How is the effectiveness of bisphosphonate therapy monitored in patients with Paget's disease?

1.

Ralston, Stuart H. (2024). In Goldman-Cecil Medicine (pp. 1665). DOI: 10.1016/B978-0-323-93038-3.00228-8

Bisphosphonates can cause kidney injury and are contraindicated in patients with significant renal impairment.Other Drug TreatmentsAnalgesics, nonsteroidal anti-inflammatory drugs (seeTable 26-4), and antineuropathic agents (e.g., amitriptyline 10 to 25mg at bedtime or gabapentin 300mg three times daily; seeTable 26-5) may be required in patients with Paget disease, particularly when osteoarthritis or a nerve compression syndrome coexists. Calcitonin, 50 to 100 IU subcutaneously three times a week for up to 3 months can improve bone pain due to metabolic activity in Paget disease but is seldom used except in patients for whom bisphosphonates are contraindicated; adverse effects such as nausea and flushing can be problematic, and resistance may develop owing to the formation of neutralizing antibodies.Nonpharmacologic TreatmentsNonpharmacologic approaches (e.g., acupuncture, physiotherapy, hydrotherapy, and transcutaneous electrical nerve stimulation) are often used to control pain, but their effectiveness has not been documented in controlled trials. Clinical experience suggests that specific problems such as limb shortening and deformity can be helped by aids and devices such as walking sticks and shoe raises.Monitoring Disease Activity and the Effects of TreatmentMetabolic activity and the response to treatment are typically assessed by measuring the alkaline phosphatase level, but levels can be normal in patients with localized disease that is metabolically active. Further courses of treatment should be considered in patients who have recurrent or persistent pain and in whom alkaline phosphatase levels remain or become elevated.SurgeryOrthopedic surgery may be required for the management of coexisting osteoarthritis, pseudofractures, fractures, bone deformity, and spinal stenosis. Osteotomy is performed infrequently, but small case series have reported good results.

The most common indication for medical treatment of Paget disease is bone pain localized to an affected site.Bone pain may be caused by increased metabolic activity, but other causes may be operative, such as nerve compression syndromes, pseudofractures, secondary osteoarthritis, and other musculoskeletal conditions. Careful assessment of the patient is therefore necessary to decide on the most appropriate treatment. Bone pain caused by increased metabolic activity is localized to the affected site and is usually accompanied by a raised alkaline phosphatase level. It is common to encounter patients in whom pain occurs in the presence of coexisting osteoarthritis, bone deformity, or other musculoskeletal conditions. In such cases, it can be difficult to be sure about the origin of the pain, and many clinicians give a therapeutic trial of bisphosphonates to aid diagnosis. If the pain responds, it is assumed to be due to increased metabolic activity; if it does not, further evaluation should be undertaken to identify the cause and treat the patient appropriately. Pseudofractures, which are areas of focal osteolysis that traverse the lateral cortex of weight-bearing bones of the lower limbs, represent a distinct management problem. Some remain stable for prolonged periods without causing symptoms; others regress spontaneously; and others progress to pathologic fracture, often in association with a localized increase in pain at the affected site.BisphosphonatesBisphosphonates are the drugs of first choice for the treatment of pain that is thought to be due to increased metabolic activity, and strong evidence indicates that they are more effective than placebo at improving bone pain in Paget disease (Table 228-1).Data comparing different bisphosphonates are limited, but intravenous zoledronic acid has been found to be superior to pamidronate and risedronate for lowering alkaline phosphatase leveland for relieving pain.Repeated courses of bisphosphonates with the aim of normalizing alkaline phosphatase (intensive treatment) is no better in terms of pain, quality of life, or complications compared with therapy primarily aimed at controlling symptoms (symptomatic therapy).

2.

Food and Drug Administration (DailyMed).

Publish date: February 2, 2021.

Clinical Pharmacology Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure. Clinical manifestations of Paget’s disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy. Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate, the free acid 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate sodium induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate. 12.3 Pharmacokinetics Absorption Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast. Alendronate, the free acid 70 mg oral solution and alendronate, the free acid 70 mg tablet are equally bioavailable. A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast. Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast.

3.

Food and Drug Administration (DailyMed).

Publish date: April 2, 2024.

Pharmacodynamics Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy. FOSAMAX (alendronate sodium) decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, FOSAMAX (alendronate sodium) 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, FOSAMAX (alendronate sodium) induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.

Clinical Pharmacology Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy. FOSAMAX (alendronate sodium) decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, FOSAMAX (alendronate sodium) 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, FOSAMAX (alendronate sodium) induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate. 12.3 Pharmacokinetics Absorption Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.