Bisphosphonates and osteonecrosis of the jaw.
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Bone Density Conservation Agents↗
Biomedical subjects
Steven T Harris
Publications and source records attributed to Steven T Harris.
Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases.
OBJECTIVE: To characterize the relationships between adherence (complance and persistence) to bisphosphonate therapy and risk of specific fracture types in postmenopausal women. PATIENTS AND METHODS: Data were collected from 45 employers and 100 health plans in the continental United States from 2 claims databases during a 5-year period (January 1, 1999, through December 31, 2003). Claims from patients receiving a bisphosphonate prescription (alendronate or risedronate) were evaluated for 6 months before the Index prescription and during 24 months of follow-up to determine total, vertebral, and nonvertebral osteoporotic fractures, persistence (no gap in refills for >30 days during 24 months), and refill compliance (medication possession ratio > or = 0.80). RESULTS: The eligible cohort included 35,537 women (age, > or = 45 years) who received a bisphosphonate prescription. A subgroup with a specified diagnosis of postmenopausal osteoporosis was also evaluated. Forty-three percent were refill compliant, and 20% persisted with bisphosphonate therapy during the 24-month study period. Total, vertebral, nonvertebral, and hip fractures were significantly lower in refill-compliant and persistent patients, with relative risk reductions of 20% to 45%. The relationship between adherence and fracture risk remained significant after adjustment for baseline age, concomitant medications, and fracture history. There was a progressive relationship between refill compliance and fracture risk reduction, commencing at refill compliance rates of approximately 50% and becoming more pronounced at compliance rates of 75% and higher. CONCLUSIONS: Adherence to bisphosphonate therapy was associated with significantly fewer fractures at 24 months. Increasing refill compliance levels were associated with progressively lower fracture rates. These findings suggest that incremental changes in medication-taking habits could improve clinical outcomes of osteoporosis treatment.
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Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.
UNLABELLED: In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. INTRODUCTION: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. MATERIALS AND METHODS: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were > or =80% compliant with study medication in CORE. RESULTS: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene. CONCLUSION: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.
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Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.
All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.
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Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE.
OBJECTIVES: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. PATIENTS AND METHODS: BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. RESULTS: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. CONCLUSIONS: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.
Administration, Oral↗
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.
Administration, Oral↗
Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.
The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr. New vertebral fractures was assessed from radiographs taken at baseline, yr 2-4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr. The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr. Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.
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Classification algorithms for hip fracture prediction based on recursive partitioning methods.
This article presents 2 modifications to the classification and regression tree. The authors improved the robustness of a split in the test sample approach and developed a cost-saving classification algorithm by selecting noninferior to the optimum splits from variables with lower cost or being used in parent splits. The new algorithm was illustrated by 43 predictive variables for 5-year hip fracture previously documented in the Study of Osteoporotic Fractures. The authors generated the robust optimum classification rule without consideration of classification variable costs and then generated an alternative cost-saving rule with equivalent diagnostic utility. A 6-fold cross-validation study proved that the cost-saving alternative classification is statistically noninferior to the optimal one. Their modified classification and regression tree algorithm can be useful in clinical applications. A dual X-ray absorptiometry hip scan and information from clinical examinations can identify subjects with elevated 5-year hip fracture risk without loss of efficiency to more costly and complicated algorithms.
Absorptiometry, Photon↗
Clinical use of teriparatide in the real world: initial insights.
OBJECTIVE: To summarize expert opinion regarding clinical application of the recently introduced anabolic agent teriparatide [human parathyroid hormone (1-34)] in treatment of postmenopausal osteoporosis in women, and osteoporosis in men. SUMMARY: The anabolic agent teriparatide was approved for clinical use by the Food and Drug Administration (FDA) on November 26, 2002. Since the launch of teriparatide, many more questions about clinical use of this exciting agent have emerged than there are answers provided by clinical trials or FDA-approved product labeling. A group of physicians with a broad range of experience in research and clinical applications of teriparatide met recently to address practical issues related to its use. This manuscript is a compendium of the consensus opinions of the authors that attempts to provide practical answers to many real-world questions being asked about teriparatide therapy since its approval by the FDA.
Anabolic Agents↗