1. Introduction 1.1. Epidemiology Osteoporosis () affects over 75 million people in the United States, Europe and Japan, and causes more than 8.9 million fractures annually worldwide. 1 It affects both men and women, but particularly common in post-menopausal women, and its prevalence increases with age. 2 It is three times more common in women than men as a result of the decline in level of oestrogen usually after menopause. 3 The annual incidence of fractures is estimated to rise markedly with the worldwide increase in the aging population, thus giving rise to significant morbidity and mortality to some extent. 4 The relevant clinical consequences of osteoporosis are fractures and their significant complications such as pain, physical limitation and other psychological symptoms, most notably depression and loss of self-esteem. 5 The estimated lifetime risk for a wrist, hip or vertebral fracture is 30-40% in developed countries, which is actually very close to that for coronary heart disease. 1
Osteoporosis is a silent disease which is asymptomatic and is not clinically evident until fractures take place, causing medical and personal burdens on aging individuals as well as an economic burden to the society. 3,5 It is associated with three categories of adverse outcomes: mortality, morbidity, and cost. 4 The fractures of the vertebrae (spine), proximal femur (hip) and distal forearm (wrist) have been identified to be the most typical fracture sites, in which the hip fractures have been regarded as the most serious, resulting in 10-20% excess mortality in the first year after fracture. 4,5 In addition, a hip fracture is associated with a 2.5-fold increased risk of future fractures at the same site whereas a vertebral fracture is associated with a 10-fold increase in subsequent vertebral fractures. 4, 5
1.2. Pathogenesis According to the World Health Organisation (WHO), Osteoporosis is a systemic skeletal disease characterised by low bone density and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. 1,3 The microarchitecture of bone tissues of a young female compared with an elderly woman is shown in Figure 1, illustrating many of the plate-like structures converted to thin rods in older age. 6
Ask Yourself 1 How can osteoporosis affect us? 2 What elements are important for maintaining bone health? 3 What pharmacological and non-pharmacological interventions can be used for preventing and treating osteoporosis? Figure 1
Scanning electron micrographs to show the structure of L3 Vertebra in a 31 year old woman (top) and in a 70 year old woman (bottom). 6
2
Bone loss occurs as a result of imbalance between the activity of osteoclasts (; bone cells that break down bone) and osteoblasts (; bone cells responsible for bone formation) in which there is an increase in osteoclasts activity and decreased bone formation by osteoblasts. 4,6
Such imbalance leading to skeletal fragility can be resulted from: (i) failure to produce a skeleton of optimal mass and strength during growth; (ii) excessive bone resorption (breakdown of bone) resulting in decreased bone mass and microarchitectural deterioration of the skeleton; and (iii) an inadequate formation response to increased resorption during bone remodelling. 7
The bone remodelling in an adult is a process in which skeleton is continually remodelled in an orderly sequence of bone resorption followed by bone formation. 4,7 As illustrated in Figure 2, bone remodelling process occurs on the surface of trabecular bone (spongy bone) and it begins with the activation of hematopoietic precursors through interaction with cells of the osteoblast lineage or with inflammatory cells, particularly T-cells, to become osteoclasts. Upon formation of osteoclasts, there is a resorption phase of limited duration and a brief reversal phase, during which the bone formation has not yet begun. The formation phase is then initiated, possibly by factors produced by the osteoclast or reversal cells or released from the bone matrix. 7 The formation phase is substantially longer than the first 3 phases and involves the production of matrix and osteocytes embedded in the bone. 7 Since the resorption and reversal phases of bone remodelling are relatively short and the period required for bone formation is long, increase in the rate of bone remodelling will result in imbalance between resorption and formation processes and cause loss of bone mass. 4,7 The remodelling process is controlled by systemic and locally produced cytokines and imbalance between bone resorption and formation results in net bone loss, leading to osteoporosis. Osteoporosis can result from inadequate intake of nutritional calcium, vitamin D or protein, deficiency of sex hormone, primary hyperparathyroidism ( ), hyperthyroidism ( ) or exposure to excess glucocorticoid. 3
Oestrogen has been shown to play a critical role in the normal physiology of bone remodelling. A deficiency in oestrogen after menopause, accelerates the rate of bone turnover, upsetting the balance between bone formation and bone resorption. 3,4,7 Oestrogen causes a reduction in the proinflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor- (TNF-), released by the bone marrow and Figure 2
The bone remodelling unit. 7
3
Table 1 - Risk factors for osteoporosis Non-modifiable Increased age Female gender Asian, Caucasians Early menopause Family history of osteoporosis Modifiable Low BMI Smoking Physical inactivity
Learning Points 1. Osteoporosis is an asymptomatic systemic skeletal disease which is common in post-menopausal women. 2. Osteoporosis is characterised by low bone density and microarchitectural deterioration of bone tissue. 3. Fractures are clinical consequences of osteoporosis, which lead to pain, physical limitation and other psychological symptoms. 4. Bone loss occurs as a result of imbalance between bone resorption and bone formation. hence oestrogen deficiency increases the production of these cytokines which further enhance formation of osteoclasts to resorb bone, causing progressive loss of trabecular bone. 3,4 1.3. Risk Factors 2,3,5,6,8-10
Table 1 lists different risk factors, non-modifiable and modifiable, causing an increase in risk for development of osteoporosis. The causes of osteoporosis can be primary or secondary to other conditions, in which are listed in tables 2 and 3 respectively. Some medications can induce osteoporosis and corticosteroid is being the most well understood example. Examples of drug-related osteoporosis are outlined in table 4. Pharmacists are placed in a prominent role to recognize medicationinduced osteoporosis and take part in the prevention of fractures. 2. Screening and Diagnosis of Osteoporosis The measurement of bone mineral density (BMD) has been well-established in confirming diagnosis of osteoporosis, prediction of fracture risk and identification of individuals who are at higher risk of fracture. 5, 11
Table 2 - Causes for primary osteoporosis Trauma e.g. falls Low bone density Menopause Age-related conditions Reduced calcium absorption from the gut Secondary hyperparathyroidism Previous fracture Genetics Family history of fragility fracture, particularly hip fracture Nutrition Deficiency of calcium, vitamin D, vitamin K, protein High dietary intake of phosphate Physical inactivity Immobility Cigarette smoking Alcohol consumption 3units/day Low body mass index < BMI of 19kg/m 2
Sex hormone deficiency Primary hypogonadism () Oestrogen deficiency at the menopause
4
Table 4 - Examples of drug-induced osteoporosis Thyroid replacement hormone Excess thyroid replacement hormone Causes hyperthyroidism and suppresses TSH, resulting in bone loss Anticonvulsants e.g. Phenytoin, Phenobarbital CYP induction increases the metabolism of vitamin D, leading to reduction in calcium absorption CYP induction lowers circulating oestrogen and testosterone, causing bone loss Anticonvulsants inhibit osteoblasts to decrease bone formation Antidepressants e.g. Selective serotonin reuptake inhibitors (SSRI) e.g. Tricyclic antidepressants (TCA) Antipsychotics Increase in prolactin concentrations lowers oestrogen and testosterone concentrations, leading to bone loss Thiazolidinediones e.g. Pioglitazone Glucocorticoids With prolonged use Drugs that cause hypogonadism Parenteral progesterone Methotrexate Gonadotropin-releasing hormone agonists Lithium Heparin Long-term use in particular with unfractionated heparin Aromatase inhibitors Drugs e.g. Anastrozole, exemestane, letrozole used in treatment of oestrogen-receptor positive breast cancer lowers oestrogen level Proton pump inhibitors High dose and long term use
The gold standard technique used to assess bone mass, bone mineral or other related aspects of skeletal mass or structure is the dual-energy x-ray absorptiometry (DXA), which measures bone mineral at sites such as the spine and hip and total body bone mineral. 3 BMD is expressed in terms of grams of mineral per square centimetre scanned (g/cm 2 ) and in relationship to two norms: (i) Z-score in which patients BMD compared to the expected BMD for a gender, ethnicity and age-matched population, or (ii) T-score in which patients BMD compared to the expected BMD for a gender and ethnicity-matched young adult healthy population. 5, 11
Standard deviation (SD) above or below the mean is applied as an expression of the difference between the patients score and the norm. 3,5,11 Table 5 illustrated the WHO diagnostic classification, which adopts the DXA devices for BMD measurement at the femoral neck. 1,3 This classification applies to postmenopausal women and men aged 50 and above. Other central sites (e.g. lumbar spine, total hip) can also be used for diagnosis in clinical practice. Table 3 - Causes for secondary osteoporosis Chronic medical and systemic diseases Chronic obstructive pulmonary disease Inflammatory bowel diseases Liver disease (severe)
Endocrine and metabolic disorders Diabetes mellitus, Type 1 Hyperparathyroidism (primary) Hyperthyroidism
Hypogonadism (primary and secondary) Hypophosphatasia Cushings syndrome
5
Key Points DXA (Dual-energy X-ray Absorptiometry) is a technique for measuring the bone mineral density (BMD). FRAX is a tool for calculating the 10-year probability of bone fracture. Other clinical and biological tests Other clinical and biological tests should be performed to: (i) exclude a disease which can mimic osteoporosis; (ii) establish the causes of osteoporosis and the contributory factors; (iii) assess the severity of osteoporosis and determine the risk of subsequent fractures; (iv) select the most appropriate treatment; and (v) establish baseline measurements for subsequent monitoring of treatment. 3 A list of other screening tests are described in table 6. 8 The FRAX, a fracture risk assessment tool adopted by the WHO, is used to calculate the 10-year probability of a hip fracture and the 10-year probability of a major osteoporotic fracture which is defined as clinical vertebral, hip, forearm or proximal humerus fracture. The FRAX tool uses sex, age, body mass index, prior fracture, parental hip fracture, usage of glucocorticoid, rheumatoid arthritis, current smoking status, alcohol intake (three or more units daily) and BMD of the femoral neck for estimation of the fracture risk. 5, 12
3. Pharmacological Interventions Therapeutic options for osteoporosis have increased considerably in recent years and recommendations for choices of treatment vary among individuals. In summary, postmenopausal Table 5 - WHO diagnostic classification for osteoporosis by measurement of BMD Normal BMD within 1 SD of the young adult reference mean T-score -1.0 Low bone mass (osteopenia) BMD is between 1.0 and 2.5 SD below that of the young adult mean -2.5 < T-score < -1 Osteoporosis BMD is 2.5 SD or more below that of the young adult mean T-score -2.5 Severe osteoporosis (established osteoporosis) BMD is 2.5 SD or more below that of the young adult mean in the presence of one or more fragility fractures T-score -2.5
Table 6 - other biological and chemical screening tests for diagnosis of osteoporosis 8
Tests Possible aetiology Alkaline phosphatase (ALP) High level in Pagets disease, immobilisation Calcium Vitamin D deficiency, malabsorption Liver or kidney function Liver or kidney disease Complete blood count Bone marrow malignancy, malabsorption Estradiol (pre- or perimenopausal women) Hypogonadism Thyroid-stimulating hormone Hyperthyroidism Total testosterone (in men) Hypogonadism 25-hydroxyvitamin D Vitamin D deficiency Parathyroid hormone Hyperparathyroidism Serum protein electrophoresis Multiple myeloma ()
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women and men aged 50 and above presenting with the following should be considered for treatment: (i) A hip or vertebral fracture;
(ii) T-score -2.5 at the femoral neck or spine after appropriate evaluation to exclude secondary causes;
(iii) low bone mass (osteopenia) with a T-score between -1.0 and -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% based on the WHO FRAX fracture risk assessment tool. 5 3.1. Bisphosphonates 3.1.1. Indications Bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) are licensed in the prevention and treatment of postmenopausal osteoporosis and osteoporosis in men. 3.1.2. Pharmacological action Bisphosphonates are synthetic analogues of naturally-occurring inorganic pyrophosphate. 13,14
Pyrophosphate itself is a natural circulating inhibitor of mineralisation in the blood and urine but cannot diffuse into the bones. 14 Bisphosphonate accumulates in bone where it exerts its actions by binding to hydroxyapatite crystals in bone mineral and thus inhibiting mineralisation. It is because bisphosphonates adsorb to bone mineral especially at sites of bone resorption during the bone remodelling process. They inhibit and induce apoptosis (cell death) of osteoclasts, contributing to the reduction of bone turnover rate and increase of bone mineral mass. 15 The relative anti-resorptive potency of different bisphosphonates is stated in table 7. 14
3.1.3. Adverse effects The common adverse effects and the management to reduce incidence of developing such effects are described in table 8. 5,16,17 It is important to note that other rare and serious complications such as osteonecrosis of the jaw, atypical fractures and oesophageal cancer have been reported and addressed as safety concerns by the FDA. 18
Bisphosphonate-associated osteonecrosis of the jaw has been defined as exposed or necrotic bone in the maxillofacial region, which has persisted for more than 8 weeks in those receiving bisphosphonates without history of irradiation of the jaw. 17,19 Osteonecrosis occurs more frequently in cancer patients receiving IV bisphosphonates and is associated with dental surgery in many cases. 17 Recommendations to reduce the development of osteonecrosis of the jaw are that any dental procedures are ought to be completed before initiation of bisphosphonates, and during treatment, patients should be advised to maintain good oral hygiene, have regular check-ups, and report any oral symptoms. 17,19
Long-term use of bisphosphonate has been associated with atypical femur fractures, defined as atypical by their location in the subtrochanteric region and femoral shaft with minimal or no associated trauma and absence of comminution (breakage of bones into several pieces). 17 Table 7 - The anti-resorptive potency of different bisphosphonates 14
In addition, the use of oral bisphosphonates has been linked with an increased risk of oesophageal cancer. 17,18 There have been conflicting findings from studies evaluating this risk and a review by the FDA is still ongoing. Nevertheless, bisphosphonates, especially etidronate, alendronate and risedronate, are still most widely used in prevention and/or treatment of osteoporosis at present as the benefits of bisphosphonates outweigh the risk. 3.2. Strontium ranelate 20,21
3.2.1. Indications Strontium ranelate, available as a sachet to be mixed with water and taken daily, has a therapeutic indication for treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures. 3.2.2. Pharmacological action Strontium is adsorbed onto the crystal surface and only slightly substitutes for calcium in the apatite crystal (composition of bone mineral) of newly formed bone, without modifying the bone crystal characteristics. By this action, it reduces bone resorption by decreasing osteoclast differentiation and resorbing activity. Moreover, it also increases bone formation Table 8 - Adverse effects of bisphosphonates 5,16,17
Type Examples Management Mineral metabolism Hypocalcaemia Hypophosphataemia Existing hypocalcaemia should be treated before starting bisphosphonates Adequate intake of calcium and vitamin D Gastrointestinal Oesophagitis Peptic ulceration Abdominal pain, nausea and vomiting Diarrhoea or constipation Swallow tablets whole with plenty of water (not less than 200mL) Stay in an upright position (standing or sitting) for at least 30mins after taking tablets Tablets should be taken on rising for the day, on an empty stomach, at least 30mins before breakfast or any other oral medication Musculoskeletal Severe bone, joint, and/or muscle pain reported Aetiology unknown Renal Renal toxicity Associated with IV infusion of zoledronic acid especially with rapid infusion rate Monitor renal function before and during treatment Maintain appropriate hydration Recommended to infuse over 15 mins Contraindicated in CrCl < 35 ml/min Acute-phase reaction Fever, arthralgia (), headache, myalgia() Associated with IV zoledronic acid Usually transient Patients may be pre-treated with paracetamol to reduce the risk These symptoms occurred in 32% of patients after first dose, 7% after the second dose and 3% after the third dose
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through stimulation of osteoblast precursor replication and collagen synthesis in bone cell culture. As a result, strontium rebalances the bone turnover, in which favouring the process of bone formation. 3.2.3. Adverse effects Adverse reactions associated with the use of strontium ranelate were usually mild and transient, with nausea and diarrhoea being the most common ones, which were generally reported at the beginning of treatment. Phase III clinical trials showed that, compared with placebo, strontium ranelate was associated with an increased annual incidence of venous thromboembolism (; VTE) of 0.7% but the mechanism is still unknown. Therefore, it should be used with caution in patients at increased risk of VTE. Food, milk and derivative products, and medicinal products containing calcium reduce the bioavailability of strontium ranelate by approximately 60-70%. Therefore, administration of strontium ranelate and such products including antacids should be at least two hours apart, preferably at bedtime. Co-administration of strontium ranelate with oral tetracycline or quinolone antibiotics can form poorly soluble chelates at the gastrointestinal level, thereby reducing their absorption. Treatment of strontium ranelate should be suspended during treatment with these antibiotics. It is an alternative treatment option to bisphosphonates, particularly in patients for whom these drugs are contraindicated or not tolerated. 3.3. Raloxifene 8, 21,22
3.3.1. Indications Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women to reduce the risk of vertebral fractures but not hip fractures. It is indicated to decrease the risk of invasive breast cancer in postmenopausal women with osteoporosis. 3.3.2. Pharmacological action Raloxifene, a selective oestrogen receptor modulator (SERM), has selective agonist or antagonist activities on tissues responsive to oestrogen. It has oestrogen agonist activity on the bones and lipids, whereas oestrogen antagonist effect on the breast and uterus. It decreases bone resorption and normalises bone turnover to the pre-menopausal range, which manifests as reductions in serum and urine levels of bone turnover markers, increases in bone mineral density and decreases in incidences of fractures. Additionally, significant reduction in total cholesterol and LDL cholesterol were shown in clinical trials but raloxifene did not significantly affect the risk of cardiovascular events. However, raloxifene is associated with a three-fold increase in the risk of venous thromboembolism (VTE) and therefore it is contraindicated in people with a history of VTE. 3.3.3. Adverse effects The most common adverse effects are vasomotor symptoms such as hot flushes. Raloxifene is not recommended as the first-line treatment option for primary prevention and treatment of osteoporosis as bisphosphonates can reduce the risk of fractures in all sites whereas raloxifene has been proven to reduce vertebral fractures only. Perhaps, it can be considered as a treatment option in postmenopausal patients with osteoporosis, who are unable to tolerate bisphosphonates, have no vasomotor symptoms or history of VTE, and have a high breast cancer risk score. 3.4. Hormone replacement therapy 5,23
Oestrogen deficiency is considered to be a major factor predisposing to osteoporosis. Hormone replacement therapy (HRT), oestrogen with or without progesterone, is approved for the prevention of osteoporosis, relief of vasomotor symptoms and vulvovaginal atrophy associated with menopause. The Womens Health Initiative (WHI) randomised clinical trial demonstrated that 5 years treatment with oestrogen plus progesterone increase BMD and reduces the risk of clinical vertebral fractures and hip fractures by 34% and other 9
Counselling Points
1. When taking bisphosphonate tablets, swallow with plenty of water and stay in an upright position for at least 30mins afterwards.
2. Products containing calcium reduce the absorption of strontium ranelate, which should be taken at least 2hrs apart. osteoporotic fractures by 23%. However, the WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, and VTE during 5-year treatment with conjugated oestrogen and medroxyprogesterone. The benefit of fracture reduction does not outweigh the risks of cardiovascular disease and breast cancer, even in women at higher risk of fracture. Therefore, given the overall unfavourable risk-benefit ratio and the availability of other agents for prevention and treatment of osteoporosis, HRT should not be recommended as first-line agent for prevention or for treatment of osteoporosis in women without vasomotor symptoms. 3.5. Calcitonin (Salmon) 8,12,21,24,25
3.5.1. Indications Calcitonin is approved in the treatment of established post-menopausal osteoporosis to reduce the risk of vertebral fractures but a reduction in hip fractures has not been demonstrated in clinical trials. It is not considered as a first line agent for osteoporosis unless first line treatment with bisphosphonates is not tolerated. 3.5.2. Pharmacological action Calcitonin is a naturally occurring 32-amino acid polypeptide hormone that is produced by the parafollicular cells of the thyroid. Synthetic or recombinant calcitonin has been derived from a number of different species and salmon calcitonin is the most widely used preparation as it is 50 to 100 times more potent than human calcitonin. Calcitonin secretion is stimulated by high plasma concentrations of calcium. Calcitonin binds to calcitonin receptors on osteoclasts, resulting in diminished osteoclastic binding to mineralised bone and decreased osteoclast activity, hence inhibiting bone resorption and markedly reducing bone turnover. 3.5.3. Dosage recommendation It is available commercially as subcutaneous injection and nasal spray preparations. Calcitonin nasal spray (Miacalcic) can be given at a dosage of 200 IU in alternating nostril each day. 3.5.4. Adverse effects The use of parenteral calcitonin was significantly limited by the common adverse effects of nausea, flushing of the face and hands, and local injection sites reactions, which affects patients compliance and acceptability. The most common adverse effect of nasal calcitonin is rhinitis which is usually mild and not a major cause for drug discontinuation. The safety of nasal preparation has therefore been considered as an advantage. 3.6. Recombinant parathyroid hormone 6,8,26,27
3.6.1. Indications Teriparatide, a recombinant parathyroid hormone, is indicated in the treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture. Teriparatide is associated with a significant reduction in incidence of vertebral and non-vertebral fractures but not hip fractures. It is also approved in the treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. 3.6.2. Pharmacological action Teriparatide, an anabolic steroid, acts predominantly on osteoblasts to increase bone formation on trabecular and cortical surfaces by more selective stimulation of osteoblastic activity over osteoclastic activity. It exerts its 10
effect by increasing the lifespan of osteoblast through reduction of osteoblast apoptosis and induction on recruitment and formation of new osteoblasts. Skeletal mass and bone strength are also increased. 3.6.3. Dosage recommendation The recommended dosage of teriparatide is 20 micrograms administered once daily by subcutaneous injection in the thigh or abdomen and the maximum total duration of treatment should be 24 months. The 24-month course of teriparatide should not be repeated over a patients lifetime as the safety and efficacy of teriparatide have not been evaluated beyond 2 years of treatment. Patients may be continued on other osteoporosis treatment after stopping 24 month treatment with teriparatide therapy. 3.6.4. Adverse effects Dizziness, leg cramps, nausea, injection site reactions and headache are the most commonly reported side-effects which are generally mild and not requiring discontinuation. Increase of uric acid concentration without the development of acute gout and small increases in urinary calcium excretion without nephrolithiasis ( ) have been reported. Increased risk of osteosarcoma ( )is seen in rats exposed to high doses. Consequently, teriparatide is contraindicated in patients with risk of osteosarcoma, such as those with Pagets disease, previous skeletal radiation, or unexplained elevation of alkaline phosphatase level. Due to its high cost, teriparatide is generally reserved for those with severe osteoporosis who are unable to tolerate or seem to be unresponsive to other treatments. 3.7. Denosumab 12,28,29
3.7.1. Indications Denosumab is approved in the treatment of osteoporosis in postmenopausal women at increased risk of fractures and it significantly reduces the risk of vertebral, non-vertebral and hip fractures. 3.7.2. Pharmacological action Denosumab, a human monoclonal antibody (IgG2), targets and binds with high affinity and specificity to RANK-L, preventing activation of its receptor RANK on the surface of osteoclast precursors and osteoclasts. Activated RANK-L/RANK pathway (a cell signalling pathway) is associated with enhanced bone resorption, resulting in bone loss. Denosumab inhibits this pathway, thus inhibiting osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone. 3.7.3. Dosage recommendation The recommended dosage of denosumab is 60mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or back of arm. 3.7.4. Adverse effects The most common adverse effects include infections of the urinary and respiratory tract, cataract, constipation, rashes and pain in extremities. The increase in infections under denosumab treatment might be related to the role of RANK-L in the immune system. Denosumab is contraindicated in hypocalcaemia which must be corrected by adequate intake of calcium and vitamin D before starting therapy with denosumab. Similar to bisphosphonates, osteonecrosis of the jaw has been reported in patients treated with denosumab. To minimise the risk of osteonecrosis of the jaw, patients who are scheduled to start denosumab should be seen by a dentist if they have additional systemic (glucocorticoid therapy, chemotherapy) or local risk factors (radiation, dental disease). In addition to recommending improved oral hygiene, invasive dental procedures should be avoided during denosumab treatment. According to the practice guidelines for the management of osteoporosis published by the Canadian Medical Association, denosumab can be used as first-line therapy for prevention of hip, non-vertebral and vertebral fractures in menopausal women requiring treatment of osteoporosis. There are several 11
Practical Pearls 1. Adequate dietary intake of calcium (at least 1200mg per day) is important for maintenance of bone health. 2. Elderly people with malabsorption, chronic kidney disease or limited sunlight exposure are at risk of vitamin D deficiency. characteristics clearly separating denosumab from bisphosphonates: (i) reversibility of denosumab as it targets RANK-L and is not incorporated into the bone mineral; (ii) lack of gastrointestinal side-effects and convenient bi-annual subcutaneous administration which can improve long-term adherence; and (iii) potential use in impaired renal function as it is not eliminated by the kidneys. Although no dose adjustment is required in patients with renal impairment, patients with severe renal impairment or on long term haemodialysis are at greater risk of developing hypocalcaemia. 3.8. Combination therapy 2,5,8
Combination therapy, usually a bisphosphonate with a non-bisphosphonate, can provide additional small increases in bone mineral density when compared with monotherapy. However, anti-fracture effectiveness of this combination has not been shown and there is currently a limited role for combination therapy until further supportive data is available. 4. Non-pharmacological Interventions 4.1. Fall prevention 5,8
Vision deficits, balance and gait abnormalities, cognitive impairment and dizziness should be addressed for fall prevention. In additions, improving lighting, removing loose rugs, and adding grab bars near bathtubs, toilets, and stairways can enhance safety. Medications such as hypnotics and benzodiazepines, which affect alertness and balance, should be avoided. 4.2. Calcium and Vitamin D 5,8,30
An inadequate intake of either calcium, vitamin D or both will affect the calcium-regulating hormones, particularly the parathyroid hormone (PTH) which is responsible for calcium and phosphate balance in the body. A deficiency of either calcium or vitamin D will lead to reduced calcium absorption and a lower concentration of circulating ionised calcium. When this occurs, PTH secretion is stimulated and the cumulative increase in the PTH levels, secondary to low intake of calcium and vitamin D, increases the rate of bone remodelling process and results in bone loss. All individuals should be advised to obtain an adequate intake of dietary calcium (at least 1200mg per day, including supplements if necessary) for the acquisition of peak bone mass and maintenance of bone health. If supplementation is required, it should optimally be taken in doses containing 500mg or less of elemental calcium at a time to maximise absorption, because absorption decreases with greater calcium load. Calcium supplement should be taken with meals as it is better absorbed with food. An intake of 800-1000 IU of vitamin D per day for adults aged 50 and above is recommended as vitamin D enhances calcium absorption, maintains bone health and muscle performance. For patients with vitamin D deficiency, vitamin D supplemented in amounts sufficient to sustain the serum 25-hydroxyvitamin D level to 30ng/mL (75nmol/L) or higher is needed. Suboptimal serum vitamin D levels are common in elderly with malabsorption, chronic renal insufficient and housebound with limited sun exposure. Serum 25-hydroxyvitamin D level should be measured in these patients at risk of deficiency. A higher intake of vitamin D of up to 2000 IU may be required in some elderly patients to maintain optimal serum 25-hydroxyvitamin D level. 12
4.3. Regular weight-bearing exercise 5
Weight-bearing and muscle-strengthening exercises can improve agility, strength, posture and balance, which may reduce the risk of falls and fracture. In addition, exercise may increase bone density modestly. 5. Conclusions Osteoporosis is becoming more common with the ageing population. There are many different treatment options available which are effective but are not without problems. Bisphosphonates have been most widely used in both the prevention and treatment of osteoporosis in both men and women. However, more rare and serious complications such as the atypical femur fractures, osteonecrosis of the jaw have been reported and causing safety concerns. Other second line agents such as calcitonin, raloxifene and teriparatide have been linked with reduction of vertebral fractures only, but not hip fractures. The novel target agents, RANK-L inhibitors, are undergoing active development but their long-term safety profiles remain to be determined. Moreover, long term follow-up after treatment should be elucidated for further evaluations on drug efficacy and safety. In addition, other non-pharmacological interventions such as prevention of falls, adequate intake of calcium and vitamin D to maintain bone health, and increase of weight-bearing exercises are also of great importance in management and prevention of osteoporosis.
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