Effect of inappropriate and continuous therapy with alendronate for ten years on skeletal integrity - observations in two elderly patients

Alendronate is a potent aminobisphosphonate that has been used worldwide to decrease fracture risk in millions of post-menopausal women with and without osteoporosis, men with low bone mass, and in those with glucocorticoid- induced osteoporosis. A recent report of 9 patients with spontaneous atypical non-vertebral fractures during treatment with alendronate for up to 8 yr raised questions suggesting the possibility of severe suppression of bone turnover and resultant susceptibility to fracture. Our recent observations in 2 elderly women with inactive monostotic Paget's disease of bone who had been treated elsewhere continuously for this disease with alendronate for 10 yr at doses overall of 2 and 4 times the osteoporotic dose provided an opportunity to engage in the ongoing controversy over long-term safety of bisphosphonate therapy. Despite such therapy, skeletal integrity was maintained with normal bone densities and the absence of skeletal fractures. These observations do not support the suggestion of deleterious effects with longterm alendronate therapy.     

The use of bisphosphonates in the treatment of osteoporosis

PURPOSE OF REVIEW: The bisphosphonates alendronate and risedronate, given orally once weekly, are the cornerstone of treatment of postmenopausal osteoporosis, as well as of male and secondary osteoporosis. They reduce significantly the risk of vertebral and nonvertebral fractures; their effects appear early, within 6-12 months, and appear to be sustained. Several questions remain unanswered, however. In addition, data on a new bisphosphonate became available in 2004. RECENT FINDINGS: The optimal duration of treatment has not been clearly established. Long-term data with alendronate are now available, indicating a persistence of alendronate effects on bone mineral density and bone turnover markers several years after stopping treatment given for 5 years. Whether these effects translate into sustained reduction of fractures needs to be further analyzed. Because of their efficacy, bisphosphonate use has been explored in other forms of osteoporosis, such as after androgen deprivation therapy for prostatic cancer. The challenge of long-term compliance with treatment of osteoporosis has triggered the use of intermittent bisphosphonate. The effects of intermittent oral and intravenous ibandronate on bone mineral density, bone turnover, and fractures have been recently reported. SUMMARY: The mechanism by which bisphosphonates improve bone strength is not yet fully understood but probably involves complex effects on different components of bone strength, such as microarchitecture.     

Treating osteoporosis to prevent fractures: current concepts and future developments

Antiresorptive drugs, such as the bisphosphonates and the RANKL inhibitor denosumab, are currently the most widely used osteoporosis medications. These drugs increase bone mineral density (BMD) and reduce the risk of vertebral (by 40–70%), nonvertebral (by 25–40%) and hip fractures (by 40–53%) in postmenopausal women with osteoporosis. Due to the risk of rare side‐effects, the use of bisphosphonates has been limited to up to 10 years with oral bisphosphonates and 6 years with intravenous zoledronic acid. Despite their well‐proven efficacy and safety, few women at high risk of fracture are started on treatment. Case finding strategies, such as fracture risk‐based screening in primary care using the fracture risk assessment tool (FRAX) and Fracture Liaison Services, have proved effective in increasing treatment rates and reducing fracture rates. Recently, anabolic therapy with teriparatide was demonstrated to be superior to the bisphosphonate risedronate in preventing vertebral and clinical fractures in postmenopausal women with vertebral fracture. Treatment with the sclerostin antibody romosozumab increases BMD more profoundly and rapidly than alendronate and is also superior to alendronate in reducing the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis. For patients with severe osteoporosis and high fracture risk, bisphosphonates alone are unlikely to be able to provide long‐term protection against fracture and restore BMD. For those patients, sequential treatment, starting with a bone‐building drug (e.g. teriparatide), followed by an antiresorptive, will likely provide better long‐term fracture prevention and should be the golden standard of future osteoporosis treatment.     

Severely suppressed bone turnover: a potential complication of alendronate therapy

Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.     

Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures

Glucocorticoids are the most common cause of drug-related osteoporosis. We reviewed current evidence on risk factors for glucocorticoid-induced osteoporosis (GIOP) and prevention and treatment of GIOP-related fractures. Guidelines for GIOP management published since 2000 were also reviewed. Significant bone loss and increased fracture risk is seen with daily prednisone doses as low as 5 mg. Alternate-day glucocorticoid therapy can lead to similar bone loss. No conclusive evidence exists for a safe minimum dose or duration of glucocorticoid exposure. Physicians should consider risk factors for involutional osteoporosis such as older age, postmenopausal status, and baseline bone density measurements as they assess patients for prevention or treatment of GIOP. Bisphosphonates were reported to reduce GIOP-related vertebral fractures, but inconclusive data exist for hip fractures associated with glucocorticoid use. Hormone replacement therapy and parathyroid hormone analogs are effective in preserving bone density in GIOP. The risk of osteoporosis and fractures should be routinely assessed in patients receiving glucocorticoid therapy. Effective prevention and treatment options are available and can result in meaningful reduction of GIOP-related morbidity and mortality. Current guidelines for GIOP management recommend bisphosphonates, especially alendronate and risedronate, as first-line agents for GIOP, and these guidelines propose the preventive use of bisphosphonates early in the course of glucocorticoid therapy in high-risk patient subgroups.     

Aging bone and osteoporosis: strategies for preventing fractures in the elderly

As the older population increases, the incidence of osteoporotic fractures is expected to dramatically rise during the next few decades. Older patients are much more susceptible to fracture at any given bone mineral density (BMD) than are younger patients because of various factors, including the quality of aging bone, which involves more than BMD. Suppression of increased bone turnover by antiresorptive therapies, even with only small changes in BMD, can reduce fracture risk, especially in the lumbar spine. Bisphosphonate treatment can significantly reduce vertebral and nonvertebral fractures, including hip fractures, even in the very elderly. Prospective analyses show that risedronate therapy consistently and significantly reduces the risk of new morphometric vertebral fractures after 1 year in postmenopausal women. Post hoc analyses report significant reductions in the risk of 1 new clinical vertebral fracture after 6 months of risedronate therapy and after 1 year of alendronate therapy. Oral raloxifene therapy and salmon calcitonin nasal spray therapy have been shown to reduce the risk of vertebral fracture after 3 and 5 years, respectively, and post hoc data show a significant reduction in clinical vertebral fracture risk at 1 year with raloxifene use. However, neither raloxifene therapy nor calcitonin therapy reduce the risk of nonvertebral and hip fractures at currently approved doses. Bisphosphonates have been shown to be safe and efficacious with 7 years' risedronate sodium and 10 years' alendronate sodium data published, and bisphosphonates reduce bone turnover and increase BMD to a greater degree than raloxifene and calcitonin, which may partly account for their nonvertebral and hip fracture reduction effect. Therefore, bisphosphonate therapy with risedronate or alendronate should be considered in patients with low BMD at the hip and in older patients with osteoporosis and osteopenia, particularly those with an existing fracture.     

Bilateral atypical femoral diaphyseal fractures in a patient treated with alendronate sodium

Antiresorptive agents have been used as primary or first‐line therapy in managing patients with osteoporosis. Bisphosphonates in particular are used widely to reduce bone resorption, increase bone mineral density, improve bone quality and therefore reduce fracture risk. However, prolonged use of bisphosphonates may cause over‐suppression of bone resorption, leading on to accumulation of micro‐damage in bone. This in turn might lead on to atypical femoral fractures. A patient treated with alendronate sodium for 8 years, and presenting with bilateral atypical femoral diaphyseal fractures is reported. X‐rays of both femurs showed typical horizontal fracture line involving the thick lateral cortex with short oblique fracture pattern over the medial cortex. This fracture pattern was further confirmed with intra‐operative examination of the fracture ends. Histopathological examination of the endocortical fragment removed from the proximal fracture end showed absence of osteoclasts and osteoblasts. Bone mineral density with dual energy X‐ray absorptiometry (DXA) scan showed osteopenia over the femoral neck. Blood investigations did not show significant abnormalities. Bone turnover marker levels were not reliable, as presence of fracture might have altered the marker levels. Both femoral fractures united well. The patient reported here had complete pictures on X‐ray examination, intra‐operative findings, histopathological examination, DXA, as well as blood test results. Complete data should be collected from patients treated with alendronate sodium presenting with atypical femoral fractures to show any link between the use of alendronate sodium with atypical fracture of femur.     

Efficacy and safety assessments of pharmaceutical agents

There have been several clinical end-points available for efficacy assessments of pharmaceutical agents for osteoporosis in clinical trials. In such trials with alendronate and risedronate, new generation of bisphosphonates, either bone mass measurements or incidental fractures assessments are primary end-points. Markers for bone turnover are frequently measured in trials with protocols for dose finding and action mechanisms of agents. Bone biopsy and bone histomorphometry are needed for assessments of long-term safety. Therefore, multiple clinical trials should be completed to establish efficacy and safety of bisphosphonates.     

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.     

Postmenopausal osteoporosis. What have we learned since the introduction of bisphosphonates?

Over the past 12 years bisphosphonates have become a mainstay of treatment for postmenopausal osteoporosis. As a class, bisphosphonates significantly suppress bone turnover and increase BMD at the lumbar spine and other site through their direct inhibitory effects on osteoclasts. Alendronate and risedronate reduce the incidence of clinical vertebral and non-vertebral fractures. Etidronate and both oral and intravenous ibandronate reduce the incidence of clinical vertebral fractures, but data from primary analyses for reduction in non-vertebral fractures are currently less robust. Intravenous administration of zoledronate is under late-stage investigation for use in postmenopausal osteoporosis. Combinations of alendronate with estrogen or raloxifene provide a greater reduction in bone turnover markers and greater increases in BMD, but fracture risk reduction has not been determined. Overall, bisphosphonates are well tolerated. The most common side effects of oral bisphosphonates are upper gastrointestinal symptoms. Newer safety concerns about the use of bisphosphonates include osteonecrosis of the jaw and oversuppression of bone turnover. The optimal duration of bisphosphonate treatment has not been clearly established.     

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.     

Additional beneficial effects of alendronate in growth hormone (GH)-deficient adults with osteoporosis receiving long-term recombinant human GH replacement therapy: a randomized controlled trial.

We conducted a randomized controlled trial in osteoporotic adult GH-deficient (GHD) patients to assess whether additional treatment with a bisphosphonate would further favorably influence parameters of bone turnover and bone mineral density measurements (BMD). All patients were receiving stable recombinant human (rhGH) replacement therapy for 4 yr at the start of the study. Eighteen GHD patients with osteoporosis were randomized to continue their rhGH maintenance dose or to receive combination therapy with rhGH and alendronate for 12 months. All patients were calcium and vitamin replete, and there were no changes in calcium, vitamin D, or hormone replacement therapy for the duration of the study. At baseline there were no significant differences between the alendronate and the control group in parameters of bone turnover, BMD, or prevalence of vertebral fractures. Childhood-onset and adult-onset GHD were equally distributed between the groups, with no statistical differences in age and gender or other parameters between groups. Mean serum osteocalcin, serum bone-specific alkaline phosphatase, and urinary N-telopeptide/creatinine ratio were within the normal range at the start of the study. In the alendronate group all measured parameters of bone turnover, i.e. bone-specific alkaline phosphatase, osteocalcin, and urinary N-telopeptide/creatinine ratio, significantly decreased after 6 months, with no further decrease thereafter. No changes were observed in the control group. In the alendronate-treated patients serum bone-specific alkaline phosphatase decreased from 10.9 +/- 0.9 to 6.8 +/- 0.7 microg/L at 6 months (P < 0.001), serum osteocalcin decreased from 3.9 +/- 0.4 to 1.7 +/- 0.3 microg/L (P < 0.001), and the urinary N-telopeptide/creatinine ratio decreased from 27.3 +/- 7.0 to 6.4 +/- 0.8 nmol/mmol (P = 0.01). In this group, lumbar spine BMD significantly increased from baseline by 3.4% at 6 months (P = 0.001) and by 4.4% at 12 months (P < 0.001) of treatment, with no further significant increase between 6 and 12 months (P = 0.217). No changes in lumbar spine BMD were observed in the control group. There were no significant changes in femoral neck BMD in either group for the duration of the study. No incident vertebral or peripheral fractures were documented in either group at the end of the study. In summary, this is the first report indicating that treatment with alendronate was able to significantly increase BMD at the lumbar spine in GHD patients with osteoporosis receiving stable rhGH replacement for 4 yr. This increase was significantly greater in alendronate-treated patients than in patients maintained on rhGH. The increase in lumbar spine BMD in the alendronate-treated patients was associated with a decrease in the measured markers of bone turnover, whereas these markers did not change further in the patients maintained on rhGH. This controlled study suggests that additional treatment with alendronate in GHD patients with osteoporosis receiving stable rhGH replacement therapy is effective in increasing BMD at the lumbar spine. Further investigation is required to assess whether rhGH replacement alone or combined treatment with rhGH and alendronate is able to reduce the increased fracture risk associated with GHD.     

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.     

Glucocorticoid‐induced osteoporosis

Introduction: Glucocorticoids have major effects on bone metabolism, leading to accelerated osteoporosis and fracture. Methods: This review will attempt to summarize current knowledge about their effects in light of new information and important remaining questions, especially with respect to management of this common clinical problem. Results: Glucocorticoids affect bone through multiple pathways, influencing both bone formation and bone resorption. Evidence from randomised trials suggests that postmenopausal women receiving glucocorticoids are at greatest risk of rapid bone loss and consequent fracture and should be actively considered for prophylaxis. Based upon available evidence, the rank order of choice for prophylaxis would be a bisphosphonate followed by vitamin D. For established glucocorticoid induced osteoporosis, parathyroid hormone followed by a bisphosphonate appears useful. Conclusions: Glucocorticoid‐induced bone loss can be effectively prevented or reversed.     

Combining Bisphosphonates with Hormone Therapy for Postmenopausal Osteoporosis

Osteoporosis affects many women after menopause. It is a major health problem, as fragility fractures create significant morbidity in this population, especially with advancing age. Available therapies include estrogens, selective estrogen receptor modulators, bisphosphonates, and calcitonin. They all inhibit bone resorption, although through different mechanisms. Several combinations of these agents have been studied in order to determine their effectiveness in comparison with monotherapy. We reviewed eight prospective randomized clinical trials of hormone therapies combined with bisphosphonates (etidronate, alendronate, and risedronate) and one study of a selective estrogen receptor modulator (raloxifene) in combination with a bisphosphonate (alendronate). Bone mineral density change at the lumbar spine was the primary endpoint of all the studies, with one or more measurements of the bone density at the femur as secondary endpoints. None of the studies had the statistical power to determine the relative reduction in fracture risk. All the studies reported greater increases in bone mineral density in patients treated with combination therapies as opposed to single agents. The bone turnover markers were also suppressed to a greater degree in the combination treatment groups, remaining however within normal premenopausal ranges. Four studies reported bone histomorphometry data, indicating no impairment of bone quality by combination therapies. The combination treatments were well tolerated in all the trials and the discontinuation rates did not vary among the groups. However, most patients will not require combination therapy. Combining bisphosphonates with hormone therapy may offer an additional benefit to women who either continue to lose bone mass despite taking estrogen or who need estrogen to control postmenopausal symptoms. The benefit of adding raloxifene to a bisphosphonate is smaller. However, it may be clinically useful if raloxifene reduces the risk of breast cancer.     

The use of i. v. bisphosphonate in pregnancy-associated osteoporosis--case study.

OBJECTIVE: Diagnosis of pregnancy-associated osteoporosis is often delayed and therapeutic interventions insufficient. STUDY DESIGN: A 28-year-old patient (BMI=18.6) with no additional risks for osteoporosis experienced acute lumbosacral pain two months postpartum, while lactating. After conservative therapy, thoracic and lumbar spine were X-rayed: severe pregnancy-associated osteoporosis with vertebral fractures was diagnosed. 2-year treatment with i. v. bisphosphonate ibandronate was initiated (2 mg every 3 months) and calcium and vitamin D supplementation. RESULTS: Rapid improvement was observed. Conclusion: In cases with multiple fractures i. v. bisphosphonate leads to substantial decrease of symptoms and further fractures and significant increase of bone mass density (BMD). CONCLUSION: In severe cases of pregnancy-associated osteoporosis with multiple fractures i. v. biphosphonate therapy leads to a decrease of symptoms and fracture risk and an increase of bone mass density (BMD).     

Glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Glucocorticoids cause a rapid bone loss in the first few months of use, but the most important effect of the drug is suppression of bone formation. The administration of oral glucocorticoid is associated with an increased risk of fractures at the spine and hip. The risk is related to the dose, but even small doses can increase the risk. Patients on glucocorticoid therapy lose more trabecular than cortical bone and the fractures are more frequent at the spine than at the hip. Calcium, vitamin D and activated forms of vitamin D can prevent bone loss and antiresorptive agents are effective for prevention and treatment of bone loss and to decrease fracture risk. Despite the known effects of glucocorticoids on bone, only a few patients are advised to take preventive measures and treat glucocorticoid-induced osteoporosis.     

Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group

The bisphosphonate alendronate and conjugated equine estrogens are both widely used for the treatment of postmenopausal osteoporosis. Acting by different mechanisms, these two agents decrease bone resorption and thereby increase or preserve bone mineral density (BMD). The comparative and combined effects of these medications have not been rigorously studied. This prospective, double blind, placebo-controlled, randomized clinical trial examined the effects of oral alendronate and conjugated estrogen, in combination and separately, on BMD, biochemical markers of bone turnover, safety, and tolerability in 425 hysterectomized postmenopausal women with low bone mass. In addition, bone biopsy with histomorphometry was performed in a subset of subjects. Treatment included placebo, alendronate (10 mg daily), conjugated equine estrogen (CEE; 0.625 mg daily), or alendronate (10 mg daily) plus CEE (0.625 mg daily) for 2 yr. All of the women received a supplement of 500 mg calcium daily. At 2 yr, placebo-treated patients showed a mean 0.6% loss in lumbar spine BMD, compared with mean increases in women receiving alendronate, CEE, and alendronate plus CEE of 6.0% (P < 0.001 vs. placebo), 6.0% (P < 0.001 vs. placebo), and 8.3% (P < 0.001 vs. placebo and CEE; P = 0.022 vs. alendronate), respectively. The corresponding changes in total proximal femur bone mineral density were +4.0%, +3.4%, +4.7%, and +0.3% for the alendronate, estrogen, alendronate plus estrogen, and placebo groups, respectively. Both alendronate and CEE significantly decreased biochemical markers of bone turnover, specifically urinary N-telopeptide of type I collagen and serum bone-specific alkaline phosphatase. The alendronate plus CEE combination produced slightly greater decreases in these markers than either treatment alone, but the mean absolute values remained within the normal premenopausal range. Alendronate, alone or in combination with CEE, was well tolerated. In the subset of patients who underwent bone biopsies, histomorphometry showed normal bone histology with the expected decrease in bone turnover, which was somewhat more pronounced in the combination group. Thus, alendronate and estrogen produced favorable effects on BMD. Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated.