You are on page 1of 8

REVIEW

Drug-induced Osteoporosis: Mechanisms and Clinical Implications
Gherardo Mazziotti, MD, PhD,a Ernesto Canalis, MD,b,c Andrea Giustina, MDa
a Department of Medical and Surgical Sciences, University of Brescia, Montichiari, Italy; bDepartment of Research, Saint Francis Hospital and Medical Center, Hartford, Conn; cUniversity of Connecticut School of Medicine, Farmington.

ABSTRACT Drug-induced osteoporosis is common and has a significant impact on the prognosis of patients suffering from chronic debilitating diseases. Glucocorticoids are the drugs causing osteoporotic fractures most frequently, but osteoporosis with fractures is observed also in women treated with aromatase inhibitors for breast cancer, in men receiving anti-androgen therapy for prostate cancer, in postmenopausal women treated with high doses of thyroxine, and in men and women treated with thiazolinediones for type 2 diabetes mellitus. Bone loss with fractures also occurs in patients treated with drugs targeting the immune system, such as calcineurin inhibitors, antiretroviral drugs, selective inhibitors of serotonin reuptake, anticonvulsants, loop diuretics, heparin, oral anticoagulants, and proton pump inhibitors. © 2010 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2010) 123, 877-884 KEYWORDS: Drugs; Fractures; Osteoporosis; Secondary osteoporosis

Osteoporosis is a skeletal disorder characterized by a decrease in bone mineral density (BMD) and loss of structural and biomechanical properties of the skeleton, leading to an increased risk of fractures. Individual patients have genetic and acquired risks for osteoporosis. Among acquired risks, pharmacological interventions are important contributors to the bone loss observed in osteoporosis (Table 1). Druginduced osteoporosis is common, and has a significant impact on the morbidity and mortality of patients suffering from chronic debilitating diseases for which drug intervention is necessary. Unfortunately, awareness of this form of
Funding: This work was supported by MIUR and Centro di Ricerca sull’Osteoporosi-University of Brescia/EULO (A. Giustina). Conflict of Interest: Dr. Mazziotti has nothing to declare. Dr. Canalis reports receiving consulting or lecture fees from Eli Lilly, GlaxoSmithKline, Novartis, and Amgen. Dr. Giustina reports receiving consulting or lecture fees from Abiogen, Eli Lilly, GlaxoSmithKline, Merck, Amgen, and Stroder. No pharmaceutical industry funds were received for the preparation of the manuscript or related research. Authorship: Each author has participated in the writing of the manuscript and has seen and approved the submitted version. Further, each author has been involved in the conception and design of the study and the analysis of the data. Requests for reprints should be addressed to Andrea Giustina, MD, Department of Medical and Surgical Sciences, University of Brescia, c/o Endocrinology Service, Montichiari Hospital, Via Ciotti 154, Montichiari 25018, Italy. E-mail address: a.giustina@libero.it

secondary osteoporosis is limited. This article reviews the mechanisms and clinical implications of drug-induced osteoporosis (Tables 2 and 3). We performed a formal search of the electronic literature (MEDLINE) from 1990 to 2009 using the following search terms: osteoporosis, bone fractures and glucocorticoids, thyroxine, aromatase inhibitors, ovarian suppressing agents, androgen deprivation therapy, thiazolidinediones, selective serotonin reuptake inhibitors, anticonvulsants, heparins, oral anticoagulants, loop diuretics, calcineurin inhibitors, antiretroviral therapy, proton pump inhibitors. One hundred and eighty-nine original articles, systematic reviews, and meta-analyses from studies in humans published in the English language were considered.

HORMONAL THERAPY Glucocorticoids
Glucocorticoids are used in the treatment of inflammatory and autoimmune diseases, neoplasias, and following organ transplantation. Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. The central mechanism of action of glucocorticoids is decreased bone formation, secondary to impaired osteoblastic differentiation and function.1 However, during the initial phases of glucocorticoid exposure, bone resorption is increased, ex-

0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2010.02.028

Alendronate. a radiolog● Diagnostic criteria for postmenopausal for the skeleton. Vol 123. and menopausal females and elderly males. In glucocorticoid-induced osteotropic and cardiovascular) drugs may which occur in 30%-50% of paporosis. The risk in(prednisone equivalents 5 mg/day) creases by 5-fold. drug-induced osteoporosis. inporosis. with prednisone for 3-6 months. which may be asymposteoporosis are not applicable to premenopausal women and men are also tomatic and occur early during the glucocorticoid-induced osteoporosignificantly affected.2 Glucocorticoids inhibit bone forcyclic corticosteroid treatment at high doses. Vitamin D and calif drug discontinuation is not feasible. is CLINICAL SIGNIFICANCE Glucocorticoid-induced osteosmall because their absorption is porosis is characterized by low limited. first months of glucocorticoid sis. doses above 7. It is noteworthy mation and have additional indirect effects on bone metabothat fracture risk decreases after discontinuation of oral corticostelism. 2. As expected. cardiac dysfunction.0%). thyroid replacement therapy is used to normalize serum thyroid hormone levels. Patients with thyroid carcinoma are treated with high doses of thyroxine to suppress endogenous thyrotropin (TSH).0 to cause of drug-induced osteoporosis. ● Hormonal and nonhormonal (psychobone turnover and fractures. Regimens of ical evaluation is often necessary osteoporosis do not necessarily apply to daily prednisone at doses as low for their identification. and teriparatide causes a greater inAromatase inhibitors crease in BMD than alendronate and greater reduction in the Ovarian suppressing agents risk of vertebral fractures.878 The American Journal of Medicine.8 In fact. 1). tients. In hypothyroidism. fractures occur at higher cause osteoporosis. suggest that there is no dose of 1.2 Glucocorticoids affect preBMDs than in postmenopausal osteo● Drug-induced osteoporosis occurs pridominantly cancellous bone. but creasing the risk of vertebral the treatment of postmenopausal fractures. and reduced budesonide.5. October 2010 porotic fractures remains increased in patients undergoing plaining an early bone loss. However. explaining an increased risk of fractures (for a complete roids. The risk of osteozoledronic acid were shown to prevent and reverse the loss of BMD in glucocorticoid-induced osteoporosis with greater effects than those observed with vitamin D and calcium. The underlying disorder for which glube variable. because they can prevent the initial loss of greatest increase in fracture incidence was seen in postbone mass in this disorder. goiter. a topical steroid used physical activity.5 mg have been associated It is appropriate to treat indivi● Anti-osteoporotic treatments may be with an increased risk of hip and duals exposed to glucocorticoids effective in drug-induced osteoporosis.10 Subclinical thyrotoxicosis causes atrial fibrillation. and bone loss in elderly subjects and postmenopausal women. bisphosphonates induce improvement of Table 1 Drugs Associated with Osteoporosis BMD that is 2-fold greater than that observed during vitaHormonal therapy min D treatment (ie.11 Thyroid hormones increase bone resorption directly and indirectly by inducing the production of bone-resorbing cyto- .9 Androgen deprivation therapy Thiazolidinediones Psychotropic and anticonvulsant therapy Selective serotonin reuptake inhibitors Anticonvulsants Drugs used for cardiovascular diseases Heparins Oral anticoagulants Loop diuretics Drugs targeting the immune system Calcineurin inhibitors Anti-retroviral therapy Drugs used for gastrointestinal diseases Proton pump inhibitors Thyroxine Thyroxine is prescribed for the treatment of hypothyroidism.5 Consequently.1 in inflammatory bowel disease. risedronate.6 Because vertebral fractures glucocorticoid therapy that is safe may be asymptomatic.4 The risk of osteoporosis associated with incocorticoids are administered is often associated with bone loss as a consequence of chronic inflamhaled glucocorticoids or with mation. although the time it takes to reduce the risk appears to review. about 25% of these patients are over-treated and display suppressed serum levels of TSH. as 2. and thyroid carcinoma following thyroid ablation. No 10.2. and patients should be treated ● Glucocorticoids are the most common treatment.7.6% vs. see ref. guidelines for marily in postmenopausal women. vertebral fractures. malnutrition.8 Anabolic therapy Glucocorticoids appears to be ideal for the treatment of glucocorticoidThyroid hormone induced osteoporosis. A dracium are recommended for the matic 17-fold increase in vertebral management of all patients treated fracture incidence was observed in with glucocorticoids.5 mg daily. Bisphosphosubjects who used prednisone continuously more than 10 nates should be considered for the prevention and treatment mg per day for longer than 3 months.3 Published reports at BMD T-scores of 1. the of this disorder. 4.

12 Recently. Anastrazole and letrozole are nonsteroidal aromatase inhibitors.19. TSH was reported to inhibit bone resorption directly. The impact of subclinical hyperthyroidism on the skeleton is dependent on the age and sex of patients. decrease BMD. cerebrovascular and venous thromboembolic events. and the presence of additional factors predisposing them to bone loss.18.14 Thyrotoxicosis increases bone turnover. aromatase inhibitors induce bone loss. Aromatase inhibitors inhibit the aromatization of androgens and their conversion to estrogens in peripheral tissues. suggesting that the suppression of TSH itself may cause bone loss.16 There are no specific guidelines for the prevention of bone loss when thyroid suppression is necessary. Whereas tamoxifen can have estrogen-like effects on bone. when compared with tamoxifen. Supplemental calcium and vitamin D should be used.17 Table 3 Clinical Aspects of Drug-induced Osteoporosis: Impact on Bone Mineral Density and Fractures Bone Mineral Density Aromatase Inhibitors Aromatase inhibitors are more effective than tamoxifen as adjuvant therapy of estrogen-receptor-positive breast cancer. kines. 2 decreased.15 Thyroid suppression therapy causes bone loss in postmenopausal women. and increase the relative risk of vertebral and nonvertebral fractures by 40%.20 There is only a partial recovery of BMD following the withdrawal of aromatase inhibitors. 1 increased. long-term TSH-suppressive therapy with thyroxine may reduce the beneficial effects of bisphosphonates on BMD. Letrozole and anastrozole increase bone turnover. and osteoporosis is more prevalent in women starting aromatase inhibitors early after menopause. ↔ 1 1 1 1 1 ↔ Not determined 1 1 Not determined 1 1 1 1 determined determined determined determined determined determined determined determined unchanged.19 The skeletal effects observed are correlated inversely with baseline BMD and serum estradiol concentrations. with longer disease-free survival and without the risk of endometrial hyperplasia and cancer. duration of thyroxine treatment.15. and patients with increased fracture risk should be treated with antiresorptive drugs. The substantial reduction in estrogen concentrations caused by the suppression of androgen aromatization causes bone loss.11. *Fractures were assessed by a clinical approach.13. and increases the risk of fractures.11. However. ↔ unchanged. Bone loss with increased risk of fra- Fractures Lumbar Spine Hip Vertebral Nonvertebral Glucocorticoids Thyroid hormone Aromatase inhibitors Ovarian suppressing agents Androgen deprivation therapy Thiazolidinediones Selective serotonin reuptake inhibitors Anticonvulsants Heparin Oral anticoagulants Loop diuretics Calcineurin inhibitors Anti-retroviral therapy Proton pump inhibitors 2 2 2 2 2 2 2 2 2 ↔ ↔2 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 Not determined ↔1 1 1 1 1 2 1 2 ↔* 2 2 ↔ 2 2 2 ↔ ↔* 1 1 ↔1* 1 1 1 1 increased. and exemestane is a steroid similar to androstenedione that binds and irreversibly inhibits aromatase. increasing the risk of vertebral and hip fractures by 3. . 2 decreased.to 4-fold. decreases BMD.Mazziotti et al Table 2 Drugs and Osteoporosis 879 Mechanisms of Drug-induced Osteoporosis in Vivo Effects on Bone Remodeling Bone Resorption Bone Formation 2 1 1 1 1 2 2 1 2 2 1 1 2 1 Effects on Calcium Metabolism Vitamin D Levels or Action 2 ↔ Not 2 ↔ ↔ Not 2 Not Not 2 2 2 2 PTH Secretion ↔ ↔ 2 Not ↔ ↔ Not 1 Not Not 1 1 1 1 Glucocorticoids Thyroid hormone Aromatase inhibitors Ovarian suppressing agents Androgen deprivation therapy Thiazolidinediones Selective serotonin reuptake inhibitors Anticonvulsants Heparin Oral anticoagulants Loop diuretics Calcineurin inhibitors Anti-retroviral therapy Proton pump inhibitors PTH Parathyroid hormone.

They suppress estrogen levels and cause bone loss. may be preferable in the management of prostate carcinoma in patients with osteoporosis because this drug has comparable effectiveness to gonadotropin-releasing hormone agonists without deleterious effects on bone.23 Zoledronic acid was more effective in preventing than in reversing bone loss. and duration of therapy. and impaired muscular strength are observed and may contribute to increased risk of fractures. Indeed.38. suppressing ovulation and production of estrogens by the ovary.41 gility fractures also is observed in women receiving exemestane. A decrease of about 6%/year in BMD is observed in patients on gonadotropin-releasing hormone agonists with a recovery of bone mass after discontinuation. it increased disease-free survival in subjects with carcinoma of the breast. and lumbar spine decreases by 2%-5% after 12 months of androgen deprivation therapy.30 Decrease in lean body mass. but data on fracture reduction efficacy are scanty. BMD at hip. T-scores 2. are selective agonists of peroxisome proliferator-activated receptor.37 Selective estrogen receptor modulators. Gonadotropin-releasing hormone analogs reduce serum tes- .24 Denosumab. Ovarian Suppressing Agents Gonadotropin-releasing Hormone Agonists.36. established osteoporosis (T score 2. Gonadotropin-releasing hormone agonists are effective in the management of endometriosis and breast cancer in premenopausal women. in whom effects on survival have not been documented.33 The risk of fractures correlates with the degree and rate of BMD decrease.39 Recently. rosiglitazone and pioglitazone. Currently available thiazolidinediones.33. No 10. In vitro and in vivo studies demonstrate that peroxisome proliferator-activated receptor. Vol 123. and the relative risk of vertebral and hip fractures increases by 40%-50%. patient age. such as raloxifene and toremifene. Consequently.28.27 Medroxyprogesterone Acetate. and as an additional benefit. Gonadotropin-releasing hormone agonists are drugs with increased receptor affinity or prolonged half lives.5 SD).45. Its discontinuation results in BMD restoration.47 Thiazolidinediones should be avoided in patients with established osteoporosis or at high risk for fractures. also have beneficial effects on BMD.44 Long-term treatment with thiazolidinediones increases the risk of fractures by up to 4-fold in postmenopausal women and in men.40 An assessment of riskbenefit ratio of androgen deprivation therapy should be performed. but data on fracture reduction effects are scanty. Alternatives to androgen deprivation therapy. ovarian sex-steroid production is suppressed.46 This risk correlates with the duration of treatment with thiazolidinediones and is significant after 12 to 18 months. is effective in preventing aromatase inhibitor-induced bone loss in women with nonmetastatic breast carcinoma.42 Thiazolidinediones also decrease the expression of insulin-like growth factor I. Bisphosphonates are effective in the prevention and reversal of androgen deprivation therapy-induced bone loss.21 Zoledronic acid and risedronate were shown to prevent and reverse aromatase inhibitor-induced bone loss.22.46 Patients on thiazolidinediones should be assessed by dualenergy X-ray absorptiometry and thiazolidinediones should be Androgen Deprivation Therapy Androgen deprivation therapy is used in the treatment of metastatic and locally advanced prostate carcinoma.43 In addition. androgen deprivation therapy is frequently administered to patients with nonmetastatic prostate cancer. Bisphosphonates should be prescribed to individuals with fractures.induction in mesenchymal cells leads to increased adipogenesis and decreased osteoblastogenesis. causing an initial release of pituitary gonadotropins followed by a downregulation of gonadotropin-releasing hormone receptor and suppression of gonadotropin secretion.5 or between 1 and 2.31 In men with carcinoma of the prostate. and additional risk factors. and this may contribute to decreased bone formation. denosumab was shown to prevent bone loss and the incidence of vertebral fractures in men receiving androgen deprivation therapy. a monoclonal antibody against receptor activator of nuclear factor– kappa B ligand.26 Women with normal BMD and without osteoporosis risk factors should be monitored with dual-energy X-ray absorptiometry every 12 to 24 months. leading to persistent activation of gonadotropin-releasing hormone receptors. Medroxyprogesterone acetate inhibits gonadotropin secretion. such as the nonsteroidal anti-androgen bicalutamide.29 Thiazolidinediones Thiazolidinediones are insulin-sensitizing drugs used for the treatment or prevention of type 2 diabetes mellitus. It is effective in the treatment of endometriosis and as a contraceptive agent. Gonadotropin-releasing hormone agonists may not increase the risk of fragility fractures in women with normal BMD.5) or osteopenia (T-score between 1 and 2. October 2010 tosterone and estradiol levels and increase bone turnover and bone loss. increase in fat mass. and is effective in reducing tumor growth and improving survival of men affected by this tumor. but not with tumor stage..5 with significant risk factors for fractures. thiazolidinediones promote osteoclast differentiation and bone resorption.880 The American Journal of Medicine.34 Treatment is recommended for patients with pre-existing osteoporotic fractures. Thiazolidinediones may cause side effects on the cardiovascular system. liver and skeleton.25 Patients should receive supplemental calcium and vitamin D.45.32.22. Androgen deprivation therapy is achieved with gonadotropin-releasing hormone analogs alone or in combination with anti-androgenic therapy. Medroxyprogesterone acetate causes a decrease in BMD and increases the risk of fractures. ultradistal radius. although fragility fractures may occur independently of BMD.35 Calcium and vitamin D are indicated.

57. and serotonin can influence bone metabolism. and consequently inhibit the accumulation of osteocalcin in the extracellular matrix. but screening of women on these drugs for osteoporosis and appropriate therapy should be considered. Loop diuretics are often used in the management of congestive heart failure. This has clinical relevance because patients taking these drugs are often elderly and frail. the incidence of fractures is higher. high bone turnover. Anticoagulants are vitamin K antagonists that interfere with gamma-carboxyglutamate formation.53 In nonpregnant women.50 BMD loss correlates with treatment duration. so diagnostic and therapeutic guidelines have not been established. treatment should be instituted early. a decoy receptor for receptor activator of nuclear factor– kappa B ligand. Oral Anticoagulant Therapy Oral anticoagulants are often used in older subjects to prevent or treat deep vein thrombosis.64 Changes in T-cell cytokine production and altered vitamin D metabolism with secondary hyperparathyroidism may contribute to the effects of calcineurin inhibitors. heparin inhibits the differentiation and function of osteoblasts. decreasing BMD and increasing the risk of fractures by 2-fold. suggesting that epilepsy itself may contribute to an increased risk of osteoporosis and fractures. Most of the fractures are nonvertebral and tend to occur in younger individuals. and 15% of patients experience vertebral fractures 3-6 months after starting heparin. prevalent vertebral fractures are the only predictors of future vertebral fractures. Calcium and vitamin D supplementation is recommended.51 . In vitro.63 However.54 Fragility fractures are less frequent in patients on low-weight heparin than unfractionated heparin. although reversibility of bone loss is unknown. There is limited understanding of the pathogenesis of this skeletal disorder.45.58 Loop Diuretics Anticonvulsants Anticonvulsants are used in epilepsy. Because anticonvulsants accelerate vitamin D metabolism. Functional serotonin receptors and transporters are present in osteoblasts and osteocytes. evidence that these drugs cause osteoporosis and fractures in the general population is insufficient.65 Fracture risk is related to the patient age and the underlying disease. consequently. psychiatric conditions and in chronic pain management.65 Older age and lower BMD are predictors of vertebral fractures in patients with cardiac disease.56 Although these are potentially negative effects.46 PSYCHOTROPIC AND ANTICONVULSANT THERAPY Selected drugs with central nervous system effects may alter skeletal metabolism. In vitro.66 BMD is of modest value in patients with endstage renal disease because of renal osteodystrophy. up to one third of patients placed on heparin have a significant decrease in BMD. heparin decreases bone formation and increases bone resorption. DRUGS USED FOR CARDIOVASCULAR DISEASES Heparin Heparin is effective in the prevention and treatment of venous thromboembolism. cyclosporine and tacrolimus inhibit osteoclastogenesis and bone resorption.6% of all cases. but not in those with liver disease.54 Moreover. Furthermore.50 Low serum 25-hydroxyvitamin D levels. in vivo. agents used for the treatment of depression.55 discontinued if significant bone loss occurs. can cause bone loss.61. these drugs cause bone loss due to markedly increased bone resorption. increasing its renal excretion and bone turnover.Mazziotti et al Drugs and Osteoporosis 881 In pregnant women.2%-3. In this condition. which itself is associated with an increased risk of fragility fractures.49 There are no specific guidelines for the prevention of the bone loss observed with selective serotonin reuptake inhibitors. with a propensity to fall and.59 Loop diuretics inhibit sodium and chloride reabsorption and consequently inhibit calcium reabsorption. and secondary hyperparathyroidism can occur in patients on anticonvulsants.48 Postmenopausal women on selective serotonin reuptake inhibitors exhibit bone loss and a 2-fold increase in the risk of nonvertebral fractures.60 This results in decreased BMD and increased risk of fractures in men and postmenopausal women on long-term treatment with these drugs. DRUGS TARGETING THE IMMUNE SYSTEM Calcineurin Inhibitors Calcineurin inhibitors are immunosuppressants used in combination with glucocorticoids in patients undergoing organ transplantation. doses required to correct vitamin D deficiency may be greater than those required in the general population. to fracture. their effects on bone metabolism are controversial. the latter by inhibiting the expression of osteoprotegerin. Selective Serotonin Reuptake Inhibitors Selective serotonin reuptake inhibitors. Anticonvulsants may cause bone loss. and valproate and carbamazepine have anti-androgenic effects. with fractures occurring in only 2. the newly developed anticoagulant fondaparinux does not cause bone loss and may be considered as an alternative to heparin in osteoporotic patients.62 Most of the fractures are nonvertebral. but the mechanisms are unclear. it is not possible to isolate the contribution of the underlying disease and glucocorticoids from their effects on BMD and fragility fractures. There is accelerated vitamin D metabolism.51 In vivo.52. but anticonvulsants also may have direct inhibitory effects on osteoblast differentiation. Because bone loss occurs in the initial months of immunosuppressive therapy.

Guglielmi G. Panico A. 2007. These effects lead to a decrease in BMD. 2004. and consequently. The clinical significance of subclinical thyroid dysfunction. Shane E. Arch Intern Med. Recombinant human TSH modulates in vivo C-telopeptides of type-1 collagen and bone alkaline phosphatase. 2002. 2007. 2000. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. 2009. Saag KG.74 Fracture risk is reversed 1 year after proton pump inhibitors withdrawal. Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Thyroid hormones: beneficial or deleterious for bone? Calcif Tissue Int. Dovio A. The relative risk of vertebral and nonvertebral fractures increases by about 40% and 70%. Felson DT. Lavalley MP. bone biomarkers. Use of oral corticosteroids and risk of fractures. 2007. Nevitt MC. Fontana A. et al. Giustina A.68 Data on fracture incidence are limited. Sun Z. 43:107-109. Ann Intern Med. the inhibition of proton pumps on the osteoclast ruffled border may decrease bone resorption. but their benefit on fracture reduction is not documented. Vestergaard P. Cooper DS. 1993. Cross KW. Bone. Stone KL. 6. Piscopo M. Price KN.73. The comparative efficacy of drug therapies used for the management of corticosteroidinduced osteoporosis: a meta-regression. J Endocrinol Invest. Patelli I. Prevention with bisphosphonates. and antiresorptive agents should be considered for the prevention of bone loss occurring after transplantation with uncertain effects on fracture risk. 2008. 2006. 2001. Porcelli T. No 10. Thyroid. 2002. Laan RF. Mazziotti G. Rabaglio M. preventive measures are often not undertaken.82:249257. impairing osteoblastic function and bone formation. Bauer DC. Mazziotti G. Boonen S. et al. Endocr Rev. 2008.46(3):747-751. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy.73:205-209. Rejnmark L. 12. Confavreux CB. Sorvillo F. J Bone Miner Res. 7. Mazziotti G. Mazziotti G. 21. Bonadonna S. Osteoporos Int. increasing bone resorption in vivo.15:993-1000.134:561-568. et al. Levothyroxine treatment and occurrence of fracture of the hip. 4. Bilezikian JP. Alendronate and zoledronic acid increase BMD in HIV patients. et al. Prevention and treatment of glucocorticoid-induced osteoporosis. J Bone Miner Res. van Staa TP. in females and males with HIV infection. 9. Proton pump inhibitors decrease BMD at the lumbar spine and hip. Abenhaim L. Glucocorticoidinduced osteoporosis: pathophysiology and therapy. 15. Curr Rheumatol Rep. Khan AA. N Engl J Med. 11. 13. respectively. Antiretroviral drugs cause bone loss by increasing osteoclastogenesis and bone resorption. 20. Fracture risk associated with different types of oral corticosteroids and effect of termination of corticosteroids on the risk of fractures. 2003. et al. Ettinger B. et al. 2008.48:3224-3229. In vitro.6: 66-69. et al. 2008. particularly in patients with additional risk factors for osteoporosis. Teriparatide or alendronate in glucocorticoid-induced osteoporosis.72 However. Barton IP.882 The American Journal of Medicine. and studies on HIV patients do not discriminate between those receiving and not receiving antiretroviral therapy. et al. depending on drug dose and duration of therapy. US and UK guidelines for glucocorticoid-induced osteoporosis: similarities and differences. Girgis SI. Holder R. Sheppard MC. 16. 2005. Lakatos P. October 2010 Calcium and vitamin D supplementation. Vol 123. Doga M.162:338-343. 2003. 5. Cancer treatment-related bone loss: a review and synthesis of the literature. Parle JV. Giustina A.29:76-131. and physical exercise.39:253-259.19:437-442. and fracture incidence in postmenopausal women with early breast cancer participating in the Antiretroviral Therapy The introduction of antiretroviral therapy significantly reduced morbidity and mortality in patients suffering from human immunodeficiency virus (HIV). Canalis E. Awareness of this clinical problem is limited. et al. ACKNOWLEDGMENT The authors thank Mary Yurczak for secretarial assistance. Compston J. . Banks LM.20:1489-1498.357:20282039. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. antiretroviral therapy-induced bone loss is managed with a reduction of risk factors.18:1319-1328. 18.67 References 1. 2. Arthritis Rheum. supplemental calcium and vitamin D. et al. Lupoli GA. Osteoporosis and thyrotropin-suppressive therapy: reduced effectiveness of alendronate. 19.75 CONCLUSIONS Drugs routinely used for treatment of multiple diseases have detrimental effects on the skeleton. proton pump inhibitors decrease intestinal calcium absorption. Franklyn JA. et al. Leufkens HG. Histamine-receptor 2 blockers do not cause bone loss. Fonderico F. and increase the risk of vertebral and nonvertebral fragility fractures. Amin S. Guastalla JP. Vescovi PP. 8. 31(7 Suppl):53-88. 14. J Bone Miner Res. Franklyn JA. 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. Adequate monitoring of bone health and therapeutic intervention are recommended when drugs with an adverse bone safety profile are used. 10. 2010. Ann Oncol. Skeletal effects of exemestane on bone-mineral density. Coleman RE. Curr Oncol. Bone. Serum TSH values and risk of vertebral fractures in euthyroid post-menopausal women with low bone mineral density.69 Currently. Simms RW.15:S30-S40.41:346-352. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. and by causing mitochondrial damage.20:480-486.17: 1512-1526. Br J Gen Pract. Mosekilde L. Angeli A. Calcif Tissue Int. 17. 3. 2009. Khan MN. Bone.71 DRUGS USED FOR GASTROINTESTINAL DISEASES Proton Pump Inhibitors Proton pump inhibitors are commonly used in the treatment of diseases of the upper gastrointestinal tract. but not osteoprotegerin production in postmenopausal women monitored for differentiated thyroid carcinoma.70. van Staa TP. Biondi B.

Study of Osteoporotic Fractures Research Group. Papaioannou A. Gnant M. Intergroup Exemestane Study (IES): a randomised controlled study.26:4875-4882. 2008.8:119-127. Chu F. Approach to the prostate cancer patient with bone disease. Ellis GK. Mapping the prescriptiome to fractures in men—a national analysis of prescription history and fracture risk. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. The effects of heparin and low molecular weight heparins on bone. 29. Evans MC. 360:679-691. 43. 36. et al.71:7-11. 2009.128:829-832. et al. Northfelt DW. 49. Warfarin use and risk for osteoporosis in elderly women. Price PA. Majumdar SR. The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women. Smith MR.256: 12754-12759. van DS. et al. Abrahamsen B. Bone HG. 1991. Petty SJ. Heickendorff L. Malkowicz SB. 2008. 60. Woo C. Risedronate prevents bone loss in breast cancer survivors: a 2-year. Ingle JN. Endocrinology. 31. et al. Vertebral fractures in males with type 2 diabetes treated with rosiglitazone.23:7897-7903. Cell. 2008. et al. 33. Ginsberg JS. Egerdie B. 59. Lancet Oncol. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Cummings SR. Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide. 2004. Kahn SE. J Clin Oncol. 34. Goode M. Brufsky A. 26. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Johnson KC. et al.169:132-140. Growth hormone.104:1633-1637. et al.31:845-851. placebo-controlled clinical trial. N Engl J Med.56:1171-1176. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Loop diuretic use and fracture in postmenopausal women: findings from the Women’s Health Initiative.180: 32-39. and the skeleton. Smith MR. 22. Shaughnessy SG. 41. Zinman B. J Bone Miner Res. Douketis JD. Smith MR. Cyclosporin-A in vitro decreases bone resorption. 2010. Planas J. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. and the fusion of cells of the monocyte-macrophage lineage. et al. Evans RM.18:129-142. 38. Recovery of bone density in women who stop using medroxyprogesterone acetate.45:784788. 52. et al. Doga M. 56. Arch Intern Med. Giustina A. 2007.93:2-7. Arch Intern Med. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. 2009. J Clin Oncol. 2005. Mazziotti G. 40. J Am Geriatr Soc. A prospective matched cohort study. 2009. Raventos C. Cancer. J Clin Oncol. insulin-like growth factors. J Clin Endocrinol Metab. Support Care Cancer. Richards JB. osteoclast formation. Bauer DC. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.18(3):321-328. Dahlman TC. Bone. Coates P.104(11): 1637-1640. N Engl J Med. Denne MA. Loke YK. 2007. Cornish J. 2008. Mazziotti G. Ewing SK. 57. Center JR. 2005. Greenspan SL. et al. Diabetes Care.308: 247-248. Endocr Rev. Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma.361:745-755. Single-point assessment of warfarin use and risk of osteoporosis in elderly men. Cann CE. Thromb Res. BJU Int. 53. Bone densitometry as an adjunct to GnRH agonist therapy. Kearns AE. Rajgopal R. Lee WC. Suda N. J Clin Endocrinol Metab. Zietman AL. 55. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). J Clin Oncol. Furberg CD. 1998. 28. et al. Canalis E. The effects of long-term heparin therapy during pregnancy on bone density. J Reprod Med. Effects of fondaparinux compared with dalteparin. 62.167:188-194.90:6410-6417. Finkelstein JS.135:825837. 2004. 23. 2008. Ann Intern Med. 1981. et al. 25. 352:154-164. Vestergaard P.75:254-257. Rejnmark L. 2008. Butcher MK. Brufsky A.78:459-464. Bush AJ. Contraception. 39. O’Brien TJ. 32. Sereika SM. Bakal JA. Bear M. CMAJ. Smith MR. Effects of warfarin on bone. 1993.357:905-916. Mosekilde L. 51. Ahlborg HG. 2006. Osteoporos Int. 2008. Brixen K. Orcel P.118:1946-1952. 2009. et al. et al. Bundred N. 21:4042-4057. J Biol Chem. 2005. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer.22: 2546-2553. Oncologist. 1998. 2003. Wan Y.29:535-559. 37. 2008. Lafoz E. Giustina A. enoxaparin and unfractionated heparin on human osteoblasts. Dueck AC. Disch A. et al. et al. Kuo YF.13:1496-1503. doubleblind. Finkelstein JS. 27. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone 42.73:370-379. 2008. Hillner BE. Risk of fracture after androgen deprivation for prostate cancer. Wark JD. Olive A. Calcif Tissue Int. Chlebowski R. 2009. 50. 1996. Burrows RF. Anti-epileptic medication and bone health.26:26442652. 2008. Smith MR. Greenspan SL. Bauer DC. 2005. Trilla E. . J Clin Oncol. Brandman J.128:1638-1646. Rejnmark L. 30. Bone.21:163-170. Monreal M. Lee H. et al. Mlineritsch B. Chlebowski RT. Heart failure is a risk factor for orthopedic fracture: a population-based analysis of 16. 63.43: 556-560. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Nat Med. Hernandez TN. Singh S. 47. Thromb Haemost. Browner WS. Nguyen ND. 2007. 2008. Schippinger W. Fallon MA. de Vernejoul MC. Vestergaard P. Thromb Haemost. Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study. 58. 1994. Chong LW. 54. Chang LL. Greenspan SL.294 patients. Shahinian VB. BMJ. Matziolis G. 44. Williamson MK. 2008. Lembersky BC. Mancini T.26:1824-1829. Perka C. Freeman JL. Ryu JH. et al. Goodwin JS. PPAR-gamma regulates osteoclastogenesis in mice. 2009.20:585-597. J Clin Oncol. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. 2007. et al. Zippel H. 46. Lachin JM. 168:1265-1270. et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial.122:293-298. Am J Obstet Gynecol. Cundy T. et al. Osteoporos Int. 61. 48. 2008. Adachi JD.Mazziotti et al Drugs and Osteoporosis 883 mineral density and body composition. randomized. Jamal SA. Bilezikian JP.43:321-330. Osteoporosis prevention in prostate cancer patients receiving androgen ablation therapy: placebo-controlled double-blind study of estradiol and risedronate: N01C8. 24. Incidence and risk factors for low trauma fractures in men with prostate cancer. 2003. 35. J Clin Endocrinol Metab. N Engl J Med. Studies on the vitamin K-dependent protein of rat bone. Lee H. 2009. et al. 1994. Canalis E. McGovern K. Carbone LD. 45. Yadav VK. et al. Circulation.13:503-514.89:3841-3846. Mechanisms of anabolic therapies for osteoporosis. 2007. Smith MR. Alendronate decreases the fracture risk in patients with prostate cancer on androgen-deprivation therapy and with severe osteopenia or osteoporosis. Coleman R. N Engl J Med.

2009. and other antacid medications and the risk of fracture. J Clin Endocrinol Metab. 66. 64. Kulak JJ. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. 2006. Brown TT. 75. et al. J Acquir Immune Defic Syndr. Shane E. Transplantation osteoporosis. Lee H. Proton pump inhibitors.38:426-431. et al.884 The American Journal of Medicine. Approach to the patient with transplantation-related bone loss.20: 2165-2174. Hosch S. 2009. vitamin D. JAMA. Huang J. 69. et al.84: 13-19.357:342-347. Epstein S.79:76-83. 71. Calcif Tissue Int. Cyclosporin A in the oophorectomized rat: unexpected severe bone resorption. Ebeling PR. Brown TT.94:1483-1490. October 2010 70.50:783-792.93:3499-3504. Mondy K. 2001. Briot K. Metz DC. Mosekilde L. J Clin Endocrinol Metab. 2006. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Calcif Tissue Int. Ismail F. J Bone Miner Res. Tuukkanen J. Lancet. and calcium for the treatment of osteopenia/osteoporosis associated with HIV infection. Vaananen HK. No 10. inhibits bone resorption in vitro. Powderly WG. Leidig-Bruckner G. 2006. . Alendronate. Movsowitz C. Lewis JD. Vestergaard P. Yang YX. Rejnmark L. 38:123-125. 68. Triant VA. 2009. Grinspoon SK. Qaqish RB. McCutchan JA.4:393-398. Increase in vertebral fracture risk in postmenopausal women using omeprazole. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus nonHIV-infected patients in a large U. Gossec L. Dodidou P. Epstein S. 2006. A double-blinded. Fernandez S. 67. Vol 123. 73. randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis. Omeprazole. 72.23:51-57. Borba VZ. Meixner L. histamine H2 receptor antagonists. Arq Bras Endocrinol Metabol. Roux C. et al. 2005. AIDS. 65.296:2947-2953.S. 1989. Kulak CA. a specific inhibitor of H K -ATPase. Long-term proton pump inhibitor therapy and risk of hip fracture. Claxton SA. healthcare system. AIDS. 1986. Calcif Tissue Int. 2008. 74.