Content Reviewers:Yifan Xiao, MD
Osteoporosis medications are medications used to treat osteoporosis, which is a condition where decreased bone strength increases the risk of a broken bone.
So, the underlying cause of osteoporosis is an imbalance between bone resorption and bone formation, which are normal processes of bone remodeling.
Now in bone remodeling, the process begins when osteoblasts sense micro fractures near their location.
The osteoblasts produce a substance called RANKL, or receptor activator of nuclear factor κβ ligand, which binds to RANK receptors on the surface of nearby monocytes.
RANKL induces those monocytes to fuse together to form a multinucleated osteoclast cell.
RANKL also helps the osteoclast mature and activate so that they can start resorbing bones.
The osteoclast starts secreting lysosomal enzymes, mostly collagenase, which digests the collagen protein in the organic matrix. This drills pits on the bone surface known as the Howship’s lacunae.
Osteoclasts also start producing hydrochloric acid, or HCl, which dissolves hydroxyapatite into soluble calcium – Ca2+ and phosphate – PO42- ions, and these ions get released into the bloodstream.
At low concentrations, parathyroid hormone works by stimulating the activity of osteoblasts, thereby promoting bone formation; while at high concentrations, parathyroid hormone stimulates bone resorption.
On the other hand, calcitonin works by inhibiting osteoclast activity, thereby decreasing bone resorption.
Alright, moving on to pharmacology! Osteoporosis medications are subdivided into two main groups: non-hormonal medications, which include bisphosphonates and denosumab; and hormonal modulators, which include teriparatide, calcitonin, and raloxifene.
First, let’s start with bisphosphonates, which are first-line therapy for the prevention and treatment of osteoporosis.
Bisphosphonates can be subdivided into two main groups: simple, non-nitrogenous bisphosphonates, which include etidronate and tiludronate; and potent, nitrogenous bisphosphonates, which include alendronate, ibandronate, pamidronate, risedronate, and zoledronate.
Bisphosphonates work by binding to hydroxyapatite, which is the mineralized form of calcium found in bones.
When osteoclasts break down bones, they also take in the bisphosphonates.
Simple, non-nitrogenous bisphosphonates are very similar to pyrophosphate, which is used to synthesize the ATP that provides energy in living cells.
So, bisphosphonates work by getting added to ADP to form nonfunctional ATP analogues that don’t provide energy and instead, they build up in the osteoclast. This eventually leads to apoptosis or cell death.
And ultimately, fewer osteoclasts mean less bone resorption.
On the other hand, potent, nitrogenous bisphosphonates work by inhibiting the osteoclast’s mevalonate pathway, which disrupts the synthesis of cholesterol.
Since cholesterol is important for the function of the cell membrane and many enzymes, this decrease in cholesterol causes the osteoclast to become nonfunctional.
Besides osteoporosis, other indications for bisphosphonates include Paget’s disease of bone, which is a condition characterized by abnormal bone remodeling that results in fragile, misshapen bones; osteogenesis imperfecta, which is a genetic condition characterized by increased bone fragility; and metastatic bone disease, which occurs when cancer spreads from another organ to bone.
Since osteoclasts can break down bones to release calcium into the blood, their inhibition will decrease blood calcium levels, making it effective in the treatment of hypercalcemia.
Alright, moving onto the side effects of bisphosphonates. Oral bisphosphonates are most commonly associated with upper gastrointestinal side effects, such as esophagitis, esophageal ulcers, and gastric irritation. In order to prevent this, individuals are advised to take oral bisphosphonates with plenty of water and stay in the upright position for at least 30 minutes.
On the other hand, intravenous bisphosphonates don’t cause any gastrointestinal disturbances, but they can lead to rare and more severe side effects, such as osteonecrosis of the jaw.
Let’s move on to denosumab, which is a human monoclonal antibody that binds RANKL and prevents its binding to RANK receptors on the surface of osteoclasts and their precursors. This prevents the activation and maturation of osteoclasts, which limits bone breakdown.
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