Therapeutic Treatment Options for Osteoporosis in the Surgical Weight Loss Population

| April 15, 2011

by Siggi Ming, MS, ARNP, NP-C, and Russell S. Gornichec, MD, FACS

Ms. Ming and Dr. Gornichec are both from the Weight Loss Center of Oklahoma, Oklahoma City, Oklahoma.

financial disclosure: Ms. Ming and Dr. Gornichec report no conflicts of interest relevant to the content of this article.
Bariatric Times. 2011;8(4):8–10

Abstract
Studies have shown that patients undergoing malabsorptive procedures like gastric bypass may have a higher incidence of osteoporosis and require a higher degree of surveillance and more specific treatment options for diagnosed bone mineral deficiency than was previously thought. Multiple pharmacologic agents are available to assist with bone mineral deposition diseases. This article reviews the current options for treatment of osteoporosis, identifying the therapeutic and preventative options available to healthcare professionals who treat bariatric patients, and the rationale for their use. Surveillance modalities are also explored regarding serum nutritional parameter levels and bone mineral density testing.

Introduction
Osteoporosis is a disease of the bone leading to increased risk of fractures. The pathophysiology involves reduced bone mineral density and disruption in the bone microarchitecture. Osteoporosis is more common in women, but may also develop in men. Given its influence on the risk of fracture, this disease may significantly affect life expectancy and quality of life. Studies have shown that patients undergoing malabsorptive procedures like gastric bypass may have a higher incidence of osteoporosis and require a higher degree of surveillance and more specific treatment options for diagnosed bone mineral deficiency than was previously thought.
Multiple pharmacologic agents are available to assist with bone mineral deposition diseases. The multitude of choices can be confusing regarding therapeutic versus preventative options. This article reviews the current options for treatment of osteoporosis, identifying the therapeutic and preventative options available to healthcare professionals who treat bariatric patients, and the rationale for their use. Surveillance modalities are also explored regarding serum nutritional parameter levels and bone mineral density testing.

Obesity is now considered an epidemic as one-third of adult Americans are overweight.[1] According to a paper published in Obesity (Silver Spring),[2] that analyzed The National Health and Nutrition Examination Survey data, 86.3 percent of Americans will be overweight or obese by 2030, and nobody will be of normal weight by 2048 if current weight trends continue.[2]

Obesity is now considered an epidemic as one-third of adult Americans are overweight.1 According to a paper published in Obesity (Silver Spring),[2] that analyzed The National Health and Nutrition Examination Survey data, 86.3 percent of Americans will be overweight or obese by 2030, and nobody will be of normal weight by 2048 if current weight trends continue.[2]

Many individiuals with obesity who are unable to lose weight long term through diet and exercise choose surgical weight loss intervention. From 1998 to 2004, the total number of bariatric surgeries performed in the United States increased from 13,400 to more than 140,000. The number of Roux-en-Y gastric bypass (RYGB) procedures performed is predicted to exceed 110,000 by 2011.[3]

After RYGB, as much as 60 to 70 percent of excessive weight is lost during the first two postoperative years.[25] This may be due to restrictive and malabsorptive mechanisms. These mechanisms result in consumption and absorption of fewer calories due to the small gastric pouch capacity, diminished appetite due to decreased appetite-stimulating hormones, negative consequences of overeating, such as pain and vomiting, increased physical activity, which becomes more possible after patients lose weight, and malabsorption of calories and nutrients as the result of bypassed anatomy.[4]

During RYGB, the stomach is divided into a small, proximal pouch and a separate, distal remnant. The upper pouch is joined to the proximal jejunum through a narrow gastrojejunal anastomosis. Thus, gastric capacity is reduced to approximately 15–30cc, and ingested food bypasses the remnant stomach, the entire duodenum, and a small portion (15–20 cm) of the proximal jejunum. Patients typically lose 35 to 70 percent of excess body weight. Such massive weight loss can relieve or resolve many obesity-related comorbidities, but the bypassing of the remnant stomach and duodenum may impair absorption of iron, calcium, thiamine, vitamin D, and vitamin B 12, which can have important implications for the patient’s overall health.

Malabsorptive Surgical Weight Loss Alters Calcium Homeostasis
Bone physiology is affected by a multitude of complex issues. Patients with morbid obesity frequently have decreased mineral bone density due to their lack of activity, decreased vitamin D levels (possibly due to lack of sunlight exposure), and poor nutritional intake. Bariatric surgical intervention may accentuate the excessive bone demineralization by decreasing calcium absorption in the bypassed anatomy, decreasing vitamin D absorption secondary to rapid transit, and decreasing consumption of dairy products and recommended supplements.

Decreased serum vitamin D levels will stimulate parathyroid hormone (PTH) secretion leading to increased bone resorption to maintain serum calcium levels. Weight loss after bariatric surgery can also lead to a lower load on the axial skeleton, which can lead to osteoporosis. In addition, attention to the frequent use of proton pump inhibitors (PPIs) to reduce gastric ulceration in the bariatric patient has revealed a possible additional mechanism. Hypochlorhydria resulting from these medications has been shown to impair the release of absorbable calcium from insoluble calcium sources like supplements.

These multiple effects are cumulative in increasing the incidence of osteoporosis in the surgical weight loss community. A 2004 study by Coates et al[5] showed that, compared to obese controls, patients who underwent laparoscopic gastric bypass procedures (LGBP) had significantly decreased bone mineral density at the hip, trochanter, and total body with significant decreases in bone mineral content. The researchers found that within as little as three months after surgery, patients had an increase in bone resorption associated with a decrease in bone mass.

Pharmacotherapeutic Options
Available pharmacotherapeutic options for osteoporosis at this time include the following:
1.    Antiresorptive agents, which inhibit osteoclast-mediated bone loss, such as the bisphosphonates alendronate (Fosamax. Merck and Co., Inc., Whitehouse Station, New Jersey,), risedronate (Actonel, Warner Chilcott, Rockaway, New Jersey), ibendronate (Boniva, Genentech USA, Inc., South Sam Francisco, California), and zoledronic acid (Reclast, Novartis Pharmaceuticals Corp., East Hanover, New Jersey). All of these are approved for the prevention and treatment of osteoporosis. Alendronate, risedronate, and ibendronate are oral medications, while zoledronic acid is given intravenously.
2.    Selective estrogen receptor modulator, raloxifene (Evista), which inhibits bone resorption and turnover, is also approved for the prevention and treatment of osteoporosis.
3.    Hormonal agents like estrogen, which helps to maintain bone loss after menopause, are approved for the prevention, (not treatment) of osteoporosis. Conversely, calcitonin, which can be given as an injection or intranasally, is approved for the treatment, but not prevention, of osteoporosis. Human parathyroid hormone, teriparatide (Forteo, Lilly USA, LLC, Indianapolis, Indiana), which regulates bone metabolism and stimulates bone turnover, resulting in increased bone mass and bone formation, is given as a daily injection and is approved for the treatment of severe osteoporosis only.
Of the bisphosphonates, only alendronate and risedronate have been shown to reduce vertebral and nonvertebral fracture risk as oral agents and are approved for both genders. Zoledronic acid, the only intravenous agent, may be cost prohibitive for some patients.

Raloxifene provides some of the same advantages as estrogen with fewer side effects associated with hormone replacement therapy (HRT) and may lower cholesterol levels and breast cancer risk, but increases the risk for deep venous thrombosis (DVT), pulmonary embolisms (PEs), cerebrovascular accident (i.e., a stroke), and hot flashes. The side effect profile may outweigh its benefits for surgical weight loss patients.

Calcitonin reduces only vertebral fracture risk and has been found to be the least potent of all osteoporosis treatments, making it a poorer choice.[6] Conversely, teriparatide (Forteo) reduces vertebral and nonvertebral fracture risk, but the expense of almost $700.00 per month may be cost prohibitive for many patients.

A 2002 review of osteoporosis treatments (e.g., vitamin D, calcium, HRT, calcitonin, alendronate, risedronate, ibendronate) by Cranney et al6 showed that the oral bisphosphonates alendronate and risedronate were most effective in reducing vertebral and nonvertebral fracture risk in osteoporotic patients. This makes the oral bisphosphonates good initial choices for the treatment of osteoporosis in the nonsurgical weight loss population. The question of which one of these drugs is the better choice for patients after malabsorptive surgical weight loss procedures still remains.

Alendronate. Alendronate is a second-generation bisphosphonate, given either daily at 10mg or weekly at 70mg 30 minutes before the first drink or food. The patient needs to remain upright for at least 30 minutes after taking the drug. Side effects include esophagitis, esophageal and gastric ulcers, abdominal pain, acid regurgitation, dyspepsia, musculoskeletal pain, and cardiac arrhythmias. The most common side effect is gastrointestinal (GI) distress. Supplemental calcium or antacids need to be taken at least two hours after alendronate to avoid decreased efficacy of alendronate.
Black and Cummings[7] described a study about the effect of alendronate on fracture risk in women with existing vertebral fractures. The study involved 2,027 postmenopausal women and lasted 36 months. It showed a 55-percent reduction of fracture risk among women on alendronate compared to placebo with no significant differences in GI symptoms, although none of the participants had a history of peptic ulcer disease or were taking medications for dyspepsia.[7]

Greenspan et al[8] described a study involving 450 participants, half of whom took 70mg alendronate weekly, the other half took a placebo. Eleven versus 13 percent reported adverse GI effects and three versus one percent discontinued participation due to GI effects. This study was funded by Merck, the maker of Fosamax.[8]

Risedronate. Risedronate is a third-generation bisphosphonate. It is given either daily, weekly, or monthly orally 30 minutes before the first drink or food. The patient needs to remain upright for at least 30 minutes after taking the drug. Side effects include esophagitis, esophageal and gastric ulcers, abdominal pain, hypertension (HTN), peripheral edema, dyspepsia, chest pain, depression, and musculoskeletal pain. The most common side effect is GI distress. Supplemental calcium or antacids need to be taken at least two hours after risedronate to avoid decreased efficacy of risedronate.
Cranney et al[9] performed a Cochrane systematic review of eight randomized trials. They found clinically and statistically significant reductions in vertebral and nonvertebral fracture risks with the use of risedronate. Eleven percent of the risedronate group suffered vertebral fractures compared to 17 percent of the placebo group, and three percent of the risedronate group suffered nonvertebral fractures compared to 4.6 percent of the placebo group.

Harris et al[10] described a randomized, controlled trial with 2,458 participants. The treatments were risedronate 2.5mg orally daily, risedronate 5mg orally daily, and placebo. All participants received 1,000mg calcium daily and vitamin D if their levels were low. The 2.5mg risedronate arm was discontinued after one year due to minimal efficacy. The other two groups completed three years of study. The researchers found new vertebral fracture reduction of 41 percent after three years of 5mg risedronate daily, and a 39-percent reduction of nonvertebral fractures after three years compared to placebo. The most common adverse events leading to study discontinuance were GI related (gastritis, dyspepsia). Of the risedronate group, 4.2 percent underwent esophagogastroduodenoscopy (EGD) for GI complaints with 85 percent having abnormal findings versus 3.7 and 83 percent, respectively in the control group.10
Alendronate versus risedronate. A 2006 meta-analysis of randomized, controlled trials by Liberman et al11 compared several antiresorptive agents (alendronate, risedronate, ibandronate, raloxifene, HRT). Alendronate was found superior to other agents with an overall risk reduction of 34 percent, with risedronate providing a 26-percent reduction of vertebral and nonvertebral fracture risk. Several of the authors were Merck employees.

A 2004 retrospective, cohort study by Watts et al12 involving a total of 7,081 patients on either calcitonin, alendronate, or risedronate, showed after six months that 1.4 percent of patients on alendronate suffered a nonvertebral fracture compared to 0.6 percent of patients on risedronate. After 12 months, the fractures were 2.4 percent with alendronate and 0.9 percent with risedronate. Three of the study authors were affiliated with the company that manufactures Actonel.[12]

A 2005 National Institute for Clinical Excellence (NICE) systematic review found no significant difference in effectiveness between alendronate and risedronate.[13]
GI side effects of alendronate versus risedronate. As mentioned previously, the most common adverse effects of oral bisphosphonates are GI related, and include esophagitis, esophageal and gastric ulcers, and abdominal pain. It behooves the practitioner to exercise extreme caution when prescribing any medication that has the potential to adversely affect GI structures in postgastric bypass patients. Ulceration of the small gastric pouch can cause significant morbidity.[14] It is therefore important to choose the least-ulcerogenic agent available.

A 2004 Japanese study15 compared mucosal irritative action of both alendronate and risedronate on the stomachs of rats. The researchers found that gastric mucosa exposed to alendronate exhibited widespread exfoliation of epithelial cells without deep damage of the basement membrane, while no gastric mucosal damage was observed with risedronate exposure. They also observed a significant delay in gastric ulcer healing when the gastric mucosa was exposed to 60mg/kg or more of alendronate, while the same effect was seen with risedronate at only the highest dose of 100mg/kg.[15]

Upper GI Tract Safety
A pooled analysis of nine clinical trials (multicenter, double-blind, placebo controlled) to determine the frequency of upper GI adverse effects associated with risedronate use involved a total of 10,068 patients who received risedronate 5mg orally daily over the course of 1 to 3 years. The control group received a placebo. More than 1,900 participants in both groups had active GI disease at baseline, and 11.9 percent of participants in the risedronate group used either H2 blockers or PPIs, compared to 11.8 percent in the control group. In comparison, upper GI hemorrhage occurred in 0.7 percent of participants in the risedronate group and in 0.9 percent in the control group. Esophagitis occurred in 1.8 versus 1.7 percent, esophageal ulcer 0.5 versus 0.3 percent, duodenal ulcer 0.3 percent in both groups, peptic ulcer 0.1 versus 0.2 percent, respectively. Gastric ulcer hemorrhage 0.1 versus 0.2 percent, and gastric ulcer perforation did not occur in either group. Upper GI adverse effects were slightly higher in patients in both groups who used acetylsalicylic acid (i.e., aspirin) or nonsteroidal antiinflammatory drugs (NSAIDs). The authors concluded that there are no significant differences between the placebo and risedronate groups, and that patients receiving risedronate are at no additional risk of significant upper GI adverse events.[16]
Lanza et al[17] conducted a study involving 515 postmenopausal women who received either risedronate 5mg orally daily or alendronate 10mg orally daily for two weeks. The development of gastric ulcers was observed in 4.1 percent in the risedronate group and 13.2 percent in the alendronate group. Esophageal ulcers did not occur in the risedronate group, but occured in 1.3 percent of participants who received alendronate. The researchers concluded that risedronate is associated with significantly lower incidence of gastric and esophageal ulcer than alendronate.[17]

Osteoporosis in Male Gastric Bypass Patients
Osteoporosis is usually considered a disease of women, but about 30 percent of hip fractures occur in men, and one in eight men older than 50 will have an osteoporotic fracture. Due to their greater peak bone mass, men usually present with hip, vertebral, or wrist fractures approximately 10 years later than women.[18] Evidence shows that advanced age, physical inactivity, and weight loss are strong predictors of an increased risk for osteoporosis in men. The new osteoporosis screening guidelines for men suggest that they should be assessed for risk factors before age 65, when approximately six percent of men have osteoporosis, confirmed by dual energy x-ray absorptiometry (DEXA) scan. Men who are at increased risk for osteoporosis are candidates for a DEXA scan.[19]

There is a paucity of studies investigating osteoporosis in male gastric bypass patients. A small Canadian study included five premenopausal women, 13 postmenopausal women, seven postmenopausal women on HRT, five men, and six women who had undergone bypass reversal. All had undergone weight loss surgery several years prior to the study. Bone mineral density was measured at the lumbar spine (L2-L4) and the femoral neck using DEXA scan. The bone mineral density at the lumbar spine was significantly lower in men and postmenopausal women not on HRT compared to the other groups, with the men most severely affected. No specific reason for this striking change in men was found.[20]

Since men may be at an even higher risk for osteoporosis than women after weight loss surgery, and mortality rates in men after hip fracture are twice that in women,[21] it is important that male gastric bypass patients receive baseline evaluation, such as height measurement and calcium, vitamin D, and testosterone levels, and are treated in a timely fashion to prevent osteoporotic fractures. Based on the Canadian study,20 one cannot conclude that osteoporosis occurs at a considerably later age in male gastric bypass patients than in women, a phenomenon that can be observed among the normal population.

Bone Mineral Density Testing
Current recommendations are to perform DEXA scans in postmenopausal women over the age of 65 or younger in the presence of risk factors, and in men over the age of 70. Given the fact that gastric bypass surgery can result in increased bone resorption and decreased bone mass after as little as three months, it appears reasonable to test bone mineral density within no more than one year after surgery, regardless of the patient’s age.

Conclusion
After careful consideration of these studies, one may conclude that risedronate may be the safer drug to prescribe for the treatment of osteoporosis in gastric bypass patients. Risedronate is available as a daily 5mg dose, a once-weekly 35mg dose, a twice-monthly 70mg dose on two consecutive days, or a once-monthly 150mg dose. All doses have been found to be similarly effective in osteoporotic fracture risk reduction with similar adverse event profiles.[22] The patient can be given the choice between daily, weekly, or monthly dosing, depending on lifestyle and personal preference, and this flexibility may induce better adherence. In-depth patient education regarding how risedronate is to be taken is important to minimize the risk of adverse GI effects.

We are not aware of any sizable studies addressing the safety and efficacy of oral bisphosphonates in the surgical weight loss population. The site of absorption of these drugs in humans is not known, although it is believed that most of the absorption takes place throughout the small intestine.[23] There are no published studies regarding possible decreased absorption due to altered anatomy and physiology after gastric bypass. Practitioners who are treating gastric bypass patients should discuss these concerns with their patients and take them into consideration when initiating oral osteoporosis treatment. If financially feasible, other routes of bisphosphonate administration, such as intravenous zoledronic acid, should be considered.

The patient’s nutritional status should be evaluated at baseline and regularly during postoperative visits. Follow up should include labs such as calcium and vitamin D levels. Calcium and vitamin D supplementation is recommended for all bariatric patients.
Bone density testing in one- to two-year intervals should be implemented for both women and men, regardless of age, if the provider and the patient are willing and able to initiate therapy. If the patient is not able or willing to follow a risedronate (or other osteoporosis treatment) regimen, regular bone density testing may not be cost effective.

References
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