The Journal of Family Practice

Tender erythematous nodules or plaques on the extensor surfaces—usually on the legs and occasionally on the arms—are the hallmarks for erythema nodosum, which was diagnosed in this case. It typically occurs in young women, ages 15 to 30, and the nodules or plaques are often accompanied by prodromal fever and malaise. The lesions often are painful and tender to pressure or palpation; they are thought to be caused by a reaction to a stimulus, leading to inflammation of the septa in the subcutaneous fat. While the trigger is often unknown, in some cases, an underlying infection, particularly Streptococcus or tuberculosis (TB), is identified. Sarcoidosis, malignancy, or an increase in estrogen (exogenous or endogenous) also can provoke the disorder.

Due to the risk of underlying disease or triggers, it is prudent to perform radiography of the chest, as well as obtain a complete blood count, sedimentation rate or C reactive protein, and an antistreptolysin O titer when you suspect erythema nodosum. TB testing is also advised. Biopsy typically is not performed because the diagnosis usually is made clinically. If the diagnosis is in doubt, a biopsy can offer confirmation or lead to a different diagnosis such as vasculitis—especially if the lesions are eroded. Since erythema nodosum is an inflammation of the subcutaneous fat, it is important to sample skin lesions deeper than the usual punch biopsy; an incisional biopsy may be required to get an adequate sample.

Erythema nodosum typically resolves spontaneously over a period of weeks, even if there is underlying disease. Therefore, it may be possible to defer treatment if minimal symptoms are present. Otherwise, first-line treatment for the pain and malaise is a nonsteroidal anti-inflammatory drug (NSAID). Oral potassium iodide (360-900 mg/d) is considered second-line treatment and systemic corticosteroids are a third-line option.

For this patient, biopsy was deferred and diagnostic tests were all negative. She had notable pain and a history of good resolution of symptoms with prednisone (5 mg/d), so this drug was prescribed for a 7-day course. She was counseled to avoid taking the NSAIDs and prednisone together due to increased risk of gastritis and ulceration. Recurrent disease can be treated with dapsone (100 mg/d) or hydroxychloroquine (200 mg bid).

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Tender erythematous nodules or plaques on the extensor surfaces—usually on the legs and occasionally on the arms—are the hallmarks for erythema nodosum, which was diagnosed in this case. It typically occurs in young women, ages 15 to 30, and the nodules or plaques are often accompanied by prodromal fever and malaise. The lesions often are painful and tender to pressure or palpation; they are thought to be caused by a reaction to a stimulus, leading to inflammation of the septa in the subcutaneous fat. While the trigger is often unknown, in some cases, an underlying infection, particularly Streptococcus or tuberculosis (TB), is identified. Sarcoidosis, malignancy, or an increase in estrogen (exogenous or endogenous) also can provoke the disorder.

Due to the risk of underlying disease or triggers, it is prudent to perform radiography of the chest, as well as obtain a complete blood count, sedimentation rate or C reactive protein, and an antistreptolysin O titer when you suspect erythema nodosum. TB testing is also advised. Biopsy typically is not performed because the diagnosis usually is made clinically. If the diagnosis is in doubt, a biopsy can offer confirmation or lead to a different diagnosis such as vasculitis—especially if the lesions are eroded. Since erythema nodosum is an inflammation of the subcutaneous fat, it is important to sample skin lesions deeper than the usual punch biopsy; an incisional biopsy may be required to get an adequate sample.

Erythema nodosum typically resolves spontaneously over a period of weeks, even if there is underlying disease. Therefore, it may be possible to defer treatment if minimal symptoms are present. Otherwise, first-line treatment for the pain and malaise is a nonsteroidal anti-inflammatory drug (NSAID). Oral potassium iodide (360-900 mg/d) is considered second-line treatment and systemic corticosteroids are a third-line option.

For this patient, biopsy was deferred and diagnostic tests were all negative. She had notable pain and a history of good resolution of symptoms with prednisone (5 mg/d), so this drug was prescribed for a 7-day course. She was counseled to avoid taking the NSAIDs and prednisone together due to increased risk of gastritis and ulceration. Recurrent disease can be treated with dapsone (100 mg/d) or hydroxychloroquine (200 mg bid).

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Tender erythematous nodules or plaques on the extensor surfaces—usually on the legs and occasionally on the arms—are the hallmarks for erythema nodosum, which was diagnosed in this case. It typically occurs in young women, ages 15 to 30, and the nodules or plaques are often accompanied by prodromal fever and malaise. The lesions often are painful and tender to pressure or palpation; they are thought to be caused by a reaction to a stimulus, leading to inflammation of the septa in the subcutaneous fat. While the trigger is often unknown, in some cases, an underlying infection, particularly Streptococcus or tuberculosis (TB), is identified. Sarcoidosis, malignancy, or an increase in estrogen (exogenous or endogenous) also can provoke the disorder.

Due to the risk of underlying disease or triggers, it is prudent to perform radiography of the chest, as well as obtain a complete blood count, sedimentation rate or C reactive protein, and an antistreptolysin O titer when you suspect erythema nodosum. TB testing is also advised. Biopsy typically is not performed because the diagnosis usually is made clinically. If the diagnosis is in doubt, a biopsy can offer confirmation or lead to a different diagnosis such as vasculitis—especially if the lesions are eroded. Since erythema nodosum is an inflammation of the subcutaneous fat, it is important to sample skin lesions deeper than the usual punch biopsy; an incisional biopsy may be required to get an adequate sample.

Erythema nodosum typically resolves spontaneously over a period of weeks, even if there is underlying disease. Therefore, it may be possible to defer treatment if minimal symptoms are present. Otherwise, first-line treatment for the pain and malaise is a nonsteroidal anti-inflammatory drug (NSAID). Oral potassium iodide (360-900 mg/d) is considered second-line treatment and systemic corticosteroids are a third-line option.

For this patient, biopsy was deferred and diagnostic tests were all negative. She had notable pain and a history of good resolution of symptoms with prednisone (5 mg/d), so this drug was prescribed for a 7-day course. She was counseled to avoid taking the NSAIDs and prednisone together due to increased risk of gastritis and ulceration. Recurrent disease can be treated with dapsone (100 mg/d) or hydroxychloroquine (200 mg bid).

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The punch biopsies were consistent with lichen planopilaris, an idiopathic, immune-mediated scarring alopecia that largely affects women between the ages of 40 and 70 years. In this variant of lichen planus, T cells target hair bulbs and cause destruction with scarring and permanent hair loss. Distribution may be patchy or may be more concentrated on the crown or involve the frontal scalp—a subtype called frontal fibrosing alopecia. Early recognition and intervention may save hair follicles and minimize disease severity.

The differential diagnosis includes traction alopecia, discoid lupus erythematosus, alopecia areata, centrifugal cicatricial alopecia, and folliculitis decalvans. The diagnosis may be confirmed with a scalp biopsy of actively inflamed follicles. Biopsy of scarred areas is likely to be nonspecific and unhelpful.

Treatment is targeted at slowing progression and symptom management. First-line therapy often includes potent corticosteroids (intralesional, topical, or systemic). Longer courses of steroid-sparing agents may be considered, including hydroxychloroquine, tacrolimus, ciclosporin, methotrexate, or acitretin. Hair styling and coloring, as well as hairpieces, often are used to conceal patches of hair loss. Hair transplantation is expensive but can be used to increase hair density in scarred areas once disease is controlled.

In this case, the patient was started on clobetasol solution 0.05% to be applied nightly to affected areas of the scalp. This treatment helped with the itching, but the inflammation and hair loss continued to worsen after 2 months. At that point, hydroxychloroquine 200 mg bid was added to the regimen, and hair loss and associated symptoms stopped. The patient remained on this therapy for 16 months. The hydroxychloroquine was then stopped, and the patient was advised to use the topical clobetasol, as needed.

‌

Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

The punch biopsies were consistent with lichen planopilaris, an idiopathic, immune-mediated scarring alopecia that largely affects women between the ages of 40 and 70 years. In this variant of lichen planus, T cells target hair bulbs and cause destruction with scarring and permanent hair loss. Distribution may be patchy or may be more concentrated on the crown or involve the frontal scalp—a subtype called frontal fibrosing alopecia. Early recognition and intervention may save hair follicles and minimize disease severity.

The differential diagnosis includes traction alopecia, discoid lupus erythematosus, alopecia areata, centrifugal cicatricial alopecia, and folliculitis decalvans. The diagnosis may be confirmed with a scalp biopsy of actively inflamed follicles. Biopsy of scarred areas is likely to be nonspecific and unhelpful.

Treatment is targeted at slowing progression and symptom management. First-line therapy often includes potent corticosteroids (intralesional, topical, or systemic). Longer courses of steroid-sparing agents may be considered, including hydroxychloroquine, tacrolimus, ciclosporin, methotrexate, or acitretin. Hair styling and coloring, as well as hairpieces, often are used to conceal patches of hair loss. Hair transplantation is expensive but can be used to increase hair density in scarred areas once disease is controlled.

In this case, the patient was started on clobetasol solution 0.05% to be applied nightly to affected areas of the scalp. This treatment helped with the itching, but the inflammation and hair loss continued to worsen after 2 months. At that point, hydroxychloroquine 200 mg bid was added to the regimen, and hair loss and associated symptoms stopped. The patient remained on this therapy for 16 months. The hydroxychloroquine was then stopped, and the patient was advised to use the topical clobetasol, as needed.

‌

Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

The punch biopsies were consistent with lichen planopilaris, an idiopathic, immune-mediated scarring alopecia that largely affects women between the ages of 40 and 70 years. In this variant of lichen planus, T cells target hair bulbs and cause destruction with scarring and permanent hair loss. Distribution may be patchy or may be more concentrated on the crown or involve the frontal scalp—a subtype called frontal fibrosing alopecia. Early recognition and intervention may save hair follicles and minimize disease severity.

The differential diagnosis includes traction alopecia, discoid lupus erythematosus, alopecia areata, centrifugal cicatricial alopecia, and folliculitis decalvans. The diagnosis may be confirmed with a scalp biopsy of actively inflamed follicles. Biopsy of scarred areas is likely to be nonspecific and unhelpful.

Treatment is targeted at slowing progression and symptom management. First-line therapy often includes potent corticosteroids (intralesional, topical, or systemic). Longer courses of steroid-sparing agents may be considered, including hydroxychloroquine, tacrolimus, ciclosporin, methotrexate, or acitretin. Hair styling and coloring, as well as hairpieces, often are used to conceal patches of hair loss. Hair transplantation is expensive but can be used to increase hair density in scarred areas once disease is controlled.

In this case, the patient was started on clobetasol solution 0.05% to be applied nightly to affected areas of the scalp. This treatment helped with the itching, but the inflammation and hair loss continued to worsen after 2 months. At that point, hydroxychloroquine 200 mg bid was added to the regimen, and hair loss and associated symptoms stopped. The patient remained on this therapy for 16 months. The hydroxychloroquine was then stopped, and the patient was advised to use the topical clobetasol, as needed.

‌

Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

References 

1. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;32:369-380.
2. The North American Menopause Society. Menopause Guidebook. 8th ed. www.menopause.org/publications/consumer-publications/-em-menopause-guidebook-em-8th-edition. Accessed September 25, 2020.
3. US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;318:2224-2233.

References 

1. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;32:369-380.
2. The North American Menopause Society. Menopause Guidebook. 8th ed. www.menopause.org/publications/consumer-publications/-em-menopause-guidebook-em-8th-edition. Accessed September 25, 2020.
3. US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;318:2224-2233.

References 

1. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;32:369-380.
2. The North American Menopause Society. Menopause Guidebook. 8th ed. www.menopause.org/publications/consumer-publications/-em-menopause-guidebook-em-8th-edition. Accessed September 25, 2020.
3. US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;318:2224-2233.

This patient was given a diagnosis of primary herpes simplex virus (HSV) based on the appearance of her eyelid. Swabs were performed for bacterial culture, and polymerase chain reaction (PCR) testing was done for HSV and varicella, but results were pending prior to her transfer to the Emergency Department (ED).

The patient was given a single dose of 800 mg oral acyclovir (200 mg/5mL) and 500 mg of oral cephalexin (250 mg/5mL) and referred to the ED for a more detailed eye exam and to exclude orbital erosions.

HSV classically causes clustered vesicles on an erythematous base. Superinfection with skin flora can cause pustules instead of vesicles. Severe complications of HSV can include widespread skin involvement, eczema herpeticum, local destruction, central nervous system involvement, throat infections (affecting airway and oral intake), and dissemination in immunocompromised hosts. Ocular or periorbital infections increase the risk of keratitis, corneal ulcers, and loss of sight. Viral involvement of the cornea is best seen with fluorescein staining.

In cases like this one, PCR is the preferred method of testing over viral cultures or serology, given its speed, accuracy, and temporal relevance. Ophthalmology referral is warranted, although it should not delay treatment. Topical and oral antivirals are both effective when treating corneal disease; patient preference should be considered.

Most cases of HSV may resolve without treatment; however, treatment started while vesicles are present and within 72 hours of infection may shorten the time of viral replication and prevent progression to stromal involvement.

After a 12-hour wait in the ED, this patient was seen by an ophthalmology resident who did not observe orbital erosions but did note umbilication and misdiagnosed molluscum contagiosum. Umbilication is not pathognomonic for molluscum; few experienced in diagnosing molluscum contagiosum would make this error.

The patient was instructed to stop the acyclovir. Two days later when the PCR came back positive for HSV-1 and the bacterial culture confirmed growth of superimposed Staphylococcus aureus, the patient had been lost to follow-up. A better approach would have been for the ophthalmology resident to continue the acyclovir until PCR excluded herpetic disease.

‌

Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

This patient was given a diagnosis of primary herpes simplex virus (HSV) based on the appearance of her eyelid. Swabs were performed for bacterial culture, and polymerase chain reaction (PCR) testing was done for HSV and varicella, but results were pending prior to her transfer to the Emergency Department (ED).

The patient was given a single dose of 800 mg oral acyclovir (200 mg/5mL) and 500 mg of oral cephalexin (250 mg/5mL) and referred to the ED for a more detailed eye exam and to exclude orbital erosions.

HSV classically causes clustered vesicles on an erythematous base. Superinfection with skin flora can cause pustules instead of vesicles. Severe complications of HSV can include widespread skin involvement, eczema herpeticum, local destruction, central nervous system involvement, throat infections (affecting airway and oral intake), and dissemination in immunocompromised hosts. Ocular or periorbital infections increase the risk of keratitis, corneal ulcers, and loss of sight. Viral involvement of the cornea is best seen with fluorescein staining.

In cases like this one, PCR is the preferred method of testing over viral cultures or serology, given its speed, accuracy, and temporal relevance. Ophthalmology referral is warranted, although it should not delay treatment. Topical and oral antivirals are both effective when treating corneal disease; patient preference should be considered.

Most cases of HSV may resolve without treatment; however, treatment started while vesicles are present and within 72 hours of infection may shorten the time of viral replication and prevent progression to stromal involvement.

After a 12-hour wait in the ED, this patient was seen by an ophthalmology resident who did not observe orbital erosions but did note umbilication and misdiagnosed molluscum contagiosum. Umbilication is not pathognomonic for molluscum; few experienced in diagnosing molluscum contagiosum would make this error.

The patient was instructed to stop the acyclovir. Two days later when the PCR came back positive for HSV-1 and the bacterial culture confirmed growth of superimposed Staphylococcus aureus, the patient had been lost to follow-up. A better approach would have been for the ophthalmology resident to continue the acyclovir until PCR excluded herpetic disease.

‌

Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

This patient was given a diagnosis of primary herpes simplex virus (HSV) based on the appearance of her eyelid. Swabs were performed for bacterial culture, and polymerase chain reaction (PCR) testing was done for HSV and varicella, but results were pending prior to her transfer to the Emergency Department (ED).

The patient was given a single dose of 800 mg oral acyclovir (200 mg/5mL) and 500 mg of oral cephalexin (250 mg/5mL) and referred to the ED for a more detailed eye exam and to exclude orbital erosions.

HSV classically causes clustered vesicles on an erythematous base. Superinfection with skin flora can cause pustules instead of vesicles. Severe complications of HSV can include widespread skin involvement, eczema herpeticum, local destruction, central nervous system involvement, throat infections (affecting airway and oral intake), and dissemination in immunocompromised hosts. Ocular or periorbital infections increase the risk of keratitis, corneal ulcers, and loss of sight. Viral involvement of the cornea is best seen with fluorescein staining.

In cases like this one, PCR is the preferred method of testing over viral cultures or serology, given its speed, accuracy, and temporal relevance. Ophthalmology referral is warranted, although it should not delay treatment. Topical and oral antivirals are both effective when treating corneal disease; patient preference should be considered.

Most cases of HSV may resolve without treatment; however, treatment started while vesicles are present and within 72 hours of infection may shorten the time of viral replication and prevent progression to stromal involvement.

After a 12-hour wait in the ED, this patient was seen by an ophthalmology resident who did not observe orbital erosions but did note umbilication and misdiagnosed molluscum contagiosum. Umbilication is not pathognomonic for molluscum; few experienced in diagnosing molluscum contagiosum would make this error.

The patient was instructed to stop the acyclovir. Two days later when the PCR came back positive for HSV-1 and the bacterial culture confirmed growth of superimposed Staphylococcus aureus, the patient had been lost to follow-up. A better approach would have been for the ophthalmology resident to continue the acyclovir until PCR excluded herpetic disease.

‌

Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

EVIDENCE SUMMARY

Cocoa. A 2017 Cochrane review evaluated data from more than 1800 patients (401 in hypertension studies) to determine the effect of cocoa on BP.¹ Compared with placebo (in flavanol-free or low-flavanol controls), cocoa lowered systolic BP by 1.8 mm Hg (confidence interval [CI], –3.1 to –0.4) and diastolic BP by 1.8 mm Hg (CI, –2.6 to –0.9). Further analysis of patients with hypertension (only) showed a reduction in systolic BP of 4 mm Hg (CI, –6.7 to –1.3).

Omega-3 fatty acids. Similarly, a 2014 meta-analysis investigating omega-3 fatty acids (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) included data from 4489 patients (956 with hypertension) and showed reductions in systolic BP of 1.5 mm Hg (CI, –2.3 to –0.8) and diastolic BP of 1 mm Hg (CI, –1.5 to –0.4), compared with placebo.² Again, subgroup analysis of patients with hypertension (only) at baseline revealed a greater decrease in systolic and diastolic BP: 4.5 mm Hg (CI, –6.1 to –2.8) and 3.1 mm Hg (CI, –4.4 to –1.8), respectively.

Garlic and potassium chloride. Separate meta-analyses that included only patients with hypertension found that both garlic and potassium significantly lowered BP.^3,4 A 2015 meta-analysis comparing a variety of garlic preparations with placebo in patients with hypertension showed decreases in systolic BP of 9.1 mm Hg (CI, –12.7 to –5.4) and in diastolic BP of 3.8 mm Hg (CI, –6.7 to –1).³ Meanwhile, a meta-analysis in 2017 comparing different doses of potassium chloride with placebo demonstrated reductions in systolic BP of 4.3 mm Hg (CI, –6 to –2.5) and diastolic BP of 2.5 mm Hg (CI, –4.1 to –1).⁴

L-arginine. Another meta-analysis of randomized controlled trials reported evidence that oral L-arginine, compared with placebo, significantly reduced systolic BP by 5.4 mm Hg (CI, –8.5 to –2.3) and diastolic BP by 2.7 mm Hg (CI, –3.8 to –1.5).⁵ Close to one-third of patients had hypertension at baseline.

Beetroot juice. A double-blind, placebo-controlled study showed that consumption of beetroot juice (with nitrate) once daily reduced BP in 3 different settings (clinic, 24-hour ambulatory, and home readings) when compared with placebo (nitrate-free beetroot juice).⁶ Study participants were mostly British women, overweight, without significant c­ardiovascular or renal disease, and with uncontrolled ambulatory BP (> 135/85 mm Hg).

Flax seed. A prospective, double-blind trial of patients with peripheral artery disease compared the antihypertensive effects of flax seed with placebo in patients with and without hypertension and found marked decreases in systolic and diastolic BP.⁷ Study participants were all older than 40 years without other major cardiac or renal disease, and the majority of enrolled patients with hypertension were concurrently taking medications to treat hypertension during the study.

Olive leaf extract. A double-blind, parallel, and active-control clinical trial in Indonesia compared the BP-lowering effect of olive leaf extract (Olea europaea) to captopril as monotherapies in patients with stage 1 hypertension.⁸ After a 4-week period of dietary intervention, individuals who were still hypertensive (range, 140/90 to 159/99 mm Hg) were treated with either olive leaf extract or captopril. After 8 weeks of treatment, both groups saw comparable reductions in BP.   

Continue to: Editor's takeaway

Editor’s takeaway

Many studies have demonstrated BP benefits from a variety of natural supplements. Although the studies’ durations are short, the effects sometimes modest, and the outcomes disease-oriented rather than patient-oriented, the findings can provide a useful complement to our efforts to manage this most common chronic disease.

EVIDENCE SUMMARY

Cocoa. A 2017 Cochrane review evaluated data from more than 1800 patients (401 in hypertension studies) to determine the effect of cocoa on BP.¹ Compared with placebo (in flavanol-free or low-flavanol controls), cocoa lowered systolic BP by 1.8 mm Hg (confidence interval [CI], –3.1 to –0.4) and diastolic BP by 1.8 mm Hg (CI, –2.6 to –0.9). Further analysis of patients with hypertension (only) showed a reduction in systolic BP of 4 mm Hg (CI, –6.7 to –1.3).

Omega-3 fatty acids. Similarly, a 2014 meta-analysis investigating omega-3 fatty acids (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) included data from 4489 patients (956 with hypertension) and showed reductions in systolic BP of 1.5 mm Hg (CI, –2.3 to –0.8) and diastolic BP of 1 mm Hg (CI, –1.5 to –0.4), compared with placebo.² Again, subgroup analysis of patients with hypertension (only) at baseline revealed a greater decrease in systolic and diastolic BP: 4.5 mm Hg (CI, –6.1 to –2.8) and 3.1 mm Hg (CI, –4.4 to –1.8), respectively.

Garlic and potassium chloride. Separate meta-analyses that included only patients with hypertension found that both garlic and potassium significantly lowered BP.^3,4 A 2015 meta-analysis comparing a variety of garlic preparations with placebo in patients with hypertension showed decreases in systolic BP of 9.1 mm Hg (CI, –12.7 to –5.4) and in diastolic BP of 3.8 mm Hg (CI, –6.7 to –1).³ Meanwhile, a meta-analysis in 2017 comparing different doses of potassium chloride with placebo demonstrated reductions in systolic BP of 4.3 mm Hg (CI, –6 to –2.5) and diastolic BP of 2.5 mm Hg (CI, –4.1 to –1).⁴

L-arginine. Another meta-analysis of randomized controlled trials reported evidence that oral L-arginine, compared with placebo, significantly reduced systolic BP by 5.4 mm Hg (CI, –8.5 to –2.3) and diastolic BP by 2.7 mm Hg (CI, –3.8 to –1.5).⁵ Close to one-third of patients had hypertension at baseline.

Beetroot juice. A double-blind, placebo-controlled study showed that consumption of beetroot juice (with nitrate) once daily reduced BP in 3 different settings (clinic, 24-hour ambulatory, and home readings) when compared with placebo (nitrate-free beetroot juice).⁶ Study participants were mostly British women, overweight, without significant c­ardiovascular or renal disease, and with uncontrolled ambulatory BP (> 135/85 mm Hg).

Flax seed. A prospective, double-blind trial of patients with peripheral artery disease compared the antihypertensive effects of flax seed with placebo in patients with and without hypertension and found marked decreases in systolic and diastolic BP.⁷ Study participants were all older than 40 years without other major cardiac or renal disease, and the majority of enrolled patients with hypertension were concurrently taking medications to treat hypertension during the study.

Olive leaf extract. A double-blind, parallel, and active-control clinical trial in Indonesia compared the BP-lowering effect of olive leaf extract (Olea europaea) to captopril as monotherapies in patients with stage 1 hypertension.⁸ After a 4-week period of dietary intervention, individuals who were still hypertensive (range, 140/90 to 159/99 mm Hg) were treated with either olive leaf extract or captopril. After 8 weeks of treatment, both groups saw comparable reductions in BP.   

Continue to: Editor's takeaway

Editor’s takeaway

Many studies have demonstrated BP benefits from a variety of natural supplements. Although the studies’ durations are short, the effects sometimes modest, and the outcomes disease-oriented rather than patient-oriented, the findings can provide a useful complement to our efforts to manage this most common chronic disease.

EVIDENCE SUMMARY

Cocoa. A 2017 Cochrane review evaluated data from more than 1800 patients (401 in hypertension studies) to determine the effect of cocoa on BP.¹ Compared with placebo (in flavanol-free or low-flavanol controls), cocoa lowered systolic BP by 1.8 mm Hg (confidence interval [CI], –3.1 to –0.4) and diastolic BP by 1.8 mm Hg (CI, –2.6 to –0.9). Further analysis of patients with hypertension (only) showed a reduction in systolic BP of 4 mm Hg (CI, –6.7 to –1.3).

Omega-3 fatty acids. Similarly, a 2014 meta-analysis investigating omega-3 fatty acids (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) included data from 4489 patients (956 with hypertension) and showed reductions in systolic BP of 1.5 mm Hg (CI, –2.3 to –0.8) and diastolic BP of 1 mm Hg (CI, –1.5 to –0.4), compared with placebo.² Again, subgroup analysis of patients with hypertension (only) at baseline revealed a greater decrease in systolic and diastolic BP: 4.5 mm Hg (CI, –6.1 to –2.8) and 3.1 mm Hg (CI, –4.4 to –1.8), respectively.

Garlic and potassium chloride. Separate meta-analyses that included only patients with hypertension found that both garlic and potassium significantly lowered BP.^3,4 A 2015 meta-analysis comparing a variety of garlic preparations with placebo in patients with hypertension showed decreases in systolic BP of 9.1 mm Hg (CI, –12.7 to –5.4) and in diastolic BP of 3.8 mm Hg (CI, –6.7 to –1).³ Meanwhile, a meta-analysis in 2017 comparing different doses of potassium chloride with placebo demonstrated reductions in systolic BP of 4.3 mm Hg (CI, –6 to –2.5) and diastolic BP of 2.5 mm Hg (CI, –4.1 to –1).⁴

L-arginine. Another meta-analysis of randomized controlled trials reported evidence that oral L-arginine, compared with placebo, significantly reduced systolic BP by 5.4 mm Hg (CI, –8.5 to –2.3) and diastolic BP by 2.7 mm Hg (CI, –3.8 to –1.5).⁵ Close to one-third of patients had hypertension at baseline.

Beetroot juice. A double-blind, placebo-controlled study showed that consumption of beetroot juice (with nitrate) once daily reduced BP in 3 different settings (clinic, 24-hour ambulatory, and home readings) when compared with placebo (nitrate-free beetroot juice).⁶ Study participants were mostly British women, overweight, without significant c­ardiovascular or renal disease, and with uncontrolled ambulatory BP (> 135/85 mm Hg).

Flax seed. A prospective, double-blind trial of patients with peripheral artery disease compared the antihypertensive effects of flax seed with placebo in patients with and without hypertension and found marked decreases in systolic and diastolic BP.⁷ Study participants were all older than 40 years without other major cardiac or renal disease, and the majority of enrolled patients with hypertension were concurrently taking medications to treat hypertension during the study.

Olive leaf extract. A double-blind, parallel, and active-control clinical trial in Indonesia compared the BP-lowering effect of olive leaf extract (Olea europaea) to captopril as monotherapies in patients with stage 1 hypertension.⁸ After a 4-week period of dietary intervention, individuals who were still hypertensive (range, 140/90 to 159/99 mm Hg) were treated with either olive leaf extract or captopril. After 8 weeks of treatment, both groups saw comparable reductions in BP.   

Continue to: Editor's takeaway

Editor’s takeaway

Many studies have demonstrated BP benefits from a variety of natural supplements. Although the studies’ durations are short, the effects sometimes modest, and the outcomes disease-oriented rather than patient-oriented, the findings can provide a useful complement to our efforts to manage this most common chronic disease.

EVIDENCE SUMMARY

A 2015 Cochrane review of the LNG-IUS for menorrhagia included 1 placebo-controlled RCT; most of the remaining 21 RCTs compared the LNG-IUS to invasive procedures such as endometrial ablation or hysterectomy.¹ The placebo-controlled trial compared the LNG-IUS with placebo in 40 women on anticoagulation therapy and found a mean beneficial difference of 100 mL (95% confidence interval [CI], –116 to –83) using a subjective pictorial blood assessment chart.

Women are less likely to withdraw from LNG-IUS treatment

Four trials (379 patients) included in the Cochrane review compared LNG-IUS with combination or progesterone-only pills. All of the trials excluded women with palpable or large (> 5 cm) fibroids. In 3 trials (2 against OCPs and 1 against a 10-day course of oral progesterone), the LNG-IUS decreased MBL more than OCPs did. A fourth trial found LNG-IUS comparable to oral progesterone dosed 3 times a day from Day 5 to Day 26 of each menstrual cycle.

A recent large RCT (571 patients) that compared LNG-IUS with usual medical treatment (mefenamic acid [MFA], tranexamic acid, norethindrone, OCPs, progesterone-­only pill, medroxyprogesterone acetate injection) found women significantly less likely to withdraw from LNG-IUS at 2 years (relative risk [RR] = 0.58; 95% CI, 0.49-0.70).²

Estrogen and progestin contraceptives significantly reduce bleeding

In addition to the trials in the 2015 Cochrane review comparing OCPs with LNG-IUS, a 2009 Cochrane review included a single 2-month crossover trial of 45 patients.³ This RCT compared OCPs with naproxen, MFA, and danazol to treat heavy menstrual bleeding (assessed using the alkaline haematin method).

Researchers didn’t analyze the data using intention-to-treat. No group was found to be superior. The OCP group (6 women) had a 43% reduction in MBL over baseline (no P value reported).

Tranexamic acid outperforms oral progesterone and NSAIDs but not ...

A 2018 Cochrane meta-analysis of 13 RCTs (1312 patients) of antifibrinolytics for reproductive-age women with regular heavy periods and no known underlying pathology included 4 RCTs (565 patients) that used placebo as a comparator.⁴ Therapy with tranexamic acid decreased blood loss by53 mL per cycle (95% CI, 44-63 mL), a 40% to 50% improvement compared with placebo. Three of the RCTs (271 patients) reported the percent of women improving on tranexamic acid as 43% to 63%, compared with 11% for placebo, resulting in an NNT of 2 to 3.

In head-to-head comparisons, women were more likely to improve with the LNG-IUS than tranexamic acid for reducing menstrual blood loss.

One trial (46 patients) found tranexamic acid superior to luteal phase oral progesterone, and another study (48 patients) demonstrated superiority to NSAIDs, with a mean decrease in MBL of 86 mL compared with 43 mL (P < .0027).

Continue to: On the other hand...

On the other hand, tranexamic acid compared unfavorably with LNG-IUS (1 RCT, 42 patients), showing a lower likelihood of improvement (RR = 0.43; 95% CI, 0.24-0.77). Whereas 85% of women improved with LNG-IUS, only 20% to 65% of women improved with tranexamic acid (NNT = 2 to 6). 

No statistical difference was found in gastrointestinal adverse effects, headache, vaginal dryness, or dysmenorrhea.⁴ Only 1 thromboembolic event occurred in the 2 studies that reported this outcome, a known risk that prohibits its concomitant use with combination OCPs.

Different NSAIDs, equivalent efficacy

A 2013 Cochrane review of 18 RCTs included 8 (84 patients) that compared NSAIDs (5 MFA, 2 naproxen, 1 ibuprofen) with placebo.⁵ In 6 trials, NSAIDs produced a significant reduction in MBL compared with placebo, although most were crossover trials that couldn’t be compiled into the meta-analysis.

One trial (11 patients) showed a mean reduction of 124 mL (95% CI, 62-186 mL) in the MFA group. In another trial, women were less likely to report no improvement in the MFA group than in the placebo group (odds ratio [OR] = 0.08; 95% CI, 0.03-0.18). No NSAID had significantly higher efficacy than the others.

Danazol was superior to NSAIDs in a meta-analysis of 3 trials (79 patients) with a mean difference of 45 mL (95% CI, 19-71 mL), as was tranexamic acid in a single trial (48 patients) with a mean difference of 73 mL (95% CI, 22-124 mL).⁵ Comparisons with OCPs, oral progesterone, and an older model of LNG-IUS showed no significant ­differences. The most common adverse effects were gastrointestinal.

Continue to: Danazol linked to weight gain and other adverse effects

A 2010 Cochrane review evaluated 9 RCTs, including 1 (66 patients) comparing danazol 200 mg with placebo that showed a significant decrease in subjectively assessed MBL in the danazol group.⁶ The study, which only 22 women finished, didn’t address ­intention-to-treat and used an unidentified scoring system. Patients also reported a significant 6.7-kg weight gain (95% CI, 1-12.4) after 3 months of treatment.

In addition to the 2013 meta-analysis showing danazol to be superior to NSAIDs, several studies⁶ compared danazol favorably with oral progesterone, although not all results reached significance. One study (37 patients) showed that women were more likely to rate the efficacy of danazol as moderate or high compared with progesterone (OR = 4.3; 95% CI, 1.1-17.0), but the mean difference in MBL (–36 mL; 95% CI, −102 to 31 mL) wasn’t statistically significant.

Of note, both a meta-analysis of 4 of the studies (117 patients) and another study comparing danazol with NSAIDs (20 patients) found significantly more adverse effects in the danazol group. Commonly reported adverse effects were acne, weight gain, headache, nausea, and tiredness.

RECOMMENDATIONS

A comparative effectiveness review by the Agency for Healthcare Research and Quality concluded that evidence showed efficacy for 4 primary care interventions for heavy cyclic bleeding: LNG-IUS, NSAIDs, tranexamic acid, and combination OCPs.⁷

The United Kingdom’s National Institute for Health Care and Excellence (NICE) recommends pharmaceutical treatment when no structural or histologic abnormality is present or when fibroids are < 3 cm in diameter.⁸ NICE advises considering pharmaceutical treatments in the following order: first, LNG-IUS if long-term use (at least 12 months) is anticipated; second, tranexamic acid or NSAIDs; and third, combination OCPs, norethisterone (15 mg) daily from Days 5 to 26 of the menstrual cycle, or injected long-acting progestogen.

Editor’s takeaway

I was taught to use combination OCPs as first-line treatment for menorrhagia, but better evidence supports using any of these 4: LNG-IUS, tranexamic acid, danazol, or NSAIDs. In the absence of clear evidence demonstrating differences in efficacy, I would use them in the reverse order for cost-effectiveness reasons.

EVIDENCE SUMMARY

A 2015 Cochrane review of the LNG-IUS for menorrhagia included 1 placebo-controlled RCT; most of the remaining 21 RCTs compared the LNG-IUS to invasive procedures such as endometrial ablation or hysterectomy.¹ The placebo-controlled trial compared the LNG-IUS with placebo in 40 women on anticoagulation therapy and found a mean beneficial difference of 100 mL (95% confidence interval [CI], –116 to –83) using a subjective pictorial blood assessment chart.

Women are less likely to withdraw from LNG-IUS treatment

Four trials (379 patients) included in the Cochrane review compared LNG-IUS with combination or progesterone-only pills. All of the trials excluded women with palpable or large (> 5 cm) fibroids. In 3 trials (2 against OCPs and 1 against a 10-day course of oral progesterone), the LNG-IUS decreased MBL more than OCPs did. A fourth trial found LNG-IUS comparable to oral progesterone dosed 3 times a day from Day 5 to Day 26 of each menstrual cycle.

A recent large RCT (571 patients) that compared LNG-IUS with usual medical treatment (mefenamic acid [MFA], tranexamic acid, norethindrone, OCPs, progesterone-­only pill, medroxyprogesterone acetate injection) found women significantly less likely to withdraw from LNG-IUS at 2 years (relative risk [RR] = 0.58; 95% CI, 0.49-0.70).²

Estrogen and progestin contraceptives significantly reduce bleeding

In addition to the trials in the 2015 Cochrane review comparing OCPs with LNG-IUS, a 2009 Cochrane review included a single 2-month crossover trial of 45 patients.³ This RCT compared OCPs with naproxen, MFA, and danazol to treat heavy menstrual bleeding (assessed using the alkaline haematin method).

Researchers didn’t analyze the data using intention-to-treat. No group was found to be superior. The OCP group (6 women) had a 43% reduction in MBL over baseline (no P value reported).

Tranexamic acid outperforms oral progesterone and NSAIDs but not ...

A 2018 Cochrane meta-analysis of 13 RCTs (1312 patients) of antifibrinolytics for reproductive-age women with regular heavy periods and no known underlying pathology included 4 RCTs (565 patients) that used placebo as a comparator.⁴ Therapy with tranexamic acid decreased blood loss by53 mL per cycle (95% CI, 44-63 mL), a 40% to 50% improvement compared with placebo. Three of the RCTs (271 patients) reported the percent of women improving on tranexamic acid as 43% to 63%, compared with 11% for placebo, resulting in an NNT of 2 to 3.

In head-to-head comparisons, women were more likely to improve with the LNG-IUS than tranexamic acid for reducing menstrual blood loss.

One trial (46 patients) found tranexamic acid superior to luteal phase oral progesterone, and another study (48 patients) demonstrated superiority to NSAIDs, with a mean decrease in MBL of 86 mL compared with 43 mL (P < .0027).

Continue to: On the other hand...

On the other hand, tranexamic acid compared unfavorably with LNG-IUS (1 RCT, 42 patients), showing a lower likelihood of improvement (RR = 0.43; 95% CI, 0.24-0.77). Whereas 85% of women improved with LNG-IUS, only 20% to 65% of women improved with tranexamic acid (NNT = 2 to 6). 

No statistical difference was found in gastrointestinal adverse effects, headache, vaginal dryness, or dysmenorrhea.⁴ Only 1 thromboembolic event occurred in the 2 studies that reported this outcome, a known risk that prohibits its concomitant use with combination OCPs.

Different NSAIDs, equivalent efficacy

A 2013 Cochrane review of 18 RCTs included 8 (84 patients) that compared NSAIDs (5 MFA, 2 naproxen, 1 ibuprofen) with placebo.⁵ In 6 trials, NSAIDs produced a significant reduction in MBL compared with placebo, although most were crossover trials that couldn’t be compiled into the meta-analysis.

One trial (11 patients) showed a mean reduction of 124 mL (95% CI, 62-186 mL) in the MFA group. In another trial, women were less likely to report no improvement in the MFA group than in the placebo group (odds ratio [OR] = 0.08; 95% CI, 0.03-0.18). No NSAID had significantly higher efficacy than the others.

Danazol was superior to NSAIDs in a meta-analysis of 3 trials (79 patients) with a mean difference of 45 mL (95% CI, 19-71 mL), as was tranexamic acid in a single trial (48 patients) with a mean difference of 73 mL (95% CI, 22-124 mL).⁵ Comparisons with OCPs, oral progesterone, and an older model of LNG-IUS showed no significant ­differences. The most common adverse effects were gastrointestinal.

Continue to: Danazol linked to weight gain and other adverse effects

A 2010 Cochrane review evaluated 9 RCTs, including 1 (66 patients) comparing danazol 200 mg with placebo that showed a significant decrease in subjectively assessed MBL in the danazol group.⁶ The study, which only 22 women finished, didn’t address ­intention-to-treat and used an unidentified scoring system. Patients also reported a significant 6.7-kg weight gain (95% CI, 1-12.4) after 3 months of treatment.

In addition to the 2013 meta-analysis showing danazol to be superior to NSAIDs, several studies⁶ compared danazol favorably with oral progesterone, although not all results reached significance. One study (37 patients) showed that women were more likely to rate the efficacy of danazol as moderate or high compared with progesterone (OR = 4.3; 95% CI, 1.1-17.0), but the mean difference in MBL (–36 mL; 95% CI, −102 to 31 mL) wasn’t statistically significant.

Of note, both a meta-analysis of 4 of the studies (117 patients) and another study comparing danazol with NSAIDs (20 patients) found significantly more adverse effects in the danazol group. Commonly reported adverse effects were acne, weight gain, headache, nausea, and tiredness.

RECOMMENDATIONS

A comparative effectiveness review by the Agency for Healthcare Research and Quality concluded that evidence showed efficacy for 4 primary care interventions for heavy cyclic bleeding: LNG-IUS, NSAIDs, tranexamic acid, and combination OCPs.⁷

The United Kingdom’s National Institute for Health Care and Excellence (NICE) recommends pharmaceutical treatment when no structural or histologic abnormality is present or when fibroids are < 3 cm in diameter.⁸ NICE advises considering pharmaceutical treatments in the following order: first, LNG-IUS if long-term use (at least 12 months) is anticipated; second, tranexamic acid or NSAIDs; and third, combination OCPs, norethisterone (15 mg) daily from Days 5 to 26 of the menstrual cycle, or injected long-acting progestogen.

Editor’s takeaway

I was taught to use combination OCPs as first-line treatment for menorrhagia, but better evidence supports using any of these 4: LNG-IUS, tranexamic acid, danazol, or NSAIDs. In the absence of clear evidence demonstrating differences in efficacy, I would use them in the reverse order for cost-effectiveness reasons.

EVIDENCE SUMMARY

A 2015 Cochrane review of the LNG-IUS for menorrhagia included 1 placebo-controlled RCT; most of the remaining 21 RCTs compared the LNG-IUS to invasive procedures such as endometrial ablation or hysterectomy.¹ The placebo-controlled trial compared the LNG-IUS with placebo in 40 women on anticoagulation therapy and found a mean beneficial difference of 100 mL (95% confidence interval [CI], –116 to –83) using a subjective pictorial blood assessment chart.

Women are less likely to withdraw from LNG-IUS treatment

Four trials (379 patients) included in the Cochrane review compared LNG-IUS with combination or progesterone-only pills. All of the trials excluded women with palpable or large (> 5 cm) fibroids. In 3 trials (2 against OCPs and 1 against a 10-day course of oral progesterone), the LNG-IUS decreased MBL more than OCPs did. A fourth trial found LNG-IUS comparable to oral progesterone dosed 3 times a day from Day 5 to Day 26 of each menstrual cycle.

A recent large RCT (571 patients) that compared LNG-IUS with usual medical treatment (mefenamic acid [MFA], tranexamic acid, norethindrone, OCPs, progesterone-­only pill, medroxyprogesterone acetate injection) found women significantly less likely to withdraw from LNG-IUS at 2 years (relative risk [RR] = 0.58; 95% CI, 0.49-0.70).²

Estrogen and progestin contraceptives significantly reduce bleeding

In addition to the trials in the 2015 Cochrane review comparing OCPs with LNG-IUS, a 2009 Cochrane review included a single 2-month crossover trial of 45 patients.³ This RCT compared OCPs with naproxen, MFA, and danazol to treat heavy menstrual bleeding (assessed using the alkaline haematin method).

Researchers didn’t analyze the data using intention-to-treat. No group was found to be superior. The OCP group (6 women) had a 43% reduction in MBL over baseline (no P value reported).

Tranexamic acid outperforms oral progesterone and NSAIDs but not ...

A 2018 Cochrane meta-analysis of 13 RCTs (1312 patients) of antifibrinolytics for reproductive-age women with regular heavy periods and no known underlying pathology included 4 RCTs (565 patients) that used placebo as a comparator.⁴ Therapy with tranexamic acid decreased blood loss by53 mL per cycle (95% CI, 44-63 mL), a 40% to 50% improvement compared with placebo. Three of the RCTs (271 patients) reported the percent of women improving on tranexamic acid as 43% to 63%, compared with 11% for placebo, resulting in an NNT of 2 to 3.

In head-to-head comparisons, women were more likely to improve with the LNG-IUS than tranexamic acid for reducing menstrual blood loss.

One trial (46 patients) found tranexamic acid superior to luteal phase oral progesterone, and another study (48 patients) demonstrated superiority to NSAIDs, with a mean decrease in MBL of 86 mL compared with 43 mL (P < .0027).

Continue to: On the other hand...

On the other hand, tranexamic acid compared unfavorably with LNG-IUS (1 RCT, 42 patients), showing a lower likelihood of improvement (RR = 0.43; 95% CI, 0.24-0.77). Whereas 85% of women improved with LNG-IUS, only 20% to 65% of women improved with tranexamic acid (NNT = 2 to 6). 

No statistical difference was found in gastrointestinal adverse effects, headache, vaginal dryness, or dysmenorrhea.⁴ Only 1 thromboembolic event occurred in the 2 studies that reported this outcome, a known risk that prohibits its concomitant use with combination OCPs.

Different NSAIDs, equivalent efficacy

A 2013 Cochrane review of 18 RCTs included 8 (84 patients) that compared NSAIDs (5 MFA, 2 naproxen, 1 ibuprofen) with placebo.⁵ In 6 trials, NSAIDs produced a significant reduction in MBL compared with placebo, although most were crossover trials that couldn’t be compiled into the meta-analysis.

One trial (11 patients) showed a mean reduction of 124 mL (95% CI, 62-186 mL) in the MFA group. In another trial, women were less likely to report no improvement in the MFA group than in the placebo group (odds ratio [OR] = 0.08; 95% CI, 0.03-0.18). No NSAID had significantly higher efficacy than the others.

Danazol was superior to NSAIDs in a meta-analysis of 3 trials (79 patients) with a mean difference of 45 mL (95% CI, 19-71 mL), as was tranexamic acid in a single trial (48 patients) with a mean difference of 73 mL (95% CI, 22-124 mL).⁵ Comparisons with OCPs, oral progesterone, and an older model of LNG-IUS showed no significant ­differences. The most common adverse effects were gastrointestinal.

Continue to: Danazol linked to weight gain and other adverse effects

A 2010 Cochrane review evaluated 9 RCTs, including 1 (66 patients) comparing danazol 200 mg with placebo that showed a significant decrease in subjectively assessed MBL in the danazol group.⁶ The study, which only 22 women finished, didn’t address ­intention-to-treat and used an unidentified scoring system. Patients also reported a significant 6.7-kg weight gain (95% CI, 1-12.4) after 3 months of treatment.

In addition to the 2013 meta-analysis showing danazol to be superior to NSAIDs, several studies⁶ compared danazol favorably with oral progesterone, although not all results reached significance. One study (37 patients) showed that women were more likely to rate the efficacy of danazol as moderate or high compared with progesterone (OR = 4.3; 95% CI, 1.1-17.0), but the mean difference in MBL (–36 mL; 95% CI, −102 to 31 mL) wasn’t statistically significant.

Of note, both a meta-analysis of 4 of the studies (117 patients) and another study comparing danazol with NSAIDs (20 patients) found significantly more adverse effects in the danazol group. Commonly reported adverse effects were acne, weight gain, headache, nausea, and tiredness.

RECOMMENDATIONS

A comparative effectiveness review by the Agency for Healthcare Research and Quality concluded that evidence showed efficacy for 4 primary care interventions for heavy cyclic bleeding: LNG-IUS, NSAIDs, tranexamic acid, and combination OCPs.⁷

The United Kingdom’s National Institute for Health Care and Excellence (NICE) recommends pharmaceutical treatment when no structural or histologic abnormality is present or when fibroids are < 3 cm in diameter.⁸ NICE advises considering pharmaceutical treatments in the following order: first, LNG-IUS if long-term use (at least 12 months) is anticipated; second, tranexamic acid or NSAIDs; and third, combination OCPs, norethisterone (15 mg) daily from Days 5 to 26 of the menstrual cycle, or injected long-acting progestogen.

Editor’s takeaway

I was taught to use combination OCPs as first-line treatment for menorrhagia, but better evidence supports using any of these 4: LNG-IUS, tranexamic acid, danazol, or NSAIDs. In the absence of clear evidence demonstrating differences in efficacy, I would use them in the reverse order for cost-effectiveness reasons.

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; bob.anderson@vumc.org

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; bob.anderson@vumc.org

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; bob.anderson@vumc.org

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; ksweeney2@kumc.edu.

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.