Biphosphonate trial

Subsequent analyses of data from the Fracture Intervention Trial 19 suggested alendronate use may be associated with a slightly increased risk of atrial fibrillation, but this finding was not confirmed in other large studies of alendronate 20 or risedronate.

Key point: No clear association between atrial fibrillation and bisphosphonate use has been established. Patients receiving bisphosphonate therapy are primarily older and represent the population most likely to have atrial fibrillation independent of bisphosphonate use. Patients who are currently receiving bisphosphonate therapy are advised to continue their medication as prescribed. In , Odvina et al 22 reported on 9 patients who sustained atypical fractures, including some with delayed healing, while receiving alendronate therapy.

These authors raised the concern that long-term bisphosphonate therapy might lead to oversuppression of bone remodeling, an impaired ability to repair skeletal microfractures, and increased skeletal fragility. However, case reports such as these are hard to generalize to patient care because these patients were exposed to varying doses of bisphosphonates, could have been taking other medications that affect bone eg, glucocorticoids , or may have had another undiagnosed abnormality of bone before beginning bisphosphonate therapy.

Two studies of long-term alendronate use failed to show an increased risk of fracture or abnormalities of bone remodeling after 10 years of therapy. Key point: If an adverse effect of bisphosphonate therapy in bone eg, difficult-to-explain fractures, especially if multiple; unexpected radiographic findings; impaired bone healing is suspected, clinicians should consider the limitations of short-term clinical trials and subsequent extensions to capture rare adverse events.

Such patients may benefit from referral to a metabolic bone specialist for further evaluation. Such an evaluation may include a labeled bone biopsy for histomorphometric analysis. As with other possible adverse effects, the association of subtrochanteric femoral fractures with bisphosphonate therapy was not identified in clinical trials.

Although these bisphosphonate-associated fractures are uncommon, several case reports have described some of their typical clinical features. Recently, the association between such fractures and bisphosphonates has been questioned, and these fractures were suggested to be merely an uncommon subtype of osteoporotic femur fracture 27 or a manifestation of a rare metabolic bone disease adult hypophosphatasia with coincident bisphosphonate exposure.

Key point: Patients who are receiving bisphosphonate therapy and who have a subtrochanteric femoral fracture should be referred to a metabolic bone disease specialist. Radiographic examination of the femur should be considered in patients who are receiving bisphosphonate therapy and who report symptoms of pain that may be originating from the femur.

Ensuring adequate calcium and vitamin D intake both before and after initiation of bisphosphonate therapy is an extremely important but frequently overlooked aspect of providing optimal care of skeletal health. Vitamin D insufficiency is widely acknowledged to be prevalent in nearly all patient populations prescribed bisphosphonate therapy, particularly in the elderly, who are more likely to have limited sun exposure, reduced dietary intake, and renal impairment.

Vitamin D levels below the optimal range limit dietary absorption of calcium, lead to secondary hyperparathyroidism with loss of skeletal calcium to maintain normocalcemia, contribute to falling risk in the elderly, 29 and blunt the bone mineral density BMD response and antifracture efficacy of bisphosphonates. This recommendation likely applies to all adults as a minimum intake required for optimal bone health.

Key point: Bisphosphonates are most effective at limiting fracture risk when taken in conjunction with adequate calcium and vitamin D. All patients for whom bisphosphonates are considered should be counseled on this important requirement before and during bisphosphonate therapy.

There is general agreement that, in patients with osteoporosis as defined by the World Health Organization criterion of a BMD T-score of Less clear, however, is the optimal management of patients with low bone mass or osteopenia , defined by a T-score between -1 and Because BMD is only 1 risk factor for fracture, it cannot adequately capture the heterogeneity in fracture risk that exists across patient populations. To address this discrepancy, the World Health Organization developed an algorithm FRAX that allows calculation of absolute year probabilities of sustaining any major osteoporotic fracture defined as clinical vertebral, hip, forearm, or humeral.

Importantly, the FRAX algorithm is intended only for postmenopausal women and men 50 years and older. In addition, it applies only to patients who have not previously received pharmacological treatment.

When combined with an estimate of the relative risk reduction that therapeutic intervention can provide, the degree to which an individual's risk of fracture would be altered with pharmacological intervention can be assessed.

The algorithm is freely available and allows physicians and patients to make more informed decisions on the basis of potential risk of fracture without treatment vs the benefits and potential adverse effects of different therapeutic agents, including bisphosphonates. It is easy to use and can facilitate dialogue between physicians and patients and help inform shared treatment decisions.

The Fracture Intervention Trial Long-term Extension FLEX , in which postmenopausal women who had received alendronate therapy for 5 years were randomized to continue receiving alendronate for 5 additional years or switched to placebo, provided clinical evidence that the effect of bisphosphonate therapy was maintained after discontinuation of therapy. Although the length of skeletal retention differs depending on the agent, such differences are of uncertain clinical importance for guiding duration of therapy.

Drug holidays are becoming common practice for some patients, particularly those at relatively low risk of fracture. Although limited data are available to guide practice, monitoring for offset of effect and consideration for reinitiation of treatment are generally recommended. Patients in whom bisphosphonate therapy is discontinued are typically followed up with BMD measurements at 1- to 2-year intervals, with some experts advocating periodic measurement of biochemical markers of bone turnover eg, serum CTX to detect loss of the antiresorptive effect.

These unanswered questions may also be relevant to IV bisphosphonate use; a recent study noted that the antiresorptive effects of zoledronic acid last more than 12 months, raising the question that zoledronate could be administered less frequently than annually. Key point: The optimal dose and duration of bisphosphonate administration for osteoporosis are unclear once treatment extends beyond the duration of placebo-controlled trials.

The clinical scenarios in which bisphosphonates are used are heterogeneous. Furthermore, patient factors, including revised goals for care, may well change over an extended period of follow-up. Once treatment has extended beyond the duration of placebo-controlled trials, patients will be suboptimally treated by a strictly uniform approach. Bisphosphonates have transformed the clinical care of an array of skeletal disorders characterized by excessive osteoclast-mediated bone resorption.

Their widest clinical effect is shown in our current approach to the management of osteoporosis, in which bisphosphonates are considered first-line pharmacological therapy for most patients.

Bisphosphonate therapy can be associated with mild adverse effects in some patients and, more rarely, with serious adverse effects. A discussion of these potential adverse effects with patients and other health and dental care professionals should begin with discussion of fracture risk that is the primary basis for their use. The informed and judicious use of bisphosphonates confers a clear clinical benefit in most carefully selected patients that outweighs potential risks associated with bisphosphonate use.

On completion of this article, you should be able to: 1 recognize and, when possible, identify patients at risk of adverse effects of bisphosphonate therapy, 2 counsel patients about the risk of bisphosphonates relative to the risk of osteoporotic fracture as estimated by the World Health Organization fracture risk assessment tool, and 3 critique the optimal dose and duration of bisphosphonate therapy for osteoporosis.

Which one of the following symptoms or physical signs is least likely to be related to the recent administration of an oral or intravenous IV bisphosphonate for the treatment of osteoporosis in an otherwise healthy patient? A year-old recently menopausal and otherwise healthy woman is found to have osteopenia on the basis of bone mineral density BMD screening by dual energy x-ray absorptiometry.

On follow-up testing 2 years later, her BMD has substantially decreased despite optimization of lifestyle, including adequate calcium and vitamin D intake. She chooses to begin taking alendronate therapy for the prevention of osteoporosis and continues to receive this therapy with stable BMD and no fractures during the next 5 years.

Which one of the following considerations regarding long-term bisphosphonate therapy is true in this patient? Imaging should include femur radiography to assess for femoral cortex changes that may precede a subtrochanteric hip fracture. A fracture while receiving bisphosphonate therapy should raise suspicion for excessive suppression of bone remodeling. Duration of bisphosphonate therapy is dictated by clinical guidelines on the basis of clinical trials.

Which one of the following statements regarding the World Health Organization fracture risk assessment FRAX tool for estimating absolute fracture risk is true when considering the risks and benefits of bisphosphonate therapy? The calculator estimates the risk reduction afforded by specific bisphosphonate treatment regimens.

An estimate of absolute fracture risk by the FRAX tool can inform a discussion of risks and benefits of bisphosphonate therapy. The FRAX tool is required to identify patients at high risk of fracture who are most likely to benefit from bisphosphonate therapy.

The lumbar spine is the preferred BMD measurement site to enter in the FRAX risk calculator tool, given these fractures are consistently prevented by bisphosphonate therapy. Which one of the following statements regarding the role of calcium and vitamin D intake in the bisphosphonate-treated patient is true? Bisphosphonates reduce the requirement for nutritional calcium by decreasing bone remodeling.

Adequate vitamin D nutrition is needed only to reduce risk of fractures associated with falling. Acute suppression of bone remodeling with bisphosphonates may result in hypocalcemia in patients with suboptimal calcium and vitamin D intake. Increasing doses and potency of bisphosphonates has minimized the role of calcium and vitamin D intake in achieving optimal response to bisphosphonate therapy.

Which one of the following statements regarding clinically important features of bisphosphonate action is true? Bisphosphonates have limited bioavailability when given intravenously because of rapid clearance by the kidney. After incorporation into bone, bisphosphonates remain biologically active in vivo for years after discontinuation.

Drug Information available for: Alendronic acid Anastrozole Alendronate sodium. FDA Resources. Arms and Interventions. Other Names: Fosamax Alendro Adronat. Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. Overall, the 5-year risk of fractures was 5.

Information about the occurrence of bone fractures was available for only 71 percent of the women included in the analysis 13, participants. Additional studies are needed to help researchers determine whether different bisphosphonate regimens have different effects. Reporting their initial results in abstract form, trial investigators said they found no differences in efficacy by type of bisphosphonate but there were differences in toxicities.

More research is also needed to help clarify the relationship between menopausal status and the response to bisphosphonates. Jo Anne Zujewski, M.

Zujewski commented. Physicians should consider the new results when making treatment decisions and in their discussions with patients about the risks and benefits of using bisphosphonates, she added. Menu Contact Dictionary Search. Understanding Cancer. What Is Cancer? Cancer Statistics. Cancer Disparities. Cancer Causes and Prevention. Risk Factors. Cancer Prevention Overview.

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