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Dentaljuce Shorts: 500 words, 10 MCQs, on general medicine and surgery.

Bisphosphonates

Bisphosphonates are a class of drugs that prevent bone density loss, primarily used to treat osteoporosis and similar conditions. They are among the most commonly prescribed medications for osteoporosis and are known for their high affinity for calcium hydroxyapatite, facilitating specific targeting of the skeletal system.

Bisphosphonates are also referred to as diphosphonates due to their two phosphonate groups.

Medical Uses

Bisphosphonates are used in treating various conditions associated with bone fragility, including osteoporosis, Paget's disease of bone, bone metastasis, multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, and fibrous dysplasia.

In osteoporosis and Paget's disease, first-line bisphosphonates include alendronate and risedronate. Intravenous pamidronate may be used if oral medications are ineffective or cause digestive issues.

Alternative treatments such as strontium ranelate and teriparatide are reserved for refractory cases, with strontium ranelate use being restricted due to risks of venous thromboembolism and cardiovascular disorders. Raloxifene, a selective oestrogen receptor modulator, is occasionally used as an alternative in postmenopausal women.

Post-Menopausal Osteoporosis

Bisphosphonates are recommended as first-line treatments for post-menopausal osteoporosis. Long-term use (3-5 years) of bisphosphonates like alendronate and zoledronate significantly reduces the risk of fractures, including hip, vertebral, and wrist fractures.

After initial treatment, medication may be stopped or continued based on the patient's risk profile.

Cancer

Bisphosphonates help reduce fracture risk and bone pain in metastatic cancers and multiple myeloma. Evidence on bisphosphonates improving survival in breast cancer is mixed, though they may reduce the risk of bone metastasis in early breast cancer.

These drugs can also reduce mortality in multiple myeloma and prostate cancer patients.

Other Uses

Bisphosphonates show potential in treating complex regional pain syndrome (CRPS) and reducing fracture rates in children with osteogenesis imperfecta. They are also used to treat otosclerosis by minimising bone loss and in bone imaging when mixed with radioactive technetium.

Adverse Effects

Common Side Effects

Oral bisphosphonates can cause gastrointestinal issues such as upset stomach and esophageal inflammation, which can be mitigated by remaining upright post-administration. Intravenous bisphosphonates may induce fever and flu-like symptoms after the first infusion due to activation of γδ T cells.

Osteonecrosis of the jaw (ONJ) is a severe but rare side effect, primarily in cancer patients receiving high-dose intravenous bisphosphonates. Dental procedures can trigger ONJ, so preventive dental work is advised before starting bisphosphonate treatment.

There are reports of severe musculoskeletal pain and potential associations with atrial fibrillation (AF). However, the US FDA does not currently recommend altering bisphosphonate prescribing based on AF concerns.

Long-Term Risks

Long-term bisphosphonate use may lead to atypical femoral fractures due to over-suppression of bone turnover. These fractures are rare compared to the reduction in typical hip fractures.

There are concerns about impaired bone healing and micro-crack accumulation, which may require bone grafting for proper healing.

Chemistry and Classes

HMG-CoA Reductase Pathway
HMG-CoA reductase pathway. This pathway is disrupted by nitrogenous bisphosphonates, preventing the formation of essential metabolites for sub-cellular protein trafficking.

Bisphosphonates share a common phosphorus-carbon-phosphorus backbone, with the R-groups determining their properties. Non-nitrogenous bisphosphonates induce osteoclast apoptosis by forming non-functional ATP analogues, while nitrogenous bisphosphonates inhibit the enzyme farnesyl diphosphate synthase, disrupting protein prenylation necessary for osteoclast function.

Nitrogenous bisphosphonates are more potent and have fewer negative effects compared to non-nitrogenous types.

Pharmacokinetics and Mechanism of Action

Bisphosphonates are either resorbed orally or infused intravenously, with about 50% excreted by the kidneys. The remainder binds to bone tissue, where they can remain for over ten years.

Bisphosphonates preferentially bind to calcium ions, accumulating in bones and inhibiting osteoclasts, thereby reducing bone resorption.


Self-assessment MCQs (single best answer)

Which of the following is NOT a primary use of bisphosphonates?


Bisphosphonates are most commonly associated with which adverse effect?


Which bisphosphonate is known to reduce the risk of hip, vertebral, and wrist fractures by 35-39%?


What is the main benefit of bisphosphonates in cancer patients?


Long-term use of bisphosphonates can lead to which rare type of fracture?


Which of the following bisphosphonates is administered intravenously for patients who cannot tolerate oral forms?


The mechanism of action for nitrogenous bisphosphonates involves inhibition of which enzyme?


Which of the following is a risk associated with strontium ranelate?


What is the primary action of bisphosphonates on osteoclasts?


Which adverse effect is most commonly associated with oral bisphosphonates?


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