Years Of Bisphosphonate Treatment Research Articles

Skeletal outcomes of patients with osteogenesis imperfecta during drug holiday of bisphosphonates: a real-world study

PurposeThis study aimed to investigate the skeletal outcomes of patients with osteogenesis imperfecta (OI) who received bisphosphonate (BP) treatment and entered drug holiday after achieving an age- and sex-specific bone mineral density (BMD) reference.MethodsPatients with OI receiving BP treatment were enrolled when they entered drug holidays of BPs. The skeletal outcomes were evaluated in detail during the drug holiday, including BMD, X-ray of the bone, bone fracture incidence, and bone turnover biomarkers. The pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing.ResultsA total of 149 OI patients (127 juveniles and 22 adults) who entered drug holidays after nearly 4 years of BP treatment were included. Areal BMD at the lumbar spine increased from 0.934 ± 0.151 to 0.990 ± 0.142 g/cm2 and was stable in the second (1.029 ± 0.176 g/cm2) and third years (1.023 ± 0.174 g/cm2) of BP drug holidays, and BMD at the femoral neck, trochanter, and total hip had no significant change, but it was gradually inferior to that of the same-gender juveniles in the second and third years of the drug holiday. BMD at the lumbar spine and proximal hip did not change and was inferior to that of the same-gender adults. The average time of fractures fluctuated from 0.18 to 0.08 per year in juveniles, while only one adult suffered from a fracture during BP drug holidays. Bone turnover markers were in the normal range, except for a mildly high level of β-carboxy-terminal cross-linked telopeptide of type 1 collagen in the juvenile group. A total of 17 (11.4%) patients received BP retreatment because of bone loss during the drug holiday. OI type III and type IV and COL1A2 mutation were correlated to a longer duration of BP treatment to enter drug holidays (all p < 0.05). Old age at initial treatment (OR, 1.056) and OI type III (OR, 10.880) were correlated to a higher risk of BP retreatment.ConclusionsOI patients will undergo nearly 4 years of BP treatment to achieve drug holidays. During the 3 years of the drug holiday, the patients’ BMD is stable, and fracture incidence does not increase significantly. Patients are more inclined to need retreatment during drug holidays owing to the late start of BP treatment and more severe OI phenotypes.

Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years.

ABSTRACTOral bisphosphonates are the primary medication for osteoporosis, but concerns exist regarding potential bone‐quality changes or low‐energy fractures. This cross‐sectional study used artificial intelligence methods to analyze relationships among bisphosphonate treatment duration, a wide variety of bone‐quality parameters, and low‐energy fractures. Fourier transform infrared spectroscopy and histomorphometry quantified bone‐quality parameters in 67 osteoporotic women treated with oral bisphosphonates for 1 to 14 years. Artificial intelligence methods established two models relating bisphosphonate treatment duration to bone‐quality changes and to low‐energy clinical fractures. The model relating bisphosphonate treatment duration to bone quality demonstrated optimal performance when treatment durations of 1 to 8 years were separated from treatment durations of 9 to 14 years. This may be due to a change in relationship of bone‐quality parameters with treatment duration. This model also showed that the effects of bisphosphonate treatment duration were most highly correlated with changes in means and standard deviations of infrared spectroscopically derived mineral and matrix parameters and histomorphometric bone turnover parameters. A second model related treatment duration to bone fracture in all 22 patients who fractured while on treatment with bisphosphonates for more than 8 years. This second model showed that bisphosphonate treatment duration, not hip bone mineral density (BMD), was the most strongly correlated parameter to these low‐energy bone fractures. Application of artificial intelligence enabled analysis of large quantities of structural, cellular, mineral, and matrix bone‐quality parameters to determine relationships with long‐term oral bisphosphonate treatment and fracture. Infrared spectroscopy provides clinically relevant bone‐quality information of which bone mineral purity is among the most relevant. Nine or more years of bisphosphonate treatment was associated with abnormal bone mineral purity, matrix abnormalities, and low‐energy fractures. These data justify limiting bisphosphonate treatment duration to 8 years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bisphosphonate treatment and the risk of atypical femoral fracture among patients participating in a Fracture Liaison Service of a tertiary medical center.

Atypical femoral fractures (AFF) are a rare complication of bisphosphonate (BP) treatment. We evaluated the correlation between BP exposure and AFF risk among hip fracture patients. This retrospective nested case-control study included patients over age 50years, operated for osteoporotic hip fracture between July 2014 and November 2018, who attended our Fracture Liaison Service. We classified fracture radiographs and compared demographic, clinical, biochemical, and drug purchase data between patients with AFF and those with typical osteoporotic hip fracture (controls). To correct for the younger age of patients with AFF, we matched each case (AFF) with three controls according to age ([Formula: see text] 1year) and sex and performed a conditional logistic regression model. Of 989 patients, 31 (3%) had AFF. Patients with AFF were younger than those with inter-trochanteric fractures (mean ± SD: 72.3 ± 10.3 vs. 80.2 ± 9.6years, p < 0.001). Following matching, the mean Charlson's Comorbidity Index (CCI) was lower in the AFF than in the control group (2.9 ± 3.7 vs. 4.7 ± 4.2; p = 0.030) and a higher proportion of them were treated with BP for 5years or more (58.1 vs. 16.0%; p < 0.001). Among patients admitted with hip fracture who were treated with BP for 5years or more, the odds ratio of this fracture being atypical was significantly higher compared with no BP treatment (21.7; 95% CI-4.1-113.9). Patients with AFF compared to typical hip fractures showed better baseline medical conditions irrespective of their younger age. Five years of BP treatment may be associated with an increased risk for AFF, though the absolute risk remains very low.

Extended Bisphosphonate Therapy not Associated with Reduced hip Fracture Risk.

According to this study: Among women who completed five years of bisphosphonate treatment, an additional five years of treatment wasn't associated with a lower risk of hip fracture.

Osteoporosis in women in menopause/postmenopause: what to do?

An analytical review of domestic and foreign literature on the problem of osteoporosis was performed, and the principles of the approach to diagnosis and treatment of this disease are described.The probability of vertebral fracture should be assumed if there is a history of growth loss of 4 cm or more, the appearance of kyphosis in patients who received long-term therapy with glucocorticoids, with bone mineral density (BMD) less than 2.5 points In the treatment of patients with osteoporosis at the initial stage there is a tendency to limit oneself to non-drug measures, advising to change lifestyle and diet, to increase intake of vitamin D and calcium with food, to optimize physical activity. However, the main place in the prevention and treatment of osteoporosis in postmenopausal women is occupied by medication therapy, which can reduce the risk of fractures by 70%: bisphosphonates, drugs derived from parathyroid hormone, denosumab and selective estrogen receptor modulators. It is advisable to start therapy with oral bisphosphonates in most cases. They are powerful inhibitors of bone resorption and act by reducing the activity of osteoclasts and increasing their apoptosis. In 2020, the patent protection period of the main original bisphosphonates expired and generics of Russian production appeared: Rezoviva (ibandronic acid 3 mg for intravenous injection once every 3 months) and Osteostatix (zoledronic acid 5 mg 100 ml solution for intravenous drip once a year). After 3–5 years of bisphosphonate treatment, treatment should be reconsidered. The risk of recurrent fractures should be reassessed after the injury occurs. The risk of new fractures increases in patients who stop treatment. Study results have recommended ibandronate as a first-line drug in women with postmenopausal osteoporosis. Studies comparing intermittent intravenous ibandronate administration with daily oral treatment in women with postmenopausal osteoporosis allowed to recommend intravenous ibandronate at a dose of 3 mg every 3 months as the preferred therapy.

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women

Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

Young's modulus and hardness of human trabecular bone with bisphosphonate treatment durations up to 20years.

Bisphosphonates are widely used for treating osteoporosis, but the relationship between treatment duration and bone quality is unclear. Since material properties partially determine bone quality, the present study quantified the relationship between human bone modulus and hardness with bisphosphonate treatment duration. Iliac crest bone samples from a consecutive case series of 86 osteoporotic Caucasian women continuously treated with oral bisphosphonates for 1.1-20years were histologically evaluated to assess bone turnover and then tested using nanoindentation. Young's modulus and hardness were measured and related to bisphosphonate treatment duration by statistical modeling. All bone samples had low bone turnover. Statistical models showed that with increasing bisphosphonate treatment duration, modulus and hardness increased, peaked, and plateaued. These models used quadratic terms to model modulus increases from 1 to 6years of bisphosphonate treatment and linear terms to model modulus plateaus from 6 to 20years of treatment. The treatment duration at which the quadratic-linear transition (join point) occurred also depended upon trabecular location. Hardness increased and peaked at 12.4years of treatment; it remained constant for the next 7.6years of treatment and was insensitive to trabecular location. Bone modulus increases with bisphosphonate treatment durations up to 6years, no additional modulus increases occurred after 6years of treatment. Although hardness increased, peaked at 12.4years and remained constant for the next 7.6years of BP treatment, the clinical relevance of hardness remains unclear.

Bisphosphonate Treatment in Osteoporosis: Optimal Duration of Therapy and the Incorporation of a Drug Holiday.

Bisphosphonates are the most widely used treatment for osteoporosis. They accumulate in the bone for years, and therefore, their inhibitory effects on osteoclasts may persist after drug discontinuation. The ideal duration of therapy remains controversial. The purpose of this study is to review the literature to determine the (1) indications for drug holiday, (2) the duration of drug holiday, (3) the evaluation during drug holiday, and (4) the proper treatment and maintenance after drug holiday. A review of two electronic databases (PubMed/MEDLINE and EMBASE) was conducted using the term "(Drug holiday)," in January 29, 2015. Inclusion criteria were as follows: (1) clinical trials and case control, (2) human studies, (3) published in a peer-review journal, and (4) written in English. Exclusion criteria were as follows: (1) case reports, (2) case series, and (3) in vitro studies. The literature supports a therapeutic pause after 3-5years of bisphosphonate treatment in patients with minor bone deficiencies and no recent fragility fracture (low risk) and in patients with moderate bone deficiencies and/or recent fragility fracture (moderate risk). In these patients, a bone health reevaluation is recommended every 1-3years. Patients with high fracture risk should be maintained on bisphosphonate therapy without drug holiday. The duration and length of drug holiday should be individualized for each patient. Evaluation should be based on serial bone mass measurements, bone turnover rates, and fracture history evaluation. If after drug therapy, assessments show an increased risk of fracture, the patient may benefit from initiating another treatment. Raloxifene, teriparatide, or denosumab are available options.

Childhood Osteoporosis and Presentation of Two Cases with Osteogenesis Imperfecta Type V.

IntroductionOsteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good.MethodsTwo individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed.ResultsIn patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452.ConclusionsThe paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.

The skeletal muscle cross sectional area in long-term bisphosphonate users is smaller than that of bone mineral density-matched controls with increased serum pentosidine concentrations

Bisphosphonates are effective in increasing bone mineral density (BMD), but fragility fractures can still occur despite bisphosphonate treatment. The purpose of this study was to determine if long-term bisphosphonate users have characteristic findings in the musculoskeletal system, which could put them at risk of developing typical or atypical femoral fractures. We recruited 40 female patients who had taken bisphosphonates for more than 3years. The control group included 60 volunteers who were matched by age, body mass index, and dual-energy X-ray absorptiometry-derived BMDs. We measured the skeletal muscle cross sectional area around the proximal thigh and buckling ratio of the femoral neck using quantitative computed tomography (qCT) and several biochemical markers of bone metabolism. Those parameters were compared between the groups. While no significant differences of buckling ratio derived from qCT were detected, the skeletal muscle cross sectional area was significantly smaller in the long-term bisphosphonate users than in the controls. Furthermore, the serum pentosidine level was significantly higher in the bisphosphonate users than in the controls. To determine if those differences were attributable to bisphosphonate treatment, we further compared those parameters between before and after 3years of bisphosphonate treatment in 32 patients. After 3years of bisphosphonate treatment, the BMD of the femoral neck and serum pentosidine level increased but not the skeletal muscle cross sectional area. In the present study, the skeletal muscle mass did not match the bone mass in long-term bisphosphonate users, thus suggesting that increases in BMD by bisphosphonates are unlikely to have secondary positive effects on the surrounding skeletal muscles. Also, serum pentosidine levels were greater in the long-term bisphosphonate users. Further study is necessary to test if such patients are prone to develop typical or atypical femoral fractures.

Serum pentosidine levels after 3 years of bisphosphonate treatment in post-menopausal osteoporotic women

The present study measured changes in plasma pentosidine and bone turnover markers in elderly patients with osteoporosis treated using bisphosphonate. The relationship between pentosidine and bone turnover markers and bone mineral density (BMD) was investigated. This study consisted of post-menopausal osteoporotic women who could be treated using bisphosphonate for 3 years were included in the present analysis. The study population consisted of 58 cases, all women, ranging in age from 53 to 86 years (mean, 67.1 years). Bisphosphonate treatment significantly increased BMD of the lumbar spine to 0.914 ± 0.141 g/cm2 and BMD of the femoral neck to 0.708 ± 0.086 g/cm2 after 3 years (p < 0.001 versus baseline). The mean BAP level was 27.3 ± 8.3 U/L in patients at baseline. After bisphosphonate treatment, BAP significantly decreased to 18.1 ± 7.2 U/L at 3 years (p < 0.001). Urinary NTX also decreased after bisphosphonate treatment. After 3 years of treatment, urinary NTX significantly decreased from 50.0 ± 19.0 nmol BCE/mmol Cr to 24.6 ± 10.2 nmol BCE/mmol Cr at 3 years (p < 0.001). Serum pentosidine levels were 0.0413 ± 0.0094 μg/mL at baseline and 0.0413 ± 0.0122 μg/mL after 3 years. They were not significantly changed by bisphosphonate treatment. Serum pentosidine levels were not changed by treatment with bisphosphonates. Thus, serum pentosidine may not be suitable as a marker of bone quality after 3 years of bisphosphonate treatment.

Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid.

Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63]). These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer. clinicaltrials.gov Identifier: NCT00049829 (HORIZON-PFT).

G.P.98 : Changes in height and age adjusted DXA bone indices with oral bisphosphonate treatment in Duchenne muscular dystrophy

Osteoporosis is a major problem in Duchenne Muscular Dystrophy (DMD) due to long term glucocorticoid (GC) therapy and impaired mobility. There are currently no standard of care guidelines for detection or treatment of osteoporosis in DMD. There is limited data on bisphosphonate (BP) treatment of osteoporosis in pediatric DMD patients. This is the first study using height and age adjusted Z scores to assess changes in bone mineral density (BMD) and bone mineral content (BMC) in DMD boys treated with oral BP. To assess changes in bone mineral density (BMD) and bone mineral content (BMC) in DMD boys treated with oral BP. Retrospective study of total body (TB) and lumbar spine (LS) BMD and BMC by DXA in DMD boys treated with oral alendronate, studied between January 2005 and July 2012. Height- and age-adjusted Z-scores (HAZ) were derived. Paired t -tests were used to compare changes in BMD and BMC one year prior and one year post BP treatment. We studied 26 BP-treated DMD boys (mean age ± SD 10.9 ± 3.8 yrs and daily GC duration 3.3 ± 1.5 yrs at BP start). BP treatment duration at the end of the study period was 2.8 ± 1.1 yrs. Prior to starting BP, TB BMD and BMC-HAZ decreased progressively, while LS BMD and BMC-HAZ remained stable. Mean TB BMD and BMC-HAZ were −1.89 and −2.90 and mean LS BMD and BMC-HAZ were −0.89 and −1.07 at BP initiation. DXA bone indices stabilized or improved with BP treatment. There was significant improvement in LS BMD-HAZ ( p p p = 0.0092) after one year of BP treatment. Oral BP treatment stabilized further decline of TB bone indices, and improved LS BMD and BMC HAZ and TB BMC HAZ. Our study suggests that oral BP may be beneficial for bone health in DMD boys. Further study to assess clinical correlation of changes in DXA bone indices is needed to evaluate efficacy of oral BP treatment for osteoporosis in DMD patients.

SAT0480 Effects of A Previous Treatment With18 Months of Teriparatide on the Cortical Bone Mineral Density Response to Three Years of Bisphosphonate Treatment in Severe Osteoporosis

BackgroundThe actual challenge in the management of the severe osteoporosis is to find the best therapeutic strategy to increase bone mineral density (BMD) at the cortical sites, where gains with...

Atypical Femoral Fractures in a Patient with Continuous Decreasing BMD after Only 1.5 Years of Bisphosphonate Treatment

Objective: Bisphosphonates were accepted first line treatment for osteoporosis. Long-term bisphosphonate treatment has been reported to be complicated with osteonecrosis of jaw (ONJ) and atypical fracture of femur. It is proposed to be the result of impaired remodeling of minor injury of bone. An atypical fracture occurs on a patient received only 1.5 years of bisphosphonate treatment with continuous decreasing bone mineral density. Case Presentation: This is a 53-year-old female Taiwanese. She has rheumatoid arthritis and has received long-term glucocorticoid treatment. Continuous decrease of bone mineral density in the serial BMD examination after alendronate treatment can be found. Thigh pain occurs after only 1.5 years of bisphosphonate treatment and it progresses to atypical fracture. Conclusions: Atypical fracture can occur in patients receive only short-term bisphosphonate treatment even BMD is still decreased after bisphosphonate treatment. Autoimmune disease, glucocorticoid treatment, Asian and female may be the possible risk factors.

Long Term Outcome of Bisphosphonate Therapy in Patients with Primary Hyperparathyroidism

Context: Primary hyperparathyroidism (PHPT) is commonly associated with reduced bone mineral density (BMD) presenting with osteoporosis, increasing the risk of bone fragility fractures in these patients. Bisphosphonates, due to their anti-resorptive action, are known to improve the BMD and reduce the risk of bone fragility fractures. Therefore, bisphosphonates are considered as an alternative to surgical treatment in managing osteoporosis in PHPT patients. Aim: The aim of this observational study was to assess the effect of long term bisphosphonate therapy on BMD, bone fragility fracture and biochemical markers of bone metabolism in patients with PHPT. Methodology: Fifty patients (mean age 74 years) with PHPT who were treated with long term bisphosphonate therapy were studied retrospectively. The mean baseline (before commencing bisphosphonate therapy) BMD T-scores for lumbar spine (L2-L4) and left femoral neck were -2.5 and -2.1, respectively. Fourteen patients had bone fragility fractures before initiation of bisphosphonate therapy. Results: After an average of 5 years of bisphosphonate treatment, there was a significant increase in lumbar BMD T-score (-2.5 to -2.1, p = 0.013) and a non-significant change in left femoral neck BMD T-score (-2.1 to -2.2, p = 0.497). There was no increase in bone fragility fracture rate (p = 0.167). Serum corrected calcium reduced from 2.74 mmol/L to 2.60 mmol/L (p 0.001) and urine calcium to creatinine ratio from 0.70 to 0.55 (p 0.0001), both within the reference range. Conclusions: Our study suggests that long term bisphosphonate therapy improves lumbar BMD and prevents increase in bone fragility fracture rate. Additionally it improves hypercalcaemia in PHPT.

Long-Term Follow-up of patients on Drug Holiday from Bisphosphonates: Real-World Setting

ObjectiveAtypical femoral fractures and osteoporosis of the jaw have been associated with prolonged bisphosphonate therapy for postmenopausal osteoporosis. American Association of Clinical Endocrinologists guidelines suggest a drug holiday after 4 to 5 years of bisphosphonate treatment for moderate-risk patients and 10 years for high-risk patients, but there are minimal data on safe holiday durations. A recent U.S. Food and Drug Administration perspective suggests a treatment duration of 3 to 5 years. Our aim was to describe a group of patients on drug holiday and identify fracture risk. MethodsA retrospective chart review was conducted of 209 patients who started a bisphosphonate drug holiday between 2005 and 2010. Collected data included bone mineral density (BMD), markers of bone turnover, vitamin D status, and clinical and radiographic reports of fractures. ResultsEleven of 209 patients (5.2%) developed a fracture. Their mean age was 69.36 years (±15.58), and the mean lumbar spine and femoral neck T-scores were −2.225 (±1.779) and −2.137 (±0.950), respectively. All patients had a significant increase in bone-specific alkaline phosphatase at 6 months, which was more pronounced in the fracture group (3.0 ± 0.6083 μg/L vs. 1.16 ± 1.9267 μg/L). Over 4 years, there was no significant change in mean lumbar spine BMD for the entire cohort, but there was a statistically significant decline in the femoral neck BMD at year 2 (−0.0084 ± 0.03 gm/cm2). ConclusionThe current practice of initiating BP holidays needs further evaluation, particularly in the real-world setting. Elderly patients and those with very low BMD warrant close follow-up during a drug holiday. A fracture, early significant rise in bone turnover markers, and/or a decline in BMD should warrant resumption of osteoporosis therapy. (Endocr Pract. 2013;19:989-994)

Atypical Femoral Fracture Risk in Patients Treated With Bisphosphonates

There is increasing evidence that the use of bisphosphonates to prevent osteoporotic fractures, particularly long-term use, is associated with an increased risk of unusual fractures of the proximal femur. Numerous case reports of these “atypical” fractures of the femur among bisphosphonate-treated women have appeared over the last 5 years or more.1,2 A case definition for atypical femur fractures has now been proposed3 that includes subtrochanteric (below the lesser trochanter) or diaphyseal (above the distal metaphysis) location, transverse or nearly transverse “chalklike” fracture line (as opposed to the more typical spiral or comminuted fractures), and paucity of trauma. Additional features may include the presence of prodromal thigh pain, bilateral involvement, cortical thickening, and the presence of other selected diseases (such as rheumatoid arthritis or diabetes) or medication use (such as corticosteroids or proton pump inhibitors). Some reports, but certainly not all, suggest marked suppression of bone turnover as assessed by bone turnover markers and iliac crest histomorphometry.1 Even if causally related, these atypical fractures must be quite rare among osteoporotic women treated with bisphosphonates, as a recent pooled analysis of 3 large clinical trials (FIT, FLEX, and HORIZON) with up to 10 years of follow-up4 found that all types of subtrochanteric and diaphyseal fractures were infrequent and similar among placebo- and bisphospho-nate-treated women. Although these findings are reassuring, important limitations were that relatively few women received more than 5 years of bisphosphonate treatment, information on atypical features was not specifically collected, and only radiographic reports were reviewed. Clearly, because atypical subtrochanteric fractures occur infrequently, they are unlikely to be easily studied in randomized trials, and other study designs will be necessary.

Analysis Downplays Bisphosphonates' Risk

The risk of subtrochanteric and diaphyseal femur fractures is not significantly increased in women taking bisphosphonates, even among those treated for up to 10 years, a secondary analysis of data from three large randomized bisphosphonate trials suggests. The findings follow several case reports that hinted at an increased risk of these atypical fractures in bisphosphonate users. However, the current study, which included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up showed that only 12 subtrochanteric or diaphyseal femur fractures occurred in 10 women, for a rate of 2.3 per 10,000 patient-years, Dennis M. Black, PhD, of the University of California, San Francisco and his colleagues wrote. The data analyzed in the current study were from the phase III Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N. Engl. J. Med. 2010 March 24[doi10.1056/NEJMoa1001086]). Even in the FLEX trial, which included up to 10 years of treatment with alendronate, the risk of femur fracture and atypical femur fracture was low, with no significantly increased risk of fracture among those who continued treatment for the full 10 years and those who discontinued treatment. “Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals (resulting from the very low incidence of events) preclude definitive conclusions regarding the relative risk of treatment,” the investigators wrote. However, using data they analyzed, the investigators estimated that 3 years of bisphosphonate treatment in 1,000 women with osteoporosis would prevent about 100 fractures, including 71 vertebral fractures and 29 nonvertebral fractures—including 11 hip fractures. Balanced against the annual rate of 2.3 subtrochanteric and diaphyseal femur fractures seen in the three trials, “the hypothetical risk is quite small,” the researchers concluded. Additional research is needed to more fully address the matter of bisphosphonate use and the risk of subtrochanteric and diaphyseal fractures, Elizabeth Shane, MD, of Columbia University, New York wrote in an accompanying editorial. It is reasonable to consider drug holidays, particularly in those with substantially reduced levels of bone turnover markers, but again, the evidence of persistent antifracture efficacy after discontinuation must be balanced with data showing that 10 vs. 5 years of alendronate use is associated with significantly fewer new vertebral and nonvertebral fractures in those with bone mineral density T scores of −2.5 or lower, she wrote. This study was supported by Merck and Novartis. The investigators reported support from those and other pharmaceutical manufacturers, as well. Sharon Worcester is with the Southeast bureau of Elsevier Global Medical News. The data on bisphosphonates are good, and this is one area where we may be able to change outcomes (reducing fractures). There are obviously patients for whom these drugs are contraindicated for various reasons, including esophageal sensitivity, but it behooves us to consider their use in many more patients than are currently receiving them. The minuscule risks of complications such as jaw osteonecrosis and atypical fractures, in my opinion, are far outweighed by the drugs' benefits. —Karl Steinberg, MD, CMD Editor in Chief

The Cost-Effectiveness of an RCT to Establish Whether 5 or 10 Years of Bisphosphonate Treatment Is the Better Duration for Women With a Prior Fracture

Five years of bisphosphonate treatment have proven efficacy in reducing fractures. Concerns exist that long-term bisphosphonate treatment may actually result in an increased number of fractures. This study evaluates, in the context of England and Wales, whether it is cost-effective to conduct a randomized controlled trial (RCT) and what sample size may be optimal to estimate the efficacy of bisphosphonates in fracture prevention beyond 5 years. An osteoporosis model was constructed to evaluate the cost-effectiveness of extending bisphosphonate treatment from 5 years to 10 years. Two scenarios were run. The 1st uses long-term efficacy data from published literature, and the 2nd uses distributions elicited from clinical experts. of a proposed RCT were simulated. The expected value of sample information technique was applied to calculate the expected net benefit of sampling from conducting such an RCT at varying levels of participants per arm and to compare this with proposed trial costs. Results. Without further information, the better duration of bisphosphonate treatment was estimated to be 5 years using the published data but 10 years using the elicited expert opinions, although in both cases uncertainty was substantial. The net benefit of sampling was consistently high when between 2000 and 5000 participants per arm were recruited. An RCT to evaluate the long-term efficacy of bisphosphonates in fracture prevention appears to be cost-effective for informing decision making in England and Wales.