Prophylaxis and Pharmacotherapy of Osteoporosis PDF

Prophylaxis and Pharmacotherapy of Osteoporosis Osteoporosis, – porous bone, – disease low bone mass Normal bone Osteoporotic bone structural deterioration of bone tissue, bone fragility increased susceptibility to fractures of the hip, spine, and wrist. Men as well as women suffer from osteoporosis...

Prophylaxis and Pharmacotherapy of Osteoporosis Osteoporosis, – porous bone, – disease low bone mass Normal bone Osteoporotic bone structural deterioration of bone tissue, bone fragility increased susceptibility to fractures of the hip, spine, and wrist. Men as well as women suffer from osteoporosis, Disease that can be prevented and treated. – “Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk” Khosla and Hofbauer, Lancet, 2017 2 Bone is – living, – growing tissue. – It is made mostly of collagen, a protein that provides a soft framework, and calcium phosphate, a mineral that adds strength and hardens the framework. This combination of collagen and calcium makes bone strong, yet flexible to withstand stress. More than 99 % of the body's calcium is contained in the bones and teeth. The remaining 1% is found in the blood. The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25-dihydroxy vitamin D (1,25[OH] 2D) is produced by the kidney under the control of parathyroid hormone (P TH), which stimulates its production, and fibroblast growth factor 23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)2D is the principal regulator of intestinal calcium and phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell. PTH also stimulates osteoblast formation indirectly by inhibiting the osteocyte’s production of sclerostin, a protein that blocks osteoblast proliferation by inhibiting the wnt pathway (not shown). PTH and 1,25(OH)2 D stimulate the expression of RANKL by the osteoblast, which, with mCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone-resorbing cell. OPG blocks RANKL action, and may be inhibited by PTH and 1,25(OH)2 D. FGF23 in excess leads to osteomalacia indirectly by inhibiting 1,25(OH)2 D production and lowering phosphate levels. mCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-κB. 3 Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13e; 2015 Copyright © 2017 McGraw-Hill Education. All rights reserved Age-Associated Changes in Bone Mass Menopausal bone loss Bone Mass Peak bone mass 0 20 40 Age (Years) 60 80 S.H. Tella, J.C. Gallagher / Journal of Steroid Biochemistry & Molecular Biology 142 (2014) 155–170 American College of Physicians. 2000. 4 Risk Factors Risk factors you cannot change: Risk factors you can change: Gender - “Women have less bone tissue and lose bone more rapidly than men because of the changes involved in menopause. Age - the older the age, the greater the risk of osteoporosis. Body size - Small, thin-boned women are at greater risk. Ethnicity - Caucasian and Asian women are at highest risk. AfricanAmerican and Latino women have a lower but significant risk. Family history - Susceptibility to fracture may be, in part, hereditary. Sex hormones: – – – abnormal absence of menstrual periods (amenorrhea), low estrogen level (menopause), and low testosterone level in men. Diseases: Anorexia. A lifetime diet low in calcium and vitamin D. Use of certain medications, such as glucocorticoids or some anticonvulsants. An inactive lifestyle or extended bed rest. Cigarette smoking. Excessive use of alcohol. 5 S.H. Tella, J.C. Gallagher / Journal of Steroid Biochemistry & Molecular Biology 142 (2014) 155–170 6 Fig. 3. Figure depicting the decrease of T score with age and simultaneous increase in fracture risk. Adapted from. Sri Harsha Tella, J. Christopher Gallagher. Prevention and treatment of postmenopausal osteoporosis. The Journal of Steroid Biochemistry and Molecular Biology, Volume 142, 2014, 155–170 Symptoms the "silent disease" because bone loss occurs without symptoms – bones become so weak that sudden strain, bump, or fall → a hip fracture or a vertebra to collapse → severe back pain, loss of height, or spinal deformities such as kyphosis, or severely stooped posture. Detection Bone mass should be measured. – dual x-ray absorptiometry (DXA) – Bone mineral density (BMD) tests measure bone density in the spine, wrist, and/or hip (the most common sites of fractures) – high-resolution peripheral CT that yield volumetric bone-density – These tests are painless, non-invasive, and safe. fracture-risk assessment tool (FRAX) 8 Treatment A comprehensive osteoporosis treatment program includes a focus on lifestyle modifications: – vitamin D and calcium supplementation – proper nutrition, – cessation of smoking, reduction of alcohol consumption, – increased physical activity: exercise, – safety issues to prevent falls that may result in fractures 9 Concerns Calcium. An inadequate supply of calcium over the lifetime is thought to play a significant role in contributing to the development of osteoporosis. – low calcium intakes appear to be associated with low bone mass, rapid bone loss, and high fracture rates. – many people consume less than half the amount of calcium recommended to build and maintain healthy bones. 10 Calcium needs change during one's lifetime: – greater during childhood and adolescence, when the skeleton is growing rapidly, and during pregnancy and breastfeeding. Postmenopausal women and older men also need to consume more calcium. – This may be caused by inadequate amounts of vitamin D, which is necessary for intestinal absorption of calcium. – Also, as we age, our bodies become less efficient at absorbing calcium and other nutrients. – Older adults also are more likely to have chronic medical problems and to use medications that may impair calcium absorption. 11 Vitamin D Vitamin D plays an important role in calcium absorption and in bone health. It is synthesized in the skin through exposure to sunlight. – While many people are able to obtain enough vitamin D naturally, studies show that vitamin D production decreases in the elderly, in people who are housebound, and during the winter. These individuals may require vitamin D supplementation to ensure a daily intake of between 400 to 800 IU of vitamin D. – Massive doses are not recommended. – One large trial showed a reduction of 33 percent in hip fracture among nursing home residents who were randomly assigned to receive calcium supplements and vitamin D, as compared with those given placebo. 12 Vitamin D Serum concentrations of 25-hydroxyvitamin D of at least 30 ng/mL are the target →usually requires a dose of vitamin D of at least 800 IU per day. – – – A meta-analysis raised concerns that calcium supplementation could be associated with an increased risk of cardiovascular events. The risk of having a myocardial infarction was 27% higher in individuals receiving at least 500 mg per day of calcium supplementation than in those not receiving calcium supplementation on the basis of 11 trials that included almost 11921 patients. As a caveat, only studies with calcium supplementation but no vitamin-D supplementation were included. Therefore concurrent vitamin-D deficiency could have been present, which itself increases the risk of cardiovascular events. The Women’s Health Initiative showed that calcium in combination with vitamin D had no effect on the risk of coronary heart disease, which is reassuring in this regard. Nonetheless, the American Society for Bone and Mineral Research has issued a statement and recommends the use of combined vitamin D and calcium supplementation instead of onlycalcium supplementation, and the preference for an increased dietary uptake of calcium over calcium supplements. Osteoporosis: now and the future,Tilman D Rachner, Sundeep Khosla, Lorenz C Hofb auer Lancet 2011; 377: 1276–87 13 C. Rosen, N Engl J Med 2005;353:595-603. 14 Exercise Like muscle, bone is living tissue that responds to exercise by becoming stronger. The best exercise: weight-bearing exercise, to work against gravity. – walking, hiking, jogging, stair-climbing, weight training, tennis, and dancing. Smoking is bad for bones Women who smoke have lower levels of estrogen compared to nonsmokers and frequently go through menopause earlier. Postmenopausal women who smoke may require higher doses of hormone replacement therapy and may have more side effects. Smokers also may absorb less calcium from their diets. Alcohol Regular consumption of 2 to 3 ounces a day of alcohol may be damaging to the skeleton, even in young women and men. – poor nutrition as well as increased risk of falling. 15 Medications that cause bone loss which pateint grops using which durgs are more suuceptble to bone loss ? The long-term use of glucocorticoids (medications prescribed for a arthritis, asthma, Crohn's disease, lupus, etc) can lead to a loss of bone density and fractures. Other forms of drug therapy that can cause bone loss include long-term treatment with certain antiseizure drugs, such as phenytoin and barbiturates Gonadotropin releasing hormone (GnRH) analogs used to treat endometriosis; Excessive use of aluminum-containing antacids; Certain cancer treatments; Excessive thyroid hormone. 16 Therapeutic Medications Figure 2 Key milestones in the lifecourse of osteoporosis therapy. Strontium ranelate is not approved by the FDA but all other agents have been approved both by the FDA and EMA. Note: The dates shown represent the year that they were first approved by the FDA (or EMA for strontium ranelate) for use in the treatment of osteoporosis. Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration; IV, intravenous. Osteoporosis - a current view of pharmacological prevention and treatment Drug Des Devel Ther. 2013;7:435-448. 17 Katzung, Basic and Clinical Pharmacology, 12th Ed. Osteoblast Osteoclast 18 From: Chapter 44. Agents Affecting Mineral Ion Homeostasis and Bone Turnover Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e, 2011 Legend: Relative efficacy of different therapeutic interventions on bone mineral density of the lumbar spine. Teriparatide (40 μg) (Neer et al., 2001), PTH (25 μg) + estradiol, alendronate (10 mg), estradiol (0.625 mg/day), raloxifene (120 mg), calcitonin (200 IU). Typical results with placebo treatment underscore the inexorable bone loss without intervention. Some of the indicated treatment interventions involved combination therapy, and absolute comparisons should not be made. For additional references, see legend to Figure 61-13 in the 11th edition of this text. Copyright © 2012 McGraw-Hill Medical. All rights reserved. Therapeutic Medications in whic pateints do we use alendronat e or risedronate for osteoprosis ? Alendronate, risedronate and raloxifene are approved by the (FDA) for the prevention and treatment of postmenopausal osteoporosis. – In addition, alendronate is approved for the treatment of osteoporosis in men, and both alendronate and risedronate are approved for use by men and women with glucocorticoid-induced osteoporosis. Estrogen/hormone replacement therapy (ERT/HRT) is approved for the prevention of postmenopausal osteoporosis. Calcitonin is approved for treatment. Vit. D and Calcium Salts PTH : Teriparatide 20 Osteoporosis: now and the future,Tilman D Rachner, Sundeep Khosla, Lorenz C Hofb auer Lancet 2011; 377: 1276–87 21 Biphosphonates Enzyme-resistant analogues of pyrophosphates – farnesyl pyrophosphate synthase, which generates isoprenoid lipids that are used for the post-translational modifications of small guanosine triphosphate (GTP)-binding proteins required for osteoclast viability and function Inhibits mineralization in bone – Reduce the turnover of bone in a dose dependent manner By inhibiting recruitment and promoting apoptosis of osteoclasts Indirectly stimulate osteoblast activity Retard bone loss in the elderly Reduce incidence of fractures 22 Biphosphonates Available ones in clinical use: – – – – Alendronate (Fosamax) Risedronate (Actonel) Zoledronate (Zometa) İbondronate (Boniva) – Disodium etidronate (Didronat) – Disodium pamidronate (Aredia) – Sodium clodronate (Bonefos) 23 Biphosphonates: clinical use which drug is recommended in a patient with malignant hypercalcemia ? donate can be seen in the name of these deugs Paget’s disease Malignant hypercalcemia Postmenapausal osteoporosis Glucocorticoid-induced osteoporosis Cancer metastasis in bone 24 Biphosphonates Generally given orally-poorly absorbed 50% of dose accumulates at sites of bone mineralisation and remains there until the bone is resorbed Free drug is excreted unchanged from the kidney Absorption is impaired by food: esp milk – Must be taken on an empty stomach with a full glass of water and avoid lying down for 30-60 min.!!; this may cause gastric pain and oesophagitis 25 Biphosphonates: Side effects Mainly gastrointestinal upset Occasionally bone pain Transient fever, myalgias Occasionally leukopenia, symptomatic hypocalcemia, hypophosphatemia may develop. Osteonecrosis of the jaw Subtrochanteric (femur) fractures Allendronate -- oesophagitis Etidronate -- renal toxicity 26 Teriparatide Recombinant formulation of endogenous parathyroid hormone (PTH), – The pharmacologic activity is similar to the physiologic activity of PTH: – – – containing a 34-amino-acid sequence which is identical to the N-terminal portion of this hormone. stimulating osteoblast function, in a post menopasl women with vertebral fractures whivh drug is recommended ? increasing gastrointestinal calcium absorption increasing renal tubular reabsorption of calcium. results in increased bone mineral density, bone mass, and strength. In postmenopausal women, teriparatide has been shown to decrease osteoporosis-related vertebral fractures by 65%. administered by once-daily subcutaneous injection of 20 μg into the thigh or abdomen and the duration of treatment is limited to 24 months. – – – – Bioavailability: 95%, Time to peak, serum: ~30 minutes, Distribution: Vd: ~0.12 L/kg Metabolism: Hepatic (nonspecific proteolysis) Half-life elimination: I.V.: 5 minutes; SubQ: ~1 hour Excretion: Urine (as metabolites) Abaloparatide, a parathyroid hormone-related peptide analogue (approved in 2017) 27 Teriparatide: Adverse effects Full-length PTH(1-84) has been associated with osteosarcomas in rats although not in humans. The significance and interpretation of the toxicological findings has been questioned. – Because of these findings, a black box warning appears on the FORTEO package insert. The clinical relevance of this finding is unclear, especially because patients with primary hyperparathyroidism have marked elevation of serum PTH without a greater incidence of osteosarcoma. Nonetheless, teriparatide should not be used in patients who are at increased baseline risk for osteosarcoma (including those with Paget's disease of bone, unexplained elevations of alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton). The safety and efficacy of FORTEO have not been evaluated for extended use beyond 2 years of treatment and therapy should be limited to no more than 2 years. A tumor registry-based analysis of the occurrence of osteosarcoma in teriparatide-treated patients is ongoing; cases of osteosarcoma associated with the drug should be reported to the FDA. Increases in bone density acquired during therapy with teriparatide can maintained or extended with subsequent use of bisphosphonates. Headache, nausea, dizziness and postural hypotension Slight and transient elevations of serum calcium, exacerbation of nephrolithiasis and elevation of serum uric acid levels 28 Teriparatide: Adverse effects Contraindicated in patients with: – – – – – imp hypercalcaemia, pregnancy and lactation, metabolic bone diseases other than osteoporosis, severe renal impairment, prior radiation to the skeleton and malignant disease affecting the skeleton It should be used with caution in patients with moderate renal impairment. which osteoprosis treatment can not be used in pateints with renal impairment ? or hypercalcemia or in lactation. 29 Denosumab trpiarades only for vertebral fractures fully humanised monoclonal antibody – against Receptor Activator of Nuclear factor Kappa B Ligand (RANKL), a major regulator of osteoclast development and activity. Reduce the incidence of vertebral, non-vertebral and hip fractures Approved for the treatment of – osteoporosis in postmenopausal women and men at increased risk of fractures, – and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. It is given as a subcutaneous injection of 60 mg once every 6 months. which draug is typically recommended in pateints with prostate cancer ? 30 Denosumab Side-effects include skin infection, predominantly cellulitis, and hypocalcaemia. – Adequate intake of calcium and vitamin D is important in all patients, especially in those with severe renal impairment. Monitoring of calcium levels should be conducted prior to each dose of denosumab and within 2 weeks after the initial dose in patients predisposed to hypocalcaemia – Rare occasions of osteonecrosis of the jaw and atypical femoral fractures. While on treatment, patients should avoid invasive dental procedures if possible. Contraindicated in women with hypocalcaemia or with hypersensitivity to the formulation. which one of the drugs below can not be used in a patient with hypocalcemia ? 31 Calcitonin Rapidly acting peptide hormone Secreted in response to hypercalcemia by the parafollicular cells (C cells) of the thyroid Lower plasma Ca by inhibiting osteoclastic activity and thus the rate of Ca release from bone Available ones in clinical use: – Porcrine (natural) calcitonin: – Salcatonin (synthetic salmon calcitonin) (Miacalcic, tonocalcin, calsynar) – Synthetic human calcitonin (cibacalcin) S.C., I.M., Or nasal spray Plasma half-life is 4-12 minutes but its action lasts for several hours 32 Calcitonin Post-menapausal and corticosteroid-induced osteoporosis: As a part of the therapy Paget’s disease: it releives the pain and reduces some neurological complications In women who are at least 5 years beyond menopause, – – – – slows bone loss, increases spinal bone density, relieves the pain associated with bone fractures. reduces the risk of spinal fractures and may reduce hip fracture risk as well. While it does not affect other organs or systems in the body, injectable calcitonin may cause an allergic reaction and unpleasant side effects. 33 Calcitonin: Side effects Nausea, vomiting Facial flushing, skin rash Tingling sensation in the hand and unpleasant taste in the mouth Urinary frequency 34 Raloxifene Approved for the prevention and treatment of postmenopausal osteoporosis. Selective Estrogen Receptor Modulators (SERMs): appear to prevent bone loss at the spine, hip, and total body. SERMs are competitive antagonists of Estrogen receptors in the breast tissue and endometrium but stimulate the Estrogen receptors in the bone tissues. 35 Estrogen Estrogen/hormone replacement therapy (ERT/HRT): – reduce bone loss, – increase bone density in both the spine and hip, and – reduce the risk of hip and spine fractures in postmenopausal women. – approved for the prevention of postmenopausal osteoporosis – most commonly administered in the form of a pill or skin patch When estrogen (estrogen replacement therapy or ERT) is taken alone, it can increase a woman’s risk of developing endometrial cancer. 36 To eliminate this risk, physicians prescribe the hormone progestin in combination with estrogen (hormone replacement therapy/HRT) for those women who have not had a hysterectomy. The Women’s Health Initiative (WHI) study recently demonstrated that HRT is associated with a modest increase in the risk of breast cancer. The WHI also found that HRT increases the risk of cardiovascular events upon initiation and does not appear to provide long-term protection against cardiovascular events. A large-scale study from the National Cancer Institute (NCI) has recently indicated that long-term use of ERT may be associated with an increase in the risk of ovarian cancer. 37 It is not yet clear whether HRT carries a similar risk. Both ERT and HRT increase the risk of venous thromboembolism. The decision to use ERT/HRT should be made after discussing the benefits and risks for the patient Fall Prevention 38 Figure 2. Scheme to show the efficacy of treatments for the prevention of non-vertebral and hip fractures. Figure adapted from Reid [136 ]. Note that these results come from different studies with different entry criteria and patient characteristics, and are... R Graham G Russell. Pharmacological diversity among drugs that inhibit bone resorption. Current Opinion in Pharmacology, Volume 22, 2015, 115–130 2017 Strontium production has been permanently discontinued and only limited stock will be available after August, 2017, because of safety concerns (myocardial infarction, thromboembolic events, and rare but serious skin reactions (DRESS syndrome)). 40 Annals of Internal Medicine Vol. 166 No. 11 6 June 2017 41 Conclusions Treatment for osteoporosis should prevent fracture Best indicator of fracture protection is unclear Increases in BMD contributes to, but is not the only mechanism by which antiresorptive drugs decrease fracture risk Bisphosphonates have the strongest clinical evidence supporting vertebral, nonvertebral and hip fracture reduction 42