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Osteoporosis and teriparatide

Teriparatide (brand name Forteo) is a form of parathyroid hormone that stimulates new bone formation. It is the only osteoporosis drug approved to build new bone. The document discusses how teriparatide works by activating osteoblasts through intermittent exposure to parathyroid hormone. This leads to increased bone mineral density, especially in the spine and hip. Clinical trials showed teriparatide reduced the risk of vertebral fractures by 65% and nonvertebral fractures by 53% compared to placebo. Teriparatide is recommended for patients with severe osteoporosis who have failed or cannot tolerate bisphosphonate therapy. It may also be used off-label to

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Advances in use of TERIPARATIDE !!! 8/7/2019 PSPatki 1 OSTEOPOROSIS SERIES
Osteoporosis ā€¢ ā€œSilent diseaseā€ until complicated by fractures ā€¢ Most common bone disease in humans ā€¢ Characterized by: ā€“ Low bone mass ā€“ Microarchitectural deterioration ā€“ Compromised bone strength ā€“ Increased risk for fracture 8/7/2019 PSPatki 2
World Health Organization Diagnostic Criteria DIAGNOSIS BMD CRITERIA* ā€¢ Normal within 1 SD of a ā€œyoung normalā€ adult (T-score at -1.0 and above) ā€¢ Osteopenia between 1 and 2.5 SD below that of a ā€œyoung normalā€ adult (T-score between -1 and -2.5) ā€¢ Osteoporosis 2.5 SD or more below that of a ā€œyoung normalā€ adult (T-score at or below -2.5) ā€¢ Severe Osteoporosis 2.5 SD or more below that of a ā€œyoung normalā€ adult and fracture(s) ā€¢ T-score is the number of SDs above or below the average BMD value for young, normal adults of the same sex BMD = Bone mineral density SD = Standard deviation *Measured at the hip, spine, or wrist 8/7/2019 PSPatki 3
FRAXĀ® ā€¢ Statistically robust fracture risk prediction tool developed by the WHO for world-wide use ā€¢ Combines BMD + clinical risk factors to predict fracture risk better than either alone ā€¢ Predicts the 10-year probability of major osteoporotic fractureHip, spine, wrist, or humerus.Use when the decision to treat is uncertain 8/7/2019 PSPatki 4
8/7/2019 PSPatki 5 RISK FACTORS ā€¢ History of fracture as an adult ā€¢ Fragility fracture in first degree relative ā€¢ Caucasian/Asian postmenopausal woman ā€¢ Low body weight (< 127 lb) ā€¢ Current smoking ā€¢ Use of oral corticosteroids > 3 mo. ā€¢ Calcium intake ā€¢ Physical activity/strength ā€¢ But the least bothered by all is,,,,,
Considered as poison throughout the world !!! That is 8/7/2019 PSPatki 6
SALT High salt intake,,,,, Risk factor for renal excretion of calcium. 8/7/2019 PSPatki 7
Universal Recommendations ā€¢ Adequate intake of calcium, vitamin D ā€¢ Weight-bearing and muscle-strengthening exercises to reduce risk of falls/fracture ā€¢ Provide strategies for fall prevention ā€¢ Avoidance of tobacco use/excessive alcohol use ā€¢ Have a bone density test and take medication when appropriate 8/7/2019 PSPatki 8
Calcium/Vitamin D ā€¢ Adequate intakes of dietary calcium and vitamin D, including supplements if necessary ā€¢ Elemental calcium per day (> 50 YOA) = at least 1200 -1500 mg ā€¢ Vitamin D3 per day (> 50 YOA) = 800 - 1000 international units (IU) ā€¢ Vitamin D3 (cholecalciferol) plays major role in Ca absorption ā€¢ Inexpensive, well-tolerated 8/7/2019 PSPatki 9
Who Should Be Treated? ā€¢ Initiate therapy to reduce fractures in postmenopausal women/men > 50 with: 1. BMD T-scores < -2.5 at hip or spine 2. Prior vertebral or hip fracture 3. Low bone mass (T-scores -1.0 to -2.5 at hip or spine) 8/7/2019 PSPatki 10
FDA-Approved Drugs for Osteoporosis ā€¢ Bisphosphonates- alendronate, risedronate ā€¢ Selective Estrogen Receptor Modulators (SERMs)- raloxifene ā€¢ Calcitonin, Estrogen/Hormone Therapy (ET/HT) ā€¢ Parathyroid Hormone- Teriparatide 8/7/2019 PSPatki 11
Antiresorptive Agents ā€¢ Estrogen ā€¢ Calcitonin ā€¢ Bisphosphonates ā€¢ SERMs (selective estrogen receptor modulators) ā€¢ Anti-RANK ligand antibody (in Development) ā€¢ Cathepsin K inhibitors (in Development) 8/7/2019 PSPatki 12
Why do you need TERIPARATIDE ? 8/7/2019 PSPatki 13
Treatment of Osteoporosis: Unmet Needs and Emerging Solutions.( J Bone Metab. 2018 Aug;25(3) ā€¢ Efficient therapies are available for the treatment of osteoporosis, however, there are still unmet needs. Anti-resorptive therapies only increase bone mineral density to a certain extent and reduce the risk of non-vertebral fractures by 20%. 8/7/2019 PSPatki 14
Parathyroid Hormone [PTH (1-34)] Teriparatide Anabolic agent ā€¢ Mechanism: recombinant formulation of endogenous parathyroid hormone (PTH) . ā€“ stimulates osteoblast function, increases gastrointestinal calcium absorption, increases renal tubular reabsorption of calcium ā€“ Enhances bone turnover by initiating greater bone formation ā€“ Abaloparatide-under development 8/7/2019 PSPatki 15
8/7/2019 PSPatki 16 TERIPARATIDE STRUCTURE
Teriparatide: rhPTH [1-34] ā€¢ The only treatment agent that is anabolicā€” stimulates bone formation rather than inhibiting bone resorption 20 Ī¼g daily (subcutaneously) for no more than 2 years, The patents will expire in the United States and in Europe in August 2019. ā€¢ Indication: treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture ā€¢ Effects- ā€“ Increased bone density in spine by 9% and hip by 3% vs placebo over 18 months ā€“ Reduced incidence of vertebral fractures (65%) and nonvertebral fragility fractures (53%) in women with pre-existing vertebral fractures. ā€“ Adverse reactions: arthralgia, pain, nausea; warning about osteosarcoma risk in rats8/7/2019 PSPatki 17
Mechanism of action ā€¢ Teriparatide is a portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids). Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Intermittent exposure to PTH will activate osteoblasts . Thus, once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density. 8/7/2019 PSPatki 18
8/7/2019 PSPatki 19 CD- CALLUS DIFF
8/7/2019 PSPatki 20 Based upon the difference in kinetics of changes between bone formation and bone resorption markers, an "anabolic window" is formed during which the actions of parathyroid hormone are seen. believed to be maximally anabolic
Mechanism of Fracture Risk Reduction Anabolic therapy Stabilize or improve microarchitecture Increase bone turnover Decrease in fracture risk Increase BMD 8/7/2019 PSPatki 21
What is the advantage ? ā€¢ Unlike anti-resportive agents which stop high bone turnover, teriparatide creates new bone tissue. ā€¢ Osteoanabolic hormone for bone formation. 8/7/2019 PSPatki 22
Clinical Efficacy ā€¢ Shown to decrease the risk of new vertebral fractures by 65% and nonvertebral fractures by 53% versus placebo after median exposure of 19 months ā€¢ Increases lumbar spine BMD as well as at the femoral neck, total hip, and total body 8/7/2019 PSPatki 23
Effect of Teriparatide on Risk of Vertebral Fractures in Postmenopausal Women 0 2 4 6 8 10 12 14 16 Placebo Teriparatide 20 Āµg %ofPatientswithā‰„1Fracture RR 0.35 (95% CI = 0.22ā€“0.55) a 65% ļ‚Æ a P <.001 vs placebo. Neer RM, et al. N Engl J Med. 2001;344:1434-1441. Graphic courtesy of Dr. Paul Miller. 8/7/2019 PSPatki 24
Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial LANCET. VOLUME 391, ISSUE 10117, P230- 240, JANUARY 20, 2018 ā€¢ Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. (680 patients in each group.) 8/7/2019 PSPatki 25
PTH (1-34) Place in Therapy: ā€¢ Recommend PTH for women or men with severe osteoporosis (low bone mineral density [T-score < - 2.5] and at least one fragility fracture) who are refractory to or unable to tolerate bisphosphonate therapy ā€¢ It is also occasionally used off-label to speed fracture healing. ā€¢ In patients considered to be bisphosphonate "failures," PTH may be started approximately 3 months after bisphosphonates are discontinued ā€¢ Antiresorptive therapy may be considered after discontinuation of PTH to maintain gains in BMD acquired with PTH alone in those at high risk for subsequent fracture8/7/2019 PSPatki 26
teraparatide ā€¢ Teriparatide is the only anabolic (i.e., bone growing) agent indicated for use in postmenopausal women with osteoporosis at a high risk for fracture or with a history of osteoporotic fracture, patients with multiple risk factors for fracture, and for patients who have failed or are intolerant to other available osteoporosis therapy. It has been FDA- approved since 2002. It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year) and reducing the risk of fragility fractures. Osteoporosis medications are generally safe, but some side effects of teriparatide include headache, nausea, dizziness, and limb pain. 8/7/2019 PSPatki 27
Osteoporos Int. 2018 Aug 13. 4658-7. [Epub ahead of print] The effects of teriparatide on acceleration of bone healing following atypical femoral fracture: comparison between daily and weekly administration. ā€¢ When all patents were included, the fracture healing time was not significantly different between the two groups. Only patients with complete AFFs had significantly fewer daily bisphosphonate or denosumab injections than the weekly group . The fracture healing time in the daily group was significantly shorter than that in the weekly group (P < 0.05). Even if the influence of bisphosphonate or denosumab usage was excluded, a similar significant difference was observed in the fracture healing time (P < 0.05). There was no significant difference between the two groups among patients with incomplete AFFs. ā€¢ CONCLUSIONS:Daily teriparatide injections enhance bone union more than weekly injections in complete AFF patients. 8/7/2019 PSPatki 28
Bone. 2018 Nov;116:58-66. 2018.07.013. 2018 Jul 18. Real-world effectiveness of teriparatide on fracture reduction in patients with osteoporosis and comorbidities or risk factors for fractures: Integrated analysis of 4 prospective observational studies. ā€¢ Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies. ā€¢ CVF-CLINICAL VERTEBRAL FRACTURES, NVF- NON VERTEBRAL. 8/7/2019 PSPatki 29
BALTIMORE STUDY, 2018 Effect of an intensive conservative therapy with daily teriparatide administration and rehabilitation for osteoporotic delayed vertebral collapse and paralysis. ā€¢ Eventually 12 out of 30 patients avoided surgical treatment because their symptoms were improved. The results that 40% of patients with osteoporotic delayed vertebral collapse (ODVC) did not need further surgical treatment after the intensive conservative treatment was of great significance. Patients with greater mobility of collapsed vertebrae might be treated surgically as quickly as possible. 8/7/2019 PSPatki 30
Arch Osteoporos. 2018 May 2;13(1):50. doi: 10.1007/s11657- 018-0444-6. Long-term benefits and risks of parathyroid hormone treatment in compliant osteoporotic patients. A Danish national register based cohort study. ā€¢ PTH treatment is effective and safe. Following PTH treatment in compliant patients, neither fracture incidence nor drug consumption differed between PTH- treated and BP-treated patients, despite the fact that PTH-treated patients had more severe osteoporosis. No increased incidence of malignant diseases or other diseases was detected. 8/7/2019 PSPatki 31
Teriparatide ā€¢ Use 20 mcg/d by sc injection ā€¢ Contraindicated in : Hypercalcemia Hyperparathyroidism Unexplained elevated ALP Exposure to external beam radiation or prior skeletal radiation8/7/2019 PSPatki 32
FDA Label Contraindications to Teriparatide ā€¢ Unexplained hypercalcemia ā€¢ Unexplained elevated alkaline phosphatase ā€¢ Pagetā€™s disease ā€¢ Prior skeletal (therapeutic) radiation ā€¢ Metastatic cancer ā€¢ Unfused epiphysis ā€¢ GFR <30 mL/min 8/7/2019 PSPatki 33
8/7/2019 PSPatki 34 Differences between Anabolics: Teriparatide and Romosozumab ā€¢ Teriparatide is an amino acid terminal fragment 1ā€34 of par athyroid hormone ā€“ Stimulates osteoblastic and osteoclastic activity Promotes the formation of new bone by increased remodeling ā€¢ Romosozumab is a monoclonal antibody that binds sclerostin, an osteocyteā€derive d inhibitor of bone formation ā€“ Stimulates osteoblastic activity and reduces osteoclastic activity ā€“ Promotes the formation of new bone and decreases bone resorption
Support THE BONE They support you !!! 8/7/2019 PSPatki 35 drpatki@gmail.com
8/7/2019 PSPatki 36