Reviews

Drugs that may harm bone: Mitigating the risk

Cleveland Clinic Journal of Medicine. 2016 April;83(4):281-288

References

Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 2002; 966:73–81.
Manolagas SC. Corticosteroids and fractures: a close encounter of the third cell kind. J Bone Miner Res 2000; 15:1001–1005.
Papaioannou A, Ferko NC, Adachi JD. Corticosteroids and the skeletal system. In: Lin AN, Paget SA, eds. Principles of corticosteroid therapy. New York, NY: Arnold Publishers; 2002:69–86.
Van Staa TP. The pathogenesis, epidemiology, and management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 2006; 79:129–137.
Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis Int 2002; 13:777–787.
Clowes JA, Riggs BL, Khosla S. The role of the immune system in the pathophysiology of osteoporosis. Immunol Rev 2005; 208:207–227.
LoCascio V, Bonucci E, Imbimbo B, et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990; 8:39–51.
Lane NE, Lukert B. The science and therapy of glucocorticoid-induced bone loss. Endocrinol Metab Clin North Am 1998; 27:465–483.
Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19:893–899.
Van Staa TP, Geusens P, Pols HA, de Laet C, Leufkens HG, Cooper C. A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 2005; 98:191–198.
Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39:1383–1389.
Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of corticosteroids and risk of fractures. J Bone Miner Res 2000; 15:993–1000.
Van Staa TP, Laan RF, Barton IP, Cohen S, Reid DM, Cooper C. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 2003; 48:3224–3229.
Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM, Setoain J. Vertebral fractures in steroid dependent asthma and involutional osteoporosis: a comparative study. Thorax 1991; 46:803–806.
Selby PL, Halsey JP, Adams KRH, et al. Corticosteroids do not alter the threshold for vertebral fracture. J Bone Miner Res 2000; 15:952–956.
Gonnelli S, Caffarelli C, Maggi S, et al. Effect of inhaled glucocorticoids and beta(2) agonists on vertebral fracture risk in COPD patients: the EOLO study. Calcif Tissue Int 2010; 87:137–143.
Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts G. Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; 1:CD003537.
Weatherall M, James K, Clay J, et al. Dose-response relationship for risk of non-vertebral fracture with inhaled corticosteroids. Clin Exp Allergy 2008; 38:1451–1458
Buehring B, Viswanathan R, Binkley N, Busse W. Glucocorticoid-induced osteoporosis: an update on effects and management. J Allergy Clin Immunol 2013; 132:1019–1030.
Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010; 62:1515–1526.
Naunton M, Peterson GM, Bleasel MD. Overuse of proton pump inhibitors. J Clin Pharm Ther 2000; 25:333–340.
Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol 2013; 6:443–451.
Sheikh MS, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med 1987; 317:532–536.
Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296:2947–2953.
Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 2006; 79:76–83.
Food and Drug Administration (FDA). FDA drug safety communication: possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm. Accessed March 7, 2016.
Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179:319–326.
Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28:951–959.
Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 2010; 139:93–101.
Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med 2010; 170:765–771.
Yu EW, Blackwell T, Ensrud KE, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008; 83:251–259.
Leontiadis GI, Moayyedi P. Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol 2014; 12:414–423.
Chen F, Hahn TJ, Weintraub NT. Do SSRIs play a role in decreasing bone mineral density? J Am Med Dir Assoc 2012; 13:413–417.
Bruyere O, Reginster JY. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine 2015; 48:65–68.
Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol 2010; 191:7–13.
Eom CS, Lee HK, Ye S, Park SM, Cho KH. Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis. J Bone Miner Res 2012; 27:1186–1195.
Rabenda V, Nicolet D, Beaudart C, Bruyere O, Reginster JY. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporosis Int 2013; 24:121–137.
Richards JB, Papaioannou A, Adachi JD, et al; Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 2007; 22;167:188–194.
Hahn TJ, Hendin BA, Scharp CR, Boisseau VC, Haddad JG Jr. Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy. N Engl J Med 1975; 292:550–554.
Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58:1003–1009.
Koch HU, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972; 13:829–834.
Shane E. Osteoporosis associated with illness and medications. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. San Diego, CA: Academic Press; 1996.
Vestergaard P. Epilepsy, osteoporosis and fracture risk—a meta-analysis. Acta Neurol Scand 2005; 112:277–286.
Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia 2004; 45:1330–1337.
Petty SJ, O’Brien TJ, Wark JD. Anti-epileptic medication and bone health. Osteoporos Int 2007; 18:129–142.
Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 2010; 123:877–884.
Rabaglio M, Sun Z, Price KN, et al; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 2009; 20:1489–1498.
Khan MN, Khan AA. Cancer treatment-related bone loss: a review and synthesis of the literature. Curr Oncol 2008; 15:S30–S40.
Hadji P, Aapro MS, Body JJ, et al. Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol 2011; 22:2546–2555.
Hillner BE, Ingle JN, Chlebowski RT, et al; American Society of Clinical Oncology. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in breast cancer. J Clin Oncol 2003; 21:4042–4057.

ANTIEPILEPTIC DRUGS

Antiepileptic drugs are used to treat not only seizure disorders but also migraine headaches, neuropathy, and psychiatric and pain disorders. Many studies have linked their use to an increased risk of fractures.

The mechanism of this effect remains controversial. Early studies reported that inducers of cytochrome P450 enzymes (eg, phenobarbital, phenytoin) lead to increased vitamin D degradation, causing osteomalacia.³⁹ Another study suggested that changes in calcium metabolism and reduced bone mineral density occur without vitamin D deficiency and that drugs such as valproate that do not induce cytochrome P450 enzymes may also affect bone health.⁴⁰ Other bone effects may include direct inhibition of intestinal calcium absorption (seen in animal studies) and the induction of a high remodeling state leading to osteomalacia.^41,42

Epilepsy itself increases risk of fractures

Patients with seizure disorders may also have an increased risk of fractures because of falls, trauma, impaired balance, use of glucocorticoids and benzodiazepines, and comorbid conditions (eg, mental retardation, cerebral palsy, and brain neoplasm).⁴³

A 2005 meta-analysis⁴³of 11 studies of epilepsy and fracture risk and 12 studies of epilepsy and bone mineral density found that the risks of fractures were increased. The following relative risks and 95% CIs were noted:

The benefit of preventing seizures outweighs the risks of fractures

Any fracture 2.2 (1.9–2.5), in five studies
Forearm 1.7 (1.2–2.3), in six studies
Hip 5.3 (3.2–8.8), six studies
Spine 6.2 (2.5–15.5), in three studies.

A large proportion of fractures (35%) seemed related to seizures.

Certain drugs increase risk

A large 2004 population-based, case-control, study⁴⁴ (124,655 fracture cases and 373,962 controls) found an association between the use of antiepileptic drugs and increased fracture risk. After adjusting for current or prior use of glucocorticoids, prior fracture, social variables, comorbid conditions, and epilepsy diagnosis, excess fracture risk was found to be associated with the following drugs (odds ratios and 95% CIs):

Oxcarbazepine 1.14 (1.03–1.26)
Valproate 1.15 (1.05–1.26)
Carbamazepine 1.18 (1.10-1.26)
Phenobarbital 1.79 (1.64–1.95).

The risk was higher with higher doses. Fracture risk was higher with cytochrome P450 enzyme-inducing drugs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone; odds ratio 1.38, 95% CI 1.31–1.45) than for noninducing drugs (clonazepam, ethosuximide, lamotrigine, tiagabine, topiramate, valproate, and vigabatrin; odds ratio 1.19, 95% CI 1.11–1.27). No significant increased risk of fracture was found with use of phenytoin, tiagabine, topiramate, ethosuximide, lamotrigine, vigabatrin, or primidone after adjusting for confounders.

Bottom line: Monitor bone health

With antiepileptic drugs, the benefit of preventing seizures outweighs the risks of fractures. Patients on long-term antiepileptic drug therapy should be monitored for bone mineral density and vitamin D levels and receive counseling on lifestyle measures including tobacco cessation, alcohol moderation, and fall prevention.⁴⁵ As there are no evidence-based guidelines for bone health in patients on antiepileptic drugs, management should be based on current guidelines for treating osteoporosis.

AROMATASE INHIBITORS

Depression itself may be a risk factor for fracture

Breast cancer is the most common cancer in women and is the second-leading cause of cancer-associated deaths in women after lung cancer. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, are the standard of care in adjuvant treatment for hormone-receptor-positive breast cancer, leading to longer disease-free survival.

However, aromatase inhibitors increase bone loss and fracture risk, and only partial recovery of bone mineral density occurs after treatment is stopped. The drugs deter the aromatization of androgens and their conversion to estrogens in peripheral tissue, leading to reduced estrogen levels and resulting bone loss.⁴⁶ Anastrozole and letrozole have been found to reduce bone mineral density, increase bone turnover, and increase the relative risk for nonvertebral and vertebral fractures in postmenopausal women by 40% compared with tamoxifen.^47,48

Base osteoporosis treatment on risk

Several groups have issued guidelines for preventing and treating bone loss in postmenopausal women being treated with an aromatase inhibitor. When initiating treatment, women should be counseled about modifiable risk factors, exercise, and calcium and vitamin D supplementation.

Baseline bone mineral testing should also be obtained when starting treatment. Hadji et al,⁴⁹in a review article, recommend starting bone-directed therapy if the patient’s T score is less than –2.0 (using the lowest score from three sites) or if she has any of at least two of the following fracture risk factors:

T score less than –1.5
Age over 65
Family history of hip fracture
Personal history of fragility fracture after age 50
Low body mass index (< 20 kg/m²)
Current or prior history of tobacco use
Oral glucocorticoid use for longer than 6 months.

Patients with a T score at or above –2.0 and no risk factors should have bone mineral density reassessed after 1 to 2 years. Antiresorptive therapy with intravenous zoledronic acid and evaluation for other secondary causes of bone loss should be initiated for either:

An annual decrease of at least 10% or
An annual decrease of at least 4% in patients with osteopenia at baseline.⁴⁹

In 2003, the American Society of Clinical Oncology updated its recommendations on the role of bisphosphonates and bone health in women with breast cancer.⁵⁰ They recommend the following:

If the T score is –2.5 or less, prescribe a bisphosphonate (alendronate, risedronate, or zoledronic acid)
If the T score is –1.0 to –2.5, tailor treatment individually and monitor bone mineral density annually
If the T score is greater than –1.0, monitor bone mineral density annually.

All patients should receive lifestyle counseling, calcium and vitamin D supplementation, and monitoring of additional risk factors for osteoporosis as appropriate.⁵⁰

References

Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 2002; 966:73–81.
Manolagas SC. Corticosteroids and fractures: a close encounter of the third cell kind. J Bone Miner Res 2000; 15:1001–1005.
Papaioannou A, Ferko NC, Adachi JD. Corticosteroids and the skeletal system. In: Lin AN, Paget SA, eds. Principles of corticosteroid therapy. New York, NY: Arnold Publishers; 2002:69–86.
Van Staa TP. The pathogenesis, epidemiology, and management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 2006; 79:129–137.
Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis Int 2002; 13:777–787.
Clowes JA, Riggs BL, Khosla S. The role of the immune system in the pathophysiology of osteoporosis. Immunol Rev 2005; 208:207–227.
LoCascio V, Bonucci E, Imbimbo B, et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990; 8:39–51.
Lane NE, Lukert B. The science and therapy of glucocorticoid-induced bone loss. Endocrinol Metab Clin North Am 1998; 27:465–483.
Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19:893–899.
Van Staa TP, Geusens P, Pols HA, de Laet C, Leufkens HG, Cooper C. A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 2005; 98:191–198.
Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39:1383–1389.
Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of corticosteroids and risk of fractures. J Bone Miner Res 2000; 15:993–1000.
Van Staa TP, Laan RF, Barton IP, Cohen S, Reid DM, Cooper C. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 2003; 48:3224–3229.
Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM, Setoain J. Vertebral fractures in steroid dependent asthma and involutional osteoporosis: a comparative study. Thorax 1991; 46:803–806.
Selby PL, Halsey JP, Adams KRH, et al. Corticosteroids do not alter the threshold for vertebral fracture. J Bone Miner Res 2000; 15:952–956.
Gonnelli S, Caffarelli C, Maggi S, et al. Effect of inhaled glucocorticoids and beta(2) agonists on vertebral fracture risk in COPD patients: the EOLO study. Calcif Tissue Int 2010; 87:137–143.
Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts G. Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; 1:CD003537.
Weatherall M, James K, Clay J, et al. Dose-response relationship for risk of non-vertebral fracture with inhaled corticosteroids. Clin Exp Allergy 2008; 38:1451–1458
Buehring B, Viswanathan R, Binkley N, Busse W. Glucocorticoid-induced osteoporosis: an update on effects and management. J Allergy Clin Immunol 2013; 132:1019–1030.
Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010; 62:1515–1526.
Naunton M, Peterson GM, Bleasel MD. Overuse of proton pump inhibitors. J Clin Pharm Ther 2000; 25:333–340.
Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol 2013; 6:443–451.
Sheikh MS, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med 1987; 317:532–536.
Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296:2947–2953.
Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 2006; 79:76–83.
Food and Drug Administration (FDA). FDA drug safety communication: possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm. Accessed March 7, 2016.
Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179:319–326.
Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28:951–959.
Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 2010; 139:93–101.
Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med 2010; 170:765–771.
Yu EW, Blackwell T, Ensrud KE, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008; 83:251–259.
Leontiadis GI, Moayyedi P. Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol 2014; 12:414–423.
Chen F, Hahn TJ, Weintraub NT. Do SSRIs play a role in decreasing bone mineral density? J Am Med Dir Assoc 2012; 13:413–417.
Bruyere O, Reginster JY. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine 2015; 48:65–68.
Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol 2010; 191:7–13.
Eom CS, Lee HK, Ye S, Park SM, Cho KH. Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis. J Bone Miner Res 2012; 27:1186–1195.
Rabenda V, Nicolet D, Beaudart C, Bruyere O, Reginster JY. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporosis Int 2013; 24:121–137.
Richards JB, Papaioannou A, Adachi JD, et al; Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 2007; 22;167:188–194.
Hahn TJ, Hendin BA, Scharp CR, Boisseau VC, Haddad JG Jr. Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy. N Engl J Med 1975; 292:550–554.
Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58:1003–1009.
Koch HU, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972; 13:829–834.
Shane E. Osteoporosis associated with illness and medications. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. San Diego, CA: Academic Press; 1996.
Vestergaard P. Epilepsy, osteoporosis and fracture risk—a meta-analysis. Acta Neurol Scand 2005; 112:277–286.
Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia 2004; 45:1330–1337.
Petty SJ, O’Brien TJ, Wark JD. Anti-epileptic medication and bone health. Osteoporos Int 2007; 18:129–142.
Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 2010; 123:877–884.
Rabaglio M, Sun Z, Price KN, et al; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 2009; 20:1489–1498.
Khan MN, Khan AA. Cancer treatment-related bone loss: a review and synthesis of the literature. Curr Oncol 2008; 15:S30–S40.
Hadji P, Aapro MS, Body JJ, et al. Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol 2011; 22:2546–2555.
Hillner BE, Ingle JN, Chlebowski RT, et al; American Society of Clinical Oncology. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in breast cancer. J Clin Oncol 2003; 21:4042–4057.

Prescribing opioids in primary care: Safely starting, monitoring, and stopping

Drugs that may harm bone: Mitigating the risk

References

Epilepsy itself increases risk of fractures

Certain drugs increase risk

Bottom line: Monitor bone health

Base osteoporosis treatment on risk

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