Metabolic Bone Disease

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Metabolic Bone Disease
Metabolic Bone Disease Emilene Galvin Normal Bone Physiology • When crystals of hydroxyapa>te (a complex of calcium, hydroxyl and phosphate ions) are laid down between collagen fibres, bone calcifica>on occurs. • Major skeletal growth occurs in childhood, adult bone is con>nually being remodelled with bone forma>on and resorp>on. • These ions in bone are in dynamic equilibrium with ions present in the bloodstream, an equilibrium which is regulated by Vitamin D and by two pep>de hormones, Parathyroid Hormone (PTH) and calcitonin. • Func>on of bone: Mechanical, Metabolic & Protec>ve Bone remodelling • Osteoblasts are involved in synthesis of bone matrix before it is calcified. AQer bone mineraliza>on some of these cells become embedded in calcified bone as osteocytes. • Osteoclasts are responsible foe resorp>on. Lysosomal enzymes are secreted into the extracellular compartment exposing the matrix. • Bone remodelling takes place in groups of cells called the basic mul>cellular unit. This complex process is regulated by circula>ng hormones and local factors such as cytokines, growth factors and prostaglandins. Hormonal regula>on of bone remodelling • Parathyroid hormone s>mulates bone resorp>on. Doesn’t act directly on osteoclasts, mediated by osteoblasts. • Calcitonin: inhibits bone resorp>on by direct ac>on on osteoclasts • Vitamin D and Calcium • Insulin • Growth hormone • Glucocor>coids • Oestrogens – Decrease bone resorp>on • Androgens • Thyroid hormones Rickets / Osteomalacia • Vitamin D deficiency or phosphate deple>on • Inadequate exposure to sunlight • Rickets was known as the children’s disease of England in the 17th Century • Leads to bowing of the long bones • Osteomalacia is the soQening and weakening of adult bones Bedouin Women Due to clothing worn bedouin women sunlight exposure is limited, and osteomalacia is recognised in these women Osteoporosis • A disease characterised by low bone mass and microarchitectural deteriora>on, leading to enhanced bone fragility and increased risk of fracture. • Defined by WHO as a bone density more than 2.5 standard devia>ons below the young adult mean (sex and age matched) Diagnosis of Osteoporosis • Xray • History of fracture • Loss of height, vertebral collapse typified by dowager’s hump • DEXA Dual energy X‐ray densiometry • Serum Calcium, phosphate and alkaline phosphatase should be normal. DEXA Machine Causes of Osteoporosis Primary Secondary • Post menopausal • Senile • Idiopathic Juvenile • Rheumatological • Drug / Toxin • Endocrine e.g. Hyperparathyroidism, thyroid disorder, Type 1 DM • Neoplasia e.g. myeloma • Gastrointes>nal e.g. Malnutri>on, Vitamin D Deficiency, Malabsorp>on • COPD • Anaemia Risk Factors for Osteoporosis • Gender • Family history • Age / Menopause • Smoking – Decreases sex hormone binding globulin • Poor dietary intake of calcium • Immobility. Regular weight bearing exercise is protec>ve • Drugs especially steroid or an>convulsant use • Thin people at higher risk of Osteoporosis • Lack of sunlight The Bone Density of Female Twins Discordant for Tobacco Use • John Llewelyn Hopper, and Ego Seeman Melbourne • • • 41 pairs of twins (21 monozygous pairs) Bone density was measured by dual‐photon absorp>ometry For every 10 pack‐years of smoking, the bone density of the twin who smoked more heavily was – 2.0 percent lower at the lumbar spine (P = 0.01) – 0.9 percent lower at the femoral neck (P = 0.25) – 1.4 percent lower at the femoral shaQ (P = 0.04). • • Smoking was associated with higher serum concentra>ons of FSH, LH and lower serum concentra>ons of PTH. Differences in spinal bone density between members of a pair were associated with differences in the serum concentra>ons of PTH(P = 0.01) and calcium (P = 0.05). • Conclusions Women who smoke one pack of cigareges each day throughout adulthood will, by the >me of menopause, have an average deficit of 5 to 10 percent in bone density, which is sufficient to increase the risk of fracture. Vitamin D • Most naturally occurring foods have low levels of vitamin D. Fish oils are notable excep>ons. Many foods are now for>fied with Vitamin D • Cholesterol is a precursor to vitamin D • UV Light is involved in the pathway of conver>ng cholesterol to previtamin D3. • Hepa>c and Renal modifica>on are required for synthesis of calcitriol (1,25 Dihydroxycholecalciferol) • Vitamin D acts on mucosal cells of the intes>ne, where it s>mulates calcium absorp>on and retrieval to the blood stream, as well as in the proximal tubules of the kidney, where it promotes re‐absorp>on of phosphate which would otherwise be excreted in urine. Exercise • Aerobics, weight bearing and resistance exercises are all effec>ve in increasing the bone mineral density of the spine in postmenopausal women. • Walking is also effec>ve on the hip. • The quality of the repor>ng of the trials in the meta‐analysis was low, in par>cular, in the areas of alloca>on concealment and blinding. Cochrane database analysed 13 trials. • Astronauts opera>ng in a weightless environment for long periods are subject to a form of bone deteriora>on known as disuse osteoporosis, which can pose a serious hazard for crews on future space missions that might run two years or more. AQer long exposure to microgravity, weight bearing bones lose calcium and density, become very brigle and are easily fractured. Gene>c Factors Physical Ac>vity Nutri>on Peak Bone Mass What factors decrease bone mass to result in Osteoporosis? Menopause Ageing ↓Serum Oestrogen ↑Levels of IL1 and IL6 ↑Osteoclast ac>vity ↓Replica>ve ac>vity of osteoprogenitor cells ↓synthe>c ac>vity of Osteoblasts ↓Biological ac>vity of matrix bound growth factors ↓Physical ac>vity Treatment The goal of osteoporosis treatment is to reduce fracture risk. • Lifestyle changes i.e. smoking cessa>on, reduc>on in Alcohol intake. • Increased Dietary Calcium and Vitamin D3 – low level evidence to suggest decrease fractures • Hormone replacement Therapy (HRT) in women • Raloxifene ‐ Selec>ve Oestrogen receptor modulator (Post Menopausal women) SERM • Bisphosphonates • Calcitonin nasal spray – reduces risk of vertebral fracture • Sodium Flouride Further treatments • Parathyroid Hormone • Vitamin D Analogues • Stron>um Ranelate – Inhibits Osteoclast func>on • Ipriflurone Bisphosphonates • Alendronate, Risedronate, and Zoledronic acid • Once weekly or once monthly dosing. Taken on empty stomach, siqng upright due to low oral bioavailability. Can cause oesophageal inflamma>on or, rarely, ulcera>on. • Poor compliance with treatment • Rare complica>on is osteonecrosis of the jaw. Reported with cancer pa>ents on high doses Alendronate • • • • • Alendronate Phase III Osteoporosis Treatment Study Group mul>na>onal randomized, double‐blind study postmenopausal women with osteoporosis Treatment with 10 mg of alendronate daily for 10 years mean increases in bone mineral density of – 13.7 percent at the lumbar spine – 10.3 percent at the trochanter – 5.4 percent at the femoral neck – 6.7 percent at the total proximal femur • The primary end point was the change in bone mineral density at the lumbar spine. • Secondary end points were changes in bone mineral density at the femoral neck, trochanter, total proximal femur ("total hip"), total body, and forearm regions; Bisphosphonate Studies • HORIZON: zoledronic acid, Black et al. At 3 years – vertebral fractures ↓70%, – hip fractures ↓ 41% – nonvertebral fractures ↓ 25% Efficacy proven one year post dose Compliance not an issue due to iv dosing Mean Serum Calcium Levels post [email protected] of zolendronic acid or placebo Serial Changes in Mean Serum Calcium Levels in Pa>ents with Stroke Treated with Zoledronic Acid or Placebo. Parathyroid Hormone Teripara>de 20mcg od sc x 18/12 Hi Tech Prescrip>on Endogenous Hormone. S>mulates osteoblast ac>vity,increases ac>ve vitamin D synthesis, increases absorp>on of calcium, and increases resbsorp>on of calcium from the renal tubules. • PTH acts directly on osteoblasts, facilita>ng their interac>on via other chemical ac>vators with osteoclasts. • Increases ac>vity of pre osteoblasts, which in turn increases expression of RANK‐L • • • • Teripara>de • Pa>ent over 65 years • One of the following – Extremely low bone mineral density – 2 or more fracture – BMI less that 19 – Premature menopause – History of Maternal hip fracture under the age of 75 • Dura>on of Treatment currently 18 Months • Full work up to outrule hyperparathyroidism prior to commencing treatment • DEXA • Bloods – Serum Bone profile Calcium, phosphate, Albumin, Alkaline phosphatase – ESR – Immunoglobulins and serum protein electrophoresis – Endogenous PTH levels – immediate delivery to lab, where it is stored at minus 25 degrees – Vitamin D Levels ‐ fas>ng, light sensi>ve • 24 Hour urine collec>on for urinary calcium and crea>nine Stron>um Ranelate • Cochrane Database 2006. Four trials met the inclusion criteria. Studies on postmenopausal osteoporo>c women. • Three included a treatment popula>on (0.5 to 2 g of stron>um ranelate daily) and one a preven>on popula>on (0.125 g, 0.5 g and 1 g daily). • A 37% reduc>on in vertebral fractures and a 14% reduc>on in non‐vertebral fractures were demonstrated over three years with 2 g of stron>um ranelate daily in a treatment popula>on. • An increase in BMD was shown at all BMD sites aQer two to three years in both popula>ons. • Higher doses showed greatest reduc>ons in fractures and increases in BMD> Benefits of [email protected] ranelate In women aQer menopause who have osteoporosis: stron>um ranelate decreases spine fractures • 13 out of 100 women had spine fractures taking stron>um ranelate • 21 out of 100 women had spine fractures taking a placebo stron>um ranelate may decrease fractures that are not in the spine • 10 out of 100 women had non‐spine fractures taking stron>um ranelate • 12 out of 100 women had non‐spine fractures taking a placebo stron>um ranelate increases bone mineral density 1 in 3 women had an increase in spine and hip bone mineral density taking stron>um ranelate Three [email protected] of Womens References • [email protected] ranelate for [email protected] and [email protected] postmenopausal osteoporosis S O'Donnell, A Cranney, GA Wells, JD Adachi, JY Reginster • Treatments for Osteoporosis — Looking beyond the HORIZON Juliet Compston, M.D., F.R.C.P., F.R.C.Path., F.Med.Sci. • Bisphosphonates and Osteoporosis Caren G. Solomon, M.D., M.P.H. NEJM Volume 346:642 • Serial Changes in Mean Serum Calcium Levels in [email protected] with Stroke Treated with Zoledronic Acid or Placebo. Ron N.J. de Nijs, M.D., Ph.D. • The Bone Density of Female Twins Discordant for Tobacco Use John Llewelyn Hopper, and Ego Seeman • Ten Years' Experience with Alendronate for Osteoporosis in Postmenopausal Women Henry G. Bone, M.D., David Hosking, M.D., Jean‐Pierre Devogelaer, M.D., Joseph R. Tucci, M.D., Ronald D. Emkey, M.D., Richard P. Tonino, M.D., Jose Adolfo Rodriguez‐Portales, M.D., Robert W. Downs, M.D., JayanN Gupta, Ph.D., Arthur C. Santora, M.D., Ph.D., Uri A. Liberman, M.D., Ph.D., for the Alendronate Phase III Osteoporosis Treatment Study Group 

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