Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD.

Pharmacologic Pharmacologic Options for Options for

Osteoporosis Osteoporosis Prevention Prevention

and and TreatmentTreatment

Alireza Khabbazi, Alireza Khabbazi, MDMD

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– Osteoclast

• Bone Formation– Osteoblast

• Bone Multicellular Unit (BMU)– Positive < age 30– Negative > age 30

Lining cells

Remodeling (Resorption)

Bone Multicellular Unit (BMU)


RANKLRANK

Macrophage

CSF

Lymphocyte



RANKL

Macrophage

CSFPTH Vit D

IL

1, T

NFα

, IL6

, IL1

1

Lymphocyte


Osteoblast

RANKL

RANK


RANKL

Macrophage

Preosteoclast

CSFPTH Vit D

IL

1, T

NFα

, IL6

, IL1

1

Lymphocyte


Osteoblast

RANKL

RANK


RANKL

Macrophage

Preosteoclast

Osteoclast

CSFPTH Vit D

RANKL RANK

IL1,TNFα,IL6

IL

1, T

NFα

, IL6

, IL1

1

Lymphocyte


Osteoblast

RANKL

RANK


RANKLRANK

Macrophage

Preosteoclast

Osteoclast

CSFPTH Vit D

RANKL RANK

IL1,TNFα,IL6

IL

1, T

NFα

, IL6

, IL1

1

Lymphocyte

Osteoblast


RANKL

Cathepsin K

Remodeling (Formation)

Osteoclast inhibition

RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG

Osteoblast

IL

1

Lymphocyte



RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG

Osteoblast

IL

1

Lymphocyte

-



RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG

PTH Vit D

Estrogen

AndrogenIGF

Osteoblast stimulationOsteoblast

Mechanical stimuli

IL

1

Lymphocyte

-


Osteoblast proliferation


Osteoid

Osteocyte

Lining cells

Etiology and pathogenesis of Osteoporosis

PTH Vit D

IL1 TN

Fα IL6 IL11

RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG

PTH Vit D

EstrogenProgestrone

AndrogenIGF

Osteoblast

Hyperparathyroidism Estrogen deficiency Inflammation

Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs

toxins

Osteoblast

Lym

ph

ocy

tePathogenesis

Cathepsin K

Osteoclast

PTH Vit D

IL1 TN

Fα IL6 IL11

RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG

PTH Vit D

Estrogen

AndrogenIGF

Osteoblast



toxins

Osteoblast

Lym

ph

ocy

te

Progestrone

Pathogenesis

Cathepsin K

Osteoclast

PTH Vit D

IL1 TN

Fα IL6 IL11

RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG

PTH Vit D

EstrogenProgestrone

AndrogenIGF

Osteoblast



toxins

Osteoblast

Lym

ph

ocy

tePathogenesis

Cathepsin K

Osteoclast

Drugs used for osteoporosis treatment

Treatment

Osteoclast

PTH

RANKL RANK

IL1,TNFα,IL6

Estrogen

OPG Estrogen

AndrogenIGF

OsteoblastOsteoblast

IL1 TN

Fα IL6 IL11

Lym

ph

ocy

te

Progestrone

Ca, Vit D

Biphosphonates

SERMs

Teriparatide

Strontium Denosumab

+

Calcitonine

_

+

_+ _

PTH Vit D

Exercise

Cathepsin K

Odanacatib

_

Drugs used for osteoporosis

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

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


• 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.


• 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.


• 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)

Papapoulos et al. 2013

Mc Clung et al. 2006

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 nonvertebral 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%

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 randomisedtrial. Lancet 2013; 382:50–56.

Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD.

Documents

Transcript of Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD.