Osteoporosis

SAN FRANCISCO – Before initiating osteoporosis therapy on the basis of a T score, investigate any correctable cases of secondary osteoporosis, urged Dr. Steven T. Harris of the University of California, San Francisco.

Screening for secondary causes of low bone mineral density (BMD) that starts with a careful history and examination, plus laboratory tests, identifies roughly 90% of new diagnoses of secondary osteoporosis at modest cost, he said at a meeting on osteoporosis sponsored by the university.

The differential diagnosis of low BMD includes a "hopelessly bewildering" list of problems that can cause secondary osteoporosis in adults, but these can be narrowed down to relatively common causes, including vitamin D deficiency, hypercalciuria, hypogonadism, malabsorption, chronic obstructive pulmonary disease, rheumatoid arthritis, and myeloma. Drug-induced causes – including secondary osteoporosis related to taking steroid therapy, antiepileptics, GnRH agonists, Depo-Provera, aromatase inhibitors, and excess thyroxine – also make the short list.

Neither age nor disease identifies patients who are most likely to have an occult disorder that’s causing osteoporosis. "All patients deserve at least a limited laboratory evaluation prior to [initiating] treatment," he said. Persistent, additional testing is warranted if BMD decreases significantly in patients who are on therapy for primary osteoporosis.

Patients with low z scores (indicating that they have BMD that is lower than expected for their age) require extra scrutiny because they’re more likely to have an occult disease as the cause, and thus deserve closer attention and laboratory testing for secondary causes. "There is no research evidence to support that, but it’s my clinical bias," Dr. Harris added.

Regarding lab tests, he orders a complete blood count to look for myeloma or malabsorption of iron, vitamin B12, and folate. He also advises checking the serum 25-hydroxyvitamin D level for vitamin D deficiency. He gets a 24-hour urine calcium and creatinine screen to check for hypercalciuria or malabsorption.

In a serum chemistry panel, the albumin level may point to malabsorption or malnutrition. Globulin results screen for myeloma. Alkaline phosphatase results help identify malignancy, cirrhosis, or vitamin D deficiency. Calcium levels may suggest hyperparathyroidism or malabsorption. Phosphate results can suggest malnutrition or osteomalacia. Creatinine or BUN results may point to renal disease.

He orders thyroid function testing if the patient is on thyroid replacement therapy or if symptoms warrant it.

Other tests to consider (based on symptoms and results of the laboratory tests) include parathyroid hormone levels if the urine or serum calcium level is abnormally high or low. He orders serum protein electrophoresis if the CBC is abnormal, and he tests for celiac disease if the patient has low 24-hour urine calcium or anemia.

Getting a 24-hour urine calcium is particularly important because it effectively identifies hypercalciuria or malabsorption, two disorders that are associated with higher rates of bone loss. Without a 24-hour urine calcium test, 38% of new diagnoses of hypercalciuria or malabsorption would be missed, data suggest. "Spot urine calcium does not detect malabsorption," he said.

Secondary causes of low BMD are common, multiple studies show. In one study of 664 consecutive postmenopausal women with a T score of –2.5 or below, 54% had known secondary causes of osteoporosis. Laboratory evaluations in 173 women without known secondary causes or prior laboratory abnormalities showed that 32% (55) had a previously unknown secondary cause of low BMD (J. Clin. Endocrinol. Metab. 2002;87:4431-7). A reanalysis of the data suggested that 44% of the 173 had secondary causes of low BMD, most commonly low vitamin D levels, Dr. Harris said.

The prevalence of occult secondary osteoporosis has been estimated at 37%-63% in women and men at various ages, at 60%-80% in patients after hip fracture, and at 50% or more in patients on pharmacologic therapy. The estimates are based on studies with varying criteria for inclusion, the extent of testing, and the definition of vitamin D deficiency. There have been no large, population-based studies of the prevalence of occult disorders causing osteoporosis, he said.

Dr. Harris disclosed financial relationships with Amgen, Eli Lilly & Co., Genentech, Gilead Sciences, Merck, Novartis, Roche, Sanofi-Aventis, and Warner Chilcott.

SAN FRANCISCO – Before initiating osteoporosis therapy on the basis of a T score, investigate any correctable cases of secondary osteoporosis, urged Dr. Steven T. Harris of the University of California, San Francisco.

Screening for secondary causes of low bone mineral density (BMD) that starts with a careful history and examination, plus laboratory tests, identifies roughly 90% of new diagnoses of secondary osteoporosis at modest cost, he said at a meeting on osteoporosis sponsored by the university.

The differential diagnosis of low BMD includes a "hopelessly bewildering" list of problems that can cause secondary osteoporosis in adults, but these can be narrowed down to relatively common causes, including vitamin D deficiency, hypercalciuria, hypogonadism, malabsorption, chronic obstructive pulmonary disease, rheumatoid arthritis, and myeloma. Drug-induced causes – including secondary osteoporosis related to taking steroid therapy, antiepileptics, GnRH agonists, Depo-Provera, aromatase inhibitors, and excess thyroxine – also make the short list.

Neither age nor disease identifies patients who are most likely to have an occult disorder that’s causing osteoporosis. "All patients deserve at least a limited laboratory evaluation prior to [initiating] treatment," he said. Persistent, additional testing is warranted if BMD decreases significantly in patients who are on therapy for primary osteoporosis.

Patients with low z scores (indicating that they have BMD that is lower than expected for their age) require extra scrutiny because they’re more likely to have an occult disease as the cause, and thus deserve closer attention and laboratory testing for secondary causes. "There is no research evidence to support that, but it’s my clinical bias," Dr. Harris added.

Regarding lab tests, he orders a complete blood count to look for myeloma or malabsorption of iron, vitamin B12, and folate. He also advises checking the serum 25-hydroxyvitamin D level for vitamin D deficiency. He gets a 24-hour urine calcium and creatinine screen to check for hypercalciuria or malabsorption.

In a serum chemistry panel, the albumin level may point to malabsorption or malnutrition. Globulin results screen for myeloma. Alkaline phosphatase results help identify malignancy, cirrhosis, or vitamin D deficiency. Calcium levels may suggest hyperparathyroidism or malabsorption. Phosphate results can suggest malnutrition or osteomalacia. Creatinine or BUN results may point to renal disease.

He orders thyroid function testing if the patient is on thyroid replacement therapy or if symptoms warrant it.

Other tests to consider (based on symptoms and results of the laboratory tests) include parathyroid hormone levels if the urine or serum calcium level is abnormally high or low. He orders serum protein electrophoresis if the CBC is abnormal, and he tests for celiac disease if the patient has low 24-hour urine calcium or anemia.

Getting a 24-hour urine calcium is particularly important because it effectively identifies hypercalciuria or malabsorption, two disorders that are associated with higher rates of bone loss. Without a 24-hour urine calcium test, 38% of new diagnoses of hypercalciuria or malabsorption would be missed, data suggest. "Spot urine calcium does not detect malabsorption," he said.

Secondary causes of low BMD are common, multiple studies show. In one study of 664 consecutive postmenopausal women with a T score of –2.5 or below, 54% had known secondary causes of osteoporosis. Laboratory evaluations in 173 women without known secondary causes or prior laboratory abnormalities showed that 32% (55) had a previously unknown secondary cause of low BMD (J. Clin. Endocrinol. Metab. 2002;87:4431-7). A reanalysis of the data suggested that 44% of the 173 had secondary causes of low BMD, most commonly low vitamin D levels, Dr. Harris said.

The prevalence of occult secondary osteoporosis has been estimated at 37%-63% in women and men at various ages, at 60%-80% in patients after hip fracture, and at 50% or more in patients on pharmacologic therapy. The estimates are based on studies with varying criteria for inclusion, the extent of testing, and the definition of vitamin D deficiency. There have been no large, population-based studies of the prevalence of occult disorders causing osteoporosis, he said.

Dr. Harris disclosed financial relationships with Amgen, Eli Lilly & Co., Genentech, Gilead Sciences, Merck, Novartis, Roche, Sanofi-Aventis, and Warner Chilcott.

SAN FRANCISCO – Before initiating osteoporosis therapy on the basis of a T score, investigate any correctable cases of secondary osteoporosis, urged Dr. Steven T. Harris of the University of California, San Francisco.

Screening for secondary causes of low bone mineral density (BMD) that starts with a careful history and examination, plus laboratory tests, identifies roughly 90% of new diagnoses of secondary osteoporosis at modest cost, he said at a meeting on osteoporosis sponsored by the university.

The differential diagnosis of low BMD includes a "hopelessly bewildering" list of problems that can cause secondary osteoporosis in adults, but these can be narrowed down to relatively common causes, including vitamin D deficiency, hypercalciuria, hypogonadism, malabsorption, chronic obstructive pulmonary disease, rheumatoid arthritis, and myeloma. Drug-induced causes – including secondary osteoporosis related to taking steroid therapy, antiepileptics, GnRH agonists, Depo-Provera, aromatase inhibitors, and excess thyroxine – also make the short list.

Neither age nor disease identifies patients who are most likely to have an occult disorder that’s causing osteoporosis. "All patients deserve at least a limited laboratory evaluation prior to [initiating] treatment," he said. Persistent, additional testing is warranted if BMD decreases significantly in patients who are on therapy for primary osteoporosis.

Patients with low z scores (indicating that they have BMD that is lower than expected for their age) require extra scrutiny because they’re more likely to have an occult disease as the cause, and thus deserve closer attention and laboratory testing for secondary causes. "There is no research evidence to support that, but it’s my clinical bias," Dr. Harris added.

Regarding lab tests, he orders a complete blood count to look for myeloma or malabsorption of iron, vitamin B12, and folate. He also advises checking the serum 25-hydroxyvitamin D level for vitamin D deficiency. He gets a 24-hour urine calcium and creatinine screen to check for hypercalciuria or malabsorption.

In a serum chemistry panel, the albumin level may point to malabsorption or malnutrition. Globulin results screen for myeloma. Alkaline phosphatase results help identify malignancy, cirrhosis, or vitamin D deficiency. Calcium levels may suggest hyperparathyroidism or malabsorption. Phosphate results can suggest malnutrition or osteomalacia. Creatinine or BUN results may point to renal disease.

He orders thyroid function testing if the patient is on thyroid replacement therapy or if symptoms warrant it.

Other tests to consider (based on symptoms and results of the laboratory tests) include parathyroid hormone levels if the urine or serum calcium level is abnormally high or low. He orders serum protein electrophoresis if the CBC is abnormal, and he tests for celiac disease if the patient has low 24-hour urine calcium or anemia.

Getting a 24-hour urine calcium is particularly important because it effectively identifies hypercalciuria or malabsorption, two disorders that are associated with higher rates of bone loss. Without a 24-hour urine calcium test, 38% of new diagnoses of hypercalciuria or malabsorption would be missed, data suggest. "Spot urine calcium does not detect malabsorption," he said.

Secondary causes of low BMD are common, multiple studies show. In one study of 664 consecutive postmenopausal women with a T score of –2.5 or below, 54% had known secondary causes of osteoporosis. Laboratory evaluations in 173 women without known secondary causes or prior laboratory abnormalities showed that 32% (55) had a previously unknown secondary cause of low BMD (J. Clin. Endocrinol. Metab. 2002;87:4431-7). A reanalysis of the data suggested that 44% of the 173 had secondary causes of low BMD, most commonly low vitamin D levels, Dr. Harris said.

The prevalence of occult secondary osteoporosis has been estimated at 37%-63% in women and men at various ages, at 60%-80% in patients after hip fracture, and at 50% or more in patients on pharmacologic therapy. The estimates are based on studies with varying criteria for inclusion, the extent of testing, and the definition of vitamin D deficiency. There have been no large, population-based studies of the prevalence of occult disorders causing osteoporosis, he said.

Dr. Harris disclosed financial relationships with Amgen, Eli Lilly & Co., Genentech, Gilead Sciences, Merck, Novartis, Roche, Sanofi-Aventis, and Warner Chilcott.

SAN FRANCISCO – Bariatric surgery can be beneficial for obese people, but it also can lead to significant bone loss.

The limited data so far suggest that decreased bone mineral density after bariatric surgery is a real problem that increases the risk for fracture, Dr. Anne Schafer said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

The extent of bone loss within a year after the most common bariatric surgery, Roux-en-Y gastric bypass, can be equivalent to "what you would expect in the first 5 years of menopause" in some women, said Dr. Schafer of the division of endocrinology at the University of California, San Francisco.

A 2011 study not yet published by the Mayo Clinic, Rochester, Minn., compared fracture rates in 277 patients undergoing bariatric surgery with local age- and sex-matched fracture rates. The surgeries occurred in 1985-2004, and 94% were gastric bypasses. The retrospective chart study found 138 fractures in 82 patients since the surgery, with a standardized incidence ratio of 2.1 for any fracture and 1.9 for fractures of the hip, spine, wrist, or arm after bariatric surgery, she said.

Dr. Schafer incorporated her own clinical experience with recommendations from the Endocrine Society and from Tufts University in advising clinicians to take the following steps in managing patients undergoing bariatric surgery.

Prior to surgery, check serum 25-hydroxyvitamin D (25[OH]D) levels and prescribe preoperative treatment to augment vitamin D in patients with low levels.

After surgery, all patients should take two multivitamins per day to make sure their micronutrient needs are met.

After malabsorptive bariatric surgery, such as gastric bypass, patients also should take calcium supplements, though there aren’t enough data to pinpoint the best dose or to identify which patients might most need the calcium, Dr. Schafer said. She recommended 1,200-2,000 mg/day (preferably in citrate form) after malabsorptive surgery and possibly after restrictive bariatric surgery such as adjustable gastric banding.

Based on the preoperative vitamin D level, prescribe 800-2,000 IU/day of vitamin D₃ supplementation after malabsorptive surgery and possibly after restrictive bariatric surgery. "I’ve had people who need more" than that dose range, she added.

For postoperative surveillance, check calcium homeostasis laboratory tests every 6 months for the first 2 years and then annually after malabsorptive surgery and possibly after any bariatric surgery. The tests include calcium, albumin, phosphate, creatinine, 24(OH)D, and parathyroid hormone.

If the parathyroid hormone level is high, but the 25(OH)D level is low, treat with vitamin D supplementation. If the parathyroid hormone level is high and the 25(OH)D level is ideal, check the patient’s 24-hour urinary calcium, and if that is low, increase calcium intake.

Because some of the etiology of bariatric surgery–induced bone loss may be the preferential loss of lean mass over fat mass, or changes in fat distribution, encourage patients to consume protein and to exercise, she said.

The Endocrine Society recommends dual-energy x-ray absorptiometry (DXA) at baseline and annually in people who are undergoing malabsorptive bariatric surgery. No data show that such monitoring actually improves outcomes, "but I do think that you should consider it for any people who can fit on the DXA scan before the operation," Dr. Schafer said. The weight limit for the scanner is approximately 275-350 pounds.

Dr. Schafer also said that she advises a DXA scan 1-2 years postoperatively. Incorporate those results into "your clinical judgment and other risk factors like age or prior history of fractures to set up an individualized plan for monitoring bone density from there."

In general, high body mass index has been associated with high bone mineral density, and either voluntary or involuntary weight loss is associated with bone loss and increased fracture risk. Bariatric surgery leads to loss of bone mass for multiple reasons, she said, including nutritional deficiencies from malabsorption, the body’s signals about decreased skeletal loading with weight loss, and changes in fat-secreted hormone.

Most of the data on bone loss after bariatric surgery are for Roux-en-Y gastric bypass, which induces early and sustained increases in bone turnover and decreases in bone mineral density. Fewer data are available on other procedures, but a handful of studies suggest that another malabsorptive procedure, biliopancreatic diversion, may produce effects similar to those of gastric bypass, and that adjustable gastric banding may have less of an impact on bone, she said.

For gastric bypass, one study of 15 patients reported an 8% decrease in total hip bone mineral density within 9 months (J. Clin. Endocrinol. Metab. 2004;89:1061-5). Femoral neck bone density decreased by 9% within 1 year of gastric bypass in a separate study of 23 patients (J. Clin. Endocrinol. Metab. 2008;93:3735-40). A third study of 42 patients reported a 7% decrease in spine bone density and a 10% decrease in total hip bone density a year after gastric bypass (Obes. Surg.2009;19:41-6).

Vitamin D deficiency can be a problem after bariatric surgery because many patients have low vitamin D levels before surgery, some of the surgeries are designed to create malabsorption, and patients eat less food and different kinds of food after surgery. In the worst cases, patients may develop secondary hyperparathyroidism or bone loss, and there have been case reports of osteomalacia.

All the studies used DXA scans to assess bone density after bariatric surgery, but DXA assessment may be biased in the setting of marked weight loss because of changes in soft tissue surrounding the bones. The informal consensus among experts is that the bone density losses reported by studies are real, "but we need nonbiased methods of assessing bone mineral density" for future studies of bariatric surgery’s effects, she said.

Dr. Schafer said that she has no relevant conflicts of interest.

SAN FRANCISCO – Bariatric surgery can be beneficial for obese people, but it also can lead to significant bone loss.

The limited data so far suggest that decreased bone mineral density after bariatric surgery is a real problem that increases the risk for fracture, Dr. Anne Schafer said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

The extent of bone loss within a year after the most common bariatric surgery, Roux-en-Y gastric bypass, can be equivalent to "what you would expect in the first 5 years of menopause" in some women, said Dr. Schafer of the division of endocrinology at the University of California, San Francisco.

A 2011 study not yet published by the Mayo Clinic, Rochester, Minn., compared fracture rates in 277 patients undergoing bariatric surgery with local age- and sex-matched fracture rates. The surgeries occurred in 1985-2004, and 94% were gastric bypasses. The retrospective chart study found 138 fractures in 82 patients since the surgery, with a standardized incidence ratio of 2.1 for any fracture and 1.9 for fractures of the hip, spine, wrist, or arm after bariatric surgery, she said.

Dr. Schafer incorporated her own clinical experience with recommendations from the Endocrine Society and from Tufts University in advising clinicians to take the following steps in managing patients undergoing bariatric surgery.

Prior to surgery, check serum 25-hydroxyvitamin D (25[OH]D) levels and prescribe preoperative treatment to augment vitamin D in patients with low levels.

After surgery, all patients should take two multivitamins per day to make sure their micronutrient needs are met.

After malabsorptive bariatric surgery, such as gastric bypass, patients also should take calcium supplements, though there aren’t enough data to pinpoint the best dose or to identify which patients might most need the calcium, Dr. Schafer said. She recommended 1,200-2,000 mg/day (preferably in citrate form) after malabsorptive surgery and possibly after restrictive bariatric surgery such as adjustable gastric banding.

Based on the preoperative vitamin D level, prescribe 800-2,000 IU/day of vitamin D₃ supplementation after malabsorptive surgery and possibly after restrictive bariatric surgery. "I’ve had people who need more" than that dose range, she added.

For postoperative surveillance, check calcium homeostasis laboratory tests every 6 months for the first 2 years and then annually after malabsorptive surgery and possibly after any bariatric surgery. The tests include calcium, albumin, phosphate, creatinine, 24(OH)D, and parathyroid hormone.

If the parathyroid hormone level is high, but the 25(OH)D level is low, treat with vitamin D supplementation. If the parathyroid hormone level is high and the 25(OH)D level is ideal, check the patient’s 24-hour urinary calcium, and if that is low, increase calcium intake.

Because some of the etiology of bariatric surgery–induced bone loss may be the preferential loss of lean mass over fat mass, or changes in fat distribution, encourage patients to consume protein and to exercise, she said.

The Endocrine Society recommends dual-energy x-ray absorptiometry (DXA) at baseline and annually in people who are undergoing malabsorptive bariatric surgery. No data show that such monitoring actually improves outcomes, "but I do think that you should consider it for any people who can fit on the DXA scan before the operation," Dr. Schafer said. The weight limit for the scanner is approximately 275-350 pounds.

Dr. Schafer also said that she advises a DXA scan 1-2 years postoperatively. Incorporate those results into "your clinical judgment and other risk factors like age or prior history of fractures to set up an individualized plan for monitoring bone density from there."

In general, high body mass index has been associated with high bone mineral density, and either voluntary or involuntary weight loss is associated with bone loss and increased fracture risk. Bariatric surgery leads to loss of bone mass for multiple reasons, she said, including nutritional deficiencies from malabsorption, the body’s signals about decreased skeletal loading with weight loss, and changes in fat-secreted hormone.

Most of the data on bone loss after bariatric surgery are for Roux-en-Y gastric bypass, which induces early and sustained increases in bone turnover and decreases in bone mineral density. Fewer data are available on other procedures, but a handful of studies suggest that another malabsorptive procedure, biliopancreatic diversion, may produce effects similar to those of gastric bypass, and that adjustable gastric banding may have less of an impact on bone, she said.

For gastric bypass, one study of 15 patients reported an 8% decrease in total hip bone mineral density within 9 months (J. Clin. Endocrinol. Metab. 2004;89:1061-5). Femoral neck bone density decreased by 9% within 1 year of gastric bypass in a separate study of 23 patients (J. Clin. Endocrinol. Metab. 2008;93:3735-40). A third study of 42 patients reported a 7% decrease in spine bone density and a 10% decrease in total hip bone density a year after gastric bypass (Obes. Surg.2009;19:41-6).

Vitamin D deficiency can be a problem after bariatric surgery because many patients have low vitamin D levels before surgery, some of the surgeries are designed to create malabsorption, and patients eat less food and different kinds of food after surgery. In the worst cases, patients may develop secondary hyperparathyroidism or bone loss, and there have been case reports of osteomalacia.

All the studies used DXA scans to assess bone density after bariatric surgery, but DXA assessment may be biased in the setting of marked weight loss because of changes in soft tissue surrounding the bones. The informal consensus among experts is that the bone density losses reported by studies are real, "but we need nonbiased methods of assessing bone mineral density" for future studies of bariatric surgery’s effects, she said.

Dr. Schafer said that she has no relevant conflicts of interest.

SAN FRANCISCO – Bariatric surgery can be beneficial for obese people, but it also can lead to significant bone loss.

The limited data so far suggest that decreased bone mineral density after bariatric surgery is a real problem that increases the risk for fracture, Dr. Anne Schafer said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

The extent of bone loss within a year after the most common bariatric surgery, Roux-en-Y gastric bypass, can be equivalent to "what you would expect in the first 5 years of menopause" in some women, said Dr. Schafer of the division of endocrinology at the University of California, San Francisco.

A 2011 study not yet published by the Mayo Clinic, Rochester, Minn., compared fracture rates in 277 patients undergoing bariatric surgery with local age- and sex-matched fracture rates. The surgeries occurred in 1985-2004, and 94% were gastric bypasses. The retrospective chart study found 138 fractures in 82 patients since the surgery, with a standardized incidence ratio of 2.1 for any fracture and 1.9 for fractures of the hip, spine, wrist, or arm after bariatric surgery, she said.

Dr. Schafer incorporated her own clinical experience with recommendations from the Endocrine Society and from Tufts University in advising clinicians to take the following steps in managing patients undergoing bariatric surgery.

Prior to surgery, check serum 25-hydroxyvitamin D (25[OH]D) levels and prescribe preoperative treatment to augment vitamin D in patients with low levels.

After surgery, all patients should take two multivitamins per day to make sure their micronutrient needs are met.

After malabsorptive bariatric surgery, such as gastric bypass, patients also should take calcium supplements, though there aren’t enough data to pinpoint the best dose or to identify which patients might most need the calcium, Dr. Schafer said. She recommended 1,200-2,000 mg/day (preferably in citrate form) after malabsorptive surgery and possibly after restrictive bariatric surgery such as adjustable gastric banding.

Based on the preoperative vitamin D level, prescribe 800-2,000 IU/day of vitamin D₃ supplementation after malabsorptive surgery and possibly after restrictive bariatric surgery. "I’ve had people who need more" than that dose range, she added.

For postoperative surveillance, check calcium homeostasis laboratory tests every 6 months for the first 2 years and then annually after malabsorptive surgery and possibly after any bariatric surgery. The tests include calcium, albumin, phosphate, creatinine, 24(OH)D, and parathyroid hormone.

If the parathyroid hormone level is high, but the 25(OH)D level is low, treat with vitamin D supplementation. If the parathyroid hormone level is high and the 25(OH)D level is ideal, check the patient’s 24-hour urinary calcium, and if that is low, increase calcium intake.

Because some of the etiology of bariatric surgery–induced bone loss may be the preferential loss of lean mass over fat mass, or changes in fat distribution, encourage patients to consume protein and to exercise, she said.

The Endocrine Society recommends dual-energy x-ray absorptiometry (DXA) at baseline and annually in people who are undergoing malabsorptive bariatric surgery. No data show that such monitoring actually improves outcomes, "but I do think that you should consider it for any people who can fit on the DXA scan before the operation," Dr. Schafer said. The weight limit for the scanner is approximately 275-350 pounds.

Dr. Schafer also said that she advises a DXA scan 1-2 years postoperatively. Incorporate those results into "your clinical judgment and other risk factors like age or prior history of fractures to set up an individualized plan for monitoring bone density from there."

In general, high body mass index has been associated with high bone mineral density, and either voluntary or involuntary weight loss is associated with bone loss and increased fracture risk. Bariatric surgery leads to loss of bone mass for multiple reasons, she said, including nutritional deficiencies from malabsorption, the body’s signals about decreased skeletal loading with weight loss, and changes in fat-secreted hormone.

Most of the data on bone loss after bariatric surgery are for Roux-en-Y gastric bypass, which induces early and sustained increases in bone turnover and decreases in bone mineral density. Fewer data are available on other procedures, but a handful of studies suggest that another malabsorptive procedure, biliopancreatic diversion, may produce effects similar to those of gastric bypass, and that adjustable gastric banding may have less of an impact on bone, she said.

For gastric bypass, one study of 15 patients reported an 8% decrease in total hip bone mineral density within 9 months (J. Clin. Endocrinol. Metab. 2004;89:1061-5). Femoral neck bone density decreased by 9% within 1 year of gastric bypass in a separate study of 23 patients (J. Clin. Endocrinol. Metab. 2008;93:3735-40). A third study of 42 patients reported a 7% decrease in spine bone density and a 10% decrease in total hip bone density a year after gastric bypass (Obes. Surg.2009;19:41-6).

Vitamin D deficiency can be a problem after bariatric surgery because many patients have low vitamin D levels before surgery, some of the surgeries are designed to create malabsorption, and patients eat less food and different kinds of food after surgery. In the worst cases, patients may develop secondary hyperparathyroidism or bone loss, and there have been case reports of osteomalacia.

All the studies used DXA scans to assess bone density after bariatric surgery, but DXA assessment may be biased in the setting of marked weight loss because of changes in soft tissue surrounding the bones. The informal consensus among experts is that the bone density losses reported by studies are real, "but we need nonbiased methods of assessing bone mineral density" for future studies of bariatric surgery’s effects, she said.

Dr. Schafer said that she has no relevant conflicts of interest.

SAN FRANCISCO – Physicians know that corticosteroids are bad for bones. So bad that rheumatologist Dr. Jonathan D. Graf calls them "a case of skeletal cruelty."

Given the bad reputation of chronic steroid use when it comes to bone health, one might expect physicians to be aware of the medical evidence for choosing a drug to prevent or treat glucocorticoid-induced osteoporosis. Many physicians may be unaware of the evidence, however, judging by a poll Dr. Graf conducted at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Nearly everyone present believed that there have been no comparative head-to-head studies of different medications to manage glucocorticoid-induced osteoporosis.

In reality, two of the approved drugs for managing glucocorticoid-induced osteoporosis – alendronate and risedronate – were shown to be effective in only placebo-controlled trials. But two others – zoledronic acid and teriparatide – showed some advantages over risedronate or alendronate, respectively, in head-to-head comparisons, said Dr. Graf of San Francisco General Hospital.

• Alendronate: A 48-week study randomized 477 patients who were taking at least 7.5 mg/day of prednisone (or the equivalent) to treatment with alendronate 5 mg/day or 10 mg/day or placebo. The 10 mg alendronate group showed significantly improved lumbar bone mineral density at 48 weeks, compared with the placebo group. Bone density benefits were less impressive but statistically significant for the femoral neck, trochanter, and total body, compared with placebo (New Engl. J. Med. 1998;339:292-9).

The bone density improvements on 10 mg alendronate were seen in all subgroups of patients but especially in postmenopausal women who were not taking estrogen. The risk for fractures did not differ significantly between groups for the cohort as a whole, but postmenopausal women had a significantly lower risk of fracture if they were on 10 mg alendronate, compared with placebo (4% vs. 13%).

In an extension study that followed 208 of the patients on their same regimens for another 12 months, the difference in fracture risk became significant for the cohort as a whole at 2 years: 1% in the alendronate groups and 7% on placebo. All patients in the extension study received calcium and vitamin D supplementation (Arthritis Rheum. 2001;44:202-11).

• Risedronate: Two separate multicenter, double-blind studies randomized patients to 2.5 mg/day or 5 mg/day risedronate or placebo, and all received calcium and vitamin D supplementation.

In one study of 224 adults starting long-term glucocorticoid therapy, patients on risedronate maintained or improved bone mineral density, which decreased significantly in patients on placebo. There was a trend toward a lower rate of new vertebral fractures at 1 year on risedronate 5 mg (6%) than on placebo (17%), but the difference was not statistically significant (Arthritis Rheum. 1999;42:2309-18).

In a separate study of 290 adults who already had been using at least 7.5 mg/day of prednisone for at least 6 months, the rate of new vertebral fractures was significantly lower at 1 year in the combined risedronate groups (5%), compared with the placebo group (15%), while rates of adverse events did not differ significantly. The risedronate groups also showed significantly higher bone mineral density at the hip and spine, compared with the placebo group (J. Bone Miner. Res. 2000;15:1006-13).

• Zoledronic acid: A multicenter double-blind, double-dummy trial randomized 833 patients who were on steroid therapy to either a single intravenous infusion of 5 mg zoledronic acid or oral risedronate 5 mg/day. The cohort was "very representative of patients that I see" in practice, Dr. Graf said. Most were on more than 7.5 mg/day or more of prednisone daily, mostly for rheumatologic disorders.

Patients receiving zoledronic acid showed significantly better bone density at the lumbar spine after 1 year, compared with patients on risedronate (Lancet 2009;373:1253-63). The advantage was true both for preventing osteoporosis in "new" steroid users (less than 3 months use) and for treating chronic steroid users (more than 3 months).

"There are a whole bunch of issues with toxicity with zoledronic acid, compared with the other bisphosphonates, and there are cost issues and infusion issues," Dr. Graf said. "Whether or not you should use it in your practice is your choice, but I think you have to be aware of the fact that this drug has been studied head to head."

The study did not assess fracture risk. "Clinically speaking, we really don’t know if this improves fracture risk, but we do know that there is a superior effect on bone mineral density," he said.

• Teriparatide: A 3-year double-blinded trial randomized 428 adults who had been on the equivalent of 5 mg/day of prednisone for at least 3 months to treatment with 20 mcg/day of teriparatide or 10 mg/day of alendronate. These were high-risk patients with baseline bone mineral densities less than 2.0 or less than 1.0 with a history of fragility fracture. In all, 20% in each group had a history of nonvertebral fragility fracture. The reason for taking glucocorticoids was rheumatologic disease in 75% of each group.

A quarter of patients in each group dropped out of the study. In intent-to-treat analyses, bone mineral densities were higher in the teriparatide group than on alendronate at 18 months at 36 months. A highly significant difference emerged in radiographically identified vertebral fractures in the teriparatide group (1%), compared with the alendronate group (6%) at the interim 18-month analysis (New Engl. J. Med. 2007;357:2028-39).

By 36 months, the teriparatide group showed significantly lower rates of radiographic vertebral fractures (2%) and clinical vertebral fractures (0%), compared with the alendronate group (8% and 12%). No significant differences in nonvertebral fractures were seen at either time point.

"So, this primarily is of clinical benefit in the spine," Dr. Graf said, "but the overall rate of clinical fractures is low in both groups."

He suggested that clinicians consider teriparatide for patients with the most severe glucocorticoid-induced osteoporosis or patients at highest risk for fracture, such as those with previous fragility fractures.

• Denosumab: Although this drug is not yet approved for managing glucocorticoid-induced osteoporosis, a subgroup analysis from phase II trial data on 218 patients who were taking either glucocorticoids or bisphosphonates showed that adding denosumab significantly improved lumbar bone mineral density "on top of what you would normally see from the bisphosphonate," Dr. Graf said (Ann. Rheum. Dis. 2010;69:872-5).

Dr. Graf said he has no conflicts of interest.

SAN FRANCISCO – Physicians know that corticosteroids are bad for bones. So bad that rheumatologist Dr. Jonathan D. Graf calls them "a case of skeletal cruelty."

Given the bad reputation of chronic steroid use when it comes to bone health, one might expect physicians to be aware of the medical evidence for choosing a drug to prevent or treat glucocorticoid-induced osteoporosis. Many physicians may be unaware of the evidence, however, judging by a poll Dr. Graf conducted at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Nearly everyone present believed that there have been no comparative head-to-head studies of different medications to manage glucocorticoid-induced osteoporosis.

In reality, two of the approved drugs for managing glucocorticoid-induced osteoporosis – alendronate and risedronate – were shown to be effective in only placebo-controlled trials. But two others – zoledronic acid and teriparatide – showed some advantages over risedronate or alendronate, respectively, in head-to-head comparisons, said Dr. Graf of San Francisco General Hospital.

• Alendronate: A 48-week study randomized 477 patients who were taking at least 7.5 mg/day of prednisone (or the equivalent) to treatment with alendronate 5 mg/day or 10 mg/day or placebo. The 10 mg alendronate group showed significantly improved lumbar bone mineral density at 48 weeks, compared with the placebo group. Bone density benefits were less impressive but statistically significant for the femoral neck, trochanter, and total body, compared with placebo (New Engl. J. Med. 1998;339:292-9).

The bone density improvements on 10 mg alendronate were seen in all subgroups of patients but especially in postmenopausal women who were not taking estrogen. The risk for fractures did not differ significantly between groups for the cohort as a whole, but postmenopausal women had a significantly lower risk of fracture if they were on 10 mg alendronate, compared with placebo (4% vs. 13%).

In an extension study that followed 208 of the patients on their same regimens for another 12 months, the difference in fracture risk became significant for the cohort as a whole at 2 years: 1% in the alendronate groups and 7% on placebo. All patients in the extension study received calcium and vitamin D supplementation (Arthritis Rheum. 2001;44:202-11).

• Risedronate: Two separate multicenter, double-blind studies randomized patients to 2.5 mg/day or 5 mg/day risedronate or placebo, and all received calcium and vitamin D supplementation.

In one study of 224 adults starting long-term glucocorticoid therapy, patients on risedronate maintained or improved bone mineral density, which decreased significantly in patients on placebo. There was a trend toward a lower rate of new vertebral fractures at 1 year on risedronate 5 mg (6%) than on placebo (17%), but the difference was not statistically significant (Arthritis Rheum. 1999;42:2309-18).

In a separate study of 290 adults who already had been using at least 7.5 mg/day of prednisone for at least 6 months, the rate of new vertebral fractures was significantly lower at 1 year in the combined risedronate groups (5%), compared with the placebo group (15%), while rates of adverse events did not differ significantly. The risedronate groups also showed significantly higher bone mineral density at the hip and spine, compared with the placebo group (J. Bone Miner. Res. 2000;15:1006-13).

• Zoledronic acid: A multicenter double-blind, double-dummy trial randomized 833 patients who were on steroid therapy to either a single intravenous infusion of 5 mg zoledronic acid or oral risedronate 5 mg/day. The cohort was "very representative of patients that I see" in practice, Dr. Graf said. Most were on more than 7.5 mg/day or more of prednisone daily, mostly for rheumatologic disorders.

Patients receiving zoledronic acid showed significantly better bone density at the lumbar spine after 1 year, compared with patients on risedronate (Lancet 2009;373:1253-63). The advantage was true both for preventing osteoporosis in "new" steroid users (less than 3 months use) and for treating chronic steroid users (more than 3 months).

"There are a whole bunch of issues with toxicity with zoledronic acid, compared with the other bisphosphonates, and there are cost issues and infusion issues," Dr. Graf said. "Whether or not you should use it in your practice is your choice, but I think you have to be aware of the fact that this drug has been studied head to head."

The study did not assess fracture risk. "Clinically speaking, we really don’t know if this improves fracture risk, but we do know that there is a superior effect on bone mineral density," he said.

• Teriparatide: A 3-year double-blinded trial randomized 428 adults who had been on the equivalent of 5 mg/day of prednisone for at least 3 months to treatment with 20 mcg/day of teriparatide or 10 mg/day of alendronate. These were high-risk patients with baseline bone mineral densities less than 2.0 or less than 1.0 with a history of fragility fracture. In all, 20% in each group had a history of nonvertebral fragility fracture. The reason for taking glucocorticoids was rheumatologic disease in 75% of each group.

A quarter of patients in each group dropped out of the study. In intent-to-treat analyses, bone mineral densities were higher in the teriparatide group than on alendronate at 18 months at 36 months. A highly significant difference emerged in radiographically identified vertebral fractures in the teriparatide group (1%), compared with the alendronate group (6%) at the interim 18-month analysis (New Engl. J. Med. 2007;357:2028-39).

By 36 months, the teriparatide group showed significantly lower rates of radiographic vertebral fractures (2%) and clinical vertebral fractures (0%), compared with the alendronate group (8% and 12%). No significant differences in nonvertebral fractures were seen at either time point.

"So, this primarily is of clinical benefit in the spine," Dr. Graf said, "but the overall rate of clinical fractures is low in both groups."

He suggested that clinicians consider teriparatide for patients with the most severe glucocorticoid-induced osteoporosis or patients at highest risk for fracture, such as those with previous fragility fractures.

• Denosumab: Although this drug is not yet approved for managing glucocorticoid-induced osteoporosis, a subgroup analysis from phase II trial data on 218 patients who were taking either glucocorticoids or bisphosphonates showed that adding denosumab significantly improved lumbar bone mineral density "on top of what you would normally see from the bisphosphonate," Dr. Graf said (Ann. Rheum. Dis. 2010;69:872-5).

Dr. Graf said he has no conflicts of interest.

SAN FRANCISCO – Physicians know that corticosteroids are bad for bones. So bad that rheumatologist Dr. Jonathan D. Graf calls them "a case of skeletal cruelty."

Given the bad reputation of chronic steroid use when it comes to bone health, one might expect physicians to be aware of the medical evidence for choosing a drug to prevent or treat glucocorticoid-induced osteoporosis. Many physicians may be unaware of the evidence, however, judging by a poll Dr. Graf conducted at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Nearly everyone present believed that there have been no comparative head-to-head studies of different medications to manage glucocorticoid-induced osteoporosis.

In reality, two of the approved drugs for managing glucocorticoid-induced osteoporosis – alendronate and risedronate – were shown to be effective in only placebo-controlled trials. But two others – zoledronic acid and teriparatide – showed some advantages over risedronate or alendronate, respectively, in head-to-head comparisons, said Dr. Graf of San Francisco General Hospital.

• Alendronate: A 48-week study randomized 477 patients who were taking at least 7.5 mg/day of prednisone (or the equivalent) to treatment with alendronate 5 mg/day or 10 mg/day or placebo. The 10 mg alendronate group showed significantly improved lumbar bone mineral density at 48 weeks, compared with the placebo group. Bone density benefits were less impressive but statistically significant for the femoral neck, trochanter, and total body, compared with placebo (New Engl. J. Med. 1998;339:292-9).

The bone density improvements on 10 mg alendronate were seen in all subgroups of patients but especially in postmenopausal women who were not taking estrogen. The risk for fractures did not differ significantly between groups for the cohort as a whole, but postmenopausal women had a significantly lower risk of fracture if they were on 10 mg alendronate, compared with placebo (4% vs. 13%).

In an extension study that followed 208 of the patients on their same regimens for another 12 months, the difference in fracture risk became significant for the cohort as a whole at 2 years: 1% in the alendronate groups and 7% on placebo. All patients in the extension study received calcium and vitamin D supplementation (Arthritis Rheum. 2001;44:202-11).

• Risedronate: Two separate multicenter, double-blind studies randomized patients to 2.5 mg/day or 5 mg/day risedronate or placebo, and all received calcium and vitamin D supplementation.

In one study of 224 adults starting long-term glucocorticoid therapy, patients on risedronate maintained or improved bone mineral density, which decreased significantly in patients on placebo. There was a trend toward a lower rate of new vertebral fractures at 1 year on risedronate 5 mg (6%) than on placebo (17%), but the difference was not statistically significant (Arthritis Rheum. 1999;42:2309-18).

In a separate study of 290 adults who already had been using at least 7.5 mg/day of prednisone for at least 6 months, the rate of new vertebral fractures was significantly lower at 1 year in the combined risedronate groups (5%), compared with the placebo group (15%), while rates of adverse events did not differ significantly. The risedronate groups also showed significantly higher bone mineral density at the hip and spine, compared with the placebo group (J. Bone Miner. Res. 2000;15:1006-13).

• Zoledronic acid: A multicenter double-blind, double-dummy trial randomized 833 patients who were on steroid therapy to either a single intravenous infusion of 5 mg zoledronic acid or oral risedronate 5 mg/day. The cohort was "very representative of patients that I see" in practice, Dr. Graf said. Most were on more than 7.5 mg/day or more of prednisone daily, mostly for rheumatologic disorders.

Patients receiving zoledronic acid showed significantly better bone density at the lumbar spine after 1 year, compared with patients on risedronate (Lancet 2009;373:1253-63). The advantage was true both for preventing osteoporosis in "new" steroid users (less than 3 months use) and for treating chronic steroid users (more than 3 months).

"There are a whole bunch of issues with toxicity with zoledronic acid, compared with the other bisphosphonates, and there are cost issues and infusion issues," Dr. Graf said. "Whether or not you should use it in your practice is your choice, but I think you have to be aware of the fact that this drug has been studied head to head."

The study did not assess fracture risk. "Clinically speaking, we really don’t know if this improves fracture risk, but we do know that there is a superior effect on bone mineral density," he said.

• Teriparatide: A 3-year double-blinded trial randomized 428 adults who had been on the equivalent of 5 mg/day of prednisone for at least 3 months to treatment with 20 mcg/day of teriparatide or 10 mg/day of alendronate. These were high-risk patients with baseline bone mineral densities less than 2.0 or less than 1.0 with a history of fragility fracture. In all, 20% in each group had a history of nonvertebral fragility fracture. The reason for taking glucocorticoids was rheumatologic disease in 75% of each group.

A quarter of patients in each group dropped out of the study. In intent-to-treat analyses, bone mineral densities were higher in the teriparatide group than on alendronate at 18 months at 36 months. A highly significant difference emerged in radiographically identified vertebral fractures in the teriparatide group (1%), compared with the alendronate group (6%) at the interim 18-month analysis (New Engl. J. Med. 2007;357:2028-39).

By 36 months, the teriparatide group showed significantly lower rates of radiographic vertebral fractures (2%) and clinical vertebral fractures (0%), compared with the alendronate group (8% and 12%). No significant differences in nonvertebral fractures were seen at either time point.

"So, this primarily is of clinical benefit in the spine," Dr. Graf said, "but the overall rate of clinical fractures is low in both groups."

He suggested that clinicians consider teriparatide for patients with the most severe glucocorticoid-induced osteoporosis or patients at highest risk for fracture, such as those with previous fragility fractures.

• Denosumab: Although this drug is not yet approved for managing glucocorticoid-induced osteoporosis, a subgroup analysis from phase II trial data on 218 patients who were taking either glucocorticoids or bisphosphonates showed that adding denosumab significantly improved lumbar bone mineral density "on top of what you would normally see from the bisphosphonate," Dr. Graf said (Ann. Rheum. Dis. 2010;69:872-5).

Dr. Graf said he has no conflicts of interest.

Major Finding: Neither antiretroviral therapy with tenofovir nor ART with boosted protease inhibitors was significantly associated with an increased risk of osteoporotic fracture in HIV-infected patients after a median 4.5 years of follow-up and adjustment for possibly confounding variables.

Data Source: A retrospective cohort study of 56,660 people with HIV (mean age, 45), 98% of whom were male. Patients received different antiretroviral regimens between 1988 and 2009.

Disclosures: The investigators did not report whether they had any relevant financial disclosures.

ROME – Exposure to tenofovir and other antiretroviral agents over time is not independently associated with an increased risk of bone fracture in aging men living with HIV, investigators reported.

Complications of HIV and antiretroviral treatment are particularly important to identify – and separate from traditional risk factors – in aging HIV-positive populations. Several presenters at the meeting focused on complications of long-term infection and exposure to treatment agents. The antiretroviral drug tenofovir, for example, is known to be associated with decreased bone mineral density.

Dr. Roger Bedimo of the VA North Texas Health Care System and the University of Texas Southwestern Medical Center in Dallas told the conference that his group's retrospective cohort study looked at 56,660 people with HIV (mean age, 45), 98% of whom were male. Patients received different antiretroviral regimens during 1988-2009.

Antiretroviral therapy (ART) with tenofovir and ART with boosted protease inhibitors were regimens found to linked with a modest increased risk of osteoporotic fracture after a median 4.5 years of follow-up – but this risk was no longer significant after adjustment for the traditional risk factors of race, body mass index, age, tobacco use, and diabetes.

Though an increased risk of fracture was seen in the cohort as a whole after the introduction of highly active antiretroviral therapy in 1996, this was believed to be attributable to aging and longer survival of subjects. Bone mineral density was not measured in the study.

Separately, Italian researchers, led by Dr. Giovanni Guaraldi of the University of Modena, presented findings from a smaller study designed to test interactions between bone density and elevated coronary artery calcium – a known risk factor for cardiovascular disease – in a group of 681 HIV-infected patients. They found elevated coronary artery calcium to be significantly associated with low femoral BMD (OR, 2.24) but not low lumbar BMD.

Dr. Guaraldi said that further studies were needed to determine “how heart and bone disease talk to each other” in aging HIV-positive populations, and that he felt that nondrug interventions might be able to simultaneously mediate bone density and cardiovascular risks in this patient group.

Major Finding: Neither antiretroviral therapy with tenofovir nor ART with boosted protease inhibitors was significantly associated with an increased risk of osteoporotic fracture in HIV-infected patients after a median 4.5 years of follow-up and adjustment for possibly confounding variables.

Data Source: A retrospective cohort study of 56,660 people with HIV (mean age, 45), 98% of whom were male. Patients received different antiretroviral regimens between 1988 and 2009.

Disclosures: The investigators did not report whether they had any relevant financial disclosures.

ROME – Exposure to tenofovir and other antiretroviral agents over time is not independently associated with an increased risk of bone fracture in aging men living with HIV, investigators reported.

Complications of HIV and antiretroviral treatment are particularly important to identify – and separate from traditional risk factors – in aging HIV-positive populations. Several presenters at the meeting focused on complications of long-term infection and exposure to treatment agents. The antiretroviral drug tenofovir, for example, is known to be associated with decreased bone mineral density.

Dr. Roger Bedimo of the VA North Texas Health Care System and the University of Texas Southwestern Medical Center in Dallas told the conference that his group's retrospective cohort study looked at 56,660 people with HIV (mean age, 45), 98% of whom were male. Patients received different antiretroviral regimens during 1988-2009.

Antiretroviral therapy (ART) with tenofovir and ART with boosted protease inhibitors were regimens found to linked with a modest increased risk of osteoporotic fracture after a median 4.5 years of follow-up – but this risk was no longer significant after adjustment for the traditional risk factors of race, body mass index, age, tobacco use, and diabetes.

Though an increased risk of fracture was seen in the cohort as a whole after the introduction of highly active antiretroviral therapy in 1996, this was believed to be attributable to aging and longer survival of subjects. Bone mineral density was not measured in the study.

Separately, Italian researchers, led by Dr. Giovanni Guaraldi of the University of Modena, presented findings from a smaller study designed to test interactions between bone density and elevated coronary artery calcium – a known risk factor for cardiovascular disease – in a group of 681 HIV-infected patients. They found elevated coronary artery calcium to be significantly associated with low femoral BMD (OR, 2.24) but not low lumbar BMD.

Dr. Guaraldi said that further studies were needed to determine “how heart and bone disease talk to each other” in aging HIV-positive populations, and that he felt that nondrug interventions might be able to simultaneously mediate bone density and cardiovascular risks in this patient group.

Major Finding: Neither antiretroviral therapy with tenofovir nor ART with boosted protease inhibitors was significantly associated with an increased risk of osteoporotic fracture in HIV-infected patients after a median 4.5 years of follow-up and adjustment for possibly confounding variables.

Data Source: A retrospective cohort study of 56,660 people with HIV (mean age, 45), 98% of whom were male. Patients received different antiretroviral regimens between 1988 and 2009.

Disclosures: The investigators did not report whether they had any relevant financial disclosures.

ROME – Exposure to tenofovir and other antiretroviral agents over time is not independently associated with an increased risk of bone fracture in aging men living with HIV, investigators reported.

Complications of HIV and antiretroviral treatment are particularly important to identify – and separate from traditional risk factors – in aging HIV-positive populations. Several presenters at the meeting focused on complications of long-term infection and exposure to treatment agents. The antiretroviral drug tenofovir, for example, is known to be associated with decreased bone mineral density.

Dr. Roger Bedimo of the VA North Texas Health Care System and the University of Texas Southwestern Medical Center in Dallas told the conference that his group's retrospective cohort study looked at 56,660 people with HIV (mean age, 45), 98% of whom were male. Patients received different antiretroviral regimens during 1988-2009.

Antiretroviral therapy (ART) with tenofovir and ART with boosted protease inhibitors were regimens found to linked with a modest increased risk of osteoporotic fracture after a median 4.5 years of follow-up – but this risk was no longer significant after adjustment for the traditional risk factors of race, body mass index, age, tobacco use, and diabetes.

Though an increased risk of fracture was seen in the cohort as a whole after the introduction of highly active antiretroviral therapy in 1996, this was believed to be attributable to aging and longer survival of subjects. Bone mineral density was not measured in the study.

Separately, Italian researchers, led by Dr. Giovanni Guaraldi of the University of Modena, presented findings from a smaller study designed to test interactions between bone density and elevated coronary artery calcium – a known risk factor for cardiovascular disease – in a group of 681 HIV-infected patients. They found elevated coronary artery calcium to be significantly associated with low femoral BMD (OR, 2.24) but not low lumbar BMD.

Dr. Guaraldi said that further studies were needed to determine “how heart and bone disease talk to each other” in aging HIV-positive populations, and that he felt that nondrug interventions might be able to simultaneously mediate bone density and cardiovascular risks in this patient group.

Major Finding: 25(OH)D concentration increments caused by supplementation prevented aromatase inhibitor–associated bone loss, independently of baseline 25(OH)D concentrations. Increasing levels of 25(OH)D at 3 months were inversely correlated to absolute bone loss (–0.004 g/cm

Data Source: Prospective cohort study of 156 postmenopausal nonosteoporotic women using adjuvant aromatase inhibitors in early breast cancer.

Disclosures: Dr. Sonia Servitja disclosed no relevant relationships. Chair and invited discussant Dr. Thomas J. Smith disclosed receiving research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – The bone loss associated with aromatase inhibitors was significantly slowed with increasing supplements of vitamin D in a prospective cohort study of 156 postmenopausal women.

“The bone loss was less, the higher your vitamin D level was maintained,” said session chair Dr. Thomas J. Smith of Massey Cancer Center of Virginia Commonwealth University. “This is one of the first intervention studies,” he said. “And the results are pretty striking.”

Dr. Sonia Servitja of Hospital del Mar in Barcelona, and colleagues, assessed the association between 25-hydroxy-vitamin D [25(OH)D] concentrations and bone loss at baseline, after 3 months of supplementation, and after 1 year, in patients receiving aromatase inhibitor therapy for early-stage breast cancer.

The 156 women in the prospective cohort had hormone-positive breast cancer and had initiated aromatase inhibitors during January 2006–June 2009.

All patients received daily oral calcium (1 g) and vitamin D₃ (800 IU). Patients with a baseline level of 25(OH)D less than 30 ng/mL received additional oral vitamin D₃. The women were a mean age of 62 years with a mean age of menopause onset of 50 years.

The magnitude of the bone-loss prevention correlated with incremental increases in 25(OH)D concentrations.

Each 10-ng/mL increase in 25(OH)D concentration at 3 months appeared to be associated with a 0.55% decrease in bone loss, which was almost a third of the average bone loss experienced by these patients, according to the study findings, presented as a poster at the meeting.

The findings suggest that vitamin D supplementation at doses higher than the standard of 400 to 800 IU/day might be useful to minimize bone loss in women starting out on aromatase inhibitors and who are not eligible for bisphosphonate therapy according to current guidelines.

Patients who achieved 25(OH)D concentrations of at leaset 40 ng/mL at 3 months experienced significantly reduced bone loss. In addition, 25(OH)D increases at 3 months were protective for relative bone loss.

Major Finding: 25(OH)D concentration increments caused by supplementation prevented aromatase inhibitor–associated bone loss, independently of baseline 25(OH)D concentrations. Increasing levels of 25(OH)D at 3 months were inversely correlated to absolute bone loss (–0.004 g/cm

Data Source: Prospective cohort study of 156 postmenopausal nonosteoporotic women using adjuvant aromatase inhibitors in early breast cancer.

Disclosures: Dr. Sonia Servitja disclosed no relevant relationships. Chair and invited discussant Dr. Thomas J. Smith disclosed receiving research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – The bone loss associated with aromatase inhibitors was significantly slowed with increasing supplements of vitamin D in a prospective cohort study of 156 postmenopausal women.

“The bone loss was less, the higher your vitamin D level was maintained,” said session chair Dr. Thomas J. Smith of Massey Cancer Center of Virginia Commonwealth University. “This is one of the first intervention studies,” he said. “And the results are pretty striking.”

Dr. Sonia Servitja of Hospital del Mar in Barcelona, and colleagues, assessed the association between 25-hydroxy-vitamin D [25(OH)D] concentrations and bone loss at baseline, after 3 months of supplementation, and after 1 year, in patients receiving aromatase inhibitor therapy for early-stage breast cancer.

The 156 women in the prospective cohort had hormone-positive breast cancer and had initiated aromatase inhibitors during January 2006–June 2009.

All patients received daily oral calcium (1 g) and vitamin D₃ (800 IU). Patients with a baseline level of 25(OH)D less than 30 ng/mL received additional oral vitamin D₃. The women were a mean age of 62 years with a mean age of menopause onset of 50 years.

The magnitude of the bone-loss prevention correlated with incremental increases in 25(OH)D concentrations.

Each 10-ng/mL increase in 25(OH)D concentration at 3 months appeared to be associated with a 0.55% decrease in bone loss, which was almost a third of the average bone loss experienced by these patients, according to the study findings, presented as a poster at the meeting.

The findings suggest that vitamin D supplementation at doses higher than the standard of 400 to 800 IU/day might be useful to minimize bone loss in women starting out on aromatase inhibitors and who are not eligible for bisphosphonate therapy according to current guidelines.

Patients who achieved 25(OH)D concentrations of at leaset 40 ng/mL at 3 months experienced significantly reduced bone loss. In addition, 25(OH)D increases at 3 months were protective for relative bone loss.

Major Finding: 25(OH)D concentration increments caused by supplementation prevented aromatase inhibitor–associated bone loss, independently of baseline 25(OH)D concentrations. Increasing levels of 25(OH)D at 3 months were inversely correlated to absolute bone loss (–0.004 g/cm

Data Source: Prospective cohort study of 156 postmenopausal nonosteoporotic women using adjuvant aromatase inhibitors in early breast cancer.

Disclosures: Dr. Sonia Servitja disclosed no relevant relationships. Chair and invited discussant Dr. Thomas J. Smith disclosed receiving research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – The bone loss associated with aromatase inhibitors was significantly slowed with increasing supplements of vitamin D in a prospective cohort study of 156 postmenopausal women.

“The bone loss was less, the higher your vitamin D level was maintained,” said session chair Dr. Thomas J. Smith of Massey Cancer Center of Virginia Commonwealth University. “This is one of the first intervention studies,” he said. “And the results are pretty striking.”

Dr. Sonia Servitja of Hospital del Mar in Barcelona, and colleagues, assessed the association between 25-hydroxy-vitamin D [25(OH)D] concentrations and bone loss at baseline, after 3 months of supplementation, and after 1 year, in patients receiving aromatase inhibitor therapy for early-stage breast cancer.

The 156 women in the prospective cohort had hormone-positive breast cancer and had initiated aromatase inhibitors during January 2006–June 2009.

All patients received daily oral calcium (1 g) and vitamin D₃ (800 IU). Patients with a baseline level of 25(OH)D less than 30 ng/mL received additional oral vitamin D₃. The women were a mean age of 62 years with a mean age of menopause onset of 50 years.

The magnitude of the bone-loss prevention correlated with incremental increases in 25(OH)D concentrations.

Each 10-ng/mL increase in 25(OH)D concentration at 3 months appeared to be associated with a 0.55% decrease in bone loss, which was almost a third of the average bone loss experienced by these patients, according to the study findings, presented as a poster at the meeting.

The findings suggest that vitamin D supplementation at doses higher than the standard of 400 to 800 IU/day might be useful to minimize bone loss in women starting out on aromatase inhibitors and who are not eligible for bisphosphonate therapy according to current guidelines.

Patients who achieved 25(OH)D concentrations of at leaset 40 ng/mL at 3 months experienced significantly reduced bone loss. In addition, 25(OH)D increases at 3 months were protective for relative bone loss.

Major Finding: The worse the skin wrinkles were in terms of depth and number, the lower BMD was in that individual.

Data Source: A skin ancillary study of 114 women also enrolled in the Kronos Early Estrogen Prevention Study, a longitudinal trial of menopausal hormone therapy.

Disclosures: Dr. Pal and her coinvestigators reported that they have no relevant financial relationships.

BOSTON – Skin wrinkling and rigidity could give physicians a clue to bone mineral density, at least among early postmenopausal women.

“In the women that we're talking about, skin wrinkling and skin rigidity – features that are easily appreciable across the table when you are looking at the patient – tie in with bone mineral density as assessed by clinical gold standards, such as dual x-ray absorptiometry,” Dr. Lubna Pal said at the meeting.

The researchers explored possible relationships between skin wrinkling/rigidity and bone mineral density (BMD) in a cohort of early menopausal women who were enrolled in the Kronos Early Estrogen Prevention Study, a longitudinal trial of menopausal hormone therapy.

The skin ancillary study to the ongoing Kronos clinical trial included 114 women who had their last menstrual period within the past 3 years. Most of the participants were white, although 30% were not. Cross-sectional baseline data were used, said Dr. Pal, a reproductive endocrinologist at Yale University, New Haven, Conn.

Skin wrinkles were assessed at 11 sites on the face and neck using the validated Lemperle wrinkle scale. Skin rigidity was assessed at the forehead and cheek using a durometer. Participants also underwent BMD assessment by dual-energy x-ray absorptiometry at the lumbar spine, left hip, and total body. The patients also underwent quantitative heel ultrasound.

Stepwise multivariable linear regression analyses explored the relationship between skin parameters and BMD. Covariates included age, body mass, race/ethnicity, age at menopause, history of smoking, multivitamin intake, and enrollment site.

The researchers found that skin wrinkle severity correlates with BMD. In particular, when wrinkles are severe, BMD is low.

“Our hypothesis, I'm very pleased to say, was substantiated by these findings,” said Dr. Pal. “But we are really seeing the tip of the iceberg here. This is a tantalizing association.

“The quest for all of us really is, can we pick out markers in a cost-effective manner that may translate into overall risk detection that would prevent [fractures]?” she added.

Why look at skin wrinkles and bone density? “Well, when you look at the architecture of the skeleton and the architecture of the skin, about 90% of shared properties within tissues exist, which are the protein building blocks,” Dr. Pal said.

In the skeleton, bone mineral must be deposited on some struts, and proteins provide that infrastructure, she explained. So, loss of protein in the skeleton translates into increased skeletal fragility. That structural deterioration is also seen in the skin. “As we age, the protein texture in our dermis and the deeper layers of our skin also deteriorate,” Dr. Pal noted.

Major Finding: The worse the skin wrinkles were in terms of depth and number, the lower BMD was in that individual.

Data Source: A skin ancillary study of 114 women also enrolled in the Kronos Early Estrogen Prevention Study, a longitudinal trial of menopausal hormone therapy.

Disclosures: Dr. Pal and her coinvestigators reported that they have no relevant financial relationships.

BOSTON – Skin wrinkling and rigidity could give physicians a clue to bone mineral density, at least among early postmenopausal women.

“In the women that we're talking about, skin wrinkling and skin rigidity – features that are easily appreciable across the table when you are looking at the patient – tie in with bone mineral density as assessed by clinical gold standards, such as dual x-ray absorptiometry,” Dr. Lubna Pal said at the meeting.

The researchers explored possible relationships between skin wrinkling/rigidity and bone mineral density (BMD) in a cohort of early menopausal women who were enrolled in the Kronos Early Estrogen Prevention Study, a longitudinal trial of menopausal hormone therapy.

The skin ancillary study to the ongoing Kronos clinical trial included 114 women who had their last menstrual period within the past 3 years. Most of the participants were white, although 30% were not. Cross-sectional baseline data were used, said Dr. Pal, a reproductive endocrinologist at Yale University, New Haven, Conn.

Skin wrinkles were assessed at 11 sites on the face and neck using the validated Lemperle wrinkle scale. Skin rigidity was assessed at the forehead and cheek using a durometer. Participants also underwent BMD assessment by dual-energy x-ray absorptiometry at the lumbar spine, left hip, and total body. The patients also underwent quantitative heel ultrasound.

Stepwise multivariable linear regression analyses explored the relationship between skin parameters and BMD. Covariates included age, body mass, race/ethnicity, age at menopause, history of smoking, multivitamin intake, and enrollment site.

The researchers found that skin wrinkle severity correlates with BMD. In particular, when wrinkles are severe, BMD is low.

“Our hypothesis, I'm very pleased to say, was substantiated by these findings,” said Dr. Pal. “But we are really seeing the tip of the iceberg here. This is a tantalizing association.

“The quest for all of us really is, can we pick out markers in a cost-effective manner that may translate into overall risk detection that would prevent [fractures]?” she added.

Why look at skin wrinkles and bone density? “Well, when you look at the architecture of the skeleton and the architecture of the skin, about 90% of shared properties within tissues exist, which are the protein building blocks,” Dr. Pal said.

In the skeleton, bone mineral must be deposited on some struts, and proteins provide that infrastructure, she explained. So, loss of protein in the skeleton translates into increased skeletal fragility. That structural deterioration is also seen in the skin. “As we age, the protein texture in our dermis and the deeper layers of our skin also deteriorate,” Dr. Pal noted.

Major Finding: The worse the skin wrinkles were in terms of depth and number, the lower BMD was in that individual.

Data Source: A skin ancillary study of 114 women also enrolled in the Kronos Early Estrogen Prevention Study, a longitudinal trial of menopausal hormone therapy.

Disclosures: Dr. Pal and her coinvestigators reported that they have no relevant financial relationships.

BOSTON – Skin wrinkling and rigidity could give physicians a clue to bone mineral density, at least among early postmenopausal women.

“In the women that we're talking about, skin wrinkling and skin rigidity – features that are easily appreciable across the table when you are looking at the patient – tie in with bone mineral density as assessed by clinical gold standards, such as dual x-ray absorptiometry,” Dr. Lubna Pal said at the meeting.

The researchers explored possible relationships between skin wrinkling/rigidity and bone mineral density (BMD) in a cohort of early menopausal women who were enrolled in the Kronos Early Estrogen Prevention Study, a longitudinal trial of menopausal hormone therapy.

The skin ancillary study to the ongoing Kronos clinical trial included 114 women who had their last menstrual period within the past 3 years. Most of the participants were white, although 30% were not. Cross-sectional baseline data were used, said Dr. Pal, a reproductive endocrinologist at Yale University, New Haven, Conn.

Skin wrinkles were assessed at 11 sites on the face and neck using the validated Lemperle wrinkle scale. Skin rigidity was assessed at the forehead and cheek using a durometer. Participants also underwent BMD assessment by dual-energy x-ray absorptiometry at the lumbar spine, left hip, and total body. The patients also underwent quantitative heel ultrasound.

Stepwise multivariable linear regression analyses explored the relationship between skin parameters and BMD. Covariates included age, body mass, race/ethnicity, age at menopause, history of smoking, multivitamin intake, and enrollment site.

The researchers found that skin wrinkle severity correlates with BMD. In particular, when wrinkles are severe, BMD is low.

“Our hypothesis, I'm very pleased to say, was substantiated by these findings,” said Dr. Pal. “But we are really seeing the tip of the iceberg here. This is a tantalizing association.

“The quest for all of us really is, can we pick out markers in a cost-effective manner that may translate into overall risk detection that would prevent [fractures]?” she added.

Why look at skin wrinkles and bone density? “Well, when you look at the architecture of the skeleton and the architecture of the skin, about 90% of shared properties within tissues exist, which are the protein building blocks,” Dr. Pal said.

In the skeleton, bone mineral must be deposited on some struts, and proteins provide that infrastructure, she explained. So, loss of protein in the skeleton translates into increased skeletal fragility. That structural deterioration is also seen in the skin. “As we age, the protein texture in our dermis and the deeper layers of our skin also deteriorate,” Dr. Pal noted.

Steroids Should Be Discontinued as Soon as Possible in All Patients

There is a compelling case for taking all heart transplant recipients off corticosteroids as early as possible, and certainly no later than 3 months after transplantation.

Patients undergoing heart transplantation are in essence trading a disease that will kill them for a disease that is more treatable: immunosuppression. But we physicians can control immunosuppression, which begs the question: Can’t we do better?

We use steroids in more than 80% of our patients. Steroids are our security blanket; they are the drugs that make us feel better. As I was told in training, we sleep better when our patients are on steroids, because we tend to think that they are safe.

But there is no denying that steroids can have life-altering adverse effects for our patients. What if steroids were unnecessary? In fact, they are, but we just haven’t recognized that universally. Steroids are not necessary. This is a not a new idea, as is evident from reports dating back to 1985 (Circulation 1990;82[5 suppl.]:IV318-21).

At least 10 studies have shown the safety of stopping steroids early in heart transplant recipients. Additionally, a recurring finding is that survival is, in fact, better with this practice. You could argue that the patients who are not taken off steroids have a better risk profile, but the weight of evidence does not suggest that this is the case. The following are a few of these studies:

• A case-control study among 420 heart transplant recipients found that steroid withdrawal starting 6 months or more post transplantation was associated with a higher rate of rejection over 7 years, but despite this, survival was better (Am. J. Transplant. 2005;5 [4 Pt. 1]:720-8).

• In a prospective study of 33 heart transplant recipients who were given tacrolimus or sirolimus, all patients were taken off steroids within 6 months (J. Heart Lung Transplant. 2007;26:598-603). There was a single treated rejection and no deaths.

• A retrospective single-institution study of 220 patients found that steroid weaning after heart transplantation was an independent predictor of survival, conferring a significant 40% reduction in the risk of death (Transplant Proc. 2006;38:1501-6).

• In the randomized TICTAC (Tacrolimus in Combination, Tacrolimus Alone Compared) trial, which compared tacrolimus with and without mycophenolate mofetil (MMF), steroids were discontinued in all patients by 8-9 weeks (Circ. Heart Fail. 2011;4:129-37). Over a median follow-up of 3-4 years, none has had to resume steroid maintenance. There was a slight nonsignificant increase in rejection with the monotherapy, but survival – the standard – was identical between groups.

One fear when we began this study was that we would pay the price in allograft vasculopathy if we didn’t provide adequate immunosuppression. Over a 5-year period, however, we have not: The patients on monotherapy and the patients on combination therapy (again, all of them steroid free during follow-up) were indistinguishable in terms of this outcome.

So why do we cling to corticosteroids? What are they doing for us? It’s time to finally admit that they are not necessary. Steroids should be discontinued as rapidly possible among all heart transplant recipients – certainly within 3 months post transplant. We now have good evidence proving the safety and efficacy of this approach.

Dr. Baran is the director of heart failure and transplant research at the Newark (N.J.) Beth Israel Medical Center.

Only Selected Patients Benefit From Early Discontinuation of Steroids

Given current evidence, it is extreme and premature to take all patients off corticosteroids within 3 months of heart transplantation.

Steroids have been used since the beginning of heart transplant therapy, and are still among our most useful drugs for achieving immunosuppression.

We all know about their adverse effects. But they are less common today now that we use lower doses (enabled by combination therapy), and we have other means for preventing some of the adverse effects associated with steroids.

Although other classes of immunosuppressants – such as calcineurin inhibitors, MMF, and mTOR (mammalian target of rapamycin) inhibitors – have become available, it is important to remember that they, too, have adverse effects.

The different classes of immunosuppressants have different mechanisms of action, and this is the theoretical basis of triple-drug therapy. Nonreliance on a single drug also allows us to use smaller doses of each.

Nearly all of the major clinical trials in heart transplantation have used corticosteroids (J. Heart Lung Transplant. 2010;29:914-56). And certainly it is now clear that none of the leading causes of death after heart transplantation in adults (except for infection) seems attributable to these drugs (J. Heart Lung Transplant. 2010;29:1089-103). On the contrary, lack of steroid maintenance therapy has been identified as an independent risk factor for death, conferring a doubling of risk (J. Thorac. Cardiovasc. Surg. 2010;140:161-8).

The TICTAC trial was well done and had some important findings. Unfortunately, it was not a clinical trial of steroid discontinuation because there was no group of patients kept on steroids.

Also, when compared with patients in a similar trial who were given tacrolimus-MMF (Am. J. Transplant. 2006;6:1377-86), patients in the TICTAC trial had higher levels of tacrolimus and serum creatinine. These differences are a little worrisome in terms of long-term outcomes.

At my institution, even later withdrawal of steroids (that is, among patients who were on steroids for at least 4 years without any acute rejection episodes) was associated with a 25% incidence of acute rejection (Transplant Proc. 2007;39:2372-4). In Spain, centers typically stop steroids only in patients who have unacceptable adverse effects and a low immunologic risk for rejection.

Only one trial has directly compared early steroid withdrawal with standard steroid therapy in transplant recipients (Am. J. Transplant. 2008;8:307-16). In that study, in kidney transplant patients who either did not receive any steroids or received them for just the first week, acute rejection occurred both earlier and more often than in the standard therapy group. And there were only modest reductions in adverse events.

In heart transplantation, immunosuppressive therapy is not a one-size-fits-all undertaking. Some patients (for example, those who have preexisting osteoporosis, are elderly, or have diabetes) do benefit from early withdrawal of steroids.

Indeed, guidelines recommend steroid weaning in patients who experience significant adverse effects and have not had a recent acute rejection episode (J. Heart Transplant. 2010;29:914-56). But they also note that although several studies have shown that it is feasible and safe to wean most patients by 6-12 months, and that doing so is desirable to reduce adverse effects, there has not been a randomized trial testing this practice.

It is possible that future well-designed studies will show that the risk of rejection is a reasonable price to pay for avoiding the adverse effects of steroids. These studies must have long-term follow-up and assess the key outcomes of graft and patient survival, rather than just rejection.

In conclusion, there are certainly patients who benefit from early withdrawal of steroids, but current evidence does not support the generalization of this practice.

Dr. Crespo-Leiro is with the heart failure and heart transplant unit at the Hospital Universitario a Coruña (Spain).

Steroids Should Be Discontinued as Soon as Possible in All Patients

There is a compelling case for taking all heart transplant recipients off corticosteroids as early as possible, and certainly no later than 3 months after transplantation.

Patients undergoing heart transplantation are in essence trading a disease that will kill them for a disease that is more treatable: immunosuppression. But we physicians can control immunosuppression, which begs the question: Can’t we do better?

We use steroids in more than 80% of our patients. Steroids are our security blanket; they are the drugs that make us feel better. As I was told in training, we sleep better when our patients are on steroids, because we tend to think that they are safe.

But there is no denying that steroids can have life-altering adverse effects for our patients. What if steroids were unnecessary? In fact, they are, but we just haven’t recognized that universally. Steroids are not necessary. This is a not a new idea, as is evident from reports dating back to 1985 (Circulation 1990;82[5 suppl.]:IV318-21).

At least 10 studies have shown the safety of stopping steroids early in heart transplant recipients. Additionally, a recurring finding is that survival is, in fact, better with this practice. You could argue that the patients who are not taken off steroids have a better risk profile, but the weight of evidence does not suggest that this is the case. The following are a few of these studies:

• A case-control study among 420 heart transplant recipients found that steroid withdrawal starting 6 months or more post transplantation was associated with a higher rate of rejection over 7 years, but despite this, survival was better (Am. J. Transplant. 2005;5 [4 Pt. 1]:720-8).

• In a prospective study of 33 heart transplant recipients who were given tacrolimus or sirolimus, all patients were taken off steroids within 6 months (J. Heart Lung Transplant. 2007;26:598-603). There was a single treated rejection and no deaths.

• A retrospective single-institution study of 220 patients found that steroid weaning after heart transplantation was an independent predictor of survival, conferring a significant 40% reduction in the risk of death (Transplant Proc. 2006;38:1501-6).

• In the randomized TICTAC (Tacrolimus in Combination, Tacrolimus Alone Compared) trial, which compared tacrolimus with and without mycophenolate mofetil (MMF), steroids were discontinued in all patients by 8-9 weeks (Circ. Heart Fail. 2011;4:129-37). Over a median follow-up of 3-4 years, none has had to resume steroid maintenance. There was a slight nonsignificant increase in rejection with the monotherapy, but survival – the standard – was identical between groups.

One fear when we began this study was that we would pay the price in allograft vasculopathy if we didn’t provide adequate immunosuppression. Over a 5-year period, however, we have not: The patients on monotherapy and the patients on combination therapy (again, all of them steroid free during follow-up) were indistinguishable in terms of this outcome.

So why do we cling to corticosteroids? What are they doing for us? It’s time to finally admit that they are not necessary. Steroids should be discontinued as rapidly possible among all heart transplant recipients – certainly within 3 months post transplant. We now have good evidence proving the safety and efficacy of this approach.

Dr. Baran is the director of heart failure and transplant research at the Newark (N.J.) Beth Israel Medical Center.

Only Selected Patients Benefit From Early Discontinuation of Steroids

Given current evidence, it is extreme and premature to take all patients off corticosteroids within 3 months of heart transplantation.

Steroids have been used since the beginning of heart transplant therapy, and are still among our most useful drugs for achieving immunosuppression.

We all know about their adverse effects. But they are less common today now that we use lower doses (enabled by combination therapy), and we have other means for preventing some of the adverse effects associated with steroids.

Although other classes of immunosuppressants – such as calcineurin inhibitors, MMF, and mTOR (mammalian target of rapamycin) inhibitors – have become available, it is important to remember that they, too, have adverse effects.

The different classes of immunosuppressants have different mechanisms of action, and this is the theoretical basis of triple-drug therapy. Nonreliance on a single drug also allows us to use smaller doses of each.

Nearly all of the major clinical trials in heart transplantation have used corticosteroids (J. Heart Lung Transplant. 2010;29:914-56). And certainly it is now clear that none of the leading causes of death after heart transplantation in adults (except for infection) seems attributable to these drugs (J. Heart Lung Transplant. 2010;29:1089-103). On the contrary, lack of steroid maintenance therapy has been identified as an independent risk factor for death, conferring a doubling of risk (J. Thorac. Cardiovasc. Surg. 2010;140:161-8).

The TICTAC trial was well done and had some important findings. Unfortunately, it was not a clinical trial of steroid discontinuation because there was no group of patients kept on steroids.

Also, when compared with patients in a similar trial who were given tacrolimus-MMF (Am. J. Transplant. 2006;6:1377-86), patients in the TICTAC trial had higher levels of tacrolimus and serum creatinine. These differences are a little worrisome in terms of long-term outcomes.

At my institution, even later withdrawal of steroids (that is, among patients who were on steroids for at least 4 years without any acute rejection episodes) was associated with a 25% incidence of acute rejection (Transplant Proc. 2007;39:2372-4). In Spain, centers typically stop steroids only in patients who have unacceptable adverse effects and a low immunologic risk for rejection.

Only one trial has directly compared early steroid withdrawal with standard steroid therapy in transplant recipients (Am. J. Transplant. 2008;8:307-16). In that study, in kidney transplant patients who either did not receive any steroids or received them for just the first week, acute rejection occurred both earlier and more often than in the standard therapy group. And there were only modest reductions in adverse events.

In heart transplantation, immunosuppressive therapy is not a one-size-fits-all undertaking. Some patients (for example, those who have preexisting osteoporosis, are elderly, or have diabetes) do benefit from early withdrawal of steroids.

Indeed, guidelines recommend steroid weaning in patients who experience significant adverse effects and have not had a recent acute rejection episode (J. Heart Transplant. 2010;29:914-56). But they also note that although several studies have shown that it is feasible and safe to wean most patients by 6-12 months, and that doing so is desirable to reduce adverse effects, there has not been a randomized trial testing this practice.

It is possible that future well-designed studies will show that the risk of rejection is a reasonable price to pay for avoiding the adverse effects of steroids. These studies must have long-term follow-up and assess the key outcomes of graft and patient survival, rather than just rejection.

In conclusion, there are certainly patients who benefit from early withdrawal of steroids, but current evidence does not support the generalization of this practice.

Dr. Crespo-Leiro is with the heart failure and heart transplant unit at the Hospital Universitario a Coruña (Spain).

Steroids Should Be Discontinued as Soon as Possible in All Patients

There is a compelling case for taking all heart transplant recipients off corticosteroids as early as possible, and certainly no later than 3 months after transplantation.

Patients undergoing heart transplantation are in essence trading a disease that will kill them for a disease that is more treatable: immunosuppression. But we physicians can control immunosuppression, which begs the question: Can’t we do better?

We use steroids in more than 80% of our patients. Steroids are our security blanket; they are the drugs that make us feel better. As I was told in training, we sleep better when our patients are on steroids, because we tend to think that they are safe.

But there is no denying that steroids can have life-altering adverse effects for our patients. What if steroids were unnecessary? In fact, they are, but we just haven’t recognized that universally. Steroids are not necessary. This is a not a new idea, as is evident from reports dating back to 1985 (Circulation 1990;82[5 suppl.]:IV318-21).

At least 10 studies have shown the safety of stopping steroids early in heart transplant recipients. Additionally, a recurring finding is that survival is, in fact, better with this practice. You could argue that the patients who are not taken off steroids have a better risk profile, but the weight of evidence does not suggest that this is the case. The following are a few of these studies:

• A case-control study among 420 heart transplant recipients found that steroid withdrawal starting 6 months or more post transplantation was associated with a higher rate of rejection over 7 years, but despite this, survival was better (Am. J. Transplant. 2005;5 [4 Pt. 1]:720-8).

• In a prospective study of 33 heart transplant recipients who were given tacrolimus or sirolimus, all patients were taken off steroids within 6 months (J. Heart Lung Transplant. 2007;26:598-603). There was a single treated rejection and no deaths.

• A retrospective single-institution study of 220 patients found that steroid weaning after heart transplantation was an independent predictor of survival, conferring a significant 40% reduction in the risk of death (Transplant Proc. 2006;38:1501-6).

• In the randomized TICTAC (Tacrolimus in Combination, Tacrolimus Alone Compared) trial, which compared tacrolimus with and without mycophenolate mofetil (MMF), steroids were discontinued in all patients by 8-9 weeks (Circ. Heart Fail. 2011;4:129-37). Over a median follow-up of 3-4 years, none has had to resume steroid maintenance. There was a slight nonsignificant increase in rejection with the monotherapy, but survival – the standard – was identical between groups.

One fear when we began this study was that we would pay the price in allograft vasculopathy if we didn’t provide adequate immunosuppression. Over a 5-year period, however, we have not: The patients on monotherapy and the patients on combination therapy (again, all of them steroid free during follow-up) were indistinguishable in terms of this outcome.

So why do we cling to corticosteroids? What are they doing for us? It’s time to finally admit that they are not necessary. Steroids should be discontinued as rapidly possible among all heart transplant recipients – certainly within 3 months post transplant. We now have good evidence proving the safety and efficacy of this approach.

Dr. Baran is the director of heart failure and transplant research at the Newark (N.J.) Beth Israel Medical Center.

Only Selected Patients Benefit From Early Discontinuation of Steroids

Given current evidence, it is extreme and premature to take all patients off corticosteroids within 3 months of heart transplantation.

Steroids have been used since the beginning of heart transplant therapy, and are still among our most useful drugs for achieving immunosuppression.

We all know about their adverse effects. But they are less common today now that we use lower doses (enabled by combination therapy), and we have other means for preventing some of the adverse effects associated with steroids.

Although other classes of immunosuppressants – such as calcineurin inhibitors, MMF, and mTOR (mammalian target of rapamycin) inhibitors – have become available, it is important to remember that they, too, have adverse effects.

The different classes of immunosuppressants have different mechanisms of action, and this is the theoretical basis of triple-drug therapy. Nonreliance on a single drug also allows us to use smaller doses of each.

Nearly all of the major clinical trials in heart transplantation have used corticosteroids (J. Heart Lung Transplant. 2010;29:914-56). And certainly it is now clear that none of the leading causes of death after heart transplantation in adults (except for infection) seems attributable to these drugs (J. Heart Lung Transplant. 2010;29:1089-103). On the contrary, lack of steroid maintenance therapy has been identified as an independent risk factor for death, conferring a doubling of risk (J. Thorac. Cardiovasc. Surg. 2010;140:161-8).

The TICTAC trial was well done and had some important findings. Unfortunately, it was not a clinical trial of steroid discontinuation because there was no group of patients kept on steroids.

Also, when compared with patients in a similar trial who were given tacrolimus-MMF (Am. J. Transplant. 2006;6:1377-86), patients in the TICTAC trial had higher levels of tacrolimus and serum creatinine. These differences are a little worrisome in terms of long-term outcomes.

At my institution, even later withdrawal of steroids (that is, among patients who were on steroids for at least 4 years without any acute rejection episodes) was associated with a 25% incidence of acute rejection (Transplant Proc. 2007;39:2372-4). In Spain, centers typically stop steroids only in patients who have unacceptable adverse effects and a low immunologic risk for rejection.

Only one trial has directly compared early steroid withdrawal with standard steroid therapy in transplant recipients (Am. J. Transplant. 2008;8:307-16). In that study, in kidney transplant patients who either did not receive any steroids or received them for just the first week, acute rejection occurred both earlier and more often than in the standard therapy group. And there were only modest reductions in adverse events.

In heart transplantation, immunosuppressive therapy is not a one-size-fits-all undertaking. Some patients (for example, those who have preexisting osteoporosis, are elderly, or have diabetes) do benefit from early withdrawal of steroids.

Indeed, guidelines recommend steroid weaning in patients who experience significant adverse effects and have not had a recent acute rejection episode (J. Heart Transplant. 2010;29:914-56). But they also note that although several studies have shown that it is feasible and safe to wean most patients by 6-12 months, and that doing so is desirable to reduce adverse effects, there has not been a randomized trial testing this practice.

It is possible that future well-designed studies will show that the risk of rejection is a reasonable price to pay for avoiding the adverse effects of steroids. These studies must have long-term follow-up and assess the key outcomes of graft and patient survival, rather than just rejection.

In conclusion, there are certainly patients who benefit from early withdrawal of steroids, but current evidence does not support the generalization of this practice.

Dr. Crespo-Leiro is with the heart failure and heart transplant unit at the Hospital Universitario a Coruña (Spain).

BOSTON - The density of facial bone seems to decrease significantly with age, a finding that suggests that the maxilla and mandible are subject to the same metabolic factors that cause osteoporosis in the axial skeleton, according to Dr. Robert B. Shaw Jr.

In a study designed to quantify age-related changes to facial bone density and compare them with age-related bone density decreases in the axial skeleton, Dr. Shaw, of the University of Rochester (N.Y.) Medical Center and his colleagues obtained dual-emission x-ray absorptiometry (DXA) scans of the facial bones and lumbar spine from 30 female and 30 male patients. The study included 10 patients of each gender in each of three age categories: 20-40 years, 41-60 years, and older than 60 years. Patients with osteoporosis were excluded from the study.

For each subject, the investigators recorded maxillary bone density (mean density of the left and right maxilla), mandibular ramus bone density (mean density of the left and right mandibular ramus), and lumbar spine bone density (mean density of L1-L4 vertebrae), Dr. Shaw said at the annual  meeting of the American Society for Aesthetic Plastic Surgery.

The investigators observed significant decreases with age for both genders between the middle- and old-age groups for lumbar spine density and between the young and middle-age groups for the maxillary and mandibular ramus bone density, Dr. Shaw reported.

Specifically, the respective mean lumbar spine densities for the young, middle-age, and older-age groups of men were 1.29, 1.29, and 1.15 g/cm², and for the women were 1.23, 1.24, and 1.08 g/cm². For the maxillary bone density, the respective measures across the age groups for the men were 1.90, 1.58, and 1.56 g/cm², and for the women they were 1.75, 1.55, and 1.50 g/cm². For the mandibular bone density, the respective measures for the male subjects were 1.52, 1.33, and 1.35 g/cm², and for the female subjects they were 1.52, 1.32, and 1.18 g/cm².

Within each age group, "lumbar spine and maxilla bone density decreases were more pronounced in female vs. male subjects," he said.

The study findings are consistent with those of an investigation published earlier this year in which Dr. Shaw and his colleagues compared three-dimensional reconstructions of CT scans of the facial bones in 120 men and women in young, middle-age, and older-age groups. The investigators observed recession of the eye socket bones and volume loss to midface bones, including the brow bone, nose, and upper jaw. The bone-loss patterns observed in the study differed by gender, with men experiencing the most pronounced decrease in bone volume beginning in the oldest age category, while the process starts in earnest for women in the middle age group, he said (Plast. Reconstr. Surg. 2011;127:374-83).

The results of the current study suggest that "facial bone aging may be linked to the same metabolic factors that cause osteoporosis in the axial skeleton," said Dr. Shaw. They also offer insight into why certain facial rejuvenation strategies may not meet patients' expectations, he said, noting, for example, that although skin tightening alone may effectively minimize wrinkles and improve skin texture, it won't compensate for the underlying structural changes that alter the three-dimensional contour of the face.

Skeletal augmentation via dermal fillers or facial implants, together with skin tightening, can potentially improve outcomes by making up for some of the lost volume, he said, "but it will not make a 60-year-old look 20 years old again." Gaining a better understanding of facial bone strength, however, may lead to new possibilities for facial rejuvenation, he said.

Dr. Shaw reported having no financial conflicts of interest with respect to his presentation.

BOSTON - The density of facial bone seems to decrease significantly with age, a finding that suggests that the maxilla and mandible are subject to the same metabolic factors that cause osteoporosis in the axial skeleton, according to Dr. Robert B. Shaw Jr.

In a study designed to quantify age-related changes to facial bone density and compare them with age-related bone density decreases in the axial skeleton, Dr. Shaw, of the University of Rochester (N.Y.) Medical Center and his colleagues obtained dual-emission x-ray absorptiometry (DXA) scans of the facial bones and lumbar spine from 30 female and 30 male patients. The study included 10 patients of each gender in each of three age categories: 20-40 years, 41-60 years, and older than 60 years. Patients with osteoporosis were excluded from the study.

For each subject, the investigators recorded maxillary bone density (mean density of the left and right maxilla), mandibular ramus bone density (mean density of the left and right mandibular ramus), and lumbar spine bone density (mean density of L1-L4 vertebrae), Dr. Shaw said at the annual  meeting of the American Society for Aesthetic Plastic Surgery.

The investigators observed significant decreases with age for both genders between the middle- and old-age groups for lumbar spine density and between the young and middle-age groups for the maxillary and mandibular ramus bone density, Dr. Shaw reported.

Specifically, the respective mean lumbar spine densities for the young, middle-age, and older-age groups of men were 1.29, 1.29, and 1.15 g/cm², and for the women were 1.23, 1.24, and 1.08 g/cm². For the maxillary bone density, the respective measures across the age groups for the men were 1.90, 1.58, and 1.56 g/cm², and for the women they were 1.75, 1.55, and 1.50 g/cm². For the mandibular bone density, the respective measures for the male subjects were 1.52, 1.33, and 1.35 g/cm², and for the female subjects they were 1.52, 1.32, and 1.18 g/cm².

Within each age group, "lumbar spine and maxilla bone density decreases were more pronounced in female vs. male subjects," he said.

The study findings are consistent with those of an investigation published earlier this year in which Dr. Shaw and his colleagues compared three-dimensional reconstructions of CT scans of the facial bones in 120 men and women in young, middle-age, and older-age groups. The investigators observed recession of the eye socket bones and volume loss to midface bones, including the brow bone, nose, and upper jaw. The bone-loss patterns observed in the study differed by gender, with men experiencing the most pronounced decrease in bone volume beginning in the oldest age category, while the process starts in earnest for women in the middle age group, he said (Plast. Reconstr. Surg. 2011;127:374-83).

The results of the current study suggest that "facial bone aging may be linked to the same metabolic factors that cause osteoporosis in the axial skeleton," said Dr. Shaw. They also offer insight into why certain facial rejuvenation strategies may not meet patients' expectations, he said, noting, for example, that although skin tightening alone may effectively minimize wrinkles and improve skin texture, it won't compensate for the underlying structural changes that alter the three-dimensional contour of the face.

Skeletal augmentation via dermal fillers or facial implants, together with skin tightening, can potentially improve outcomes by making up for some of the lost volume, he said, "but it will not make a 60-year-old look 20 years old again." Gaining a better understanding of facial bone strength, however, may lead to new possibilities for facial rejuvenation, he said.

Dr. Shaw reported having no financial conflicts of interest with respect to his presentation.

BOSTON - The density of facial bone seems to decrease significantly with age, a finding that suggests that the maxilla and mandible are subject to the same metabolic factors that cause osteoporosis in the axial skeleton, according to Dr. Robert B. Shaw Jr.

In a study designed to quantify age-related changes to facial bone density and compare them with age-related bone density decreases in the axial skeleton, Dr. Shaw, of the University of Rochester (N.Y.) Medical Center and his colleagues obtained dual-emission x-ray absorptiometry (DXA) scans of the facial bones and lumbar spine from 30 female and 30 male patients. The study included 10 patients of each gender in each of three age categories: 20-40 years, 41-60 years, and older than 60 years. Patients with osteoporosis were excluded from the study.

For each subject, the investigators recorded maxillary bone density (mean density of the left and right maxilla), mandibular ramus bone density (mean density of the left and right mandibular ramus), and lumbar spine bone density (mean density of L1-L4 vertebrae), Dr. Shaw said at the annual  meeting of the American Society for Aesthetic Plastic Surgery.

The investigators observed significant decreases with age for both genders between the middle- and old-age groups for lumbar spine density and between the young and middle-age groups for the maxillary and mandibular ramus bone density, Dr. Shaw reported.

Specifically, the respective mean lumbar spine densities for the young, middle-age, and older-age groups of men were 1.29, 1.29, and 1.15 g/cm², and for the women were 1.23, 1.24, and 1.08 g/cm². For the maxillary bone density, the respective measures across the age groups for the men were 1.90, 1.58, and 1.56 g/cm², and for the women they were 1.75, 1.55, and 1.50 g/cm². For the mandibular bone density, the respective measures for the male subjects were 1.52, 1.33, and 1.35 g/cm², and for the female subjects they were 1.52, 1.32, and 1.18 g/cm².

Within each age group, "lumbar spine and maxilla bone density decreases were more pronounced in female vs. male subjects," he said.

The study findings are consistent with those of an investigation published earlier this year in which Dr. Shaw and his colleagues compared three-dimensional reconstructions of CT scans of the facial bones in 120 men and women in young, middle-age, and older-age groups. The investigators observed recession of the eye socket bones and volume loss to midface bones, including the brow bone, nose, and upper jaw. The bone-loss patterns observed in the study differed by gender, with men experiencing the most pronounced decrease in bone volume beginning in the oldest age category, while the process starts in earnest for women in the middle age group, he said (Plast. Reconstr. Surg. 2011;127:374-83).

The results of the current study suggest that "facial bone aging may be linked to the same metabolic factors that cause osteoporosis in the axial skeleton," said Dr. Shaw. They also offer insight into why certain facial rejuvenation strategies may not meet patients' expectations, he said, noting, for example, that although skin tightening alone may effectively minimize wrinkles and improve skin texture, it won't compensate for the underlying structural changes that alter the three-dimensional contour of the face.

Skeletal augmentation via dermal fillers or facial implants, together with skin tightening, can potentially improve outcomes by making up for some of the lost volume, he said, "but it will not make a 60-year-old look 20 years old again." Gaining a better understanding of facial bone strength, however, may lead to new possibilities for facial rejuvenation, he said.

Dr. Shaw reported having no financial conflicts of interest with respect to his presentation.

BOSTON – An annual dose of zoledronate that has been reduced by 50% or even 80% appears to be as effective as the recommended 5-mg dose in increasing bone mineral density and decreasing markers of bone turnover in osteopenic postmenopausal women, according to Dr. Andrew Grey, who presented the findings at the annual meeting of the Endocrine Society.

"We know that annual administration of intravenous zoledronate (also known as zoldedronic acid) at the 5-mg dose is an effective treatment for preventing fractures and decreasing fractures in osteoporotic, postmenopausal women by 25%-70%, depending on the skeletal site. Such treatment also reduces the risk of dying after hip fracture by 30%. Yet we don’t know the optimum dosing schedule," said Dr. Grey of the University of Auckland (New Zealand). The results of this study are important because reducing the dose can result in significant cost savings as well as decrease the risk of dose-dependent side effects.

In this prospective, controlled trial, 180 osteopenic postmenopausal women were randomized to receive a single dose of placebo or 1 mg, 2.5 mg, or 5 mg of zoledronate. The women had never been treated with zoledronate or any other bisphosphonate medication. The women underwent bone mineral density (BMD) evaluations at baseline and then 12 months after treatment.

For the primary end point (change in lumbar spine BMD at 12 months), the BMD increased significantly in each of the zoledronate groups, compared with placebo (P less than .001 for each dose). Notably, the magnitude of change was comparable for each dose: 3.5% for the 1-mg group, 4% for the 2.5-mg group, and 3.6% for the standard 5-mg group.

Similar results were observed for increases in total hip BMD (2.7% for the 1-mg group, 3.6% for the 2.5-mg group, and 3.6% for the 5-mg group). All results were significantly different from those with placebo (P less than .001).

Dr. Gray also looked at treatment effects on two blood markers of bone resorption, including beta-CTx (beta C-terminal telopeptide) and P1NP (procollagen type 1 N-terminal peptide). At all doses for both bone markers, zoledronate led to significant decreases, compared with placebo (P less than .001). For beta-CTx, the results were –44% for the 1-mg dose, –68% for the 2.5-mg dose and –73% for the 5-mg dose. For P1NP, the reductions were 41% for the 1-mg dose, 58% for the 2.5-mg dose, and 64% for the 5-mg dose.

An acute phase reaction is a side effect of intravenous bisphosphonate use. Fever is the most commonly associated symptom, but occasionally patients experience a flulike syndrome consisting of fever, chills, flushing, myalgias, and bone pain and/or arthralgias. In this study, acute phase reaction occurred less frequently in the zoledronate low-dose 1-mg group (odds ratio, 2.8) compared with either of the higher-dose groups (OR, 8.7 for the 2.5-mg group and 7.4 for the 5-mg group).

"These results show that lower doses than are currently prescribed have substantial antiresorptive effects that approximate those of the 5-mg dose, and suggest that these lower doses will be effective in preventing fractures in people with osteoporosis. Clinical trials should be undertaken to confirm whether annual low doses of zoledronate prevent fractures," according to Dr. Gray.

Dr. Grey had nothing to disclose; he said that the study was funded by public funds.

BOSTON – An annual dose of zoledronate that has been reduced by 50% or even 80% appears to be as effective as the recommended 5-mg dose in increasing bone mineral density and decreasing markers of bone turnover in osteopenic postmenopausal women, according to Dr. Andrew Grey, who presented the findings at the annual meeting of the Endocrine Society.

"We know that annual administration of intravenous zoledronate (also known as zoldedronic acid) at the 5-mg dose is an effective treatment for preventing fractures and decreasing fractures in osteoporotic, postmenopausal women by 25%-70%, depending on the skeletal site. Such treatment also reduces the risk of dying after hip fracture by 30%. Yet we don’t know the optimum dosing schedule," said Dr. Grey of the University of Auckland (New Zealand). The results of this study are important because reducing the dose can result in significant cost savings as well as decrease the risk of dose-dependent side effects.

In this prospective, controlled trial, 180 osteopenic postmenopausal women were randomized to receive a single dose of placebo or 1 mg, 2.5 mg, or 5 mg of zoledronate. The women had never been treated with zoledronate or any other bisphosphonate medication. The women underwent bone mineral density (BMD) evaluations at baseline and then 12 months after treatment.

For the primary end point (change in lumbar spine BMD at 12 months), the BMD increased significantly in each of the zoledronate groups, compared with placebo (P less than .001 for each dose). Notably, the magnitude of change was comparable for each dose: 3.5% for the 1-mg group, 4% for the 2.5-mg group, and 3.6% for the standard 5-mg group.

Similar results were observed for increases in total hip BMD (2.7% for the 1-mg group, 3.6% for the 2.5-mg group, and 3.6% for the 5-mg group). All results were significantly different from those with placebo (P less than .001).

Dr. Gray also looked at treatment effects on two blood markers of bone resorption, including beta-CTx (beta C-terminal telopeptide) and P1NP (procollagen type 1 N-terminal peptide). At all doses for both bone markers, zoledronate led to significant decreases, compared with placebo (P less than .001). For beta-CTx, the results were –44% for the 1-mg dose, –68% for the 2.5-mg dose and –73% for the 5-mg dose. For P1NP, the reductions were 41% for the 1-mg dose, 58% for the 2.5-mg dose, and 64% for the 5-mg dose.

An acute phase reaction is a side effect of intravenous bisphosphonate use. Fever is the most commonly associated symptom, but occasionally patients experience a flulike syndrome consisting of fever, chills, flushing, myalgias, and bone pain and/or arthralgias. In this study, acute phase reaction occurred less frequently in the zoledronate low-dose 1-mg group (odds ratio, 2.8) compared with either of the higher-dose groups (OR, 8.7 for the 2.5-mg group and 7.4 for the 5-mg group).

"These results show that lower doses than are currently prescribed have substantial antiresorptive effects that approximate those of the 5-mg dose, and suggest that these lower doses will be effective in preventing fractures in people with osteoporosis. Clinical trials should be undertaken to confirm whether annual low doses of zoledronate prevent fractures," according to Dr. Gray.

Dr. Grey had nothing to disclose; he said that the study was funded by public funds.

BOSTON – An annual dose of zoledronate that has been reduced by 50% or even 80% appears to be as effective as the recommended 5-mg dose in increasing bone mineral density and decreasing markers of bone turnover in osteopenic postmenopausal women, according to Dr. Andrew Grey, who presented the findings at the annual meeting of the Endocrine Society.

"We know that annual administration of intravenous zoledronate (also known as zoldedronic acid) at the 5-mg dose is an effective treatment for preventing fractures and decreasing fractures in osteoporotic, postmenopausal women by 25%-70%, depending on the skeletal site. Such treatment also reduces the risk of dying after hip fracture by 30%. Yet we don’t know the optimum dosing schedule," said Dr. Grey of the University of Auckland (New Zealand). The results of this study are important because reducing the dose can result in significant cost savings as well as decrease the risk of dose-dependent side effects.

In this prospective, controlled trial, 180 osteopenic postmenopausal women were randomized to receive a single dose of placebo or 1 mg, 2.5 mg, or 5 mg of zoledronate. The women had never been treated with zoledronate or any other bisphosphonate medication. The women underwent bone mineral density (BMD) evaluations at baseline and then 12 months after treatment.

For the primary end point (change in lumbar spine BMD at 12 months), the BMD increased significantly in each of the zoledronate groups, compared with placebo (P less than .001 for each dose). Notably, the magnitude of change was comparable for each dose: 3.5% for the 1-mg group, 4% for the 2.5-mg group, and 3.6% for the standard 5-mg group.

Similar results were observed for increases in total hip BMD (2.7% for the 1-mg group, 3.6% for the 2.5-mg group, and 3.6% for the 5-mg group). All results were significantly different from those with placebo (P less than .001).

Dr. Gray also looked at treatment effects on two blood markers of bone resorption, including beta-CTx (beta C-terminal telopeptide) and P1NP (procollagen type 1 N-terminal peptide). At all doses for both bone markers, zoledronate led to significant decreases, compared with placebo (P less than .001). For beta-CTx, the results were –44% for the 1-mg dose, –68% for the 2.5-mg dose and –73% for the 5-mg dose. For P1NP, the reductions were 41% for the 1-mg dose, 58% for the 2.5-mg dose, and 64% for the 5-mg dose.

An acute phase reaction is a side effect of intravenous bisphosphonate use. Fever is the most commonly associated symptom, but occasionally patients experience a flulike syndrome consisting of fever, chills, flushing, myalgias, and bone pain and/or arthralgias. In this study, acute phase reaction occurred less frequently in the zoledronate low-dose 1-mg group (odds ratio, 2.8) compared with either of the higher-dose groups (OR, 8.7 for the 2.5-mg group and 7.4 for the 5-mg group).

"These results show that lower doses than are currently prescribed have substantial antiresorptive effects that approximate those of the 5-mg dose, and suggest that these lower doses will be effective in preventing fractures in people with osteoporosis. Clinical trials should be undertaken to confirm whether annual low doses of zoledronate prevent fractures," according to Dr. Gray.

Dr. Grey had nothing to disclose; he said that the study was funded by public funds.

LONDON – Strontium ranelate continued to safely and effectively prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis during 5-10 years of continuous treatment, in a "modified" case-control study that included 233 women who maintained daily 2 g/day strontium dosing for 10 years.

"Strontium ranelate should not be considered a second-line alternative to bisphosphonates or to any other [osteoporosis] treatment," Dr. Jean-Yves Reginster said at the annual European Congress of Rheumatology. Treatment with strontium ranelate "gives you a chance to bring bone turnover back to premenopausal values," said Dr. Reginster, professor of epidemiology and chairman of the department of public health at the University of Liège in Belgium.

The ability of strontium ranelate to maintain a reduced rate of both vertebral and nonvertebral fractures over 10 years of continuous use in this study marks the first reported evidence of an antiosteoporotic drug exerting an unequivocal antifracture benefit for such a prolonged period. The only other report on 10-year treatment came from the Fracture Intervention Trial Long Term Extension, which included 1,099 women randomized to alendronate or placebo for 10 years (JAMA 2006;296:2927-38). Those results showed that 5-10 years of extended alendronate treatment did not result in a reduction of all clinical fractures or nonvertebral fracture, compared with women maintained on placebo during years 5-10, but extended alendronate did reduce the clinical vertebral fracture rate, compared with placebo.

"In our study [of strontium ranelate], we had no placebo group, but we showed that you can reduce fractures over 10 years with this drug." Strontium maintained its efficacy over 10 years "probably because of its mechanism of action, a dual action," Dr. Reginster said in an interview. "With bisphosphonates you reduce bone resorption. With strontium ranelate you reduce bone resorption by 20%-25%, and you increase bone formation by 20%-25%, so you bring the bone back to what you see in younger women. I think it is a more physiologic approach" than treatment with a bisphosphonate.

In addition, "safety is most important to me when you treat for 10 years. One of the biggest advantages of strontium ranelate is that it is a very safe drug, with little risk of adverse effects over time. I think that calculating the risk/benefit ratio of a drug over time is very important."

In his report, Dr. Reginster emphasized that the women maintained on the drug for 10 years did not have a single episode of atypical fracture, osteonecrosis of the jaw or atrial fibrillation, and their adverse-event profile showed better safety than in the original, pivotal trials of strontium ranelate. He also noted that while the extension only included 233 women on the drug, registry data on about one million patients who have taken the drug also show no reported cases of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation.

The 233 women followed for 10 years on continuous strontium ranelate treatment came from either of the two pivotal, 5-year trials of the drug: the Treatment of Peripheral Osteoporosis Study (TROPOS) (J. Clin. Endocrinol. Met. 2005;90:2816-22), and the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (New. Engl. J. Med. 2004;350:459-68). They continued to receive 2 g/day strontium ranelate, and 73% of the women completed the full extension period. Their average duration of drug use was 9.8 years, and their average compliance with the regimen was 89%.

During their additional 5 years on the drug, average lumbar spine bone mineral density continued to rise, increasing from about 20% above baseline at the start of the extension to about 27% above baseline at 10 years.

To assess the efficacy of treatment for preventing vertebral and nonvertebral fractures, Dr. Reginster and his associates "rebuilt" a control population by selecting placebo patients from the TROPOS study who matched the 233 extended-treatment women based on their baseline Fracture Risk Assessment scores. The researchers matched two TROPOS placebo-group women with each women in the extension study, assembling a total of 458 controls.

The incidence of vertebral fractures during years 5-10 in the women on strontium ranelate was 21%, compared with a 28% rate in the rebuilt control group, a statistically significant difference. In addition, the 21% reduction during the 5-10 year period was statistically similar to the 19% vertebral fracture rate among women treated during 0-5 years in SOTI.

The incidence of nonvertebral fractures during years 5-10 with strontium ranelate was 14%, significantly less than the 20% rate in the derived placebo group and statistically similar to the 13% rate seen in TROPOS, Dr. Reginster reported.

The SOTI and TROPOS trials were funded by Servier, which markets strontium ranelate (Protelos). Dr. Reginster reported financial relationships with Amgen, Analis, Bristol-Myers Squibb, Ebewe, Genévrier, GlaxoSmithKline, IBSA, Eli Lilly, Merck Sharp & Dohme, Merckle, Negma, Novartis, Novo Nordisk, NPS Pharmaceuticals, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, Wyeth, UCB, and Zodiac.

LONDON – Strontium ranelate continued to safely and effectively prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis during 5-10 years of continuous treatment, in a "modified" case-control study that included 233 women who maintained daily 2 g/day strontium dosing for 10 years.

"Strontium ranelate should not be considered a second-line alternative to bisphosphonates or to any other [osteoporosis] treatment," Dr. Jean-Yves Reginster said at the annual European Congress of Rheumatology. Treatment with strontium ranelate "gives you a chance to bring bone turnover back to premenopausal values," said Dr. Reginster, professor of epidemiology and chairman of the department of public health at the University of Liège in Belgium.

The ability of strontium ranelate to maintain a reduced rate of both vertebral and nonvertebral fractures over 10 years of continuous use in this study marks the first reported evidence of an antiosteoporotic drug exerting an unequivocal antifracture benefit for such a prolonged period. The only other report on 10-year treatment came from the Fracture Intervention Trial Long Term Extension, which included 1,099 women randomized to alendronate or placebo for 10 years (JAMA 2006;296:2927-38). Those results showed that 5-10 years of extended alendronate treatment did not result in a reduction of all clinical fractures or nonvertebral fracture, compared with women maintained on placebo during years 5-10, but extended alendronate did reduce the clinical vertebral fracture rate, compared with placebo.

"In our study [of strontium ranelate], we had no placebo group, but we showed that you can reduce fractures over 10 years with this drug." Strontium maintained its efficacy over 10 years "probably because of its mechanism of action, a dual action," Dr. Reginster said in an interview. "With bisphosphonates you reduce bone resorption. With strontium ranelate you reduce bone resorption by 20%-25%, and you increase bone formation by 20%-25%, so you bring the bone back to what you see in younger women. I think it is a more physiologic approach" than treatment with a bisphosphonate.

In addition, "safety is most important to me when you treat for 10 years. One of the biggest advantages of strontium ranelate is that it is a very safe drug, with little risk of adverse effects over time. I think that calculating the risk/benefit ratio of a drug over time is very important."

In his report, Dr. Reginster emphasized that the women maintained on the drug for 10 years did not have a single episode of atypical fracture, osteonecrosis of the jaw or atrial fibrillation, and their adverse-event profile showed better safety than in the original, pivotal trials of strontium ranelate. He also noted that while the extension only included 233 women on the drug, registry data on about one million patients who have taken the drug also show no reported cases of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation.

The 233 women followed for 10 years on continuous strontium ranelate treatment came from either of the two pivotal, 5-year trials of the drug: the Treatment of Peripheral Osteoporosis Study (TROPOS) (J. Clin. Endocrinol. Met. 2005;90:2816-22), and the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (New. Engl. J. Med. 2004;350:459-68). They continued to receive 2 g/day strontium ranelate, and 73% of the women completed the full extension period. Their average duration of drug use was 9.8 years, and their average compliance with the regimen was 89%.

During their additional 5 years on the drug, average lumbar spine bone mineral density continued to rise, increasing from about 20% above baseline at the start of the extension to about 27% above baseline at 10 years.

To assess the efficacy of treatment for preventing vertebral and nonvertebral fractures, Dr. Reginster and his associates "rebuilt" a control population by selecting placebo patients from the TROPOS study who matched the 233 extended-treatment women based on their baseline Fracture Risk Assessment scores. The researchers matched two TROPOS placebo-group women with each women in the extension study, assembling a total of 458 controls.

The incidence of vertebral fractures during years 5-10 in the women on strontium ranelate was 21%, compared with a 28% rate in the rebuilt control group, a statistically significant difference. In addition, the 21% reduction during the 5-10 year period was statistically similar to the 19% vertebral fracture rate among women treated during 0-5 years in SOTI.

The incidence of nonvertebral fractures during years 5-10 with strontium ranelate was 14%, significantly less than the 20% rate in the derived placebo group and statistically similar to the 13% rate seen in TROPOS, Dr. Reginster reported.

The SOTI and TROPOS trials were funded by Servier, which markets strontium ranelate (Protelos). Dr. Reginster reported financial relationships with Amgen, Analis, Bristol-Myers Squibb, Ebewe, Genévrier, GlaxoSmithKline, IBSA, Eli Lilly, Merck Sharp & Dohme, Merckle, Negma, Novartis, Novo Nordisk, NPS Pharmaceuticals, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, Wyeth, UCB, and Zodiac.

LONDON – Strontium ranelate continued to safely and effectively prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis during 5-10 years of continuous treatment, in a "modified" case-control study that included 233 women who maintained daily 2 g/day strontium dosing for 10 years.

"Strontium ranelate should not be considered a second-line alternative to bisphosphonates or to any other [osteoporosis] treatment," Dr. Jean-Yves Reginster said at the annual European Congress of Rheumatology. Treatment with strontium ranelate "gives you a chance to bring bone turnover back to premenopausal values," said Dr. Reginster, professor of epidemiology and chairman of the department of public health at the University of Liège in Belgium.

The ability of strontium ranelate to maintain a reduced rate of both vertebral and nonvertebral fractures over 10 years of continuous use in this study marks the first reported evidence of an antiosteoporotic drug exerting an unequivocal antifracture benefit for such a prolonged period. The only other report on 10-year treatment came from the Fracture Intervention Trial Long Term Extension, which included 1,099 women randomized to alendronate or placebo for 10 years (JAMA 2006;296:2927-38). Those results showed that 5-10 years of extended alendronate treatment did not result in a reduction of all clinical fractures or nonvertebral fracture, compared with women maintained on placebo during years 5-10, but extended alendronate did reduce the clinical vertebral fracture rate, compared with placebo.

"In our study [of strontium ranelate], we had no placebo group, but we showed that you can reduce fractures over 10 years with this drug." Strontium maintained its efficacy over 10 years "probably because of its mechanism of action, a dual action," Dr. Reginster said in an interview. "With bisphosphonates you reduce bone resorption. With strontium ranelate you reduce bone resorption by 20%-25%, and you increase bone formation by 20%-25%, so you bring the bone back to what you see in younger women. I think it is a more physiologic approach" than treatment with a bisphosphonate.

In addition, "safety is most important to me when you treat for 10 years. One of the biggest advantages of strontium ranelate is that it is a very safe drug, with little risk of adverse effects over time. I think that calculating the risk/benefit ratio of a drug over time is very important."

In his report, Dr. Reginster emphasized that the women maintained on the drug for 10 years did not have a single episode of atypical fracture, osteonecrosis of the jaw or atrial fibrillation, and their adverse-event profile showed better safety than in the original, pivotal trials of strontium ranelate. He also noted that while the extension only included 233 women on the drug, registry data on about one million patients who have taken the drug also show no reported cases of atypical fracture, osteonecrosis of the jaw, or atrial fibrillation.

The 233 women followed for 10 years on continuous strontium ranelate treatment came from either of the two pivotal, 5-year trials of the drug: the Treatment of Peripheral Osteoporosis Study (TROPOS) (J. Clin. Endocrinol. Met. 2005;90:2816-22), and the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (New. Engl. J. Med. 2004;350:459-68). They continued to receive 2 g/day strontium ranelate, and 73% of the women completed the full extension period. Their average duration of drug use was 9.8 years, and their average compliance with the regimen was 89%.

During their additional 5 years on the drug, average lumbar spine bone mineral density continued to rise, increasing from about 20% above baseline at the start of the extension to about 27% above baseline at 10 years.

To assess the efficacy of treatment for preventing vertebral and nonvertebral fractures, Dr. Reginster and his associates "rebuilt" a control population by selecting placebo patients from the TROPOS study who matched the 233 extended-treatment women based on their baseline Fracture Risk Assessment scores. The researchers matched two TROPOS placebo-group women with each women in the extension study, assembling a total of 458 controls.

The incidence of vertebral fractures during years 5-10 in the women on strontium ranelate was 21%, compared with a 28% rate in the rebuilt control group, a statistically significant difference. In addition, the 21% reduction during the 5-10 year period was statistically similar to the 19% vertebral fracture rate among women treated during 0-5 years in SOTI.

The incidence of nonvertebral fractures during years 5-10 with strontium ranelate was 14%, significantly less than the 20% rate in the derived placebo group and statistically similar to the 13% rate seen in TROPOS, Dr. Reginster reported.

The SOTI and TROPOS trials were funded by Servier, which markets strontium ranelate (Protelos). Dr. Reginster reported financial relationships with Amgen, Analis, Bristol-Myers Squibb, Ebewe, Genévrier, GlaxoSmithKline, IBSA, Eli Lilly, Merck Sharp & Dohme, Merckle, Negma, Novartis, Novo Nordisk, NPS Pharmaceuticals, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, Wyeth, UCB, and Zodiac.