1. CPD Presentation
OSTEOPOROSIS
by Chin Yeun, Shee (f0163)

2. Osteoporosis is defined as
‘a systemic skeletal disease characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.’
Figure 1: Representation of normal and osteoporotic bone tissue.

3. Osteoporosis Altered bone remodeling cycle
An imbalance in favor of bone resorption over bone formation
Osteoporotic bone shows an increase in the length of the remodeling cycle and reduced capacity to lay down a new mineralized bone matrix
Bone remodeling cycle consists of five phases:
1. Activation: preosteoclasts are stimulated and differentiate under the influence of cytokines and growth factors into mature active osteoclasts; 2. Resorption: osteoclasts digest mineral matrix (old bone); 3. Reversal: end of resorption; 4. Formation: osteoblasts synthesize new bone matrix; 5. Quiescence: osteoblasts become resting bone lining cells on the newly formed bone surface.
We are born with about 300 soft bones. During childhood and adolescence, the cartilage grows and is slowly replaced by hard bone. Some of these bones later fuse together, so that the adult skeleton has 206 bones.
About 20% of all bone tissue is replaced annually by the remodeling process. Bone remodeling process is the replacement of old tissue by new bone tissue. It occurs at many simultaneous sites throughout the body (mainly in adult skeleton) where bone is experiencing growth, mechanical stress, microfractures, or breaks. The total process takes about 4 to 8 months, and occurs continually throughout our lives.
Figure 2: Representation of the bone remodeling cycle in osteoporosis.
Abbreviations: BRU, bone remodeling unit; CL, cement line; LC, lining cells; OS, osteoid.
From: © 2010, Medscape.

4. Classification Based on individual bone mineral density (BMD)
Dual energy X-ray absorptiometry (DEXA) is the best current test to measure BMD
Category
Description
Normal
BMD within 1 SD of young adult reference range
(T score > -1)
Osteopenia
BMD more than 1 SD but less than 2.5 SD below the young adult mean (T score between -1 and -2.5)
Osteoporosis
BMD value of 2.5 SD or more below the young adult mean (T score ≤ -2.5)
Severe / Established Osteoporosis
BMD value of 2.5 SD or more below the young adult mean with the presence of 1 or more fragility fractures
Osteoporosis is diagnosed based upon:- BMD measurement, physical assessment, laboratory tests (e.g. FBC, creatinine, calcium), clinical risk factors, and medication history.
Fracture risk assessment 
In 2008, a WHO task force introduced a Fracture Risk Assessment Tool (FRAX), which estimates the 10-year probability of hip fracture or major osteoporotic fractures combined (hip, spine, shoulder, or wrist) for an untreated patient using femoral neck BMD and easily obtainable clinical risk factors for fracture.
BMD measurement
Criteria
BMD screening is recommended for postmenopausal women at age > 65 years with at least one risk factor.
Suggest not performing routine BMD measurements in premenopausal women unless they are under the following circumstances:
(a) History of a fragility fracture
(b) Known secondary causes of osteoporosis
-Suggest not performing routine testing in men unless: with clinical manifestations of low bone mass, such as radiographic osteopenia, history of low trauma fractures, and loss of more than 1.5 inches in height, as well as in those with risk factors for fracture, such as long-term glucocorticoid therapy, androgen deprivation therapy for prostate cancer, hypogonadism, primary hyperparathyroidism, and intestinal disorders.
Devices
DEXA is most often performed on the lower spine and hips. This test is quick, painless, and safe - is similar to an x-ray but uses much less radiation (about one-tenth of a chest X-ray). Nevertheless, it is advisable not to perform on pregnant women to avoid any risk of harming the fetus.
-DEXA scores are reported as "T-scores" and "Z-scores“.
(a) The T-score is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex. Multiplying the T-score by 10% gives a rough estimate of how much bone density has been lost;
(b) The Z-score is a comparison of a person's bone density with that of an average person of the same age and sex– less commonly used but is suitable for interpretation in children (including body size, growth and puberty stage?) .
Simple biochemical tests (e.g. ESR, x-rays) may be necessary. Osteoporosis is apparent in plain X-rays only after 30% of bone loss has occurred.
-Other less commonly used technologies can measure bone density. They include:
(a) Variations of DEXA, which measure bone density in the forearm, finger, or heel;
(b) Quantitative computerized tomography (QCT). QCT provides more detailed images, but costs more than DEXA;
(c) Ultrasound of the bones in the heel, leg, kneecap, or other areas.
Table 2: The World Health Organisation (WHO) criteria for classification of osteoporosis.
Abbreviations: BMD, body mineral density; SD, standard deviation.
WHO Fracture Risk Assessment Tool:

5. Risk factors Non-modifiable Modifiable
Older age (starting in the mid-30’s but more likely with advancing age)
Oestrogen deficiency (e.g. menopause)
Non-Hispanic white or Asian ethnic background
Low calcium and vitamin D intake
Small bone structure or low body mass index (<19kg/m²)
Sedentary (inactive) lifestyle or immobility
Family history of osteoporosis or an osteoporosis-related fracture in a parent or sibling
Cigarette smoking
Prior fracture due to a low-level injury, particularly after age 50
Excessive alcohol consumption
Medications
Long term treatment with glucocorticoids (e.g. prednisolone)
Excess thyroid hormone replacement in patients with hypothyroidism
Heparin
Treatments that deplete sex hormones (e.g. anastrozole (Arimidex) and letrozole (Femara) to treat breast cancer or leuprorelin (Lupron) to treat prostate cancer and other health problems
Diseases
Endocrine (hormone) diseases
(e.g. hyperthyroidism, hyperparathyroidism, hypogonadism, Cushing’s disease, osteogenesis imperfecta)
Inflammatory arthritis (e.g. rheumatoid arthritis)
Eating disorder (e.g. anorexia nervosa)
Malabsorption / post-gastrectomy
Multiple myeloma and malignancy
Family History
Osteoporosis can run in families, probably due to inherited factor that affects the development of bones.
Hormonal changes
Oestrogens and androgens decrease bone resorption, restrain the rate of bone remodeling, and help to maintain a focal balance between bone formation and resorption. These effects are the result of hormonal influences on the birth rate of osteoclast and osteoblast progenitors in the bone marrow, as well as pro-apoptotic effects on osteoclasts and anti-apoptotic effects on mature osteoblasts and osteocytes.
The bone loss speeds up in women after the menopause (especially in the first 5 years) because the ovaries stop producing oestrogen.
Men are less likely to develop osteoporosis than women for two reasons. First, they gain more bone during puberty, and second, they lose less bone during aging because, unlike women, men do not experience an abrupt loss of oestrogens. Osteoporosis develops in men with androgen deficiency due to less androgen aromatization into bioavailable, bone-preserving oestradiol.
Calcium and vitamin D
Without calcium, you can't rebuild new bone during the lifelong process of bone remodeling. Bones are the reservoir for two minerals -- calcium and phosphorus. You need a constant level of calcium in your blood since many of your organs, especially your heart, muscles, and nerves, depend on calcium. When these organs demand calcium, they'll steal it from the mineral storehouse in your bones. Over time, as you deplete the mineral reservoir in your bones, you end up with thin, brittle bones.
Too little vitamin D can lead to weak bones and increased bone loss. Active vitamin D, also called calcitriol, is more like a hormone than a vitamin (is synthesized in the kidney). Among its many benefits, vitamin D helps your body to absorb and use calcium.
Lifestyle
For people who are sedentary or have a condition like paralysis or muscular dystrophy, bone loss happens quickly (mechanism is unknown).
Studies on smoking and bone health have turned up a host of other dire effects, from direct toxic effects of nicotine on bone cells to blocking the body's ability to use oestrogen, calcium, and vitamin D (may accelerate of the metabolism of estrogen, thereby lowering serum estrogen concentrations).
Alcohol can arrest bone remodeling and increase your calcium loss.
Medications
Glucocorticoid excess (equivalent to ≥ 7.5 mg prednisolone daily for ≥ 1 year) directly suppresses osteoblastogenesis, strongly and rapidly stimulates osteoblast and osteocyte apoptosis, and prolongs the lifespan of osteoclasts.
The mechanism of heparin-induced osteoporosis is not well established.
Older age and diseases
Several other hormones play a role in regulating your bone density, including parathyroid hormone and growth hormone. They help orchestrate how well your bones use calcium -- and when to build up and break down bone.
Parathyroid hormone (PTH) is most responsible for maintaining serum ionized calcium concentrations within a narrow range, through its actions to stimulate renal tubular calcium reabsorption and bone resorption. Chronic exposure to high serum PTH concentrations (as seen with primary or secondary hyperparathyroidism) results in bone resorption and calcium loss in the urine at the expense of bone. Less calcium means weaker bones. And as you age, your body produces less growth hormone, which you need to build strong bone.
Oxidative stress - An increase in reactive oxygen species (ROS) has been implicated in the decreased bone formation associated with advancing age. In line with this evidence, increased ROS production in osteoblasts stimulates apoptosis and decreases bone formation.
Osteogenesis imperfecta (OI) is disorder of congenital bone fragility caused by mutations in the genes that codify for type I procollagen (e.g. COL1A1 and COL1A2).
A host of medical conditions can lead to bone loss, from genetic diseases like cystic fibrosis to digestive diseases to the tumors called multiple myeloma, which infiltrate bones with abnormal cells. Abnormal calcium excretion also contributes to bone loss.
Table 1: List of possible risk factors of osteoporosis.

6. Osteoporosis May not lead to any symptoms
Indicated when there is a broken (fractured) hip, wrist or spine after a minor fall
Often present with symptoms of back pain and potential loss of height and spinal (vertebrae) deformity, causing physical disable and even death
As the bones of the spine weaken in osteoporosis, fractures can occur, causing the bones to collapse and get shorter. This can lead to a loss of height and a forward curving of the spine.
Figure 3: Progressive spinal deformity in osteoporosis

7. Management of Osteoporosis
Prevention of osteoporosis or low BMD is preferable to treatment because bone microarchitectural changes associated with bone loss are largely irreversible. Treatment may stabilize or increase BMD and reduce the risk of fracture, but is unlikely to fully restore bone quality and bone strength.

8. Management of Osteoporosis in UMMC
Can look for the form in outpatient pharmacy (K16)

9. Lifestyle interventions
Calcium intake
Vitamin D intake
Increase physical activity
Smoking cessation
Reduce alcohol consumption
From diet or supplements
Counselling points:
- Keep healthy, balanced diet: encourage to drink 1 cup of milk / soy milk daily, or food intake which is rich in calcium or vitamin such as yogurt, cheese, and etc.
Engage in weight-bearing, aerobic exercise such as jogging. Aim for at least 2½ hours a week (30 minutes a day five times a week or 50 minutes a day three times a week); For those with older age and have fracture risk, suggest not to lift heavy stuff.
Advise to wear comfortable, flat, closed shoes (to prevent incidence of falls)
- Advise not to drink more than the daily unit guidelines of 3-4 units of alcohol for men (equivalent to a pint and a half of 4% beer) and 2-3 units of alcohol for women (equivalent to a 175 ml glass of wine).

10. Recommended Daily Calcium Intake
Category
Age / year old
Recommended Intake / mg
Neonates & Infants *
0 – 6 months
7 – 12 months
200
260
Children
1 – 3
4 – 8
9 – 13
700
1000
1300
Adolescents
14 – 18
Men
19 – 50
51 – 70
1200
Women
51 – 70 (Menopausal)
1500
Elderly (men & women)
Over 71
Pregnant (Third trimester) & Lactating
Table 3: Recommended daily calcium intake in different age groups.
*Adequate intake

11. Sources of Calcium
Diet (e.g. milk, yogurt, cereal, soy beverages, and etc)
Supplementation
Calcium Carbonate
Recommended dose: 500 mg BD (May be sucked or chewed)
2. Calcium Lactate
Doses: Adults: mg daily
Pregnant women (during 3rd trimester and lactation): mg daily
Children over 3 years: 300 mg daily
Availability:
One 500mg calcium carbonate tablet contains 200mg calcium while one 300 mg calcium lactate tablet contains 39 mg calcium or 1 mmol Ca2+.
Both are available in inpatient pharmacy, outpatient pharmacy, and accident and emergency pharmacy.
Treatment option:
Calcium carbonate is among the least expensive -- and partially well absorbed?** -- forms of calcium available.
While calcium carbonate isn't particularly well absorbed, it does have the advantage of being an effective antacid due to the presence of the carbonate particle, which reacts with excess stomach acid.
Calcium lactate is among the most soluble of the calcium supplement salts.
**Refer from this website:
‘for every 1,000 mg of calcium carbonate, 40% of 400 mg is calcium. Of this 400 mg 10% is absorbed, or only 40 mg of calcium.’
‘for every 1,000 mg of calcium lactate 37% or 370 mg is calcium. And of this 370 mg, 33% is absorbed, or only 105 mg of calcium.’
Note
Patient may experience constipation, metallic taste or vomiting after administer calcium lactate tablets. It is advised not to take within 2 hours of other oral medications upon administration of calcium lactate tablets.

12. Suggested Daily Vitamin D Intake
Adults
< age 50, 400 – 800 International Units (IU);
> age 50, 800 – 1000 IU
Sources of Vitamin D
Exposure under sunlight
Diet
(e.g. cod liver oil, milk, yogurt, salmon, egg, and etc)
Counselling point:
Exposure under sunlight for ~15 minutes few times / week is sufficient to maintain adequate amount of vitamin D in the body.

13. Sources of Vitamin D (cont.)
Supplementation
Calcitriol and Alfacalcidol
Both are prescribed only for those who fulfill the requirements as below:
1. Renal impairment;
2. Patients > 65 years;
3. Intolerant to biphosphonates and SERMs;
4. Persistently low calcium levels;
5. Secondary hyperparathyroidism.
Availability:
- Both are available in in-patient pharmacy and out-patient pharmacy.
Calcitriol cost: RM 0.80 / 0.25 mcg capsule.
Alfacalcidol cost: RM 0.70 / 0.25 mcg, RM 2.70 / 1 mcg; should only be used in pregnancy and during lactation if considered essential.

14. Sources of Vitamin D (cont.)
Supplementation
Active Vitamin D
Available forms
Dosages
Prescribers
Calcitriol (or Rocaltrol)
0.25 mcg capsule
0.25 – 0.5 mcg daily (in divided doses – usually bd)
Orthopedics, Endocrinologists, Nephrologists, Geriatricians
Alfacalcidol
1 mcg capsule
Initial dose: Adults & children > 20kg: 1 mcg daily; Children < 20 kg: 0.05 mcg/kg/day; Neonates: 0.1 mcg/kg/day
Maintenance dose: 0.25 – 2 mcg daily
Endocrinologists, Nephrologists
Counselling point:
Avoid taking magnesium supplements or magnesium-containing antacids on calcitriol administration
Treatment option:
Calcitriol and alfacalcidol are prescribed in patients with renal problems.
Differences between calcitriol and alfacalcidol
-Calcitriol is the biological active form of vitamin D3 while Alfacalcidol (1hydroxyvitamin D3) is a prodrug which possesses low biological activity;
Equal efficacy (Alfacalcidol is rapidly converted to calcitriol in the liver) but ~40% higher doses of alfacalcidol is required to achieve the same effects on calcium and phosphate metabolism;
In comparison between both compounds using same dose, alfacalcidol provides a gentle continuous reise in vitamin D3 concentrations while calcitriol gives a high plasma peak of vitamin D3 concentrations. In addition, calcitriol either binds primarily after oral intake to the vitamin D receptors of the small intestinal mucosa or, after absorption, increases vitamin D3 serum plasma levels. Both effects result in an augmented risk for hypercalcuria and hypercalcemia.
Alfacalcidol is safer for use in the treatment of osteoporosis.
For more info about the physiological activities of vitamin D and calcitriol in human body, please refer this website:
Table 4: The dosages of Calcitriol and Alfacalcidol.

15. The interrelationships between homeostatic hormones.
The interrelationships between homeostatic hormones. Augmentation and reduction of linked processes/concentrations are depicted as positive (+ve) or negative (−ve) respectively. *These relationships are qualitatively preserved in uraemia with the exception of PTH-driven phosphaturia. The absence of phosphaturia in ESRD results in PTH acting as a phosphataemic hormone, as part of a positive feedback loop with phosphate.
Cited from website:
Schroeder N J , Cunningham J Nephrol. Dial. Transplant. 2000;15:
© 2000 European Renal Association-European Dialysis and Transplant Association

16. Other supplement: Metocal Vit D3
A combination of calcium and vitamin D
Dose: 1 – 2 chewable tablets daily
Take at least 2 hr before or 2 hr after meals due to a possible decrease of iron absorption
Availability:
Each chewable tablet contains calcium carbonate 1500 mg (equivalent to calcium 600 mg) and cholecalciferol concentrate 4 mg (equivalent to vitamin D3 400 IU), and is available in PharmUMMC.

17. Treatment options Bisphosphonates (e.g. alendronate, risedronate)
SERM (e.g. raloxifene)
Calcitonin
Strontium ranelate
PTH treatment (e.g. teriparatide)
Should maintain calcium and vitamin D supplementation when treatement is initiated (to prevent progressive loss of bone mass)
Monitoring response to therapy:
Follow up DEXA screening after 2 years (due to slow bone turnover).

18. Bisphosphonates (also known as antiresorptive drugs)
Generic name
Brand name
Dosages
Prescribers
Notes
Alendronate
Fosamax
70 mg once a week
Endocrinologist, Orthopeadics , O&G, Geriatricians, Rheumatologists
Patients must take on an empty stomach at least 30 minutes before breakfast with plain water only (allow optimal drug absorption) and remain upright for at least an hour after taking medications (bisphosphonates may irritate the esophagus).
Risedronate
Actonel
35 mg once a week
Prof SP Chan, Dr Vijay, Dr Sargunan, Dr Lim Soo San, Dr Tai Cheh Chin, Prof
Vickneswaran, Prof Philip Poi, Prof Siti Zawiah Omar, Prof Tan Peng Chiong
Ibandronate
Bonviva
150 mg once a month
Not prescribed in UMMC
Zoledronic acid
Aclasta
Single IV infusion once a year
Lecturers and consultants of Orthopaedics, Endocrinology and Rheumatology
Patient must drink at least 2 glasses of water before infusion of drug. Postdose symptoms: fever,
myalgia, flu like symptoms, arthralgia and headache (Usually occur within the first 3 days after
administration of Aclasta).
Treatment option:
We recommend bisphosphonates as first-line therapy for postmenopausal osteoporosis. We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. IV zoledronate acid is available for individuals with gastrointestinal intolerance to oral bisphosphonates.
Availability:
-Alendronate cost: RM 40 / 4 tabs (full charge: PharmUMMC; subsidized price: Out Patient Pharmacy)
-Risedronate is available in outpatient pharmacy and PharmUMMC; cost: Subsidized price (Govt servants = FOC, Private = RM 70 / month; Normal price: RM / 35mg tabs
Ibandronate is not available in UMMC
Zoledronic acid inj (Aclasta) is a 100mL vial, sterile, clear and colourless solution contains 5.33mg zoledronic acid monohydrate
(zoledronic acid 5 mg); is available in PharmUMMC (cost: RM 1300 / vial)
**Zometa (zoledronic acid 4 mg) is indicated for oncology treatment
Counselling point:
Bisphosphonate must be administered (orally/inj) on the same time, same day of the week / month / year
Table 5: The available products of bisphosphonates and their dosages.
Abbreviation: O & G, obstetrics and gynaecologists.

19. Selective oestrogen receptor modulator (SERM)
Mimics oestrogen’s good effects on bones without some of the serious side effects such as breast cancer
Decreases the risk of spine fractures, but there is a risk of blood clots with use of SERMs
Raloxifene (Evista)
Dose: 60 mg daily with or without food
Prescribers: Osteoporosis clinic: Prof SP Chan, Prof Rokiah, Dr Vijay; Orthopedic clinic: Dr Tai; Menopause clinic: Prof Siti Zawiyah
Treatment option:
Approved for use only in postmenopausal women who are intolerant to bisphosphonates
Contraindicated in:
Women with child bearing potential and history of venous thromboembolic events (VTE), renal and hepatic impairment including cholestasis, unexplained uterine bleeding, patient with signs or symptoms of endometrial cancer. Discontinue therapy in the event of illness or condition leading to a prolonged period of immobilization
Availability:
Evista cost: RM 4.70 / tablet; Patients who meet guidelines: government servants / dependants - FOC; others – RM 70 / month. (Available in outpatient pharmacy and PharmUMMC)

20. Calcitonin (Miacalcin)
A hormone made from the thyroid gland
Regulates calcium homeostasis
Prevents vertebral (spine) fractures and is helpful in controlling pain after an osteoporotic vertebral fracture
Nasal spray
Recommended dose: 200 IU / day
Injection
Dose: SC/IM IU daily or every 2nd day.
Max supply: 5 days.
Prescribers: Endocrinologists or Orthopaedics
Common adverse effects: nausea, vomiting, dizziness, and flushing
Treatment option:
We usually do not use calcitonin as first-line therapy because of its expense, the relative inconvenience of nasal or parenteral administration, frequent side effects, and the possible development of resistance. In addition, more effective drugs are available for prevention of bone loss and reduction of fracture risk. We often administer calcitonin if pain from an acute osteoporotic fracture is a prominent problem, and then switch to other agents such as bisphosphonates once the pain has abated.
Availability:
Calcitonin is available in inpatient pharmacy (chiller; cost: RM 40)

21. Strontium Ranelate (Protaxos)
Stimulates bone formation and reduces bone resorption
Reduces fractures, but there is a risk of blood clots with use of this medication
In powder form; to dissolve 2g sachet in water and taken daily at bedtime, at least 2 hours after eating
Prescribers: Prof SP Chan, Dr Vijay, Dr Sargunan, Dr Lim Soo San, Dr Tai Cheh Chin, Prof Vickneswaran, Prof Philip Poi, Prof Siti Zawiah Omar, Prof Tan Peng Chiong
Availability:
Strontium is available in outpatient pharmacy and PharmUMMC; cost: RM / 28 sachets (1 box)

22. Parathyroid hormone (PTH) Treatment
PTH stimulates bone formation and activates bone remodeling, resulting in significant increases in bone mineral density and a reduction in fracture risk
Due to the potential risk of carcinogenicity (osteosarcoma) , recommended maximum duration of treatment is 18 months
Teriparatide Inj (Forteo) - Parathyroid Hormone Analog
Dose: 20 mcg daily, into the thigh or abdominal wall (initial administration should occur under circumstances in which the patient may sit or lie down, in the event of orthostasis)
Prescribers: Prof SP Chan, Dr Vijay, Dr Sargunan, Dr Lim Soo San, Ddr Tai Cheh Chin, Prof Vickneswaran, Prof Philip Poi, Prof Siti Zawiah Omar, Prof Tan Peng Chiong
Common adverse events: nausea, constipation, pain in limb, rashes, headache, sweating and dizziness
Treatment option
Potential candidates for PTH therapy include:
- Men or postmenopausal women with severe osteoporosis (T-score of -3.5 or below even in the absence of fractures; T-score of -2.5 or below plus a fragility fracture);
- Patients with osteoporosis who are unable to tolerate bisphosphonates or who have relative contraindications to bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures);
- Patients who fail other osteoporosis therapies (fracture with loss of BMD in spite of compliance with therapy)
Given its cost, subcutaneous route of administration, long-term safety concerns, and availability of other agents, PTH is generally not used as a first-line drug for treatment or prevention of osteoporosis.
Combined treatment?
Several trials have reported that PTH plus alendronate (either started concurrently or six months prior to PTH) resulted in no additional benefit for spine or hip BMD compared with PTH alone. Combined treatment (PTH and raloxifene) is not recommended.
Availability:
Teriparatide inj is available in PharmUMMC Store (fridge in RFST Store; cost: RM 1,557 / pen)
Counselling point:
Refer to User Manual for instructions on how to use the pen.
** Store pen at 2-8ºC. The pen should be refrigerated immediately after use. Do not freeze.

23. Management of Postmenopausal Osteoporosis

24. Management of Glucocorticoid Induced Osteoporosis

25. Management of Male Osteoporosis

26. References
Clinical Practice Guidelines on Management of Osteoporosis (downloaded in pdf form; Available from
American College of Rheumatology website:
International Osteoporosis Foundation website:
D. Lajeunesse, J. –P. Pelletier, J. Martel – Pelletier (2010). Osteoporosis and Osteoarthritis: Bone is the Common Battleground. Medicographia. Vol. 32. No. 4. Page
Arthritis Foundation Malaysia website:
Websites:
National Institutes of Health website:
MIMS Malaysia website
UMMC Online Formulary