Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

 

 

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

 

 

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

 

 

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

CASE: Jeff, a 15-year-old high school ice hockey player, asks you to write a note for his coach, stating that he has recovered from his concussion and can return to play. He says that 2 days ago he collided with another player and was knocked unconscious for roughly 10 seconds. He had a headache for the rest of that evening, and complained that the light was hurting his eyes. Now he has no symptoms at rest, but activity gives him a slight headache.

How would you evaluate this patient to determine whether he can return to play?

Concussions like Jeff’s are common in sports-related activities, and family physicians are frequently asked to manage the condition and decide when the injured athlete can safely return to play.

Concussions occur in both helmeted and nonhelmeted sports, and are most common in collision sports.¹ A 2007 estimate from the Centers for Disease Control and Prevention (CDC) suggests that 1.1 million people are seen in emergency departments in the United States each year for concussion-related injuries, while nearly another 235,000 people are hospitalized.² As astounding as these numbers are, many experts believe they underestimate the true incidence of concussion, given the propensity for athletes not to report symptoms for fear of being held out of sporting events.^3,4

Further complicating matters: There has historically been a lack of agreement over what, exactly, constitutes a concussion and how to manage these injuries.

Refining concussion terminology
Concussion has often been referred to as mild traumatic brain injury (MTBI), although more recent expert opinion suggests the terms refer to different injury constructs and should not be used interchangeably.⁵ Over the years there has been little agreement on the definition, grading, and treatment of these injuries.^6-8 On 3 occasions in the last decade, the sports medicine community has held symposia designed to refine an expert consensus on these issues: in 2001 in Vienna, in 2004 in Prague, and in 2008 in Zurich.^5,9,10 These recommendations provide a useful framework for caring for patients like Jeff.

A definition. According to the consensus statement that emerged from the most recent Zurich conference, sports concussion can be defined as a “complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.” Common features may include:⁵

• A direct blow to the head or elsewhere in the body with an impulsive force transmitted to the head.
• Rapid onset of neurological impairments that resolve spontaneously over time.
• Possible neuropathological changes, although the clinical symptoms reflect a functional disturbance rather than structural injury.
• A graded set of clinical symptoms that may or may not involve loss of consciousness.
• No abnormality on standard structural neuroimaging studies.

Athletes with concussion show a range of signs and symptoms

Athletes who suffer from a concussion may show signs of being dazed or disoriented, or experience retrograde amnesia (where they can’t remember things that happened before the traumatic event) or anterograde amnesia (where they can’t remember things that happened after the event). They may also suffer from poor coordination, decreased attention span, emotional lability, or loss of consciousness. After the traumatic event, they may complain of headache, dizziness, nausea or vomiting, photophobia, phonophobia, inability to concentrate, sleep disturbances, fatigue, and memory disturbances. Academic performance can also be severely impaired during the postconcussive period.

Symptoms of concussion may be short-lived or persist for many weeks. Postconcussive syndrome is a term used to describe the condition of prolonged and persistent concussive symptoms. Recent studies in military personal have also shown a strong association between post-traumatic stress disorder (PTSD) and clinical depression in soldiers who have suffered from a traumatic brain injury.¹¹

Start with the ABCs, then check the spine

If you are a team physician on the spot when the injury occurs, you can do the initial assessment on the field of play. A certified athletic trainer can also do this first assessment. Start by checking the basics: airway, breathing, and circulation. Once the ABCs have been completed, palpate the head and neck to rule out a head or cervical spine injury. If the player complains of neck pain or you can palpate bony tenderness or step-off over the spinous processes, suspect a possible cervical spine injury. Make sure the player is put onto a spine board with cervical spine precautions and transported to the nearest medical facility.

Look for neurologic deficits
If the cervical spine is cleared, you can do the rest of the assessment in a quiet location either on the sideline or in your office. Your history should include a narrative of how the injury occurred, an estimate of the force involved, the duration of any symptoms, and any previous concussions. The physical examination comes next, and should include a neurologic assessment and a full cognitive evaluation. Reassess frequently after the traumatic event to monitor for any signs of neurologic decline. If any neurologic deficits are found, the patient should be transported to the nearest medical facility for neuroimaging studies to rule out a structural brain injury.

The SCAT2: A convenient assessment tool
Standardized tools now exist to help you evaluate patients with concussion. The Pocket Sport Concussion Assessment Tool (SCAT2) on page 430 has been endorsed by the Zurich conference.⁵ It is a condensed version of the conference recommendations, suitable for use on the field of play. The SCAT2 includes a symptom scale, mental status tests, instructions on neurologic screening, and guidelines for return to play.

Pocket Sports Concussion Assessment Tool (SCAT2)

Adapted from: Pocket SCAT2. Available at: http://bjsm.bmj.com/content/43/Suppl_1/i89.full.pdf. Accessed July 7, 2010.

No system for grading severity is recommended

Many different classification systems for grading the severity of concussion have been proposed, but none of them is endorsed by the Zurich conference.^5,7,12-15 The classification schemes that have been proposed are complex, not evidence-based, and unable to encompass the full range of concussion symptoms. Thus, the 3rd International Conference on Concussion in Sport abandoned all attempts to use or create classification systems, but recommended that each case be treated clinically on the basis of the symptoms displayed and the duration of the impairment.⁵ Athletes with severe impairment or prolonged symptoms may require referral to a sport medicine specialist with expertise in the management of concussion.

The third conference did agree on a range of “modifying factors” that may influence management and possibly predict the potential for prolonged or persistent symptoms (TABLE). The conference participants endorsed that any athlete displaying these features should be managed in a multidisciplinary manner coordinated by a physician with specific expertise in the management of concussive injuries.

TABLE
"Modifying factors” that may influence concussion management

Return to play is the crucial decision

Just as multiple systems for classifying severity have been proposed, so have guidelines for return to play.^13-15 Again, each of the proposed guidelines has been based on expert opinion and no single set of guidelines has ever been proven to be accurate.¹⁰ There is, therefore, no universally accepted guide for making the decision of when an athlete can safely return to play. It is universally accepted, however, that no athlete should return to play if he or she is still symptomatic at rest or with any exertional maneuvers.^3,7,16 Additionally, the athlete should not be taking any medication that could minimize any of the signs or symptoms of concussion when the physician is determining whether he or she can return to activity.

Once you are assured that the player has no symptoms at rest, you can start him or her on a graded, step-by-step regimen for returning to play. Athletes should spend 24 to 48 hours at each level before progressing to the next. If symptoms return at any point, instruct the athlete to drop back down a step for 24 hours and then proceed with the progression as tolerated.^9,10 The stages of activity are: ^3,10

• Light aerobic exercise
• Moderate to intense aerobic exercise
• Sport-specific activities/noncontact training drills
• Full contact activities
• Game play.

Neuropsychological testing can help you decide

In 1989, Barth and colleagues evaluated 2300 college football players, 200 of whom had suspected concussion.¹⁷ Neuropsychological testing at 24 hours, 5 days, and 10 days showed a decline from baseline following a concussion, with the majority of the athletes returning to baseline by 10 days postconcussion. This finding led researchers to believe that testing could help identify concussions, and several computer-based testing products were developed.^11,18

Neuropsychological testing should include measures of concentration, motor dexterity, information processing, visual and verbal memory, executive function, and brain stem function.¹⁹ Testing can be performed in the athletic setting with a Web-based computer program, by a sports medicine specialist with an interest in concussion, or by a neuro-psychologist with expertise in concussion.

Improvement in cognitive function as a concussion resolves may come prior to, or follow, the resolution of clinical symptoms. Therefore, it is important to properly assess cognition and symptoms before you make a recommendation about returning to play.^3,10 Baseline performance parameters must be established before the season starts.

Neuropsychological testing can provide both an objective measure of the neuro-cognitive effects of concussion and the ability to track recovery. It may also assist in making return-to-play recommendations in complicated cases, but bear in mind that no data are available to suggest that return to play is safe once neuropsychological testing has returned to normal.^3,9 Test results can aid clinical decision making, but cannot substitute for it. Testing may be most helpful in athletes with repeated concussions or those with persistent symptoms.¹⁰

Educating athletes, parents, and coaches in prevention
No foolproof method exists for preventing concussion in sports. Sports medicine research has focused on designing and testing safer equipment and on devising new rules to make play safer.^20-22 At present, there is no evidence that protective equipment will prevent concussions, but recent studies by Collins and Viano suggest that newer football helmets may assist in decreasing the incidence of concussions.^20,22,23

The Zurich consensus statement warns that protective equipment can have a paradoxical effect, influencing athletes to take risks that they might otherwise avoid, thus increasing injury rates.⁵ Trials of rule changes in different sports have been and continue to be conducted, such as barring spearing in football and restricting helmet-to-helmet hits. Given the frequency of concussion, further research is clearly needed. In the meantime, family physicians can play a major role in educating players, parents, and coaches about the seriousness of concussive injury and the need for identifying concussion promptly and allowing adequate time for recovery.

What do you tell Jeff?
Your answer for Jeff is, “You’re not ready to go back to practice or play. You feel OK when you’re resting, but when you get up, your headache returns. Come back to the office in a day or 2, and I’ll re-evaluate you. If you don’t have any symptoms then, you can start a program of graduated activity, beginning with some light aerobic exercise. If you feel all right with that, you can go on to a moderate and then an intense aerobic workout. If you still feel good, you can go on to sports-specific activities with no contact training, and then full contact training.

“At each stage, you will need to be re-evaluated by me or by your team trainer. Once you’ve finished the program without any reactivation of symptoms, I’ll clear you for play.”

CORRESPONDENCE Shawn M. Ferullo, MD, One Boston Medical Center Place, Boston, MA 02118; Shawn.ferullo@bmc.org

CASE: Jeff, a 15-year-old high school ice hockey player, asks you to write a note for his coach, stating that he has recovered from his concussion and can return to play. He says that 2 days ago he collided with another player and was knocked unconscious for roughly 10 seconds. He had a headache for the rest of that evening, and complained that the light was hurting his eyes. Now he has no symptoms at rest, but activity gives him a slight headache.

How would you evaluate this patient to determine whether he can return to play?

Concussions like Jeff’s are common in sports-related activities, and family physicians are frequently asked to manage the condition and decide when the injured athlete can safely return to play.

Concussions occur in both helmeted and nonhelmeted sports, and are most common in collision sports.¹ A 2007 estimate from the Centers for Disease Control and Prevention (CDC) suggests that 1.1 million people are seen in emergency departments in the United States each year for concussion-related injuries, while nearly another 235,000 people are hospitalized.² As astounding as these numbers are, many experts believe they underestimate the true incidence of concussion, given the propensity for athletes not to report symptoms for fear of being held out of sporting events.^3,4

Further complicating matters: There has historically been a lack of agreement over what, exactly, constitutes a concussion and how to manage these injuries.

Refining concussion terminology
Concussion has often been referred to as mild traumatic brain injury (MTBI), although more recent expert opinion suggests the terms refer to different injury constructs and should not be used interchangeably.⁵ Over the years there has been little agreement on the definition, grading, and treatment of these injuries.^6-8 On 3 occasions in the last decade, the sports medicine community has held symposia designed to refine an expert consensus on these issues: in 2001 in Vienna, in 2004 in Prague, and in 2008 in Zurich.^5,9,10 These recommendations provide a useful framework for caring for patients like Jeff.

A definition. According to the consensus statement that emerged from the most recent Zurich conference, sports concussion can be defined as a “complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.” Common features may include:⁵

• A direct blow to the head or elsewhere in the body with an impulsive force transmitted to the head.
• Rapid onset of neurological impairments that resolve spontaneously over time.
• Possible neuropathological changes, although the clinical symptoms reflect a functional disturbance rather than structural injury.
• A graded set of clinical symptoms that may or may not involve loss of consciousness.
• No abnormality on standard structural neuroimaging studies.

Athletes with concussion show a range of signs and symptoms

Athletes who suffer from a concussion may show signs of being dazed or disoriented, or experience retrograde amnesia (where they can’t remember things that happened before the traumatic event) or anterograde amnesia (where they can’t remember things that happened after the event). They may also suffer from poor coordination, decreased attention span, emotional lability, or loss of consciousness. After the traumatic event, they may complain of headache, dizziness, nausea or vomiting, photophobia, phonophobia, inability to concentrate, sleep disturbances, fatigue, and memory disturbances. Academic performance can also be severely impaired during the postconcussive period.

Symptoms of concussion may be short-lived or persist for many weeks. Postconcussive syndrome is a term used to describe the condition of prolonged and persistent concussive symptoms. Recent studies in military personal have also shown a strong association between post-traumatic stress disorder (PTSD) and clinical depression in soldiers who have suffered from a traumatic brain injury.¹¹

Start with the ABCs, then check the spine

If you are a team physician on the spot when the injury occurs, you can do the initial assessment on the field of play. A certified athletic trainer can also do this first assessment. Start by checking the basics: airway, breathing, and circulation. Once the ABCs have been completed, palpate the head and neck to rule out a head or cervical spine injury. If the player complains of neck pain or you can palpate bony tenderness or step-off over the spinous processes, suspect a possible cervical spine injury. Make sure the player is put onto a spine board with cervical spine precautions and transported to the nearest medical facility.

Look for neurologic deficits
If the cervical spine is cleared, you can do the rest of the assessment in a quiet location either on the sideline or in your office. Your history should include a narrative of how the injury occurred, an estimate of the force involved, the duration of any symptoms, and any previous concussions. The physical examination comes next, and should include a neurologic assessment and a full cognitive evaluation. Reassess frequently after the traumatic event to monitor for any signs of neurologic decline. If any neurologic deficits are found, the patient should be transported to the nearest medical facility for neuroimaging studies to rule out a structural brain injury.

The SCAT2: A convenient assessment tool
Standardized tools now exist to help you evaluate patients with concussion. The Pocket Sport Concussion Assessment Tool (SCAT2) on page 430 has been endorsed by the Zurich conference.⁵ It is a condensed version of the conference recommendations, suitable for use on the field of play. The SCAT2 includes a symptom scale, mental status tests, instructions on neurologic screening, and guidelines for return to play.

Pocket Sports Concussion Assessment Tool (SCAT2)

Adapted from: Pocket SCAT2. Available at: http://bjsm.bmj.com/content/43/Suppl_1/i89.full.pdf. Accessed July 7, 2010.

No system for grading severity is recommended

Many different classification systems for grading the severity of concussion have been proposed, but none of them is endorsed by the Zurich conference.^5,7,12-15 The classification schemes that have been proposed are complex, not evidence-based, and unable to encompass the full range of concussion symptoms. Thus, the 3rd International Conference on Concussion in Sport abandoned all attempts to use or create classification systems, but recommended that each case be treated clinically on the basis of the symptoms displayed and the duration of the impairment.⁵ Athletes with severe impairment or prolonged symptoms may require referral to a sport medicine specialist with expertise in the management of concussion.

The third conference did agree on a range of “modifying factors” that may influence management and possibly predict the potential for prolonged or persistent symptoms (TABLE). The conference participants endorsed that any athlete displaying these features should be managed in a multidisciplinary manner coordinated by a physician with specific expertise in the management of concussive injuries.

TABLE
"Modifying factors” that may influence concussion management

Return to play is the crucial decision

Just as multiple systems for classifying severity have been proposed, so have guidelines for return to play.^13-15 Again, each of the proposed guidelines has been based on expert opinion and no single set of guidelines has ever been proven to be accurate.¹⁰ There is, therefore, no universally accepted guide for making the decision of when an athlete can safely return to play. It is universally accepted, however, that no athlete should return to play if he or she is still symptomatic at rest or with any exertional maneuvers.^3,7,16 Additionally, the athlete should not be taking any medication that could minimize any of the signs or symptoms of concussion when the physician is determining whether he or she can return to activity.

Once you are assured that the player has no symptoms at rest, you can start him or her on a graded, step-by-step regimen for returning to play. Athletes should spend 24 to 48 hours at each level before progressing to the next. If symptoms return at any point, instruct the athlete to drop back down a step for 24 hours and then proceed with the progression as tolerated.^9,10 The stages of activity are: ^3,10

• Light aerobic exercise
• Moderate to intense aerobic exercise
• Sport-specific activities/noncontact training drills
• Full contact activities
• Game play.

Neuropsychological testing can help you decide

In 1989, Barth and colleagues evaluated 2300 college football players, 200 of whom had suspected concussion.¹⁷ Neuropsychological testing at 24 hours, 5 days, and 10 days showed a decline from baseline following a concussion, with the majority of the athletes returning to baseline by 10 days postconcussion. This finding led researchers to believe that testing could help identify concussions, and several computer-based testing products were developed.^11,18

Neuropsychological testing should include measures of concentration, motor dexterity, information processing, visual and verbal memory, executive function, and brain stem function.¹⁹ Testing can be performed in the athletic setting with a Web-based computer program, by a sports medicine specialist with an interest in concussion, or by a neuro-psychologist with expertise in concussion.

Improvement in cognitive function as a concussion resolves may come prior to, or follow, the resolution of clinical symptoms. Therefore, it is important to properly assess cognition and symptoms before you make a recommendation about returning to play.^3,10 Baseline performance parameters must be established before the season starts.

Neuropsychological testing can provide both an objective measure of the neuro-cognitive effects of concussion and the ability to track recovery. It may also assist in making return-to-play recommendations in complicated cases, but bear in mind that no data are available to suggest that return to play is safe once neuropsychological testing has returned to normal.^3,9 Test results can aid clinical decision making, but cannot substitute for it. Testing may be most helpful in athletes with repeated concussions or those with persistent symptoms.¹⁰

Educating athletes, parents, and coaches in prevention
No foolproof method exists for preventing concussion in sports. Sports medicine research has focused on designing and testing safer equipment and on devising new rules to make play safer.^20-22 At present, there is no evidence that protective equipment will prevent concussions, but recent studies by Collins and Viano suggest that newer football helmets may assist in decreasing the incidence of concussions.^20,22,23

The Zurich consensus statement warns that protective equipment can have a paradoxical effect, influencing athletes to take risks that they might otherwise avoid, thus increasing injury rates.⁵ Trials of rule changes in different sports have been and continue to be conducted, such as barring spearing in football and restricting helmet-to-helmet hits. Given the frequency of concussion, further research is clearly needed. In the meantime, family physicians can play a major role in educating players, parents, and coaches about the seriousness of concussive injury and the need for identifying concussion promptly and allowing adequate time for recovery.

What do you tell Jeff?
Your answer for Jeff is, “You’re not ready to go back to practice or play. You feel OK when you’re resting, but when you get up, your headache returns. Come back to the office in a day or 2, and I’ll re-evaluate you. If you don’t have any symptoms then, you can start a program of graduated activity, beginning with some light aerobic exercise. If you feel all right with that, you can go on to a moderate and then an intense aerobic workout. If you still feel good, you can go on to sports-specific activities with no contact training, and then full contact training.

“At each stage, you will need to be re-evaluated by me or by your team trainer. Once you’ve finished the program without any reactivation of symptoms, I’ll clear you for play.”

CORRESPONDENCE Shawn M. Ferullo, MD, One Boston Medical Center Place, Boston, MA 02118; Shawn.ferullo@bmc.org

CASE: Jeff, a 15-year-old high school ice hockey player, asks you to write a note for his coach, stating that he has recovered from his concussion and can return to play. He says that 2 days ago he collided with another player and was knocked unconscious for roughly 10 seconds. He had a headache for the rest of that evening, and complained that the light was hurting his eyes. Now he has no symptoms at rest, but activity gives him a slight headache.

How would you evaluate this patient to determine whether he can return to play?

Concussions like Jeff’s are common in sports-related activities, and family physicians are frequently asked to manage the condition and decide when the injured athlete can safely return to play.

Concussions occur in both helmeted and nonhelmeted sports, and are most common in collision sports.¹ A 2007 estimate from the Centers for Disease Control and Prevention (CDC) suggests that 1.1 million people are seen in emergency departments in the United States each year for concussion-related injuries, while nearly another 235,000 people are hospitalized.² As astounding as these numbers are, many experts believe they underestimate the true incidence of concussion, given the propensity for athletes not to report symptoms for fear of being held out of sporting events.^3,4

Further complicating matters: There has historically been a lack of agreement over what, exactly, constitutes a concussion and how to manage these injuries.

Refining concussion terminology
Concussion has often been referred to as mild traumatic brain injury (MTBI), although more recent expert opinion suggests the terms refer to different injury constructs and should not be used interchangeably.⁵ Over the years there has been little agreement on the definition, grading, and treatment of these injuries.^6-8 On 3 occasions in the last decade, the sports medicine community has held symposia designed to refine an expert consensus on these issues: in 2001 in Vienna, in 2004 in Prague, and in 2008 in Zurich.^5,9,10 These recommendations provide a useful framework for caring for patients like Jeff.

A definition. According to the consensus statement that emerged from the most recent Zurich conference, sports concussion can be defined as a “complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.” Common features may include:⁵

• A direct blow to the head or elsewhere in the body with an impulsive force transmitted to the head.
• Rapid onset of neurological impairments that resolve spontaneously over time.
• Possible neuropathological changes, although the clinical symptoms reflect a functional disturbance rather than structural injury.
• A graded set of clinical symptoms that may or may not involve loss of consciousness.
• No abnormality on standard structural neuroimaging studies.

Athletes with concussion show a range of signs and symptoms

Athletes who suffer from a concussion may show signs of being dazed or disoriented, or experience retrograde amnesia (where they can’t remember things that happened before the traumatic event) or anterograde amnesia (where they can’t remember things that happened after the event). They may also suffer from poor coordination, decreased attention span, emotional lability, or loss of consciousness. After the traumatic event, they may complain of headache, dizziness, nausea or vomiting, photophobia, phonophobia, inability to concentrate, sleep disturbances, fatigue, and memory disturbances. Academic performance can also be severely impaired during the postconcussive period.

Symptoms of concussion may be short-lived or persist for many weeks. Postconcussive syndrome is a term used to describe the condition of prolonged and persistent concussive symptoms. Recent studies in military personal have also shown a strong association between post-traumatic stress disorder (PTSD) and clinical depression in soldiers who have suffered from a traumatic brain injury.¹¹

Start with the ABCs, then check the spine

If you are a team physician on the spot when the injury occurs, you can do the initial assessment on the field of play. A certified athletic trainer can also do this first assessment. Start by checking the basics: airway, breathing, and circulation. Once the ABCs have been completed, palpate the head and neck to rule out a head or cervical spine injury. If the player complains of neck pain or you can palpate bony tenderness or step-off over the spinous processes, suspect a possible cervical spine injury. Make sure the player is put onto a spine board with cervical spine precautions and transported to the nearest medical facility.

Look for neurologic deficits
If the cervical spine is cleared, you can do the rest of the assessment in a quiet location either on the sideline or in your office. Your history should include a narrative of how the injury occurred, an estimate of the force involved, the duration of any symptoms, and any previous concussions. The physical examination comes next, and should include a neurologic assessment and a full cognitive evaluation. Reassess frequently after the traumatic event to monitor for any signs of neurologic decline. If any neurologic deficits are found, the patient should be transported to the nearest medical facility for neuroimaging studies to rule out a structural brain injury.

The SCAT2: A convenient assessment tool
Standardized tools now exist to help you evaluate patients with concussion. The Pocket Sport Concussion Assessment Tool (SCAT2) on page 430 has been endorsed by the Zurich conference.⁵ It is a condensed version of the conference recommendations, suitable for use on the field of play. The SCAT2 includes a symptom scale, mental status tests, instructions on neurologic screening, and guidelines for return to play.

Pocket Sports Concussion Assessment Tool (SCAT2)

Adapted from: Pocket SCAT2. Available at: http://bjsm.bmj.com/content/43/Suppl_1/i89.full.pdf. Accessed July 7, 2010.

No system for grading severity is recommended

Many different classification systems for grading the severity of concussion have been proposed, but none of them is endorsed by the Zurich conference.^5,7,12-15 The classification schemes that have been proposed are complex, not evidence-based, and unable to encompass the full range of concussion symptoms. Thus, the 3rd International Conference on Concussion in Sport abandoned all attempts to use or create classification systems, but recommended that each case be treated clinically on the basis of the symptoms displayed and the duration of the impairment.⁵ Athletes with severe impairment or prolonged symptoms may require referral to a sport medicine specialist with expertise in the management of concussion.

The third conference did agree on a range of “modifying factors” that may influence management and possibly predict the potential for prolonged or persistent symptoms (TABLE). The conference participants endorsed that any athlete displaying these features should be managed in a multidisciplinary manner coordinated by a physician with specific expertise in the management of concussive injuries.

TABLE
"Modifying factors” that may influence concussion management

Return to play is the crucial decision

Just as multiple systems for classifying severity have been proposed, so have guidelines for return to play.^13-15 Again, each of the proposed guidelines has been based on expert opinion and no single set of guidelines has ever been proven to be accurate.¹⁰ There is, therefore, no universally accepted guide for making the decision of when an athlete can safely return to play. It is universally accepted, however, that no athlete should return to play if he or she is still symptomatic at rest or with any exertional maneuvers.^3,7,16 Additionally, the athlete should not be taking any medication that could minimize any of the signs or symptoms of concussion when the physician is determining whether he or she can return to activity.

Once you are assured that the player has no symptoms at rest, you can start him or her on a graded, step-by-step regimen for returning to play. Athletes should spend 24 to 48 hours at each level before progressing to the next. If symptoms return at any point, instruct the athlete to drop back down a step for 24 hours and then proceed with the progression as tolerated.^9,10 The stages of activity are: ^3,10

• Light aerobic exercise
• Moderate to intense aerobic exercise
• Sport-specific activities/noncontact training drills
• Full contact activities
• Game play.

Neuropsychological testing can help you decide

In 1989, Barth and colleagues evaluated 2300 college football players, 200 of whom had suspected concussion.¹⁷ Neuropsychological testing at 24 hours, 5 days, and 10 days showed a decline from baseline following a concussion, with the majority of the athletes returning to baseline by 10 days postconcussion. This finding led researchers to believe that testing could help identify concussions, and several computer-based testing products were developed.^11,18

Neuropsychological testing should include measures of concentration, motor dexterity, information processing, visual and verbal memory, executive function, and brain stem function.¹⁹ Testing can be performed in the athletic setting with a Web-based computer program, by a sports medicine specialist with an interest in concussion, or by a neuro-psychologist with expertise in concussion.

Improvement in cognitive function as a concussion resolves may come prior to, or follow, the resolution of clinical symptoms. Therefore, it is important to properly assess cognition and symptoms before you make a recommendation about returning to play.^3,10 Baseline performance parameters must be established before the season starts.

Neuropsychological testing can provide both an objective measure of the neuro-cognitive effects of concussion and the ability to track recovery. It may also assist in making return-to-play recommendations in complicated cases, but bear in mind that no data are available to suggest that return to play is safe once neuropsychological testing has returned to normal.^3,9 Test results can aid clinical decision making, but cannot substitute for it. Testing may be most helpful in athletes with repeated concussions or those with persistent symptoms.¹⁰

Educating athletes, parents, and coaches in prevention
No foolproof method exists for preventing concussion in sports. Sports medicine research has focused on designing and testing safer equipment and on devising new rules to make play safer.^20-22 At present, there is no evidence that protective equipment will prevent concussions, but recent studies by Collins and Viano suggest that newer football helmets may assist in decreasing the incidence of concussions.^20,22,23

The Zurich consensus statement warns that protective equipment can have a paradoxical effect, influencing athletes to take risks that they might otherwise avoid, thus increasing injury rates.⁵ Trials of rule changes in different sports have been and continue to be conducted, such as barring spearing in football and restricting helmet-to-helmet hits. Given the frequency of concussion, further research is clearly needed. In the meantime, family physicians can play a major role in educating players, parents, and coaches about the seriousness of concussive injury and the need for identifying concussion promptly and allowing adequate time for recovery.

What do you tell Jeff?
Your answer for Jeff is, “You’re not ready to go back to practice or play. You feel OK when you’re resting, but when you get up, your headache returns. Come back to the office in a day or 2, and I’ll re-evaluate you. If you don’t have any symptoms then, you can start a program of graduated activity, beginning with some light aerobic exercise. If you feel all right with that, you can go on to a moderate and then an intense aerobic workout. If you still feel good, you can go on to sports-specific activities with no contact training, and then full contact training.

“At each stage, you will need to be re-evaluated by me or by your team trainer. Once you’ve finished the program without any reactivation of symptoms, I’ll clear you for play.”

CORRESPONDENCE Shawn M. Ferullo, MD, One Boston Medical Center Place, Boston, MA 02118; Shawn.ferullo@bmc.org

Dysmenorrhea and menorrhagia beyond the norm often overlap in adolescents and can occur in up to 15% of these young women.

The normal time period from breast development (thelarche) and development of pubic hair to menses in young girls is about 2 years. A longer time course is cause for investigation.

The maturation of the hypothalamic-pituitary-ovarian axis occurs over approximately 5 years. After initiation of menses (menarche), some adolescents have anovulatory cycles, i.e., no luteinizing hormone surge with subsequent lack of ovulation and dysfunctional estrogen effect on the uterine endometrial lining. This can present with irregular bleeding that can be very heavy when the endometrial lining sheds in an unsynchronized manner. If no other cause for this bleeding is established (for example, endocrine, anatomic, or underlying chronic disease), then it is considered dysfunctional uterine bleeding (DUB).

In the same time period of 5 years from menarche, an estimated 15%-30% of young women will have primary dysmenorrhea strong enough to require pain medication, including nonsteroidal anti-inflammatory drugs (NSAIDs).

The vast majority of young adolescent girls experience some pain with their periods, ranging from discomfort to pain requiring medication to being unable to go to school.

When the pain is severe, these patients either miss school or just make it through the school day, but their attention and performance suffer. These girls with significant pain need more assistance because their dysmenorrhea may not subside for several years, and a referral to a subspecialist is warranted.

In terms of differential diagnosis, menstrual pain (dysmenorrhea) is a crampy, focal phenomenon in the mid-lower quadrant, sometimes with radiation to the back and the lower extremities. It starts with the onset of menses. If the pain precedes menses, it may be endometriosis and not primary dysmenorrhea, although there is an overlap in the pain symptoms between these two entities. A nonleading question to ask is whether the patient experiences pain before, during, or after her cycle.

A gastrointestinal etiology is more likely if the pain is nonfocal and present in all four quadrants. Ruling out other GI etiologies, particularly constipation, is important. A trial of Miralax over 2-3 weeks with a cessation in the pain easily confirms constipation as the underlying cause. Constipation is very common in children and adolescents, and the pain is not related to the menstrual cycle.

Dysmenorrhea is a clinical diagnosis. Laboratory tests for this condition are not needed. Instead, a good history, detailed description of the pain, and ultrasound examination (transabdominal, not transvaginal) aid the differential diagnosis. Ultrasound is reassuring, as it can show normal uterine development and no ovarian masses, including no benign childhood ovarian tumors. Rarely is a pelvic examination necessary.

Pediatricians are instrumental in terms of educating patients, encouraging these patients to keep a detailed menstrual and pain diary, and advocating appropriate use of NSAIDs. However, if the diagnosis and management of teenagers with dysmenorrhea are outside your comfort zone, or your focus is primarily on younger children, you can refer the patient to a pediatric and adolescent gynecologist or other adolescent medicine specialist.

One problem for these patients is the use of Tylenol, which does not work on the elevated prostaglandins in primary dysmenorrhea. Instead, recommend an NSAID such as ibuprofen (Motrin, Advil), naproxen (Naprosyn), or mefenamic acid (Ponstel).

If pain relief is inadequate, switch classes of NSAIDs instead of switching between drugs in the same class.

Birth control pills are another option for controlling painful periods. For most girls with menses painful enough to impair their activities of daily living, birth control pills are a huge benefit. Oral contraceptives for 1-2 years for irregular bleeding and dysmenorrhea can make a big difference, and then you can try a trial period without them. Prescription of birth control pills requires a lot of education, particularly because these young patients need to be compliant. Create a routine for them—such as suggesting their pills be stored in a secure location with their toothbrush.

Parents also need to be vested in this approach, and some will be resistant. I recommend that you discuss birth control pills as a strategy to control pain and bleeding when the parents and the patient are both present. Educate parents that birth control pills will not give their daughters breast cancer or cause them to become sexually active. Any generic monophasic oral contraceptive with 30 mcg of estradiol can be used.

If you add birth control pills to NSAIDs, 95% of patients experience no pain or bearable pain. It can take up to 6 months for maximum relief, however, and these teenagers need to keep a menstrual and pain diary to track and appreciate the improvements over time.

Heating pads can be a comforting, nonpharmacologic strategy for managing dysmenorrhea. Some girls who use them report taking fewer NSAIDs. There also is some literature on the benefits of acupuncture, but it is not always practical in the United States.

DUB is a diagnosis of exclusion. In your differential diagnosis, rule out thyroid dysfunction, prolactinoma (a rare brain tumor), or any underlying chronic diseases (such as lupus) that affect the menstrual cycle. If you suspect anatomic abnormalities, a transabdominal ultrasound examination is indicated. You also have to consider polycystic ovarian syndrome (PCOS), because teenagers with this syndrome can present with irregular bleeding.

Laboratory tests for DUB are thyroid function, prolactin, and markers for PCOS. These assays include free and total testosterone, sex hormone–binding globulin, and androstenedione.

Most pediatricians know this, but if the first menses (menarche) is very heavy, you have to think of a bleeding disorder. This is an important diagnostic sign that additional work-up is warranted, and early intervention may be possible. If there is a bleeding disorder, early diagnosis could mean a lesser chance of hemorrhage during childbirth. Awareness among pediatricians is important because young girls rarely see gynecologists.

Classic DUB is related to menstrual cycle irregularities. There is a cohort of eggs recruited in the first half of the cycle (follicular phase). One follicle emerges that will rupture and release the egg at midcycle after luteinizing hormone levels spike in the body. If this sequence does not occur, the menstrual cycle is affected. The endometrial lining has proliferated under the effect of estrogen, and unsynchronized shedding with irregular bleeding occurs.

Again, you can take control of the menstrual cycle with birth control pills.

Dysmenorrhea and menorrhagia beyond the norm often overlap in adolescents and can occur in up to 15% of these young women.

The normal time period from breast development (thelarche) and development of pubic hair to menses in young girls is about 2 years. A longer time course is cause for investigation.

The maturation of the hypothalamic-pituitary-ovarian axis occurs over approximately 5 years. After initiation of menses (menarche), some adolescents have anovulatory cycles, i.e., no luteinizing hormone surge with subsequent lack of ovulation and dysfunctional estrogen effect on the uterine endometrial lining. This can present with irregular bleeding that can be very heavy when the endometrial lining sheds in an unsynchronized manner. If no other cause for this bleeding is established (for example, endocrine, anatomic, or underlying chronic disease), then it is considered dysfunctional uterine bleeding (DUB).

In the same time period of 5 years from menarche, an estimated 15%-30% of young women will have primary dysmenorrhea strong enough to require pain medication, including nonsteroidal anti-inflammatory drugs (NSAIDs).

The vast majority of young adolescent girls experience some pain with their periods, ranging from discomfort to pain requiring medication to being unable to go to school.

When the pain is severe, these patients either miss school or just make it through the school day, but their attention and performance suffer. These girls with significant pain need more assistance because their dysmenorrhea may not subside for several years, and a referral to a subspecialist is warranted.

In terms of differential diagnosis, menstrual pain (dysmenorrhea) is a crampy, focal phenomenon in the mid-lower quadrant, sometimes with radiation to the back and the lower extremities. It starts with the onset of menses. If the pain precedes menses, it may be endometriosis and not primary dysmenorrhea, although there is an overlap in the pain symptoms between these two entities. A nonleading question to ask is whether the patient experiences pain before, during, or after her cycle.

A gastrointestinal etiology is more likely if the pain is nonfocal and present in all four quadrants. Ruling out other GI etiologies, particularly constipation, is important. A trial of Miralax over 2-3 weeks with a cessation in the pain easily confirms constipation as the underlying cause. Constipation is very common in children and adolescents, and the pain is not related to the menstrual cycle.

Dysmenorrhea is a clinical diagnosis. Laboratory tests for this condition are not needed. Instead, a good history, detailed description of the pain, and ultrasound examination (transabdominal, not transvaginal) aid the differential diagnosis. Ultrasound is reassuring, as it can show normal uterine development and no ovarian masses, including no benign childhood ovarian tumors. Rarely is a pelvic examination necessary.

Pediatricians are instrumental in terms of educating patients, encouraging these patients to keep a detailed menstrual and pain diary, and advocating appropriate use of NSAIDs. However, if the diagnosis and management of teenagers with dysmenorrhea are outside your comfort zone, or your focus is primarily on younger children, you can refer the patient to a pediatric and adolescent gynecologist or other adolescent medicine specialist.

One problem for these patients is the use of Tylenol, which does not work on the elevated prostaglandins in primary dysmenorrhea. Instead, recommend an NSAID such as ibuprofen (Motrin, Advil), naproxen (Naprosyn), or mefenamic acid (Ponstel).

If pain relief is inadequate, switch classes of NSAIDs instead of switching between drugs in the same class.

Birth control pills are another option for controlling painful periods. For most girls with menses painful enough to impair their activities of daily living, birth control pills are a huge benefit. Oral contraceptives for 1-2 years for irregular bleeding and dysmenorrhea can make a big difference, and then you can try a trial period without them. Prescription of birth control pills requires a lot of education, particularly because these young patients need to be compliant. Create a routine for them—such as suggesting their pills be stored in a secure location with their toothbrush.

Parents also need to be vested in this approach, and some will be resistant. I recommend that you discuss birth control pills as a strategy to control pain and bleeding when the parents and the patient are both present. Educate parents that birth control pills will not give their daughters breast cancer or cause them to become sexually active. Any generic monophasic oral contraceptive with 30 mcg of estradiol can be used.

If you add birth control pills to NSAIDs, 95% of patients experience no pain or bearable pain. It can take up to 6 months for maximum relief, however, and these teenagers need to keep a menstrual and pain diary to track and appreciate the improvements over time.

Heating pads can be a comforting, nonpharmacologic strategy for managing dysmenorrhea. Some girls who use them report taking fewer NSAIDs. There also is some literature on the benefits of acupuncture, but it is not always practical in the United States.

DUB is a diagnosis of exclusion. In your differential diagnosis, rule out thyroid dysfunction, prolactinoma (a rare brain tumor), or any underlying chronic diseases (such as lupus) that affect the menstrual cycle. If you suspect anatomic abnormalities, a transabdominal ultrasound examination is indicated. You also have to consider polycystic ovarian syndrome (PCOS), because teenagers with this syndrome can present with irregular bleeding.

Laboratory tests for DUB are thyroid function, prolactin, and markers for PCOS. These assays include free and total testosterone, sex hormone–binding globulin, and androstenedione.

Most pediatricians know this, but if the first menses (menarche) is very heavy, you have to think of a bleeding disorder. This is an important diagnostic sign that additional work-up is warranted, and early intervention may be possible. If there is a bleeding disorder, early diagnosis could mean a lesser chance of hemorrhage during childbirth. Awareness among pediatricians is important because young girls rarely see gynecologists.

Classic DUB is related to menstrual cycle irregularities. There is a cohort of eggs recruited in the first half of the cycle (follicular phase). One follicle emerges that will rupture and release the egg at midcycle after luteinizing hormone levels spike in the body. If this sequence does not occur, the menstrual cycle is affected. The endometrial lining has proliferated under the effect of estrogen, and unsynchronized shedding with irregular bleeding occurs.

Again, you can take control of the menstrual cycle with birth control pills.

Dysmenorrhea and menorrhagia beyond the norm often overlap in adolescents and can occur in up to 15% of these young women.

The normal time period from breast development (thelarche) and development of pubic hair to menses in young girls is about 2 years. A longer time course is cause for investigation.

The maturation of the hypothalamic-pituitary-ovarian axis occurs over approximately 5 years. After initiation of menses (menarche), some adolescents have anovulatory cycles, i.e., no luteinizing hormone surge with subsequent lack of ovulation and dysfunctional estrogen effect on the uterine endometrial lining. This can present with irregular bleeding that can be very heavy when the endometrial lining sheds in an unsynchronized manner. If no other cause for this bleeding is established (for example, endocrine, anatomic, or underlying chronic disease), then it is considered dysfunctional uterine bleeding (DUB).

In the same time period of 5 years from menarche, an estimated 15%-30% of young women will have primary dysmenorrhea strong enough to require pain medication, including nonsteroidal anti-inflammatory drugs (NSAIDs).

The vast majority of young adolescent girls experience some pain with their periods, ranging from discomfort to pain requiring medication to being unable to go to school.

When the pain is severe, these patients either miss school or just make it through the school day, but their attention and performance suffer. These girls with significant pain need more assistance because their dysmenorrhea may not subside for several years, and a referral to a subspecialist is warranted.

In terms of differential diagnosis, menstrual pain (dysmenorrhea) is a crampy, focal phenomenon in the mid-lower quadrant, sometimes with radiation to the back and the lower extremities. It starts with the onset of menses. If the pain precedes menses, it may be endometriosis and not primary dysmenorrhea, although there is an overlap in the pain symptoms between these two entities. A nonleading question to ask is whether the patient experiences pain before, during, or after her cycle.

A gastrointestinal etiology is more likely if the pain is nonfocal and present in all four quadrants. Ruling out other GI etiologies, particularly constipation, is important. A trial of Miralax over 2-3 weeks with a cessation in the pain easily confirms constipation as the underlying cause. Constipation is very common in children and adolescents, and the pain is not related to the menstrual cycle.

Dysmenorrhea is a clinical diagnosis. Laboratory tests for this condition are not needed. Instead, a good history, detailed description of the pain, and ultrasound examination (transabdominal, not transvaginal) aid the differential diagnosis. Ultrasound is reassuring, as it can show normal uterine development and no ovarian masses, including no benign childhood ovarian tumors. Rarely is a pelvic examination necessary.

Pediatricians are instrumental in terms of educating patients, encouraging these patients to keep a detailed menstrual and pain diary, and advocating appropriate use of NSAIDs. However, if the diagnosis and management of teenagers with dysmenorrhea are outside your comfort zone, or your focus is primarily on younger children, you can refer the patient to a pediatric and adolescent gynecologist or other adolescent medicine specialist.

One problem for these patients is the use of Tylenol, which does not work on the elevated prostaglandins in primary dysmenorrhea. Instead, recommend an NSAID such as ibuprofen (Motrin, Advil), naproxen (Naprosyn), or mefenamic acid (Ponstel).

If pain relief is inadequate, switch classes of NSAIDs instead of switching between drugs in the same class.

Birth control pills are another option for controlling painful periods. For most girls with menses painful enough to impair their activities of daily living, birth control pills are a huge benefit. Oral contraceptives for 1-2 years for irregular bleeding and dysmenorrhea can make a big difference, and then you can try a trial period without them. Prescription of birth control pills requires a lot of education, particularly because these young patients need to be compliant. Create a routine for them—such as suggesting their pills be stored in a secure location with their toothbrush.

Parents also need to be vested in this approach, and some will be resistant. I recommend that you discuss birth control pills as a strategy to control pain and bleeding when the parents and the patient are both present. Educate parents that birth control pills will not give their daughters breast cancer or cause them to become sexually active. Any generic monophasic oral contraceptive with 30 mcg of estradiol can be used.

If you add birth control pills to NSAIDs, 95% of patients experience no pain or bearable pain. It can take up to 6 months for maximum relief, however, and these teenagers need to keep a menstrual and pain diary to track and appreciate the improvements over time.

Heating pads can be a comforting, nonpharmacologic strategy for managing dysmenorrhea. Some girls who use them report taking fewer NSAIDs. There also is some literature on the benefits of acupuncture, but it is not always practical in the United States.

DUB is a diagnosis of exclusion. In your differential diagnosis, rule out thyroid dysfunction, prolactinoma (a rare brain tumor), or any underlying chronic diseases (such as lupus) that affect the menstrual cycle. If you suspect anatomic abnormalities, a transabdominal ultrasound examination is indicated. You also have to consider polycystic ovarian syndrome (PCOS), because teenagers with this syndrome can present with irregular bleeding.

Laboratory tests for DUB are thyroid function, prolactin, and markers for PCOS. These assays include free and total testosterone, sex hormone–binding globulin, and androstenedione.

Most pediatricians know this, but if the first menses (menarche) is very heavy, you have to think of a bleeding disorder. This is an important diagnostic sign that additional work-up is warranted, and early intervention may be possible. If there is a bleeding disorder, early diagnosis could mean a lesser chance of hemorrhage during childbirth. Awareness among pediatricians is important because young girls rarely see gynecologists.

Classic DUB is related to menstrual cycle irregularities. There is a cohort of eggs recruited in the first half of the cycle (follicular phase). One follicle emerges that will rupture and release the egg at midcycle after luteinizing hormone levels spike in the body. If this sequence does not occur, the menstrual cycle is affected. The endometrial lining has proliferated under the effect of estrogen, and unsynchronized shedding with irregular bleeding occurs.

Again, you can take control of the menstrual cycle with birth control pills.

pdnews@elsevier.com

Stress is nothing new to American families, who—over the generations—have endured wars, epidemics, natural disasters, and numerous economic downturns.

Today's dismal economic climate with continuing unemployment poses real challenges for families.

You should be especially attuned to warning signs that more children in your practice may be at risk for hunger, displacement from their homes and schools, and poverty-associated trauma, both physical and psychological.

The statistics are sobering.

In June 2010, unemployment stood at 14.6 million people, or 9.5% of the working-age population nationwide. Even more people are jobless in some unfortunate states and cities—more than 14% in Nevada, for instance; 14.5% in Las Vegas, Nev.; and 27.6% in tiny El Centro, Calif.

Homelessness among American families is growing, with 170,000 families seeking shelter in 2009, up from 159,000 the year before, according to the U.S. Department of Housing and Urban Development.

Every 3 months, another 250,000 families' homes enter foreclosure, putting one child in every classroom at risk of losing his or her home, according to the Mortgage Bankers Association. That statistic is so stunning—home foreclosures impacting one child in every classroom—that it bears repeating as it indicates every pediatric practice has more red flags in terms of psychosocial stressors then at any time in most pediatrician's career.

Families, as always, face crises unrelated to the economy as well: illness, marital discord, substance abuse, and intergenerational pressures, but economic downturns increase the prevalence of almost all of the crises on this list.

Poverty is the elephant in the room, exposing children to a host of contributors to an unstable environment that sets the stage for poor academic performance, increased mental health disorders, conduct problems, substance abuse, and difficulties in relationships.

The first red flag raised by a family in economic trouble probably isn't even seen in the examining room, but in your billing department, where reimbursements are likely down and delinquent accounts are likely up.

A family may be unable to produce a copay for a visit, or may have lost health insurance along with mom or dad's job. They may report multiple changes in their address. Mail from your office may be returned as undeliverable.

This is, of course, an economic problem for you and your practice, but it likely heralds medical and psychosocial problems as well. A child whose family cannot pay for your services may be twice as likely as a financially secure child to have depression, anxiety, and learning problems at school.

Your office staff may want to alert you to financial red flags not only as they appear on the office balance sheet, but as they relate to your care of the child as well.

Moving, for example, has many implications for a child's development and well-being.

A new address may mean changes in a child's school and after-school activities, the loss of friends and close access to extended family members, and a shattering of the security of familiar places and routines. If the move was involuntary, say, a forced exit from a foreclosed home, parents may be so distracted and emotionally spent, they may not have devoted time to calmly explaining to the child what will change and what will stay the same.

I always think it's a good idea, but especially so in hard times, for you to ask one screening question of every family during routine office visits.

That bushel basket question is, “Are there any ongoing tensions affecting the family?”

Answers can potentially cover a lot of ground, and may open the door to a family sharing financial concerns, as well as any other issues that may be troubling them: a recent move, concern about a family member, or signs of domestic strife.

Red flags may appear during your examination as well. Immunizations may not be up to date, problems are suddenly arising at school, or a there may be a change in trajectory of the child's weight curve due to a lack of nutritious food.

Fatigue and stress associated with family troubles may be cloaked in somatic diagnoses: headaches, stomachaches, chest pain, weakness, or dizziness in a child who never had such complaints before or where these symptoms previously have signaled stress.

Take a good look at the parent accompanying your patient as well. Does the mother or father seem more withdrawn, sadder, or more anxious than expected?

Often, you have an internal red flag, a vaguely unsettled feeling that something is not right. Do not underestimate the value of this clinical sixth sense. Listen to it. It may not be anything specific that you can put your finger on or diagnose, but if you're getting that signal from within, sit down and take the pulse of the family in these troubling times.

pdnews@elsevier.com

Stress is nothing new to American families, who—over the generations—have endured wars, epidemics, natural disasters, and numerous economic downturns.

Today's dismal economic climate with continuing unemployment poses real challenges for families.

You should be especially attuned to warning signs that more children in your practice may be at risk for hunger, displacement from their homes and schools, and poverty-associated trauma, both physical and psychological.

The statistics are sobering.

In June 2010, unemployment stood at 14.6 million people, or 9.5% of the working-age population nationwide. Even more people are jobless in some unfortunate states and cities—more than 14% in Nevada, for instance; 14.5% in Las Vegas, Nev.; and 27.6% in tiny El Centro, Calif.

Homelessness among American families is growing, with 170,000 families seeking shelter in 2009, up from 159,000 the year before, according to the U.S. Department of Housing and Urban Development.

Every 3 months, another 250,000 families' homes enter foreclosure, putting one child in every classroom at risk of losing his or her home, according to the Mortgage Bankers Association. That statistic is so stunning—home foreclosures impacting one child in every classroom—that it bears repeating as it indicates every pediatric practice has more red flags in terms of psychosocial stressors then at any time in most pediatrician's career.

Families, as always, face crises unrelated to the economy as well: illness, marital discord, substance abuse, and intergenerational pressures, but economic downturns increase the prevalence of almost all of the crises on this list.

Poverty is the elephant in the room, exposing children to a host of contributors to an unstable environment that sets the stage for poor academic performance, increased mental health disorders, conduct problems, substance abuse, and difficulties in relationships.

The first red flag raised by a family in economic trouble probably isn't even seen in the examining room, but in your billing department, where reimbursements are likely down and delinquent accounts are likely up.

A family may be unable to produce a copay for a visit, or may have lost health insurance along with mom or dad's job. They may report multiple changes in their address. Mail from your office may be returned as undeliverable.

This is, of course, an economic problem for you and your practice, but it likely heralds medical and psychosocial problems as well. A child whose family cannot pay for your services may be twice as likely as a financially secure child to have depression, anxiety, and learning problems at school.

Your office staff may want to alert you to financial red flags not only as they appear on the office balance sheet, but as they relate to your care of the child as well.

Moving, for example, has many implications for a child's development and well-being.

A new address may mean changes in a child's school and after-school activities, the loss of friends and close access to extended family members, and a shattering of the security of familiar places and routines. If the move was involuntary, say, a forced exit from a foreclosed home, parents may be so distracted and emotionally spent, they may not have devoted time to calmly explaining to the child what will change and what will stay the same.

I always think it's a good idea, but especially so in hard times, for you to ask one screening question of every family during routine office visits.

That bushel basket question is, “Are there any ongoing tensions affecting the family?”

Answers can potentially cover a lot of ground, and may open the door to a family sharing financial concerns, as well as any other issues that may be troubling them: a recent move, concern about a family member, or signs of domestic strife.

Red flags may appear during your examination as well. Immunizations may not be up to date, problems are suddenly arising at school, or a there may be a change in trajectory of the child's weight curve due to a lack of nutritious food.

Fatigue and stress associated with family troubles may be cloaked in somatic diagnoses: headaches, stomachaches, chest pain, weakness, or dizziness in a child who never had such complaints before or where these symptoms previously have signaled stress.

Take a good look at the parent accompanying your patient as well. Does the mother or father seem more withdrawn, sadder, or more anxious than expected?

Often, you have an internal red flag, a vaguely unsettled feeling that something is not right. Do not underestimate the value of this clinical sixth sense. Listen to it. It may not be anything specific that you can put your finger on or diagnose, but if you're getting that signal from within, sit down and take the pulse of the family in these troubling times.

pdnews@elsevier.com

Stress is nothing new to American families, who—over the generations—have endured wars, epidemics, natural disasters, and numerous economic downturns.

Today's dismal economic climate with continuing unemployment poses real challenges for families.

You should be especially attuned to warning signs that more children in your practice may be at risk for hunger, displacement from their homes and schools, and poverty-associated trauma, both physical and psychological.

The statistics are sobering.

In June 2010, unemployment stood at 14.6 million people, or 9.5% of the working-age population nationwide. Even more people are jobless in some unfortunate states and cities—more than 14% in Nevada, for instance; 14.5% in Las Vegas, Nev.; and 27.6% in tiny El Centro, Calif.

Homelessness among American families is growing, with 170,000 families seeking shelter in 2009, up from 159,000 the year before, according to the U.S. Department of Housing and Urban Development.

Every 3 months, another 250,000 families' homes enter foreclosure, putting one child in every classroom at risk of losing his or her home, according to the Mortgage Bankers Association. That statistic is so stunning—home foreclosures impacting one child in every classroom—that it bears repeating as it indicates every pediatric practice has more red flags in terms of psychosocial stressors then at any time in most pediatrician's career.

Families, as always, face crises unrelated to the economy as well: illness, marital discord, substance abuse, and intergenerational pressures, but economic downturns increase the prevalence of almost all of the crises on this list.

Poverty is the elephant in the room, exposing children to a host of contributors to an unstable environment that sets the stage for poor academic performance, increased mental health disorders, conduct problems, substance abuse, and difficulties in relationships.

The first red flag raised by a family in economic trouble probably isn't even seen in the examining room, but in your billing department, where reimbursements are likely down and delinquent accounts are likely up.

A family may be unable to produce a copay for a visit, or may have lost health insurance along with mom or dad's job. They may report multiple changes in their address. Mail from your office may be returned as undeliverable.

This is, of course, an economic problem for you and your practice, but it likely heralds medical and psychosocial problems as well. A child whose family cannot pay for your services may be twice as likely as a financially secure child to have depression, anxiety, and learning problems at school.

Your office staff may want to alert you to financial red flags not only as they appear on the office balance sheet, but as they relate to your care of the child as well.

Moving, for example, has many implications for a child's development and well-being.

A new address may mean changes in a child's school and after-school activities, the loss of friends and close access to extended family members, and a shattering of the security of familiar places and routines. If the move was involuntary, say, a forced exit from a foreclosed home, parents may be so distracted and emotionally spent, they may not have devoted time to calmly explaining to the child what will change and what will stay the same.

I always think it's a good idea, but especially so in hard times, for you to ask one screening question of every family during routine office visits.

That bushel basket question is, “Are there any ongoing tensions affecting the family?”

Answers can potentially cover a lot of ground, and may open the door to a family sharing financial concerns, as well as any other issues that may be troubling them: a recent move, concern about a family member, or signs of domestic strife.

Red flags may appear during your examination as well. Immunizations may not be up to date, problems are suddenly arising at school, or a there may be a change in trajectory of the child's weight curve due to a lack of nutritious food.

Fatigue and stress associated with family troubles may be cloaked in somatic diagnoses: headaches, stomachaches, chest pain, weakness, or dizziness in a child who never had such complaints before or where these symptoms previously have signaled stress.

Take a good look at the parent accompanying your patient as well. Does the mother or father seem more withdrawn, sadder, or more anxious than expected?

Often, you have an internal red flag, a vaguely unsettled feeling that something is not right. Do not underestimate the value of this clinical sixth sense. Listen to it. It may not be anything specific that you can put your finger on or diagnose, but if you're getting that signal from within, sit down and take the pulse of the family in these troubling times.

The results of a new Journal of General Internal Medicine study that associates a 10% increase in medication-error-related deaths in teaching hospitals in July should not be ignored by hospitalists, says an associate residency program director.

Majid E. Cina, MD, FACP, a hospitalist and associate director at the University of Maryland School of Medicine in Baltimore, says the implication is that errors made by new medical interns are responsible for the spike, but HM leaders in academic settings shouldn’t draw too solid a conclusion. The spike could be tied to interns across a variety of departments, or the result of a series of other factors outside the scope of researchers.

“Correlations made by such studies are inherently flawed, with no certain cause-effect relationship established despite all attempts to control variables,” Dr. Cina says. “Still, these data cannot be ignored. ... Program directors should take heed.”

Researchers reported that inside medical institutions, in counties containing teaching hospitals, fatal medication errors spiked 10% in July and in no other month (JR=1.10; [1.06-1.14]) (J Gen Intern Med. 2010 Aug;25(8):774-779). Counties without teaching hospitals in the region had no spikes, and the greater the concentration of teaching hospitals in a region, the greater the July spike (R=0.80; P=0.005).

“After assessing competing explanations, we concluded that the July mortality spike results at least partly from changes associated with the arrival of new medical residents,” the study authors wrote.

Dr. Cina says his institution prioritizes the care of patients in July. Additional staff is put in place at the beginning of internships, which start a week early to allow for a smooth transition period. Senior staff also work longer hours in July, in close contact with residents on “a steep learning curve,” he says. “I recognized my work days will be much longer in July,” Dr. Cina adds.

As an academic hospitalist, Dr. Cina noted that new rules proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident work hours might help mitigate medication-error-related deaths. Those regulations could go into effect in July 2011.

The results of a new Journal of General Internal Medicine study that associates a 10% increase in medication-error-related deaths in teaching hospitals in July should not be ignored by hospitalists, says an associate residency program director.

Majid E. Cina, MD, FACP, a hospitalist and associate director at the University of Maryland School of Medicine in Baltimore, says the implication is that errors made by new medical interns are responsible for the spike, but HM leaders in academic settings shouldn’t draw too solid a conclusion. The spike could be tied to interns across a variety of departments, or the result of a series of other factors outside the scope of researchers.

“Correlations made by such studies are inherently flawed, with no certain cause-effect relationship established despite all attempts to control variables,” Dr. Cina says. “Still, these data cannot be ignored. ... Program directors should take heed.”

Researchers reported that inside medical institutions, in counties containing teaching hospitals, fatal medication errors spiked 10% in July and in no other month (JR=1.10; [1.06-1.14]) (J Gen Intern Med. 2010 Aug;25(8):774-779). Counties without teaching hospitals in the region had no spikes, and the greater the concentration of teaching hospitals in a region, the greater the July spike (R=0.80; P=0.005).

“After assessing competing explanations, we concluded that the July mortality spike results at least partly from changes associated with the arrival of new medical residents,” the study authors wrote.

Dr. Cina says his institution prioritizes the care of patients in July. Additional staff is put in place at the beginning of internships, which start a week early to allow for a smooth transition period. Senior staff also work longer hours in July, in close contact with residents on “a steep learning curve,” he says. “I recognized my work days will be much longer in July,” Dr. Cina adds.

As an academic hospitalist, Dr. Cina noted that new rules proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident work hours might help mitigate medication-error-related deaths. Those regulations could go into effect in July 2011.

The results of a new Journal of General Internal Medicine study that associates a 10% increase in medication-error-related deaths in teaching hospitals in July should not be ignored by hospitalists, says an associate residency program director.

Majid E. Cina, MD, FACP, a hospitalist and associate director at the University of Maryland School of Medicine in Baltimore, says the implication is that errors made by new medical interns are responsible for the spike, but HM leaders in academic settings shouldn’t draw too solid a conclusion. The spike could be tied to interns across a variety of departments, or the result of a series of other factors outside the scope of researchers.

“Correlations made by such studies are inherently flawed, with no certain cause-effect relationship established despite all attempts to control variables,” Dr. Cina says. “Still, these data cannot be ignored. ... Program directors should take heed.”

Researchers reported that inside medical institutions, in counties containing teaching hospitals, fatal medication errors spiked 10% in July and in no other month (JR=1.10; [1.06-1.14]) (J Gen Intern Med. 2010 Aug;25(8):774-779). Counties without teaching hospitals in the region had no spikes, and the greater the concentration of teaching hospitals in a region, the greater the July spike (R=0.80; P=0.005).

“After assessing competing explanations, we concluded that the July mortality spike results at least partly from changes associated with the arrival of new medical residents,” the study authors wrote.

Dr. Cina says his institution prioritizes the care of patients in July. Additional staff is put in place at the beginning of internships, which start a week early to allow for a smooth transition period. Senior staff also work longer hours in July, in close contact with residents on “a steep learning curve,” he says. “I recognized my work days will be much longer in July,” Dr. Cina adds.

As an academic hospitalist, Dr. Cina noted that new rules proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident work hours might help mitigate medication-error-related deaths. Those regulations could go into effect in July 2011.