Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday

Summary  Based upon interest in a bisphosphonate drug holiday, we evaluate the risk for hip fracture after bisphosphonate discontinuation. Among women compliant with bisphosphonates for ≥2 years, the risk of hip fracture was increased after discontinuation, although with higher compliance and a longer duration of preceding bisphosphonate therapy, this risk was attenuated. Introduction  Recent data suggest that hip fracture risk was not significantly increased among women receiving 5 years of bisphosphonate therapy who were subsequently randomized to placebo. We studied older women compliant with bisphosphonates ≥2 years to evaluate the risk of hip fracture after bisphosphonate discontinuation. Methods  Using administrative databases from a large U.S. healthcare organization, we identified women initiating bisphosphonate therapy compliant (Medication Possession Ratio, MPR ≥66%) for 2 years. We examined the rate of hip fracture among women who discontinued bisphosphonates versus those who remained on therapy. Results  At 2 years, 9,063 women were eligible for analysis. Hip fracture incidence among women who discontinued bisphosphonates versus those who did not was 8.43 versus 4.67 per 1000 person years (p = 0.016). The adjusted hazard ratio of hip fracture per 90 days following discontinuation was 1.2 (1.1–1.3). For women with higher compliance at 2 years (MPR ≥80%) or compliant for 3 years, there were no significant differences in risk associated with discontinuation. Conclusions  The rate of hip fracture was increased among women compliant with bisphosphonate therapy for 2 years who subsequently discontinued, suggesting that discontinuation is not advisable under these conditions. This association was attenuated with higher compliance and a longer duration of previous bisphosphonate therapy. Funding This project was funded by Novartis Pharmaceuticals and the Arthritis Foundation. The investigators also receive support from the National Institutes of Health (AR053351, AR052361). The authors independently developed the analysis plan, extracted the data, conducted the analysis, and interpreted the results.     

Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate

Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined.Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005.Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200).Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial (Black et al. 1996).     

Fragility fractures and the osteoporosis care gap in women: the Canadian Multicentre Osteoporosis Study

Summary

Canadian women over 50?years old were studied over a 10-year period to see if those who sustained a fracture (caused by minimal trauma) were receiving the recommended osteoporosis therapy. We found that approximately half of these women were not being treated, indicating a significant care gap in osteoporosis treatment.

Introduction

Prevalent fragility fracture strongly predicts future fracture. Previous studies have indicated that women with fragility fractures are not receiving the indicated treatment. We aimed to describe post fracture care in Canadian women using a large, population-based prospective cohort that began in 1995?C1997.

Methods

We followed 5,566 women over 50?years of age from across Canada over a period of 10?years in the Canadian Multicentre Osteoporosis Study. Information on medication use and incident clinical fragility fractures was obtained during a yearly questionnaire or interview and fractures were confirmed by radiographic/medical reports.

Results

Over the 10-year study period, 42?C56% of women with yearly incident clinical fragility fractures were not treated with an osteoporosis medication. During year?1 of the study, 22% of the women who had experienced a fragility fracture were on treatment with a bisphosphonate and 26% were on hormone therapy (HT). We were not able to differentiate HT use for menopause symptoms vs osteoporosis. Use of bisphosphonate therapy increased over time; odds ratio (OR) for use at year?10 compared to use at year?1 was 3.65 (95% confidence interval (CI) 1.83?C7.26). In contrast, HT use declined, with an OR of 0.07 (95%CI 0.02?C0.24) at year?10 compared to year?1 of the study.

Conclusion

In a large population-based cohort study, we found a therapeutic care gap in women with osteoporosis and fragility fractures. Although bisphosphonate therapy usage improved over time, a substantial gap remains.     

Effect of a case-finding strategy for osteoporosis on bisphosphonate prescribing in primary care

Case-selection strategies have been advocated for identifying patients who would benefit from primary care to prevent osteoporosis. However, the effectiveness of this approach is unclear. To address this question, we performed a randomized control trial to determine whether a case-selection strategy to identify patients with clinical risk factors for osteoporosis, combined with open access to dual X-ray absorptometry (DXA) scans, influences bisphosphonate prescribing in ten GP practices in Avon. Practices were randomized to two groups: the first identified women aged 45–75 years at high risk of osteoporosis and provided open access to DXA scans for 12 months; the second had no case-finding strategy and no DXA scan access. Bisphosphonate prescribing was ascertained by searching computerized patient records every 3 months during the intervention and a subsequent 6-month follow-up period. Overall, the number of subjects in each practice who were prescribed bisphosphonates increased by 50% (p<0.001), and the proportion of bisphosphonates prescribed as aminobisphosphonates increased 3-fold (p<0.001). The magnitude of these changes was similar in both groups. However, of the patients prescribed bisphosphonates, approximately twice as many in group 1, as compared with group 2, had a previously documented low-trauma fracture, as assessed at the end of the 12-month intervention period (p=0.01). Furthermore, at studys end, of the 30 patients in group 1 receiving bisphosphonates who had received DXA scans, 80% had osteoporosis as defined by t-score<-2.5. We conclude that use of a case-selection strategy for osteoporosis in primary care, combined with open access to DXA scans, appears to target bisphosphonate therapy to those at high risk of osteoporotic fractures. In contrast, the overall rate of bisphosphonate prescribing is unaffected by this intervention.     

One-stage surgical correction of congenital thoracic lordosis--report of 2 cases

Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined.

Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005.

Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200).

Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial ().     

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Summary

Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8 % of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure.

Introduction

To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO).

Methods

We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥7.5 %, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥2 incident fragility fractures and/or a BMD decrease greater than the least significant change.

Results

Bisphosphonate treatment failure was observed in 25.8 % of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95 % CI 1.10–9.50, P?=?0.034) and baseline alkaline phosphatase total activity levels ≥66.5 U/L (OR 4.22, 95 % CI 1.48–12.01, P?=?0.007), regardless of age, number of falls, LS BMD, and baseline SDI.

Conclusions

The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.     

Bisphosphonates and osteoporotic fractures: a cross-design synthesis of results among compliant/persistent postmenopausal women in clinical practice versus randomized controlled trials

Summary  

In a cross-design synthesis, total fractures were similarly reduced by bisphosphonates among postmenopausal women in randomized trials (23.8%) and highly compliant/persistent patients in observational studies of large databases from routine practice (20.3%). Bisphosphonates also reduced nonvertebral, vertebral and hip fractures in randomized trials and observational studies. In the real-word setting, compliant/persistent patients can gain a benefit from bisphosphonates comparable to that of randomized trial participants.     

Secondary prevention program for osteoporotic fractures and long-term adherence to bisphosphonates

Summary  

Our purpose was to assess the impact of a secondary prevention program for osteoporotic fractures in patients with fragility fracture and to determine its effect on long-term compliance with bisphosphonate treatment. Persistence with bisphosphonate use was 71%. Attending follow-up visits was the only variable significantly associated with adherence to bisphosphonates.     

Incidence of atypical nontraumatic diaphyseal fractures of the femur

Bisphosphonates reduce the rate of osteoporotic fractures in clinical trials and community practice. “Atypical” nontraumatic fractures of the diaphyseal (subtrochanteric or shaft) part of the femur have been observed in patients taking bisphosphonates. We calculated the incidence of these fractures within a defined population and examined the incidence rates according to duration of bisphosphonate use. We identified all femur fractures from January 1, 2007 until December 31, 2011 in 1,835,116 patients older than 45 years who were enrolled in the Healthy Bones Program at Kaiser Southern California, an integrated health care provider. Potential atypical fractures were identified by diagnostic or procedure codes and adjudicated by examination of radiographs. Bisphosphonate exposure was derived from internal pharmacy records. The results showed that 142 patients had atypical fractures; of these, 128 had bisphosphonate exposure. There was no significant correlation between duration of use (5.5 ± 3.4 years) and age (69.3 ± 8.6 years) or bone density (T‐score ?2.1 ± 1.0). There were 188,814 patients who had used bisphosphonates. The age‐adjusted incidence rates for an atypical fracture were 1.78/100,000/year (95% confidence interval [CI], 1.5–2.0) with exposure from 0.1 to 1.9 years, and increased to 113.1/100,000/year (95% CI, 69.3–156.8) with exposure from 8 to 9.9 years. We conclude that the incidence of atypical fractures of the femur increases with longer duration of bisphosphonate use. The rate is much lower than the expected rate of devastating hip fractures in elderly osteoporotic patients. Patients at risk for osteoporotic fractures should not be discouraged from initiating bisphosphonates, because clinical trials have documented that these medicines can substantially reduce the incidence of typical hip fractures. The increased risk of atypical fractures should be taken into consideration when continuing bisphosphonates beyond 5 years. © 2012 American Society for Bone and Mineral Research.     

Corticosteroid-induced osteoporosis prevention: longitudinal practice patterns in The Netherlands 2001–2005

Summary We investigated prevention trends and predictors for osteoporosis prevention in long term corticosteroid users. The use of bisphosphonates increased from 2001 to 2005. Longer duration of corticosteroid use and DMARD use were predictors for receiving prevention. Females appear reasonably well treated; however, men require more attention. Introduction Previous studies have shown that long-term corticosteroid users are undertreated for osteoporosis prevention. Our aim was to identify prevention trends in long-term corticosteroid users from 2001–2005 in The Netherlands and to identify predictors for bisphosphonate prophylaxis. Methods Pharmacy dispensing data were used from 9 community pharmacies. All oral corticosteroid doses were converted to “prednisolone equivalents”. We then identified long-term (≥90 days) corticosteroid episodes, which required bisphosphonate prophylaxis as per 2002 Dutch guidelines; Multivariate logistic regression was used to identify predictors for receiving prevention. Results We identified 615 different corticosteroid patients requiring prophylaxis. From 2001–2005 the use of bisphosphonates increased from 38% to 54% (p = 0.001). In 2005 females were prescribed more bisphosphonates than males (61% vs. 39%; p = 0.002), or any treatment (72% vs. 45%; p < 0.001). Multivariate analysis showed that longer duration of corticosteroid use and disease-modifying anti-rheumatic drug (DMARD) use were independent predictors of bisphosphonate use. Use of respiratory medication was a negative predictor of bisphosphonate use. Conclusion There has been a significant increase in osteoporosis prophylaxis in a population at high risk for osteoporosis/fractures. In particular, females appear reasonably well treated; however, men are still not receiving prevention to the same degree as women.