Steroid-Induced Osteoporosis; Symptoms, Treatment

Steroid-Induced Osteoporosisis








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Steroid-Induced Osteoporosis is osteoporosis arising due to use of glucocorticoids (steroid hormones) – analogous to Cushing’s syndrome and involving mainly the axial skeleton. The synthetic glucocorticoid prescription drug prednisone is a main candidate after prolonged intake. Bisphosphonates are beneficial in reducing the risk of vertebral fractures.[rx] Some professional guidelines recommend prophylactic calcium and vitamin D supplementation in patients who take the equivalent of more than 30 mg hydrocortisone (7.5 mg of prednisolone), especially when this is in excess of three months.[rx][rx] The use of thiazide diuretics and gonadal hormone replacement has also been recommended, with the use of calcitonin, bisphosphonates, sodium fluoride or anabolic steroids also suggested in refractory cases.[rx] Alternate day use may not prevent this complication.[rx]

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor[rx] that is present in almost every vertebrate animal cell. The name “glucocorticoid” is a portmanteau (glucose + cortex + steroid) and is composed of its role in the regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid.

Causes of osteoporosis

A number of risk factors have been identified that raise the likelihood of getting osteoporosis – some of these are modifiable (something you can do something about) while others cannot be avoided.

Non-modifiable risk factors for osteoporosis include

Age-Related
  • Each decade beyond the fourth decade is a 1.5-fold risk
  • Reduction in the absorption of calcium
  • The rise in parathyroid hormone levels
  • Decline in calcitonin
Genetic
  • White, Asian, Latino, and black (in order of risk potential)
  • Women more than men
  • Familial prevalence
  • High concordance in monozygotic twins
Nutritional
  • Low calcium intake
  • High alcohol
  • High caffeine
  • High sodium
  • High animal protein
Lifestyle
  • Cigarette use
  • Low physical activity
Endocrine
  • Menopausal age
  • Obesity
  • Exercise-induced amenorrhea
  • Ethnicity – the risk is higher in white people and Asians
  • Bone structure – the risk is higher in those with small bone structure
  • Genetics – risk is higher if there is osteoporosis in the family, especially if a parent or sibling has the disease, particularly if a parent has incurred a hip fracture
  • Fracture history – risk is higher in people with a previous fracture during a low-level injury, especially if this occurred after the age of 50.

Drug That Causes osteoporosis

  • Thyroid replacement therapy
  • Chronic lithium therapy
  • Chemotherapy (breast cancer or lymphoma)
  • Gonadotropin-releasing hormone
  • Chronic phosphate binding antacid use
  • Extended tetracycline use
  • Diuretics producing calciuria
  • Phenothiazine derivatives
  • Cyclosporin A

Secondary causes of osteoporosis (, )

Lifestyle changes Genetic diseases Endocrine disorders Other
Vitamin D insufficiency Cystic fibrosis Central obesity AIDS/HIV
High salt intake Glycogen storage diseases Cushing’s syndrome Amyloidosis
Smoking (active or passive) Menkes steely hair syndrome Diabetes mellitus (types 1 and 2) Chronic obstructive lung disease
Alcohol abuse Osteogenesis imperfecta Hyperparathyroidism Congestive heart failure
Immobilizatıon Riley–Day syndrome Thyrotoxicosis Chronic metabolic acidosis
Excessive thinness Ehler Danlos Hypogonadal states: Depression
Frequent falling Hemochromatosis Androgen insensitivity End-stage renal disease
Low calcium intake Marfan syndrome Athletic amenorrhea Hypercalciuria
Inadequate physical activity Parental history of hip fracture Premature menopause (<40 years) Post-transplant bone disease
Excess vitamin A Gaucher’s disease Hyperprolactinemia Idiopathic scoliosis
Homocystinuria Panhypopituitarism Sarcoidosis
Hypophosphatasia Anorexia nervosa Weight loss
Porphyria Turner’s and Klinefelter’s syndromes
Gastrointestinal disorders Hematological disorders Neurological and musculoskeletal factors Rheumatologic and autoimmune diseases
Celiac disease Hemophilia Epilepsy Ankylosing spondylitis
Gastric bypass Leukemia and lymphomas Multiple sclerosis Systemic lupus
Gastrointestinal surgery Sickle cell disease Muscular dystrophy Rheumatoid arthritis
Malabsorption Multiple myeloma Parkinson’s disease Systemic lupus
Inflammatory bowel disease Monoclonal gammopathies Spinal cord injury Other rheumatic and autoimmune diseases
Pancreatic disease Systemic mastocytosis Stroke
Primary biliary cirrhosis Thalassemia Proximal myopathy
Medications
Endocrinological Abnormalities Glucocorticoid excess, hyperthyroidism, hypogonadism (androgen insensitivity, Turner’s and Klinefelter’s Syndrome, hyperprolactinemia, premature menopause), anorexia, athlete triad, vitamin D deficiency, hyperparathyroidism, Diabetes Mellitus (Types 1 and 2)
Cardiovascular, Renal, Pulmonary and Miscellaneous Disorders Chronic kidney disease, post-transplant bone disease, congestive heart failure, chronic obstructive lung disease, AIDS/HIV
Connective Tissue Disorders Osteogenesis Imperfecta, Ehlers-Danlos syndrome, Marfan Syndrome, ankylosing spondylitis,
Gastrointestinal Diseases Celiac sprue, Inflammatory bowel disease, post-gastrectomy, primary biliary cirrhosis, bariatric surgery
Hematological Disorders Multiple myeloma, mastocytosis, leukemia. Hemophilia, sickle cell disease, leukemia, lymphoma, Thalassemia
Other Genetic Disorders Homocystinuria, Cystic fibrosis, Hemochromatosis, Hypophosphatasia
Rheumatological Disorders Ankylosing spondylitis, rheumatoid arthritis
Medications Aromatase inhibitors, heparin (long-term), anticonvulsants, methotrexate, Cytoxan, gonadotropin-releasing hormone (GnRH) agonists and antagonists, tamoxifen (in premenopausal women), excess thyroid hormone, lithium, cyclosporine A, tacrolimus, glucocorticoids, thiazolidinediones, depo-medroxyprogesterone (premenopausal women) proton-pump inhibitors, selective serotonin reuptake inhibitors (SSRIs), tenofovir

Risk factors for osteoporosis

  • Reduced sex hormones, particularly in women (less estrogen after the menopause, for example)
  • Anorexia nervosa and bulimia (eating disorders), and orthorexia
  • Tobacco smoking
  • Excessive alcohol intake
  • Reduced calcium, magnesium and vitamin D status (caused by low dietary intake, malabsorption, and the use of some medications)
  • Inactivity or immobility (weight-bearing exercise that places a degree of stress on the bones is needed for bone growth).
Age
Sex
Low body mass index (≤19 kg/m2)
Previous fragility fracture, particularly of the hip, wrist and spine including morphometric vertebral fracture
Secondary causes of osteoporosis including:
Parental history of hip fracture
Current glucocorticoid treatment (any dose, by mouth for three months or more)
Current smoking Alcohol intake of three or more units daily
Rheumatoid arthritis
Untreated hypogonadism in men and women
Prolonged immobility
Organ transplantation
Type I diabetes
Hyperthyroidism
Gastrointestinal disease
Chronic liver disease
Chronic obstructive pulmonary disease
Frequent falling

Other factors that increase the risk of osteoporosis include diseases or drugs that cause changes in hormone levels and drugs that reduce bone mass. Diseases that affect hormone levels include hyperthyroidism, hyperparathyroidism and Cushing’s disease.

People who are transgender and who undergo surgery that affects hormone levels, or who take hormones for long periods of time may also face a higher risk of osteoporosis.10 Some autoimmune diseases, such as Rheumatoid arthritis and ankylosing spondylitis, are also associated with an increased risk of osteoporosis.

Medications that increase the risk of osteoporosis include

  • Glucocorticoids and corticosteroids, including prednisone (Deltasone, Orasone, for example) and prednisolone (Prelone) – glucocorticoid-induced osteoporosis is the most common type of drug-induced osteoporosis
  • Excess thyroid hormone replacement
  • Anticoagulants and blood-thinners (including heparin and warfarin)
  • Protein-pump inhibitors and other antacids that adversely affect the mineral status
  • Some antidepressant medications
  • Some vitamin A (retinoid) medications
  • Thiazolidinediones (used to treat type 2 diabetes), which decrease bone formation
  • Some immunosuppressant agents, such as cyclosporine, which increase both bone resorption and formation
  • Aromatase inhibitors and other treatments that deplete sex hormones, such as anastrozole (Arimidex)
  • Some chemotherapeutic agents, including letrozole (Femara), which is used against breast cancer, and leuprorelin (Lupron) for prostate cancer (and other conditions).

Recent developments on causes of osteoporosis

Glucocorticoid-Induced Osteoporosis
www.rxharun.com

 Risk factors

A number of factors can increase the likelihood that you’ll develop osteoporosis — including your age, race, lifestyle choices, and medical conditions and treatments.

  • Your sex – Women are much more likely to develop osteoporosis than are men.
  • Age – The older you get, the greater your risk of osteoporosis.
  • Race – You’re at greatest risk of osteoporosis if you’re white or of Asian descent.
  • Family history – Having a parent or sibling with osteoporosis puts you at greater risk, especially if your mother or father experienced a hip fracture.
  • Body frame size – Men and women who have small body frames tend to have a higher risk because they may have less bone mass to draw from as they age.
  • A 50-year-old current smoker with a body mass index (BMI) less than 21 kg/m 2, daily alcohol use, and parental fracture history
  • A 55-year-old woman with a parental fracture history
  • A 60-year-old woman with a BMI of less than 21 kg/m 2 and daily alcohol use
  • A 60-year-old current smoker with daily alcohol use

Assessment of fracture risk

A thorough history should be obtained to screen for and identify the presence of known risk factors for osteoporosis and osteoporotic fracture. Specifically, history should focus on the following  :

  • Age (>50 years), sex (female), and race (white or Asian)  the US Preventive Services Task Force (USPSTF) recommendations include screening for osteoporosis in women aged 65 years or older and in younger women with a fracture risk that is the same or greater than that of a 65-year-old white woman who has no additional risk factors
  • The family history of osteoporosis, particularly the maternal history of fractures
  • Reproductive factors, especially regarding early menopause and estrogen replacement therapy: postmenopausal women are at high risk, as are women who have undergone hysterectomy and oophorectomy
  • Hypogonadal states: men with hypogonadism secondary to any genetic or other conditions are at higher risk  the USPSTF notes that there is insufficient current evidence to assess the risk versus benefit of screening for osteoporosis in men
  • Smoking: smokers are at higher risk
  • Alcohol consumption
  • Low levels of physical activity: immobility increases the risk of spinal cord injury and stroke cause physical impairment and are common causes of immobility
  • Strenuous exercise that results in amenorrhea (such as that which occurs in marathon runners)
  • Calcium and vitamin D intake
  • History of low-trauma “fragility” fracture in patients aged 40 years or older: a fragility fracture is defined as a fracture due to trauma that would not normally cause fracture (a force equal to or less than that resulting from a fall from standing height)
  • Signs of vertebral fracture (see below)
  • Coexisting medical conditions associated with bone loss
  • Medications associated with bone loss
  • Risk factors for falls in older patients: these include poor balance, orthostatic hypotension, weakness of the lower extremity muscles and deconditioning, use of medications with sedative effects, poor vision or hearing, and cognitive impairment

Although the USPSTF did not find any studies that assessed effects of the use of risk prediction instruments on patient outcomes, either alone or in combination with bone measurement tests, there are many validated instruments for predicting the risk for low bone mineral density (BMD) in postmenopausal women; few of these, however, have been validated for use in men.  White women between the ages of 50 and 64 years with ≥10-year fracture risks based on specific risk factors include the following persons.

Differentiating fracture types by history

  • Patients with acute insufficiency fractures may report a history of minimal or no trauma resulting in pain. They may report a fall from a standing or sitting position. Patients with compression fractures resulting in thoracic kyphosis may report iliocostal friction with an associated abdominal protrusion, decreased tolerance for oral intake, and breathing difficulties. Patients with hip, pelvic, or sacral fractures may report pain that is worsened with weight-bearing.
  • Patients who have sustained a vertebral compression fracture may note progressive kyphosis with loss of height. They may also present with an episode of acute back pain after bending, lifting, or coughing. It should be noted, however, that two-thirds of vertebral fractures are asymptomatic.

With respect to those vertebral fractures that are painful, typical subjective information may include the following

  • The episode of acute pain may follow a fall or minor trauma
  • Pain is localized to a specific, identifiable, vertebral level in the midthoracic to lower thoracic or upper lumbar spine
  • The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain; in some cases, pain radiates to the abdomen
  • Pain is often accompanied by paravertebral muscle spasms exacerbated by activity and decreased by lying supine
  • Patients often remain motionless in bed because of fear of causing an exacerbation of pain
  • Acute pain usually resolves after 4-6 weeks; in the setting of multiple fractures with severe kyphosis, the pain may become chronic

Patients who have sustained a hip fracture may experience the following:

  • Pain in the groin, posterior buttock, anterior thigh, medial thigh, and/or medial knee during weight-bearing or attempted weight-bearing of the involved extremity
  • Diminished hip range of motion (ROM), particularly internal rotation and flexion
  • External rotation of the involved hip while in the resting position

Symptoms of osteoporosis

Osteoporosis generally does not become clinically apparent until a fracture occurs. Two-thirds of vertebral fractures are painless. Typical findings in patients with painful vertebral fractures may include the following:

  • The episode of acute pain may follow a fall or minor trauma
  • Pain is localized to a specific, identifiable, vertebral level in the midthoracic to lower thoracic or upper lumbar spine
  • The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain; in some cases, pain radiates to the abdomen
  • Pain is often accompanied by paravertebral muscle spasms exacerbated by activity and decreased by lying supine
  • Patients often remain motionless in bed because of fear of causing an exacerbation of pain
  • Acute pain usually resolves after 4-6 weeks; in the setting of multiple fractures with severe kyphosis, the pain may become chronic

Patients who have sustained a hip fracture may experience the following:

  • Pain in the groin, posterior buttock, anterior thigh, medial thigh, and/or medial knee during weight-bearing or attempted weight-bearing of the involved extremity
  • Diminished hip range of motion (ROM), particularly internal rotation and flexion
  • External rotation of the involved hip while in the resting position

On physical examination, patients with vertebral compression fractures may demonstrate the following:

  • With acute vertebral fractures, point tenderness over the involved vertebra
  • Thoracic kyphosis with an exaggerated cervical lordosis (dowager hump)
  • The subsequent loss of lumbar lordosis
  • A decrease in height of 2-3 cm after each vertebral compression fracture and progressive kyphosis

Patients with hip fractures may demonstrate the following:

  • Limited ROM with end-range pain on a FABER (flexion in the abduction and external rotation) hip joint test
  • Decreased weight-bearing on the fractured side or an antalgic gait pattern

Patients with Colles fractures may have the following:

  • Pain on movement of the wrist
  • Dinner fork (bayonet) deformity

Patients with pubic and sacral fractures may have the following

  • Marked pain with ambulation
  • Tenderness to palpation, percussion, or both
  • With sacral fractures, pain with physical examination techniques used to assess the sacroiliac joint (eg, FABER, Gaenslen, or squish test)

Balance difficulties may be evident, especially in patients with an altered center of gravity from severe kyphosis. Patients may have difficulty performing tandem gait and performing single limb stance.

Tests and Diagnosis of Osteoporosis

Laboratory Tests

  • Complete blood cell count
  • Sedimentation rate
  • Electrolytes
  • Creatinine
  • Blood urea nitrogen
  • Calcium
  • Phosphorus
  • Protein
  • Albumin
  • Alkaline phosphatase
  • Liver enzymes
  • 24-hour urine calcium
  • Serum protein electrophoresis
Biochemical Markers of Bone Formation and Resorption
Bone Formation
  • Osteocalcin
  • Bone-specific alkaline phosphatase
  • Procollagen extension peptides
Bone Resorption
  • Tartrate-resistant acid phosphatase
  • Urinary calcium
  • Urinary hydroxyproline
  • Urinary hydroxyproline/creatinine ratio
  • Urinary pyridinoline/deoxypyridinoline
  • Urinary N-telopeptide

Osteoporosis may be diagnosed directly through the use of a bone scan that measures bone mineral density (BMD).

  • X-ray technology is used for bone density scanning, also known as a bone mineral density test, dual-energy X-ray absorptiometry (DXA for short) and bone densitometry.
  • In combination with the determination of a patient’s risk factors, DXA offers an indication of the likelihood of fractures occurring due to osteoporosis. This test is also used to monitor response to treatment.
  • International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group evaluated BTMs in the prediction of fracture risk and for monitoring treatment; it was recommended that bone formation markers (s-PINP) and bone resorption markers (s-CTX) should be used as reference markers and measured by standardized assays in observational and intervention studies [.

Following studies are necessary to rule out secondary osteoporosis [

  • Complete blood count (CBC)
  • Serum creatinine, calcium, phosphorus, and magnesium
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP)
  • Thyroid-stimulating hormone (TSH) and free T4
  • Vitamin D (V-D) (25 (OH) D)
  • Parathyroid hormone (PTH)
  • Total testosterone and gonadotropin in younger men
  • BTMs

Considered in select patients

Serum protein electrophoresis (SPEP), serum immunofixation, and serum-free light chains

  • Tissue transglutaminase antibodies (IgA and IgG)
  • Iron and ferritin levels
  • Homocysteine
  • Prolactin
  • Tryptase
  • 24-h urinary calcium
  • Urinary protein electrophoresis (UPEP)
  • Urinary-free cortisol level
  • Urinary histamine

Two types of device are available for a DXA scan

  • Central device – a hospital-based scan that measures hip and spine bone mineral density while the patient lies on a table
  • Peripheral device – a mobile machine to test bone in the wrist, heel or finger.
  • Two X-ray readings are taken to ascertain bone density – one to detect peak energy absorbed by the bone and another for the energy absorbed by soft tissue – the difference between the two gives a measurement of bone density. The risk of side-effects from this low-dose X-ray radiation is small.
  • The results of the bone mineral density test are given as a DXA T-score; -1.0 or above is considered normal, while a DXA T-score between -1.0 and -2.5 represents a mild bone loss.

Osteoporosis is diagnosed when the T-score is -2.5 or below.

After DXA, the second most common testing option in the US does not involve radiation: quantitative ultrasonography of the calcaneus (heel bone) uses ultrasound and can be carried out in the primary care setting. It is not as widely used as DXA, however, and the measurements cannot be compared against DXA T-scores.

Treatment

Non-pharmacological treatments such as exercise, good nutrition, smoking cessation, and avoiding alcohol abuse are recommended for all adults taking GCs. Because there is insufficient evidence for the effects of these treatments in GIOP, it is recommended that treatment be based on data from these treatments in postmenopausal osteoporosis patients.

Glucocorticoid-Induced Osteoporosis

 

Prevention and treatment of systemic glucocorticoid side effects

Osteoporosis

Bone loss is one of the most common and debilitating side effects associated with prolonged high-dose glucocorticoid therapy []. Glucocorticoids reduce bone formation and increase bone resorption []. Bone loss associated with glucocorticoid therapy is most pronounced in the first few months after initiating treatment. A study showed that patients receiving high-dose glucocorticoid therapy (mean=21mg/day prednisone) lost a mean of 27% of their lumbar spine bone density during the first year of treatment []. The rate of bone loss slows considerably thereafter [, ] and bone density can increase after discontinuation of glucocorticoids []. The glucocorticoid-induced bone loss is dose-dependent and patients taking higher doses have significantly increased risk of bone loss relative to patients using glucocorticoids at lower doses [, ].

The prevention and treatment of glucocorticoid-induced bone loss include decreasing the dose of glucocorticoid, calcium and vitamin D supplementation, and pharmacologic therapy to prevent further bone loss or increase bone density []. The duration of glucocorticoid therapy and the glucocorticoid dose should be as low as possible because even low-dose glucocorticoid replacement therapy can decrease bone mineral density []. Alternative therapy with other medications is recommended. The published data on alternate-day glucocorticoid therapy suggests that this therapy can also produce osteoporosis []. Short-term high-dose pulse glucocorticoid therapy is preferred over continuous therapy with oral glucocorticoids []. In all individuals on glucocorticoid therapy, general principles include avoiding smoking and excess alcohol, weight-bearing exercises, and taking proper precautions to prevent falls. Multiple treatments have been introduced to prevent or treat bone loss and will be reviewed here.

Calcium and vitamin D


Calcium supplementation is recommended in all individuals treated with glucocorticoids because glucocorticoids decrease intestinal calcium absorption and increase renal calcium excretion. The American College of Rheumatology Ad Hoc Committee on Osteoporosis suggests that individuals receiving glucocorticoids maintain a calcium intake of 1000 to 1500 mg/day and vitamin D intake of 800 IU/day through either diet or supplements []. A study assessed the effects of calcium and vitamin D on bone density of patients with rheumatoid arthritis and the relation between this effect and low-dose glucocorticoid use []. A total of 96 patients with rheumatoid arthritis, 65 of whom receiving prednisone at a mean dosage of 5.6 mg/day, were randomly assigned to calcium carbonate (1000 mg/day) and vitamin D3 (500 IU/day) or placebo and followed for 2 years. Patients receiving prednisone therapy who were given placebo lost bone in the lumbar spine and trochanter at a rate of 2.0 and 0.9 percent per year, respectively, whereas patients receiving prednisone therapy who were given calcium and vitamin D3 gained bone in the lumbar spine and trochanter at a rate of 0.72 and 0.85 percent per year, respectively. In patients receiving prednisone therapy, bone density of the femoral neck did not increase with calcium and vitamin D3. Calcium and vitamin D3 did not improve bone density at any site in patients who were not receiving prednisone. Calcium and vitamin D is generally not sufficient to prevent bone loss in patients treated with high-dose glucocorticoids.

Active vitamin D metabolites

The data on the role of active vitamin D metabolites, such as calcitriol (1, 25-dihydroxy vitamin D), in the prevention of glucocorticoid-induced bone loss and fracture, is not sufficient. The combination of calcitriol and calcium protect against spine bone loss more than calcium alone in patients receiving glucocorticoids [, ]. Active vitamin D metabolites are associated with an increased risk for hypercalcemia and hypercalciuria in patients with an already increased rate of urinary calcium excretion [], and have been largely replaced by other safer and more effective available therapies [, ].

Bisphosphonates

Bisphosphonates are a class of drugs that are favorably used in the prevention and treatment of glucocorticoid-induced bone loss. The mechanism for the majority of the effects of these drugs is thought to be via their ability to prevent osteoclastic bone resorption []. Alendronate and risedronate are the most commonly used bisphosphonates in osteoporosis []. The bone density of the femoral neck, trochanter, and total body also increased significantly in the alendronate group. There were also proportionally fewer new vertebral fractures in the alendronate group than in the placebo group (2.3% vs. 3.7%). In a two-year randomized trial comparing once-weekly (70mg) and daily alendronate (10mg) in postmenopausal women, the once-weekly regimen is therapeutically as effective as daily dosing []. However, once-weekly administration of alendronate is more convenient for patients and can enhance their adherence to therapy. A decrease in the incidence of vertebral fractures by 70% was observed in the risedronate group in the later study.

Ibandronate is a newer and highly potent bisphosphonate and every three month IV ibandronate (2mg) has been shown to be efficacious and well-tolerated for prevention and treatment of glucocorticoid-induced osteoporosis [].

Other bisphosphonates used in the prevention and treatment of glucocorticoid-induced osteoporosis include pamidronate, zoledronic acid, etidronate, and clodronate. The efficacy of oral and intravenous pamidronate in preventing glucocorticoid-induced osteoporosis has been demonstrated []. Oral pamidronate is not available in the United States and intravenous infusions are very expensive. Intravenous bisphosphonates may be associated with flu-like symptoms and hypocalcemia. Flu-like symptoms can be prevented by acetaminophen. Hypocalcemia is more likely to occur in patients with vitamin D deficiency and can be prevented by calcium and vitamin D supplementation. Intravenous bisphosphonates are reasonable options in some patients who do not tolerate oral bisphosphonates. Zoledronic acid is one of the other IV bisphosphonates currently marketed in the United States. Etidronate has been largely replaced by alendronate and risedronate which are more potent. Clodronate, a novel drug used for inhibiting osteoclastic activity, has been shown to increase bone density in asthmatic patients treated with continuous oral and inhaled glucocorticoids []. Clodronate is not available in the United States. For further information regarding the dose and administration of bisphosphonates, [rx].

Bisphosphonates: Dosing, administration

Drug Name Dosing: Prevention Dosing: Treatment
Alendronate 5 mg/day (oral) 5 or 10 mg/day (oral)
35 mg once weekly (oral) 35 or 70 mg once weekly (oral)
Risedronate 5 mg/day (oral) 5 mg/day (oral)
35 mg once weekly (oral) 35 mg once weekly (oral)
150 mg once monthly (oral) 150 mg once monthly (oral)
Ibandronate 2.5 mg/day (oral) 2.5 mg/day (oral)
150 mg once a month (oral) 150 mg once a month (oral)
2–3 mg every three months (IV)
Pamidronate Single doses should not
exceed 90 mg (IV)
Single doses should not exceed
90 mg (IV)
Zoledronic acid 5 mg every 12 months (IV) 5 mg every 12 months (IV)

Bisphosphonates or active vitamin D metabolites?

Bisphosphonates are usually preferred over active vitamin D metabolites. In an 18-month trial in 201 patients with rheumatic diseases, who were randomly assigned to either alfacalcidol or alendronate, alendronate was more effective in the prevention of glucocorticoid-induced bone loss than was alfacalcidol. At 18 month, the absolute group difference in bone density was 4.0 percent [].

Hormone replacement

Glucocorticoid therapy reduces serum sex hormone levels due to its effect on the hypothalamic-hypophysial axis []. In a retrospective study of 15 postmenopausal or amenorrheic women taking glucocorticoids, bone density significantly increased in women treated with estrogen, while it decreased in women who didn’t receive estrogen []. However, considering its unfavorable risk-benefit profile, long-term hormone replacement therapy is no longer recommended as first-line therapy for the prevention of postmenopausal osteoporosis. American College of Rheumatology Ad Hoc Committee on Osteoporosis suggests that premenopausal women taking glucocorticoids who have menstrual irregularities receive an oral contraceptive when there is no contraindication []. However, there is no evidence to support estrogen therapy in premenopausal women with normal menstrual cycles.

Parathyroid hormone

The parathyroid hormone promotes both bone formation and resorption; however, intermittent administration promotes bone formation more than resorption. In a recent 18-month randomized, controlled trial, teriparatide (20 µg subcutaneously daily) was compared with alendronate (10 mg orally daily) in 428 women and men with osteoporosis who had received glucocorticoids for at least 3 months (5 mg or more of prednisone equivalent daily). Both treatments significantly increased lumbar spine bone density which was the primary outcome of the study. However, bone mineral density at the lumbar spine increased more in patients receiving teriparatide than in those receiving alendronate (7.2+/−0.7% vs. 3.4+/−0.7%, P<0.001) [].

Calcitonin

Calcitonin attenuates bone loss by directly reducing osteoclastic resorption. It also reduces the pain in patients who have pain-causing fractures. In a two-year prospective trial in 44 steroid-dependent asthmatic patients, patients were randomly treated with either salmon calcitonin nasal spray (200 IU every other day) or calcium alone []. Bone density in the calcitonin group increased by 2.7% in the first year, while in the group receiving calcium alone it decreased by 2.8%. Calcitonin maintained bone mass in a steady state during the second year, while bone loss continued in the calcium alone group. However, the lack of efficacy of calcitonin on the rate of vertebral or nonvertebral fractures does not permit its recommendation as a first-line therapy for the prevention or treatment of glucocorticoid-induced osteoporosis. Calcitonin can be considered in patients who cannot tolerate oral or intravenous bisphosphonates or when bisphosphonates are contraindicated. Due to its ability to reduce bone pain, calcitonin can also be considered in patients who have sustained an acute fracture.

Thiazide diuretics and dietary sodium restriction

Glucocorticoids cause hypercalciuria. Thiazides and dietary sodium restriction both reduce urinary calcium excretion and may have a favorable effect on calcium homeostasis in patients receiving glucocorticoids. A study investigating the effect of thiazide diuretics and dietary sodium restriction on calcium metabolism in patients taking glucocorticoids suggested that this regimen may have a beneficial effect on calcium balance in patients receiving glucocorticoids by decreasing the fractional excretion of calcium and increasing intestinal calcium absorption []. However, their effect on bone density is uncertain. A meta-analysis attempting to explore this uncertainty indicated that current thiazide users have a 20% reduction in osteoporotic fracture risk and that use of long-term thiazides may also reduce osteoporotic fracture risk by 20%, but short-term use has not been shown to be protective against osteoporotic fracture []. Thiazides and sodium restriction can be considered in patients with substantial hypercalciuria or hypertension.

The American College of Rheumatology recommendations for the prevention of glucocorticoid-induced osteoporosis []

Candidates for therapy:

  • Patients initiating glucocorticoids (prednisone equivalent of 5 mg/day or higher) with plans for treatment for more than three months
  • Patients taking long-term glucocorticoids (prednisone equivalent of 5 mg/day or higher)

Guidelines:

  • Modify lifestyle risk factors (avoiding smoking and excess alcohol, weight-bearing exercises).
  • Initiate Calcium (1000 to 1500 mg/day) and Vitamin D (800 IU/day) supplementation.
  • Prescribe bisphosphonates (use with caution in premenopausal women because of insufficient data on the potential for harm to the fetus in women who become pregnant while currently or recently receiving bisphosphonates).
  • Replace gonadal sex hormones if deficient.
  • Consider calcitonin as a second-line agent if bisphosphonates are contraindicated or not tolerated.
  • In patients on long-term glucocorticoids (prednisone equivalent of 5 mg/day or higher), measure bone mineral density (BMD) at the lumbar spine and/or hip at the initiation of glucocorticoid therapy. If T-score is below −1, then prescribe bisphosphonate or calcitonin. Repeat bone densitometry every year as long as glucocorticoid therapy continues.

Anabolic agents

Anabolic agents stimulate new bone formation beyond the filling in of remodeling space. Fluoride, (20 mg/day) an anabolic agent has been evaluated in SIOP. In a randomized controlled trial of CS treated patients (average prednisone dosage 1522 mg/day), sodium fluoride (50 mg/day) or placebo were given with calcium and VIT D supplementation. On comparison after two years in the fluoride group and placebo-treated group, the BMD of the femoral neck had increased by 2.2% and decreased by 3.8% respectively.[rx] Fluoride increases BMD at the lumbar spine but has no effect at the hip. Another anabolic agent is parathyroid hormone (PTH), which has been used in SIOP. Anabolic steroids are potentially useful agents in SIOP. For example, nandrolone decanoate showed increases in forearm bone mass, without significant masculinizing side effects.

Gonadal sex hormones

Patients receiving prolonged glucocorticoid therapy may develop hypogonadism due to inhibition of secretion of LH and FSH from the pituitary gland as well as the direct effect on hormone production by ovary and testis. All patients receiving steroids should be assessed for hypogonadism and if present; should be corrected if possible. In a trial of postmenopausal women with RA, who were taking prednisolone and were randomised to receive either HRT or placebo, those who had received HRT had a significant (3-4%) increase in the lumbar spine BMD compared with controls while there was no change in BMD at the femoral neck.[rx]

There is less information available regarding men with hypogonadism. A randomized cross over trial demonstrated the effectiveness of testosterone therapy in 15 men with glucocorticoid treated asthma.[rx] Lumbar spine BMD was significantly increased (4%) after 12 months of monthly intramuscular testosterone injection. Thus men with low serum levels of testosterone (<300 ng/ml) who are receiving CS should receive replacement therapy.[rx]

Myopathy

Glucocorticoids use can cause myopathy by the direct catabolic effect on skeletal muscle via activation of the glucocorticoid receptor []. Blockade of the glucocorticoid receptor has been shown to prevent myopathy in the rat []. Subjects with glucocorticoid-induced myopathy typically present with proximal muscle weakness and atrophy in both the upper and lower extremities. The onset of symptoms is usually subacute and over several weeks or months. Higher doses of glucocorticoids are associated with earlier onset of symptoms []. The diagnosis of glucocorticoid-induced myopathy is one of exclusion. The symptoms improve within three to four weeks after the reduction in glucocorticoid dose and resolve after discontinuation of glucocorticoids []. Moderate exercise has also been demonstrated to attenuate glucocorticoid-induced muscle atrophy [].

Teriparatide

Teriparatide (a recombinant PTH) has also been shown to reduce fracture risk–in fact, proving superior to alendronate in a comparison trial []. Another 2016 meta-analysis also found that teriparatide (as well as certain bisphosphonates) were associated with decreased vertebral fracture risk [].

Denosumab

Denosumab, a RANKL inhibitor, has also been considered for prevention of glucocorticoid-induced osteoporosis. Denosumab is given as a subcutaneous injection every six months, which may result in better adherence than oral bisphosphonate therapy []. However, data is more limited than that for use of bisphosphonates for GIO. Despite its proven efficacy in postmenopausal women [], there remain few studies specifically looking at GIO.

Teriparatide

Teriparatide (a recombinant PTH) has also been shown to reduce fracture risk–in fact, proving superior to alendronate in a comparison trial []. Another 2016 meta-analysis also found that teriparatide (as well as certain bisphosphonates) were associated with decreased vertebral fracture risk []. In theory, as glucocorticoids do have a suppressive effect on osteoblasts, teriparatide would be an appropriate countermeasure as an anabolic agent.

References

Glucocorticoid-Induced Osteoporosis

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