rred. Therapeutic relay may be considered whenever the benefit-risk balance is no longer deemed to be as favorable as at the beginning of menopause and/or after several years of use.

The occurrence of thrombosis during treatment is a contraindication, especially in patients with a history of thromboembolism.

The concomitant use of platelet aggregation inhibitors to prevent the risk of thrombotic injury is not associated with a change in thromboembolic risk. There was no significant difference between the two groups in the RUTH assay (HR 1.44, 95% CI 0.98, 2.10) and (HR 1.37, 95% CI 0.83, 2.27) (p = 0.88) [22] .

3.3. Strontium Ranelate

Strontium ranelate (RS) consists of 2 stable strontium atoms and ranelate salt. At the bone level, its mechanism of action is twofold: It acts on both osteoformation and resorption. Its anti-fracture efficacy has been widely demonstrated in clinical trials in patients naive to any antiosteoporotic treatment [23] . It is indicated in postmenopausal osteoporosis, in the prevention or recurrent fracture, and it represents a therapeutic alternative in case of contraindication or intolerance to bisphosphonates [24] . The optimal duration of treatment is 8 years.

However, some side effects may be associated, including venous thromboembolism and DRESS. The annual incidence reported in the regional pharmacovigilance center registry is 2.7% with strontium ranelate versus 1.9% with placebo, a relative risk of 1.42 [25] . Similarly, in the French study of Annie-Pierre et al. [26] Among cardiovascular adverse events, venous thromboembolic events were greater (93/104), deep vein thrombosis (54%), pulmonary embolism (34%), and 2% central vein thrombosis. of the retina. At least one risk factor for venous thrombosis was found in 28% of patients.

To explain their mechanisms of vascular action, some studies found a decrease in the concentration of homocysteine after treatment with RS, others did not find changes in the biological parameters of hemostasis, before and after two months of treatment [27] [28] .

Preventive Approaches under Strontium Ranelate

The French Agency for Health Safety of Health Products (AFSSAPS) and the Poison Control and Pharmacovigilance Center had issued a warning regarding the use of SR. The Transparency Committee re-evaluated this medicine on May 11, 2011 [29] . The indication was thus restricted to patients under 80 years of age, not immobilized with a contraindication/intolerance to bisphosphonates, without risk factors for venous thromboembolic events (ATEV).

Despite the low risk of reported venous thromboembolism, the benefit-risk balance has recently been re-evaluated by the European Medicines Agency. Thus, RS should not be prescribed in patients with a history of venous thromboembolic disease or in elderly patients at risk for venous thrombosis. A warning must also be given regarding the risk of hypersensitivity syndrome (or DRESS syndrome) and the appearance at the beginning of treatment of a generalized rash associated with a fever must lead to its arrest and to a specialized opinion [29] .

4. Conclusions

Although they occupy a place in the therapeutic arsenal of osteoporosis, with an efficiency close to that of bisphosphonates, the anti-osteoporotic drugs potentially associated with venous thromboembolic disease are: The hormonal treatment of menopause, selective osteogenic receptor modulators and strontium ranelate. The physiopathogenic link between these and the thrombotic risk is still heterogeneous. Despite their bone benefit, increasing evidence suggests that patients with VTE will be at greater risk for subsequent arterial events. In the future, we hope that epidemiological studies in outpatient and inpatient medicine may lead to more comprehensive analyzes of the undesirable effects of these drugs, the rationalization of their prescription and the vigilant monitoring of patients.

1) What is known about this topic

- Osteoporosis is a real public health issue, linked to the increase in morbidity and mortality.

- The therapeutic decision is based on the individual risk of fracture, the effectiveness and the degree of the therapeutic tolerance.

The anti-osteoporotic drugs potentially associated with thromboembolic venous disease are: Menopausal hormone therapy, selective oestrogenic hormone modulators and strontium ranelate.

2) What the study brings back

- The benefit and risk ratio of prescribed drugs can only be optimized by choosing the right time and the right treatment.

- Despite their bone benefit, recent, growing evidence suggests that patients with VTE may be at higher risk for subsequent events.

- The knowledge of the thromboembolic risk, the usual precautions of prescription and follow-up must be integrated in the strategies of the long-term care of the osteoporotic patients.

Authors’ Contributions

Kawtar Nassar: The author; Wafae Rachidi, Saadia Janani, Ouafa Mkinsi: Co-authors.

Abbreviation Note List

NIH: National Institue of Health

WHO: World Health Organisation

THM: Hormone Therapy in Menopause

WHI: World Health Institue

VTE: Venous Thromboembolism

SERMs: Selective Estrogen Receptor Modulators

BMD: Bone Mineral Density

RS: Stontium Ranelate

AFSSAPS: The French Agency for Health Safety of Health Products

DRESS: Drug Reaction with Eosinophilia and Systemic Symptoms

Cite this paper
Nassar, K. , Rachidi, W. , Janani, S. and Mkinsi, O. (2018) Review Venous Thromboembolism Risk with Anti-Osteoporosis Drugs. Open Journal of Rheumatology and Autoimmune Diseases, 8, 111-119. doi: 10.4236/ojra.2018.84012.

[1]   Montalcini, T., Gorgone, G., Fava, A., Castagna, A., Rondinelli, I. and Pugia, A. (2001) NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosisprevention, Diagnosis, and Therapy. JAMA, 285, 785-795.

[2]   Rousière, M. (2011) De l’importance de prendre en charge l’ostéoporose [The Importance of Taking Care of Osteoporosis]. La Presse Médicale, 40, 900-909.

[3]   Dargent-Molina, P., Benhamou, C.L., Cortet, B., Sutter, B. and Thomas, T. (2007) Vers une évaluation globale du risque fracturaire [Devising Global Strategies for Fracture-Risk Evaluation]. Revue du Rhumatisme, 74, 455-460. https://doi.org/10.1016/j.rhum.2006.11.016

[4]   Briot, K., Cortet, B., Thomas, T., Audran, M., Blaine, H., Breuil, V., et al. (2012) Actualisation 2012 des recommandations françaises du traitement médicamenteux de l’ostéoporose post-ménopausique. Revue du Rhumatisme, 79, 264-274.

[5]   Audran, M. (2006) Chronologie des traitements de l’ostéoporose [Drug Combination Strategies for Osteoporosis]. Revue du Rhumatisme, 73, 686-691.

[6]   Thomas, T. (2009) Ostéoporose postménopausique: Le point sur sa prise en charge [Postmenopausal Osteoporosis: Current Management of the Disease]. Médecine Nucléaire, 33, 2-6. https://doi.org/10.1016/j.mednuc.2008.09.009

[7]   Lacut, K., Mottier, D. and Pottier, P. (2008) Médicaments et maladie veineuse thromboembolique [Drugs and Venous Thromboembolism]. Revue de Pneumologie Clinique, 64, 290-297. https://doi.org/10.1016/j.pneumo.2008.09.005

[8]   Reginster, J.Y., Neuprez, A., Lecart, M.P., Sarlet, N., Distèche, S. and Bruyère, O. (2014) Treatment of Post-Menopausic Osteoporosis: What’s New in 2014? Revue médicale de Liège, 69, 441-453.

[9]   Tella, S.H. and Gallagher, J.C. (2014) Prevention and Treatment of Postmenopausal Osteoporosis. The Journal of Steroid Biochemistry and Molecular Biology, 142, 155-170.

[10]   Reginster, J.Y., Neuprez, A., Dardenne, N., Beaudart, C., Emonts, P. and Bruyere, O. (2014) Efficacy and Safety of Currently Marketed Anti-Osteoporosis Medications. Best Practice & Research: Clinical Endocrinology & Metabolism, 28, 809-834.

[11]   Cauley, J.A., Robbins, J., Chen, Z., Cummings, S.R., Jackson, R.D., LaCroix, A.Z., et al. (2003) Effects of Estrogenplus Progestin on the Risk of Fracture Andbone Mineral Density. The Women’s HealthInitiative Randomized Trial. JAMA, 290, 1729-1738.

[12]   Gomes, M.P. and Deitcher, S.R. (2004) Risk of Venous Thromboembolic Disease Associated with Hormonal Contraceptives and Hormone Replacement Therapy: A Clinical Review. Archives of Internal Medicine, 164, 1965-1976. https://doi.org/10.1001/archinte.164.18.1965

[13]   Claude, R. and Florence, T. (2006) Place du traitement hormonal substitutif dans la prise en charge de l’ostéoporose postménopausique et la prévention du risque fracturaire [Hormone Replacement Therapy in the Management of Postmenopausal Osteoporosis and Prevention of Fracture Risk]. La Presse Médicale, 35, 1557-1563.

[14]   Scarabin, P.Y., Oger, E., Plu-Bureau, G. and ESTHER Study Group (2003) Differential Associations of Oral Andtransdermal Oestrogen Replacement Therapy with Venous Thromboembolism Risk. The Lancet, 362, 428-432.

[15]   Grady, D., Wenger, N.K., Herrington, D., Khan, S., Furberg, C., Hunninghake, D., et al. (2000) Postmenopausal Hormone Therapyincreases Risk for Venous Thromboembolic Disease: The Heartand Estrogen/Progestin Replacement Study. Annals of Internal Medicine, 132, 689-696.

[16]   Herrington, D.M., Vittinghoff, E., Howard, T.D., Major, D.A., Owen, J., Reboussin, D.M., et al. (2002) Factor V Leiden, Hormone Replacement Therapy, and Risk of Venous Thromboembolic Events in Women with Coronary Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 1012-1017. https://doi.org/10.1161/01.ATV.0000018301.91721.94

[17]   Hoibraaten, E., Qvigstad, E., Arnesen, H., Larsen, S., Wickstrom, E. and Sandset, P.M. (2000) Increased Risk of Recurrent Venous Thromboembolism during Hormone Replacement Therapy. Thrombosis and Haemostasis, 84, 961-967.

[18]   Michalsen, B.T., Gherezghiher, T.B., Choi, J., Esala, R., Chandrasena, P., Qin, Z., Thatcher, G.R.J. and Bolton, J.L. (2012) The Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol. Chemical Research in Toxicology, 25, 1472-1483.

[19]   Trémollières, F. and Ribot, C. (2006) Indications du raloxifène chez la femme ménopausée. Gynécologie Obstétrique & Fertilité, 34, 147-153.

[20]   Barrett-Connor, E., Mosca, L., Collins, P., Geiger, M.J., Grady, D., Kornitzer, M., et al. (2006) Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women. The New England Journal of Medicine, 355, 125-137.

[21]   Adomaityte, J., Farooq, M. and Qayyum, R. (2008) Effect of Raloxifene Therapy on Venous Thromboembolism in Postmenopausal Women. A Meta-Analysis. Thrombosis and Haemostasis, 99, 338-342.

[22]   Duvernoy, C.S., Yeo, A.A., Wong, M., Cox, D.A. and Kim, H.M. (2010) Antiplatelet Therapy Use and the Risk of Venous Thromboembolic Events in the Raloxifene Use for the Heart (RUTH) Trial. Journal of Women’s Health, 19, 1459-1465. https://doi.org/10.1089/jwh.2009.1687

[23]   Meunier, P.J. (2006) Strontium Ranelate. Revue du Rhumatisme, 73, 834-837.

[24]   Reginster, J.Y., Seeman, E., DeVernejoul, M.C., Adami, S., Compston, J., Phenekos, C., et al. (2005) Strontium Ranelate Reduces the Risk of Non Vertebral Fractures in Postmenopausal Women with Osteoporosis: Treatment of Peripheral Osteoporosis (Tropos Study). The Journal of Clinical Endocrinology & Metabolism, 90, 2816-2822.

[25]   Chaabane, A., Aouam, K., Ben Fredj, N. and Boughattas, N.A. (2010) Dress Syndrome: étude de 11 cas et revue de la littérature. Therapie, 65, 443-450.

[26]   Pierre, A., Bera, J. and Autret-Leca, E. (2011) Ranélate de strontium (Protelos): Effets indésirables rapportés en France. La Presse Médicale, 40, 453-462.

[27]   Bayhan, I., Uygur, D., Ugurlu, N. and Ozaksit, G. (2009) Strontium Ranelate Decreases Plasma Homocysteine Levels in Postmenopausal Osteoporotic Women. Rheumatology International, 29, 263-266. https://doi.org/10.1007/s00296-008-0693-6

[28]   Grosso, A., Douglas, I., Hingorani, A., MacAllister, R. and Smeeth, L. (2008) Post-Marketing Assessment of the Safety of Strontium Ranelate; A Novel Case-Only Approach to the Early Detection of Adverse Drug Reactions. British Journal of Clinical Pharmacology, 66, 689-694.

[29]   Audran, M., Jakob, F.J., Palacios, S., Brandi, M.L., Broll, L., Hamdy, N.A.T., et al. (2013) A Large Prospective European Cohort Study of Patients Treated with Strontium Ranelate and Followed up over 3 Years. Rheumatology International, 33, 2231-2239.