Lecture 9 2023 Metabolic & Endocine Bone Disorders Osteoporosis & Sarcopenia PDF

PHT2012 Orthopaedics, Traumatology & Rheumatology Lecture 9 Metabolic and endocrine bone disorders, such as osteoporosis and sarcopenia. Contents of this lecture are intended for use by BSc (Hons) students of TWC only Dr Anthony Kwok, PhD, FHKHSE, FCHSM, FAIHS, RPT Associate Professor/Clinical Co-...

PHT2012 Orthopaedics, Traumatology & Rheumatology Lecture 9 Metabolic and endocrine bone disorders, such as osteoporosis and sarcopenia. Contents of this lecture are intended for use by BSc (Hons) students of TWC only Dr Anthony Kwok, PhD, FHKHSE, FCHSM, FAIHS, RPT Associate Professor/Clinical Co-ordinator (Physiotherapy) School of Medical and Health Sciences 1 Read as an adjunct: Apley & Solomon’s System of Orthopeadics & Trauma: Chapter 7 (Page 121- 156) • Kwok A.W.L., Au B.S.K, Lau E.M.C., Yurianto H., Yuktanandana P., Yoshimura N., Muraki S., Oka H., Akune T., Leung P.C.(2012). Prevalence of vertebral fracture in Asian men and women: Comparison between Hong Kong, Thailand, Indonesia and Japan. Public Health 126 (2012) 523-531. • Kwok Anthony, Gong Jing-shan, Wang Yi-Xiang, Leung Jason, Kwok Timothy, Griffith James F, Leung PC (2013). Prevalence and risk factors of radiographic vertebral fractures in elderly Chinese men and women: results of Mr. OS (Hong Kong) and Ms. OS (Hong Kong) studies. Osteoporos Int, Mar;24(3):877-85. • Kwok AW, Griffith JF, Ma HT, et al. (2008) Estimated volume of both vertebral body and disc decreases as BMD decreases though this effect is seen more in the vertebral body than the disc. Bone 2008; 43 (Suppl. 1): S66. • Kwok AWL, Wang YXJ, Griffith JF, Deng M, Leung JCS, Ahuja AT, Leung PC (2012) Morphological changes of lumbar vertebral bodies and intervertebral discs associated with decrease in bine mineral density of the spine – a cross sectional study in elderly subjects. Spine Nov 1;37(23):E1415-21. • Kwok T, Khoo CC, Leung J, Kwok A, Qin L, Woo J, Leung PC (2012). Predictive values of calcaneal quantitative ultrasound and dual energy X ray absorptiometry for non-vertebral fracture in older men: results from the MrOS study (Hong Kong). Osteoporos Int. Mar;23(3):1001-6. • Kwok A, Leung J, Law SW, Hung LK, Leung PC. (2014) Prevalence and Risk Factors of Vertebral Fracture in Asian Elderly. Paper presented in the 34th Annaul Congress of Hong Kong Orthopaedics Association, p. 48. • Kwok A, Law SW, Leung J, Hung LK, Leung PC. (2014) Fall risk with Reducing Bone Mineral Density in Hong Kong Chinese Elderly. Paper presented in the 34th Annaul Congress of Hong Kong Orthopaedics Association, p. 86. • Kwok A, Leung J, Law SW, Hung LK. (2014) Lumbar Spine Vertebral and Disc Changes with Reducing Bone Mineral Density in Elderly Hong Kong Chinese. Paper presented in the Annaul Congress of Asia Pacific Orthopaedics Association, 2014, Pattaya, Thailand (electronic proceedings) Rapid increase in the Ageing Population of age over 60 in Hong Kong: From 18% (1.2 M) in 2009 to 39% (3.4 M) in 2050 (UN Report, 2010) Metabolism-related Bone Health: Osteoporosis The issues of osteoporosis in HK is serious (in aged 50 or above): • 1 in every 3 women and 1 in every 7 men had osteoporosis (JOCOC, 2008) • 1 in every 3 women and 1 in every 5 men had osteoporosis (IOF, 2014) • 1 in every 3 women and 1 in every 4 men had osteoporosis (NOF, 2022) Ageing process affects the metabolism + decrease in sex hormones (both the males & female hormones). Women after menopause: any female sex hormone? Lx Spine Vertebral # in elderly with reduced Bone Mineral Density (BMD) is common. Elderly hospitalized for a fragility # in HK are mainly due to reduced BMD. Risk of a future # after the 1st # increases (Kwok et al., 2014). • Osteoporosis (OP): a condition of skeletal fragility due to decreased bone mass and micro-architectural deterioration of bone tissue, with consequent increased risk of #. • OP affects the Spine causing spinal deformities, hump back and loss in height greater than 3cm, causes LBP +/- vertebral #. JOCOC, CUHK 2006: the older the age, the higher the incidence of OP Global epidemic of osteoporosis (Source: IOF & NOF) 1 in every 3 women 1 in every 7 men (in 2004 HK Mr Os survey); 1 in 5 men (in 2014 IOF survey) 1 in 4 men (in 2022, NOF survey) Will suffer from osteoporosis Note the changing roles of osteoblast & osteoclast in their life cycle: In young age: osteoblast phase lasts longer In older age: osteoclast lasts longer The common sites of osteoporotic #: Spine, Hip and Wrist Consequence of # could be Fatal • Mortality rate: 20% • Permanent disability rate: 30% • In long-term care: 20% • Life span: shorten 10 years **Think about the osteoporosis in the workplace as many people are still working at aged 65 or above….. Vertebral fracture is an important risk factor (Unfortunately, misdiagnosis rate: 50 to 66% in the year 2018 in USA) One episode of vertebral #: • Future vertebral #: increase 4 X • Other # (e.g. Hip) : increase 2 X • Any prior # after age 50: RR 1.76 for further # • Once got fracture, fracture risk increases • Only 1/3 cases diagnosed clinically • Failure to identify: increases co-morbidity, disability and mortality OP related fragility fracture is a serious problem in HK • 0.32 million HK older adults are osteoporotic (may cause fragility # after a fall) • In any adult aged >50 ends up a fracture after a body-height fall = Osteoporosis (NOF, 2012) • More than 12 elderly adults sustains fragility fracture in their hip per day due to osteoporosis • Incidence rate: Females 3 times > Males • Hip # may be fatal due to the blood (up to 1500 cc in 1 limb) • Reduce QoL due to unable to ambulate Osteoporotic hip # increase in the last 2 decades Year Number 1996 3920 2020 7641 Risk factors for osteoporosis: • Low calcium intake, Low physical activity • Alcoholism, Estrogen deficiency (<45 years), Cigarette smoking Who should have DXA bone density measurement: • Above 65 years old (definitely) for both men or women • Peri-menopausal women (around 50+) • Personal Hx of fracture • History of fragility fracture in a first degree relative • Low body weight (<100 lbs) • Receiving Radiation Therapy • Thyroid hormone deficiency Definition of Osteoporosis (WHO standards) BMD > -2.5SD BMD -1~ -2.5SD BMD <1SD Below the mean peak adult Below the mean peak adult Below the mean peak adult Osteoporosis Osteopenia Normal Note: National Osteoporosis Foundation (NOF, USA) definition: BMD > -2.0 + 1 risk factor NHS (UK), Europe, Australia, HA/HK: follows WHO standards FRAX: Fracture Risk Assessment is different in different countries due to different ethnic groups & life styles • Mass screening with US BMD to raise public awareness mainly. • US BMD: Not for diagnosis, and is only an estimation of disease or progress of OP drug treatment. • Good as a gimmick to attract people’s attention • Not reliable as it could be affected by the high voltage current, noises, vibration, etc. Life time risk of osteoporotic # for risk estimation All Hip Spine forearm Women 40% 18% 16% 16% Men 13% 6% 3% 5% Age-specific incidence rates for hip, vertebral, and distal forearm # Men Women Incidence/100,000 person-yr 4000 Hip 3000 2000 Hip Vertebrae 1000 Vertebrae Colles’ Colles’ 0 35-39 85 Age group, yr 85 Age-adjusted incidence rates in women Adjusted Rates (100,000) 600 535 500 459 442 400 269 218 300 200 88 100 0 US (White) Hong Kong Singapore Thailand Malaysia Beijing Age-adjusted incidence rates in men 187 180 Adjusted Rates (100,000) 200 150 164 114 97 88 100 50 0 US (White) Hong Kong Singapore Thailand Beijing Malaysia Incidence of hip fracture in Hong Kong (HA data) Men (Trend) Women (Trend) 3500 2000 3000 1600 2500 2001 2001 1985 2000 1200 1985 1500 800 1000 1966 400 0 50-59 Age 60-69 70-79 80+ 1966 500 0 50-59 Age 60-69 70-79 80+ Hip # Prediction of men & women in 2050 Women Men (4.5 million) (1.8 million) Asia 54% Others 8% North America 13% Latin America 6% Europe 11% Middle East 8% Asia 51% Others 6% North America 12% Latin America 12% Europe 12% Middle East 6% Life style risk factors for hip fracture (Asian OP Study) (RR: 2-3) ⚫ Height in highest quartile ⚫ Calcium <500mg/day ⚫ No regular physical activity ⚫ Cigarette smoking ⚫ Daily alcohol consumption Medical risk factors for hip fractures (Asian Osteoporosis Study) (RR: 2-3) ⚫ Fall twice or more last year ⚫ History of fracture ⚫ History of stroke ⚫ Sedative use ⚫ Thyroid diseases Age (Yr) Calcium (mg) Vitamin D (IU) 3-8 800 400 9-17 1100 400 18-55 800 600 56-65 1000 800 >65 1200 800 Vertebral fracture is so important but is difficult to diagnose precisely! There are 2 main types to assess. 1. Radiological Vertebral Fracture: use visual assessment to determine a vertebral # 2. Morphological Vertebral Fracture: Use 6 points & 2 ~ 3 SD below the mean to determine a vertebral # HP HM HA Semi-quantitative method (Genant’s Method) General principles of vertebral fracture evaluation Approach Pros and Cons Qualitative visual assessment method • Less objective • Poor to fair inter- and intra-observer reliability Quantitative Morphometric method (QM) • High test-retest and inter- and intra-observer reliability and good concurrent validity •But time consuming Semi-quantitative method (SQ) • Good inter- and intra-observer reliability, concurrent validity and predictive validity • Less time consuming • Limited sensitivity to grade 1 fracture Algorithm-based qualitative assessment (ABQ) •Good inter- and intra-observer reliability and concurrent validity •Not much evidence on predictive validity FRAX (by Dr. John A Kanis, Professor Emeritus, University of Sheffield) • The FRAX® tool: Fracture Risk Assessment Tool • The FRAX® algorithms give the 10-year probability of fracture. The output is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture). • To evaluate fracture risk of patients, based on individual patient models that integrate the risks associated with clinical risk factors + their BMD at the femoral neck. • Developed from studying population-based cohorts from Europe, North America, Asia and Australia. • Computer-driven and the calculation is on the refreshing input of the data to update the mean scores to make the estimation becoming more and more precise and accurate. • Several simplified paper versions, based on the number of risk factors are also available. The IOF Osteoporosis Risk Check. Multiple languages (including Chinese) on the IOF web site. In written format. Simple to use and reliable. 骨質疏鬆症自我評估 (Chinese Version) 以下的問題中，如您於任何一條的答案為「是」的話，您便有患上骨質疏鬆症的風險。 1. 您的父母曾否跌斷股骨? 2. 您本人曾否跌斷骨? 3.您曾否服用類固醇超過3個月? 4. 您的身高是否減少超過3厘米（1吋）? 5. 您是否經常飲酒? 6. 您每天是否吸煙超過20支? 7. 您是否經常肚瀉（如腹腔病或節段性回腸炎）? 只供女士作答： 8. 您是否在45歲或以前已停經? 9. 除懷孕期間外，您曾否停經超過12個月? 只供男士作答： 10. 您曾否因雄激素過低而引致陽萎或性慾減低? Medications for Osteoporosis • Bisphosphonates • Selective Estrogen Receptor Modulators (SERMS) • Strontium • Hormonal Replacement Therapy • Calcitonin • PTH (Parathyroid Hormone) • Denosumab Bisphosphonates Anti-resorptive Therapy 1. Fosamax Plus (once weekly) (Alendronate X 70mg, Vit. D3 5600 IU): No lying for 30 minutes after taking drug 2. Actonel (once weekly) (Risedronate X 35 mg) 3. Actonel Plus (once weekly) (Risedronate X 35 mg + Vit D 880 IU effervescent granules) 4. Actonel 150 mg once a month Bisphosphonates 3. Ibandronates (Boniva): • 150mg: Once a month: Oral route • No lie down for 60 minutes after taking • 3mg: IV route once every 3 months (administration by IV gives better outcomes with lower dose) 4. Generic drug (Oral bisphosphonate) Others 5. Zoledronic Acid 唑來膦酸 • 5mg (Aclasta) – for osteoporosis • 4mg (Zometa) – for tumor-induced hyperclacemis • IV route • Once yearly Main considerations: Bisphosphonate Administration (Oral route): Irritate the GI Tract) Morning: (Empty stomach) After taking medication, No lie flat: 30 minutes for Fosamax Plus/Actonel, 60 minutes for Boniva No food or beverages except water prior taking. Between meals: 2 hours no food or beverages except water before taking the medication. After taking medication, following 2 hours no food or beverages except water. Before bed: 2 hours no food or beverages except water, After taking the medication: following 2 hours: no food or beverages except water Do not lie flat: 30 minutes for Fosamax Plus/Actonel, 60 minutes for Boniva SERMS Evista: Raloxifene X 60mg (once daily) I: Prevention of osteoporotic vertebral fractures in post-manopausal women AR: Hot flushes, leg cramps, peripheral oedema, venous thromboembolic events PTH Forteo • Teriparatide (rDNA origin) injection • Anabolic Therapy • Administrate daily • For up to 24 months, then change to use bisphosphonate • Always help to increase BMD and prevent fracture Other Medication Strontium Ranelate: Dual actions: i). Increase bone formation ii). Decrease bone resorption iii). May increase cardiovascular risk iv). CI in stroke patients Powder Form: Take before bed ** Do not use with calcium supplement. Denosumab • Prolia • A human monoclonal antibody for the treatment of osteoporosis, treatment induced bone loss, metastases to bone and giant cell tumour of bone. • Target RANK Ligand • Subcutaneous injection for every 6 months • Popular choice nowadays Evenity (romosozumab-aqqg injection) • Drug Class: Monoclonal Antibodies, Endocrine Use EVENITY alone: • Lumbar spine & hip BMD increased by over 13% and 6% respectively • Larger increases in total hip BMD then with other anabolic agents or anti-resorptive drugs If used Evenity followed by Denosumab (Anabolic & antiresorptive sequential therapy): • Lumbar spine & hip BMD increased by over 18% and 8.7% respectively, with 36 months of Evenity followed by Denosumab • The effects over 36 months was much more than achieved with treatment for 10 years with an anti-resorptive therapy only • EVENITY followed by Denosumab is associated with substantial gain in total hip BMD. Calcitonin Nasal Spray • Nasal spray • Good pain relief after a compression fracture • Usually on 2 days and start FWB walking exercise with a frame, then a patient can be sent home ***Not recommended now due to some potential harm Primary prevention for Osteoporosis • Calcium intake per day (800mg for aged 55 or under; 1000mg for aged 56 – 65; 1200mg for aged 65 and over) (Because calcium absorption has a daily threshold in our body) • Regular load-bearing activity (at least 3.5 hors per week, or 0.5 hour per day) • Quit smoking, avoid alcoholism • Balanced Diet, Low Salt, Caffeine Free, Enough Protein Adequate Daily Calcium ◆ ◆ ◆ Calcium is the main element in bone (from dairy products & legumes) Fermented dairy products are more preferable Inadequate calcium + Vit. D intake increase risk of osteoporosis Daily Need for Adult ◆ 800 ~ 1200 mg per day Leafy Green Vegetables + others good source of calcium Calcium(mg) Skim Milk (1 cup) 300 Leafy greens (2 cups) 400 Tofu (1/2 cube) 150 Orange (2 pcs) 100 950 Don’t forget your Vitamin D**** • Increase calcium absorption • Food Source: egg yolk, liver & fatty fish • Sunshine (15’ in summer, 30’ in winter) Taking in Enough Protein (to prevent osteoporosis & sarcopenia**) Daily intake of 4 – 7 Servings of Protein Going Low in Salt + Avoid alcohol Fall prevention (1) Easy access for frequently used items Hip protector for poor balance patients Avoid Polypharmacy: seek advice from doctor if feeling dizzy after taking drugs Bath table + non-slippery mat Intervention % diff spine BMD Weight-bearing 1.7 Resistance training 6.8 High-intensity training 2.8 Brisk-walking -0.1 Exercise type Times body weight at spine Walking 1 Slow running 2 Jumping Weight training 12 6 A1/A2 + B = Adequate A1 Examples of weight-bearing exercise for healthy individuals •Brisk walking, Jogging, Racquet sports A2 Examples of weight-bearing exercise for frail individuals •Walking, Low impact aerobic B Muscle strengthening •Weight lifting, Exercise machine Importance of exercise therapy (>3.5 hrs/week) Benefit of exercise Good Exercises help • Reduce the rate of bone loss • Strengthen muscles • Correct posture • Improve quality of life • Always keep your posture great • Walking helps you breathe OK • Stretching kicks off muscle ache • Moving joint helps blood circulate • Balance helps you not to fall • Strength and power add some more Before starting exercise: • Know your own ability + Seek medical advice if one has medical issue • Wear proper sports attire + non-slip runners • Select suitable venue • Drink water prior to do any exercises + eat a bit if DM • Do exercise on a regular basis (daily for 30 ~ 60 minutes) • Cumulative time > 3.5 hrs/week The exercises should include: • “Warm up + stretches, Core exercise, Cool down + stretches” • Weight bearing exercises + UL & LL muscle strengthening + Posture Warm up (Slow to Fast) (Exercise to mobilize joints + Stretching ) Core exercise (Muscle strengthening + Single-leg stand + Balance exercise: static & dynamic ) Cool Down (Fast to Slow) (Exercise to mobilize joints + Stretching ) Know the types of Weight Bearing Exercise High impact: Jump, Volley Ball, Basketball, Soccer & Football Medium Impact: Gentle aerobic dance, PUMP, Steps Exercise, Ball room dancing, Line Dancing Low Impact: Walking (+/- loading), Brisk walking, Tai Chi, Tai Chi sword, Fan Dance Ensure + consider patient’s safety at all time! Safe Weight bearing exercise & aerobic exercise for OP patients In general: Walking, Brisk walking Patients with poor physical fitness: Tai Chi, Tai Chi sword, Fan Dance Education on Fall prevention + Osteoporosis are important Sarcopenia • The degenerative loss of skeletal muscle mass, quality, and strength associated with aging and immobility. • A component of the frailty syndrome, similar in OP. • Muscle may lead to the cause of the fragility # as the muscles are weak and could not hold the upright posture of an elderly adult. • Rate of muscle loss: dependent on exercise level, comorbidities, nutrition and other factors. • In Asian: begin from the age 30. • In Whites: begin from mid to late 20’s. • Lead to reduction in functional status & disability. • The muscle loss is related to changes in muscle synthesis signalling pathways (distinct from cachexia that the muscle is degraded through cytokine-mediated degradation). • Both the sarcopenis and cachexia may co-exist. S&S: • Loss of lean muscle mass: difficult to detect due to obesity, changes in fat mass, or edema, as changes in weight, limb or waist circumference are not reliable indicators of muscle mass changes. • Reduced strength, functional decline and increased risk of falling. • May also have no symptoms and is often unrecognized (like osteoporosis as a “Silent Disease”. Causes: Multiple interacting factors: changes in hormones, immobility, age-related muscle changes, nutrition and neurodegenerative changes. Degree of severity determined by many factors as follows : i). initial amount of muscle mass and rate at which muscle mass declines (variations across the population due to the rate of progression and the threshold at which muscle loss becomes evident and affects function is variable. ii). Immobility dramatically increases the rate of muscle loss, even in younger people. iii). Decreased nutrient intake, low physical activity, or chronic disease. iv). Low birth weight is associated with reduced muscle mass and strength in adult life. Pathophysiology: changes in satellite cell recruitment, changes in anabolic signalling, protein oxidation, inflammation, and developmental factors. The pathologic changes include muscle atrophy with a reduction in muscle tissue quality + in the replacement of muscle fibers with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction. i). A decrease in type II muscle fibers/"fast twitch“/with little to no decrease in/type I muscle fibers/"slow-twitch" muscle fibers (deinervated from type II fibers to type I fibers by reinnervation by slow type I fiber motor nerves). ii). Failure to activate satellite cells upon injury/exercise also contributes to the pathophysiology of sarcopenia. iii). Oxidized proteins can lead to a buildup of lipofuscin + cross-linked proteins that causing an accumulation of non-contractile material in the skeletal muscle and contribute to sarcopenic muscle. Diagnosis: ICD-10 code (M62.84) Muscle mass that is at least 2 SD below the relevant population mean and has a slow walking speed. The European Working Group on Sarcopenia in Older People (EWGSOP): the presence of low muscle mass and either low muscular strength or low physical performance. Other criteria: walking speed, distance walked in 6 minutes, or grip strength. Hand grip strength alone is a simple, cost effective and of good predictive power (though not a comprehensive information). Screening tools: assess patient reported difficulty in doing ADL in walking, climbing stairs or chair-stand to predict sarcopenia + poor functional outcomes. Management i). Exercise: the best intervention of choice for sarcopenia: note the type, duration and intensity of exercise. Lack of exercise is a significant risk factor and exercise can dramatically slow the rate of muscle loss. Aging skeletal muscle retains ability to synthesize proteins in response to shortterm resistance exercise. Progressive resistance training in older adults can improve physical performance (gait speed) and muscular strength. ii). No approved medications though testosterone or other anabolic steroids seem to have some positive effects on muscle strength and mass, but may cause prostate cancer in men and virilization in women, and testosterone may induce adverse cardiovascular events. iii). DHEA and human growth hormone: increases muscle protein synthesis and increases muscle mass, but does not lead to gains in strength and function in most studies. iv). Vitamin D: +ve effects in maintaining muscle strength and balance v). Angiotensin converting enzyme inhibitors, and eicosapentaenoic acid: under investigation vi). Nutrition: older adults require higher amounts proteins to prevent muscle atrophy (dietary protein recommendations for older age groups is to 1.0-1.2 g/kg body weight per day) to prevent sarcopenia and frailty. vii). Larger doses of amino acids (metabolite leucine acts as a signalling molecule to stimulate protein synthesis) has been reported to counteract muscle loss with aging. Exercise work synergistically with amino acid supplementation. Epidemiology: Prevalence in 60-70 y.o: 5-13%, over 80 y.o.: 11-50% (a great risk to the longevity + ageing population, similar to Dementia….) Public health impact: given the increased longevity of industrialized populations and growing geriatric population, sarcopenia is a predictor of many adverse outcomes including increased disability, falls and mortality. Immobility or bed rest in populations predisposed to sarcopenia can cause dramatic impact on functional outcomes. i). Frailty Syndrome: the decreased biological reserve + increased vulnerability to stressors in the elderly. ii). Loss of lean body mass: associated with increased risk of infection, decreased immunity, and poor wound healing. iii). Muscle weakness & muscle atrophy: higher risk of falls, fractures, physical disability, need for institutional care, reduced quality of life, increased mortality, and increased healthcare costs. iv). Causes a significant personal and societal burden. Research on the causes & consequences to build guidelines on clinical care: • Examples: elucidation of the molecular and cellular mechanisms of sarcopenia, epidemiology in different ethnic groups, validation of diagnostic criteria and clinical tools, tracking of incidence of hospitalization admissions, morbidity, and mortality. Identification and research on potential therapeutic approaches and timing of interventions. • New pharmaceutical therapies in clinical development include myostatin and the selective androgen receptor modulators (SARMs) (they exhibit significant selectivity between the anabolic effects of testosterone on muscle, but with little to no evidence of androgenic effects, such as prostate stimulation in men). Hypercalcaemia • A high calcium (Ca2+) level in the blood serum (normal range is 2.1–2.6 mmol/L) Epidemiology: Relatively common. Primary hyperparathyroidism occurs in 1–7 per 1,000 people, and hypercalcaemia occurs in about 2.7% of those with cancer. S&S: Mild increase: no symptoms. • Greater levels or rapid onset: abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest. Causes: primary hyperparathyroidism or cancer. Other causes: sarcoidosis, tuberculosis, Paget disease, multiple endocrine neoplasia (MEN), vitamin D toxicity, familial hypocalciuric hypercalcaemia and certain medications such as lithium and hydrochlorothiazide. Dx: elevated calcium or ionized calcium level + shortened QT interval and prolonged PR interval in ECG. Treatment: IV fluids, furosemide, calcitonin or pamidronate + treat the underlying cause. Haemodialysis may be used in those who do not respond to other treatments. In those with vitamin D toxicity, steroids may be useful. Hypocalcaemia • Low calcium levels in the blood serum (normal range: 2.1–2.6 mmol/L) • Symptoms: numbness, muscle spasms, seizures, confusion, or cardiac arrest. • Causes: hypoparathyroidism and vitamin D deficiency, kidney failure, pancreatitis, calcium channel blocker overdose, rhabdomyolysis, tumor lysis syndrome, and medications such as bisphosphonates. • Diagnosis: Blood test with a corrected calcium or ionized calcium level + Electrocardiogram (ECG). • Treatment: IV calcium chloride + magnesium sulfate +/- vitamin D. • If hypoparathyroidism: use hydrochlorothiazide, phosphate binders, and a low salt diet. • 18% of hospitalized patients have hypocalcemia. Rickets (A condition that results in weak or soft bones in children) • Common in the Middle East, Africa, and Asia. • Typically between the ages of 3 & 18 months old. Males = Females. Cause: vitamin D deficiency (insufficient vitamin D, dark skin, little sun exposure, exclusive breastfeeding without vitamin D supplementation, celiac disease, and certain genetic conditions. Risk factors: insufficient intake calcium or phosphorus. • Underlying mechanism: insufficient calcification of the growth plate. Symptoms: bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications: bone fractures, muscle spasms, an abnormally curved spine, or intellectual disability. Diagnosis: Blood Test/Low calcium & phosphorus, and High alkaline phosphatase Imaging: X-rays + CXR, DXA or Bone Scan prn. Prevention: vitamin D supplements, cod liver oil. Treatment depends on the underlying cause. • Vitamin D + calcium (results in improvements within a few weeks). • Surgery: occasional to fix bone deformities. Types: • Vitamin D-related rickets, Vitamin D-resistant rickets • Hypocalcemia-related rickets, Hypophosphatemia-related rickets • Chronic renal failure (CKD-BMD), Congenital • Autosomal dominant hypophosphatemic rickets (ADHR) • Autosomal recessive hypophosphatemic rickets (ARHR) • Fanconi's syndrome (inadequate reabsorption in the proximal renal tubules of the kidney) • Dent's disease (a chronic kidney disorder that occurs in males) • Tumor-induced osteomalacia • McCune-Albright syndrome (a disorder that affects the bones, skin, and several hormone-producing tissues) • Epidermal nevus syndrome (an abnormal, benign patch of skin caused by an overgrowth of cells in the epidermis) Osteomalacia (Similar to rickets in children, but is the milder and adult form of the disease) Softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization. S&S: diffuse body pains, muscle weakness, and fragility of the bones + low systemic levels of circulating mineral ions necessary for bone and tooth mineralization. Common cause: deficiency of vitamin D, inadequate sunlight exposure & from the diet. Less common: hereditary deficiencies of vitamin D or phosphate or malignancy. Screening test for vitamin D deficiency: serum 25(OH)D level. Risk factors: Nursing home residents, homebound elderly, little sun exposure, absorption of vitamin D declines with age, malabsorption secondary to gastrointestinal bypass surgery or celiac disease, and individuals who immigrate from warm climates to cold climates (wear dresses that prevent sun exposure). S&S: Diffuse joint and bone pain (in spine, pelvis, legs) • Muscle weakness • Difficulty walking, Waddling gait • Hypocalcemia • Compressed vertebrae • Pelvic flattening • Weak/soft bones/fracture/Bending of bones • Insidiously pains in the Lx region and thighs • Weak proximal muscles in climbing up stairs and getting up from squatting. • Bones deformities • Pathologic fractures • Chronic fatigue Causes • Vitamin D deficiency or faulty metabolism of vitamin D or phosphorus • Renal tubular acidosis • Malnutrition during pregnancy • Malabsorption syndrome • Hypophosphatemia • Chronic kidney failure • Tumor-induced osteomalacia • Long-term anticonvulsant therapy Diagnosis • Biochemical findings: similar to those of rickets: low vitamin D concentration in blood serum • Low serum and urinary calcium • Low serum phosphate • Elevated serum alkaline phosphatase • Elevated parathyroid hormone • Technetium bone scan shows increased activity (due to increased osteoblasts). Radiological appearances include: • Pseudofractures (Looser's zones). • Protrusio acetabuli Tumor-induced osteomalacia Prevention: adequate intake of vitamin D and calcium. Treatment: 2,000-10,000 IU of vitamin D3 by mouth daily. Vitamin D3 is absorbed better than vitamin D2. Osteomalacia with multiple fractures Hypophosphatemia (deficiency of alkaline phosphatase, or phosphoethanolaminuria) • A rare, and sometimes fatal, metabolic bone disease. • Clinical symptoms: from the rapidly fatal, perinatal variant, with profound skeletal hypomineralization and respiratory compromise, to a milder, progressive osteomalacia later in life. • Prevalence: around 1:100,000. S&S: Perinatal hypophosphatasia: Stillbirth is common. Neonates who manage to survive suffer increasing respiratory compromise due to softening of the bones (osteomalacia) and underdeveloped lungs (hypoplastic), leading to respiratory failure. Epilepsy occurs and can prove lethal. Childhood hypophosphatasia: The baby teeth are lost before the age of 5 (incisors are lost first + all teeth are lost prematurely). Delayed walking, waddling gait, stiffness and pain, and muscle weakness (especially in the thighs). Growth retardation, frequent fractures, and low bone density. Infantile hypophosphatasia in the first 6/12 of life: poor feeding & inadequate weight gain. Cranial sutures appear to be wide. Defects in the chest, such as flail chest resulting from rib fractures, lead to respiratory compromise and pneumonia. Hypercalcemia & Hypercalcenuria. Adult hypophosphatasia: Discomfort in the thighs or hips due to femoral pseudofractures can be distinguished from other types of osteomalacia by their location in the lateral cortices of the femora. Pseudogout, pseudofractures in the lateral cortices of the proximal femora and stress fractures. Odontohypophosphatasia (“early-onset periodontitis”): When dental disease is the only clinical abnormality. Hereditary leukocyte abnormalities and other disorders usually account for this condition. Diagnosis Dental findings: exam teeth & gum. Laboratory testing: low serum activity of alkaline phosphatase enzyme (ALP). Radiography: X-ray may reveal infantile hypophosphatasia in infants, and bilateral femoral pseudofractures in the lateral subtrochanteric diaphysis in adults. Genetic analysis: gene encoding TNSALP on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760), check for mutation analysis. Treatment: maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions. • Hypercalcemia in infants: restriction of dietary calcium or administration of calciuretics. • Bony deformities and fractures: require prolonged casting or stabilization with orthopedic hardware. ORIF with intramedullary nail or rod for fractures. Dental problems: monitor patients’ dental hygiene and periodontal disease. • Physical Impairments and pain: Physiotherapy, analgesics & NSAID. • Bisphosphonate, Bone marrow cell transplantation, Enzyme replacement therapy. Chronic Kidney Disease Mineral Bone Disorder (CKDMBD) When the GFR loss aggravates, the disturbed mineral metabolism worsens the bone microstructure and remodelling – scenario. Characterized by : (i) abnormal metabolism of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; (ii) abnormalities in bone turnover, mineralization, volume linear growth or strength; (iii) soft-tissue calcifications, either vascular or extra-osseous. Uremic vascular calcification + osteoporosis: the most common complications related to CKD-MBD. • Disregulated bone turnover by uremic toxin or secondary hyperparathyroidism disturbed bone mineralization and makes it difficult for calcium and inorganic phosphate to enter into bone, resulting in increased serum calcium and inorganic phosphate. • Vascular calcification worsens by hyperphosphatemia and systemic inflammation. • supplement of nutritional vitamin D is important in treating uremic osteoporosis and vascular calcification at the same time. Hyperparathyroidism An increase in parathyroid hormone (PTH) levels in the blood (from a disorder either within the parathyroid glands (primary hyperparathyroidism) or outside the parathyroid glands (secondary hyperparathyroidism). • S&S: No symptoms but only elevated blood calcium. When prolonged: kidney stones appear. After that come the bone pain, weakness, depression, confusion, and increased urination. • 80% Primary hyperparathyroidism: parathyroid adenoma (benign tumor). Rarely due to parathyroid cancer. • Secondary hyperparathyroidism: vitamin D deficiency, chronic kidney disease, or other causes of low blood calcium. • Dx: elevated calcium + PTH in the blood biochemistry. Primary hyperparathyroidism: cured by removing the adenoma or overactive parathyroid glands. In those without symptoms, cinacalcet is used to decrease PTH levels. Epidemiology: • 1 ~ 4 %. F > M x 3 times, between the ages of 50 and 60. Hypercalcaemia of Malignancy • Hypercalcemia occurs in 20% to 30% of patients with cancer. • Result from: humoral hypercalcemia of malignancy (characterized by tumor secretion of parathyroid hormone-related peptide [PTHrP]); local osteolytic hypercalcemia (characterized by local release of factors, including PTHrP, by bony metastases that promote osteoclast differentiation and function); calcitriol (1,25dihydroxyvitamin D)-mediated hypercalcemia (characterized by autonomous production of calcitriol [(1,25dihydroxyvitamin D)] by lymphoma cells); and ectopic hyperparathyroidism (characterized by tumor production of parathyroid hormone), which is very rare. Paget’s Disease/ Osteitis Deformans • A condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. Cause: unknown (genetic/environmental factors). One or multiple bones of the body (e.g. pelvis, tibia, femur, and lumbar vertebrae, and skull) may be affected, but never the entire skeleton, or spread from bone to bone; and rarely transforms into a malignant bone cancer. Pathogenesis (4 stages): i). Osteoclastic activity, ii). Mixed osteoclastic – osteoblastic activity, iii). Osteoblastic activity, iv). Malignant degeneration Epidemiology: 1.5 - 8% of the population (especially in the British descents). In older people > 55 years of age. Men > Women. The risk increases with age. Familial trend. Complications include broken bones, hearing loss and pinched nerves in the spine. Dx: An ivory vertebra + elevated alkaline phosphatase in the blood. i). X-rays: a skeletal survey. ii). Elevated level of alkaline phosphatase & normal calcium, phosphate, and aminotransferase levels in an elderly patient iii). Markers of bone turnover in urine (eg. Pyridinoline) iv). Elevated levels of serum and urinary hydroxyproline. v). Bone scans to determine the extent and activity of the condition. S&S: deformity, pain, fracture, or arthritis of associated joints. Management: no cure and only symptomatic relief. Bisphosphonates + Calcitonin can help control the disorder and lessen pain and other symptoms, when started early. References 1. Blom, A., Warwick, DJ, & Whitehouse, M.. (2018). Apley & Solomon’s System Of Orthopaedics And Trauma. (10th ed.). Florida, CRC Press. 2. Frontera, W. R., Silver, J. K., & Rizzo, T. D. (2018). Essentials of Physical Medicine and Rehabilitation: Musculoskeletal Disorders, Pain and Rehabilitation. (4th ed.). Philadelphia: W.B. Saaunders Company. 3. Faulkner KG, Appropriate Use of Dual-Energy Vertebral Assessment. GE Healthcare 2004 4. 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