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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 1  |  Page : 166

Therapeutic dimensions of bisphosphonates: A clinical update


1 Department of Orthodontics, College of Dentistry, Gulf Medical University, Ajman, UAE
2 Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, UAE
3 Department of Pharmacology, Health City University, Saint Lucia, USA

Date of Submission30-Jan-2019
Date of Acceptance25-Jul-2019
Date of Web Publication05-Oct-2020

Correspondence Address:
Venkataramana Vannala
College of Dentistry, Gulf Medical University, Ajman
UAE
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpvm.IJPVM_33_19

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  Abstract 


Bisphosphonates (BPs) are a commonly used class of drugs for the treatment of bone disorders. An extensive review of BPs with their clinical efficacy and safety profile is unavailable. This study aimed to review the available literature on BPs, summarize their role in clinical therapy, and emphasize their safety profile. Authors reviewed the existing literature using the Google Scholar, PubMed, and Micromedex databases and analyzed the collected articles. BPs are the preferred medication for osteoporosis and other similar conditions owing to their efficient antiosteoclastic activity. Few of them are available in oral dosage forms; hence, they are patient-friendly. The mechanism of action, common adverse effects and their clinical applications, precautions and warnings pertaining to the route of administration, and safety profiles have been discussed in this manuscript. The common adverse effects are majorly related to the gastrointestinal, cardiovascular, and endocrine system. Upon chronic usage, patients may experience serious problems like osteonecrosis of the jaw and atypical bone fractures. Although BPs are effective and safe, they may cause GI adverse effects and rare cases of osteonecrosis. Patient counseling could prove beneficial in early identification and prevention of the adverse effects associated with BPs.

Keywords: Bisphosphonates, clinical efficacy, dosage regimen, osteoporosis, safety profile, treatment outcome


How to cite this article:
Vannala V, Palaian S, Shankar PR. Therapeutic dimensions of bisphosphonates: A clinical update. Int J Prev Med 2020;11:166

How to cite this URL:
Vannala V, Palaian S, Shankar PR. Therapeutic dimensions of bisphosphonates: A clinical update. Int J Prev Med [serial online] 2020 [cited 2020 Oct 28];11:166. Available from: https://www.ijpvmjournal.net/text.asp?2020/11/1/166/297326




  Introduction Top


Bisphosphonates (BPs) are synthetic pyrophosphate analogs.[1] They are commonly used as drugs for treating multiple conditions majorly related to the bones owing to their antiresorptive properties. Based on their chemical nature, they are subdivided into three classes, namely, without ammonia, with ammonia, and with the heterocyclic ring.[2] Considering the route of administration, they are also classified as oral and parenteral BPs.[3] The commonly available BPs include alendronate, clodronic acid, etidronate, ibandronate, olpadronate, risedronate, tiludronate, and zoledronate. The presence of nitrogen-containing group adds to the potency of the drugs.[4] This class of drugs became popular because of the safety concerns raised about estrogen-containing drugs that posed threats related to carcinomas.[5] The major advantage of this class of drugs is that they only act on the bones that undergo resorptive changes, and hence they do not show any concentration-related systemic effects.[6] In addition to these advantages, BP therapy is cost-effective when compared with the other available options for osteoporosis management.[7] The overall tolerability and safety of BP therapy is considered reasonable, and the major adverse effects include gastrointestinal (GI) disorder (observed with oral BPs) and bone necrosis (generally observed with parenteral BPs).[8] However, these adverse effects can be tackled by the appropriate selection of patient and drug, adequate dosage titration, and patient counseling. In this study, the researchers review the existing literature on BPs, emphasizing their clinical efficacy, safety profile, and patient counseling aspects.

Chemistry of bisphosphonates

BPs are chemically inorganic pyrophosphate compounds formed as a result of replacing the oxygen atom by a carbon atom. The P-C-P moiety thus formed is resistant to hydrolysis. Being a highly stable moiety, the central carbon atom acts as a binding site for the two additional substituents (R¹ and R²). Of them, R¹ is preferentially a hydroxy group, which allows the compound to be a powerful tridentate ligand of calcium (bone hook), whereas R² is responsible for the antiresorptive potency. BPs are divided into two categories based on their chemical structure and mechanism of action, namely, nonnitrogen containing (those that normally get incorporated into the nonhydrolysable cytotoxic adenosine triphosphate [ATP] analogs) and nitrogen containing (those that inhibit the farnesyl pyrophosphate synthase [FPPS], a key enzyme in the mevalonate pathway).[9] In general, BPs bind to the hydroxyapatite structures of the bone mineral, thereby exhibiting antiresorptive activity.[10] Two phosphonates (-PO3) groups share a covalent bond with the carbon atom and become “bisphosphonate.” The long side chain (-R2) of the BPs determines their chemical properties, the mode of action, and the strength. The short-side chain (-R1), known as the “hook,” influences the chemical properties and kinetics of BPs.[11]

Pharmacokinetics of bisphosphonates

The pharmacokinetic profiles of BPs are mentioned in [Table 1].[12],[13]
Table 1: Pharmacokinetics of bisphosphonates[12],[13]

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US FDA-approved indications: The United States Food and Drug Administration (US FDA)-approved indications for BPs are listed in [Table 2].[12],[13]
Table 2: US FDA-approved indications of bisphosphonates[12]

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Non-US FDA-approved indications: The non-US FDA-approved indications of BPs are listed in [Table 3].[12]
Table 3: Non-US FDA-approved indications of bisphosphonates[12]

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The dosage regimen of BPs: The various dosage regimens of BPs are as listed in [Table 4].[12],[13]
Table 4: Dosage regimen of bisphosphonates[12],[13]

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Clinical applications of bisphosphonates

Osteoporosis

Osteoporosis is a skeletal disorder characterized by the weakening of bone leading to risk of fracture, which is highly prevalent in postmenopausal women. This condition is a “silent disease” and progresses without symptoms until a fracture occurs. BPs are recommended as afirst-line approach to hormone replacement therapy (HRT) in postmenopausal osteoporosis.[14],[15]

Osteoporosis can be caused by various reasons; the primary cause is because of the depletion of hormones (estrogen depletion in women in the postmenopausal state and androgen depletion in elderly men).[16],[17] In particular, because of the imbalance in bone remodeling after menopause (decreased estrogen), the osteoclastic activity predominates the osteoblastic activity. BPs are antiosteoclastic agents, which suppress the osteoclastic formation and aid in increasing or maintaining the bone mineral density (BMD) in the long term.[18],[19] Among the BPs, oral alendronate therapy benefits by decreasing the hip, vertebral, and wrist fractures.[20],[21] Zoledronate therapy aids in effectively decreasing the risk of vertebral fractures compared with that of hip fractures. Risedronate is also known to be more effective in the reduction of vertebral fractures than in the reduction of hip fractures.[22]

Osteoporosis in Crohn's disease

Crohn's disease is an inflammatory bowel disease (IBD) that affects the gastrointestinal tract (GIT) anywhere from the mouth to anus, majorly affecting the lower part of GIT—small intestine and ileum. It is an immune-related disease triggered by pathogenic bacterial infections caused by Mycobacterium, Pseudomonas, Listeria, and others. It is an unregulated inflammatory condition that aids in tissue destruction. Individuals chronically suffering from Crohn's disease manifest rectal bleeding, weight loss, fever, arthritis, and osteoporosis. In such patients, osteoporosis may majorly result from two reasons, which are anemia of chronic disease or anemia because of deficiency of B12, folate, and iron, with the latter being more common.[23],[24] In general, the disease results in poor absorption of calcium and vitamin D from the affected part. Crohn's disease increases the risk of osteoporosis,[25] and these individuals are at increased risk of bone fractures.[26] Moreover, the long-term usage of corticosteroids (prednisone or cortisone), as a part of Crohn's disease management, can also cause osteoporosis.[27] Crohn's disease cases associated with osteoporosis can be treated with intravenous (IV) risedronate, alendronate, pamidronate, or ibandronate. The treatment should also be accompanied by calcium and vitamin D supplementation.[28],[29]

Osteoporosis in male hypogonadism

Similar to estrogen depletion in females, the gradual depletion of testosterone in elderly males also leads to osteoporosis, namely, secondary osteoporosis (primary osteoporosis is age-related, also known as “senile osteoporosis,” [>70 years] or idiopathic osteoporosis [<70 years]).[30] In general, male osteoporosis is linked with hip fractures,[31],[32] and vertebral fractures [33] are higher in men than in women. Testosterone depletion is the prime factor for the onset of osteoporosis in males; other mutual risk factors, such as genetics and lifestyle choices (e.g., immobilization, tobacco usage, and excess alcohol consumption), as well as specific risk factors (e.g., long-term corticosteroid medication), exacerbate the condition. Secondary osteoporosis in men is caused due to glucocorticoids, hypogonadism, alcohol intake, smoking, GI disease, hypercalciuria, and immobilization.[34] BPs, such as alendronate, ibandronate, and risedronate, are effective in treating osteoporosis in males. Alendronate as an oral medicine on a daily or weekly basis is prescribed for osteoporosis due to secondary causes, such as corticosteroid use, androgen deprivation therapy (ADT), rheumatologic disorders, and hypogonadism.[35]

Corticosteroid-induced osteoporosis

Glucocorticoids possess anti-inflammatory and immunosuppressive effects and are majorly prescribed to treat patients with asthma and rheumatoid arthritis (RA), as well as organ (kidney) transplant patients. Bone loss is one of the noticeable adverse effects of these medications.[36] The most commonly affected bones are ribs and vertebrae.[37],[38] Apart from bone loss, the inflammatory suppressive function of corticosteroids can cause muscle weakness or immobility, decreased calcium absorption, depleted testosterone levels, or a combination of any of them.[39]

Patients on long-term corticosteroid therapy are advised to undergo BMD test.[40]

BPs reduces bone loss in patients consuming glucocorticoids for a long time. Alendronate followed by risedronate are effective agent to prevent and treat bone loss, whereas pamidronate and ibandronate are less efficient.[41] Along with BPs, adequate calcium and vitamin D supplements are also important for treatment.[28],[42]

Osteoporosis in immobilized patients

In immobilized patients or those using wheelchairs for long periods because of head injuries, spinal cord injuries, and limb fractures, rapid bone loss with an eventually higher risk of fracture, hypercalcemia, and, often, nephrolithiasis was evident.[17] Oral alendronate [43] and IV pamidronate are found to be useful and effective in reducing bone loss; however, their role in reducing the risk of fracture and nephrolithiasis is unclear.[44]

Paget's disease

The condition of disorganized bone remodeling where there is extreme bone resorption (osteoclastic activity) that is counteracted with improper bone deposition (osteoblastic activity) is known as Paget's disease or osteitis deformans. The commonly affected bones are the skull, pelvis, spine, lower limbs, and others. Paget's disease is confined more locally with few bones involved, whereas in osteoporosis, the bone-weakening/loss are generalized. The affected bone with Paget's disease eventually becomes leads to arthritis in the joints near the affected bone.[45],[46] The elevated levels of serum alkaline phosphatase (ALP) are a primary indicator of Paget's disease along with bone pain.[47]

BPs are preferred to treat Paget's disease. They suppress the amplified bone resorption and aid in controlling the serum ALP levels. Owing to their greater antiosteoclastic activity, orally administered alendronate,[48] risedronate,[49] and tiludronate [50] and intravenously administered pamidronate [51] and zoledronate have gained immense attention in treating Paget's disease.[52]

Carcinomas

Most cancers that affect bones originate in other sites/organs and metastasize to the bone (secondary bone cancer). Subsequently, they cause hypocalcemia, intense pain, and eventually fracture. Thus, BPs are also widely used to treat malignant conditions, such as breast cancer, prostate cancer, multiple myeloma, renal carcinomas, and lung cancers, where there is bone metastasis in more than 80% of the cases because of the invasion of cancer cells into the bone and disruption of the bone homeostasis and remodeling process.[53]

The usage of BPs in patients with multiple myeloma, breast cancer, and prostate cancer is associated with decreased mortality.[54],[55] Patients consuming oral BPs have an increased risk of esophageal cancer, which was recorded in Europe and North America.[56] In general, long-term BP therapy (>3–5 years) and age factor (>69 years) could contribute to esophageal cancer; however, data supporting this is unavailable.[55],[57] The validated data related to BPs and esophageal cancer are extremely essential to understand this situation. In the malignant patients, BPs impede bone metastasis and also reduce bone pain. Recent research is exploring BPs for their anticarcinogenic activity and synergistic action, along with antimalignant drugs.[58],[59]

Breast cancer

Women with breast carcinoma who were prescribed clodronate on a long-term basis witnessed a significant reduction of bone metastasis and reduced mortality in a 6-year follow-up study.[60] Premenopausal women with hormone-sensitive breast cancer receiving endocrine-based therapy who were administered IV zoledronic acid for approximately 6 months had reduced bone loss.[61] In postmenopausal women, receiving aromatase inhibitor medication to prevent estrogen-sensitive breast cancer, orally administration with risedronate showed an inhibitory effect on bone loss.[62]

Prostate cancer

Prostate carcinoma is concomitant with osteoblastic (not osteoclastic) activity, which is frequently known as sclerosis metastasis where osteoblastic stimulation occurs.[63] Despite the osteoblastic activity in sclerotic metastases, the osteolysis is a regular feature of prostate cancer bone disease. Certainly, bone destruction may be an obligatory part of cancer cell invasiveness in the bone.[64] Zoledronate was found to be effective for reduction in bone-related events like bone pain, skeletal destruction, and others in prostate cancer patients with bone metastases.[65],[66] Etidronate has indicated a significant effect in lowering bone pain in prostate cancer patients with metastasis.[67]

Men with hormone-responsive prostate cancer (increased androgen levels) undergoing ADT may develop osteoporosis after the long-term usage of these androgen depriving drugs, which may, in turn, cause bone weakness and risk of fracture. These patients can benefit from the cautious administration of BPs. Administration of IV BPs like pamidronate [68] and zolendronate [69] was effective in inhibiting the skeletal destruction of hip and spine bones in patients with prostate cancer (nonmetastatic) undergoing androgen-depriving treatment. Orally administered risedronate is reported to prevent bone loss and maintain the skeletal integrity of hip and lumbar spine bones.[70]

Multiple myeloma

Multiple myeloma is the cancer of plasma cells, which plays a vital role in the immune system.[71] Initially, no symptoms are noticed; however, during the later stages, patients present with several symptoms such as bone pain, bleeding, frequent infections, and anemia. Several studies have reported that IV BPs, pamidronate, and zolendronate are very effective in impeding bone destruction and bone pain, and they are the preferred drugs in these cases because they improve survival.[72],[73],[74] However, in multiple myeloma, IV BPs (zolendronate and pamidronate) were documented with a higher incidence of developing adverse effects, that is, osteonecrosis of jaw (ONJ), which is an important reason for tailoring the drug regime in multiple myeloma cases.[75] In contrast, oral BPs therapy for multiple myeloma-associated bone disease was not documented in the literature.[17]

Osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a pediatric genetically inherited (autosomal gene mutation) skeletal disorder, which mainly occurs because of a defect in type-1 collagen synthesis, where the primary symptoms include brittleness of bone and secondary symptoms include loose joints, short height, and bluish sclera.[76],[77] OI can exist in mild to severe forms with differing symptoms. A patient with OI may suffer from a few or multiple fractures in their lifetime. Diagnosis of this disease is difficult because there is no single test that could identify it. Eventually, DNA testing may be useful based on the symptoms.[78]

To date, complete remedial medication for this condition does not exist. Only supportive treatment procedures such as surgical implantation of long bones, physiotherapy, and medication for bone pain have been suggested.[79] In addition to such treatment procedures, BPs werefirst prescribed in 1987 as a supporting medication in children suffering from OI.[80] Thereafter, the usage of BPs in OI increased, but there exists uncertainty in selecting the type of suitable BPs and the supporting evidence is also inadequate.[81],[82],[83]

Safety profile of bisphosphonates

1. Cardiovascular effects

A follow-up communication issued by the US FDA revealed that the use of BPs did not contribute to an increased risk of serious or nonserious atrial fibrillation.[84] Heart rhythm disorders, including atrial fibrillation, are common among elderly individuals aged 65 years or older, the same age range of the study population reviewed here. Most of the reported cases of serious atrial fibrillation that the FDA reviewed to date occurred more than a month after the drug infusion, and no significant difference was observed in all events of atrial fibrillation between the treatments. Collectively, the FDA concluded that atrial fibrillation events observed in the initial review that may pertain to the entire class of BPs warrants further in-depth evaluation.[85]

1.a. Alendronate

Osteoporosis (oral route): One study found a significantly increased risk of heart failure with alendronate use (1.2% vs. 0.8% with controls); however, the risk dropped significantly with greater alendronate exposure (98% increased risk with defined daily dose of 0.25 mg or less vs. 69% increased risk with a defined daily dose of 0.26–0.8 mg).[86]

Although there is a theoretical increased risk of atrial fibrillation with high potency and parenteral administration of BPs, the association with respect to oral BPs remains unclear.[87]

1.b. Pamidronate

Hypertension: Patients with hypercalcemia of malignancy, and Paget's disease, developed hypertension during the clinical trials.

Hypotension: It was reported during postmarketing surveillance with high IV doses of pamidronate, and it was not reported with lower doses of pamidronate.[88]

Syncope and tachycardia: Six percent of patients who received pamidronate developed syncope and tachycardia.

Thrombophlebitis: Mild thrombophlebitis and soft-tissue symptoms including redness, swelling, and pain were reported during treatment with IV pamidronate.[89],[90]

Residronate

Cardiac arrhythmia was observed in men during the long-term usage of risedronate for 2 years in a few cases. Moreover, in the clinical trials of risedronate, chest pain, hypertension, and peripheral edema were noticed in a few cases.[91]

Tiludronate

It was seen that 2.7% of patients receiving tiludronate sodium developed chest pain and peripheral edema.[50]

1.c. Zolendronate

Atrial fibrillation is one of the adverse effects that is more evident in postmenopausal osteoporotic women receiving zoledronate through the IV route; this was ruled out on the long-term administration of zolendronate in HORIZON Pivotal Fracture Trial.[92],[93] The etiology for this condition, which is linked with electrophysiology of the heart, is unclear. However, the risk was less likely to happen with IV zolendronate in patients suffering from malignancy.[94]

2. Dermatological effects

2.a. Alendronate sodium

During postmarketing surveillance of alendronate, Stevens–Johnson syndrome and toxic epidermal necrolysis were documented.[95]

2.b. Clodronate

During clodronate administration, allergic skin rashes were rarely reported.[96] Patients over 70 years of age were reported with skin lesions like erythroderma [97],[98] and necrobiotic palisading granuloma (NPG).[99]

2.c. Etidronate

It is known to cause angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, Stevens–Johnson syndrome, and urticaria.[100]

2.d. Ibandronate

Erythema multiforme, Stevens–Johnson syndrome and Bullous dermatosis were observed during postmarketing surveillance.[101]

2.e. Risedronate

Postmarketing surveillance has reported skin reactions like rash, blisters, and hypersensitivity.[91],[102]

2.f. Tiludronate and zolendronate

During the postmarketing surveillance, skin necrosis was noticed in addition to skin rashes and Steven–Johnson syndrome.[50]

3. Endocrine/metabolic effects

3.a. Alendronate

Hypocalcemia: It was noticed that patients having Paget's disease with high rates of osteoclast-mediated bone resorption who were treated with alendronate for a longer period suffered from hypocalcemia.[103] Very few patients were reported with hypophosphatemia.[104] Often, patients treated with IV BPs can present with hypocalcemia. It is more common in patients with osteoclast-mediated bone resorption (e.g., patients with Paget's disease). These hypocalcemic patients should be supplemented with calcium and vitamin D.[105] Patients suffering from myeloma treated with thalidomide and receiving zolendronic acid infusion can experience renal failure and hypocalcemia; hence, a certain level of caution is needed.[106]

3.b. Clodronate



Hyperkalemia: Hyperkalemia (elevated levels of serum potassium, 6.2–8.4 mEq/L) was reported in patients with parathyroid carcinoma and coexistent azotemia, and hyperchloremic acidosis was reported during IV clodronate treatment;[107] however, previous episodes of hyperkalemia had occurred in both patients, and the contributory role of clodronic acid is speculative.

Hypocalcemia: Hypocalcemia, occasionally symptomatic, were reported in a few patients during therapy with both oral and IV clodronic acids.[108]

3.c. Etidronate

Hyperphosphatemia: Can lead to increase in tubular reabsorption of phosphate.[109]

3.d. Ibandronate

Hypocalcemia: Similar to other BPs, ibandronate administration has resulted in a decrease in serum calcium. Hypocalcemia should be treated prior to initiating ibandronate therapy.[110]

3.e Pamidronate

Hypocalcemia: Serum calcium should be monitored in patients with Paget's disease undergoing pamidronate therapy at the time of initiation of treatment. Patients with hypoparathyroidism, possibly predisposing them to hypocalcemia.[88]

Hypokalemia, hypothyroidism

, hypomagnesemia, and hypophosphatemia: Hypokalemia, hypothyroidism, hypomagnesemia, and hypophosphatemia were reported in patients with Paget's disease and hypercalcemia of malignancy in patients who received etidronate therapy.[88],[111]

3.f. Residronate

Hyperparathyroidism: A daily dose of 5 mg risedronate and delayed-release risedronate 35 mg weekly dosage in postmenopausal osteoporotic patients were associated with increased levels of parathyroid hormone (PTH); however, negligible increased PTH levels were encountered in daily immediate-release risedronate-dosed patients.[112] Hypocalcemia and hypophosphatemia were also noticed in the treatment of postmenopausal osteoporotic women receiving delayed-release risedronate 150 mg/once a month and also among Paget's disease patients who received risedronate treatment.[91]

4. GIT effects

With oral alendronate, common adverse effects like diarrhea, abdominal distension, pain, constipation, and bleeding ulcers of the esophagus are noted.[95],[113] The US FDA has reported esophageal cancer in patients using oral BPs for a longer period, in contrast to some other studies that revealed that there is no risk of esophageal cancer.[114] However, more reliable concrete data are essential to study the association between BPs and esophageal cancer.[53],[115],[116]

Esophagitis, esophageal ulcers, and esophageal erosions, were reported following oral BPs treatment, including alendronate.[95],[117] Long-term usage of risedronate, ibandronate, and etidronate were also reported with esophageal cancer.[118]

5. Hepatic effects

Hepatotoxicity: Elevation in serum transaminase enzymes were reported in few hypercalcemic patients who received alendronate through the IV route.[119]

An increased concentration of hepatic enzymes and fatty changes were noticed in a case report of a 71-year-old woman and reversed to the normal range following the withdrawal of alendronate.[120],[121] Increased liver transaminase levels in serum were noticed in a 61-year-old woman receiving IV ibandronate, the enzyme levels gradually reverted to normal within 1-year after stopping the drug.[121],[122]

6. Immunologic effects

Lymphocytopenia, flu-like symptoms, urticaria, and, rarely, angioedema, were reported in postmarketing studies.[95],[123]

Anaphylaxis was observed during postmarketing surveillance.

7. Musculoskeletal effects

Musculoskeletal pain is an apparent adverse effect of BPs. The US FDA emphasized the possibility of occurrence of severe musculoskeletal pain in patients undergoing BP therapy afterfirst IV infusion, especially with amino BPs.[124] Cases of bone, joint, and/or muscle (musculoskeletal) pain were reported with the use of alendronate and risedronate.[125]Time of pain onset ranged from 1 day to 52 months (mean: 91 days, median: 14 days) after the initiation of therapy. While many patients experience relief after cessation of BPs, others have experienced a slower, partial response despite treatment with a variety of analgesics, including opioids.[126]

7.a. Atypical bone fractures

The risks of pelvic and femoral fractures were documented particularly in patients on long-term BPs. In long-term BP users, the persistent suppression of bone metabolism and impaired bone healing are the probable contributing factors predisposing to these fractures.[127] Risk of atypical femur fractures in BPs users was evaluated in various studies;[128] however, the resultant data revealed that the occurrence of atypical femur fractures is less likely.[129] Predominantly, these fractures were noticed in osteoporotic patients on BP therapy, and they are not observed in BP users of Paget's disease or hypercalcemia of malignancy.[130]

Apart from these fractures, some other features such as thickening of cortical bone, bilateral bone fractures, and delayed healing were also documented in the literature, and the occurrence of these features is unclear.[131]

7.b. Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is a severe adverse effect of BPs. A high incidence of ONJ (94%) occurs in patients receiving IV BP therapy for a longer period. In 2003, Marx reported thefirst case of ONJ following IV administration of zolendronate [132] and pamidronate in patients with malignant conditions such as myeloma (7%–10%) and breast cancer (4%).[133],[134] The incidence of this adverse effect increases with the administration of IV BPs.[135] A growing number of reports have attempted to describe the effect; however lowering dosage and increasing the dosage frequency has lessened the ONJ occurrence.[136] Moreover, orally administered BPs have slight incidence of ONJ.[137]

Presently, the BP-related osteonecrosis of the jaw (BRONJ) can be defined as the condition in which patients without a history of radiotherapy to the jawbone and with a history of BP usage or who are under BP medication develop necrotic lesions in the maxillofacial bones, particularly in the maxilla and mandible, after at least 8 weeks.[138],[139] It is also known as “bis-phossy jaw” because it is similar with “phossy jaw,” which is an occupational disease common in employees working in the phosphorous (matchstick) industry with inadequate protection.[140]

In a few recent studies, the usage of antiresorptive medications, such as denosumab (human monoclonal antibody), in cancer patients to prevent bone metastasis and antiangiogenesis medication, such as bevacizumab, for colorectal cancers were also associated with ONJ.[141] Therefore, the latest opinion is that the incidence of ONJ is not limited to BPs, and it can also flare up because of other antiresorptive medications. Hence, it is termed as medication-related osteonecrosis of the jaw (MRONJ).[142] Nevertheless, to date, the mechanism of ONJ in association with BPs and other antiresorptive agents remains unclear.

The possible mechanism may be that the antiosteoclastic effect of BPs cause osteoclastic inhibition by apoptosis [143] and suppress angiogenesis; therefore, the overall excessive obstruction of bone turnover occurs and eventually, an attempt to repair results in bone necrosis.[144],[145]

BPs have a tendency to deposit in these bones because they have an affinity to the bones, which undergoes excessive turnover; thus, BPs accumulate in the jawbones. Any surgical trauma to the jaw region (craniofacial bones) in the form of tooth extraction and the rupture of mucosa of jawbones because of artificial dentures, periodontal infections, and steroid therapy in severe immunocompromised cases leads to BRONJ.[146] BRONJ is a lethal lesion and is difficult to manage. In literature, to date, BP-associated osteonecrosis is not observed in any part or portion of human bones other than the jawbones (craniofacial bones).

Patient counseling points

The most common patient counseling points for the commonly prescribed BP areas are listed in [Table 5].[12],[27],[147]
Table 5: Counseling points for patients prescribed bisphosphonates

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Use in special population

The use of BPs in special population is listed in [Table 6].[12]
Table 6: Use of bisphosphonates in special population

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Monitoring parameters

The various monitoring parameters for patients prescribed with BPs are tabulated in [Table 7].[12]
Table 7: Monitoring parameters for patients undergoing bisphosphonate therapy

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  Conclusions Top


BPs are commonly used drugs for treating osteoporosis and are considered effective. They are effective and safe, except for causing GI effects and rare effects such as osteonecrosis. Providing patient counseling can be helpful in early identification and prevention of the side effects associated with BPs.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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