Management of osteoporosis

Learning objectives
At the end of this lecture, students are supposed to be familiar with:

1. Drugs that can increase the risk of osteoporosis

2. Medications used for management of osteoporosis - Bisphosphonates - Teriparatide and strontium ranelate - Hormonal replacement

2. Nutrational agents that may help management of osteoporosis

- Calcium - Vitamin D

What is osteoporosis?
A condition of low bone mass and microarchitectural disruption
that results in fractures with minimal trauma. Fracture risk increases exponentially with age Osteoporosis can be categorized as primary or secondary. 1) Primary osteoporosis Related to menopausal estrogen loss Related to aging. Osteoporosis is considered as the result of multiple physical, hormonal, and nutritional factors acting alone or in concert.

What is osteoporosis?
2) Secondary osteoporosis Due to systemic illness or medications The most successful approach to secondary osteoporosis is prompt resolution of the underlying cause or drug discontinuation. Both primary and secondary osteoporosis are associated with characteristic disordered bone remodeling (resorption and

ossification), so the same therapies can be used.

Drugs that can increase the risk of osteoporosis

Steroids and anticonvulsants
Steroid-induced osteoporosis (SIOP) arises due to use of glucocorticoids - analogous to Cushing's syndrome. Prednisone (synthetic glucocorticoid) is a main candidate after prolonged intake.

Prophylaxis is recommended in patients who take more than 7.5

mg of prednisolone, especially when this is in excess of 3 months. Barbiturates, phenytoin and some other enzyme-inducing

antiepileptics (probably accelerate the metabolism of vitamin D).

L-thyroxin over-replacement may contribute to osteoporosis, in a similar fashion as thyrotoxicosis.

Drugs that can increase the risk of osteoporosis

Several drugs induce hypogonadism:
aromatase inhibitors (for breast cancer) methotrexate and other anti-metabolites

depot progesterone
gonadotropin-releasing hormone agonists. Anticoagulants - long-term use of heparin and warfarin is associated

with a decrease in bone density.

Proton pump inhibitors: thought to interfere with calcium absorption. Aluminium-containing antacids: Chronic phosphate binding Rosiglitazone and pioglitazone (antidiabetics) have been linked with an increased risk of osteoporosis and fracture. Chronic lithium therapy has been associated with osteoporosis.

Management of osteoporosis
A. Medications
There are two primary types of drug therapy for osteoporosis: Antiresorptive Therapy Anabolic therapy

Act by decreasing the rate of bone resorption and By promoting bone formation. thereby slowing the rate of bone loss Bisphosphonates Estrogen Selective estrogen receptor modulators (SERMs) Calcitonin Teriparatide: the biologically active PTH fragment PTH(134) (teriparatide, FORTEO)

Since bone remodeling is a coupled process, antiresorptive drugs decrease the rate of bone formation and therefore do not promote substantial gains in BMD. They nonetheless reduce fracture risk, particularly in the spine but also in the hip.

Management of osteoporosis
A. Medications
Antiresorptive Agents I. Bisphosphonates (Antiresorptive) Bisphosphonates are the first-line treatment. The exact mechanism by which they selectively inhibit bone resorption is not clear. The most often prescribed bisphosphonates are: Sodium alendronate (Fosamax): 5 mg a day or 35 mg once a week (for prevention)

10 mg a day or 70 mg once a week (for treatment)

Risedronate(Actonel): 5 mg a day or 35 mg once a week Ibandronate (Boniva): orally 2.5 mg once daily or 150 mg once monthly

Management of osteoporosis
1. Bisphosphonates

Oral bisphosphonates are relatively poorly absorbed, and must therefore be taken on an empty stomach, with no food or drink to follow for the next 30 minutes. They are associated with esophagitis and are therefore sometimes poorly tolerated; weekly or monthly administration decreases likelihood of esophagitis, and is now standard.

Management of osteoporosis
1. Bisphosphonates

For patients in whom oral bisphosphonates cause severe esophageal distress, I.V zalendronate or pamidronate offers skeletal protection without causing adverse GI effects.

For osteoporosis, pamidronate is given as a 3-hour infusion, 30

mg every 3 months. Oral pamidronate (150 or 300 mg daily) is also effective Although intermittent dosing with the intravenous formulations avoids oral tolerance problems, these agents are implicated at higher rates in a rare unpleasant mouth disease called osteonecrosis of the jaw (Damage and death to areas of jaw bone occurs as a result of reduced local
blood supply).

Nearly half of the absorbed drug accumulates in bone; the remainder is excreted unchanged in the urine.

Management of osteoporosis
2. Hormone replacement Therapy (HRT)
Estrogen

Postmenopausal status or estrogen deficiency at any age increases a

patient's risk for osteoporosis and fractures.

Estrogen has a major role in regulation of the bone formationresorption equilibrium, as it stimulates osteoblast activity

Estrogen replacement protects against osteoporotic fracture after

menopause.

HRT for long-term prevention or treatment of osteoporosis is

associated with increased risks of heart disease and breast cancer.

Management of osteoporosis
2. Hormone replacement Therapy (HRT)
Estrogen

Experts now reserve HRT only for the short-term relief of

vasomotor symptoms associated with menopause.

HRT should be limited to osteoporosis prevention in women with

significant ongoing vasomotor symptoms who are not at an

increased risk for cardiovascular disease.

An annual individualized risk-benefit reassessment should be

performed on these patients.

Management of osteoporosis
3. Selective Estradiol Receptor Modulators (SERMs)

Estrogenic compounds with tissue-selective activities. Raloxifene (EVISTA), acts as an estrogen agonist on bone and
liver, is inactive on the uterus, and acts as an antiestrogen on the breast.

Raloxifene is approved for both the prevention and treatment of

osteoporosis in postmenopausal women.

With the decreased use of estrogen for treating osteoporosis,

raloxifene would seem to be an ideal alternative to HRT because it reduces the risk of vertebral, breast cancer, and coronary events.

The major drawback of raloxifene is that it can worsen

vasomotor symptoms.

Management of osteoporosis
4. Calcitonin

Calcitonin inhibits osteoclastic bone resorption and modestly

increases bone mass in patients with osteoporosis.

Calcitonin nasal spray (200 units/day) reduced the incidence of

vertebral compression fractures by about 40% in osteoporotic women.

Management of osteoporosis
5. Thiazide Diuretics

Not strictly antiresorptive 2+ Reduce urinary Ca excretion and constrain bone loss in
patients with hypercalciuria.

Whether they will prove to be useful in patients who are not

hypercalciuric is not clear, but data suggest that they reduce hip
fracture risk.

Hydrochlorothiazide, 25 mg once or twice daily, may reduce

urinary Ca excretion substantially.
2+

Effective doses of thiazides for reducing urinary Ca

2+

excretion

generally are lower than those necessary for blood pressure control

Management of osteoporosis
Anabolic agents
Teriparatide

Forteo, recombinant parathyroid hormone, amino acid sequence 1

through 34 of the complete molecule which contains amino acid
sequence 1 to 84 )

It stimulates osteoblasts increasing their activity and stimulate new

bone formation leading to increased bone mineral density

Management of osteoporosis
Anabolic agents
Teriparatide Indications:

1. Patients with established osteoporosis (who have already fractured),

2. Patients having low BMD or several risk factors for fracture 3. Patients who cannot tolerate the oral bisphosphonates.

It is given as a daily injection in the thigh or abdomen Teriparatide is only licensed for treatment if bisphosphonates

have failed or are contraindicated

Management of osteoporosis
Strontium ranelate (dual action bone agents)
An alternative oral treatment, belonging to a class of drugs called

"dual action bone agents" (DABAs).

Stimulates the proliferation of osteoblasts and inhibit the proliferation of osteoclasts. Strontium ranelate is taken as a 2 g oral suspension daily It does not cause upper GI side effect, which is the most

common cause for medication withdrawal in osteoporosis.

It may increase the risk of venous thromboembolism. less suitable in patients at risk for thrombosis

Management of osteoporosis
Strontium ranelate
Strontium must not be taken with food or calcium-containing preparations as calcium competes with strontium during uptake. It's essential that calcium, magnesium, and vitamin D in therapeutic amounts must be taken daily, but not at the same time as strontium.

Management of osteoporosis
B. Nutrition

Some mechanisms contributing to bone mineral homeostasis. Direct actions are shown and feedback may alter the net effect. Calcium (Ca) and phosphorus (P) concentrations in the serum are controlled principally by three hormones, 1,25(OH) 2D3 (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on excretion in the urine. PTH and 1,25(OH)2D3 increase input of calcium and phosphorus from bone into the serum and stimulate bone formation. 1,25(OH)2D3 also increases calcium and phosphate absorption from the gut. 1,25(OH)2D3 decreases urinary excretion of both calcium and phosphorus, whereas PTH reduces calcium but increases phosphorus excretion. FGF23 stimulates renal excretion of phosphate. Calcitonin (CT) is a less critical hormone for calcium homeostasis, but in pharmacologic concentrations can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example, vitamin D usually increases urinary calcium excretion because of effects on calcium absorption from the gut and effects on PTH.

Management of osteoporosis
B. Nutrition
1.Calcium

In elderly subjects, supplemental calcium suppresses bone turnover, improves BMD, and decreases the incidence of fracture Required to support bone growth, bone healing and maintain bone strength and is one aspect of treatment for osteoporosis. Calcium supplements can be used to increase dietary intake, and absorption is optimized through taking in several small (500 mg

or less) doses throughout the day.

Role of calcium in preventing and treating osteoporosis is unclear

Management of osteoporosis
B. Nutrition
1. Calcium

A possible increase in the rate of myocardial infarction (heart

attack) indicates that calcium supplementation in individuals at

low risk of fracture may cause more harm than good. Numerous oral calcium preparations are available, the most

frequently prescribed being calcium carbonate.

Dosing of calcium is 1000 mg/day. Added to the 500 to 600 mg of dietary calcium that typifies the diet of elderly, this provides a total

daily intake of about 1500 mg.

Calcium supplements are taken most often with meals to improve absorption.

Management of osteoporosis
B. Nutrition
Vitamin D and Its Analogs

Vitamin D supplementation(400 to 800 IU/day) in individuals

with marginal or deficient vitamin D status may: 1. Improve intestinal Ca2+ absorption 2. Suppress bone remodeling 3. Improve BMD 4. Reduce fracture incidence The use of calcitriol (1,25-dihydroxycholecalciferol, the hormonally active form of vit D) to treat osteoporosis is distinct from ensuring vitamin D nutritional adequacy. Here, the rationale is to suppress parathyroid function directly and reduce bone turnover.

Summary
Drugs that can increase the risk of osteoporosis Medications used for management of osteoporosis - Bisphosphonates - Teriparatide and strontium ranelate - Hormonal replacement Nutrational agents that may help management of osteoporosis

- Calcium
- Vitamin D