Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD

BONE PHYSIOLOGY Most common bone disease in humans Characterized by: Low bone mass Microarchitectural deterioration Compromised bone strength Increased risk for fracture

BONE PHYSIOLOGY Bone Resorption Bone Formation Osteoclast Bone Formation Osteoblast Bone Multicellular Unit (BMU) Positive < age 30 Negative > age 30

Remodeling (Resorption) Bone Multicellular Unit (BMU) Lining cells

Remodeling (Resorption) Bone Multicellular Unit (BMU) Lining cells

Remodeling (Resorption) Lymphocyte Bone Multicellular Unit (BMU) RANKL CSF RANK  Macrophage

Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  IL1, TNFα, IL6, IL11 Macrophage RANKL Osteoblast

Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  IL1, TNFα, IL6, IL11 Macrophage RANKL Preosteoclast Osteoblast

Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  IL1, TNFα, IL6, IL11 Macrophage RANKL Preosteoclast RANKL RANK  IL1,TNFα,IL6 Osteoclast Osteoblast

Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  IL1, TNFα, IL6, IL11 Macrophage RANKL Preosteoclast RANKL RANK  IL1,TNFα,IL6 Osteoclast Osteoblast Cathepsin K

Remodeling (Formation) Lymphocyte IL1 Estrogen OPG Osteoclast inhibition RANKL RANK  IL1,TNFα,IL6 Osteoblast

Remodeling (Formation) Lymphocyte - IL1 Estrogen OPG Osteoclast inhibition RANKL RANK  IL1,TNFα,IL6 Osteoblast

Remodeling (Formation) Lymphocyte - PTH Vit D IL1 Estrogen Mechanical stimuli Estrogen OPG Androgen IGF Osteoclast inhibition RANKL RANK  IL1,TNFα,IL6 Osteoblast stimulation Osteoblast

Remodeling (Formation) Osteoblast proliferation

Remodeling (Formation) Lining cells Osteocyte Osteoid

Etiology and pathogenesis of Osteoporosis

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

Drugs used for osteoporosis treatment

Treatment _ + + _ _ + _ + _ Odanacatib Denosumab Strontium Teriparatide SERMs _ PTH Biphosphonates Estrogen Calcitonine + PTH Vit D Ca, Vit D Lymphocyte + Exercise Estrogen IL1 TNFα IL6 IL11 OPG Progestrone _ _ + _ Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast + Osteoblast _ Osteoblast Cathepsin K

Drugs used for osteoporosis Antiresorptive drugs - Bisphosphonates - Calcitonin - Estrogen - SERM’s - Denosumab Bone formation stimulators - PTH (Teriparatide) Dual action - Strontium

Vitamin D and calcium

Vitamin D and calcium Daily 800 IU of vitamin D is associated with a reduction in hip fractures of 30% and in nonvertebral fractures of 14% Fall reduction in the elderly Therapeutic dose of vitamin D: 600-800 unit

Vitamin D and calcium Calcium: 1000-1300mg Avoid taking more than 500 mg of calcium in one dose. Take one dose before bedtime to prevent bone loss at night. If more is needed, take several doses throughout the day. Calcium supplements should be taken with meals to boost their absorption.

Vitamin D and calcium Certain substances can hinder absorption of calcium: foods rich in fibres and fat, zinc, iron, spinach, coffee, alcohol and antacids. Therefore, calcium should not be taken together with these. Calcium may interfere with certain drugs, including: thyroid medications, tetracycline, anticonvulsants and corticosteroids. Therefore, these should always be taken separately.

Vitamin D and calcium There is no need to worry about development of kidney stones if the correct dosage in the suitable form of calcium is taken together with sufficient fluid. Calcium supplements can cause gas, abdominal distension and constipation in some individuals. In this situation, it is reasonable to switch to a different preparation.

Bisphosphonates

Bisphosphonates The most commonly prescribed therapy for OP prevention and management Mechanism: inhibits bone resorption by attaching to bony surfaces undergoing active resorption and inhibiting action of osteoclasts - - - Farensyl pyrophosphate synthase GTPase Attachment of osteoclast

Bisphosphonates-place in treatment Prevention and treatment of postmenopausal osteoporosis Osteoporosis in men Prevention and treatment of GIOP

Bisphosphonates Alendronate use for 10 years cause a continuous increase in vertebral (13.7%) and hip trochanter (10.3%) bone mineral density (BMD) Decrease incidence of vertebral, hip, and all non-vertebral fractures by 50% 90% reduction of multiple radiographic vertebral fractures at year 3

Bisphosphonates-Adverse events Gastrointestinal problems, such as difficulty swallowing, gastric ulcers, and inflammation of the esophagus. Hypocalcemia (18%) Hypophosphatemia (10%) Musculoskeletal pain, cramps

Bisphosphonates-Adverse events Atrial fibrillation (3-50/100000): zoledronic acid Osteonecrosis of the jaw (1/100000): IV bisphosphonates Atypical femur fracture

Bisphosphonates-Contraindications Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia Inability to stand or sit upright for at least 30 minutes Patients at increased risk of aspiration Hypocalcemia Pregnancy Renal insufficiency (Not recommended if CrCl < 30-35 ml/min)

Bisphosphonates-Dosing Alendronate: 10 mg/day or 70 mg once weekly at least 30 minutes before eating or drinking Risedronate: 5 mg/day, 35 mg once weekly, or 150 mg once monthly Ibandronate: 150 mg once monthly at least 60 minutes before eating or drinking Zoledronate: 5 mg administered intravenously (IV) once yearly

Bisphosphonates-Duration of therapy The optimal duration: 5 years Repair (up to 12 months) Rebuilding (6–36 months) Maintenance (24–60 months) After 7 years of therapy the bone mass still increased by about 1% a year. However, a drug holiday after 5 years of alendronate therapy is advisable to avoid any possible microdamage accumulation, at least in low-risk patients.

Other medications

Raloxifene Mechanism: tissue-selective activity, acts as an estrogen agonist on bone - Estrogen antagonist on breast, uterus Approved only for the prevention and treatment of postmenopausal osteoporosis.

Raloxifene Reduce the incidence of vertebral fractures by 30-50% Reduction of 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.

Raloxifene: Adverse events Frequency > 10% Hot flashes Arthralgia Sinusitis Frequency 1-10% Chest pain Insomnia Migraines Peripheral edema Diaphoresis An increased risk of DVT: risk is similar to reported risk of HRT

Raloxifene: Containdications History of DVT/PTE or at high risk Cardiovascular disease History of uterine/cervical carcinoma Discontinue at least 72 hours prior to and during prolonged immobilization

Raloxifene-Dosing For prevention and treatment 60 mg PO once daily Can be taken any time of day without regard to meals

Calcitonin Approved for treatment of postmenopausal osteoporosis Mechanism: Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorption

Calcitonin-Dosing Nasal 200 international units daily Contraindications Clinical allergy to calcitonin-salmon Precautions Nasal ulcerations Tachyphylaxis (parenteral dosage forms) Drug interactions (DI) No formal studies designed to evaluate DI

Teriparatide Prevention and treatment of postmenopausal osteoporosis Treatment of osteoporosis in men Treatment of GIOP

Teriparatide The BMD of the lumbar spine increased by 12.2% in the women receiving teriparatide and by 5.6% in the women receiving alendronate (at 14 months) Teriparatide was found to reduce vertebral fractures by 65% and nonvertebral fractures by 53% Body et al. 2002

Teriparatide-Place in Therapy Women or men with severe osteoporosis and at least one fragility fracture Patients who are refractory to or unable to tolerate bisphosphonate In patients considered to be bisphosphonate failures PTH may be started approximately 3 months after bisphosphonates are discontinued

Teriparatide-Adverse events Hypercalcemia (11%) Dizziness (9%) Leg cramps (3%) Hyperuricemia Increased risk of osteosarcoma (rats)

Teriparatide-Dosing 20 µg daily as a daily subcutaneous injection for a maximum 2 years Anti resorptive therapy may be considered after discontinuation of PTH to maintain gains in BMD acquired with PTH alone in those at high risk for subsequent fracture

Teriparatide-contraindicated Patients with an increased risk of osteosarcoma Paget’s disease of bone Prior radiation therapy to skeleton unexplained elevations of ALP Bone metastases Hypercalcemia History of skeletal malignancy Pregnancy/nursing

Denosumab Reduces bone resorption by preventing RANK ligand, which is produced by the osteoblast, from attaching to its receptor on the osteoclast The BMD increase 3-6.7% in the spine and 1.9-3.6% at the hips (1 years) The BMD increase up to 18.5% in the spine and 8.2% at the hips (6 years) Mc Clung et al. 2006 Papapoulos et al. 2013

Denosumab A 3-year study of postmenopausal women with osteoporosis with the use of denosumab versus placebo - 68% relative decrease in the risk of new radiographic vertebral fracture - 40% relative decrease in the risk of hip fracture - 20% relative decrease in the risk of nonvertebral fracture

Denosumab Approval for the treatment of OP in - Postmenopausal women with a high risk of fracture, such as those with a history of fracture, women with multiple risk factors for fracture - Patients who failed or are intolerant of other available therapies

Denosumab The recommended dosing of denosumab is 60 mg subcutaneously every 6 months. Unlike the bisphosphonates, denosumab may be used in those with renal impairment provided that monitoring of calcium, phosphorus, and magnesium is carried out

Denosumab-adverse events Back pain (34.7%) Musculoskeletal pain (7.6%) High cholesterol (7.2%) Cystitis (5.9%)

Strontium Consisting of two atoms of stable strontium and an organic moiety (ranelic acid) Strontium (2 gm/d) for three years: - Increased in BMD at the LS as 8% - Decrease in risk of new vertebral fractures, hip fracture and non- vertebral fracture by 40%, 40% and 15% respectively

Strontium Diarrhea Drug rash with eosinophilia systemic symptoms and Stevens-Johnson syndrome (very rarely) Thromboembolic events Cardiovascular risk Strontium should be used with caution in patients who have had a thrombosis, and the treatment must be stopped in prolonged decubitus situations and in patients with skin reactions Strontium should not be be used in patients with IHD, peripheral arterial diseases, CVA, un controlled HTN

Odanakatib Selective catepsin K inhibitor Dose: 50 mg/week PO In a phase III trial the BMD of the lumbar spine increased by 5.5% and the hip increased by 3.2% Engelke et al. J Bone Miner Res. 2014

Monoclonal antibody against Sclerostin

Who should be treated All postmenopausal women who have had an osteoporotic vertebral fracture T-score ≤-2 T-score from -1.5 to -2 plus at least one of the following risk factors for fracture: thinness, history of fragility fracture (other than skull, facial bone, ankle, finger, and toe) since menopause, and history of hip fracture in a parent.

Who should be treated-NOF guideline Postmenopausal women and men age 50 and older who present with - T ≤-2.5 at the femoral neck or spine - Hip or vertebral fracture - T= -1.0 to -2.5 at the femoral neck or spine and a 10-year probability of a hip fracture ≥3% or a 10-year probability of a major osteoporosis-related fracture ≥20%

FRAX

Selection of drug Bisphosphonates recommended as first-line therapy for postmenopausal osteoporosis. Oral bisphosphonates are preferred For individuals with gastrointestinal intolerance: IV bisphosphonates

Selection of drug Raloxifene was reserved for patients who cannot tolerate any bisphosphonates or for women with osteoporosis and increased risk of invasive breast cancer.

Selection of drug Denosumab could be used as initial therapy in certain patients at high risk for fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates. Denosumab may have a role in patients who are intolerant of or unresponsive to other therapies and in those with impaired renal function.

Selection of drug Teriparatide should be reserved for treating women at high fracture risk, including those with very low bone mineral density (T-score worse than -3.0) with a previous vertebral fracture.

Follow up strategies Repeat DXA every 2 year using the same machine and technician if possible The lowest significant change is 3-4% at spine, 4-6% at hip and 2% at elbow If desired response not achieved - Re-evaluate the adherence to treatment regimen - Reconsider secondary OP - Consider changing patient medication

Combination therapy Combination of bisphosphonate-raloxifene therapy is not recommended as the additional BMD benefits are small and there is no proven additional fracture benefit. Combination therapy using PTH with raloxifene may enhance the bone forming effects of PTH.

Combination therapy Combination of PTH with alendronate blunts the effect of PTH and is not recommended Teriparatide combined with denosumab increased BMD more than either agent alone and more than has been reported with other approved Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA randomised trial. Lancet 2013; 382:50–56.