Optimising bisphosphonate treatment outcomes in postmenopausal osteoporosis: review and Italian experience

This review aims to investigate ways to optimise treatment outcomes with bisphosphonate therapy of osteoporosis in general, and in Italian clinical practice specifically. Overall, poor adherence to bisphosphonate therapy is a major limiting factor in the treatment of osteoporosis, and is associated to a large extent with gastrointestinal adverse events. An improved patient-doctor relationship and patient motivation are critical factors to improving adherence. However, other medical interventions also play a significant role. Intermittent dosing regimens decrease gastrointestinal adverse events and improve adherence, and demonstrate at least equivalent efficacy to daily regimens. Intravenous formulations also improve gastrointestinal tolerability, and are recommended in Italy for patients at high risk of this adverse event. Other recommendations in Italy to improve treatment outcomes include a case-finding approach to identify patients most suitable for bisphosphonate therapy, thus reducing the numbers needed to treat to avoid fractures. To facilitate this, a comprehensive assessment is advocated which incorporates bone mineral density, previous fractures, parental history of fractures, corticosteroid use and the presence of other diseases associated with secondary osteoporosis.     

Latest insights into the hot question of proton pump inhibitor safety – a narrative review

Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide and their use is continuously increasing. Although they have been shown to combine high therapeutic efficacy and good safety profile in many studies, in last years we have witnessed the publication of many articles reporting the possible association of long-term PPI therapy with important unexpected adverse events and these observations have created alarmism in both patients and physicians. However, the majority of these studies are observational, retrospective and prone to residual confounding. Also, the odds ratio values are generally comprised between 1 and 2 and therefore devoid of strong clinical relevance.As it is unlikely that prospective randomized trials will be ever done to reinforce these associations, we can only attempt to distinguish clear- from unclear-defined adverse events from the available literature. Nowadays we can reasonably exclude cardiovascular diseases, community-acquired pneumonia, all-cause mortality, dementia and bone fractures from PPI-related adverse events. However, physicians should be aware of the existence of possible risks when treating their patients, especially the elderly and frail ones, with long-term PPIs, which should be prescribed only to persons with defined indications and at lowest dose and duration.     

Safety and tolerability of oral daily and intermittent ibandronate are not influenced by age

OBJECTIVE: The risk of osteoporosis increases exponentially with age. Elderly patients, who are often frail, have declining functional status and take multiple medications, and require osteoporosis therapies that are not only effective, but also very well tolerated. Ibandronate is a potent nitrogen-containing bisphosphonate that can be given intermittently with extended between-dose intervals. Oral daily and intermittent ibandronate (interval between doses > 2 mo) was found to significantly reduce the risk of new morphometric vertebral fractures by 62% and 50%, respectively, compared with calcium and vitamin D supplementation alone. We investigated the effect of age on the safety profile of oral daily and intermittent ibandronate, with particular emphasis on the upper gastrointestinal (GI) safety profile of ibandronate. METHODS: A predefined subgroup analysis examined the tolerability of oral ibandronate in women aged < 70 and > or = 70 years. RESULTS: The incidence of adverse events in patients aged > or = 70 years receiving oral daily and intermittent ibandronate was similar and comparable to placebo. The incidence of upper GI adverse events, including dyspepsia and esophagitis, was also similar between the 2 treatment groups and placebo. CONCLUSION: Older patients (> or = 70 yrs) receiving oral daily and intermittent ibandronate are at no greater risk of adverse events than older patients receiving placebo. Older patients were at no greater risk of upper GI adverse events than younger patients or patients receiving placebo. As a result of the good efficacy and tolerability observed in this trial, a once-monthly oral regimen of ibandronate is in late-stage clinical development.     

Unusual mid‐shaft fractures during long‐term bisphosphonate therapy

Background Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although existing evidence supports a good safety profile, there is concern that chronic administration of these agents could result in severe suppression of bone turnover with increased risk of nonvertebral fractures. Objective The objective of this study was to report the clinical presentation, selected bone histomorphometry and X‐ray images of patients who developed mid‐shaft long bone fractures during bisphosphonate therapy, six of whom had bone biopsy for histomorphometery. Results Of the 13 patients who sustained atraumatic mid‐shaft fractures, 10 were on alendronate and three were on risedronate therapy before the fractures. In addition to bisphosphonates, three patients were on oestrogen and two on tamoxifen concomitantly. Four patients with glucocorticoid‐induced osteoporosis were on alendronate for 3–11 years along with glucocorticoid therapy. Bone histomorphometry showed severe suppression of bone turnover in five patients and low bone turnover in one patient. Conclusion Long‐term bisphosphonate therapy may increase the risk of unusual long bone mid‐shaft fractures. This is probably due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy remains unknown, but appears to be small.     

Risedronate

Risedronate has recently been approved as a drug for osteoporosis treatment in Japan. According to its chemical structure, risedronate is designated a third generation bisphosphonate, which has potent anti-resorptive activity. Clinical studies conducted in Japan, North America and/or Europe revealed that risedronate reduces the risks of hip fractures and vertebral fractures by around 30% and around 50% compared with placebo over three years, respectively, and increases lumber spine BMD by around 5% at one year after starting treatment. In addition, risedronate produces a rapid and clinically important reduction in the risk of vertebral fracture and bone formed during risedronate treatment was histologically normal. Bone turnover markers, e.g., deoxypyridinoline, NTx, are reduced by around 40% (maximum). Although some bisphosphonates have been associated with upper gastrointestinal (GI) tract adverse events, a pooled analysis of 9 placebo-controlled clinical trials conducted outside Japan revealed no evidence that risedronate was associated with an increased frequency of adverse effects in the GI tract when compared with placebo.     

Spontaneous non-traumatic stress fractures in bilateral femoral shafts in a patient treated with bisphosphonates

Bisphosphonates are potent inhibitors of bone resorption and widely used to treat osteoporosis. Extensive studies have shown that therapy with bisphosphonates improves bone density and decreases fracture risk. However, concerns have been raised about potential over-suppression of bone turnover during long-term use of bisphosphonates, resulting in increased susceptibility to and delayed healing of non-spinal fractures. We report a patient who sustained non-traumatic stress fractures in bilateral femoral shafts with delayed healing after long-term bisphosphonate therapy. She underwent open reduction and surgical internal fixation. Although bisphosphonates effectively prevent vertebral fractures, and their safety has been tested in randomized trials, we must emphasize the need for awareness of the possibility that long-term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage and adverse skeletal effects such as delayed fracture healing.     

Bisphosphonates: new indications and methods of administration

In the course of 2002, several new studies were published confirming the efficacy of bisphosphonate drugs in fracture prevention in patients with osteoporosis. Further evidence was provided of their long duration of action, making intermittent administration possible. The potent bisphosphonate zoledronate can be given at intervals of as long as 1 year and produces changes in bone density and in markers of bone turnover comparable with those seen with conventional daily oral dosing with alendronate or risedronate. If such regimens are proven to prevent fractures, their convenience is likely to result in their widespread adoption and potentially an increase in compliance with these medications. Further evidence has been presented documenting the value of bisphosphonates in preventing the skeletal complications of malignancy, and possibly in reducing mortality in patients with breast cancer. The role of bisphosphonates in osteogenesis imperfecta was further confirmed, and novel roles in ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy were suggested.     

Evaluating the safety and tolerability profile of acute treatments for migraine

Among the medications that have been used as acute treatments for migraine are nonspecific agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (either single or combination), and narcotics, as well as migraine-specific medications, including ergot alkaloids and triptans (5-hydroxytryptamine 1B/1D agonists). All of these drugs have side effects that vary in type and severity. Side effects of nonspecific medications, including gastrointestinal (GI) and renal effects with NSAIDs and cognitive effects and the potential for abuse with narcotics and butalbital-containing medications, have been documented over time, as these medications have been used for various indications. Side effects of the migraine-specific medications include GI and vascular symptoms with the ergots; for the triptans, they include chest and neurologic symptoms. Although adverse events are reported fairly frequently in patients receiving triptans, they are usually mild, and few patients discontinue therapy because of them. The most serious adverse events are cardiovascular. Because of potential vasoconstrictor effects--mild and transient increases in blood pressure and mild and transient effects on coronary artery tone--triptans as a class are contraindicated in patients with established or clinically suspected cardiovascular disease, specifically ischemic heart disease and uncontrolled hypertension. Other adverse events, including the potential for drug-drug interactions, are less common. Therefore, consideration should be given to the tolerability and safety of medications before their use as abortive medications for the treatment of migraine headache.     

Gastrointestinal Adverse Effects of Bisphosphonates

The bisphosphonate class of drugs are now utilized extensively in the treatment of patients with osteoporosis and Paget's disease. Gastrointestinal (GI) adverse effects, especially those associated with esophageal injury, have been of increasing concern to clinicians. Studies in humans and animals have shown that the mucosal erosion and ulceration seen with bisphosphonates is a result of direct contact with these agents. Numerous endoscopic studies in healthy volunteers and postmenopausal women have also demonstrated the potential of bisphosphonates to cause stomach and duodenal ulcers. However, serious GI adverse events have not been noted in several large efficacy trials. Esophageal injury has for the most part been avoided by appropriate administration instructions, and gastroduodenal injury appears to be an acute phenomenon not associated with significant complications, except in certain high-risk situations, for example in the presence of existing distal esophageal disease or motility disorders, or with concurrent use of nonsteroidal anti-inflammatory drugs or anticoagulants. From the standpoint of GI safety, the bisphosphonates are well tolerated and not associated with serious adverse events.     

Role of bisphosphonates and calcitonin in the prevention and treatment of osteoporosis

Bisphosphonates have been shown to increase bone mineral density in patients with established osteoporosis as well as those with osteopenia. The evidence conclusively shows a reduction in fracture rates in patients on the more potent nitrogen containing bisphosphonates. Indeed, significant vertebral fracture rate reduction has been demonstrated after only 1 year of therapy. Alendronate, a second-generation bisphosphonate, and risedronate, a third-generation bisphosphonate, are first line medications for the treatment of osteoporosis given their efficacy in preventing both vertebral and non-vertebral fractures. There is evidence that vertebral fractures may be prevented by intermittent cyclic therapy with etidronate. All three have been shown to increase bone mineral density in the spine, with alendronate and risedronate producing significant increases in hip bone density. Calcitonin has demonstrated the ability to reduce vertebral fracture rates with minimal changes in bone density. Calcitonin is also beneficial in reducing the bone pain associated with fractures.     

Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates

Corticosteroids are widely used as anti-inflammatory and immunosuppressive agents to treat a variety of chronic conditions. Long-term (>1 year) corticosteroid use can lead to bone loss, and therefore, osteopenia or osteoporosis. Corticosteroid-induced osteoporosis (CIO) leads to increased bone fragility and subsequently fractures, which, in turn, lead to a loss of physical, emotional and social health for the patient and increased costs for healthcare providers. A wealth of data exists demonstrating the efficacy of the oral bisphosphonates, etidronate, alendronate and risedronate in increasing bone mineral density in patients with CIO or preventing bone loss in patients commencing corticosteroid therapy. Data regarding fracture prevention are less clear, as statistically significant reductions in the incidence of fractures have only been reported for patient subgroups or meta-analyses. However, many treatment guidelines recommend the use of oral bisphosphonates for the prevention and treatment of CIO. These guidelines are, however, not reflected in prescribing practice, and the majority of patients do not receive adequate concomitant therapy. This review summarizes the available data for bisphosphonates in CIO. Therapeutic adherence with oral bisphosphonates is an issue, with approximately 50% of patients discontinuing therapy within the first year. The primary reasons for this are poor gastrointestinal tolerability and the frequency with which complex dosing requirements must be followed. The inconvenience of taking daily or weekly bisphosphonate therapy is of particular importance in patients with CIO who may be regularly taking several other medications. Data obtained in studies with ibandronate indicate that bisphosphonate administration by rapid intravenous injection provides an effective, well-tolerated and practical alternative to current oral regimens in the management of patients with CIO.     

Medication use quality and safety in older adults: 2020 update

Improving the quality of medication use and medication safety are important priorities for prescribers who care for older adults. The objective of this article was to identify four exemplary articles with this focus in 2020. We selected high-quality studies that moved the field of research forward and were not merely replication studies. The chosen articles cover domains related to deprescribing, medication safety, and optimizing medication use. The first study, a noninferiority randomized clinical trial in England, evaluated whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events over the 12-week follow-up (domain: deprescribing). The second study, a prospective cohort study of women at Kaiser Permanente Southern, California, examined the association between bisphosphonate use and atypical femur fracture (domain: medication safety). The third study examined the effectiveness and safety of a multifaceted antimicrobial stewardship and quality improvement initiative in reducing unnecessary antimicrobial use for unlikely cystitis cases in noncatheterized residents in 25 nursing homes across the United States (domain: optimizing medication use). Lastly, the fourth study, a population-based cohort study in the United Kingdom, examined the association of tramadol use with risk of hip fracture (domain: medication safety). Collectively, this review succinctly highlights pertinent topics related to promoting safe use of medications and promotes awareness of optimizing older adults' medication regimens.     

Relation of the use of lipid-lowering medications prior to percutaneous coronary intervention to the incidence of intraprocedural adverse angiographic events

The use of lipid-lowering medications at the time of percutaneouscoronary intervention (PCI) has been shown to have a favorable effect on rates of cardiac enzyme elevation and major adverse cardiac events (MACEs), but the effect of these medications on angiographically identifiable intraprocedural coronary events during PCI has not previously been investigated. A retrospective review of 81 patients was performed and demonstrated that the use of lipid-lowering medications at the time of PCI was associated with a reduced incidence of angiographically identifiable intraprocedural events (odds ratio 0.13, 95% confidence interval 0.04 to 0.40). A multivariate analysis revealed that lipid-lowering medications and hyperlipidemia did not predict MACEs independent of the occurrence of these angiographic events.     

A double-blind placebo-controlled study of the effects of the bisphosphonate risedronate on bone mass in patients with inflammatory bowel disease

BACKGROUND: Low bone density and fractures are common in patients with inflammatory bowel disease (IBD). OBJECTIVE: To determine whether the bisphosphonate risedronate and calcium are safe and effective in preserving bone mass compared to calcium alone in IBD patients with low bone mass. PATIENTS: Sixty-one ambulatory patients with Crohn's disease (n = 31) or ulcerative colitis (n = 30) and low bone density. METHODS: Using a double-blind placebo-controlled trial format, patients were randomized to 12 months of therapy with risedronate 5 mg or placebo. All received a 600 mg calcium supplement. Bone density using dual energy X-ray absorptiometry was performed at baseline and at 12 months. Disease activity, use of corticosteroid, and adverse events were noted. RESULTS: Forty-eight patients completed the trial. Compared to the placebo group risedronate resulted in a 2.0% (95%CI, 0.02-3.97) and 1.9% (95%CI, 0.21-3.62) improvement in bone density at the spine and hip, respectively. IBD diagnosis, gender, therapy, and disease status had no effect on the results. There were no significant differences in the adverse events. CONCLUSIONS: Risedronate improved bone density at the spine and hip in patients with either Crohn's disease or ulcerative colitis and low bone mass. These data suggest that risedronate is a safe and effective therapy to improve bone mass in these patients.     

The risks of PPI therapy

PPIs have become one of the most commonly used medications worldwide, as they are the treatment of choice for several acid-related gastrointestinal disorders. However, concerns have been raised about PPI therapy, including the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events. Observational studies have shown very modest associations between PPI therapy and these risks, although the association between PPI treatment and the risk of enteric infections seems to be stronger than the association with other risk factors. However, given the inherent limitations of observational studies, these associations could be attributable to bias and/or confounding factors. In addition, evidence from randomized, controlled trials does not support a clinically significant effect of PPI therapy on the risk of cardiovascular events in patients taking clopidogrel or the risk of pneumonia. Nevertheless, it is impossible to exclude the possibility that some of these associations might be causal or indeed that PPI therapy has an as yet unknown long-term adverse effect. As with any therapy, therefore, it is advisable to prescribe PPIs only to patients for whom these drugs have been proven beneficial.     

Safety of placebo controls in pediatric hypertension trials

Many clinical trials, including those in pediatric populations, use a placebo arm for medical conditions for which there are readily available therapeutic interventions. Several short-term efficacy trials of antihypertensive medications performed in response to Food and Drug Administration-issued written requests have used a placebo arm; whether the use of a placebo arm is safe in children with hypertension is unknown. We sought to define the rates of adverse events in 10 short-term antihypertensive trials to determine whether these trials resulted in increased risk to pediatric patients receiving placebo. We combined patient-level data from 10 antihypertensive efficacy trials performed in pediatric patients that were submitted to the Food and Drug Administration from 1998 to 2005. We determined the number and type of all of the adverse events reported during the placebo-controlled portion of the clinical trials and compared these numbers between the patients who received placebo and those who received active drug. Among the 1707 children in the 10 studies, we observed no differences in the rates of adverse events reported between the patients who received placebo and those who received active drug. Only 5 patients suffered a serious adverse event during the trials; none were thought by the investigators to be related to study drug, and only 1 occurred in a patient receiving placebo. Short-term exposure to placebo in pediatric trials of antihypertensive medications appears to be safe.     

The Treatment of Severe Postmenopausal Osteoporosis

Several chemical entities have shown their ability to reduce axial and/or appendicular fractures in patients with osteoporosis. Since patients who have experienced a previous fracture are at high risk for subsequent vertebral or hip fracture, it is of prime importance to treat such patients with medications that have unequivocally demonstrated their ability to reduce fracture rates in patients with prevalent fractures. Results obtained with calcium and vitamin D, in this particular population, are not fully satisfactory and these medications are probably better used in conjunction with other therapeutic regimens. Bisphosphonates have shown their ability to reduce vertebral (alendronate, risedronate, ibandronate) and non-vertebral (alendronate, risedronate) fractures in patients with established osteoporosis. Raloxifene has also shown similar properties, notwithstanding its effect on non-vertebral fractures, which has only been derived from a post hoc analysis limited to patients with prevalent severe vertebral fractures at baseline. This compound also has interesting non-skeletal benefits, including effects on the breast and heart. Teriparatide, a bone-forming agent, promptly reduces the rate of vertebral and all non-vertebral fractures, without significant adverse effects. Strontium ranelate, the first agent shown to concomitantly decrease bone resorption and stimulate bone formation, has also shown its ability to reduce rates of vertebral and non-vertebral fractures in patients with established osteoporosis. It significantly reduces hip fractures in elderly individuals at high risk for such events. Its safety profile is also excellent.     

Clinical aspects of estrogen and bone metabolism

Estrogen depletion by menopause decreases bone mineral density and the replacement of this hormone restores the bone loss. Although these are evident, there are not enough evidences for the prevention of osteoporotic fractures, particularly femoral neck fractures. Recent reports suggested that the concomitant use of progesterone is not beneficial but increases several adverse events.     

Criteria for high-risk medication use in Thai older patients

Many older patients have multiple diseases that require high-risk drug use, which may cause serious adverse effects. Criteria for the use of these drugs in older people are vital to the prevention of adverse events. This study aimed to develop explicit criteria for determining high-risk medication use in Thai older patients. It was conducted using a Delphi technique with the three-round survey of 16 geriatric medicine (GM) experts. A structured questionnaire with 56, 93, and 95 statements were devised for Rounds 1, 2, and 3, respectively. In each statement, the panelists were requested to confirm a high-risk drug in Round 1, and to rate on a 5-point Likert scale and classify the high-risk medication use in Rounds 2 and 3. The results showed that 77 practice statements (81.1%) that embraced the use of high-risk medications with potential adverse reactions, drug-disease interactions, and drug-drug interactions were agreed by the expert panel. A total of 23 statements (29.9%) were categorized as Groups 1-3 and the rest remained unclassified. Most high-risk medications were utilized in the central nervous system, musculoskeletal system, and cardiovascular system. Further studies are warranted to evaluate the criteria in terms of prescribing and monitoring medication use in older patients.