2Osteoporosis 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.
4Classification Based on individual bone mineral density (BMD) Dual energy X-ray absorptiometry (DEXA) is the best current test to measure BMDCategoryDescriptionNormalBMD within 1 SD of young adult reference range(T score > -1)OsteopeniaBMD more than 1 SD but less than 2.5 SD below the young adult mean (T score between -1 and -2.5)OsteoporosisBMD value of 2.5 SD or more below the young adult mean (T score ≤ -2.5)Severe / Established OsteoporosisBMD value of 2.5 SD or more below the young adult mean with the presence of 1 or more fragility fracturesOsteoporosis 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 measurementCriteriaBMD 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.DevicesDEXA 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:
5Risk 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 backgroundLow calcium and vitamin D intakeSmall bone structure or low body mass index (<19kg/m²)Sedentary (inactive) lifestyle or immobilityFamily history of osteoporosis or an osteoporosis-related fracture in a parent or siblingCigarette smokingPrior fracture due to a low-level injury, particularly after age 50Excessive alcohol consumptionMedicationsLong term treatment with glucocorticoids (e.g. prednisolone)Excess thyroid hormone replacement in patients with hypothyroidismHeparinTreatments 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 problemsDiseasesEndocrine (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-gastrectomyMultiple myeloma and malignancyFamily HistoryOsteoporosis can run in families, probably due to inherited factor that affects the development of bones.Hormonal changesOestrogens 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 DWithout 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.LifestyleFor 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.MedicationsGlucocorticoid 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 diseasesSeveral 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.
6Osteoporosis May not lead to any symptoms Indicated when there is a broken (fractured) hip, wrist or spine after a minor fallOften present with symptoms of back pain and potential loss of height and spinal (vertebrae) deformity, causing physical disable and even deathAs 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
7Management 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.
8Management of Osteoporosis in UMMC Can look for the form in outpatient pharmacy (K16)
9Lifestyle interventions Calcium intakeVitamin D intakeIncrease physical activitySmoking cessationReduce alcohol consumptionFrom diet or supplementsCounselling 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).
11Sources of CalciumDiet (e.g. milk, yogurt, cereal, soy beverages, and etc)SupplementationCalcium CarbonateRecommended dose: 500 mg BD (May be sucked or chewed)2. Calcium LactateDoses: Adults: mg dailyPregnant women (during 3rd trimester and lactation): mg dailyChildren over 3 years: 300 mg dailyAvailability: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.’NotePatient 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.
12Suggested Daily Vitamin D Intake Adults< age 50, 400 – 800 International Units (IU);> age 50, 800 – 1000 IUSources of Vitamin DExposure under sunlightDiet(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.
13Sources of Vitamin D (cont.) SupplementationCalcitriol and AlfacalcidolBoth 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.
14Sources of Vitamin D (cont.) SupplementationActive Vitamin DAvailable formsDosagesPrescribersCalcitriol (or Rocaltrol)0.25 mcg capsule0.25 – 0.5 mcg daily (in divided doses – usually bd)Orthopedics, Endocrinologists, Nephrologists, GeriatriciansAlfacalcidol1 mcg capsuleInitial dose: Adults & children > 20kg: 1 mcg daily; Children < 20 kg: 0.05 mcg/kg/day; Neonates: 0.1 mcg/kg/dayMaintenance dose: 0.25 – 2 mcg dailyEndocrinologists, NephrologistsCounselling point:Avoid taking magnesium supplements or magnesium-containing antacids on calcitriol administrationTreatment 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.
16Other supplement: Metocal Vit D3 A combination of calcium and vitamin DDose: 1 – 2 chewable tablets dailyTake at least 2 hr before or 2 hr after meals due to a possible decrease of iron absorptionAvailability: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.
17Treatment options Bisphosphonates (e.g. alendronate, risedronate) SERM (e.g. raloxifene)CalcitoninStrontium ranelatePTH 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).
18Bisphosphonates (also known as antiresorptive drugs) Generic nameBrand nameDosagesPrescribersNotesAlendronateFosamax70 mg once a weekEndocrinologist, Orthopeadics , O&G, Geriatricians, RheumatologistsPatients 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).RisedronateActonel35 mg once a weekProf SP Chan, Dr Vijay, Dr Sargunan, Dr Lim Soo San, Dr Tai Cheh Chin, ProfVickneswaran, Prof Philip Poi, Prof Siti Zawiah Omar, Prof Tan Peng ChiongIbandronateBonviva150 mg once a monthNot prescribed in UMMCZoledronic acidAclastaSingle IV infusion once a yearLecturers and consultants of Orthopaedics, Endocrinology and RheumatologyPatient 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 afteradministration 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 tabsIbandronate is not available in UMMCZoledronic 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 treatmentCounselling point:Bisphosphonate must be administered (orally/inj) on the same time, same day of the week / month / yearTable 5: The available products of bisphosphonates and their dosages.Abbreviation: O & G, obstetrics and gynaecologists.
19Selective oestrogen receptor modulator (SERM) Mimics oestrogen’s good effects on bones without some of the serious side effects such as breast cancerDecreases the risk of spine fractures, but there is a risk of blood clots with use of SERMsRaloxifene (Evista)Dose: 60 mg daily with or without foodPrescribers: Osteoporosis clinic: Prof SP Chan, Prof Rokiah, Dr Vijay; Orthopedic clinic: Dr Tai; Menopause clinic: Prof Siti ZawiyahTreatment option:Approved for use only in postmenopausal women who are intolerant to bisphosphonatesContraindicated 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 immobilizationAvailability:Evista cost: RM 4.70 / tablet; Patients who meet guidelines: government servants / dependants - FOC; others – RM 70 / month. (Available in outpatient pharmacy and PharmUMMC)
20Calcitonin (Miacalcin) A hormone made from the thyroid glandRegulates calcium homeostasisPrevents vertebral (spine) fractures and is helpful in controlling pain after an osteoporotic vertebral fractureNasal sprayRecommended dose: 200 IU / dayInjectionDose: SC/IM IU daily or every 2nd day.Max supply: 5 days.Prescribers: Endocrinologists or OrthopaedicsCommon adverse effects: nausea, vomiting, dizziness, and flushingTreatment 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)
21Strontium Ranelate (Protaxos) Stimulates bone formation and reduces bone resorptionReduces fractures, but there is a risk of blood clots with use of this medicationIn powder form; to dissolve 2g sachet in water and taken daily at bedtime, at least 2 hours after eatingPrescribers: 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 ChiongAvailability:Strontium is available in outpatient pharmacy and PharmUMMC; cost: RM / 28 sachets (1 box)
22Parathyroid hormone (PTH) Treatment PTH stimulates bone formation and activates bone remodeling, resulting in significant increases in bone mineral density and a reduction in fracture riskDue to the potential risk of carcinogenicity (osteosarcoma) , recommended maximum duration of treatment is 18 monthsTeriparatide Inj (Forteo) - Parathyroid Hormone AnalogDose: 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 ChiongCommon adverse events: nausea, constipation, pain in limb, rashes, headache, sweating and dizzinessTreatment optionPotential 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.
26ReferencesClinical Practice Guidelines on Management of Osteoporosis (downloaded in pdf form; Available fromAmerican 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. PageArthritis Foundation Malaysia website:Websites:National Institutes of Health website:MIMS Malaysia websiteUMMC Online Formulary