Drug-Induced Osteoporosis

US Pharm. 2006;12:HS3-HS6.

Osteoporosis is a disease characterized by low bone mass and deterioration of bone structure, which may lead to bone fragility and an increased susceptibility to fractures of the hip or spine, although any bone may be affected. An estimated 10 million Americans are affected by osteoporosis, while an additional 34 million have low bone mass, placing them at an increased risk for osteoporosis.¹ The National Osteoporosis Foundation estimates that osteoporosis results in 1.5 million fractures annually in the United States.¹ Osteoporosis can affect men and women of all ages; however, older women have a higher risk. Although there are no overt symptoms in the early stages of osteoporosis, in later stages, patients may experience height loss, change in posture, or pain secondary to a fracture. Osteoporosis typically results from an imbalance between osteoblasts (cells that build bone mass) and osteoclasts (cells that remove old bone).²

Osteoporosis is linked to aging and a lifelong low intake of calcium, low estrogen level (due to menopause or surgical ovary removal), hyperthyroidism, hypogonadism, and a family history of osteoporosis. Other well-known risk factors include cigarette smoking, excessive alcohol use, Caucasian race, and physical inactivity. However, what may be less familiar is the fact that certain medications can increase one's risk for osteoporosis. Thus, the aim of this article is to remind pharmacists of the drugs most commonly associated with osteoporosis, the mechanisms of bone loss, and possible drug alternatives to recommend in order to avoid this potentially debilitating condition.

Corticosteroids
The most common secondary cause of osteoporosis, and third most common cause overall, is systemic corticosteroid use.³ Glucocorticoids are widely used and are effective in treating many pulmonary, rheumatologic, gastrointestinal, dermatologic, and autoimmune conditions. The risk of bone loss is greatest within the first six to 12 months of long-term therapy and appears to be dose-dependent.^3,4 Many studies have evaluated the comorbidities associated with steroid-induced osteoporosis; an estimated 30% to 50% of patients taking systemic long-term steroids will eventually experience a fracture.³

Multiple factors lead to corticosteroid-induced bone loss. Glucocorticoids decrease bone formation by increasing osteoblast apoptosis and decreasing growth factors involved in regenerating bone, which include osteoprogestins and insulin-like growth factor-1.^4,5 Steroids also increase bone resorption secondary to decreased levels of gonadotropins (luteinizing hormone [LH], follicle-stimulating hormone [FSH], testosterone, and estrogen).^3,4 Lastly, steroids have been shown to induce a calcium deficiency by decreasing gastrointestinal absorption of calcium from the intestines and increasing renal excretion of calcium.^3,4 All of these factors have a role in the pathophysiology of steroid-induced osteoporosis; therefore, awareness of risks and prevention of bone loss are key aspects of any steroid treatment regimen.

If possible, using alternatives to long-term therapy is favorable to avoid not only osteoporosis but also the many other side effects of corticosteroids. Yet, this is not always possible, and the efficacy of corticosteroids in certain populations may far surpass that of other options. Measures should be taken to use steroids on a short-term basis if possible and to taper the dose or use other dosage forms, such as inhaled or topical regimens, to prevent systemic complications.⁵ Prevention of bone loss, which is very important in patients requiring systemic steroids, may be achieved by supplementation with calcium (1,200 to 1,500 mg/day) and vitamin D (400 to 800 units/day).

Patients taking chronic steroids should also receive a bisphosphonate, such as alendronate or risedronate.⁶ Both drugs are FDA approved for prevention and treatment of corticosteroid-induced osteoporosis. Bisphosphonates inhibit osteoclast activity and reduce bone resorption. For prevention of steroid-induced osteoporosis, the dosage is identical at either 5 mg once daily or 35 mg once weekly. For all bisphosphonates, it is important to counsel patients on dosage to prevent gastrointestinal side effects and promote efficacy. These medications should be taken on an empty stomach, first thing in the morning, with 8 ounces of water. After taking alendronate or risedronate, patients should remain sitting or standing for 30 minutes.²

Medications used for prevention and treatment of postmenopausal osteoporosis have not been well studied in drug-induced osteoporosis. These options include selective estrogen receptor modulators (SERMs, e.g., raloxifene, calcitonin) and estrogen. Estrogen therapy has fallen out of favor due to long-term complications, but calcitonin and SERMs may represent feasible options in appropriate patients.^2,7

Antiepileptic Drugs
Certain anticonvulsants may cause bone loss.⁷ The medications most commonly associated with osteoporosis include phenytoin, phenobarbital, carbamazepine, and primidone. ^3,7,8 These antiepileptic drugs (AEDs) are all potent inducers of CYP-450 isoenzymes. In one study of community-dwelling elderly women, bone loss nearly doubled in those receiving AEDs, compared to the general population.⁸

There are several known and proposed mechanisms for bone loss with AEDs. As mentioned previously, all of these medications induce hepatic CYP-450 enzymes, leading to rapid metabolism of vitamin D, and possibly, estrogen. AEDs are also associated with decreased fractional calcium absorption, secondary hyperparathyroidism, and increased bone turnover. ^3,7,8 At therapeutic levels, phenytoin and carbamazepine have exhibited direct effects on the bone by inhibiting osteoblast cells.⁸ A mechanism that may be solely linked to phenytoin is the inhibition of osteocalcin secretion--a hormone that regulates calcium in the bone.⁷ AEDs may exhibit any combination of these effects, and the impact on bone loss can be additive if a combination regimen is used.

To combat the loss of bone mass associated with traditional AEDs, it may be advisable to use a newer AED with a lower incidence of hepatic induction.³ Long-term studies still need to be conducted to evaluate if the newer agents cause bone loss, but to date, results appear promising. Supplementation with vitamin D and calcium is essential for the prevention of bone loss in patients who may be stabilized on an older medication. Preventive doses of at least 400 international units (IU) of vitamin D and 1,000 to 1,500 mg of calcium are recommended for those at risk.^3,7

Heparin
Unfractionated heparin (UFH) is also associated with drug-induced osteoporosis. This complication is typically seen with long-term, high-dose therapy. It has been estimated that bone loss occurs after six months of heparin therapy with daily doses greater than 15,000 units.³ With the addition of newer low-molecular-weight heparins (LMWHs), such as enoxaparin, long-term UFH is not as commonly used, but when it is prescribed, the risk of bone loss exists. LMWHs are effective, require less monitoring, are easily administered in an outpatient setting, and do not appear to induce bone loss. In one study, enoxaparin use resulted in no significant changes in bone mineral density in women treated throughout pregnancy and six weeks after giving birth.³

The exact cellular mechanism in which heparin induces bone loss is not completely understood. Heparin causes increased bone resorption by stimulating osteoclasts and suppressing osteoblast function, leading to decreased bone mass.^3,9 Other proposed mechanisms include depletion of mast cells in bone marrow and enhancement of parathyroid hormone (PTH) function, an important regulator of calcium in the body.¹⁰ The actions of PTH increase the release of calcium and phosphorus from bone into the blood to elevate serum levels; PTH is usually released in response to low serum calcium levels.

Progestins
One of the more recent classes of medications linked to osteoporosis is the progestins. Progestins are a type of hormone commonly used in many forms of contraception, as well as in hormone replacement products, and are therefore used in women of a wide age range. The progestin preparation most often associated with bone loss is medroxyprogesterone acetate (MPA). It is the injectable form of birth control known as Depo-Provera and is also part of the hormone replacement combinations known as Premphase and Prempro.^11,12 The risk of bone loss increases after two years of continuous use of MPA.¹³ Since Depo-Provera is commonly used in adolescent girls, new attention to osteoporosis prevention in this population has emerged by encouraging calcium supplementation and limiting the duration of use. In adolescents, MPA may be used for up to two years if no other options are appropriate. However, if possible, it may be advisable to use other forms of birth control, such as oral combination pills, if longer-term contraception is needed.¹⁴

Medroxyprogesterone's effects on bone loss are dependent on the dose and estrogen levels of the patient. MPA suppresses ovarian production of estrogen. Estrogen is protective against bone loss, and as previously noted, low levels of estrogen can lead to deterioration of bone mass. MPA also inhibits gonadotropin secretion of LH and FSH.^12,13 MPA also exhibits corticosteroidal properties and can decrease osteoblast differentiation by occupying the glucocorticoid receptor.¹¹ While MPA has been linked to osteoporosis, other progestins, including nortestosterone and norethindrone, may have a positive effect on bone mass. ¹¹

Other Medications
The medications discussed previously carry the highest-known risk of osteoporosis; however, others have also been linked to bone loss. Methotrexate may raise the risk of osteoporosis when used in very high doses, such as in oncology patients. The mechanism is not completely understood but is thought to involve an imbalance of bone resorption and formation.³ Loop diuretics (e.g., furosemide) may also decrease bone mass by increasing calcium excretion in the kidneys. ^9,15 Another potential cause of bone loss is excess thyroid supplementation. This usually occurs only when the thyroid-stimulating hormone level is virtually undetectable due to oversupplementation; the effect is demineralization of the bone.^3,15 Aluminum-containing antacids can bind calcium in the gastrointestinal tract and lead to decreased calcium absorption.³ Lithium has been shown to increase PTH secretion which, as stated above, can cause calcium release from the bone in order to raise serum calcium levels.⁹ Some animal models have shown increased bone turnover and loss with cyclosporine and tacrolimus use.³ There is also a controversial argument for warfarin and loss of vitamin K causing impaired bone formation.³ While these medications have been linked to osteoporosis, the evidence is not as convincing as the literature available for corticosteroids, AEDs, heparin, and progestins.

Prevention and Treatment
Awareness of osteoporosis, along with the risk factors for its development, prevention, and treatment, have become important public health concerns. Knowledge of medications that can induce bone loss in all patient populations is important to prevent long-term complications from this disease, which may not appear until later in life. Thus, it is key to maximize bone mass during adolescence and throughout life.

The first step in prevention is adequate intake of calcium and vitamin D through diet, exogenous supplementation, or both. Calcium requirements are highest during adolescence (ages 9 to 18); the recommended amount for this age-group is 1,300 mg/day. Between ages 19 and 50, the recommended intake of calcium is 1,000 mg/day. In patients older than 50, the recommended intake is 1,200 to 1,500 mg/day. If a supplement is used, dosing must not exceed 500 mg at one time during the day, since this is the maximum amount that the body can absorb. It is best to split up doses to two to three times a day. Vitamin D requirements can be met through sunlight exposure, diet, or exogenous supplementation. Experts recommend a daily intake between 400 and 800 IU. Doses higher than 800 IU/day of vitamin D are advised only with approval from a physician.¹ Patients with renal dysfunction may need lower doses of vitamin D.⁵

Implications for Pharmacy Practice
Drug-induced osteoporosis is a highly preventable condition that is currently undertreated. Osteoporosis affects a large population of patients, accounting for the spending of billions of health care dollars. Recognizing potential drug causes, monitoring therapy, and utilizing preventive measures can dramatically improve the quality of life for patients. Pharmacists who recognize patients at risk for bone loss should encourage a diet rich in calcium and vitamin D. Smoking, excessive alcohol use, and caffeine use should be discouraged. Referring patients to a registered dietician can provide specific nutritional advice. Pharmacists can also offer smoking cessation counseling with OTC aids, such as transdermal nicotine. Another helpful tip is to remember that thiazide diuretics have calcium-retaining properties and can be somewhat protective against the disease. Thiazides should be recommended as first-line drugs for treating hypertension, especially for patients with risk factors for osteoporosis. Pharmacists should encourage regular weight-bearing exercise and patient compliance with medications.

When at-risk patients are identified, pharmacists can offer to contact prescribing physicians and suggest appropriate actions. Drug alternatives to corticosteroids may be difficult to determine and may not be recommended. However, physicians should be reminded that chronic corticosteroid use unequivocally increases the risk of osteoporosis. Similarly, pharmacists should promote awareness among physicians and patients that Depo-Provera use for more than two consecutive years can increase the risk of bone mineral loss. Patients can be directed to the following Web sites for more information on drug-induced osteoporosis: www.nof.org (National Osteoporosis Foundation) and www.iofbonehealth.org (International Osteoporosis Foundation).

References
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