Continuing Education Activity

In the second half of the 20th century, bisphosphonates have emerged as a novel treatment for bone metabolism disorders. Currently, bisphosphonates are widely used in the management of cancer-related bone disease and osteoporosis. This activity reviews some of the most significant complications related to bisphosphonate toxicity and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the etiology of bisphosphonate toxicity.
• Review the appropriate evaluation of bisphosphonate toxicity.
• Outline the management options for bisphosphonate toxicity.
• Explain the importance of improving care coordination amongst interprofessional team members to enhance the delivery of care for patients with bisphosphonate toxicity.

Introduction

Bisphosphonates are the cornerstone in the management of metabolic and cancer-related bone disease. The use of bisphosphonates in patients with multiple myeloma and metastatic bone disease has led to a reduced incidence of pathological fractures.[1] Because of their antiresorptive qualities, bisphosphonates are widely used in the treatment of osteoporosis. Studies have shown that the use of bisphosphonates reduces the risk of vertebral and hip fractures by 30%-70% in women with osteoporosis.[2] 

Bisphosphonates first appeared on the industrial scene in the 19th century when their unique structural properties were used to ‘soften water’ to prevent scaling and corrosion of pipes.[3] They were then introduced to the field of medicine in the late 1960s for the treatment of diseases that affect bone metabolism.[3] Etidronate acid and clodronic acid were the first two bisphosphonates used in medical practice.[3] Since then, more potent agents have been developed with increased duration of action. The bisphosphonate zoledronic acid is widely used at present and can be given by intravenous infusion as a single dose once a year.[4] 

Despite their benefits, bisphosphonates have both short-term and long-term side effects. A good understanding of these is essential when prescribing this class of drugs.[5]

Etiology

In healthy bone, the bony tissues undergo constant remodeling. Two processes occur simultaneously: resorption of the bone executed by osteoclasts and production of new bone mediated by osteoblasts. Maintaining a healthy balance between these two processes is key in maintaining bone homeostasis.[6] Several factors play a role in sustaining this balance. Growth factors, such as insulin-like growth factor-1 (IGF) and transforming growth factor-beta (TGFB), are released during the resorption phase to induce the bone formation process, and other factors such as parathyroid hormone (PTH) and prostaglandin E, are thought to activate both processes simultaneously.[6]

Bisphosphonates and calcium pyrophosphates are similar in structure. In healthy bone, calcium pyrophosphates bind to calcium, forming a strong bond.[7] Cancer-driven osteoclasts weaken the skeleton by ingesting it. Due to the structural similarities with calcium pyrophosphates, the malignancy-activated osteoclasts ingest bisphosphonates too. This interferes with the metabolism of these osteoclasts, leading eventually to cell death.[7] Thus, by suppressing osteoclast activity, bisphosphonates suppress bone turnover. However, prolonged use of bisphosphonates is thought to be associated with over-inhibition of bone turnover, resulting in skeletal fragility and atypical fractures, especially in the femoral region [6]. Evidence suggests that these atypical stress fractures are caused by bisphosphonates interfering with the remodeling and natural healing process of the bone cortex.[7]

Bisphosphonate toxicity can be seen at both therapeutic dosing and overdoses. It is also independent of the renal or hepatic function of the patient. Ensuring adequate calcium and vitamin D intake before, during, and after bisphosphonate therapy limits some of the adverse effects, especially hypocalcemia.[8]

Epidemiology

A recent meta-analysis of 47 studies of breast cancer patients who were given intravenous (IV) bisphosphonates included 23 randomized controlled clinical trials (RCTs) with the total number of patients included being 20,607. Influenza-like illness was shown to be the most common side effect of bisphosphonate use, with no observable difference between the sexes.[9] 

Other side effects were fatigue, fever, dyspepsia, and anorexia. The overall incidence of osteonecrosis of the jaw (ONJ) was 2% compared to that for patients taking oral bisphosphonates for osteoporosis, where it ranges from about 1 in 10,000 to 1 in 100,000 patient-years[10] Atypical fractures are seen with the long-term use of bisphosphonates (median use of 7 years). The absolute risk of such fractures ranges between 3.2 to 50 cases per 100000 patient-years.[7]

History and Physical

The findings from the clinical history and examination of patients with bisphosphonate toxicity depend on the complications that arise. A thorough history of exposure, along with the physical examination, will assist in decision-making for further evaluation and treatment. Given the diversity of the complications, a detailed review of systems helps identify the organs involved.

Systemic Adverse Effects

Flu-like symptoms have been observed with intravenous bisphosphonate use.[11] Patients experience fever, fatigue, arthralgia, myalgia, nausea, and increased bone pain.[12] The symptoms usually occur within 24 to 72 hours of bisphosphonate administration. Cytokine release such as tumor necrosis factor-alpha (TNFa), interferon-Y, and interleukin-6 (IL-6) are thought to precipitate the systemic inflammatory response.[13][14] Treatment is usually aimed at relieving the symptoms, and the recurrence usually lessens with subsequent administrations (the risk declines from 30% with the first infusion to less than 7% in subsequent infusions.[15]

Upper Gastrointestinal Adverse Effects

There are several commonly encountered adverse effects from the oral use of bisphosphonates. Erosive esophagitis can be seen and is thought to be related to suboptimal oral administration of bisphosphonates. Patients should be advised to ingest the drug with a full glass of water and then maintain an upright position for 30-60 minutes. The association between bisphosphonate use and nausea, dyspepsia, and abdominal pain appears to be weaker, and the occurrence of any of these symptoms should prompt further evaluation for underlying GI conditions before discontinuation of the bisphosphonates. Proton pump inhibitors can be used to reduce these adverse effects.[8]

Hypocalcemia

Several conditions increase the risk of hypocalcemia during bisphosphonates use. Vitamin D deficiency, hypoparathyroidism, and hypomagnesemia are all predisposing factors.[5] The risk intensifies in cancer patients with osteoblastic bone metastases.[1] Clinical presentation can be variable, from nonspecific lethargy and weakness to severe tetany and seizures.[5] The symptoms can occur within days of the first infusion but can also be seen after months of repeated infusions.[5]

Ocular Complications

Even at the recommended dosing, pamidronate can cause scleritis, uveitis, and conjunctivitis.[12] Pain and redness in the eyes have also been reported following zoledronic acid infusion. The slit-lamp examination has confirmed uveitis in several cases.[11]

Osteonecrosis of the Jaw (ONJ)

Osteonecrosis of the jaw (ONJ) is a condition characterized by the destruction of bone tissue in the jaw due to a lack of blood supply associated with infection from oral flora.[5][16] The first documented case of ONJ was in 2003. The overall incidence of ONJ is 1% to 10%, and cancer patients represent the majority.[5]

There are 2 main factors that influence the likelihood of developing ONJ. The first one is the type and total dose of bisphosphonates. The more potent the drug and longer the drug is used, the higher the risk of ONJ. Also, the risk is 15-fold higher, with intravenous bisphosphonates compared to oral bisphosphonates.[16][17] The second factor is previous dental trauma, such as dental extractions or surgery, and oral infections.[17]

Pain and exposed bone are the most common presenting features.[5] Some patients report pain and numbness, with or without soft tissue swelling and tooth mobility.[18] However, a third of the cases are painless.[19] Rarely, patients present with fractures and fistula formation.[5] Imaging is usually not helpful as radiographic features are nonspecific. Suggestive history and typical clinical signs and symptoms with concurrent use of bisphosphonates are usually sufficient to make the diagnosis.[5]

Subtrochanteric Femoral Fractures

Although not clearly shown in clinical trials, several case reports describe the association between bisphosphonates and subtrochanteric femoral fractures. These typically occur either spontaneously or following low-impact trauma. They are located in the proximal or mid-femoral diaphysis, and they are seen in patients who are on long term treatment with bisphosphonates. They should be suspected in patients who report vague femoral pain or weakness. Recent reports, however, refute the association with bisphosphonate use. Rather they propose that subtrochanteric femoral fractures are an uncommon type of osteoporotic fracture or a manifestation of rare metabolic bone disorders, such as adult hypophosphatasia. Imaging helps diagnose this condition and referral to a metabolic bone disease specialist may be useful.[8]

Evaluation

Laboratory studies provide further information when diagnosing complications of bisphosphonate use. For instance, a low hemoglobin can be seen with erosive esophagitis. Calcium and vitamin D levels can help identify hypocalcemia, and a rising creatinine is a key feature in diagnosing nephrotoxicity. 

Plain X-rays can show atypical femoral fractures appearing transversely, sometimes obliquely, and with a "beaked" appearance on the cortex. Increased uptake in the affected area can be seen on the technetium (Tc)-99m bone scan. In cases with a negative X-ray and a high clinical suspicion, magnetic resonance imaging (MRI) can be useful. A low signal fracture line in T1, T2, and short TI inversion recovery (STIR) images can be seen, while the marrow signal appears low in T1 and high in T2 and STIR.

Treatment / Management

Management of Acute-phase Reactions

These systemic reactions are typically self-limiting. The mainstay of management is the supportive use of acetaminophen with or without nonsteroidal anti-inflammatory drugs (NSAIDs). Acute-phase reactions normally resolve within 48 hours. Premedication with acetaminophen is advised with recurrent doses. It is important to rule out other causes of fever, such as infection.[5] 

Management of Upper GI Adverse Effects

As mentioned earlier, the occurrence of these complications can be prevented by proper administration of the drug. The use of bisphosphonates, however, should be avoided in patients who have chronic esophageal conditions, such as Barret's esophagus. 

Management of Hypocalcemia

Managing hypocalcemia in the context of bisphosphonate use involves identifying leading causes such as previous radiotherapy to the head and neck, prior thyroidectomy, and hypomagnesemia.[5] If hypocalcemia is present, it should be corrected and then monitored during therapy.[5] Correction of pre-existing hypocalcemia and/or vitamin-D deficiency is strongly recommended before initiating bisphosphonates.

Management of Ocular Complications

Ocular complications are rare and usually not vision-threatening. However, a referral to an ophthalmologist is recommended for the management of ocular complications.[5]

Management of Osteonecrosis of the Jaw

Prevention and early identification of high-risk patients are key strategies in the management of ONJ.[20] A dental check-up and treatment, if necessary, are essential before starting bisphosphonates in high-risk patients. Patients should also be made aware of the risk of developing this condition and the benefit of ongoing prophylactic dental care.[20][21] A drug holiday has also been suggested as a prophylactic measure to reduce the risk of developing ONJ. It is defined as a temporary cessation of the drug before a planned dentoalveolar procedure.[22]

Once ONJ occurs, management becomes challenging.[20] Depending on how advanced the condition is, treatment ranges from conservative care to surgical debridement and resection of the involved tissues. Conservative care consists mainly of regular dentist visits, the use of chlorhexidine mouthwash, and antibiotic treatment for infections.[20] The surgical approach is confined to cases for whom the conservative approach has failed, or there is bone exposure.[23] Adjunctive modalities have been trialed, such as oxygen therapy and the use of mesenchymal cells to recreate bone tissue.[20]

Management of Subtrochanteric Femoral Fractures

Upon confirmation of the fracture, bisphosphonates should be discontinued, and calcium and vitamin D supplementation considered. Orthopedic referral shall be sought depending on the imaging findings.

Differential Diagnosis

It is important to be mindful of other conditions that have a similar radiographic appearance as osteonecrosis of the jaw, such as radiation-induced osteonecrosis and infections.[24] Differential diagnoses for atypical femoral fractures include trauma, osteoarthritis, and inflammatory arthritis.

Prognosis

Prognosis varies depending on the complications seen. While flu-like symptoms are benign and self-limiting, erosive esophagitis, osteonecrosis of the jaw, and nephrotoxicity are serious complications and can cause significant morbidity and mortality.

Complications

Nephrotoxicity

Particular caution should be considered while giving bisphosphonates to patients with pre-existing renal impairment.[25] The risk of renal toxicity is increased in cancer patients who are receiving chemotherapy.[5][25] Bisphosphonates usually affect the kidneys by causing acute tubular necrosis. Biochemically this can be detected by a gradual rise in creatinine levels over several months. Discontinuation of the drug usually results in normalization of the kidney function within months.[26]

Amongst the available bisphosphonates, zoledronic acid carries the highest risk of causing renal failure.[11] The risk becomes even greater with higher doses and longer infusion time.[27] Zoledronic acid affects the kidneys by altering key metabolic pathways in the renal tubular cells. Microscopically, the damage is similar to that seen in acute tubular necrosis.[11][28] Recovery from zoledronic acid kidney damage is possible but slow.[28]

Nephrotoxicity from pamidronate, however, presents clinically as nephrotic syndrome.[11] Microscopically, the findings vary between focal segmental glomerulosclerosis, acute tubular injury, and minimal change disease without involving the glomeruli.[29] These changes are usually non-reversible,[11] and are typically seen in patients receiving the maximum recommended dose (90 mg).[30] Pamidronate-related nephrotic syndrome, especially if associated with renal failure, carries a poor prognosis.[11] Only one-fifth of the patients will recover their renal function, and about 50% will eventually require renal replacement therapy.[11] Therefore, early detection and early discontinuation of pamidronate is the most important step in management.[11]

Prevention and early detection of renal failure are key in the management of bisphosphonate-related nephrotoxicity. Preventative measures include pre-infusion serum creatinine checks, adequate hydration, avoidance of simultaneous use of nephrotoxic medications, and dose adjustments in patients with mild renal insufficiency.[5][31] Generally, zoledronic acid and pamidronate are not recommended if creatinine clearance is less than 30 mL/min, or if serum creatinine doubles from baseline.[5][11]

Once nephrotoxicity occurs, the first step in management is the discontinuation of the bisphosphonate. Management is mostly supportive, as no specific treatment has shown benefit.[11] Restarting the medication is possible if the benefit outweighs the risk but shall be considered on a case-by-case basis after a detailed discussion with the patient.[5]

Atrial Fibrillation

An association between atrial fibrillation (AF) and bisphosphonate use has been proposed. Large clinical trials, such as the Fracture Intervention Trial and the HORIZON Pivotal Fracture Trial, have reported an increased risk of developing AF (1.3% risk in the zoledronic group versus 0.5% in the placebo group). This was followed, however, by several observational studies that found no association. In conclusion, the retrospective trials investigating the link found the evidence to be neither positive nor completely ruled out. It should be noted that bisphosphonates are usually given to elderly patients with pre-existing comorbidities, including AF. Further trials could clarify this association.[32]

Deterrence and Patient Education

Before starting a bisphosphonate, a discussion of the possible adverse effects and toxicities needs to be held with patients. Risk assessment is key in managing patients who are candidates for bisphosphonates. A discussion within and amongst the healthcare and dental professional teams will further help to select appropriate patients in whom the benefits of bisphosphonates outweigh the associated risks.[8]

Enhancing Healthcare Team Outcomes

Bisphosphonate use is becoming a cornerstone in the management of metastatic bone disease and osteoporosis. As with any medication, bisphosphonate use can cause toxicity. Clinicians need to be mindful of these toxic side effects. Regular check-ups and routine physical examinations, as well as frequent blood tests, are key in the ongoing management of patients receiving bisphosphonates. This is best achieved with an interprofessional team approach. Prompt recognition of toxicities is important in improving outcomes. Providing education to patients and families before and during treatment with bisphosphonates can also improve patient outcomes by early detection of toxicities. Interprofessional team input is essential in managing toxicities once they occur. [Level 5]