OBG Management

“FAREWELL TO INDIGO CARMINE”
ROBERT L. BARBIERI, MD (EDITORIAL; SEPTEMBER 2014)

Use baby formula to check for bladder integrity
There is an additional method that can be used to check for bladder injury that some of us “older” gynecologists have employed. Baby formula is packaged in sterile bottles. I have had the rare occasion to need to check for bladder integrity and have had the circulating nurse inject diluted formula through the indwelling urinary catheter. I have yet to encounter (or read about) an allergic response from this technique.
Martin E. Kanoff, DO
Sewell, New Jersey

I found Dr. Barbieri’s editorial on the indigo carmine shortage very appropriate and timely.

When intraoperatively testing a bladder repair or looking for a possible bladder injury, administration of phenazopyridine or instillation of dilute methylene blue as noted are reasonable approaches. Due to tissue staining, which can make repeat bladder assessment more difficult, I have found that instilling sterile formula, usually easily available on the obstetric unit, will allow detection of “leaks” and easily can be rinsed out of the pelvis with saline, allowing repeat instillation if necessary.

Also, if the bladder is distended with fluid when looking for defects, it pays to wait a few minutes before decompressing, as small leaks may gradually deflate the bladder and alert the surgeon to the need for further investigation.
William J. Mann, Jr, MD
Executive Medical Director
Olde Towne Medical and Dental Center
Clinical Professor, ObGyn
Virginia Commonwealth School of Medicine
Richmond, Virginia

What about using sterile milk?
Dr. Barbieri, what is your opinion and do you have any ideas on sourcing sterile milk for use in diagnostic cystoscopy and tubal patency in gynecology?
Donna G. Ivery, MD  
Titusville, Florida

Is there a methylene blue shortage too?
I commonly perform chromotubation for my infertility patients and for tubal reversals. I have been substituting methylene blue for indigo carmine. Recently, I was told by my surgical center that methylene blue is on back order. Have you noticed the methylene blue shortage? Do you have suggestions for a replacement for my indications of chromotubation and tubal reversal surgeries?

Online I have seen mention of isosulfan blue being injected into lymphatic tissue to identify sentinel nodes—although it is more expensive. I will be searching now for a supplier of isosulfan blue. Sterile milk has been used to identify bladder fistulas. Can it be used for chromotubation?
Peter G. Van Deerlin, MD
South Jersey Fertility Center
Marlton, New Jersey

Can we brainstorm a solution to the shortage?
Dr. Barbieri, once again you have demonstrated your clear thinking and reasoned approach to what is a clinical problem.

I would add the following thought: Perhaps a group of physicians from major specialty/subspecialty organizations could meet with the present manufacturers and brainstorm for a solution. Self-interest is clearly the practical path and patient safety/customer satisfaction can come into play also.
Stephen S. Schuster, MD
Queens, New York

Another way to diagnose PROM
I read with interest the editorial covering the shortage of indigo carmine. In the section “Options to diagnose PROM … ”, you stated NONE as the option for diagnosing premature rupture of membranes (PROM) when standard clinical testing is equivocal.

A recent article in Journal of Perinatal Medicine suggests that placental alpha microglobulin-1 (PAMG-1) testing is as reliable as dye studies.¹ This was a 140-patient prospective study and is certainly encouraging.

I don’t use PAMG-1 as a first-line agent for diagnosing rupture of membranes (ROM). Speculum examination with pooling of amniotic fluid, nitrozine testing, and microscopic examination for ferning confirm or rule out ROM in most cases. This article points toward avoiding the more invasive dye study. The data are timely in light of the indigo carmine shortage.
John R. Hannig, MD
Salem, Oregon

Reference

Dr. Barbieri responds
I appreciate the great suggestion by Drs. Kanoff, Mann, and Ivery to use sterile baby formula to test bladder integrity. Sterile baby formula is usually available on an obstetric unit, and less available in a main operating room environment. One small caveat about the use of the word “sterile.” Baby formula is “sterile” using criteria for a commercial food product. Injectable agents typically need to be both sterile, using criteria for a pharmaceutical agent, and pyrogen free. These criteria are more stringent than for a food product. Some surgical nursing and pharmacy administrators may focus on this technical difference and resist the use of sterile baby formula to test bladder integrity.

First it was indigo carmine, now methylene blue is on back order. As Dr. Van Deerlin suspects, isosulfan blue is expensive. A 5-mL vial of isosulfan blue has a list price of $714. If no dye were available to test tubal patency, I would consider using saline or lactated Ringer’s solution. I would hesitate to use sterile baby formula because I would be concerned about peritoneal and tubal epithelial inflammation.

Dr. Schuster has a great suggestion to better coordinate the capabilities of manufacturers with the needs of clinicians and patients. We will forward your suggestion to the ACOG leadership.

I agree with Dr. Hannig’s suggestion that measurement of placental alpha macroglobulin-1 in vaginal fluid is an excellent option for replacing intra-amniotic injection of indigo carmine. Some obstetric units have not yet deployed this test because, in many centers, only a few cases per year needed this test. With the loss of access to indigo carmine, it is a good option to consider measurement of placental alpha macroglobulin-1 in vaginal fluid in cases where it is unclear if the membranes have ruptured.

“PREVENTING POSTOPERATIVE NEUROPATHIES: PATIENT POSITIONING FOR MINIMALLY INVASIVE PROCEDURES”
TIFFANY JACKSON, MD; BICH-VAN TRAN, MD; ARNOLD ADVINCULA, MD; KAREN WIERCINSKI, RN, BSN; JULIO LOPEZ (VIDEO; SEPTEMBER 2014)

May I share the video?
The video on patient positioning to prevent postoperative neuropathies is a great resource for physicians and nurses! May I share this video with our gynecologic operative room staff as a teaching tool?
Christinne D. Canela, MD
Roanoke, Virginia

The Editors respond
This, and all of the videos at obgmanagement.com are meant to be shared with your colleagues. 

“TISSUE EXTRACTION DURING MINIMALLY INVASIVE GYN SURGERY. SECOND OF 2 PARTS: COUNSELING THE PATIENT”
(ROUNDTABLE; OCTOBER 2014)

May I morcellate your uterus please?
The laparoscopic approach to the fibroid uterus is currently a puzzle. After the FDA released a statement in April postulating that the use of power morcellation to remove uterine fibroids should be “discouraged,” a great controversy developed in the minimally invasive surgical community.

Subsequently in July, the Obstetrics and Gynecology Devices Advisory Panel of the FDA held a 2-day meeting to analyze risks, benefits, and the overall clinical role of laparoscopic power morcellation in gynecology. One recommendation was to include in the informed consent a disclosure of the risks of disseminating an occult uterine malignancy. I salute the efforts of the panel and agree on the necessity for a comprehensive consent process that discloses risks that could worsen the patient’s prognosis.

Soon after that FDA panel met in July, Ethicon, a division of Johnson and Johnson, made a business decision to initiate a worldwide withdrawal of the company’s morcellation devices.

Now, on November 24, the FDA issued an updated Safety Communication recommending that the use of power morcellators is contraindicated for removal of uterine tissue containing suspected fibroids in patients who are peri- or post-menopausal, or are candidates for en bloc tissue removal. They also said that laparoscopic power morcellators are contraindicated in gynecologic surgery in which the tissue to be morcellated is known or suspected to contain malignancy. The FDA is issuing a boxed warning, and recommends that surgeons thoroughly discuss the benefits and risks of all treatment to patients, including younger women who want to maintain their fertility or women not yet perimenopausal who wish to keep their uterus.

How will having a patient sign a consent form change the risk of unfortunate dispersion? How will it protect the surgeon from the subsequent liability? Who will be responsible for worsening the patient’s survival?

Month after month in the Medical Verdicts column, we see cases of unfortunate patients who suffer well-known surgical complications that are litigated, with different outcomes and compensations. I am certain that in most of these cases, the patients had signed at least a standard consent form that lists the most commonly known complications. Having a patient sign a consent form does not reduce the incidence of complications nor protect the physician from liability.

In my opinion, effort should be concentrated on finding a way to better preoperatively identify the patient at risk of occult uterine malignancy so that the surgical approach can be modified accordingly.

The controversy regarding morcellation is far from over. Perhaps the last tissue extractor remaining in the market should be used to morcellate the tort system and finally build a system that will protect patients and physicians.
Jose Carugno, MD
Miami, Florida

Dr. Iglesia responds
Dr. Carugno is correct. A “consent form” does not protect the surgeon from potential liability nor the patient from potential harm. Informed decision-making is a process wherein providers and patients discuss the diagnoses and conditions; the treatment options and alternatives ranging from expectant management, medical management or surgical intervention; and the potential risks and benefits of each of those options. Physicians should perform an adequate preoperative evaluation, and patients should be given the opportunity to ask questions with the understanding that no treatment is without risks (including the option for watchful waiting). Physicians should describe the steps that will be taken during the preoperative, intraoperative, and postoperative periods to mitigate those risks.

“TOTAL ABDOMINAL HYSTERECTOMY THE MAYO CLINIC WAY” JOHN B. GEBHART, MD, MS (SURGICAL TECHNIQUE; OCTOBER 2014)

We need to focus on improving vaginal hysterectomy
I found Dr. Gebhart’s article on abdominal hysterectomy technically very accurate and well written. It is with the greatest respect that I write to express my concern with the author’s response that because of the restriction of power morcellation devices, the rate of abdominal hysterectomy will increase.

Rather than focus on the improvement of the most common gynecologic surgical procedure, we should be focusing on improving techniques of vaginal hysterectomy, a route that unfortunately is under-taught in the United States.

I have been a practicing ObGyn for more than 20 years, and exclusively as a gynecologist for the last 4 years. I perform vaginal hysterectomies more than 90% of the time. My total abdominal hysterectomy and laparoscopic-assisted vaginal hysterectomy rates remain less than 5%; laparoscopic supracervical hysterectomy and total laparoscopic hysterectomy rates: 0%; and power morcellation rate: 0%. 

In conclusion, why abdominal hysterectomy?
Robert C. Raymond, MD, MBA
Fort Payne, Alabama

Dr. Gebhart responds
Dr. Raymond, I thank you for your comments and question. I applaud your surgical skill set and approach to hysterectomy. My preferred route of hysterectomy for benign disease is the vaginal route. A few years ago we published an article in OBG Management on keys to success in vaginal hysterectomy.¹ Indeed, the vaginal approach remains the least expensive and least morbid approach to hysterectomy, yet the least common. I continue to publish and lecture on the benefits of a vaginal approach and societies, such as the Society of Gynecologic Surgeons (SGS), remain committed to teaching and advocating this well-established, evidence-based yet underutilized approach.

Given the interest and controversy in the use of power morcellation after the FDA’s Safety Communication last April,² it was felt that a good technical review of abdominal hysterectomy was cogent. If surgeons have a concern about using power morcellation or their institution has banned use of a power morcellator, then the abdominal route is the most likely alternative for removing the enlarged uterus intact. As you state, the abdominal approach remains the most common route of hysterectomy. My sense is that most providers faced with an enlarged uterus that cannot be removed via laparoscopic morcellation (for reasons stated previously) are likely to turn to abdominal hysterectomy. Hopefully, the article gives readers a chance to assess and develop their technical approach to abdominal hysterectomy.

References

Share your thoughts on these letters or on another article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“FAREWELL TO INDIGO CARMINE”
ROBERT L. BARBIERI, MD (EDITORIAL; SEPTEMBER 2014)

Use baby formula to check for bladder integrity
There is an additional method that can be used to check for bladder injury that some of us “older” gynecologists have employed. Baby formula is packaged in sterile bottles. I have had the rare occasion to need to check for bladder integrity and have had the circulating nurse inject diluted formula through the indwelling urinary catheter. I have yet to encounter (or read about) an allergic response from this technique.
Martin E. Kanoff, DO
Sewell, New Jersey

I found Dr. Barbieri’s editorial on the indigo carmine shortage very appropriate and timely.

When intraoperatively testing a bladder repair or looking for a possible bladder injury, administration of phenazopyridine or instillation of dilute methylene blue as noted are reasonable approaches. Due to tissue staining, which can make repeat bladder assessment more difficult, I have found that instilling sterile formula, usually easily available on the obstetric unit, will allow detection of “leaks” and easily can be rinsed out of the pelvis with saline, allowing repeat instillation if necessary.

Also, if the bladder is distended with fluid when looking for defects, it pays to wait a few minutes before decompressing, as small leaks may gradually deflate the bladder and alert the surgeon to the need for further investigation.
William J. Mann, Jr, MD
Executive Medical Director
Olde Towne Medical and Dental Center
Clinical Professor, ObGyn
Virginia Commonwealth School of Medicine
Richmond, Virginia

What about using sterile milk?
Dr. Barbieri, what is your opinion and do you have any ideas on sourcing sterile milk for use in diagnostic cystoscopy and tubal patency in gynecology?
Donna G. Ivery, MD  
Titusville, Florida

Is there a methylene blue shortage too?
I commonly perform chromotubation for my infertility patients and for tubal reversals. I have been substituting methylene blue for indigo carmine. Recently, I was told by my surgical center that methylene blue is on back order. Have you noticed the methylene blue shortage? Do you have suggestions for a replacement for my indications of chromotubation and tubal reversal surgeries?

Online I have seen mention of isosulfan blue being injected into lymphatic tissue to identify sentinel nodes—although it is more expensive. I will be searching now for a supplier of isosulfan blue. Sterile milk has been used to identify bladder fistulas. Can it be used for chromotubation?
Peter G. Van Deerlin, MD
South Jersey Fertility Center
Marlton, New Jersey

Can we brainstorm a solution to the shortage?
Dr. Barbieri, once again you have demonstrated your clear thinking and reasoned approach to what is a clinical problem.

I would add the following thought: Perhaps a group of physicians from major specialty/subspecialty organizations could meet with the present manufacturers and brainstorm for a solution. Self-interest is clearly the practical path and patient safety/customer satisfaction can come into play also.
Stephen S. Schuster, MD
Queens, New York

Another way to diagnose PROM
I read with interest the editorial covering the shortage of indigo carmine. In the section “Options to diagnose PROM … ”, you stated NONE as the option for diagnosing premature rupture of membranes (PROM) when standard clinical testing is equivocal.

A recent article in Journal of Perinatal Medicine suggests that placental alpha microglobulin-1 (PAMG-1) testing is as reliable as dye studies.¹ This was a 140-patient prospective study and is certainly encouraging.

I don’t use PAMG-1 as a first-line agent for diagnosing rupture of membranes (ROM). Speculum examination with pooling of amniotic fluid, nitrozine testing, and microscopic examination for ferning confirm or rule out ROM in most cases. This article points toward avoiding the more invasive dye study. The data are timely in light of the indigo carmine shortage.
John R. Hannig, MD
Salem, Oregon

Reference

Dr. Barbieri responds
I appreciate the great suggestion by Drs. Kanoff, Mann, and Ivery to use sterile baby formula to test bladder integrity. Sterile baby formula is usually available on an obstetric unit, and less available in a main operating room environment. One small caveat about the use of the word “sterile.” Baby formula is “sterile” using criteria for a commercial food product. Injectable agents typically need to be both sterile, using criteria for a pharmaceutical agent, and pyrogen free. These criteria are more stringent than for a food product. Some surgical nursing and pharmacy administrators may focus on this technical difference and resist the use of sterile baby formula to test bladder integrity.

First it was indigo carmine, now methylene blue is on back order. As Dr. Van Deerlin suspects, isosulfan blue is expensive. A 5-mL vial of isosulfan blue has a list price of $714. If no dye were available to test tubal patency, I would consider using saline or lactated Ringer’s solution. I would hesitate to use sterile baby formula because I would be concerned about peritoneal and tubal epithelial inflammation.

Dr. Schuster has a great suggestion to better coordinate the capabilities of manufacturers with the needs of clinicians and patients. We will forward your suggestion to the ACOG leadership.

I agree with Dr. Hannig’s suggestion that measurement of placental alpha macroglobulin-1 in vaginal fluid is an excellent option for replacing intra-amniotic injection of indigo carmine. Some obstetric units have not yet deployed this test because, in many centers, only a few cases per year needed this test. With the loss of access to indigo carmine, it is a good option to consider measurement of placental alpha macroglobulin-1 in vaginal fluid in cases where it is unclear if the membranes have ruptured.

“PREVENTING POSTOPERATIVE NEUROPATHIES: PATIENT POSITIONING FOR MINIMALLY INVASIVE PROCEDURES”
TIFFANY JACKSON, MD; BICH-VAN TRAN, MD; ARNOLD ADVINCULA, MD; KAREN WIERCINSKI, RN, BSN; JULIO LOPEZ (VIDEO; SEPTEMBER 2014)

May I share the video?
The video on patient positioning to prevent postoperative neuropathies is a great resource for physicians and nurses! May I share this video with our gynecologic operative room staff as a teaching tool?
Christinne D. Canela, MD
Roanoke, Virginia

The Editors respond
This, and all of the videos at obgmanagement.com are meant to be shared with your colleagues. 

“TISSUE EXTRACTION DURING MINIMALLY INVASIVE GYN SURGERY. SECOND OF 2 PARTS: COUNSELING THE PATIENT”
(ROUNDTABLE; OCTOBER 2014)

May I morcellate your uterus please?
The laparoscopic approach to the fibroid uterus is currently a puzzle. After the FDA released a statement in April postulating that the use of power morcellation to remove uterine fibroids should be “discouraged,” a great controversy developed in the minimally invasive surgical community.

Subsequently in July, the Obstetrics and Gynecology Devices Advisory Panel of the FDA held a 2-day meeting to analyze risks, benefits, and the overall clinical role of laparoscopic power morcellation in gynecology. One recommendation was to include in the informed consent a disclosure of the risks of disseminating an occult uterine malignancy. I salute the efforts of the panel and agree on the necessity for a comprehensive consent process that discloses risks that could worsen the patient’s prognosis.

Soon after that FDA panel met in July, Ethicon, a division of Johnson and Johnson, made a business decision to initiate a worldwide withdrawal of the company’s morcellation devices.

Now, on November 24, the FDA issued an updated Safety Communication recommending that the use of power morcellators is contraindicated for removal of uterine tissue containing suspected fibroids in patients who are peri- or post-menopausal, or are candidates for en bloc tissue removal. They also said that laparoscopic power morcellators are contraindicated in gynecologic surgery in which the tissue to be morcellated is known or suspected to contain malignancy. The FDA is issuing a boxed warning, and recommends that surgeons thoroughly discuss the benefits and risks of all treatment to patients, including younger women who want to maintain their fertility or women not yet perimenopausal who wish to keep their uterus.

How will having a patient sign a consent form change the risk of unfortunate dispersion? How will it protect the surgeon from the subsequent liability? Who will be responsible for worsening the patient’s survival?

Month after month in the Medical Verdicts column, we see cases of unfortunate patients who suffer well-known surgical complications that are litigated, with different outcomes and compensations. I am certain that in most of these cases, the patients had signed at least a standard consent form that lists the most commonly known complications. Having a patient sign a consent form does not reduce the incidence of complications nor protect the physician from liability.

In my opinion, effort should be concentrated on finding a way to better preoperatively identify the patient at risk of occult uterine malignancy so that the surgical approach can be modified accordingly.

The controversy regarding morcellation is far from over. Perhaps the last tissue extractor remaining in the market should be used to morcellate the tort system and finally build a system that will protect patients and physicians.
Jose Carugno, MD
Miami, Florida

Dr. Iglesia responds
Dr. Carugno is correct. A “consent form” does not protect the surgeon from potential liability nor the patient from potential harm. Informed decision-making is a process wherein providers and patients discuss the diagnoses and conditions; the treatment options and alternatives ranging from expectant management, medical management or surgical intervention; and the potential risks and benefits of each of those options. Physicians should perform an adequate preoperative evaluation, and patients should be given the opportunity to ask questions with the understanding that no treatment is without risks (including the option for watchful waiting). Physicians should describe the steps that will be taken during the preoperative, intraoperative, and postoperative periods to mitigate those risks.

“TOTAL ABDOMINAL HYSTERECTOMY THE MAYO CLINIC WAY” JOHN B. GEBHART, MD, MS (SURGICAL TECHNIQUE; OCTOBER 2014)

We need to focus on improving vaginal hysterectomy
I found Dr. Gebhart’s article on abdominal hysterectomy technically very accurate and well written. It is with the greatest respect that I write to express my concern with the author’s response that because of the restriction of power morcellation devices, the rate of abdominal hysterectomy will increase.

Rather than focus on the improvement of the most common gynecologic surgical procedure, we should be focusing on improving techniques of vaginal hysterectomy, a route that unfortunately is under-taught in the United States.

I have been a practicing ObGyn for more than 20 years, and exclusively as a gynecologist for the last 4 years. I perform vaginal hysterectomies more than 90% of the time. My total abdominal hysterectomy and laparoscopic-assisted vaginal hysterectomy rates remain less than 5%; laparoscopic supracervical hysterectomy and total laparoscopic hysterectomy rates: 0%; and power morcellation rate: 0%. 

In conclusion, why abdominal hysterectomy?
Robert C. Raymond, MD, MBA
Fort Payne, Alabama

Dr. Gebhart responds
Dr. Raymond, I thank you for your comments and question. I applaud your surgical skill set and approach to hysterectomy. My preferred route of hysterectomy for benign disease is the vaginal route. A few years ago we published an article in OBG Management on keys to success in vaginal hysterectomy.¹ Indeed, the vaginal approach remains the least expensive and least morbid approach to hysterectomy, yet the least common. I continue to publish and lecture on the benefits of a vaginal approach and societies, such as the Society of Gynecologic Surgeons (SGS), remain committed to teaching and advocating this well-established, evidence-based yet underutilized approach.

Given the interest and controversy in the use of power morcellation after the FDA’s Safety Communication last April,² it was felt that a good technical review of abdominal hysterectomy was cogent. If surgeons have a concern about using power morcellation or their institution has banned use of a power morcellator, then the abdominal route is the most likely alternative for removing the enlarged uterus intact. As you state, the abdominal approach remains the most common route of hysterectomy. My sense is that most providers faced with an enlarged uterus that cannot be removed via laparoscopic morcellation (for reasons stated previously) are likely to turn to abdominal hysterectomy. Hopefully, the article gives readers a chance to assess and develop their technical approach to abdominal hysterectomy.

References

Share your thoughts on these letters or on another article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“FAREWELL TO INDIGO CARMINE”
ROBERT L. BARBIERI, MD (EDITORIAL; SEPTEMBER 2014)

Use baby formula to check for bladder integrity
There is an additional method that can be used to check for bladder injury that some of us “older” gynecologists have employed. Baby formula is packaged in sterile bottles. I have had the rare occasion to need to check for bladder integrity and have had the circulating nurse inject diluted formula through the indwelling urinary catheter. I have yet to encounter (or read about) an allergic response from this technique.
Martin E. Kanoff, DO
Sewell, New Jersey

I found Dr. Barbieri’s editorial on the indigo carmine shortage very appropriate and timely.

When intraoperatively testing a bladder repair or looking for a possible bladder injury, administration of phenazopyridine or instillation of dilute methylene blue as noted are reasonable approaches. Due to tissue staining, which can make repeat bladder assessment more difficult, I have found that instilling sterile formula, usually easily available on the obstetric unit, will allow detection of “leaks” and easily can be rinsed out of the pelvis with saline, allowing repeat instillation if necessary.

Also, if the bladder is distended with fluid when looking for defects, it pays to wait a few minutes before decompressing, as small leaks may gradually deflate the bladder and alert the surgeon to the need for further investigation.
William J. Mann, Jr, MD
Executive Medical Director
Olde Towne Medical and Dental Center
Clinical Professor, ObGyn
Virginia Commonwealth School of Medicine
Richmond, Virginia

What about using sterile milk?
Dr. Barbieri, what is your opinion and do you have any ideas on sourcing sterile milk for use in diagnostic cystoscopy and tubal patency in gynecology?
Donna G. Ivery, MD  
Titusville, Florida

Is there a methylene blue shortage too?
I commonly perform chromotubation for my infertility patients and for tubal reversals. I have been substituting methylene blue for indigo carmine. Recently, I was told by my surgical center that methylene blue is on back order. Have you noticed the methylene blue shortage? Do you have suggestions for a replacement for my indications of chromotubation and tubal reversal surgeries?

Online I have seen mention of isosulfan blue being injected into lymphatic tissue to identify sentinel nodes—although it is more expensive. I will be searching now for a supplier of isosulfan blue. Sterile milk has been used to identify bladder fistulas. Can it be used for chromotubation?
Peter G. Van Deerlin, MD
South Jersey Fertility Center
Marlton, New Jersey

Can we brainstorm a solution to the shortage?
Dr. Barbieri, once again you have demonstrated your clear thinking and reasoned approach to what is a clinical problem.

I would add the following thought: Perhaps a group of physicians from major specialty/subspecialty organizations could meet with the present manufacturers and brainstorm for a solution. Self-interest is clearly the practical path and patient safety/customer satisfaction can come into play also.
Stephen S. Schuster, MD
Queens, New York

Another way to diagnose PROM
I read with interest the editorial covering the shortage of indigo carmine. In the section “Options to diagnose PROM … ”, you stated NONE as the option for diagnosing premature rupture of membranes (PROM) when standard clinical testing is equivocal.

A recent article in Journal of Perinatal Medicine suggests that placental alpha microglobulin-1 (PAMG-1) testing is as reliable as dye studies.¹ This was a 140-patient prospective study and is certainly encouraging.

I don’t use PAMG-1 as a first-line agent for diagnosing rupture of membranes (ROM). Speculum examination with pooling of amniotic fluid, nitrozine testing, and microscopic examination for ferning confirm or rule out ROM in most cases. This article points toward avoiding the more invasive dye study. The data are timely in light of the indigo carmine shortage.
John R. Hannig, MD
Salem, Oregon

Reference

Dr. Barbieri responds
I appreciate the great suggestion by Drs. Kanoff, Mann, and Ivery to use sterile baby formula to test bladder integrity. Sterile baby formula is usually available on an obstetric unit, and less available in a main operating room environment. One small caveat about the use of the word “sterile.” Baby formula is “sterile” using criteria for a commercial food product. Injectable agents typically need to be both sterile, using criteria for a pharmaceutical agent, and pyrogen free. These criteria are more stringent than for a food product. Some surgical nursing and pharmacy administrators may focus on this technical difference and resist the use of sterile baby formula to test bladder integrity.

First it was indigo carmine, now methylene blue is on back order. As Dr. Van Deerlin suspects, isosulfan blue is expensive. A 5-mL vial of isosulfan blue has a list price of $714. If no dye were available to test tubal patency, I would consider using saline or lactated Ringer’s solution. I would hesitate to use sterile baby formula because I would be concerned about peritoneal and tubal epithelial inflammation.

Dr. Schuster has a great suggestion to better coordinate the capabilities of manufacturers with the needs of clinicians and patients. We will forward your suggestion to the ACOG leadership.

I agree with Dr. Hannig’s suggestion that measurement of placental alpha macroglobulin-1 in vaginal fluid is an excellent option for replacing intra-amniotic injection of indigo carmine. Some obstetric units have not yet deployed this test because, in many centers, only a few cases per year needed this test. With the loss of access to indigo carmine, it is a good option to consider measurement of placental alpha macroglobulin-1 in vaginal fluid in cases where it is unclear if the membranes have ruptured.

“PREVENTING POSTOPERATIVE NEUROPATHIES: PATIENT POSITIONING FOR MINIMALLY INVASIVE PROCEDURES”
TIFFANY JACKSON, MD; BICH-VAN TRAN, MD; ARNOLD ADVINCULA, MD; KAREN WIERCINSKI, RN, BSN; JULIO LOPEZ (VIDEO; SEPTEMBER 2014)

May I share the video?
The video on patient positioning to prevent postoperative neuropathies is a great resource for physicians and nurses! May I share this video with our gynecologic operative room staff as a teaching tool?
Christinne D. Canela, MD
Roanoke, Virginia

The Editors respond
This, and all of the videos at obgmanagement.com are meant to be shared with your colleagues. 

“TISSUE EXTRACTION DURING MINIMALLY INVASIVE GYN SURGERY. SECOND OF 2 PARTS: COUNSELING THE PATIENT”
(ROUNDTABLE; OCTOBER 2014)

May I morcellate your uterus please?
The laparoscopic approach to the fibroid uterus is currently a puzzle. After the FDA released a statement in April postulating that the use of power morcellation to remove uterine fibroids should be “discouraged,” a great controversy developed in the minimally invasive surgical community.

Subsequently in July, the Obstetrics and Gynecology Devices Advisory Panel of the FDA held a 2-day meeting to analyze risks, benefits, and the overall clinical role of laparoscopic power morcellation in gynecology. One recommendation was to include in the informed consent a disclosure of the risks of disseminating an occult uterine malignancy. I salute the efforts of the panel and agree on the necessity for a comprehensive consent process that discloses risks that could worsen the patient’s prognosis.

Soon after that FDA panel met in July, Ethicon, a division of Johnson and Johnson, made a business decision to initiate a worldwide withdrawal of the company’s morcellation devices.

Now, on November 24, the FDA issued an updated Safety Communication recommending that the use of power morcellators is contraindicated for removal of uterine tissue containing suspected fibroids in patients who are peri- or post-menopausal, or are candidates for en bloc tissue removal. They also said that laparoscopic power morcellators are contraindicated in gynecologic surgery in which the tissue to be morcellated is known or suspected to contain malignancy. The FDA is issuing a boxed warning, and recommends that surgeons thoroughly discuss the benefits and risks of all treatment to patients, including younger women who want to maintain their fertility or women not yet perimenopausal who wish to keep their uterus.

How will having a patient sign a consent form change the risk of unfortunate dispersion? How will it protect the surgeon from the subsequent liability? Who will be responsible for worsening the patient’s survival?

Month after month in the Medical Verdicts column, we see cases of unfortunate patients who suffer well-known surgical complications that are litigated, with different outcomes and compensations. I am certain that in most of these cases, the patients had signed at least a standard consent form that lists the most commonly known complications. Having a patient sign a consent form does not reduce the incidence of complications nor protect the physician from liability.

In my opinion, effort should be concentrated on finding a way to better preoperatively identify the patient at risk of occult uterine malignancy so that the surgical approach can be modified accordingly.

The controversy regarding morcellation is far from over. Perhaps the last tissue extractor remaining in the market should be used to morcellate the tort system and finally build a system that will protect patients and physicians.
Jose Carugno, MD
Miami, Florida

Dr. Iglesia responds
Dr. Carugno is correct. A “consent form” does not protect the surgeon from potential liability nor the patient from potential harm. Informed decision-making is a process wherein providers and patients discuss the diagnoses and conditions; the treatment options and alternatives ranging from expectant management, medical management or surgical intervention; and the potential risks and benefits of each of those options. Physicians should perform an adequate preoperative evaluation, and patients should be given the opportunity to ask questions with the understanding that no treatment is without risks (including the option for watchful waiting). Physicians should describe the steps that will be taken during the preoperative, intraoperative, and postoperative periods to mitigate those risks.

“TOTAL ABDOMINAL HYSTERECTOMY THE MAYO CLINIC WAY” JOHN B. GEBHART, MD, MS (SURGICAL TECHNIQUE; OCTOBER 2014)

We need to focus on improving vaginal hysterectomy
I found Dr. Gebhart’s article on abdominal hysterectomy technically very accurate and well written. It is with the greatest respect that I write to express my concern with the author’s response that because of the restriction of power morcellation devices, the rate of abdominal hysterectomy will increase.

Rather than focus on the improvement of the most common gynecologic surgical procedure, we should be focusing on improving techniques of vaginal hysterectomy, a route that unfortunately is under-taught in the United States.

I have been a practicing ObGyn for more than 20 years, and exclusively as a gynecologist for the last 4 years. I perform vaginal hysterectomies more than 90% of the time. My total abdominal hysterectomy and laparoscopic-assisted vaginal hysterectomy rates remain less than 5%; laparoscopic supracervical hysterectomy and total laparoscopic hysterectomy rates: 0%; and power morcellation rate: 0%. 

In conclusion, why abdominal hysterectomy?
Robert C. Raymond, MD, MBA
Fort Payne, Alabama

Dr. Gebhart responds
Dr. Raymond, I thank you for your comments and question. I applaud your surgical skill set and approach to hysterectomy. My preferred route of hysterectomy for benign disease is the vaginal route. A few years ago we published an article in OBG Management on keys to success in vaginal hysterectomy.¹ Indeed, the vaginal approach remains the least expensive and least morbid approach to hysterectomy, yet the least common. I continue to publish and lecture on the benefits of a vaginal approach and societies, such as the Society of Gynecologic Surgeons (SGS), remain committed to teaching and advocating this well-established, evidence-based yet underutilized approach.

Given the interest and controversy in the use of power morcellation after the FDA’s Safety Communication last April,² it was felt that a good technical review of abdominal hysterectomy was cogent. If surgeons have a concern about using power morcellation or their institution has banned use of a power morcellator, then the abdominal route is the most likely alternative for removing the enlarged uterus intact. As you state, the abdominal approach remains the most common route of hysterectomy. My sense is that most providers faced with an enlarged uterus that cannot be removed via laparoscopic morcellation (for reasons stated previously) are likely to turn to abdominal hysterectomy. Hopefully, the article gives readers a chance to assess and develop their technical approach to abdominal hysterectomy.

References

Share your thoughts on these letters or on another article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Neuraxial anesthesia, including epidural and combined spinal-epidural anesthetics, are the “gold standard” interventions for pain relief during labor because they provide a superb combination of reliable pain relief and safety for the mother and child.¹ Many US birthing centers also offer additional options for managing labor pain, including continuous labor support,² hydrotherapy,³ and parenteral opioids.⁴ In 2012, the US Food and Drug Administration (FDA) approved equipment to deliver a mixture of 50% nitrous oxide and 50% oxygen, which has offered a new option for laboring mothers.

Nitrous oxide is widely used for labor pain in the United Kingdom, Finland, Sweden, Canada, Australia, and New Zealand.⁵ In the United States, nitrous oxide has been a long-standing and common adjunct to general anesthetics, although it recently has fallen out of favor in place of better, more rapidly acting inhalation and intravenous general anesthetics. With these agents not suitable for labor analgesic use, however, nitrous oxide is undergoing a resurgence in popularity for obstetric analgesia in the United States, and we believe that it will evolve to have a prominent place among our interventions for labor pain.⁶ In this editorial, we detail the mechanism of action and the equipment’s use, as well as benefits for patients and cautions for clinicians.

How does nitrous oxide work?
Pharmacology. Nitrous oxide (N₂O) was first synthesized by Joseph Priestley in 1772 and was used as an anesthetic for dental surgery in the mid-1800s. In the late 19th Century, nitrous oxide was tested as an agent for labor analgesia.⁷ It was introduced into clinical practice in the United Kingdom in the 1930s.⁸

The mechanism of action of nitrous oxide is not fully characterized. It is thought that the gas may produce analgesia by activating the endo­genous opioid and noradrenergic systems, which in turn, modulate spinal cord transmission of pain signals.⁵

Administration to the laboring mother. For labor analgesia, nitrous oxide is typically administered as a mix of 50% N₂O and 50% O₂ using a portable unit with a gas mixer that is fed by small tanks of N₂O and O₂ or with a valve fed by a single tank containing a mixture of both N₂O and O₂. The portable units approved by the FDA contain an oxygen fail-safe system that ensures delivery of an appropriate oxygen concentration. The portable unit also contains a gas scavenging system that is attached to wall suction. The breathing circuit has a mask or a mouthpiece (according to patient preference) and demand valve. The patient places the mask over her nose and mouth, or uses just her mouth for the mouthpiece. With inhalation, the demand valve opens, releasing the gas mixture. On exhalation, the valve shunts the exhaled gases to the scavenging system.

Proper and safe use requires adherence to the principles of a true “patient-controlled” protocol. Only the patient is permitted to place the mask or mouthpiece over her nose and/or mouth. If the patient becomes drowsy, such that she cannot hold the mask to her face, then the internal demand valve will not deliver nitrous oxide and she will return to breathing room air. No one should hold the mask over the patient’s nose or mouth, and the mask should not be fixed in place with elastic bands because these actions may result in the inhalation of too much nitrous oxide.

Nitrous oxide has a rapid onset of action after inhalation and its action quickly dissipates after discontinuing inhalation. There is likely a dose-response relationship, with greater use of the nitrous oxide producing more drowsiness. With the intermittent inhalation method, the laboring patient using nitrous oxide is advised to initiate inhalation of nitrous oxide about 30 seconds before the onset of a contraction and discontinue inhalation at the peak of the contraction.

There is no time limit to the use of nitrous oxide. It can be used for hours during labor or only briefly for a particularly painful part of labor, such as during rapid cervical ­dilation or during the later portions of the second stage.

Patients report that nitrous oxide does not completely relieve pain but creates a diminished perception of the pain.⁹ As many as one-third of women are nonresponders and report no significant pain improvement with nitrous oxide use.¹⁰

The main side effects of inhalation of the gas are nausea, vomiting, dizziness, and drowsiness. Nausea has been reported in 5% to 40% of women, and vomiting has been reported in up to 15% of women using nitrous oxide.¹¹

Cautions
Contraindications to nitrous oxide include a baseline arterial oxygenation saturation less than 95% on room air, acute asthma, emphysema, or pneumothorax, or any other air-filled compartment within the body, such as bowel obstruction or pneumocephalus. (Nitrous oxide can displace nitrogen from closed body spaces, which may lead to an increase in the volume of the closed space.¹²)

Nitrous oxide inactivates ­vitamin B₁₂ by oxidation; therefore, vitamin B₁₂ deficiency or related disorders may be considered a relative contraindication. However, compared with more extensive continuous use, such as during prolonged general anesthesia, intermittent use for a limited time during labor is associated with minimal to no hematologic effects.

If a laboring woman is using N₂O, parenteral opioids should be administered only with great caution by an experienced ­clinician.

What do the data indicate?
The Agency for Healthcare Research and Quality (AHRQ) recently invited the Vanderbilt Evidence-based Practice Center to review the world literature on nitrous oxide for labor pain and to provide a summary of the research. Fifty-eight publications were identified, with 46 rated as poor quality.^11,13 Given this overall poor quality of available research, many of the recommendations concerning the use of nitrous oxide for labor pain are based on clinical ­experience and expert opinion.

The experts concluded that, for the relief of labor pain, neuraxial anesthesia was more effective than nitrous oxide inhalation. In one randomized trial included in their systematic review, nulliparous laboring women were randomly assigned to neuraxial anesthesia or nitrous oxide plus meperidine.¹⁴ About 94% of nulliparous laboring women reported satisfaction with neuraxial anesthesia, compared with 54% treated with nitrous oxide and meperidine.¹⁴

Nitrous oxide is believed to be generally safe for mother and fetus. Its use does not impact the ­newborn Apgar score¹⁵ or alter uterine
contractility.¹⁶

Catherine McGovern, RN, MSN, CNM

1. Do your research to determine which type of equipment is right for the size and volume of your organization.
   You need to consider ease of access and use for staff to bring this option to the bedside in a prompt and safe manner. Initial research includes visiting or speaking with practitioners on units currently using nitrous oxide. Use of nitrous oxide is growing, and networking is helpful in terms of planning your program. Making sure you have the correct gas line connectors for oxygen as well as for suction when using a scavenger system is a preliminary necessity.
   
   
2. Determine storage ability.
   Your environmental safety officer is a good resource to determine location and regulations regarding safe storage as well as tank capacity. He or she also can help you determine where else in your organization nitrous oxide is used so you may be able to develop your unit-specific protocol from hospital-wide policy that is already in place.
   
   
3. Collaborate on a protocol.
   After determining which type of equipment is best for you, propose the idea to committees that can contribute to the development of pain and sedation management protocols. The anesthesia department, pain committee, and postoperative pain management teams are knowledgeable resources and can help you write a safe protocol. Keep as the main focus the safe application and use of nitrous oxide for various patient populations. Potential medication interactions and contraindications for use should be discussed and included in a protocol.
   
   One more department you want to include in your planning is infection control. For our unit, reviewing various types of equipment to determine the best infection control revealed some interesting design benefits to reduce infection risk. Because the nitrous oxide equipment would be mobile, the types of filter options, disposal options, and cleaning ability are important components for final equipment choice.
   
   
4. Include all parties in training and final roll out.
   Once you develop your policy with input from all stakeholders, make sure you share it early and often before you go live. Include midwives, physicians, nurses, technicians, and administrative staff in training, which will help to dispel myths and increase awareness of availability within your unit. Provide background information to all trainees to ensure safe use and appropriate patient selection.
   
   The most important determinant of success is the formation of an inter­professional team that works well together to develop a safe clinician- and patient-friendly program for the use of nitrous oxide.

Nitrous oxide, a bridge to an epidural or a natural childbirth
Many women start labor unsure about whether they want to use an epidural. For these women, nitrous oxide may be an option for reducing labor pain, thereby giving the woman more time to make a decision about whether to have an epidural anesthetic. In our practice, a significant percentage of women who use nitrous oxide early in labor subsequently request a neuraxial anesthetic. However, many women planning natural childbirth use nitrous oxide to reduce labor pain and successfully achieve their goal.

Postpartum pain reliever
Some women deliver without the use of any pain medicine. Sometimes birth is complicated by perineal lacerations requiring significant surgical repair. If a woman does not have adequate analgesia after injection of a local anesthetic, nitrous oxide may help reduce her pain during the perineal repair and facilitate quick completion of the procedure by allowing her to remain still. N₂O also has been used to facilitate analgesia during manual removal of the placenta.

We predict an expanding role
There are many pharmacologic and nonpharmacologic options for managing labor pain, including a supportive birth environment, touch and massage, maternal positioning, relaxation and breathing techniques, continuous labor support, hydrotherapy, opioids, and neuraxial anesthesia. Midwives, labor nurses, and physicians have championed increasing the availability of nitrous oxide to laboring women in US birthing centers.^17–20 With the FDA approval of inexpensive portable nitrous oxide units, it is likely that we will witness a resurgence of its use and gain important clinical experience in the role of nitrous oxide for managing labor pain.  

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Neuraxial anesthesia, including epidural and combined spinal-epidural anesthetics, are the “gold standard” interventions for pain relief during labor because they provide a superb combination of reliable pain relief and safety for the mother and child.¹ Many US birthing centers also offer additional options for managing labor pain, including continuous labor support,² hydrotherapy,³ and parenteral opioids.⁴ In 2012, the US Food and Drug Administration (FDA) approved equipment to deliver a mixture of 50% nitrous oxide and 50% oxygen, which has offered a new option for laboring mothers.

Nitrous oxide is widely used for labor pain in the United Kingdom, Finland, Sweden, Canada, Australia, and New Zealand.⁵ In the United States, nitrous oxide has been a long-standing and common adjunct to general anesthetics, although it recently has fallen out of favor in place of better, more rapidly acting inhalation and intravenous general anesthetics. With these agents not suitable for labor analgesic use, however, nitrous oxide is undergoing a resurgence in popularity for obstetric analgesia in the United States, and we believe that it will evolve to have a prominent place among our interventions for labor pain.⁶ In this editorial, we detail the mechanism of action and the equipment’s use, as well as benefits for patients and cautions for clinicians.

How does nitrous oxide work?
Pharmacology. Nitrous oxide (N₂O) was first synthesized by Joseph Priestley in 1772 and was used as an anesthetic for dental surgery in the mid-1800s. In the late 19th Century, nitrous oxide was tested as an agent for labor analgesia.⁷ It was introduced into clinical practice in the United Kingdom in the 1930s.⁸

The mechanism of action of nitrous oxide is not fully characterized. It is thought that the gas may produce analgesia by activating the endo­genous opioid and noradrenergic systems, which in turn, modulate spinal cord transmission of pain signals.⁵

Administration to the laboring mother. For labor analgesia, nitrous oxide is typically administered as a mix of 50% N₂O and 50% O₂ using a portable unit with a gas mixer that is fed by small tanks of N₂O and O₂ or with a valve fed by a single tank containing a mixture of both N₂O and O₂. The portable units approved by the FDA contain an oxygen fail-safe system that ensures delivery of an appropriate oxygen concentration. The portable unit also contains a gas scavenging system that is attached to wall suction. The breathing circuit has a mask or a mouthpiece (according to patient preference) and demand valve. The patient places the mask over her nose and mouth, or uses just her mouth for the mouthpiece. With inhalation, the demand valve opens, releasing the gas mixture. On exhalation, the valve shunts the exhaled gases to the scavenging system.

Proper and safe use requires adherence to the principles of a true “patient-controlled” protocol. Only the patient is permitted to place the mask or mouthpiece over her nose and/or mouth. If the patient becomes drowsy, such that she cannot hold the mask to her face, then the internal demand valve will not deliver nitrous oxide and she will return to breathing room air. No one should hold the mask over the patient’s nose or mouth, and the mask should not be fixed in place with elastic bands because these actions may result in the inhalation of too much nitrous oxide.

Nitrous oxide has a rapid onset of action after inhalation and its action quickly dissipates after discontinuing inhalation. There is likely a dose-response relationship, with greater use of the nitrous oxide producing more drowsiness. With the intermittent inhalation method, the laboring patient using nitrous oxide is advised to initiate inhalation of nitrous oxide about 30 seconds before the onset of a contraction and discontinue inhalation at the peak of the contraction.

There is no time limit to the use of nitrous oxide. It can be used for hours during labor or only briefly for a particularly painful part of labor, such as during rapid cervical ­dilation or during the later portions of the second stage.

Patients report that nitrous oxide does not completely relieve pain but creates a diminished perception of the pain.⁹ As many as one-third of women are nonresponders and report no significant pain improvement with nitrous oxide use.¹⁰

The main side effects of inhalation of the gas are nausea, vomiting, dizziness, and drowsiness. Nausea has been reported in 5% to 40% of women, and vomiting has been reported in up to 15% of women using nitrous oxide.¹¹

Cautions
Contraindications to nitrous oxide include a baseline arterial oxygenation saturation less than 95% on room air, acute asthma, emphysema, or pneumothorax, or any other air-filled compartment within the body, such as bowel obstruction or pneumocephalus. (Nitrous oxide can displace nitrogen from closed body spaces, which may lead to an increase in the volume of the closed space.¹²)

Nitrous oxide inactivates ­vitamin B₁₂ by oxidation; therefore, vitamin B₁₂ deficiency or related disorders may be considered a relative contraindication. However, compared with more extensive continuous use, such as during prolonged general anesthesia, intermittent use for a limited time during labor is associated with minimal to no hematologic effects.

If a laboring woman is using N₂O, parenteral opioids should be administered only with great caution by an experienced ­clinician.

What do the data indicate?
The Agency for Healthcare Research and Quality (AHRQ) recently invited the Vanderbilt Evidence-based Practice Center to review the world literature on nitrous oxide for labor pain and to provide a summary of the research. Fifty-eight publications were identified, with 46 rated as poor quality.^11,13 Given this overall poor quality of available research, many of the recommendations concerning the use of nitrous oxide for labor pain are based on clinical ­experience and expert opinion.

The experts concluded that, for the relief of labor pain, neuraxial anesthesia was more effective than nitrous oxide inhalation. In one randomized trial included in their systematic review, nulliparous laboring women were randomly assigned to neuraxial anesthesia or nitrous oxide plus meperidine.¹⁴ About 94% of nulliparous laboring women reported satisfaction with neuraxial anesthesia, compared with 54% treated with nitrous oxide and meperidine.¹⁴

Nitrous oxide is believed to be generally safe for mother and fetus. Its use does not impact the ­newborn Apgar score¹⁵ or alter uterine
contractility.¹⁶

Catherine McGovern, RN, MSN, CNM

1. Do your research to determine which type of equipment is right for the size and volume of your organization.
   You need to consider ease of access and use for staff to bring this option to the bedside in a prompt and safe manner. Initial research includes visiting or speaking with practitioners on units currently using nitrous oxide. Use of nitrous oxide is growing, and networking is helpful in terms of planning your program. Making sure you have the correct gas line connectors for oxygen as well as for suction when using a scavenger system is a preliminary necessity.
   
   
2. Determine storage ability.
   Your environmental safety officer is a good resource to determine location and regulations regarding safe storage as well as tank capacity. He or she also can help you determine where else in your organization nitrous oxide is used so you may be able to develop your unit-specific protocol from hospital-wide policy that is already in place.
   
   
3. Collaborate on a protocol.
   After determining which type of equipment is best for you, propose the idea to committees that can contribute to the development of pain and sedation management protocols. The anesthesia department, pain committee, and postoperative pain management teams are knowledgeable resources and can help you write a safe protocol. Keep as the main focus the safe application and use of nitrous oxide for various patient populations. Potential medication interactions and contraindications for use should be discussed and included in a protocol.
   
   One more department you want to include in your planning is infection control. For our unit, reviewing various types of equipment to determine the best infection control revealed some interesting design benefits to reduce infection risk. Because the nitrous oxide equipment would be mobile, the types of filter options, disposal options, and cleaning ability are important components for final equipment choice.
   
   
4. Include all parties in training and final roll out.
   Once you develop your policy with input from all stakeholders, make sure you share it early and often before you go live. Include midwives, physicians, nurses, technicians, and administrative staff in training, which will help to dispel myths and increase awareness of availability within your unit. Provide background information to all trainees to ensure safe use and appropriate patient selection.
   
   The most important determinant of success is the formation of an inter­professional team that works well together to develop a safe clinician- and patient-friendly program for the use of nitrous oxide.

Nitrous oxide, a bridge to an epidural or a natural childbirth
Many women start labor unsure about whether they want to use an epidural. For these women, nitrous oxide may be an option for reducing labor pain, thereby giving the woman more time to make a decision about whether to have an epidural anesthetic. In our practice, a significant percentage of women who use nitrous oxide early in labor subsequently request a neuraxial anesthetic. However, many women planning natural childbirth use nitrous oxide to reduce labor pain and successfully achieve their goal.

Postpartum pain reliever
Some women deliver without the use of any pain medicine. Sometimes birth is complicated by perineal lacerations requiring significant surgical repair. If a woman does not have adequate analgesia after injection of a local anesthetic, nitrous oxide may help reduce her pain during the perineal repair and facilitate quick completion of the procedure by allowing her to remain still. N₂O also has been used to facilitate analgesia during manual removal of the placenta.

We predict an expanding role
There are many pharmacologic and nonpharmacologic options for managing labor pain, including a supportive birth environment, touch and massage, maternal positioning, relaxation and breathing techniques, continuous labor support, hydrotherapy, opioids, and neuraxial anesthesia. Midwives, labor nurses, and physicians have championed increasing the availability of nitrous oxide to laboring women in US birthing centers.^17–20 With the FDA approval of inexpensive portable nitrous oxide units, it is likely that we will witness a resurgence of its use and gain important clinical experience in the role of nitrous oxide for managing labor pain.  

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Neuraxial anesthesia, including epidural and combined spinal-epidural anesthetics, are the “gold standard” interventions for pain relief during labor because they provide a superb combination of reliable pain relief and safety for the mother and child.¹ Many US birthing centers also offer additional options for managing labor pain, including continuous labor support,² hydrotherapy,³ and parenteral opioids.⁴ In 2012, the US Food and Drug Administration (FDA) approved equipment to deliver a mixture of 50% nitrous oxide and 50% oxygen, which has offered a new option for laboring mothers.

Nitrous oxide is widely used for labor pain in the United Kingdom, Finland, Sweden, Canada, Australia, and New Zealand.⁵ In the United States, nitrous oxide has been a long-standing and common adjunct to general anesthetics, although it recently has fallen out of favor in place of better, more rapidly acting inhalation and intravenous general anesthetics. With these agents not suitable for labor analgesic use, however, nitrous oxide is undergoing a resurgence in popularity for obstetric analgesia in the United States, and we believe that it will evolve to have a prominent place among our interventions for labor pain.⁶ In this editorial, we detail the mechanism of action and the equipment’s use, as well as benefits for patients and cautions for clinicians.

How does nitrous oxide work?
Pharmacology. Nitrous oxide (N₂O) was first synthesized by Joseph Priestley in 1772 and was used as an anesthetic for dental surgery in the mid-1800s. In the late 19th Century, nitrous oxide was tested as an agent for labor analgesia.⁷ It was introduced into clinical practice in the United Kingdom in the 1930s.⁸

The mechanism of action of nitrous oxide is not fully characterized. It is thought that the gas may produce analgesia by activating the endo­genous opioid and noradrenergic systems, which in turn, modulate spinal cord transmission of pain signals.⁵

Administration to the laboring mother. For labor analgesia, nitrous oxide is typically administered as a mix of 50% N₂O and 50% O₂ using a portable unit with a gas mixer that is fed by small tanks of N₂O and O₂ or with a valve fed by a single tank containing a mixture of both N₂O and O₂. The portable units approved by the FDA contain an oxygen fail-safe system that ensures delivery of an appropriate oxygen concentration. The portable unit also contains a gas scavenging system that is attached to wall suction. The breathing circuit has a mask or a mouthpiece (according to patient preference) and demand valve. The patient places the mask over her nose and mouth, or uses just her mouth for the mouthpiece. With inhalation, the demand valve opens, releasing the gas mixture. On exhalation, the valve shunts the exhaled gases to the scavenging system.

Proper and safe use requires adherence to the principles of a true “patient-controlled” protocol. Only the patient is permitted to place the mask or mouthpiece over her nose and/or mouth. If the patient becomes drowsy, such that she cannot hold the mask to her face, then the internal demand valve will not deliver nitrous oxide and she will return to breathing room air. No one should hold the mask over the patient’s nose or mouth, and the mask should not be fixed in place with elastic bands because these actions may result in the inhalation of too much nitrous oxide.

Nitrous oxide has a rapid onset of action after inhalation and its action quickly dissipates after discontinuing inhalation. There is likely a dose-response relationship, with greater use of the nitrous oxide producing more drowsiness. With the intermittent inhalation method, the laboring patient using nitrous oxide is advised to initiate inhalation of nitrous oxide about 30 seconds before the onset of a contraction and discontinue inhalation at the peak of the contraction.

There is no time limit to the use of nitrous oxide. It can be used for hours during labor or only briefly for a particularly painful part of labor, such as during rapid cervical ­dilation or during the later portions of the second stage.

Patients report that nitrous oxide does not completely relieve pain but creates a diminished perception of the pain.⁹ As many as one-third of women are nonresponders and report no significant pain improvement with nitrous oxide use.¹⁰

The main side effects of inhalation of the gas are nausea, vomiting, dizziness, and drowsiness. Nausea has been reported in 5% to 40% of women, and vomiting has been reported in up to 15% of women using nitrous oxide.¹¹

Cautions
Contraindications to nitrous oxide include a baseline arterial oxygenation saturation less than 95% on room air, acute asthma, emphysema, or pneumothorax, or any other air-filled compartment within the body, such as bowel obstruction or pneumocephalus. (Nitrous oxide can displace nitrogen from closed body spaces, which may lead to an increase in the volume of the closed space.¹²)

Nitrous oxide inactivates ­vitamin B₁₂ by oxidation; therefore, vitamin B₁₂ deficiency or related disorders may be considered a relative contraindication. However, compared with more extensive continuous use, such as during prolonged general anesthesia, intermittent use for a limited time during labor is associated with minimal to no hematologic effects.

If a laboring woman is using N₂O, parenteral opioids should be administered only with great caution by an experienced ­clinician.

What do the data indicate?
The Agency for Healthcare Research and Quality (AHRQ) recently invited the Vanderbilt Evidence-based Practice Center to review the world literature on nitrous oxide for labor pain and to provide a summary of the research. Fifty-eight publications were identified, with 46 rated as poor quality.^11,13 Given this overall poor quality of available research, many of the recommendations concerning the use of nitrous oxide for labor pain are based on clinical ­experience and expert opinion.

The experts concluded that, for the relief of labor pain, neuraxial anesthesia was more effective than nitrous oxide inhalation. In one randomized trial included in their systematic review, nulliparous laboring women were randomly assigned to neuraxial anesthesia or nitrous oxide plus meperidine.¹⁴ About 94% of nulliparous laboring women reported satisfaction with neuraxial anesthesia, compared with 54% treated with nitrous oxide and meperidine.¹⁴

Nitrous oxide is believed to be generally safe for mother and fetus. Its use does not impact the ­newborn Apgar score¹⁵ or alter uterine
contractility.¹⁶

Catherine McGovern, RN, MSN, CNM

1. Do your research to determine which type of equipment is right for the size and volume of your organization.
   You need to consider ease of access and use for staff to bring this option to the bedside in a prompt and safe manner. Initial research includes visiting or speaking with practitioners on units currently using nitrous oxide. Use of nitrous oxide is growing, and networking is helpful in terms of planning your program. Making sure you have the correct gas line connectors for oxygen as well as for suction when using a scavenger system is a preliminary necessity.
   
   
2. Determine storage ability.
   Your environmental safety officer is a good resource to determine location and regulations regarding safe storage as well as tank capacity. He or she also can help you determine where else in your organization nitrous oxide is used so you may be able to develop your unit-specific protocol from hospital-wide policy that is already in place.
   
   
3. Collaborate on a protocol.
   After determining which type of equipment is best for you, propose the idea to committees that can contribute to the development of pain and sedation management protocols. The anesthesia department, pain committee, and postoperative pain management teams are knowledgeable resources and can help you write a safe protocol. Keep as the main focus the safe application and use of nitrous oxide for various patient populations. Potential medication interactions and contraindications for use should be discussed and included in a protocol.
   
   One more department you want to include in your planning is infection control. For our unit, reviewing various types of equipment to determine the best infection control revealed some interesting design benefits to reduce infection risk. Because the nitrous oxide equipment would be mobile, the types of filter options, disposal options, and cleaning ability are important components for final equipment choice.
   
   
4. Include all parties in training and final roll out.
   Once you develop your policy with input from all stakeholders, make sure you share it early and often before you go live. Include midwives, physicians, nurses, technicians, and administrative staff in training, which will help to dispel myths and increase awareness of availability within your unit. Provide background information to all trainees to ensure safe use and appropriate patient selection.
   
   The most important determinant of success is the formation of an inter­professional team that works well together to develop a safe clinician- and patient-friendly program for the use of nitrous oxide.

Nitrous oxide, a bridge to an epidural or a natural childbirth
Many women start labor unsure about whether they want to use an epidural. For these women, nitrous oxide may be an option for reducing labor pain, thereby giving the woman more time to make a decision about whether to have an epidural anesthetic. In our practice, a significant percentage of women who use nitrous oxide early in labor subsequently request a neuraxial anesthetic. However, many women planning natural childbirth use nitrous oxide to reduce labor pain and successfully achieve their goal.

Postpartum pain reliever
Some women deliver without the use of any pain medicine. Sometimes birth is complicated by perineal lacerations requiring significant surgical repair. If a woman does not have adequate analgesia after injection of a local anesthetic, nitrous oxide may help reduce her pain during the perineal repair and facilitate quick completion of the procedure by allowing her to remain still. N₂O also has been used to facilitate analgesia during manual removal of the placenta.

We predict an expanding role
There are many pharmacologic and nonpharmacologic options for managing labor pain, including a supportive birth environment, touch and massage, maternal positioning, relaxation and breathing techniques, continuous labor support, hydrotherapy, opioids, and neuraxial anesthesia. Midwives, labor nurses, and physicians have championed increasing the availability of nitrous oxide to laboring women in US birthing centers.^17–20 With the FDA approval of inexpensive portable nitrous oxide units, it is likely that we will witness a resurgence of its use and gain important clinical experience in the role of nitrous oxide for managing labor pain.  

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Gynecologists are “first-line” providers for the diagnosis and treatment of osteoporosis in women. Lest you doubt the importance of this fact, consider that there are more osteoporotic fractures annually in the United States than all myocardial infarctions, strokes, breast cancers, and gynecologic malignancies combined. It is our duty to stay abreast of current developments in the diagnosis and treatment of this potentially devastating skeletal disorder as our patients live longer and longer.

In this article, I present recent studies on:

• the use of conjugated estrogens and bazedoxifene (Duavee) to manage hot flashes and menopausal bone loss
• the need for adequate levels of vitamin D to maintain bone and overall health, with sunlight exposure remaining a viable option
• a reinterpretation of the findings on estrogen and fracture risk from the Women’s Health Initiative (WHI)
• the effects of selective serotonin reuptake inhibitors (SSRIs) on bone mineral density (BMD)
• development of blosozumab, a new agent in the fight against osteoporosis and fracture.

FIRST TISSUE-SELECTIVE ESTROGEN COMPLEX PROTECTS AGAINST BONE LOSS WITHOUT AFFECTING ENDOMETRIAL AND BREAST TISSUE

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. ­Steroids. 2014;90:71–81.

Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated ­estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):e189–e198.

Conjugated estrogens combined with the selective estrogen receptor modulator (SERM) bazedoxifene (Duavee) are a new option to alleviate menopausal symptoms and prevent postmenopausal bone loss. The rationale for development of the tissue-selective estrogen complex (TSEC) was to combine the benefits of conjugated estrogens with the SERM’s ability to offset estrogenic stimulation of the endometrium and breast.

TSECs offer a progestin-free alternative to traditional hormone therapy for women with a uterus. In preclinical studies, investigators found evidence to support bazedoxifene as the SERM of choice and demonstrated that, by combining it with conjugated estrogens, they could provide an optimal balance of estrogen-receptor agonist/antagonist activity, compared with other potential TSEC pairings. Clinical study results confirmed the efficacy of this combination in maintaining bone mass.

Given separately, conjugated estrogens and bazedoxifene each protect against the loss of BMD and help prevent fracture in postmenopausal women.

Findings in key populations
Komm and colleagues describe substudies of the Selective estrogens, Menopause, and Response to Therapy (SMART) trials to evaluate the combination of conjugated estrogens and SERMs to prevent osteoporosis in postmenopausal women with a uterus. One SMART-1 trial included two osteoporosis prevention substudies that evaluated the combination of conjugated estrogens and bazedoxifene in different subpopulations:

• women more than 5 years past the last menstrual period with a lumbar spine or hip BMD T-score between –1 and –2.5 plus one other risk factor for osteoporosis (n = 1,454)
• women 1 to 5 years past their last menstrual period (the interval during which bone loss is greatest) with at least one risk factor for osteoporosis (n = 861).

All doses of conjugated estrogens and bazedoxifene significantly increased the adjusted mean percentage of change in BMD of the lumbar spine from baseline to 24 months (a primary endpoint), compared with placebo, which was associated with decreases in BMD (P<.001). Findings were similar for total hip BMD.

In a separate study, Pinkerton and colleagues found that the dose of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg) approved by the US Food and Drug Administration does not cause a change in breast density or thickness of the endometrium, nor does it increase breast pain, compared with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This newly available TSEC—a combination of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg)—is an effective, well-tolerated alternative to traditional estrogen-progestin hormone therapy for relief of menopausal symptoms and prevention of osteoporosis in postmenopausal women with a uterus.

DON’T EXCLUDE SUNLIGHT FROM THE BONE–HEALTH EQUATION

Holick MF. Sunlight, ultraviolet radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2014;810:1–16.

Many people think of vitamin D as the “sunshine vitamin.” During exposure to sunlight, ultraviolet photons enter the skin and convert 7-dehydrocholesterol to previtamin D3, which, in turn, is converted to vitamin D3.

Throughout most of human history, people have depended on sunlight for vitamin D. Variables such as skin pigmentation, sunscreen use, aging, time of day, season, and latitude dramatically affect previtamin synthesis.

Although vitamin D deficiency was thought to have been conquered, it is now recognized that more than 50% of the world’s population is at risk for vitamin D insufficiency or low levels of 25-hydroxyvitamin D. Among the reasons are inadequate fortification of foods with vitamin D and a misconception that most balanced diets contain adequate vitamin D.

Deficiency of this vitamin causes growth retardation and rickets in children and osteomalacia in adults and can precipitate and exacerbate osteopenia or osteoporosis and increase the risk of fracture in adults.

Some evidence also suggests that vitamin D deficiency may have other serious consequences, including an increased risk for common cancers and autoimmune, infectious, and cardiovascular diseases.

In this review, Holick argues that we need to remind our patients of the beneficial effects of moderate sunlight.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
There is no question that sufficient levels of vitamin D are vital to bone health, and perhaps to overall health in numerous other organ systems as well. The pendulum of our concern over skin cancers may have moved too far in the direction of sun avoidance. In reality, moderate sunlight as a source of vitamin D is still appropriate for many of our patients.

WHEN IT COMES TO ESTROGEN AND BONE, BENEFITS OUTWEIGH RISKS

de Villiers TJ. 8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle? [published online ahead of print September 22, 2014]. Climacteric. 2014;17(suppl 2):4–7. doi:10.3109/13697137.2014.953047.

In the WHI estrogen-progestin arm, fracture rates were reported as hazard ratios:

• hip fracture, 0.66 (95% confidence interval [CI], 0.45–0.98)
• clinical vertebral fracture, 0.66 (95% CI, 0.44–0.98)
• nonvertebral fractures, 0.77 (95% CI, 0.69–0.86).

In the estrogen-only arm of the WHI, reductions in the rates of fracture were reported as percentages and were similar:

• 39% reduction in hip fracture, compared with placebo
• 38% reduction in clinical vertebral fracture
• 21% reduction in total fractures.

All of these reductions were statistically significant.

Despite the excellent anti-fracture efficacy demonstrated in the WHI, investigators concluded that the risks of hormone therapy outweighed the benefits in the general postmenopausal population.

Why we should reconsider estrogen for bone health
In his presidential address to the International Menopause Society (cited above), de Villiers observed that, in the WHI:

• Only clinical fractures were recorded. Unlike all other fracture trials, routine radiographs were not obtained to record morphometric fractures. This decision, he believes (and I concur), led to a significant understatement of estrogen’s protective effects against vertebral fracture.
• The general population studied had a low risk of fracture, with an average spinal T-score of –1.3. This, too, contributed to an understatement of estrogen’s protective effects, compared with the findings of other randomized controlled trials involving patients at much higher risk.
• From a bone-centric point of view, the WHI findings represent a favorable ratio of benefits to risks.

No bone-active drugs are completely free of potential adverse effects and restrictions, many of which become apparent only after FDA approval and general use of the drug. Bisphosphonates have been implicated in atrial fibrillation, osteonecrosis of the jaw, and atypical femur shaft fracture after extended use. Like estrogen, SERMs can increase the risk of death from deep venous thrombosis and stroke.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Estrogen is the only agent proved to be effective against all types of osteoporotic fractures during primary analysis of a large randomized controlled trial. This efficacy is of special importance for the patient with osteopenia who is at risk for fracture. Estrogen remains a serious option for the prevention of postmenopausal bone loss and osteoporosis-related fractures, especially in younger patients. Individualization of therapy is key.

COUNSEL SSRI AND SNRI USERS THAT BMD MAY DECLINE OVER THE LONG TERM

Ak E, Bulut SD, Bulut S, et al. Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study [published online ahead of print September 4, 2014]. ­Osteoporos Int. doi:10.10007/s00198-014-2859-2.

Moura C, Bernatsky S, Ambrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473–1481.

Bruyère O, Reginster J-V. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome [published online ahead of print August 5, 2014]. Endocrine. doi:10.1007/s12020-014-0357-0.

Evidence from longitudinal, cross-­sectional, and prospective cohort studies suggests that the use of antidepressants at therapeutic doses is associated with a reduction in BMD and an increase in the risk of falls and fracture. These associations have been demonstrated in several distinct populations using various study designs, and with bone density, bone loss, or fractures as outcomes. They remain consistent even after adjustment for confounding variables such as age, body mass index, lifestyle factors such as alcohol and tobacco use, and fracture history.

Ak and colleagues recruited 60 patients given a diagnosis of generalized anxiety disorder and treated with paroxetine, sertraline, or citalopram for at least 12 months, comparing their BMD with that of 40 healthy volunteers. BMD was measured by dual-energy x-ray absorptiometry at the femoral and lumbar regions. BMD of the L2–L4 vertebrae, total lumbar vertebrae, and femoral intertrochanteric region, as well as total femoral Z-scores and femoral Ward’s region T-scores, were lower in the treatment group (P<.05). There was a significant negative correlation between the duration of treatment and the change in BMD values.

Moura and colleagues reviewed data from a large prospective Canadian cohort to assess the association between SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and fracture in adults aged 50 and older. They used the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based community cohort.

Among 6,645 subjects, 192 (2.9%) were using SSRIs or SNRIs, or both, at baseline. During the 10-year study period, 978 participants (14.7%) experienced at least one fragility fracture. SSRI/SNRI use was associated with an increased risk of fragility fracture (hazard ratio [HR], 1.88; 95% CI, 1.48–2.39). After controlling for multiple risk factors, previous falls, and BMD of the hip and lumbar bone, the adjusted hazard ratio for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32–2.14). The authors concluded that these results lend additional support to an association between SSRI/SNRI use and fragility fractures.

A few possible underlying mechanisms support the biological plausibility of these observations. One explanation is that increased fracture risk is mediated simply by falling. Another explanation could involve the influence of serotonin on bone. Besides their effects on balance, SSRIs may influence bone turnover and BMD. Whatever the mechanism, sufficient evidence exists to warrant the addition of SSRIs to the list of medications that contribute to osteoporosis.

Antidepressant use is not listed as a secondary cause of osteoporosis in the FRAX algorithm. Because the association between SSRI use and fracture risk appears to be independent of BMD, it may be useful to consider the possibility of including it in FRAX.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Consider BMD assessment for patients who take an SSRI, or who take an SSRI and have additional risk factors for fracture. Given the body of data on this issue, it seems appropriate to expect providers of SSRIs to conduct at least some discussion of bone health with patients.

IN THE PIPELINE: A HIGHLY EFFECTIVE AGENT TARGETING SCLEROSTIN

Recker R, Benson C, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density [published online ahead of print September 5, 2014]. J Bone Miner Res. doi:10.1002/jbmr.2351.

Sclerostin is a protein secreted by osteocytes that negatively regulates the formation of mineralized bone matrix and bone mass. Recker and colleagues conducted a randomized, double-blind, placebo-
controlled, multicenter, phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin. The year-long trial involved 120 postmenopausal women with low BMD (lumbar spine T-score, –2.0 to –3.5) who were randomly allocated to:

• subcutaneous blosozumab 180 mg every 4 weeks
• subcutaneous blosozumab 180 mg every 2 weeks
• subcutaneous blosozumab 270 mg every 2 weeks
• placebo.

All groups also received calcium and vitamin D and underwent serial measurement of spine and hip BMD and testing of biochemical markers of bone turnover. The mean age was 65.8 years, and the mean lumbar spine T-score was –2.8.

Women treated with blosozumab experienced statistically significant, dose-related increases in spine, femoral neck, and total hip BMD, compared with placebo. In the highest dose group, BMD increased 17.7% from baseline at the spine and 6.2% at the total hip. Biochemical markers of bone ­formation increased rapidly during treatment with blosozumab, trending toward pretreatment levels by the study’s end. CTX, a biochemical marker of bone resorption, decreased early during blosozumab treatment to a concentration lower than that in the placebo group by 2 weeks, and it remained low throughout treatment.

Mild injection-site reactions were reported more frequently with blosozumab than with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although blosozumab is not yet available, clinicians should be aware of the potential of sclerostin-antibody therapies like it. Such therapies appear to have substantial anabolic effects on the skeleton and may become promising agents in the treatment of osteoporosis.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Gynecologists are “first-line” providers for the diagnosis and treatment of osteoporosis in women. Lest you doubt the importance of this fact, consider that there are more osteoporotic fractures annually in the United States than all myocardial infarctions, strokes, breast cancers, and gynecologic malignancies combined. It is our duty to stay abreast of current developments in the diagnosis and treatment of this potentially devastating skeletal disorder as our patients live longer and longer.

In this article, I present recent studies on:

• the use of conjugated estrogens and bazedoxifene (Duavee) to manage hot flashes and menopausal bone loss
• the need for adequate levels of vitamin D to maintain bone and overall health, with sunlight exposure remaining a viable option
• a reinterpretation of the findings on estrogen and fracture risk from the Women’s Health Initiative (WHI)
• the effects of selective serotonin reuptake inhibitors (SSRIs) on bone mineral density (BMD)
• development of blosozumab, a new agent in the fight against osteoporosis and fracture.

FIRST TISSUE-SELECTIVE ESTROGEN COMPLEX PROTECTS AGAINST BONE LOSS WITHOUT AFFECTING ENDOMETRIAL AND BREAST TISSUE

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. ­Steroids. 2014;90:71–81.

Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated ­estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):e189–e198.

Conjugated estrogens combined with the selective estrogen receptor modulator (SERM) bazedoxifene (Duavee) are a new option to alleviate menopausal symptoms and prevent postmenopausal bone loss. The rationale for development of the tissue-selective estrogen complex (TSEC) was to combine the benefits of conjugated estrogens with the SERM’s ability to offset estrogenic stimulation of the endometrium and breast.

TSECs offer a progestin-free alternative to traditional hormone therapy for women with a uterus. In preclinical studies, investigators found evidence to support bazedoxifene as the SERM of choice and demonstrated that, by combining it with conjugated estrogens, they could provide an optimal balance of estrogen-receptor agonist/antagonist activity, compared with other potential TSEC pairings. Clinical study results confirmed the efficacy of this combination in maintaining bone mass.

Given separately, conjugated estrogens and bazedoxifene each protect against the loss of BMD and help prevent fracture in postmenopausal women.

Findings in key populations
Komm and colleagues describe substudies of the Selective estrogens, Menopause, and Response to Therapy (SMART) trials to evaluate the combination of conjugated estrogens and SERMs to prevent osteoporosis in postmenopausal women with a uterus. One SMART-1 trial included two osteoporosis prevention substudies that evaluated the combination of conjugated estrogens and bazedoxifene in different subpopulations:

• women more than 5 years past the last menstrual period with a lumbar spine or hip BMD T-score between –1 and –2.5 plus one other risk factor for osteoporosis (n = 1,454)
• women 1 to 5 years past their last menstrual period (the interval during which bone loss is greatest) with at least one risk factor for osteoporosis (n = 861).

All doses of conjugated estrogens and bazedoxifene significantly increased the adjusted mean percentage of change in BMD of the lumbar spine from baseline to 24 months (a primary endpoint), compared with placebo, which was associated with decreases in BMD (P<.001). Findings were similar for total hip BMD.

In a separate study, Pinkerton and colleagues found that the dose of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg) approved by the US Food and Drug Administration does not cause a change in breast density or thickness of the endometrium, nor does it increase breast pain, compared with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This newly available TSEC—a combination of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg)—is an effective, well-tolerated alternative to traditional estrogen-progestin hormone therapy for relief of menopausal symptoms and prevention of osteoporosis in postmenopausal women with a uterus.

DON’T EXCLUDE SUNLIGHT FROM THE BONE–HEALTH EQUATION

Holick MF. Sunlight, ultraviolet radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2014;810:1–16.

Many people think of vitamin D as the “sunshine vitamin.” During exposure to sunlight, ultraviolet photons enter the skin and convert 7-dehydrocholesterol to previtamin D3, which, in turn, is converted to vitamin D3.

Throughout most of human history, people have depended on sunlight for vitamin D. Variables such as skin pigmentation, sunscreen use, aging, time of day, season, and latitude dramatically affect previtamin synthesis.

Although vitamin D deficiency was thought to have been conquered, it is now recognized that more than 50% of the world’s population is at risk for vitamin D insufficiency or low levels of 25-hydroxyvitamin D. Among the reasons are inadequate fortification of foods with vitamin D and a misconception that most balanced diets contain adequate vitamin D.

Deficiency of this vitamin causes growth retardation and rickets in children and osteomalacia in adults and can precipitate and exacerbate osteopenia or osteoporosis and increase the risk of fracture in adults.

Some evidence also suggests that vitamin D deficiency may have other serious consequences, including an increased risk for common cancers and autoimmune, infectious, and cardiovascular diseases.

In this review, Holick argues that we need to remind our patients of the beneficial effects of moderate sunlight.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
There is no question that sufficient levels of vitamin D are vital to bone health, and perhaps to overall health in numerous other organ systems as well. The pendulum of our concern over skin cancers may have moved too far in the direction of sun avoidance. In reality, moderate sunlight as a source of vitamin D is still appropriate for many of our patients.

WHEN IT COMES TO ESTROGEN AND BONE, BENEFITS OUTWEIGH RISKS

de Villiers TJ. 8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle? [published online ahead of print September 22, 2014]. Climacteric. 2014;17(suppl 2):4–7. doi:10.3109/13697137.2014.953047.

In the WHI estrogen-progestin arm, fracture rates were reported as hazard ratios:

• hip fracture, 0.66 (95% confidence interval [CI], 0.45–0.98)
• clinical vertebral fracture, 0.66 (95% CI, 0.44–0.98)
• nonvertebral fractures, 0.77 (95% CI, 0.69–0.86).

In the estrogen-only arm of the WHI, reductions in the rates of fracture were reported as percentages and were similar:

• 39% reduction in hip fracture, compared with placebo
• 38% reduction in clinical vertebral fracture
• 21% reduction in total fractures.

All of these reductions were statistically significant.

Despite the excellent anti-fracture efficacy demonstrated in the WHI, investigators concluded that the risks of hormone therapy outweighed the benefits in the general postmenopausal population.

Why we should reconsider estrogen for bone health
In his presidential address to the International Menopause Society (cited above), de Villiers observed that, in the WHI:

• Only clinical fractures were recorded. Unlike all other fracture trials, routine radiographs were not obtained to record morphometric fractures. This decision, he believes (and I concur), led to a significant understatement of estrogen’s protective effects against vertebral fracture.
• The general population studied had a low risk of fracture, with an average spinal T-score of –1.3. This, too, contributed to an understatement of estrogen’s protective effects, compared with the findings of other randomized controlled trials involving patients at much higher risk.
• From a bone-centric point of view, the WHI findings represent a favorable ratio of benefits to risks.

No bone-active drugs are completely free of potential adverse effects and restrictions, many of which become apparent only after FDA approval and general use of the drug. Bisphosphonates have been implicated in atrial fibrillation, osteonecrosis of the jaw, and atypical femur shaft fracture after extended use. Like estrogen, SERMs can increase the risk of death from deep venous thrombosis and stroke.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Estrogen is the only agent proved to be effective against all types of osteoporotic fractures during primary analysis of a large randomized controlled trial. This efficacy is of special importance for the patient with osteopenia who is at risk for fracture. Estrogen remains a serious option for the prevention of postmenopausal bone loss and osteoporosis-related fractures, especially in younger patients. Individualization of therapy is key.

COUNSEL SSRI AND SNRI USERS THAT BMD MAY DECLINE OVER THE LONG TERM

Ak E, Bulut SD, Bulut S, et al. Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study [published online ahead of print September 4, 2014]. ­Osteoporos Int. doi:10.10007/s00198-014-2859-2.

Moura C, Bernatsky S, Ambrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473–1481.

Bruyère O, Reginster J-V. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome [published online ahead of print August 5, 2014]. Endocrine. doi:10.1007/s12020-014-0357-0.

Evidence from longitudinal, cross-­sectional, and prospective cohort studies suggests that the use of antidepressants at therapeutic doses is associated with a reduction in BMD and an increase in the risk of falls and fracture. These associations have been demonstrated in several distinct populations using various study designs, and with bone density, bone loss, or fractures as outcomes. They remain consistent even after adjustment for confounding variables such as age, body mass index, lifestyle factors such as alcohol and tobacco use, and fracture history.

Ak and colleagues recruited 60 patients given a diagnosis of generalized anxiety disorder and treated with paroxetine, sertraline, or citalopram for at least 12 months, comparing their BMD with that of 40 healthy volunteers. BMD was measured by dual-energy x-ray absorptiometry at the femoral and lumbar regions. BMD of the L2–L4 vertebrae, total lumbar vertebrae, and femoral intertrochanteric region, as well as total femoral Z-scores and femoral Ward’s region T-scores, were lower in the treatment group (P<.05). There was a significant negative correlation between the duration of treatment and the change in BMD values.

Moura and colleagues reviewed data from a large prospective Canadian cohort to assess the association between SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and fracture in adults aged 50 and older. They used the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based community cohort.

Among 6,645 subjects, 192 (2.9%) were using SSRIs or SNRIs, or both, at baseline. During the 10-year study period, 978 participants (14.7%) experienced at least one fragility fracture. SSRI/SNRI use was associated with an increased risk of fragility fracture (hazard ratio [HR], 1.88; 95% CI, 1.48–2.39). After controlling for multiple risk factors, previous falls, and BMD of the hip and lumbar bone, the adjusted hazard ratio for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32–2.14). The authors concluded that these results lend additional support to an association between SSRI/SNRI use and fragility fractures.

A few possible underlying mechanisms support the biological plausibility of these observations. One explanation is that increased fracture risk is mediated simply by falling. Another explanation could involve the influence of serotonin on bone. Besides their effects on balance, SSRIs may influence bone turnover and BMD. Whatever the mechanism, sufficient evidence exists to warrant the addition of SSRIs to the list of medications that contribute to osteoporosis.

Antidepressant use is not listed as a secondary cause of osteoporosis in the FRAX algorithm. Because the association between SSRI use and fracture risk appears to be independent of BMD, it may be useful to consider the possibility of including it in FRAX.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Consider BMD assessment for patients who take an SSRI, or who take an SSRI and have additional risk factors for fracture. Given the body of data on this issue, it seems appropriate to expect providers of SSRIs to conduct at least some discussion of bone health with patients.

IN THE PIPELINE: A HIGHLY EFFECTIVE AGENT TARGETING SCLEROSTIN

Recker R, Benson C, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density [published online ahead of print September 5, 2014]. J Bone Miner Res. doi:10.1002/jbmr.2351.

Sclerostin is a protein secreted by osteocytes that negatively regulates the formation of mineralized bone matrix and bone mass. Recker and colleagues conducted a randomized, double-blind, placebo-
controlled, multicenter, phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin. The year-long trial involved 120 postmenopausal women with low BMD (lumbar spine T-score, –2.0 to –3.5) who were randomly allocated to:

• subcutaneous blosozumab 180 mg every 4 weeks
• subcutaneous blosozumab 180 mg every 2 weeks
• subcutaneous blosozumab 270 mg every 2 weeks
• placebo.

All groups also received calcium and vitamin D and underwent serial measurement of spine and hip BMD and testing of biochemical markers of bone turnover. The mean age was 65.8 years, and the mean lumbar spine T-score was –2.8.

Women treated with blosozumab experienced statistically significant, dose-related increases in spine, femoral neck, and total hip BMD, compared with placebo. In the highest dose group, BMD increased 17.7% from baseline at the spine and 6.2% at the total hip. Biochemical markers of bone ­formation increased rapidly during treatment with blosozumab, trending toward pretreatment levels by the study’s end. CTX, a biochemical marker of bone resorption, decreased early during blosozumab treatment to a concentration lower than that in the placebo group by 2 weeks, and it remained low throughout treatment.

Mild injection-site reactions were reported more frequently with blosozumab than with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although blosozumab is not yet available, clinicians should be aware of the potential of sclerostin-antibody therapies like it. Such therapies appear to have substantial anabolic effects on the skeleton and may become promising agents in the treatment of osteoporosis.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Gynecologists are “first-line” providers for the diagnosis and treatment of osteoporosis in women. Lest you doubt the importance of this fact, consider that there are more osteoporotic fractures annually in the United States than all myocardial infarctions, strokes, breast cancers, and gynecologic malignancies combined. It is our duty to stay abreast of current developments in the diagnosis and treatment of this potentially devastating skeletal disorder as our patients live longer and longer.

In this article, I present recent studies on:

• the use of conjugated estrogens and bazedoxifene (Duavee) to manage hot flashes and menopausal bone loss
• the need for adequate levels of vitamin D to maintain bone and overall health, with sunlight exposure remaining a viable option
• a reinterpretation of the findings on estrogen and fracture risk from the Women’s Health Initiative (WHI)
• the effects of selective serotonin reuptake inhibitors (SSRIs) on bone mineral density (BMD)
• development of blosozumab, a new agent in the fight against osteoporosis and fracture.

FIRST TISSUE-SELECTIVE ESTROGEN COMPLEX PROTECTS AGAINST BONE LOSS WITHOUT AFFECTING ENDOMETRIAL AND BREAST TISSUE

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. ­Steroids. 2014;90:71–81.

Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated ­estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):e189–e198.

Conjugated estrogens combined with the selective estrogen receptor modulator (SERM) bazedoxifene (Duavee) are a new option to alleviate menopausal symptoms and prevent postmenopausal bone loss. The rationale for development of the tissue-selective estrogen complex (TSEC) was to combine the benefits of conjugated estrogens with the SERM’s ability to offset estrogenic stimulation of the endometrium and breast.

TSECs offer a progestin-free alternative to traditional hormone therapy for women with a uterus. In preclinical studies, investigators found evidence to support bazedoxifene as the SERM of choice and demonstrated that, by combining it with conjugated estrogens, they could provide an optimal balance of estrogen-receptor agonist/antagonist activity, compared with other potential TSEC pairings. Clinical study results confirmed the efficacy of this combination in maintaining bone mass.

Given separately, conjugated estrogens and bazedoxifene each protect against the loss of BMD and help prevent fracture in postmenopausal women.

Findings in key populations
Komm and colleagues describe substudies of the Selective estrogens, Menopause, and Response to Therapy (SMART) trials to evaluate the combination of conjugated estrogens and SERMs to prevent osteoporosis in postmenopausal women with a uterus. One SMART-1 trial included two osteoporosis prevention substudies that evaluated the combination of conjugated estrogens and bazedoxifene in different subpopulations:

• women more than 5 years past the last menstrual period with a lumbar spine or hip BMD T-score between –1 and –2.5 plus one other risk factor for osteoporosis (n = 1,454)
• women 1 to 5 years past their last menstrual period (the interval during which bone loss is greatest) with at least one risk factor for osteoporosis (n = 861).

All doses of conjugated estrogens and bazedoxifene significantly increased the adjusted mean percentage of change in BMD of the lumbar spine from baseline to 24 months (a primary endpoint), compared with placebo, which was associated with decreases in BMD (P<.001). Findings were similar for total hip BMD.

In a separate study, Pinkerton and colleagues found that the dose of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg) approved by the US Food and Drug Administration does not cause a change in breast density or thickness of the endometrium, nor does it increase breast pain, compared with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This newly available TSEC—a combination of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg)—is an effective, well-tolerated alternative to traditional estrogen-progestin hormone therapy for relief of menopausal symptoms and prevention of osteoporosis in postmenopausal women with a uterus.

DON’T EXCLUDE SUNLIGHT FROM THE BONE–HEALTH EQUATION

Holick MF. Sunlight, ultraviolet radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2014;810:1–16.

Many people think of vitamin D as the “sunshine vitamin.” During exposure to sunlight, ultraviolet photons enter the skin and convert 7-dehydrocholesterol to previtamin D3, which, in turn, is converted to vitamin D3.

Throughout most of human history, people have depended on sunlight for vitamin D. Variables such as skin pigmentation, sunscreen use, aging, time of day, season, and latitude dramatically affect previtamin synthesis.

Although vitamin D deficiency was thought to have been conquered, it is now recognized that more than 50% of the world’s population is at risk for vitamin D insufficiency or low levels of 25-hydroxyvitamin D. Among the reasons are inadequate fortification of foods with vitamin D and a misconception that most balanced diets contain adequate vitamin D.

Deficiency of this vitamin causes growth retardation and rickets in children and osteomalacia in adults and can precipitate and exacerbate osteopenia or osteoporosis and increase the risk of fracture in adults.

Some evidence also suggests that vitamin D deficiency may have other serious consequences, including an increased risk for common cancers and autoimmune, infectious, and cardiovascular diseases.

In this review, Holick argues that we need to remind our patients of the beneficial effects of moderate sunlight.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
There is no question that sufficient levels of vitamin D are vital to bone health, and perhaps to overall health in numerous other organ systems as well. The pendulum of our concern over skin cancers may have moved too far in the direction of sun avoidance. In reality, moderate sunlight as a source of vitamin D is still appropriate for many of our patients.

WHEN IT COMES TO ESTROGEN AND BONE, BENEFITS OUTWEIGH RISKS

de Villiers TJ. 8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle? [published online ahead of print September 22, 2014]. Climacteric. 2014;17(suppl 2):4–7. doi:10.3109/13697137.2014.953047.

In the WHI estrogen-progestin arm, fracture rates were reported as hazard ratios:

• hip fracture, 0.66 (95% confidence interval [CI], 0.45–0.98)
• clinical vertebral fracture, 0.66 (95% CI, 0.44–0.98)
• nonvertebral fractures, 0.77 (95% CI, 0.69–0.86).

In the estrogen-only arm of the WHI, reductions in the rates of fracture were reported as percentages and were similar:

• 39% reduction in hip fracture, compared with placebo
• 38% reduction in clinical vertebral fracture
• 21% reduction in total fractures.

All of these reductions were statistically significant.

Despite the excellent anti-fracture efficacy demonstrated in the WHI, investigators concluded that the risks of hormone therapy outweighed the benefits in the general postmenopausal population.

Why we should reconsider estrogen for bone health
In his presidential address to the International Menopause Society (cited above), de Villiers observed that, in the WHI:

• Only clinical fractures were recorded. Unlike all other fracture trials, routine radiographs were not obtained to record morphometric fractures. This decision, he believes (and I concur), led to a significant understatement of estrogen’s protective effects against vertebral fracture.
• The general population studied had a low risk of fracture, with an average spinal T-score of –1.3. This, too, contributed to an understatement of estrogen’s protective effects, compared with the findings of other randomized controlled trials involving patients at much higher risk.
• From a bone-centric point of view, the WHI findings represent a favorable ratio of benefits to risks.

No bone-active drugs are completely free of potential adverse effects and restrictions, many of which become apparent only after FDA approval and general use of the drug. Bisphosphonates have been implicated in atrial fibrillation, osteonecrosis of the jaw, and atypical femur shaft fracture after extended use. Like estrogen, SERMs can increase the risk of death from deep venous thrombosis and stroke.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Estrogen is the only agent proved to be effective against all types of osteoporotic fractures during primary analysis of a large randomized controlled trial. This efficacy is of special importance for the patient with osteopenia who is at risk for fracture. Estrogen remains a serious option for the prevention of postmenopausal bone loss and osteoporosis-related fractures, especially in younger patients. Individualization of therapy is key.

COUNSEL SSRI AND SNRI USERS THAT BMD MAY DECLINE OVER THE LONG TERM

Ak E, Bulut SD, Bulut S, et al. Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study [published online ahead of print September 4, 2014]. ­Osteoporos Int. doi:10.10007/s00198-014-2859-2.

Moura C, Bernatsky S, Ambrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473–1481.

Bruyère O, Reginster J-V. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome [published online ahead of print August 5, 2014]. Endocrine. doi:10.1007/s12020-014-0357-0.

Evidence from longitudinal, cross-­sectional, and prospective cohort studies suggests that the use of antidepressants at therapeutic doses is associated with a reduction in BMD and an increase in the risk of falls and fracture. These associations have been demonstrated in several distinct populations using various study designs, and with bone density, bone loss, or fractures as outcomes. They remain consistent even after adjustment for confounding variables such as age, body mass index, lifestyle factors such as alcohol and tobacco use, and fracture history.

Ak and colleagues recruited 60 patients given a diagnosis of generalized anxiety disorder and treated with paroxetine, sertraline, or citalopram for at least 12 months, comparing their BMD with that of 40 healthy volunteers. BMD was measured by dual-energy x-ray absorptiometry at the femoral and lumbar regions. BMD of the L2–L4 vertebrae, total lumbar vertebrae, and femoral intertrochanteric region, as well as total femoral Z-scores and femoral Ward’s region T-scores, were lower in the treatment group (P<.05). There was a significant negative correlation between the duration of treatment and the change in BMD values.

Moura and colleagues reviewed data from a large prospective Canadian cohort to assess the association between SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and fracture in adults aged 50 and older. They used the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based community cohort.

Among 6,645 subjects, 192 (2.9%) were using SSRIs or SNRIs, or both, at baseline. During the 10-year study period, 978 participants (14.7%) experienced at least one fragility fracture. SSRI/SNRI use was associated with an increased risk of fragility fracture (hazard ratio [HR], 1.88; 95% CI, 1.48–2.39). After controlling for multiple risk factors, previous falls, and BMD of the hip and lumbar bone, the adjusted hazard ratio for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32–2.14). The authors concluded that these results lend additional support to an association between SSRI/SNRI use and fragility fractures.

A few possible underlying mechanisms support the biological plausibility of these observations. One explanation is that increased fracture risk is mediated simply by falling. Another explanation could involve the influence of serotonin on bone. Besides their effects on balance, SSRIs may influence bone turnover and BMD. Whatever the mechanism, sufficient evidence exists to warrant the addition of SSRIs to the list of medications that contribute to osteoporosis.

Antidepressant use is not listed as a secondary cause of osteoporosis in the FRAX algorithm. Because the association between SSRI use and fracture risk appears to be independent of BMD, it may be useful to consider the possibility of including it in FRAX.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Consider BMD assessment for patients who take an SSRI, or who take an SSRI and have additional risk factors for fracture. Given the body of data on this issue, it seems appropriate to expect providers of SSRIs to conduct at least some discussion of bone health with patients.

IN THE PIPELINE: A HIGHLY EFFECTIVE AGENT TARGETING SCLEROSTIN

Recker R, Benson C, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density [published online ahead of print September 5, 2014]. J Bone Miner Res. doi:10.1002/jbmr.2351.

Sclerostin is a protein secreted by osteocytes that negatively regulates the formation of mineralized bone matrix and bone mass. Recker and colleagues conducted a randomized, double-blind, placebo-
controlled, multicenter, phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin. The year-long trial involved 120 postmenopausal women with low BMD (lumbar spine T-score, –2.0 to –3.5) who were randomly allocated to:

• subcutaneous blosozumab 180 mg every 4 weeks
• subcutaneous blosozumab 180 mg every 2 weeks
• subcutaneous blosozumab 270 mg every 2 weeks
• placebo.

All groups also received calcium and vitamin D and underwent serial measurement of spine and hip BMD and testing of biochemical markers of bone turnover. The mean age was 65.8 years, and the mean lumbar spine T-score was –2.8.

Women treated with blosozumab experienced statistically significant, dose-related increases in spine, femoral neck, and total hip BMD, compared with placebo. In the highest dose group, BMD increased 17.7% from baseline at the spine and 6.2% at the total hip. Biochemical markers of bone ­formation increased rapidly during treatment with blosozumab, trending toward pretreatment levels by the study’s end. CTX, a biochemical marker of bone resorption, decreased early during blosozumab treatment to a concentration lower than that in the placebo group by 2 weeks, and it remained low throughout treatment.

Mild injection-site reactions were reported more frequently with blosozumab than with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although blosozumab is not yet available, clinicians should be aware of the potential of sclerostin-antibody therapies like it. Such therapies appear to have substantial anabolic effects on the skeleton and may become promising agents in the treatment of osteoporosis.

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