Drugs for Osteoporosis 2024 PDF

Pharmacology of Anti-Osteoporosis Drugs - osteoclasts —> macrophages - Micro CT scans - lots of gaps, which leads to a higher chance of fracture - Inhibit osteoclast (antiresorptive therapy) —> inhibits breakdown - Recently we now have anabo...

Pharmacology of Anti-Osteoporosis Drugs - osteoclasts —> macrophages - Micro CT scans - lots of gaps, which leads to a higher chance of fracture - Inhibit osteoclast (antiresorptive therapy) —> inhibits breakdown - Recently we now have anabolic? therapy Mary Erclik PhD. April 5th 2024  OUTLINE - Physiology of calcium homeostasis - Physiology of bone turnover - Pharmacology - Preventative - Vitamin D - SERMs - Bisphosphonates - Denosumab - PTH (anabolic therapy) - Novel Therapies; Romosozumab  OBJECTIVES At the end of today’s class you will be able to: Recall the primary cellular events involved in bone turnover Recall the key regulators that control extracellular calcium concentration Recall and then compare the mechanism of action of SERMS, bisphosphonates, Denosumab, Teriparatide and Romosozumab Apply your understanding of the pharmacology of drugs used in the treatment of osteoporosis to how they modify processes involved in bone turnover and/or control of calcium concentration  Overview: Calcium Homeostasis - Major sources of calcium is through our diet or our bones - remodelling —> comes from our bone - we know we need calcium from bone but we try not to. - Get adequate calcium from diet so we don’t rely on bones. - we won’t be able to build bone anymore at some point. - bone loading —> weight resistance training - concerned for Astronauts so they don’t experience severe bone deterioration :( If dietary intake, intestinal absorption or kidney reabsorption of calcium is not sufficient then Ca is mobilized from bone by parathyroid hormone (PTH)  Calcium Homeostasis Circulating calcium levels in the plasma are between 2.15 and 2.55 mM or 8.7 to 10.3 mg/dL Levels are controlled by: - Parathyroid hormone (PTH), increases circulating Parathyroid glands: embedded in the thyroid gland, calcium levels regulates conc. of calcium, by secreting PTH - Vitamin D, increase can get vitamin D from sunlight or dietary sources - Calcitonin, decrease also secreted from thyroid gland Levels are affected by: What controls calcium conc.? dietary intake - GI absorption and how much of it is coming from bone - Renal clearance - Bone absorption and release 5  Key regulator: PTH Overview: Bone Turnover - receptors for PTH are expressed in osteoblasts - PTH binds to osteoblasts, which then signals, tells osteclast (no PTH receptors on osteoclasts) To accommodate changing mechanical stresses and the demands of calcium homeostasis, all bones in the body are in a dynamic state of growth and resorption throughout life - There are other types of autocoids that regulate bone turnover but won’t go in details The process of bone remodeling is under the control of local growth factors and endocrine factors including parathyroid hormone (PTH) PTH will signal to osteoclast to turn some bone - comes there and starts chewing up the bone - somehow osteoblast in bone …??? - osteoid: has collagen in it, it becomes mineralized and it returns to normal Osteoblasts on Surface Osteoclasts on Bone Surface Resorb old Bone Osteoid is Mineralized Osteoblasts Appear on Bone Surface Osteoblasts fill cavity with osteoid Schematic: Bone Turnover  Overview: Osteoporosis Osteoporosis When the rate of bone deposition is no longer able to match the rate of bone resorption there is a net loss of bone leading to decreased BMD and bone strength The strategy of therapeutic approaches to treat osteoporosis is to either decrease the rate of target osteoclast resorption (anti-resporptive therapies) or increase the deposition of bone (anabolic target osteoblast therapies) - you’re building bone  Osteoporosis Treatment - Some people are concerned how ozempic can affect bone metabolism. Prevention - Bone Loading - Calcium - Vitamin D Anti-resorptive therapies Anabolic therapies - Hormone Replacement Therapy Parathyroid Hormone (HRT) - Selective estrogen-receptor modulators (SERMs) - Bisphosphonates - Denosumab cool mechanism of action!!!!  Osteoporosis: Preventative Methods In Adults: In order to ensure that there is sufficient dietary calcium, calcium and vitamin D supplements are recommended Both calcium and vitD do little to increase bone mineral density but adequate levels of both agents ensures that PTH with not be released we’re not building bone, we’re maintaing calcium levels (when physician says to keep adequate levels of calcium) There is some evidence that they may slightly reduce the risk of vertebral fractures in postmenopausal women In Children: Peak bone mass not achieved until 20-22 years; calcium and Vit D are essential for maximal bone mass  Vitamin D Metabolism Vit D Metabolism - multiple forms of Vitamin D in our body - most biologically active form is 1,25 Dihydroxy D3 (calcitriol) - Vitamin D can be obtained through dietary sources or though conversion of precursors by sunlight then goes to liver followed by the kidney where it is hydroxylated into 1,25(OH)2D3 reduces amount of excretion of calcium in kidney has maximum activity  Vitamin D Metabolism - nuclear hormone receptor agonist - biological actions of 1,25(OH)2D3 are to increase serum calcium by increasing absorption, decreasing elimination and increase release from bone - There are high affinity receptors for calcitriol in intestine and kidneys  Osteoporosis: Therapy Table for reference  Antiresorptive Therapy: HRT -hormone replacement therapy (HRT) improves BMD all over the body in post-menopausal women -the use of HRT in post-menopausal women is associated with costs and benefits Negative Effects in reproductive tissues Positive Effects Increased incidence of uterine cancer Increases BMD bone marrow density (reduced with co-use of progestational Improves most symptoms of menopause agent) Increased incidence of breast cancer Increased venous thromboembolisms increased risk with CV events  Antiresorptive Therapy: HRT Oral forms of 17-oestradiol, oestrone and conjugated equine oestrogens Estrogen deficiency results in increased bone remodelling favouring resorption mostly through increased osteoclast activity link to menopause Specifically, estrogen deficiency results in increased levels of the cytokine, IL-1, IL-6 and TNF which favour osteoclast formation HRT(estrogen) increased BMD in a dose-dependent way  Antiresorptive Therapy: SERMS SERMS - Selective estrogen receptor modulators - eg. Raloxifene and Tamoxifene - Non-hormonal partial agonists at estrogen receptor  Antiresorptive Therapy: SERMS Tamoxifene - Mostly used as treatment for breast cancer Raloxifene enhances bone marrow density - Acts as an agonist in bone and an antagonist in breast and endometrial tissue - Reduces risk of vertebral fractures by as much as 50% - Very low oral bioavailability (~2%) and half-life is >28 hrs  Anti-Resorptive Therapy- SERMs Raloxifene Mechanism of Action - Estradiol binds to receptor, will recruit activators, which will enhance growth. - Binding of raloxifene to estrogen receptor - raloxifene is better than tamoxifen in bone tissue, good for bone growth From: Open Orthop J. 2009; 3: 14–21. Antiresorptive Therapy: Bisphosphonates Bisphosphonates Analogues of pyrophosphates (P–O–P) in which a carbon atom replaces the oxygen atom Have high affinity for hydroxyapatite and are deposited in bone, where they gain access to the osteoclast when bone is resorbed Inhibit osteoclast: recruitment differentiation activity Mechanism of action is different depending on type of analogue  Bisphosphonates: Mechanism Bisphosphonates (BPs) have high affinity for hydroxyapatite which leads to preferential localization on bone resorption surfaces Active osteoclasts while resorbing bone take up BPs which will either induce apoptosis (non-nitrogen containing BPs) or inhibit enzymes responsible for cholesterol synthesis (amino- BPs) mechanism for non-nitrogen containing vs nitrogen containing ones is diff —> next slide  Bisphosphonates Non-nitrogen containing analogues: - very closely resemble pyrophosphate - are incorporated into cytotoxic ATP analogues and favor osteoclast apoptosis - e.g. etidronate Nitrogen containing analogues: - have greater potency - inhibit the mevalonate pathway of cholesterol biosynthesis - e.g. alendronate, risedronate Bisphosphonates  Bisphosphonates: Examples Etidronate dosed intermittently for two weeks (with calcium) - First generation, less potent than subsequent - well tolerated - effective in preventing new vertebral fractures in post-menopausal women (PMW) - maintains bone mass in individuals undergoing glucocorticoid therapy - Only bisphosphonate that inhibits mineralization and may cause osteomalacia - When dosed intermittently effects on mineralization are minimized and risk of osteomalacia is reduced  Bisphosphonates: Examples Alendronate - administered continuously; well tolerated - reduces risk of vertebral fractures and fractures of the spine, hip and wrist - causes irritation of the esophagus and gastric mucosa Risedronate - administered continuously - well tolerated - reduces risk of vertebral fractures very significantly - also reduced risk of non-vertebral fractures - beneficial in prevention of glucocorticoid-induced bone-loss - causes irritation of the esophagus and gastric mucosa Anti-Resorptive Therapy: Denosumab - osteoblast and osteoclast communicate through receptor known as RANK - membrane embedded - strong signal for osteoblast to activate osteoclast - once osteoclast get activated, they go chew a bone until they get turned off - osteoblast produces ligand, r-OPG to activate RANK - osteoblast controls when osteoclast is activated and also something about decoil receptor - antibody does same thing as OPG - doing job of OPG - by inhibiting interaction, the osteoclast precursors do not differentiate - becomes a good antiresorptive therapy 26  Denosumab - RANK is expressed on the surface of osteoclast precursors and RANK ligand (RANKL) on the surface of osteoblasts - When the two molecules bind it results in the activation of osteoclast differentiation and activity - Denosumab: - human monoclonal antibody to RANKL - reduces osteoclast differentiation and reduces bone resorption  Anabolic Therapies: PTH Communication between Osteoblasts and Osteoclasts ANABOLIC PTH Osteoblast Osteoclast CATABOLIC RANKL OPG Osteoid Mineralized Bone  Parathyroid Hormone -secreted from the parathyroid glands in conditions where there is low serum [Ca2+] -acts in kidney to stimulate Ca2+ reabsorption and in bone it stimulates bone resorption which results in the release of stored Ca2+ When used pharmacologically, intermittent treatment with teriparatide (PTH 1-34) stimulates bone turnover and reduces the risk of fractures in osteoporotic patients; one of only a few anabolic agents for the treatment of osteoporosis  Parathyroid Hormone Marketed as Teriparatide When given intermittently stimulates bone deposition (anabolic) When given continuously stimulates bone resorption Significantly reduces vertebral and non-vertebral fractures Therapy is limited to 2 years  Novel Anabolic Therapy: Sclerostin Antibodies Human Disease to Novel Drug Therapies: Sclerostin Antibodies BMP signals through Wnt signalling (we learnt this in mol. pharm class) - mutation in SOST gene, Wnt signalling results in hyperplasia of activates B-catenin certain bones in the body which enhances - gene imp in determining osteoclast activity so bone density in scleostin we inhibit this pathway; inhibits osteoclast activity Yavropoulou et al. Hormones, 13(4): 476 (2014) Sclerostin Antibody: Romosozumab - By inhibiting antibody, we’re inhibiting osteosclastogenesis  Differential effects of bone-forming agents on bone surfaces - In severe cases, inhibiting osteoclast activity is not enough. Ferrari, S. L. (2018) Romosozumab to rebuild the foundations of bone strength Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2018.5  Romosozumab Recently approved by Health Canada (June 2019) Clinical trials comparing romosozumab and alendronate for 12 months demonstrated risk of vertebral fractures was 48% lower in romosozumab group (non-vertebral lower by 19% and hip lower by 38%) However, romosozumab group has higher rate of serious cardiovascular events (romosozumab 50/2040 patients versus alendronate 38/2014 patients)  Summary Drugs used in the treatment of osteoporosis are considered either anti-resorptive or anabolic Anti-resorptive therapy inhibit osteoclast activity; anabolic therapy stimulates osteoblast activity Use of SERMS can be useful in post-menopausal women due to beneficial role of estrogen in controlling bone density Bisphosphonates are first-line therapy in osteoporosis; they are anti-resorptive, efficacious and reasonably safe Denosumab is monoclonal antibody that inhibits the interaction of RANKL and RANK to inhibit osteoclast activity Teriparatide and romosozumab are the only available anabolic agent available to treat osteoporosis