Presentation for osteoporosis in bones of

osteoporosis

1. Osteoporosis

2. Introduction Osteoporosis is a common metabolic bone disease character- ized by reduced bone mass, microarchitectural deterioration of bone tissue, and an increased risk of fragility fractures The diagnosis is made by measurements of bone mineral density (BMD) using dual energy x-ray absorptiometry (DEXA). Indi- viduals with BMD values more than 2.5 standard deviations below the average in young healthy subjects (T-score <-2.5) are classified as having osteoporosis. People with lesser reduc- tions in BMD (T-score between -1 and -2.5) are classified as having osteopenia whereas people with T-score values between -1 and +2.5 are said to have normal bone mass Patients with T-score values above +2.5 in the absence of a known cause such as osteoarthritis of the spine considered to have abnormally high bone mass.

3. The clinical importance of osteoporosis lies in the fact that it is a risk factor for fractures and the risk of fracture increases by a factor of 1.5- to 3-fold for each standard deviation reduc- tion in BMD Osteoporosis is classically associated with an increased risk of low-trauma fractures (fragility fractures), but recent studies indicate that perhaps not surprisingly, low levels of BMD are associated with the risk of all types of fractures including high energy fractures.

4. pathophysiology Bone is a composite material comprising matrix and mineral phases. The main component of bone matrix is type I collagen which is a fibrillar protein comprising two alpha 1 and one alpha 2 chains wound together in a triple helix. Bone matrix also contains small amounts of other collagens, growth factors, and other noncollagenous proteins and glycoproteins The mineral phase of bone consists of calcium and phosphate in the form of hydroxyapatite crystals (Ca10(PO4)6(OH)2) which are deposited in the spaces between collagen fibrils. Anatomically bone is divided into cortical and trabecular subtypes. Most of the skeleton consists of cortical bone which forms the shafts of the long bones such as the femur, tibia, humerus, and radius and forms a thin envelope around the trabecular bone which is abundant at the metaphyses of long bones and in the vertebral bodies. Bone structure

5. During bone remodeling old and dam- aged bone is removed by multinucleated osteoclasts which dis- solve bone mineral through secretion of acid and degrade bone matrix through secretion of proteases. Following completion of bone resorption, bone marrow stromal cells are attracted to the resorption lacuna and differentiate into osteoblasts The osteoblasts lead to the formation of unmineralised bone I.e.osteoid which leads to formation of mature mineralised bone During the process of bone formation some osteo- blasts become trapped in the bone matrix and differentiate into osteocytes. Osteocytes are the most abundant cells in bone. Communicated through the canaliculi

6. They sense and respond to mechanical stimuli by producing regula- tory molecules including receptor activator of nuclear factor kappa B (RANK) which regulates bone resorption and sclerostin (SOST) which regulates bone formation. Osteocytes also have an important endocrine function by producing a circulating hor- mone called fibroblast growth factor 23 (FGF23) which acts on the renal tubule to regulate serum phosphate levels.

7. Bone resorption is carried out by osteoclasts which are multinu- cleated cells derived from the monocytes/macrophage lineage. The RANK receptor is a member of the tumor necrosis factor (TNF) recep- tor superfamily which is expressed on osteoclast precursors and mature osteoclasts. When RANKL binds to RANK several intracellular signaling pathways are activated which cause osteoclast differen- tiation and bone resorption. Osteoprotegerin (OPG) has homol- ogy to RANK, but lacks a signaling domain and acts as a decoy receptor for RANKL. In the presence of OPG, the stimulatory effects of RANKL on osteoclasts are blocked causing osteoclast inhibition. loss of function mutations in OPG result in juvenile Paget’s disease, a condition associated with markedly elevated bone turnover, fractures, and bone deformity. Bone resorption

8. The acid dissolves hydroxyapatite, allowing the proteolytic enzymes to degrade collagen and other bone matrix proteins. CA2 gene which encodes carbonic anhydrase type II, which is necessary for acid generation in osteoclasts CLCN7 gene which encodes the osteoclast chloride channel; and the CATK gene which encodes cathepsin K, a protease that is necessary for collagen degradation.

9. Bone is formed by osteoblasts which are mononuclear cells derived from mesenchymal stem cells. core-binding factor alpha 1 (Cbfa1) and osterix which are tran- scription factors that promote differentiation of mesenchymal stem cells to osteoblasts Bone morphogenic proteins which are members of the transforming growth factor beta superfam- ily that upregulate Cbfa1 expression in osteoblast precursors; and members of the Wnt superfamily which affect osteoblast dif- ferentiation and function by regulating the transcription factor beta-catenin The importance of SOST in regulating bone mass is reflected by the fact that recessive (loss of function) mutations in SOST result in bone overgrowth and high bone mass in the syndromes of sclerosteosis and van Buchem disease Bone formation

10. Risk factors for osteoporosis

11. Hypogonadism is an important cause of osteoporosis in both genders. This may be physiologic as in the case of postmeno- pausal osteoporosis or pathologic as in patients with pituitary disease, Klinefelter syndrome, and Turner syndrom Although testos- terone protects against osteoporosis in men, current evidence suggests that it does so through peripheral conversion to estrogen through aromatization Crohn disease and ulcer- ative colitis. Celiac disease is associated with an increased risk of osteoporosis and fractures presumably due to impaired intestinal absorption of calcium, vitamin D, and other nutrients Thyrotoxicosis is associated with osteoporosis due to increased bone turnover as is over-replacement with thyroxin Primary hyperparathyroidism is associated with osteoporosis due to increased bone turnover with relative uncoupling of bone resorption from bone formation. Corticosteroids -reduced intestinal calcium absorption, increased renal calcium losses by an effect of glucocorticoids on renal tubular calcium absorption, and reduced bone formation and inhibition of bone formation by apoptosis of osteoblasts and osteocytes.

12. Over-replacement with thyroxine in patients with hypothyroid- ism is associated with reduced bone mass, presumed to be due to a direct stimulatory effect on bone turnover.4

13. Bone density Assessment of BMD by DEXA has a pivotal role in the diagnosis of osteoporosis, in fracture risk assessment, and in selecting patients for treatment. Measurements of BMD are usually made at the femoral neck and lumbar spine in routine practice increased risk of fracture such that fracture risk increases by a factor of 1.5 to 3-fold for each standard deviation reduction in BMD. Osteoporosis is diagnosed if T-score values at either the lumbar spine (typically the average of lumbar vertebrae L1 to L4), femoral neck, or total hip sites lie below -2.5 FRCTURE RISK ASSESSMENT Several risk factor tools have been developed, but the ones that are used most commonly are the FRAX tool and the Qfracture Scores Clinical assessment

14. Both provide estimates of 10-year fracture risk by combining information on weight, height, age, and gender with other clinical risk fac- tors such as corticosteroid use, smoking, alcohol intake, and other diseases. RADIOGRAPHY Standard radiographs have poor sensitivity for the detection and monitoring of osteoporosis since large amounts of bone mineral (up to 30%) must be lost or gained from the skeleton before it can be reliably detected on plain radiographs. The principal application of radiographic examination in the assessment of patients with osteoporosis is in the diagnosis of fractures. BIOCHEMICAL MARKERS Bone turnover can be assessed biochemically by analysis of bone cell-specific proteins or products of matrix formation and degradation, which are released during bone remodel- ing.

15. Management Diet :it has been suggested that premenopausal women and men should take 1,000 mg daily and postmenopausal women 1,500 mg daily. Vitamin D is required for optimal absorption of calcium and there is evidence (summarized later) that calcium and vita- min D supplements reduce the risk of fractures. daily intake of 400 International Units of vitamin D to maintain serum 25(OH)D levels above 50 nmol/L which is considered optimal for bone health Exercise Smoking and alcohol Fall’s reduction Life style modification

16. Bisphosphonates

17. Bisphosphonates bind strongly to calcium ions causing the drugs to preferentially target bone and become incorporated within hydroxyapatite The potency with which bisphosphonates inhibit bone resorption incor- poration of nitrogen into the side chain markedly increases potency. When bone containing the bisphosphonate under- goes resorption, the drug is released at high concentration within the osteoclast, causing osteoclast inhibition and inhibi- tion of bone resorption. Etidronate Etidronate is now seldom used in the treatment of osteoporosis due to the fact that it has not been shown to prevent nonverte- bral fractures It is given in a dose of 400 mg daily for 2 weeks followed by calcium supplementation of 500 mg daily for 11 weeks

18. Alendronic acid It has been shown to reduce vertebral fractures by about 50%, nonvertebral fractures by about 17%, and hip fractures by 40% in women with postmenopausal osteoporo- sis when given in a dose of 10 mg daily in combination with calcium and vitamin D supplements Also effective in corticosteroid induced osteoporosis68 and men with osteoporo- sis, Alendronic acid is poorly absorbed from the GI tract and should be taken at least 30 minutes before food Common adverse effects - upper GI upset,severe esophagitis,ulcer Rare -osteonecrosis of jaw

19. Risedronate Risedronate has similar antifracture efficacy to alendronic acid in patients with postmenopausal osteoporosis when given in a dose of 5 mg daily in combination with calcium and vita- min D supplements. Adverse effects are as described for alendronic acid Zolindronic acid When given intravenously at a dose of 5 mg once a year, along with calcium and vitamin D supplements, it has been shown to reduce the risk of vertebral, nonvertebral, and hip fractures in patients with postmenopausal osteoporosiS Zoledronic acid is the only agent that has been shown to reduce mor- tality in osteoporosis. When administered to men and post- menopausal women who had suffered hip fractures, treatment reduced overall mortality by 28% and reduced the risk of recurrent fracture by about 35%. The most common adverse effect is a transient influenza-like illness for 2 to 3 days after the first infusion which is self limiting

20. Other less common adverse effects include hypocalce- mia, atrial fibrillation, and renal impairment. Rare side effects include osteonecrosis of the jaw and uveitis Prior to admin- istration of zoledronic acid renal function should be checked and the drug administered only if the estimated GFR is greater than 35 mL/min Vitamin D deficiency should also be cor- rected to reduce the risk of hypocalcemia Ibadronate Ibandronate can be given orally or intravenously in the man- agement of osteoporosis. reduced the risk of vertebral fractures by about 50% when given orally in a dose of 2.5 mg daily Intravenous iban- dronate is given in a dose of 3 mg every 3 months in osteopo- rosis The antifracture efficacy of the 3-mg/3-month regimen patients treated with oral ibandronate 150 mg monthly and various doses of intravenous ibandronate showed evidence of efficacy at preventing vertebral and nonvertebral fractures with higher cumulative doses of the drug.

21. Denosumab Denosumab is a fully humanized monoclonal antibody directed against RANKL, a key stimulator of bone resorption It has powerful inhibitory effects on bone resorp- tion and is given subcutaneously in a dose of 60 mg every 6 months in the treatment of osteoporosis. denosumab reduces the risk of vertebral fractures by about 68%, hip fractures by 40%, and nonvertebral fractures by 20% in patients with postmenopausal osteoporo- sis. Denosumab is not subject to clear- ance by the kidney and because of this can be used in osteo- porotic patients with renal impairment, Unlike bisphosphonates, the effect of denosumab on bone resorption is relatively short lived and when treatment is stopped there is a rebound increase in bone turnover with significant bone loss.

22. Strontium renelate Strontium ranelate has weak inhibitory effects on bone resorp- tion and weak stimulatory effects on biochemical markers of bone formation Randomized trials have shown that strontium ranelate 2 g daily reduces the risk of verte- bral fractures by about 50% and nonvertebral fractures by about 16% in women with postmenopausal osteoporosis. Absorption of strontium is inhibited by food and it is usually given as a single dose at night at least 2 hours after eating. most common side effect is diarrhea and other GI side effects, but other less common adverse effects include skin rashes and venous thrombosis. Strontium ranelate has recently been found to increase the risk of myocardial infarction and is contraindi- cated in patients with known cardiovascular disease

23. Parathyroid glands an anabolic agent which works by stimulating bone remodeling and producing new bone Although bone resorption and bone formation are both increased by PTH, the cyclical mode of administration causes bone formation to increase more than bone resorption, resulting in a net gain of bone This differs from the situation in primary hyperparathyroidism where the sustained elevation in PTH levels causes bone resorption to increase more than bone formation resulting in bone loss, especially in cortical bone PTH 1-34 20 mcg daily given by subcutane- ous injection has been shown to be effective in reducing the risk of vertebral fractures by 65% and nonvertebral fractures by 50% in women with postmenopausal osteoporosis 31 Adverse effects of PTH include headache, muscle cramps, and mild hypercalcemia which is usually asymptomatic and does not require therapy to be stopped.

24. The recommended duration of therapy is 2 years at which point patients should be given an antiresorptive agent to prevent loss of the bone that has been newly formeD , concomitant administration of intravenous zoledronic acid with PTH does not appear to blunt the anabolic response.16

25. Hormone replacement therapy Hormone replacement therapy (HRT) is effective at preventing postmenopausal bone loss and has been shown to be effective in preventing vertebral fractures, nonvertebral fractures, and hip fractures in postmenopausal women it is seldom used clinically in the treatment of osteoporosis because long-term use in older women has been associated with an increased risk of cardiovascular disease, venous thrombosis, and breast cancer. I Raloxifene Raloxifene belongs to a class of compounds termed selec- tive estrogen receptor modulators (SERM) It acts an estrogen receptor agonist in bone and as an antagonist in other tissues, most notably the breast. Raloxifene, given orally at a dose of 60 mg/day, has been shown to reduce the risk of vertebral frac- tures in postmenopausal women

26. Tibolone Tibolone is a steroid hormone which acts as a partial agonist at estrogen, progesterone, and androgen receptors. It alleviates vasomotor symptoms and enhances libido in postmenopausal women with similar efficacy to HRT. study tibolone treatment was associated with a reduced risk of breast cancer (68% reduction) but an increased risk of stroke (119% increase Testosterone replacement therapy is often used in the treatment of osteoporosis in men who have hypogonadism where it has added benefits of increasing muscle strength and general well- being. Treatment can either be given by injection every 4 to 6 weeks or by transdermal patches.

27. Treatments, including physical therapy, the use of orthoses such as the posture training support and hip protectors, and the minimally invasive spine procedures vertebro- plasty and kyphoplasty Balance exercises and strengthening exercises of the bilateral lower extremities and weight-bearing exercises may help to decrease fall risks. Back extensor strengthening exercises can decrease thoracic kyphosis and possibly prevent vertebral compres- sion fractures aerobics and weight- bearing and resistance exercises can increase bone mineral density in the spine, and walking can result in increased bone mineral density in the hip. The posture training support, CASH (cruciform anterior spinal hyperextension) brace, and the Jewett brace can all be used in individuals with symptomatic vertebral compression fractures to minimize thora- columbar flexion. Vertebroplasty and kyphoplasty are two mini- mally invasive spine procedures utilized in the man- agement of painful vertebral compression fractures that have demonstrated excellent results in allevia- tion of pain Non medical management of osteoporosis

28. Thank you References Rockwood and greens fractures in adults Tureks orthopaedics