Dr. Anant Patil reviews oral and intravenous bisphosphonates which though widely used, requires different indications and formulations based on prevalent underlying condition.

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Osteoporosis is a clinical condition characterised by reduced bone strength leading to higher risk of fracture. [1] It is one of the important health-related concerns globally as well as in the Indian population. Increase in life expectancy due to development in health and economy sectors is one of the contributing factors to the development of osteoporosis. The world has witnessed several developments in terms of research, diagnosis and treatment of osteoporosis; however, a lot still needs to be done in this field. [2]

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Osteoporosis- Primary & Secondary

Osteoporosis can be primary or secondary. [3] Age-related osteoporosis is a prevalent condition. Hormones play an important role in maintaining functions of the bone. Oestrogen and testosterone are important for prevention of bone breakdown. Hormone-related causes of osteoporosis are post-menopausal osteoporosis and androgen deficiency.

Secondary osteoporosis can be caused by comorbid diseases or it can be drug-induced. [3] These causes include Paget disease of bone, metastasis of cancer affecting bone, drug induced osteoporosis and hypercalcaemia of malignancy.[2] Immobility and genetic causes may be the cause of bone loss in some cases.

Although any bone can be affected by osteoporosis, the most common bones affected are hip, spine, and wrist. [1] Increasing the strength of bones and reducing the risk of fracture is an important goal in the treatment of osteoporosis.

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Management of osteoporosis

Diagnosis of osteoporosis is done by performing analysis of bone mineral density (BMD) with dual-energy X-ray absorptiometry. It is measured especially in the hip and lumbar spine. Occurrence of hip or vertebral fractures without any history of trauma also suggests presence of osteoporosis. [3]

Intake of calcium and vitamin D are important in the management of osteoporosis. The pharmacological agents used in the treatment of osteoporosis can be broadly classified into two types:

• Antiresorptive agents: Those which mainly reduce the bone resoption; Examples are oestrogen, bisphosphonates, denosumab, calcitonin and raloxifene [3]
• Anabolic agents: Mainly increase bone formation; Teriparatide is an example [3]

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Bisphosphonates

Bisphosphonates have been there in clinical practice since more than four decades and are increasingly used for treatment of different bone-related conditions. Their high affinity towards bone mineral, deposition in the bone, binding to hydroxyapatite crystals and inhibition of breakdown of hydroxyapatite, helps in suppression of bone resorption. These agents are of considerable clinical value in disorders in which underlying pathology is associated with imbalance between osteoclast mediated formation of bone and osteoclast-mediated boss loss. [4]

Examples of bisphosphonates

 

Bisphosphonates are broadly divided into first-generation agents and newer-generation agents. First-generation agents are non-nitrogen containing compounds whereas second- and third-generation agents have nitrogen containing side chains in their structure. Today, most of the patients receive treatment with nitrogen containing bisphosphonates. [4] Examples of bisphosphonates are given in table 1.

 

Table 1: Examples of bisphosphonates

First-generation bisphosphonates	Second- and third-generation bisphosphonates
Etidronate Clodronate	Alendronate Risedronate Ibadronate Pamidronate Zolendronic acid

Some of these drugs are available for oral administration and some are given intravenously. [5] Examples of bisphosphonates given by intravenous route are pamidronate, ibadronate, zolendronate. [6]

One of the important characteristics of oral bisphosphonate therapy is their limited bioavailability due to the chemical nature. Being high hydrophilic compounds, they are not absorbed well from the intestine. The absorption is less than or about 1% after administration of oral dose. [4,5] The other clinically important aspect related to use of oral bisphosphonates is need to remain upright for half an hour and no meal for two hours before and at least half an hour after the oral intake of medicine. In addition, occurrence of gastrointestinal effects may be associated with reduction in the compliance to therapy with oral bisphosphonate therapy. [4]

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Adverse events associated with bisphosphonates

As discussed before, oral bisphosphonate treatment may be associated with gastrointestinal adverse effects. Intravenous bisphosphonate therapy may be associated with flu-like symptoms. [4] Clinicians also should be aware about association of these drugs with other clinically important adverse effects including osteonecrosis of the jaw, [4] and atrial fibrillation. [7]

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Use of bisphosphonates in clinical practice

Considering the mechanism of action and benefits, bisphosphonates have an important place in the management of bone-related disorders associated with high rate of osteoclast-mediated bone resorption. Different pathological conditions with these features include osteoporosis due to various reasons (post-menopausal, senile, associated with glucocorticoid use etc), Paget's disease, cancer metastasis affecting bones etc. [4]

Alendronate & Risedronate

Indications for the use of alendronate [8] and risedronate tablets [9] include treatment and prevention of post-menopausal osteoporosis, treatment for increasing bone mass in male patients with osteoporosis, treatment and prevention of glucocorticoid-induced osteoporosis and treatment of Paget’s disease. It should not be used if the patient is unable to stand or sit upright for a minimum of 30 minutes. It should also be avoided in patients with hypocalcaemia and in those having hypersensitivity to the product.

Oral Ibadronate

Oral ibadronate is indicated for the treatment and prevention of post-menopausal osteoporosis. Tablet should be taken a minimum of one hour before taking anything (food, drink, or medicine) by mouth and should not take anything except water for one hour after its intake. Patient should not lie down for a minimum of one hour after taking the tablet. [10]

Intravenous ibadronate injection

Intravenous ibadronate injection is indicated for the treatment of postmenopausal osteoporosis. For patients having low risk of fractures, therapy discontinuation after three to five years of use can be considered. It should not be used in patients having hypocalcaemia, those with hypersensitivity to its use or those with severe renal impairment. [11]

Zolendronic acid injection

Zolendronic acid injection is indicated for the treatment of hypercalcaemia of malignancy, multiple myeloma and those with bone metastasis from solid cancers. [12]

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Conclusion

Osteoporosis is a common health problem worldwide. Although there are several medicines, it should be noted that approved indications may be different for different medications. Second- and third-generations bisphosphonates (oral and intravenous) are important agents in the armamentarium for the management of osteoporosis. These agents are generally well-tolerated; oral agents can be associated with gastrointestinal adverse effects whereas intravenous bisphosphonates may be associated with flu- like symptoms. Association with other clinically important adverse effects should also be considered while using these drugs.

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Disclaimers:

Information given in this article is for education purpose. Physicians are requested to refer the latest approved prescribing information before using specific bisphosphonate.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anant Patil is Assistant Professor of Pharmacology.