OSTEOPOROSISOSTEOPOROSIS

Definition

• Osteoporosis is a “disease characterized by low bone mass and microar-chitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.”

• Osteoporosis as “a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.”

Consensus Development Conference: Diagnosis, prophylaxis, and treatment of osteoporosis.

(1993) Am J Med 94:646-650.

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy March

7-29, 2000: highlights of the conference. (2001) South Med J 94:569-573

Pathophysiology

• Osteoblasts and osteoclasts.

• Osteoporosis results from loss of bone mass when the rate of bone resorption exceeds that of bone formation.

• Clinically, osteoporosis can be classified as primary and secondary. Primary osteoporosis includes postmenopausal osteoporosis and senile osteoporosis.

J Korean Soc Endocrinol. 2005 Dec;20(6):543-555. Korean.

Type 1 primary osteoporosis

Postmenopausal osteoporosis

•Postmenopausal women, especially those who have been menopausal for 15-20 years.

•Estrogen level drops drastically, and increased activity of osteoclasts to promote the resorption of the trabecular bone, weakening of bone strength.

•Compression spine fracture, wrist fracture and intertrochanteric fracture of the femur.

Type 2 primary osteoporosis

Senile osteoporosis

•Women aged ≥70 years or men aged ≥80 years.

•Decreased bone formation caused by diminished function of osteoblasts, insufficient intake of calcium and vitamin D, and poor intestinal absorption.

•Multiple vertebral wedge fracture, and fracture of humerus, tibia and femoral neck (hip).

Secondary osteoporosis

“Secondary osteoporosis” is usually related to bone mass loss from certain conditions

• Steroid use

• Hyperparathyroidism

• Thyroid disease

• Hypogonadism

• Rheumatoid arthritis

• Kidney disorders

• Liver disorders

• Diabetes mellitus

• Smoking, alcohol abuse

• Organ transplantation

• Fracture

• Insufficient intestinal absorption

Epidemiology

Age Male Female All

50 ~ 64 years old 8.4 % 16.7 % 12.6 %

65 ~ 74 years old 13.2 % 29.6 % 21.9 %

Over 75 years old 17.4 % 32.7 % 24.1 %

• Incidence of hip fracture in Taiwan, women were twice as likely to experience bone fracture as men.

• Patient increases the number of cases by 3~5% annually, and the gross one-year death rate of men is 22% and 15% for women.

Epidemiology

• In Taiwan, the incidence rate of vertebral body fracture in women aged 65~70 was

14% and 30% for the group of ≥80

• The prevalence in men is about sixty percent of that in women.

• The incidence of hip fracture or spine fracture of the middle-aged and aged patient

is higher than the world average.

Diagnosis

Difference between present height and height at youth

•A ≥3-cm difference between the present height and the height at youth strongly suggests the possibility of osteoporosis.

Weight

•Body weight is inversely proportional to bone density, indicating that low body weight is a risk factor of osteoporosis, and this is especially true when body mass index is lower than 18.5 kg/m2.

Diagnosis

Wall-Occiput Distance (WOD)

•This is a quick method for screening subclinical

compression fracture of the thoracic spine.

•A gap of 3 cm is found, a problem is strongly

suggested, and it is confirmed when it is >6 cm

Diagnosis

Rib-pelvis distance (RPD)

•This is a quick method for screening subclinical

compression fracture of the lumbar spine.

•In normal individuals, it should be 2-3 fingerbreadths

or >5 cm. A distance of

Diagnosis

Quantitative Ultrasound (QUS)

•Ultrasound can be used to obtain more information

about bones to define the resilience and stiffness of

bone mass.

•Calcaneus or tibia is the most frequently used for

measurement

•QUS can be used for the effective evaluation of bone

fracture risk in postmenopausal women and aged men

Diagnosis

Dual energy X-ray Absorptiometry (DXA)

•It uses X-ray emitters of two different levels for

scanning, and BMD value (g/cm2) is calculated with

the amount of absorption by dorsal bone and soft

tissue, and the scanned area.

•It is usually used on the lumbar spine and hip bone.

•It can be used for estimation of the risk of bone

fracture, the response and efficacy of treatment

Diagnosis

Bone mineral density (BMD)

World Health Organization Definitions Based on Bone Density Levels

Level Definition

Normal +1 ≦ T score≦ −1

Low bone mass −1≦ T score≦ −2.5

Osteoporosis −2.5 ≦ T score

Severe (established)

osteoporosis

−2.5 ≦ T score , and there have been one or more osteoporotic fractures.

NIH Osteoporosis and Related Bone Diseases ~ National Resource

Diagnosis

• The Fracture Risk Assessment Tool (FRAX) published by the International

Osteoporosis Foundation (IOF) in 2008 provides effective prediction of fracture risk

in the following decade.

• For high risk patients (defined as individuals with a major fracture risk of ≥20% or

hip fracture risk of ≥3%), active preventive intervention is recommended.

Prevention and Treatmentof Osteoporosis without MedicationDiet- Calcium

blood

calcium

level

100 mg / L

bone formation bone resorption

Prevention and Treatmentof Osteoporosis without MedicationIn Taiwan, the dietary reference intake (DRI) of calcium for adults aged ≥19 is 1000 (the adequate intake) – 2500 (upper limit) mg/d.

含鈣量含鈣量含鈣量含鈣量 (mg) 食物食物食物食物 份量份量份量份量

> 350 mg 高鈣奶粉 25 g

300-349 mg起司 40 g

補體素 25 g

250-299 mg 鮮乳、保久乳 240 ml

200-249 mg

黑芝麻 15 g

小魚乾 10 g

芥蘭菜 100 g

120-199 mg魚鬆 35 g

莧菜、紅鳳菜 100 g行政院衛生署食品工業研究所

Diet- Vitamin D

•Vitamin D maintains the balance of calcium and phosphorus in the human body and regulates active calcium absorption in the intestines.

•Its limited supply in natural foods, sun exposure is the main source of vitamin D

other than fortified foods and supplements.

•The recommended dietary allowance (RDA) of vitamin D for adults aged 19-50 in Taiwan is 200 IU/d (5 μg/d), and 400 IU/d (10 μg/d) for those aged 51-70. The limit is 2000 IU/d (50 μg/d).

Prevention and Treatmentof Osteoporosis without Medication

Exercise

•Low to Moderate Intensity Weight-Bearing Impact

Exercise

• Walking - femoral neck

•High Intensity Weight-Bearing Impact Exercise

• Jogging - lumbar spine, femoral neck

•Mixed Weight-Bearing Impact Exercise

• Walking, Jogging and Stair Climbing - lumbar spine,

femoral neck, calcaneus calcaneu

lumbar

spine

Prevention and Treatmentof Osteoporosis without Medication

femoral neck

Lifestyle

•The bone density of somkers at the femoral neck, radius and calcaneus is lower.

•Alcoholics have lower bone density and bone formation, and a higher risk of bone fracture

Prevention and Treatmentof Osteoporosis without Medication

Prevention and Treatment of Osteoporosiswith MedicationMechanisms

1.anti-osteoclast/anti-resorptive activities

• calcium supplements, vitamin D, bisphosphates, sex hormones, selective estrogen receptor modulators (SERMs), and RANKL monoclonal antibodies

2.osteoblast and bone formation activators

• parathyroid hormone and its active fragments

3.Mixed activities

• strontium salts

Calcium supplements

• According to the International Osteoporosis Foundation, the recommended

calcium intake of postmenopausal women and elders aged >65 is 1300 mg/day.

• Calcium carbonate is the most common and cheapest form of calcium supplement.

• calcium citrate is recommended for individuals with inadequate gastric acid

secretion, constipation, bloating or a history of kidney stones

Vitamin D

• Adequate vitamin D (at least 800 IU/day) and calcium intake is a basic and

important element in the prevention of osteoporosis.

• All clinical trials of medication with proven efficacy for treating osteoporosis and

reducing bone fractures are must provided with critically sufficient vitamin D and

calcium nutrition.

Bisphosphates

• When entering the human body, its high plasma clearance is associated with rapid

elimination through urine, but still allows about 50% of the administered dose to

accumulate in bone, where the half-life in bone is much longer.

• The mechanism of bisphosphates involves the inhibition of osteoclast activity and

bone resorption.

• Bisphosphates include

• Alendronic acid

• Ibandronic acid

• Zoledronic acid

Bisphosphates

Alendronic acid (Alendronate Sandoz®) : 70mg F.C. tablet oral QW

Alendronic acid (Fosamax Plus®) : 70mg + Colecalciferol 5600IU tablet oral QW

•It have an extremely low bioavailability and should be taken with 200ml water.

•When taken with food, calcium supplements, iron supplements, coffee, tea or

orange juice, its absorption is likely to be affected.

•Not lie down for at least 30 minutes after taking

alendronate and until after food.

•It is not recommended for patients with creatinine

clearance less than 35 mL/min.

Bisphosphates

Ibandronic acid (Bonviva®) : 3mg/3mL IV Q3M

•For the treatment of post-menopausal women with osteoporosis to reduce spine

fractures.

•Intravenous injection 3 mg over 15 to 30 seconds.

•The missed dose should be given as soon as it can be

rescheduled. After you receive the missed dose, your

next injection should be scheduled 3 months from the

date of your last injection.

Bisphosphates

Zoledronic acid (Aclasta®) : 5mg/ 100ml IVF over 15 mins once of year

•Zolendronic acid is the only effective bisphosphate molecule against spinal, non-

spinal and hip fractures, but long-term (>3 years) safety data is lacking.

•When patient receive zoledronic acid, be sure to drink at

least 500 c.c. of water before and after the treatment.

Bisphosphates

Generic Name Alendronic acid Ibandronic acid Zoledronic acid

Brand NameFosamax plus

Alendronate Sandoz

Boniva Aclasta

IndicationsPostmenopausal osteoporosis

Senile osteoporosis

Postmenopausal osteoporosis Postmenopausal osteoporosis

Senile osteoporosis

Dosage and

administration70 mg PO QW 3mg/3mL IV Q3M 5mg/100mL IVF once of year

Renal Impairment Clcr less than 35 mL/min Clcr less than 30 mL/min Clcr less than 35 mL/min

Lower risk spinal, hip fractures spinal fractures spinal, non-spinal and hip fractures

Adverse Events

Osteonecrosis of the jaw

The risk of ONJ may increase with duration of exposure to bisphosphonates.

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may

reduce the risk for ONJ.

Bisphosphates

Patient’s fracture risk Suggested duration of treatment Suggested duration of drug holiday

Low Treatment rarely indicated NA

Mildly increased Treat for approximately 5 yrStay off bisphosphonate until BMD decreases

significantly or fracture occurs

Moderately increased Treat for 5–10 yrStay off bisphosphonate for 2–3 yr (or less if BMD

decreases or fracture occurs)

High Treat for 10 yr

Stay off bisphosphonate for 1–2 yr (or less if BMD

decreases or fracture occurs); alternate

medication (e.g. raloxifene, teriparatide) may be

given during the holiday from bisphosphonates

Suggested duration of bisphosphonate treatment and drug holidays

Watts NB, Diab DL: Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 2010; 95: 1555-65.

Selective Tissue Estrogenic Activity Regulator

Tibolone (Livial®) : 2.5mg tablet oral QD

•It is metabolized in the liver and intestines, and the metabolites from different enzymatic activities act as estrogen analogs and/or antagonists and progesterone in various tissues

•Tibolone may be used in the prevention of osteoporosis because of its estrogenic effect of improving bone density.

•Tibolone can be used for postmenopausal syndrome because its actions are similar to estrogen and progesterone, and it is associated with a lower risk of uterine bleeding than the hormone therapy with progesterone

Selective estrogen receptor modulator (SERM)

Raloxifene (Evista®) : 60mg tablet oral QD

•SERM is a non-estrogenic medication that induces estrogenic or anti-estrogenicactivity by binding with estrogen receptors on the cells.

•It can be taken with food, drinks, vitamin D and calcium supplements.

•VTE is a more serious side effect, And mainly occurs in the first two years of use.

RANKL monoclonal antibodies

• In the cell differentiation process of bone remodeling, receptor activator of NF-kB (RANK) binds with RANK ligand (RANKL) to activate the differentiation of osteoclasts.

• RANKL monoclonal antibodies act on RANKL to block activation, which inhibits osteoclastic activity, and is followed by decreased bone loss, increased bone density and a decreased risk of bone fractures

RANKL mature and active osteoclasts

RANKL monoclonal antibodies blocks RANKL and activation of osteoclasts

RANKL monoclonal antibodies

RANKL monoclonal antibodies

Denosumab (Prolia®): 60 mg subcutaneous injection every 6 months.

•It’s bioavailability of 61% and a half-life of 26 days, peak blood level is reached 10 days after administration.

•Side effects identified include infection, constipation, sore throat and rash that are usually mild.

•When you remove Prolia from the refrigerator, Prolia must be kept at room temperature [up to 77°F (25°C)] in the original carton and must be used within 14 days.

Parathyroid hormone

• It’s regulates calcium homeostasis by promoting bone metabolism, renal calcium reabsorption and intestinal calcium absorption.

• When chronic or continuous exposure as seen in hyperparathyroidism, which causes higher osteoclastic activity and rapid progression of osteoporosis.

• When exogenous administered once a day, the risk of bone fractures is lower because intermittent use is associated with higher osteoblastic activity, which reinforces bone microstructure, mass and strength.

Parathyroid hormone

Teriparatide (Forteo®): 20μμμμg subcutaneous injection QD.

•It is bioavailability of 95% and a plasma half-life of 1 hour, peak blood level is reached 30 minutes after injection and became undetectable 3 hours after injection.

•Indications include postmenopausal osteoporosis and senile osteoporosis

Parathyroid hormone

• Adverse reactions include hypercalcemia, hypercalciuria, nausea, headache, leg cramps and orthostatic hypotension, and usually temporary and mild

• Teriparatide is not recommended for patients with history of metastatic bone tumors or bone malignancy because its long-term use at high doses has been associated with a higher risk of osteosarcoma in the animal model.

• PTH should not exceed 24 months.

• The bone density decline after the cessation of teriparatide, which means that other medications should be followed when the regimen is discontinous.

Strontium salts

• Stimulate promotes bone formation through the stimulation of calcium sensing receptors (CaSRs) that activates pre-osteoblasts to osteoblasts, while the inhibition of bone resorption is achieved by interfering with the binding of the receptor activator of NF-kB (RANK) with RANK ligand (RANKL) that strontium ranelate stimulate to secrete osteoprotegerin (OPG).

Strontium salts

Strontium ranelate (Protos®): one package (2 grams) QD or HS

•One package (2 grams) of strontium ranelate added to water to prepare oral suspension taken once a day.

•For adequate absorption, at least two hours should be kept between strontium ranelate and the use of calcium, antacids and antibiotics (e.g. tetracycline, quinolone).

•Precaution is advised in patients, e.g. phenylketouria (PKU) and venous thromboembolism (VTE)

•Cessation is recommended for patients experiencing drugrash with eosinophilia

CONCLUSION

Conclusion

藥物種類藥物種類藥物種類藥物種類/作用作用作用作用 健保規範健保規範健保規範健保規範 副作用副作用副作用副作用 禁忌症禁忌症禁忌症禁忌症

抗破骨類藥物 1. 停經後婦女因骨質疏鬆症 (須附 DXA BMD 之T score≦ -2.5SD)引起脊椎或髖部骨折。

2. 停經後婦女因骨質疏少症 (經DXA檢測BMD之-2.5SD

Reference

• Taiwan osteoporosis practice guidelines. Taiwan (ROC): Bureau of Health Promotion, Department of Health, Taiwan; 2011 Dec.

• Consensus Development Conference: Diagnosis, prophylaxis, and treatment of osteoporosis. (1993) Am J Med 94:646-650.

• NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy March 7-29, 2000: highlights of the conference. (2001) South Med J 94:569-573

•國民健康署103年國民健康訪問調查

• NIH Osteoporosis and Related Bone Diseases ~ National Resource Center; https://www.niams.nih.gov/Health_Info/Bone/

• FRAX® , http://www.shef.ac.uk/FRAX/index.aspx?lang=cht

• Prolia® (denosumab) prescribing information, Amgen

•行政院衛生署：台灣地區食品營養成分資料庫2010，http://www.doh.gov.tw/FoodAnalysis/ingredients.htm

• RAO WHO (2002) Human Vitamin and Mineral Requirements

• Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P (2007) Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 92:1415-1423

• Sidney M. Wolfe, “Kidney Damage Due to Osteoporosis Treatment”, WorstPills.org, 12 Mar. 2011.

•于振東：治療骨質疏鬆的新利器—間歇式注射副甲狀腺素。台灣醫界 2008: 51: 22-23

• Hwang JS, Chen JF, Yang TS, Wu DJ, Tsai KS, Ho C, Wu CH, Su SL, Wang CJ, Tu ST (2008) The effects of strontium ranelate in Asian women with postmenopausal osteoporosis.[Erratum appears in Calcif Tissue Int. 2009 Apr;84(4):334]. Calcified Tissue International 83:308-314

•余傑明：骨質疏鬆症的藥物治療。臺灣老年醫學暨老年學雜誌 2012；7(2)：77-90

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