Drugs Associated with Osteoporosis and Related Fractures

Osteoporosis occurs when there is a decrease in bone mineral density and bone quality that can weaken bones, making them susceptible to fracture easily. It is a silent condition because people with osteoporotic bones may not observe any changes in their bone health until they have a broken bone, usually in the hip, spine or wrist.[1]

Many people know that certain factors — such as aging, low estrogen levels in women (mostly after menopause) and poor dietary intake of calcium, protein or vitamin D — increase the risk of osteoporosis and factures.

Fewer people, however, are aware that certain drugs — especially when they are taken in higher doses or for a prolonged time — also are associated with osteoporosis and fractures. The increased risk may or may not subside after discontinuation of these drugs. Therefore, it is important to learn about the various medications associated with these risks, to protect yourself and your loved ones.

Corticosteroids

Synthetic corticosteroids (also called glucocorticoids) are a family of adrenal steroid drugs that are used to treat many conditions, including autoimmune diseases and certain allergic or inflammatory conditions. Corticosteroids also are used as an immunosuppressive therapy after bone marrow and solid organ transplant. Oral formulations of these drugs include dexamethasone (HEMADY and generics), hydrocortisone (ALKINDI SPRINKLE, CORTEF and generics), methylprednisolone (MEDROL and generics) and prednisone (RAYOS and generics).

Inducing osteoporosis in a dose- and time-dependent manner, corticosteroids are the most common cause of drug-related osteoporosis.[2] Without treatment, bone mineral density decreases within the first three months of initiating oral corticosteroids with this adverse effect peaking after six months of their use.[3] Subsequently, bone mineral density can continue to decrease by up to 3% per year with continuous use of these drugs.

Importantly, inhaled corticosteroids — which are used to treat asthma and chronic obstructive pulmonary disease — have a lower risk of osteoporosis because they tend to act locally on the respiratory airways.

Diabetes drugs

Two drug classes that are used to treat type 2 diabetes are associated with osteoporosis or fractures. The first class, thiazolidinediones — mainly pioglitazone (ACTOS and generic) — decrease bone mineral density and increase fracture risk.[4] The increased fracture risk associated with use of these drugs has occurred even in young women without other risk factors for osteoporosis.

In addition, the use of sodium-glucose cotransporter-2 inhibitors — often referred to as “flozins” or “gliflozins,” including canagliflozin (INVOKANA) and dapagliflozin (FARXIGA) — increases the risk of fractures.[5] For example, in a pivotal clinical trial, the use of canagliflozin resulted in an increased risk of fracture starting after 26 weeks of therapy and lasting until the end of the trial (about 6 years).[6] In that trial, fractures were more likely to occur after low trauma (such as a fall from no more than standing height) and affected distal parts of upper and lower extremities.

Epilepsy drugs

Epilepsy can cause fractures due to falls caused by convulsions or loss of consciousness. Furthermore, the use of all antiepileptic drugs — including carbamazepine (CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL and generics), phenobarbital (SEZABY) and phenytoin (DILANTIN, PHENYTEK and generics) — is linked to osteoporosis and increased risk of fractures in both children and adults.[7],[8]

The fracture risk due to antiepileptic drugs is dependent on the cumulative dose and duration of therapy. Therefore, patients taking these drugs on a long-term basis should be screened for osteoporosis before and during their treatment.

Heparin

Unfractionated heparin (generic only) is an injectable blood thinner that is used to prevent and treat deep vein thrombosis (blood clots in a large vein) and pulmonary embolism (blood clots in the lung). Long-term use of high doses of heparin is associated with osteoporosis and fractures.[9] Specifically, there is evidence that up to one-third of long-term heparin users experience a reduction in their bone mineral density. Additionally, symptomatic vertebral fractures have occurred in 2% of women taking heparin to prevent blood clots.

Importantly, the use of low molecular weight heparins — such as dalteparin (FRAGMIN) and enoxaparin (LOVENOX and generics) — has not been associated with a decrease in bone mineral density and an increase in fracture risk.[10]

Hormone therapy to treat certain cancers

Used to treat estrogen-receptor positive breast cancer, aromatase inhibitors — such as anastrozole (ARIMIDEX and generics) and exemestane (AROMASIN and generics) — decrease bone mineral density and bone quality.

Likewise, the use of the injectable drugs gonadotropin-releasing hormone agonists — such as leuprolide (ELIGARD, LUPRON DEPOT, other brands and generics) and triptorelin (TRELSTAR, TRIPTODUR) — which are commonly used to treat hormone-dependent breast and prostate cancers, can cause bone loss.[11] Specifically, the use of these drugs has been linked to an approximately 6% decrease in bone mineral density per year.

Medroxyprogesterone

Of all hormonal contraceptives, only the injectable drug medroxyprogesterone (DEPO-PROVERA, DEPO-SUBQ PROVERA and generic) is associated with osteoporosis. This drug can cause up to 8% loss of mineral density, especially in the first two years of treatment.[12]

Therefore, the labeling of medroxyprogesterone carries a black-box warning — the most prominent warning required by the Food and Drug Administration — indicating that women who use this drug may lose significant bone mineral density and that bone loss is greater with increased duration in the use of this drug.[13] The warning also cautions that the use of medroxyprogesterone during adolescence or early adulthood lowers peak bone mass, increasing the risk of fractures in later life.

Proton pump inhibitors

The use of stomach acid-blocking proton pump inhibitors — such as dexlansoprazole (DEXILANT and generics), esomeprazole (NEXIUM and generics) and omeprazole (PRILOSEC and generics) — is associated with decreased bone mineral density at the lumbar spine and hip as well as increased risk of vertebral and nonvertebral fragility fractures.[14]

The risk of fracture with the use of these drugs is increased in patients who receive multiple daily doses of these drugs over at least one year.[15]

Thyroid hormone therapy

When used in appropriate dosages, medications that treat hypothyroidism (underactive thyroid) — such as levothyroxine (LEVO-T, SYNTHROID, TIROSINT, other brands and generics) — are not associated with a decrease in bone mineral density.[16]

However, the use of higher than needed doses of thyroid hormones can cause bone loss.[17] Therefore, laboratory testing of thyroid hormones should be done twice a year for all long-term users of these hormonal drugs and their dosages should be adjusted accordingly.

Other drugs

Several other drugs can cause bone loss and fractures. Among those is the immune-suppressive and cancer drug methotrexate (TREXALL, XATMEP and generics), when used in high doses.[18] Other examples include organ transplant immunosuppressants, such as cyclosporine (GENGRAF, NEORAL, SANDIMMUNE and generic) and tacrolimus (ASTAGRAF XL, ENVARSUS XR, PROGRAF and generics).

In addition, certain chemotherapeutic drugs — such as cyclophosphamide (CYTOXAN and generics), — are associated with osteoporosis.

What You Can Do

If you are taking a drug that can cause bone loss or fractures, consult your clinician regarding switching to another safe drug alternative. If that is not possible, work with your clinician to use the lowest possible dose of this drug for the shortest time.

When taking these drugs, it is essential to maximize your bone health by consuming a balanced diet with high amounts of calcium and vitamin D, performing daily weight-bearing exercises — such as gardening, stair climbing and walking — and taking calcium or vitamin D supplements, when necessary.[19] It is also important to avoid alcohol use and smoking.

Check with your clinician regarding whether you need to be screened for osteoporosis before and during long-term treatment with medications that cause bone loss, such as antiepileptics and corticosteroids.
 

References

[1] National Institute on Aging. Osteoporosis. November 15, 2022. https://www.nia.nih.gov/health/osteoporosis. Accessed October 31, 2023.

[2] Wang LT, Chen LR, Chen KH. Hormone-related and drug-induced osteoporosis: A cellular and molecular overview. Int J Mol Sci. 2023;24(6):5814.

[3] Hant FN, Bolster MB. Drugs that may harm bone: Mitigating the risk. Cleve Clin J Med. 2016;83(4):281-288.

[4] Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: Screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014;6(5):185-202.

[5] Blau JE, Taylor SI. Adverse effects of SGLT2 inhibitors on bone. Nat Rev Nephrol. 2018;14(8):473-474.

[6] Janssen Pharmaceuticals, Inc. Label: canagliflozin (INVOKANA). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204353s042,205879s019lbl.pdf. Accessed October 31, 2023.

[7] Nguyen KD, Bagheri B, Bagheri H. Drug-induced bone loss: a major safety concern in Europe. Expert Opin Drug Saf. 2018;17(10):1005-1014.

[8] Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: Screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014;6(5):185-202.

[9] Tannirandorn P, Epstein S. Drug-Induced Bone Loss. Osteoporos Int. 2000;11(8):637-659.

[10] Vestergaard P. Drugs causing bone loss. In: Stern PH, ed. Bone Regulators and Osteoporosis Therapy (Handbook of Experimental Pharmacology, 262). Springer; 2020:475-497.

[11] Nguyen KD, Bagheri B, Bagheri H. Drug-induced bone loss: a major safety concern in Europe. Expert Opin Drug Saf. 2018;17(10):1005-1014.

[12] Ibid.

[13] Pfizer Inc. Label: medroxyprogesterone (DEPO-PROVERA). December 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020246s060s062lbl.pdf. Accessed October 31, 2023.

[14] Nguyen KD, Bagheri B, Bagheri H. Drug-induced bone loss: a major safety concern in Europe. Expert Opin Drug Saf. 2018;17(10):1005-1014.

[15] Covis Pharma. Label: omeprazole (PRILOSEC). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022056s026lbl.pdf. Accessed October 31, 2023.

[16] Vestergaard P. Drugs causing bone loss. In: Stern PH, ed. Bone Regulators and Osteoporosis Therapy (Handbook of Experimental Pharmacology, 262). Springer; 2020:475-497.

[17] Pizzorno J, Pizzorno L. Commonly prescribed and over-the-counter drugs as secondary causes of osteoporosis—part two. Integr Med. 2021;20(3):8-14.

[18] Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: Screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014;6(5):185-202.

[19] Lewiecki EM. Prevention of osteoporosis. UpToDate. September 2023.