, if possible, sew the peritoneum beneath the bladder over the repair for an additional layer of reinforcement.

WATCH THE VIDEO: Transvaginal cystotomy repair

Cystoscopy helps to visualize the repair and test for water-tightness, and assess ureteral patency.

Keep the bladder on catheter drainage for 10 to 14 days.

4. Gaining mobility

In the setting of nulliparity or a small, well-supported uterus, it may be necessary to create mobility to accomplish the hysterectomy vaginally. Begin by entering the posterior cul-de-sac and cutting and suture ligating the uterosacral ligaments. Then take the first bite of the cardinal pedicles bilaterally. This typically facilitates uterine descent, making it possible to enter the anterior culde-sac and accomplish the hysterectomy.

On occasion, once the uterine arteries have been secured, you can split (bi-valve) the uterus to gain access to the utero-ovarian pedicles and complete the hysterectomy.

5. Good morcellation technique

Morcellation facilitates removal of the large uterus. As experience with morcellation increases, the surgeon will be able to remove larger and larger uteri vaginally. However, it is critical to secure the uterine vessels before morcellation begins, and it is preferable to have entered both cul-de-sacs as well. Once those steps have been accomplished, bi-valve the cervix in the midline, following the endocervical canal to stay in the midline (FIGURES 9,10). Use a tenaculum to grasp bites of the uterus in an anterior and posterior fashion (FIGURE 11). This step reduces uterine size until the fundus can be inverted and the utero-ovarian pedicles secured. Be sure to excise uterine tissue under direct visualization to avoid inadvertent injury to the bowel and bladder.

FIGURE 9 Begin morcellation

Once the uterine vessels have been controlled, morcellation may begin.

FIGURE 10 Bi-valve the cervix

Bi-valve the cervix in the midline, following the endocervical canal.

FIGURE 11 Excise the fibroid

Fibroids may be excised sharply with the aid of a scalpel and traction supplied by a tenaculum.

WATCH THE VIDEO: Vaginal hysterectomy with morcellation for the enlarged uterus

We need to do more vaginal procedures

Of the roughly 600,000 hysterectomies performed each year in the United States, roughly 60% are performed abdominally.^13,14 More and more hysterectomies are being done laparoscopically or with robotic assistance, and fewer straight vaginal hysterectomies are performed.¹⁵ Recent graduates are less likely than their predecessors to be up-to-date on this important skill set—a fact that may lead to further decreases in the number of hysterectomies performed vaginally each year.¹⁶

We need to make every effort to increase the rate of vaginal hysterectomy. Not only is it better for the patient; it saves precious health-care dollars.

CASE: resolved

The vaginal approach was chosen for this patient. After ligation of the uterine vessels, morcellation allowed for a successful hysterectomy without complication.

We want to hear from you! Tell us what you think.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.