Therapeutic Class Overview Bone Density Regulators INTRODUCTION Osteoporosis is the most common bone disease and is characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to bone fragility and consequent susceptibility to fracture (Cosman et al 2014). The National Osteoporosis Foundation (NOF) estimates that 10.2 million Americans have osteoporosis and more than 2 million osteoporosis-related fractures occur annually, with more than 70% of these occurring in women. Age is an important risk factor for bone loss; by age 60, half of white women have osteopenia or osteoporosis (Camacho et al 2016). According to the World Health Organization, osteoporosis is defined by a bone mineral density (BMD) at the hip or spine that is less than or equal to 2.5 standard deviations below the expected average for a healthy young person. Utilizing a reference population of young healthy individuals is common when measuring BMD and is known as a T-score (World Health Organization 1994). Fractures are the most clinically significant physical manifestation of postmenopausal osteoporosis, and low bone mass is the primary indicator of fracture risk (Camacho et al 2016). Osteoporotic fractures commonly occur in the wrist, spine, or hip, and can result in complications such as chronic pain, disability, depression, or even death (Cosman et al 2014). To decrease the risk of fractures, the general population should be advised to consume 1200 mg of calcium and 800 to 1000 mg of vitamin D per day from dietary sources or supplements. All individuals should also participate in regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures. Strategies for preventing falls should be implemented when needed. Smoking cessation and avoidance of excessive alcohol intake are other initiatives to prevent osteoporosis (Camacho et al 2016, Cosman et al 2014). Bisphosphonates are used to prevent and treat postmenopausal osteoporosis, osteoporosis in men, glucocorticoid- induced osteoporosis, and Paget’s disease. There are several bisphosphonates approved for treatment of Paget’s disease and malignancy-induced bone conditions, but not for osteoporosis. These agents include Aredia (pamidronate), Didronel (etidronate), and Zometa (zoledronic acid), which will not be discussed in this review (Micromedex 2.0 2018). Other agents used to treat postmenopausal osteoporosis include calcitonin (Miacalcin), an estrogen agonist/antagonist (Evista), the parathyroid hormone analogs (Forteo and Tymlos), and receptor activator of nuclear factor K-B ligand inhibitor (Prolia). These agents also have other indications, such as: reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis; reduction in the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer; increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture; treatment of Paget’s disease; treatment of hypercalcemia; treatment of glucocorticoid-induced osteoporosis at high risk of fracture; treatment of bone loss in men receiving androgen deprivation therapy for prostate cancer; and treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. Other agents in the estrogen agonist/antagonist class include Clomid or Serophene (clomiphene), tamoxifen, Fareston (toremifene), and Osphena (ospemifene). These agents have different indications, including: to induce ovulation in appropriately selected anovulatory women desiring pregnancy; the treatment and prevention of breast cancer; and treatment of women experiencing moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause (Micromedex 2.0 2018). These agents are not approved for treatment of osteoporosis and will not be discussed in this review. Another agent in the receptor activator of nuclear factor K-B ligand inhibitor class is Xgeva (denosumab). It is approved to prevent skeletal-related events in patients with bone metastases from solid tumors, treat hypercalcemia of malignancy refractory to bisphosphonates, and treat adults with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity (Micromedex 2.0 2018). It will not be further discussed in this review. The Food and Drug Administration (FDA) has approved estrogen/hormone therapy for the prevention of osteoporosis and relief of vasomotor symptoms and vulvovaginal atrophy associated with menopause. The Women’s Health Initiative (WHI) found that 5 years of hormone therapy in the form of Prempro (conjugated estrogen/medroxyprogesterone) reduced the risk of clinical vertebral fractures and hip fractures by 34% and other osteoporotic fractures by 23% (Writing Group for the WHI 2002). However, the study also reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis during 5 years of treatment. It is now recommended to use estrogen/hormone therapy in the lowest effective doses for the shortest duration necessary. Thus, these agents are not recommended for long-term prevention and will not be further discussed in this review. Data as of February 14, 2018 MG-U/RR-U/KAL Page 1 of 16 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions. Medispan Class: Bone Density Regulators; Hormone Receptor Modulators Table 1. Medications Included Within Class Review Drug Generic Availability Bisphosphonates Actonel (risedronate) Atelvia (risedronate, delayed release tablet) Binosto (alendronate, effervescent tablet) - Boniva (ibandronate) Fosamax* (alendronate) Fosamax Plus D (alendronate/cholecalciferol) - Reclast (zoledronic acid) Calcitonin Miacalcin† (calcitonin salmon synthetic) (nasal spray only) Estrogen Agonist-Antagonist Evista (raloxifene) Parathyroid Hormone Analogs Forteo (teriparatide) - Tymlos (abaloparatide) - Receptor Activator of Nuclear Factor K-B Ligand Inhibitors Prolia (denosumab) - * Brand Fosamax oral solution is not currently marketed; however, a generic is available. † Brand Miacalcin nasal spray is not currently marketed; however, a generic is available. Miacalcin injection is only available as a branded product. (Drugs@FDA 2018, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations 2018) INDICATIONS Table 2. FDA Approved Indications for Bisphosphonates alendronate* ibandronate* risedronate* zoledronic acid* Indication (Binosto, Fosamax, (Boniva) (Actonel, Atelvia)* (Reclast) Fosamax Plus D) Treatment of postmenopausal osteoporosis Prevention of postmenopausal osteoporosis (Fosamax only) (tablets only) (Actonel only) Treatment to increase bone mass in men with osteoporosis (Actonel only) Treatment of glucocorticoid- induced osteoporosis (Fosamax only) (Actonel only) Prevention of glucocorticoid- induced osteoporosis (Actonel only) Treatment of Paget’s disease (Fosamax only) (Actonel only) * Limitations of use: The optimal duration of use has not been determined. The safety and effectiveness of Actonel, Reclast and Boniva for the treatment of osteoporosis are based on clinical data of 3 years duration. The safety and effectiveness of Atelvia for the treatment of osteoporosis are based on clinical data of 1 year duration. The safety and effectiveness of Binosto and Fosamax/Fosamax PLUS D for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically. (Prescribing information: Actonel 2015, Atelvia 2015, Binosto 2016, Boniva injection 2016, Boniva tablets 2016, Fosamax 2016, Fosamax Plus D 2016, Reclast 2017) Data as of February 14, 2018 MG-U/RR-U/KAL Page 2 of 16 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions. Table 3: FDA Approved Indications for Calcitonins, Estrogen Agonist-Antagonist, Parathyroid Hormone Analogs, and Receptor Activator of Nuclear Factor K-B Ligand Inhibitor Evista Forteo Miacalcin Prolia Tymlos Indication (raloxifene) (teriparatide) (calcitonin) (denosumab) (abaloparatide) Treatment of postmenopausal